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Bibliography on: Publications by FHCRC Researchers

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ESP: PubMed Auto Bibliography 15 Sep 2019 at 01:37 Created: 

Publications by FHCRC Researchers

The Fred Hutchinson Cancer Research Center began in 1975, with critical help from Washington State's U.S. Senator Warren Magnuson. Fred Hutch quickly became the permanent home to Dr. E. Donnall Thomas, who had spent decades developing an innovative treatment for leukemia and other blood cancers. Thomas and his colleagues were working to cure cancer by transplanting human bone marrow after otherwise lethal doses of chemotherapy and radiation. At the Hutch, Thomas improved this treatment and readied it for widespread use. Since then, the pioneering procedure has saved hundreds of thousands of lives worldwide. While improving bone marrow transplantation remains central to Fred Hutch's research, it is now only part of its efforts. The Hutch is home to five scientific divisions, three Nobel laureates and more than 2,700 faculty, who collectively have published more than 10,000 scientific papers, presented here as a full bibliography.

NOTE: From 1995 to 2009 I served as the Hutch's vice president for information technology — hence my interest in the organization. Although my role was in the admin division, if you dig through this bibliography, you will find a couple of papers with me as an author.

Created with PubMed® Query: "Fred Hutchinson Cancer Research"[AFFL] or FHCRC[AFFL] or "Fred Hutch"[AFFL] NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)

RevDate: 2019-09-14

Seaton ME, Peters U, Johnson KC, et al (2019)

Effects of Colorectal Cancer Risk Factors on the Association Between Aspirin and Colorectal Cancer.

Anticancer research, 39(9):4877-4884.

BACKGROUND/AIM: We investigated the effect of aspirin on colorectal cancer (CRC) risk among subgroups of women with and without risk factors for CRC.

PATIENTS AND METHODS: Using data from the Women's Health Initiative, we estimated hazard ratios for CRC in association with aspirin use, with stratifications by cardiovascular disease (CVD) risk status, family history of CRC, and history of colorectal polypectomy.

RESULTS: Aspirin was associated with a lower risk of CRC among women with low/normal or high CVD-risk status; no family history of CRC; or a history of colonoscopy with polypectomy. Aspirin was not associated with CRC among women with a family history of CRC or a history of colonoscopy without polypectomy.

CONCLUSION: Aspirin was associated with a lower risk of CRC in women at all levels of CVD-risk, in those with a history of colonoscopy with polypectomy, and in those without a family history of CRC.

RevDate: 2019-09-14

Chereji RV, Bryson TD, S Henikoff (2019)

Quantitative MNase-seq accurately maps nucleosome occupancy levels.

Genome biology, 20(1):198 pii:10.1186/s13059-019-1815-z.

Micrococcal nuclease (MNase) is widely used to map nucleosomes. However, its aggressive endo-/exo-nuclease activities make MNase-seq unreliable for determining nucleosome occupancies, because cleavages within linker regions produce oligo- and mono-nucleosomes, whereas cleavages within nucleosomes destroy them. Here, we introduce a theoretical framework for predicting nucleosome occupancies and an experimental protocol with appropriate spike-in normalization that confirms our theory and provides accurate occupancy levels over an MNase digestion time course. As with human cells, we observe no overall differences in nucleosome occupancies between Drosophila euchromatin and heterochromatin, which implies that heterochromatic compaction does not reduce MNase accessibility of linker DNA.

RevDate: 2019-09-12

Pegu A, Borate B, Huang Y, et al (2019)

A Meta-analysis of Passive Immunization Studies Shows that Serum-Neutralizing Antibody Titer Associates with Protection against SHIV Challenge.

Cell host & microbe, 26(3):336-346.e3.

Passively administered broadly neutralizing antibodies (bNAbs) targeting the HIV-1 envelope glycoprotein (Env) have been shown to protect non-human primates (NHPs) against chimeric simian-human immunodeficiency virus (SHIV) infection. With data from multiple non-human primate SHIV challenge studies that used single bNAbs, we conducted a meta-analysis to examine the relationship between predicted serum 50% neutralization titer (ID50) against the challenge virus and infection outcome. In a logistic model that adjusts for bNAb epitopes and challenge viruses, serum ID50 had a highly significant effect on infection risk (p < 0.001). The estimated ID50 to achieve 50%, 75%, and 95% protection was 91 (95% confidence interval [CI]: 55, 153), 219 (117, 410), and 685 (319, 1471), respectively. This analysis indicates that serum neutralizing titer against the relevant virus is a key parameter of protection and that protection from acquisition by a single bNAb might require substantial levels of neutralization at the time of exposure.

RevDate: 2019-09-12

Cohen JT, Lin PJ, Sheinson DM, et al (2019)

Are National Comprehensive Cancer Network Evidence Block Affordability Ratings Representative of Real-World Costs? An Evaluation of Advanced Non-Small-Cell Lung Cancer.

Journal of oncology practice [Epub ahead of print].

PURPOSE: The National Comprehensive Cancer Network (NCCN) developed the Evidence Blocks framework to assess the value of oncology regimens. This study characterizes the relationship between real-world costs and NCCN affordability ratings (ARs) for advanced non-small-cell lung cancer (aNSCLC) treatments.

METHODS: Using the MarketScan and PharMetrics Plus databases, we identified patients treated between 2012 and 2017 with an aNSCLC regimen evaluated by the NCCN Evidence Blocks. We estimated adjusted mean total per-patient-per-month (PPPM) costs and drug costs for each regimen using a log-linked gamma generalized linear model. Weighted regression was used to examine the correlation between adjusted mean PPPM costs per regimen and NCCN AR.

RESULTS: A total of 25,162 patients with aNSCLC (mean age, 63 years [standard deviation, 10 years]; 52% male) had identifiable regimens. Mean total PPPM cost by therapeutic class ranged from $16,824 for epidermal growth factor receptors to $41,815 for immunotherapy-based treatment. Epidermal growth factor receptor and anaplastic lymphoma kinase inhibitor treatment had lower ARs compared with generic chemotherapy. No therapy was listed as AR group 5 (least expensive). In pairwise comparisons, AR group 1 had significantly higher PPPM total costs compared with AR groups 2 and 4. There were no significant differences in PPPM total cost among AR groups 2, 3, and 4.

CONCLUSION: Real-world aNSCLC treatment costs are often inconsistent with the NCCN ARs. Given that NCCN Evidence Blocks are intended to inform provider-patient discussions and other decision support resources, such as the NCCN Categories of Preference, our results suggest that the NCCN ARs require further refinement and validation.

RevDate: 2019-09-12

Henikoff S, K Ahmad (2019)

Nucleosomes remember where they were.

Proceedings of the National Academy of Sciences of the United States of America pii:1914581116 [Epub ahead of print].

RevDate: 2019-09-12

Sourisseau M, Lawrence DJP, Schwarz MC, et al (2019)

Deep mutational scanning comprehensively maps how Zika envelope protein mutations affect viral growth and antibody escape.

Journal of virology pii:JVI.01291-19 [Epub ahead of print].

Functional constraints on viral proteins are often assessed by examining sequence conservation among natural strains, but this approach is relatively ineffective for Zika virus because all known sequences are highly similar. Here we take an alternative approach to map functional constraints on Zika virus's envelope (E) protein by using deep mutational scanning to measure how all amino-acid mutations to the protein affect viral growth in cell culture. The resulting sequence-function map is consistent with existing knowledge about E protein structure and function, but also provides insight into mutation-level constraints in many regions of the protein that have not been well characterized in prior functional work. In addition, we extend our approach to completely map how mutations affect viral neutralization by two monoclonal antibodies, thereby precisely defining their functional epitopes. Overall, our study provides a valuable resource for understanding the effects of mutations to this important viral protein, and also offers a roadmap for future work to map functional and antigenic selection to Zika virus at high resolution.IMPORTANCE Zika virus has recently been shown to be associated with severe birth defects. The virus's E protein mediates its ability to infect cells, and is also the primary target of the antibodies that are elicited by natural infection and vaccines that are being developed against the virus. Therefore, determining the effects of mutations to this protein is important for understanding its function, its susceptibility to vaccine-mediated immunity, and its potential for future evolution. We completely mapped how amino-acid mutations to E protein affected the virus's ability to grow in cells in the lab and escape from several antibodies. The resulting maps relate changes in the E protein's sequence to changes in viral function, and therefore provide a valuable complement to existing maps of the physical structure of the protein.

RevDate: 2019-09-12

Kiani Z, Dupuy FP, Bruneau J, et al (2019)

The Education of NK Cells Determines Their Responsiveness to Autologous HIV-Infected CD4 T Cells.

Journal of virology pii:JVI.01185-19 [Epub ahead of print].

Several studies support a role for specific Killer Immunoglobulin-like Receptor (KIR)/HLA combinations in protection from HIV infection and slower time to AIDS. NK cells acquire effector functions through education, a process that requires the interaction of inhibitory Natural Killer (NK) cell receptors with their major histocompatibility complex (MHC) class I (or HLA-I) ligands. HLA-C allotypes are ligands for the inhibitory KIRs (iKIRs) KIR2DL1, KIR2DL2 and KIR2DL3 whereas the ligand for KIR3DL1 is HLA-Bw4. HIV infection reduces the expression of cell surface HLA-A, B and C on infected CD4 T cells (iCD4). Here, we investigated whether education through iKIR/HLA interactions influenced NK responses to autologous iCD4. Enriched NK cells were stimulated with autologous iCD4 or uninfected CD4 cells as controls. The capacity of NK cells to produce CCL4, IFN-γ and/or CD107a by single positive (sp) KIR2DL1, KIR2DL2, KIR2DL3 and KIR3DL1 NK cells was assessed by flow cytometry. Overall, we observed that NK cell education potency was directly related to the frequency of each spiKIR+ NK cell's ability to respond to the reduction of their cognate HLA-ligand on autologous iCD4 as measured by the frequency of spiKIR+ NK cells producing CCL4, IFN-γ and/or CD107a. Both NK cell education and HIV mediated changes in HLA expression influenced NK responses to iCD4 cells.IMPORTANCE Epidemiological studies show that natural killer (NK) cells have anti-HIV activity able to reduce the risk of HIV infection and/or slow HIV disease progression. How NK cells contribute to these outcomes is not fully characterized. We used primary NK and autologous HIV-infected cells to examine the role of education through four inhibitory Killer Immunoglobulin Receptors (iKIRs) from persons having HLA types able to educate, versus not, NK cells bearing one of these iKIRS. HIV-infected cells activated NK cells through missing-self mechanisms due HIV Nef and Vpu mediated downmodulation of cell surface HLA expression. A higher frequency of educated than uneducated NK cells expressing each of these iKIRs responded to autologous HIV+ cells by producing CCL4, IFN-γ and CD107a. As NK cells were from HIV uninfected individuals, they model the consequences of healthy NK/HIV+ cell interactions occurring in the HIV eclipse phase when new infections are susceptible to extinction.

RevDate: 2019-09-12

Longino NV, Yang J, Iyer JG, et al (2019)

Human CD4+ T Cells Specific for Merkel Cell Polyomavirus Localize to Merkel Cell Carcinomas and Target a Required Oncogenic Domain.

Cancer immunology research pii:2326-6066.CIR-19-0103 [Epub ahead of print].

Although CD4+ T cells likely play key roles in antitumor immune responses, most immuno-oncology studies have been limited to CD8+ T-cell responses due to multiple technical barriers and a lack of shared antigens across patients. Merkel cell carcinoma (MCC) is an aggressive skin cancer caused by Merkel cell polyomavirus (MCPyV) oncoproteins in 80% of cases. Because MCPyV oncoproteins are shared across most patients with MCC, it is unusually feasible to identify, characterize, and potentially augment tumor-specific CD4+ T cells. Here, we report the identification of CD4+ T-cell responses against six MCPyV epitopes, one of which included a conserved, essential viral oncogenic domain that binds/disables the cellular retinoblastoma (Rb) tumor suppressor. We found that this epitope (WEDLT209-228) could be presented by three population-prevalent HLA class II alleles, making it a relevant target in 64% of virus-positive MCC patients. Cellular staining with a WEDLT209-228-HLA-DRB1*0401 tetramer indicated that specific CD4+ T cells were detectable in 78% (14 of 18) of evaluable MCC patients, were 250-fold enriched within MCC tumors relative to peripheral blood, and had diverse T-cell receptor sequences. We also identified a modification of this domain that still allowed recognition by these CD4+ T cells but disabled binding to the Rb tumor suppressor, a key step in the detoxification of a possible therapeutic vaccine. The use of these new tools for deeper study of MCPyV-specific CD4+ T cells may provide broader insight into cancer-specific CD4+ T-cell responses.

RevDate: 2019-09-11

Savage TM, Shonts BA, Lau S, et al (2019)

Deletion of donor-reactive T cell clones following human liver transplantation.

American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons [Epub ahead of print].

We recently developed a high throughput T cell receptor β chain (TCRβ) sequencing-based approach to identifying and tracking donor-reactive T cells. To address the role of clonal deletion in liver allograft tolerance, we applied this method in samples from a recent randomized study, ITN030ST, in which immunosuppression withdrawal was attempted within 2 years of liver transplantation. We identified donor-reactive T cell clones via TCRβ sequencing following a pre-transplant mixed lymphocyte reaction and tracked these clones in the circulation following transplantation in 3 tolerant and 5 non-tolerant subjects. All subjects showed a downward trend and significant reductions in donor-reactive TCRβ sequences were detected post-transplant in 6 of 8 subjects, including 2 tolerant and 4 non-tolerant recipients. Reductions in donor-reactive TCRβ sequences were greater than those of all other TCRβ sequences, including 3rd party-reactive sequences, in all 8 subjects, demonstrating an impact of the liver allograft after accounting for repertoire turnover. Although limited by patient number and heterogeneity, our results suggest that partial deletion of donor-reactive T cell clones may be a consequence of liver transplantation and does not correlate with success or failure of early immunosuppression withdrawal. These observations underscore the organ- and/or protocol-specific nature of tolerance mechanisms in humans. This article is protected by copyright. All rights reserved.

RevDate: 2019-09-11

Martin PJ, EW Petersdorf (2019)

In Memoriam: John A. Hansen (1943-2019).

HLA [Epub ahead of print].

RevDate: 2019-09-10

Kebriaei P, Hayes J, Daly A, et al (2019)

A Phase 3 randomized study of Remestemcel-L versus placebo added to second line therapy in patients with steroid refractory acute graft versus host disease.

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(19)30573-7 [Epub ahead of print].

BACKGROUND: Uncontrolled studies have suggested that bone marrow-derived mesenchymal stem cells (MSC) may be effective against acute graft-versus-host disease (aGvHD). We conducted a multicenter, randomized study to assess the efficacy of using ex vivo cultured adult human MSC (remestemcel-L) in addition to second-line therapy to treat steroid refractory aGvHD (NCT00366145).

METHODS: Two-hundred sixty patients, 6 months to 70 years of age, were enrolled from August 2006 to May 2009, and were randomized 2:1 to receive 8 intravenous infusions of remestemcel-L or placebo, given over 4 weeks, in addition to second-line therapy according to institutional standards. Four additional infusions over 4 weeks were indicated for patients with incomplete response at Day 28. Randomization was stratified by aGVHD grade. Efficacy and safety were assessed through 180 days of follow-up, with the primary endpoint being durable complete response (DCR), defined as complete resolution of aGvHD symptoms for any period of at least 28 days after beginning treatment.

FINDINGS: Remestemcel-L did not meet the primary endpoint of greater DCR in the intent-to-treat population (35% vs. 30%; p=0.42). In post-hoc analyses patients with liver involvement who received at least one infusion of remestemcel-L had a higher DCR, and higher overall complete or partial response rate (OR) than those who received placebo (29% vs. 5%; p=0.047). Furthermore, pediatric patients had a higher OR with MSC compared with placebo (64% vs. 23%; p=0.05). Similar rates of adverse events were observed between treatment groups.

INTERPRETATION: Remestemcel-L was safe and well-tolerated. Results of this study did not demonstrate superior DCR compared to placebo when added to standard of care. The favorable clinical responses seen in some patient subsets may warrant further investigation.

RevDate: 2019-09-10

Fourment M, Magee AF, Whidden C, et al (2019)

19 dubious ways to compute the marginal likelihood of a phylogenetic tree topology.

Systematic biology pii:5555782 [Epub ahead of print].

The marginal likelihood of a model is a key quantity for assessing the evidence provided by the data in support of a model. The marginal likelihood is the normalizing constant for the posterior density, obtained by integrating the product of the likelihood and the prior with respect to model parameters. Thus, the computational burden of computing the marginal likelihood scales with the dimension of the parameter space. In phylogenetics, where we work with tree topologies that are high-dimensional models, standard approaches to computing marginal likelihoods are very slow. Here we study methods to quickly compute the marginal likelihood of a single fixed tree topology. We benchmark the speed and accuracy of 19 different methods to compute the marginal likelihood of phylogenetic topologies on a suite of real datasets under the JC69 model. These methods include several new ones that we develop explicitly to solve this problem, as well as existing algorithms that we apply to phylogenetic models for the first time. Altogether, our results show that the accuracy of these methods varies widely, and that accuracy does not necessarily correlate with computational burden. Our newly developed methods are orders of magnitude faster than standard approaches, and in some cases, their accuracy rivals the best established estimators.

RevDate: 2019-09-10

Whidden C, Claywell BC, Fisher T, et al (2019)

Systematic exploration of the high likelihood set of phylogenetic tree topologies.

Systematic biology pii:5555780 [Epub ahead of print].

Bayesian Markov chain Monte Carlo explores tree space slowly, in part because it frequently returns to the same tree topology. An alternative strategy would be to explore tree space systematically, and never return to the same topology. In this paper, we present an efficient parallelized method to map out the high likelihood set of phylogenetic tree topologies via systematic search, which we show to be a good approximation of the high posterior set of tree topologies on the data sets analyzed. Here "likelihood" of a topology refers to the tree likelihood for the corresponding tree with optimized branch lengths. We call this method "phylogenetic topographer" (PT). The PT strategy is very simple: starting in a number of local topology maxima (obtained by hill-climbing from random starting points), explore out using local topology rearrangements, only continuing through topologies that are better than some likelihood threshold below the best observed topology. We show that the normalized topology likelihoods are a useful proxy for the Bayesian posterior probability of those topologies. By using a non-blocking hash table keyed on unique representations of tree topologies, we avoid visiting topologies more than once across all concurrent threads exploring tree space. We demonstrate that PT can be used directly to approximate a Bayesian consensus tree topology. When combined with an accurate means of evaluating per-topology marginal likelihoods, PT gives an alternative procedure for obtaining Bayesian posterior distributions on phylogenetic tree topologies.

RevDate: 2019-09-10

Naiman NE, Slyker J, Nduati R, et al (2019)

Maternal envelope gp41 ectodomain-specific antibodies are associated with increased mother-to-child transmission of HIV-1.

The Journal of infectious diseases pii:5556469 [Epub ahead of print].

Mother-to-child transmission of HIV occurs in the setting of maternal and passively-acquired antibodies, providing a unique window into immune correlates of HIV risk. We compared plasma antibody binding to HIV antigens between 51 non-transmitting mother-infant pairs and 21 transmitting mother-infant pairs. Plasma antibody binding to a variety of gp41 ectodomain-containing antigens was associated with increased odds of transmission. Understanding the reasons why gp41 ectodomain-targeting antibodies are associated with transmission risk will be important in determining whether they can directly enhance infection or whether their presence reflects a redirecting of the humoral response away from targeting more protective epitopes.

RevDate: 2019-09-10

Hanna DB, Ramaswamy C, Kaplan RC, et al (2019)

Sex- and Poverty-Specific Patterns in Hiv-Associated Cardiovascular Disease Mortality in New York City, 2007-2017.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America pii:5555887 [Epub ahead of print].

BACKGROUND: HIV may affect the risk of death due to cardiovascular disease (CVD) differently in men versus women.

METHODS: We examined CVD mortality rates between 2007 and 2017 among all HIV-positive New York City residents age 13+ by sex, using data from city HIV surveillance and vital statistics and the National Death Index. Residents without HIV were enumerated using modified US intercensal estimates. We determined associations of HIV status with CVD mortality by sex after accounting for age, race/ethnicity, year, and neighborhood poverty, defined as the percent living below the federal poverty level.

RESULTS: There were 3,234 CVD deaths reported among 147,915 HIV-positive New Yorkers, with the proportion of deaths due to CVD increasing from 11% in 2007 to 22% in 2017. The age-standardized CVD mortality rate was 2.7/1,000 person-years among both men and women with HIV. The relative rate of CVD mortality associated with HIV status was significantly higher among women (adjusted rate ratio [aRR] 1.7, 95% CI 1.6-1.8) than men (aRR 1.2, 95% CI 1.1-1.3) overall, and within strata defined by neighborhood poverty. Sex differences in CVD mortality rates were the greatest comparing HIV-positive individuals having detectable HIV RNA and CD4+ T-cell counts <500 cells/uL with HIV-negative individuals.

CONCLUSIONS: One in five deaths among people with HIV is now associated with CVD. HIV providers should recognize CVD risk among women with HIV, and reinforce preventive measures (e.g., smoking cessation, blood pressure control, lipid management) and viremic control among all people living with HIV to reduce CVD mortality.

RevDate: 2019-09-10

Porter J, Nguo K, Collins J, et al (2019)

Total energy expenditure measured using doubly labeled water compared with estimated energy requirements in older adults (≥65 y): analysis of primary data.

The American journal of clinical nutrition pii:5556067 [Epub ahead of print].

BACKGROUND: Contemporary energy expenditure data are crucial to inform and guide nutrition policy in older adults to optimize nutrition and health.

OBJECTIVE: The aim was to determine the optimal method of estimating total energy expenditure (TEE) in adults (aged ≥65 y) through 1) establishing which published predictive equations have the closest agreement between measured resting metabolic rate (RMR) and predicted RMR and 2) utilizing the RMR equations with the best agreement to predict TEE against the reference method of doubly labeled water (DLW).

METHODS: A database consisting of international participant-level TEE data from DLW studies was developed to enable comparison with energy requirements estimated by 17 commonly used predictive equations. This database included 31 studies comprising 988 participant-level RMR data and 1488 participant-level TEE data. Mean physical activity level (PAL) was determined for men (PAL = 1.69, n = 320) and women (PAL = 1.66, n = 668). Bland-Altman plots assessed agreement of measured RMR and TEE with predicted RMR and TEE in adults aged ≥65 y, and subgroups of 65-79 y and ≥80 y. Linear regression assessed proportional bias.

RESULTS: The Ikeda, Livingston, and Mifflin equations most closely agreed with measured RMR and TEE in all adults aged ≥65 y and in the 65-79 y and ≥80 y subgroups. In adults aged ≥65 y, the Ikeda and Livingston equations overestimated TEE by a mean ± SD of 175 ± 1362 kJ/d and 86 ± 1344 kJ/d, respectively. The Mifflin equation underestimated TEE by a mean ± SD of 24 ± 1401 kJ/d. Proportional bias was present as energy expenditure increased.

CONCLUSIONS: The Ikeda, Livingston, or Mifflin equations are recommended for estimating energy requirements of older adults. Future research should focus on developing predictive equations to meet the requirements of the older population with consideration given to body composition and functional measures.

RevDate: 2019-09-10

Fahrmann JF, Vykoukal J, Fleury A, et al (2019)

Association between plasma diacetylspermine and tumor spermine synthase with outcome in triple negative breast cancer.

Journal of the National Cancer Institute pii:5567103 [Epub ahead of print].

BACKGROUND: MYC is an oncogenic driver of development and progression in triple-negative breast cancer (TNBC). Ornithine decarboxylase, the rate-limiting enzyme in polyamine metabolism, is a transcriptional target of MYC. We therefore hypothesized that a plasma polyamine signature may be predictive of TNBC development and progression.

METHODS: Using liquid chromatography mass spectrometry, polyamine levels were determined in plasma samples from newly diagnosed patients with TNBC (n = 87) and cancer-free controls (n = 115). Findings were validated in plasma samples from an independent prospective cohort of 54 TNBC, 55 ER-/PR-/HER2+, and 73 ER+ cases, and 30 cancer-free controls. Gene expression data and clinical data for 921 and 2359 breast cancer tumors were obtained from The Cancer Genome Atlas (TCGA) repository and the Oncomine database, respectively. Relationships between plasma diacetylspermine (DAS) and tumor spermine synthase (SMS) mRNA expression with metastasis free survival and overall survival were determined using Cox proportional hazard models; Fisher's exact tests were used to assess risk of distant metastasis in relation to tumor SMS mRNA expression.

RESULTS: An increase in plasma DAS, a catabolic product of spermine mediated through SMS, was observed in the TNBC subtype of breast cancer. Plasma levels of DAS in TNBC associated with increased risk of metastasis (plasma DAS value ≥ 1.16 HR= 3.06, 95% CI = 1.15-8.13, 2-sided P = .03). SMS mRNA expression in TNBC tumor tissue was also found to be predictive of poor overall survival (top 25th percentile HR = 2.06, 95% CI = 1.04-4.08, 1-sided P= .04) and increased risk of distant metastasis in TNBC (comparison of lowest SMS quartile (reference) to highest SMS quartile Relative Risk= 1.90, 95% CI = 0.97-4.06, 1-sided Fisher's exact test P=.03).

CONCLUSION: Metabolomic profiling identified plasma DAS as a predictive marker for TNBC progression and metastasis.

RevDate: 2019-09-10

Wang J, Asante I, Baron JA, et al (2019)

Genome-wide association study of circulating folate one-carbon metabolites.

Genetic epidemiology [Epub ahead of print].

Experimental, observational, and clinical trials support a critical role of folate one-carbon metabolism (FOCM) in colorectal cancer (CRC) development. In this report, we focus on understanding the relationship between common genetic variants and metabolites of FOCM. We conducted a genome-wide association study of FOCM biomarkers among 1,788 unaffected (without CRC) individuals of European ancestry from the Colon Cancer Family Registry. Twelve metabolites, including 5-methyltetrahydrofolate, vitamin B2 (flavin mononucleotide and riboflavin), vitamin B6 (4-pyridoxic acid, pyridoxal, and pyridoxamine), total homocysteine, methionine, S-adenosylmethionine, S-adenosylhomocysteine, cystathionine, and creatinine were measured from plasma using liquid chromatography-mass spectrometry (LC-MS) or LC-MS/MS. For each individual biomarker, we estimated genotype array-specific associations followed by a fixed-effect meta-analysis. We identified the variant rs35976024 (at 2p11.2 and intronic of ATOH8) associated with total homocysteine (p = 4.9 × 10-8). We found a group of six highly correlated variants on chromosome 15q14 associated with cystathionine (all p < 5 × 10-8), with the most significant variant rs28391580 (p = 2.8 × 10-8). Two variants (rs139435405 and rs149119426) on chromosome 14q13 showed significant (p < 5 × 10-8) associations with S-adenosylhomocysteine. These three biomarkers with significant associations are closely involved in homocysteine metabolism. Furthermore, when assessing the principal components (PCs) derived from seven individual biomarkers, we identified the variant rs12665366 (at 6p25.3 and intronic of EXOC2) associated with the first PC (p = 2.3 × 10-8). Our data suggest that common genetic variants may play an important role in FOCM, particularly in homocysteine metabolism.

RevDate: 2019-09-10

Forsberg KJ, Bhatt IV, Schmidtke DT, et al (2019)

Functional metagenomics-guided discovery of potent Cas9 inhibitors in the human microbiome.

eLife, 8: pii:46540.

CRISPR-Cas systems protect bacteria and archaea from phages and other mobile genetic elements, which use small anti-CRISPR (Acr) proteins to overcome CRISPR-Cas immunity. Because Acrs are challenging to identify, their natural diversity and impact on microbial ecosystems are underappreciated. To overcome this discovery bottleneck, we developed a high-throughput functional selection to isolate ten DNA fragments from human oral and fecal metagenomes that inhibit Streptococcus pyogenes Cas9 (SpyCas9) in Escherichia coli. The most potent Acr from this set, AcrIIA11, was recovered from a Lachnospiraceae phage. We found that AcrIIA11 inhibits SpyCas9 in bacteria and in human cells. AcrIIA11 homologs are distributed across diverse bacteria; many distantly-related homologs inhibit both SpyCas9 and a divergent Cas9 from Treponema denticola. We find that AcrIIA11 antagonizes SpyCas9 using a different mechanism than other previously characterized Type II-A Acrs. Our study highlights the power of functional selection to uncover widespread Cas9 inhibitors within diverse microbiomes.

RevDate: 2019-09-10

Zhao YQ, Redman MW, ML LeBlanc (2019)

Quantifying treatment effects using the personalized chance of longer survival.

Statistics in medicine [Epub ahead of print].

The hazard ratio is widely used to measure or to summarize the magnitude of treatment effects, but it is justifiably difficult to interpret in a meaningful way to patients and perhaps for clinicians as well. In addition, it is most meaningful when the hazard functions are approximately proportional over time. We propose a new measure, termed personalized chance of longer survival. The measure, which quantifies the probability of living longer with one treatment over the another, accounts for individualized characteristics to directly address personalized treatment effects. Hence, the measure is patient focused, which can be used to evaluate subgroups easily. We believe it is intuitive to understand and clinically interpretable in the presence of nonproportionality. Furthermore, because it estimates the probability of living longer by some fixed amount of time, it encodes the probabilistic part of treatment effect estimation. We provide nonparametric estimation and inference procedures that can accommodate censored survival outcomes. We conduct extensive simulation studies, which characterize performance of the proposed method, and data from a large randomized Phase III clinical trial (SWOG S0819) are analyzed using the proposed method.

RevDate: 2019-09-10

Thompson B, Hohl SD, Molina Y, et al (2018)

Breast Cancer Disparities Among Women in Underserved Communities in the USA.

Current breast cancer reports, 10(3):131-141.

Purpose of Review: Breast cancer disparities that exist between high-income countries (HIC) and low- and middle-income countries (LMICs) are also reflected within population subgroups throughout the United States (US). Here we examine three case studies of US populations "left behind" in breast cancer outcomes/equity.

Recent Findings: African Americans in Chicago, non-Latina White women in Appalachia, and Latinas in the Yakima Valley of Washington State all experience a myriad of factors that contribute to lower rates of breast cancer detection and appropriate treatment as well as poorer survival. These factors, related to the social determinants of health, including geographic isolation, lack of availability of care, and personal constraints, can be addressed with interventions at multiple levels.

Summary: Although HICs have reduced mortality of breast cancer compared to LMICs, there remain inequities in the US healthcare system. Concerted efforts are needed to ensure that all women have access to equitable screening, detection, treatment, and survivorship resources.

RevDate: 2019-09-10

Kanaan SB, Sensoy O, Yan Z, et al (2019)

Immunogenicity of a rheumatoid arthritis protective sequence when acquired through microchimerism.

Proceedings of the National Academy of Sciences of the United States of America pii:1904779116 [Epub ahead of print].

HLA class II genes provide the strongest genetic contribution to rheumatoid arthritis (RA). HLA-DRB1 alleles encoding the sequence DERAA are RA-protective. Paradoxically, RA risk is increased in women with DERAA+ children born prior to onset. We developed a sensitive qPCR assay specific for DERAA, and found 53% of DERAA-/- women with RA had microchimerism (Mc; pregnancy-derived allogeneic cells) carrying DERAA (DERAA-Mc) vs. 6% of healthy women. DERAA-Mc quantities correlated with an RA-risk genetic background including DERAA-binding HLA-DQ alleles, early RA onset, and aspects of RA severity. CD4+ T cells showed stronger response against DERAA+ vs. DERAA- allogeneic cell lines in vitro, in line with an immunogenic role of allogeneic DERAA. Results indicate a model where DERAA-Mc activates DERAA-directed T cells that are naturally present in DERAA-/- individuals and can have cross-reactivity against joint antigens. Moreover, we provide an explanation for the enigmatic observation that the same HLA sequence differentially affects RA risk through Mendelian inheritance vs. microchimeric cell acquisition.

RevDate: 2019-09-10

Naiman NE, Slyker J, Richardson BA, et al (2019)

Antibody-dependent cellular cytotoxicity targeting CD4-inducible epitopes predicts mortality in HIV-infected infants.

EBioMedicine pii:S2352-3964(19)30594-8 [Epub ahead of print].

BACKGROUND: Antibody-dependent cellular cytotoxicity (ADCC) has been associated with improved infant outcome in mother-to-child transmission (MTCT) of HIV-1. Epitopes of these ADCC-mediating antibodies remain unidentified. CD4-inducible (CD4i) epitopes on gp120 are common ADCC targets in natural infection and vaccination. We tested whether CD4i epitope-specific ADCC mediated by maternal antibodies or passively-acquired antibodies in infants is associated with reduced MTCT and improved infant survival.

METHODS: We used variants of CD4i cluster A-specific antibodies, A32 and C11, and a cluster C-specific antibody, 17b, with mutations abolishing Fc-Fc receptor interactions as inhibitors in a competition rapid and fluorometric ADCC assay using gp120-coated CEM-nkr target cells with plasma from 51 non-transmitting and 21 transmitting breastfeeding mother-infant pairs.

FINDINGS: Cluster A-specific ADCC was common. Individually, neither A32-like nor C11-like ADCC was statistically significantly associated with risk of MTCT or infected infant survival. In combination, total maternal cluster A-specific ADCC was statistically significantly associated with decreased infected infant survival in a log-rank test (p = 0·017). There was a non-significant association for infant passively-acquired total cluster A-specific ADCC and decreased infected infant survival (p = 0·14). Surprisingly, plasma ADCC was enhanced in the presence of the defective Fc 17b competitor. Defective Fc 17b competitor-mediated maternal ADCC enhancement was statistically significantly associated with reduced infected infant survival (p = 0·011). A non-significant association was observed for passively-acquired infant ADCC enhancement and decreased survival (p = 0·19).

INTERPRETATIONS: These data suggest that ADCC targeting CD4i epitopes is not associated with protection against breast milk HIV transmission but is associated with decreased survival of infected infants. FUND: This study was funded by NIH grant R01AI076105 and NIH fellowship F30AI136636.

RevDate: 2019-09-10

Andersch L, Radke J, Klaus A, et al (2019)

CD171- and GD2-specific CAR-T cells potently target retinoblastoma cells in preclinical in vitro testing.

BMC cancer, 19(1):895 pii:10.1186/s12885-019-6131-1.

BACKGROUND: Chimeric antigen receptor (CAR)-based T cell therapy is in early clinical trials to target the neuroectodermal tumor, neuroblastoma. No preclinical or clinical efficacy data are available for retinoblastoma to date. Whereas unilateral intraocular retinoblastoma is cured by enucleation of the eye, infiltration of the optic nerve indicates potential diffuse scattering and tumor spread leading to a major therapeutic challenge. CAR-T cell therapy could improve the currently limited therapeutic strategies for metastasized retinoblastoma by simultaneously killing both primary tumor and metastasizing malignant cells and by reducing chemotherapy-related late effects.

METHODS: CD171 and GD2 expression was flow cytometrically analyzed in 11 retinoblastoma cell lines. CD171 expression and T cell infiltration (CD3+) was immunohistochemically assessed in retrospectively collected primary retinoblastomas. The efficacy of CAR-T cells targeting the CD171 and GD2 tumor-associated antigens was preclinically tested against three antigen-expressing retinoblastoma cell lines. CAR-T cell activation and exhaustion were assessed by cytokine release assays and flow cytometric detection of cell surface markers, and killing ability was assessed in cytotoxic assays. CAR constructs harboring different extracellular spacer lengths (short/long) and intracellular co-stimulatory domains (CD28/4-1BB) were compared to select the most potent constructs.

RESULTS: All retinoblastoma cell lines investigated expressed CD171 and GD2. CD171 was expressed in 15/30 primary retinoblastomas. Retinoblastoma cell encounter strongly activated both CD171-specific and GD2-specific CAR-T cells. Targeting either CD171 or GD2 effectively killed all retinoblastoma cell lines examined. Similar activation and killing ability for either target was achieved by all CAR constructs irrespective of the length of the extracellular spacers and the co-stimulatory domain. Cell lines differentially lost tumor antigen expression upon CAR-T cell encounter, with CD171 being completely lost by all tested cell lines and GD2 further down-regulated in cell lines expressing low GD2 levels before CAR-T cell challenge. Alternating the CAR-T cell target in sequential challenges enhanced retinoblastoma cell killing.

CONCLUSION: Both CD171 and GD2 are effective targets on human retinoblastoma cell lines, and CAR-T cell therapy is highly effective against retinoblastoma in vitro. Targeting of two different antigens by sequential CAR-T cell applications enhanced tumor cell killing and preempted tumor antigen loss in preclinical testing.

RevDate: 2019-09-10

Ose J, Gigic B, Lin T, et al (2019)

Multiplatform Urinary Metabolomics Profiling to Discriminate Cachectic from Non-Cachectic Colorectal Cancer Patients: Pilot Results from the ColoCare Study.

Metabolites, 9(9): pii:metabo9090178.

Cachexia is a multifactorial syndrome that is characterized by loss of skeletal muscle mass in cancer patients. The biological pathways involved remain poorly characterized. Here, we compare urinary metabolic profiles in newly diagnosed colorectal cancer patients (stage I-IV) from the ColoCare Study in Heidelberg, Germany. Patients were classified as cachectic (n = 16), pre-cachectic (n = 13), or non-cachectic (n = 23) based on standard criteria on weight loss over time at two time points. Urine samples were collected pre-surgery, and 6 and 12 months thereafter. Fat and muscle mass area were assessed utilizing computed tomography scans at the time of surgery. N = 152 compounds were detected using untargeted metabolomics with gas chromatography-mass spectrometry and n = 154 features with proton nuclear magnetic resonance spectroscopy. Thirty-four metabolites were overlapping across platforms. We calculated differences across groups and performed discriminant and overrepresentation enrichment analysis. We observed a trend for 32 compounds that were nominally significantly different across groups, although not statistically significant after adjustment for multiple testing. Nineteen compounds could be identified, including acetone, hydroquinone, and glycine. Comparing cachectic to non-cachectic patients, higher levels of metabolites such as acetone (Fold change (FC) = 3.17; p = 0.02) and arginine (FC = 0.33; p = 0.04) were observed. The two top pathways identified were glycerol phosphate shuttle metabolism and glycine and serine metabolism pathways. Larger subsequent studies are needed to replicate and validate these results.

RevDate: 2019-09-09

Manson JE, Aragaki AK, Bassuk SS, et al (2019)

Menopausal Estrogen-Alone Therapy and Health Outcomes in Women With and Without Bilateral Oophorectomy: A Randomized Trial.

Annals of internal medicine pii:2749725 [Epub ahead of print].

Background: Whether health outcomes of menopausal estrogen therapy differ between women with and without bilateral salpingo-oophorectomy (BSO) is unknown.

Objective: To examine estrogen therapy outcomes by BSO status, with additional stratification by 10-year age groups.

Design: Subgroup analyses of the randomized Women's Health Initiative Estrogen-Alone Trial. (ClinicalTrials.gov: NCT00000611).

Setting: 40 U.S. clinical centers.

Participants: 9939 women aged 50 to 79 years with prior hysterectomy and known oophorectomy status.

Intervention: Conjugated equine estrogens (CEE) (0.625 mg/d) or placebo for a median of 7.2 years.

Measurements: Incidence of coronary heart disease and invasive breast cancer (the trial's 2 primary end points), all-cause mortality, and a "global index" (these end points plus stroke, pulmonary embolism, colorectal cancer, and hip fracture) during the intervention phase and 18-year cumulative follow-up.

Results: The effects of CEE alone did not differ significantly according to BSO status. However, age modified the effect of CEE in women with prior BSO. During the intervention phase, CEE was significantly associated with a net adverse effect (hazard ratio for global index, 1.42 [95% CI, 1.09 to 1.86]) in older women (aged ≥70 years), but the global index was not elevated in younger women (P trend by age = 0.016). During cumulative follow-up, women aged 50 to 59 years with BSO had a treatment-associated reduction in all-cause mortality (hazard ratio, 0.68 [CI, 0.48 to 0.96]), whereas older women with BSO had no reduction (P trend by age = 0.034). There was no significant association between CEE and outcomes among women with conserved ovaries, regardless of age.

Limitations: The timing of CEE in relation to BSO varied; several comparisons were made without adjustment for multiple testing.

Conclusion: The effects of CEE did not differ by BSO status in the overall cohort, but some findings varied by age. Among women with prior BSO, in those aged 70 years or older, CEE led to adverse effects during the treatment period, whereas women randomly assigned to CEE before age 60 seemed to derive mortality benefit over the long term.

Primary Funding Source: The WHI program is funded by the National Heart, Lung, and Blood Institute; National Institutes of Health; and U.S. Department of Health and Human Services. Wyeth Ayerst donated the study drugs.

RevDate: 2019-09-09

Pidala J, Jaglowski S, Im A, et al (2019)

Carfilzomib for treatment of refractory chronic graft vs. host disease: A Chronic GVHD Consortium pilot phase II trial.

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(19)30570-1 [Epub ahead of print].

Prior experimental and clinical data suggest proteasome inhibition may have immunomodulatory activity relevant to graft vs. host disease (GVHD). To explore the safety and activity of carfilzomib in advanced chronic GVHD, we conducted a multi-center pilot phase II trial through the Chronic GVHD Consortium. Carfilzomib was administered at 20 mg/m2 on day 1, and then 36mg/m2 on days 8 and 15 of a 28-day treatment cycle (cycle 1), and then 36 mg/m2 on days 1, 8, and 15 of a 28-day treatment cycle (cycles 2-6). The primary endpoint was 6 month treatment failure, a composite endpoint including death, relapse, and requirement for an additional line of systemic immune suppressive (IS) therapy. A total of 20 subjects were enrolled at 4 institutions. Median time from chronic GVHD onset to enrollment was 1.5 years (IQR 0.5-3.7). Chronic GVHD was NIH moderate (30%) or severe (70%), predominantly classic (90% vs. overlap 10%), and involved multiple diverse organ sites. Prior lines of systemic therapy for chronic GVHD were ≤ 2 (n=6, 30%) or ≥ 3 (n=14, 70%). Doses were held primarily for infection (50% of total held doses); only 3 patients (15%) completed all planned doses of the 6 cycles of carfilzomib. SAEs occurred in 40% of subjects, and 7 deaths occurred among study participants occurring between 0.3-9 months after last carfilzomib dose, but none were attributed to carfilzomib. The 6 month treatment failure rate was not significantly improved vs. the historical benchmark (40% vs. 44%, p=0.36). Overall survival at 6 and 12 months was 80% and 65%. Failure-free survival at 12 months was 32%. These pilot phase II data suggest that carfilzomib therapy in this advanced chronic GVHD population did not improve expected 6 month treatment failure rates achieved under conventional practices and is not recommended for further study for this indication.

RevDate: 2019-09-09

VanderWeele DJ, Antonarakis ES, Carducci MA, et al (2019)

Metastatic Hormone-Sensitive Prostate Cancer: Clinical Decision Making in a Rapidly Evolving Landscape of Life-Prolonging Therapy.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology [Epub ahead of print].

RevDate: 2019-09-09

Tran DM, Zhang F, Morrison KP, et al (2019)

Transcutaneous Ultrasound-Mediated Nonviral Gene Delivery to the Liver in a Porcine Model.

Molecular therapy. Methods & clinical development, 14:275-284 pii:S2329-0501(19)30077-4.

Ultrasound (US)-mediated gene delivery (UMGD) of nonviral vectors was demonstrated in this study to be an effective method to transfer genes into the livers of large animals via a minimally invasive approach. We developed a transhepatic venous nonviral gene delivery protocol in combination with transcutaneous, therapeutic US (tUS) to facilitate significant gene transfer in pig livers. A balloon catheter was inserted into the pig hepatic veins of the target liver lobes via jugular vein access under fluoroscopic guidance. tUS exposure was continuously applied to the lobe with simultaneous infusion of pGL4 plasmid (encoding a luciferase reporter gene) and microbubbles. tUS was delivered via an unfocused, two-element disc transducer (H105) or a novel focused, single-element transducer (H114). We found applying transcutaneous US using H114 and H105 with longer pulses and reduced acoustic pressures resulted in an over 100-fold increase in luciferase activity relative to untreated lobes. We also showed effective UMGD by achieving focal regions of >105 relative light units (RLUs)/mg protein with minimal tissue damage, demonstrating the feasibility for clinical translation of this technique to treat patients with genetic diseases.

RevDate: 2019-09-09

Zheng J, SC Chow (2019)

Criteria for dose-finding in two-stage seamless adaptive design.

Journal of biopharmaceutical statistics [Epub ahead of print].

In pharmaceutical/clinical development, two-stage seamless adaptive designs are commonly considered. Such designs include a two-stage phase I/II or phase II/III adaptive trial that combines one phase IIb study for dose-finding or treatment selection and one phase III study for efficacy confirmation into a single study. At the end of stage 1, promising dose(s) will be selected based on pre-specified selection criteria. In practice, since there is little power with limited subjects available at interim, commonly considered selection criteria for critical decision-making include (i) conditional power, (ii) precision analysis, (iii) predictive probability of success, and (iv) probability of being the best dose or treatment. The selected promising dose(s) will then proceed to the next stage for efficacy confirmation. In this article, we introduce, compare, and evaluate these criteria. Simulation studies and a numeric example are given to illustrate those criteria. Besides, we attempt to address some concerns for the two-stage seamless adaptive clinical trial.

RevDate: 2019-09-08

Graham LS, Schade G, MT Schweizer (2019)

Multimodality Treatment of Bilateral Wilms Tumor in a Pregnant Female.

Urology pii:S0090-4295(19)30794-0 [Epub ahead of print].

RevDate: 2019-09-07

Osoti AO, Page ST, Richardson BA, et al (2019)

Postpartum metabolic syndrome after gestational hypertension and preeclampsia, a prospective cohort study.

Pregnancy hypertension, 18:35-41 pii:S2210-7789(18)30779-7 [Epub ahead of print].

OBJECTIVE: We evaluated the 6-month postpartum risk of metabolic syndrome (MetS), a marker of future cardiovascular disease (CVD) risk, comparing women whose most recent pregnancies were complicated with gestational hypertension (GH) or preeclampsia (PE) versus those who had normotensive pregnancies.

STUDY DESIGN: This was a prospective cohort study in which women with GH or PE and normotensive women were actively enrolled during the first 12 weeks after delivery in Nairobi, Kenya. Participants were interviewed, blood pressures and anthropometric measurements including waist circumference obtained at enrollment and 6 months postpartum. Fasting lipid profile and plasma glucose were measured at 6 months postpartum. A generalized linear regression model with Poisson distribution was used to estimate crude relative risk (RR) of 6-month postpartum MetS and adjusted RR (ARR) after adjusting for apriori potential confounders.

RESULTS: Among 194 postpartum women, 63 (32%) had experienced GH or PE. Prevalence of MetS at 6 months postpartum was higher among women whose pregnancies were complicated with GH or PE (34.9%) compared to those who were normotensive (11.5%). GH and PE were associated with a 3-fold or greater risk of MetS (ARR) 3.01; 95% Confidence interval [CI] 1.58, 5.71; p < 0.001) overall and three of the five components, namely hypertension (ARR 3.35 [2.04, 5.51], p < 0.001), hypertriglyceridemia (ARR 3.25 [1.16-9.10], p = 0.01), and fasting hyperglycemia (ARR 6.20 [1.07-35.76], p = 0.03), compared to having normal blood pressures during pregnancy.

CONCLUSION: At 6 months postpartum, GH and PE were associated with three-fold or higher risk of MetS and especially hypertension, fasting hypertriglyceridemia, and fasting hyperglycemia.

RevDate: 2019-09-07

Kocarnik J (2019)

Cancer's global epidemiological transition and growth.

Lancet (London, England) pii:S0140-6736(19)32046-X [Epub ahead of print].

RevDate: 2019-09-06

Holtz TH, Chitwarakorn A, Hughes JP, et al (2019)

HPTN 067/ADAPT: Correlates of sex-related pre-exposure prophylaxis adherence, Thai men who have sex with men, and transgender women, 2012-2013.

Journal of acquired immune deficiency syndromes (1999) [Epub ahead of print].

BACKGROUND: We identified correlates of sex-related pre-exposure prophylaxis (PrEP) adherence in HPTN067/ADAPT, a phase 2, open-label feasibility study of daily and non-daily regimens of emtricitabine/tenofovir disoproxil fumarate (FTC/TDF)-based PrEP, among Thai men who have sex with men (MSM), and transgender women (TGW), Bangkok.

METHODS: Participants were randomly assigned to one of three self-administered dosing regimens for 24 weeks: daily, time-driven, or event-driven. Demographic and behavioral information was obtained at screening. Pill-container opening was recorded with electronic dose monitoring, and self-reported information on PrEP use, sex events, and substance use were obtained during weekly interviews to confirm dose data. Sex-related PrEP adherence was calculated the proportion of sex events covered by PrEP use (at least one tablet taken within four days before sex and at least one tablet taken within 24 hours after sex) to total sex events. We used multivariate modeling with sex event as the unit of analysis to evaluate correlates associated with sex-related PrEP adherence.

RESULTS: Among 178 MSM and TGW, sex-related PrEP adherence was similar in the daily and time-driven arms (p=0.79), both significantly greater than the event-driven arm (p=0.02 compared to daily). Sex-related PrEP adherence by those reporting stimulant use (74.2%) was similar to those reporting other non-alcohol drug use (76.3%, p=0.80), but lower than those reporting no substance use (84.6%, p=0.04). In a multivariable model, randomization to the event-driven arm, a higher pre-study number of reported sex events, and use of stimulant drugs were associated with significantly lower sex-related PrEP adherence.

CONCLUSION: Adherence was influenced by treatment schedule and adversely impacted by non-alcoholic substance use. Regardless of these factors, Thai MSM and TGW maintained high adherence levels to oral PrEP dosing regimens and coverage of sexual exposures.

RevDate: 2019-09-06

Navajas Acedo J, Voas MG, Alexander R, et al (2019)

PCP and Wnt pathway components act in parallel during zebrafish mechanosensory hair cell orientation.

Nature communications, 10(1):3993 pii:10.1038/s41467-019-12005-y.

Planar cell polarity (PCP) plays crucial roles in developmental processes such as gastrulation, neural tube closure and hearing. Wnt pathway mutants are often classified as PCP mutants due to similarities between their phenotypes. Here, we show that in the zebrafish lateral line, disruptions of the PCP and Wnt pathways have differential effects on hair cell orientations. While mutations in the PCP genes vangl2 and scrib cause random orientations of hair cells, mutations in wnt11f1, gpc4 and fzd7a/b induce hair cells to adopt a concentric pattern. This concentric pattern is not caused by defects in PCP but is due to misaligned support cells. The molecular basis of the support cell defect is unknown but we demonstrate that the PCP and Wnt pathways work in parallel to establish proper hair cell orientation. Consequently, hair cell orientation defects are not solely explained by defects in PCP signaling, and some hair cell phenotypes warrant re-evaluation.

RevDate: 2019-09-06

Pineda CM, Gonzalez DG, Matte-Martone C, et al (2019)

Hair follicle regeneration suppresses Ras-driven oncogenic growth.

The Journal of cell biology pii:jcb.201907178 [Epub ahead of print].

Mutations associated with tumor development in certain tissues can be nontumorigenic in others, yet the mechanisms underlying these different outcomes remains poorly understood. To address this, we targeted an activating Hras mutation to hair follicle stem cells and discovered that Hras mutant cells outcompete wild-type neighbors yet are integrated into clinically normal skin hair follicles. In contrast, targeting the Hras mutation to the upper noncycling region of the skin epithelium leads to benign outgrowths. Follicular Hras mutant cells autonomously and nonautonomously enhance regeneration, which directs mutant cells into continuous tissue cycling to promote integration rather than aberrancy. This follicular tolerance is maintained under additional challenges that promote tumorigenesis in the epidermis, including aging, injury, and a secondary mutation. Thus, the hair follicle possesses a unique, enhanced capacity to integrate and contain Hras mutant cells within both homeostatic and perturbed tissue, demonstrating that in the skin, multiple, distinct mechanisms exist to suppress oncogenic growth.

RevDate: 2019-09-06

López-Yglesias AH, Lu CC, Zhao X, et al (2019)

FliC's Hypervariable D3 Domain Is Required for Robust Anti-Flagellin Primary Antibody Responses.

ImmunoHorizons, 3(9):422-432 pii:3/9/422.

Bacterial flagellin is a well-known agonist of the innate immune system that induces proinflammatory responses through the TLR5 and Naip5/6 recognition pathways. Several clinical trials investigating flagellin fusion proteins have demonstrated promising results for inducing protective immunity toward influenza virus, which has been largely attributed to flagellin's ability to activate TLR5. Our laboratory previously demonstrated that the Salmonella enterica serovar Typhimurium flagellin protein, FliC, induces Ab responses in mice through a third pathway that is independent of TLR5, Casp1/11, and MyD88. In this study, we further define the structural features of FliC that contribute to this unknown third pathway. By destroying the Naip5/6 and TLR5 recognition sites, we demonstrate that neither were required for the TLR5-, inflammasome- and MyD88-independent Ab responses toward FliC. In contrast, deletion of FliC's D3 or D0/D1 domains eliminated primary anti-flagellin Ab responses. For optimal primary and secondary anti-flagellin Ab responses we show that TLR5, inflammasome recognition, and the D3 domain of FliC are essential for flagellin's robust immunogenicity. Our data demonstrate that the D3 domain of FliC influences immunogenicity independent of the known innate recognition sites in the D0/D1 domains to augment Ab production. Our results suggest full-length FliC is critical for optimal immunogenicity and Ab responses in flagellin-based vaccines.

RevDate: 2019-09-06

Anderson LJ, Yin C, Burciaga R, et al (2019)

Assessing Cachexia Acutely after Autologous Stem Cell Transplant.

Cancers, 11(9): pii:cancers11091300.

Autologous hematopoietic stem cell transplantation (AHCT) is an accepted strategy for various hematologic malignancies that can lead to functional impairment, fatigue, muscle wasting, and reduced quality of life (QOL). In cancer cachexia, these symptoms are associated with inflammation, hypermetabolism, and decreased anabolic hormones. The relative significance of these factors soon after AHCT setting is unclear. The purpose of this study was to characterize the acute effects of AHCT on physical function, body composition, QOL, energy expenditure, cytokines, and testosterone. Outcomes were assessed before (PRE) and 30 ± 10 days after (FU) AHCT in patients with multiple myeloma (n = 15) and non-Hodgkin lymphoma (n = 6). Six-minute walk test (6MWT; p = 0.014), lean mass (p = 0.002), and fat mass (p = 0.02) decreased; nausea and fatigue increased at FU (both p = 0.039). Recent weight change and steroid exposure were predictors of reduced aerobic capacity (p < 0.001). There were no significant changes in interleukin (IL)-1β, IL-6, tumor necrosis factor (TNF), energy expenditure, or bioavailable testosterone. Alterations in cytokines, energy expenditure, and testosterone were not associated with functional impairment acutely following AHCT. Recent history of weight loss and steroid exposure were predictors of worse physical function after AHCT, suggesting that targeting nutritional status and myopathy may be viable strategies to mitigate these effects.

RevDate: 2019-09-05

Davidsen K, Olson BJ, DeWitt WS, et al (2019)

Deep generative models for T cell receptor protein sequences.

eLife, 8: pii:46935.

Probabilistic models of adaptive immune repertoire sequence distributions can be used to infer the expansion of immune cells in response to stimulus, differentiate genetic from environmental factors that determine repertoire sharing, and evaluate the suitability of various target immune sequences for stimulation via vaccination. Classically, these models are defined in terms of a probabilistic V(D)J recombination model which is sometimes combined with a selection model. In this paper we take a different approach, fitting variational autoencoder (VAE) models parameterized by deep neural networks to T cell receptor (TCR) repertoires. We show that simple VAE models can perform accurate cohort frequency estimation, learn the rules of VDJ recombination, and generalize well to unseen sequences. Further, we demonstrate that VAE-like models can distinguish between real sequences and sequences generated according to a recombination-selection model, and that many characteristics of VAE-generated sequences are similar to those of real sequences.

RevDate: 2019-09-05

Unger JM (2019)

Reproducible Findings in Systematic Reviews and Meta-analyses in Oncology: Verify, Then Trust.

JAMA oncology pii:2749252 [Epub ahead of print].

RevDate: 2019-09-05

Stannah J, Silhol R, Elmes J, et al (2019)

Increases in HIV Incidence Following Receptive Anal Intercourse Among Women: A Systematic Review and Meta-analysis.

AIDS and behavior pii:10.1007/s10461-019-02651-0 [Epub ahead of print].

Receptive anal intercourse (RAI) carries a greater per-act risk of HIV acquisition than receptive vaginal intercourse (RVI) and may influence HIV epidemics driven by heterosexual sex. This systematic review explores the association between RAI and incident HIV among women, globally. We searched Embase and Medline through September 2018 for longitudinal studies reporting crude (cRR) or adjusted (aRR) relative risks of HIV acquisition by RAI practice among women. Of 27,563 articles identified, 17 eligible studies were included. We pooled independent study estimates using random-effects models. Women reporting RAI were more likely to acquire HIV than women not reporting RAI (pooled cRR = 1.56 95% CI 1.03-2.38, N = 18, I2 = 72%; pooled aRR = 2.23, 1.01-4.92, N = 5, I2 = 70%). In subgroup analyses the association was lower for women in Africa (pooled cRR = 1.16, N = 13, I2 = 21%) than outside Africa (pooled cRR = 4.10, N = 5, I2 = 79%) and for high-risk (pooled aRR = 1.69, N = 4, I2 = 63%) than general-risk women (pooled aRR = 8.50, N = 1). Interview method slightly influenced cRR estimates (p value = 0.04). In leave-one-out sensitivity analyses pooled estimates were generally robust to removing individual study estimates. Main limitations included poor exposure definition, incomplete adjustment for confounders, particularly condom use, and use of non-confidential interview methods. More and better data are needed to explain differences in risk by world region and risk population. Women require better counselling and greater choice in prevention modalities that are effective during RVI and RAI.

RevDate: 2019-09-04

Weigl K, Chang-Claude J, Hsu L, et al (2019)

Establishing a valid approach for estimating familial risk of cancer explained by common genetic variants.

International journal of cancer [Epub ahead of print].

We critically examined existing approaches for the estimation of the excess familial risk of cancer which can be attributed to identified common genetic risk variants and propose an alternative, more straightforward approach for calculating this proportion using well-established epidemiological methodology. We applied the underlying equations of the traditional approaches and the new epidemiological approach for colorectal cancer (CRC) in a large population-based case-control study in Germany with 4,447 cases and 3,480 controls, who were recruited from 2003 to 2016 and for whom interview, medical and genomic data were available. Having a family history of CRC (FH) was associated with a 1.77-fold risk increase in our study population (95% CI 1.52-2.07). Traditional approaches yielded estimates of the FH-associated risk explained by 97 common genetics variants from 9.6% to 23.1%, depending on various assumptions. Our alternative approach resulted in smaller and more consistent estimates of this proportion, ranging from 5.4% to 14.3%. Commonly employed methods may lead to strongly divergent and possibly exaggerated estimates of excess familial risk of cancer explained by associated known common genetic variants. Our results suggest that familial risk and risk associated with known common genetic variants might reflect two complementary major sources of risk. This article is protected by copyright. All rights reserved.

RevDate: 2019-09-04

Higano CS, Armstrong AJ, Sartor AO, et al (2019)

Real-world outcomes of sipuleucel-T treatment in PROCEED, a prospective registry of men with metastatic castration-resistant prostate cancer.

Cancer [Epub ahead of print].

BACKGROUND: The large registry, PROVENGE Registry for the Observation, Collection, and Evaluation of Experience Data (PROCEED)(NCT01306890), evaluated sipuleucel-T immunotherapy for asymptomatic/minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC).

METHODS: PROCEED enrolled patients with mCRPC receiving 3 biweekly sipuleucel-T infusions. Assessments included overall survival (OS), serious adverse events (SAEs), cerebrovascular events (CVEs), and anticancer interventions (ACIs). Follow-up was for ≥3 years or until death or study withdrawal.

RESULTS: In 2011-2017, 1976 patients were followed for 46.6 months (median). The median age was 72 years, and the baseline median prostate-specific antigen level was 15.0 ng/mL; 86.7% were white, and 11.6% were African American. Among the patients, 1902 had 1 or more sipuleucel-T infusions. The median OS was 30.7 months (95% confidence interval [CI], 28.6-32.2 months). Known prognostic factors were independently associated with OS in a multivariable analysis. Among the 1255 patients who died, 964 (76.8%) died of prostate cancer (PC) progression. The median time from the first infusion to PC death was 42.7 months (95% CI, 39.4-46.2 months). The incidence of sipuleucel-T-related SAEs was 3.9%. The incidence of CVEs was 2.8%, and the rate per 100 person-years was 1.2 (95% CI, 0.9-1.6). The CVE incidence among 11,972 patients with mCRPC from the Surveillance, Epidemiology, and End Results-Medicare database was 2.8%; the rate per 100 person-years was 1.5 (95% CI, 1.4-1.7). One or more ACIs (abiraterone, enzalutamide, docetaxel, cabazitaxel, or radium 223) were received by 77.1% of the patients after sipuleucel-T; 32.5% and 17.4% of the patients experienced 1- and 2-year treatment-free intervals, respectively.

CONCLUSIONS: PROCEED provides contemporary survival data for sipuleucel-T-treated men in a real-world setting of new life-prolonging agents, which will be useful in discussing treatment options with patients and in powering future trials with sipuleucel-T. The safety and tolerability of sipuleucel-T in PROCEED were consistent with previous findings.

RevDate: 2019-09-04

Unger JM, Nghiem VT, Hershman DL, et al (2019)

Association of National Cancer Institute-Sponsored Clinical Trial Network Group Studies With Guideline Care and New Drug Indications.

JAMA network open, 2(9):e1910593 pii:2749235.

Importance: National Cancer Institute Clinical Trial Network (NCTN) groups serve a vital role in identifying effective new antineoplastic regimens. However, the downstream clinical effect of their trials has not been systematically examined.

Objective: To examine the association of NCTN trials with guideline care and new drug indications.

This retrospective cohort study evaluated phase 3 SWOG Cancer Research Network clinical trials from January 1, 1980, through June 30, 2017. Only completed trials with published results were included. To be considered practice influential (PI), a trial must have been associated with guideline care through its inclusion in National Comprehensive Cancer Network (NCCN) clinical guidelines or US Food and Drug Administration (FDA) new drug approvals in favor of a recommended treatment. Data were analyzed from June 15, 2018, through March 29, 2019.

Main Outcomes and Measures: Estimated overall rate of PI trials, as well as trends over time. The total federal investment supporting the set of trials was also determined.

Results: In total, 182 trials consisting of 148 028 patients were studied. Eighty-two studies (45.1%; 95% CI, 37.7%-52.6%) were PI, of which 70 (38.5%) influenced NCCN guidelines, 6 (3.3%) influenced FDA new drug approvals, and 6 (3.3%) influenced both. The number of PI trials was 47 of 65 (72.3%) among those with positive findings and 35 of 117 (29.9%) among those with negative findings. Thus, 35 of 82 PI trials (42.7%) were based on studies with negative findings, with nearly half of these studies (17 of 35 [48.6%]) reaffirming standard of care compared with experimental therapy. The total federal investment spent in conducting the trials was $1.36 billion (2017 US dollars), a rate of $7.5 million per study or $16.6 million per PI trial.

Conclusions and Relevance: Nearly half of all phase 3 trials by one of the NCTN's largest groups were associated with guideline care or new drug indications, including those with positive and negative findings. Compared with the costs of a new drug approval in pharmaceutical companies, typically estimated at more than $1 billion, the amount of federal funds invested to provide this valuable evidence was modest. These results suggest that the NCTN program contributes clinically meaningful, cost-efficient evidence to guide patient care.

RevDate: 2019-09-04

Fiorenza S, Routledge D, Collins J, et al (2019)

Time from autologous to allogeneic hematopoietic stem cell transplantation impacts post-transplant outcomes in multiple myeloma.

RevDate: 2019-09-04

Shadman M, Maloney DG, Storer B, et al (2019)

Rituximab-based allogeneic transplant for chronic lymphocytic leukemia with comparison to historical experience.

Bone marrow transplantation pii:10.1038/s41409-019-0660-8 [Epub ahead of print].

Relapse of chronic lymphocytic leukemia (CLL) after allogeneic hematopoietic cell transplantation (HCT) remains a clinical challenge. We studied in a phase II trial whether the addition of peri-transplant rituximab would reduce the relapse risk compared with historical controls (n = 157). Patients (n = 55) received fludarabine and low-dose total body irradiation combined with rituximab on days -3, + 10, + 24, + 36. Relapse rate at 3 years was significantly lower among rituximab-treated patients versus controls (17% versus 31%; P = 0.04). Overall survival (OS), progression-free survival (PFS) and nonrelapse mortality (NRM) were statistically similar: (53% versus 50%; P = 0.8), (44% versus 42%; P = 0.63), and (38% versus 28%; P = 0.2), respectively. In multivariate analysis, rituximab treatment was associated with lower relapse rates both in the overall cohort [hazard ratio (HR): 0.34, P = 0.006] and in patients with high-risk cytogenetics (HR: 0.21, P = 0.0003). Patients with no comorbidities who received rituximab conditioning had an OS rate of 100% and 75% at 1 and 3 years, respectively, with no NRM. Peri-transplant rituximab reduced relapse rates regardless of high-risk cytogenetics. HCT is associated with minimal NRM in patients without comorbidities and is a viable option for patients with high-risk CLL. Clinical trial information: NCT00867529.

RevDate: 2019-09-04

Zhang F, Parayath NN, Ene CI, et al (2019)

Genetic programming of macrophages to perform anti-tumor functions using targeted mRNA nanocarriers.

Nature communications, 10(1):3974 pii:10.1038/s41467-019-11911-5.

Tumor-associated macrophages (TAMs) usually express an M2 phenotype, which enables them to perform immunosuppressive and tumor-promoting functions. Reprogramming these TAMs toward an M1 phenotype could thwart their pro-cancer activities and unleash anti-tumor immunity, but efforts to accomplish this are nonspecific and elicit systemic inflammation. Here we describe a targeted nanocarrier that can deliver in vitro-transcribed mRNA encoding M1-polarizing transcription factors to reprogram TAMs without causing systemic toxicity. We demonstrate in models of ovarian cancer, melanoma, and glioblastoma that infusions of nanoparticles formulated with mRNAs encoding interferon regulatory factor 5 in combination with its activating kinase IKKβ reverse the immunosuppressive, tumor-supporting state of TAMs and reprogram them to a phenotype that induces anti-tumor immunity and promotes tumor regression. We further establish that these nanoreagents are safe for repeated dosing. Implemented in the clinic, this immunotherapy could enable physicians to obviate suppressive tumors while avoiding systemic treatments that disrupt immune homeostasis.

RevDate: 2019-09-04

Cassaday RD, Press OW, Pagel JM, et al (2019)

Phase I Study of a CD45-Targeted Antibody-Radionuclide Conjugate for High-Risk Lymphoma.

Clinical cancer research : an official journal of the American Association for Cancer Research pii:1078-0432.CCR-19-1567 [Epub ahead of print].

PURPOSE: External-beam radiation is the single most effective therapy for localized lymphoma. However, toxicity limits its use for multifocal disease. We evaluated CD45 as a therapeutic target for an antibody-radionuclide conjugate (ARC) for the treatment of lymphoma based on its ubiquitous expression, infrequent antigen loss or blockade, and the ability to target minimal disease based on panhematopoietic expression.

EXPERIMENTAL DESIGN: We performed a phase I trial of escalating doses of single-agent CD45-targeted ARC based on per-patient dosimetry using the BC8 antibody labeled with iodine-131 (131I) followed by autologous stem cell support in adults with relapsed, refractory, or high-risk B-cell non-Hodgkin lymphoma (NHL), T-NHL, or Hodgkin lymphoma (HL). The primary objective was to estimate the maximum tolerated radiation absorbed dose.

RESULTS: Sixteen patients were enrolled: 7 patients had B-NHL, 6 had HL, and 3 had T-NHL. Median number of prior therapies was 3 (range: 2-12). Absorbed doses up to 32 Gy to liver were delivered. No dose-limiting toxicities occurred. Non-hematologic toxicity was infrequent and manageable. Objective responses were seen across histologies. Fourteen patients had measurable disease at enrollment, 57% of whom achieved complete remission (CR), including all 3 with T-NHL. Three patients with B-NHL treated among the highest dose levels (26-32 Gy) remain in CR without subsequent therapy 35-41 months later.

CONCLUSIONS: CD45-targeted ARC therapy is well-tolerated at doses up to at least 32 Gy to the liver. Objective responses and long-term remissions were observed in patients with relapsed/refractory lymphoma. These data validate continued evaluation of anti-CD45 ARCs in lymphoma.

RevDate: 2019-09-03

Ko LK, Jang SH, Friedman DB, et al (2019)

An application of the Science Impact Framework to the Cancer Prevention and Control Research Network from 2014-2018.

Preventive medicine pii:S0091-7435(19)30297-X [Epub ahead of print].

The Cancer Prevention and Control Research Network (CPCRN) is a strategic collaborative effort focused on accelerating the dissemination and implementation of evidence-based cancer prevention and control interventions to communities. In 2014, the CPCRN Coordinating Center began collecting information in alignment with the Centers for Disease Control and Prevention's (CDC) Science Impact Framework. The Science Impact Framework is a CDC-developed approach to trace and link CDC science to events and/or actions recognized as influential to public health, beyond peer-reviewed publications. The purpose of this paper is to highlight the impact of CPCRN activities using key indicators guided by the CDC's Science Impact Framework. We reviewed annual progress reports submitted by CPCRN centers from 2014 to 2019 to identify the impact indicators. The CPCRN activities were linked to four domains from the Science Impact Framework and its key indicators: Disseminating Science (presentations, training, general communication, and other communication reports), Creating Awareness (requests for expertise, and feedback), Catalyzing Action (grant applications, partnerships and collaborations, research & development, advocacy groups, office practice/point of care changes, and technology creating), and Effecting Change (building public health practice, creation of registries/surveillance, legal/policy changes, and change instilled). Overall, CPCRN activities demonstrate impact beyond peer-reviewed publications and thus should continue building scientific impact to ultimately influence health outcomes.

RevDate: 2019-09-05

Dieterich IA, Lawton AJ, Peng Y, et al (2019)

Acetyl-CoA flux regulates the proteome and acetyl-proteome to maintain intracellular metabolic crosstalk.

Nature communications, 10(1):3929 pii:10.1038/s41467-019-11945-9.

AT-1/SLC33A1 is a key member of the endoplasmic reticulum (ER) acetylation machinery, transporting acetyl-CoA from the cytosol into the ER lumen where acetyl-CoA serves as the acetyl-group donor for Nε-lysine acetylation. Dysfunctional ER acetylation, as caused by heterozygous or homozygous mutations as well as gene duplication events of AT-1/SLC33A1, has been linked to both developmental and degenerative diseases. Here, we investigate two models of AT-1 dysregulation and altered acetyl-CoA flux: AT-1S113R/+ mice, a model of AT-1 haploinsufficiency, and AT-1 sTg mice, a model of AT-1 overexpression. The animals display distinct metabolic adaptation across intracellular compartments, including reprogramming of lipid metabolism and mitochondria bioenergetics. Mechanistically, the perturbations to AT-1-dependent acetyl-CoA flux result in global and specific changes in both the proteome and the acetyl-proteome (protein acetylation). Collectively, our results suggest that AT-1 acts as an important metabolic regulator that maintains acetyl-CoA homeostasis by promoting functional crosstalk between different intracellular organelles.

RevDate: 2019-09-05

Pajtler KW, Wei Y, Okonechnikov K, et al (2019)

YAP1 subgroup supratentorial ependymoma requires TEAD and nuclear factor I-mediated transcriptional programmes for tumorigenesis.

Nature communications, 10(1):3914 pii:10.1038/s41467-019-11884-5.

YAP1 fusion-positive supratentorial ependymomas predominantly occur in infants, but the molecular mechanisms of oncogenesis are unknown. Here we show YAP1-MAMLD1 fusions are sufficient to drive malignant transformation in mice, and the resulting tumors share histo-molecular characteristics of human ependymomas. Nuclear localization of YAP1-MAMLD1 protein is mediated by MAMLD1 and independent of YAP1-Ser127 phosphorylation. Chromatin immunoprecipitation-sequencing analyses of human YAP1-MAMLD1-positive ependymoma reveal enrichment of NFI and TEAD transcription factor binding site motifs in YAP1-bound regulatory elements, suggesting a role for these transcription factors in YAP1-MAMLD1-driven tumorigenesis. Mutation of the TEAD binding site in the YAP1 fusion or repression of NFI targets prevents tumor induction in mice. Together, these results demonstrate that the YAP1-MAMLD1 fusion functions as an oncogenic driver of ependymoma through recruitment of TEADs and NFIs, indicating a rationale for preclinical studies to block the interaction between YAP1 fusions and NFI and TEAD transcription factors.

RevDate: 2019-09-02

Walsh CA, Rosenberg AR, Lau N, et al (2019)

Key Considerations for Advancing the Development and Testing of mHealth Interventions in Adolescent and Young Adult Oncology.

Psycho-oncology [Epub ahead of print].

RevDate: 2019-09-02

Zhang L, He X, Liu X, et al (2019)

Single-Cell Transcriptomics in Medulloblastoma Reveals Tumor-Initiating Progenitors and Oncogenic Cascades during Tumorigenesis and Relapse.

Cancer cell pii:S1535-6108(19)30336-8 [Epub ahead of print].

Progenitor heterogeneity and identities underlying tumor initiation and relapse in medulloblastomas remain elusive. Utilizing single-cell transcriptomic analysis, we demonstrated a developmental hierarchy of progenitor pools in Sonic Hedgehog (SHH) medulloblastomas, and identified OLIG2-expressing glial progenitors as transit-amplifying cells at the tumorigenic onset. Although OLIG2+ progenitors become quiescent stem-like cells in full-blown tumors, they are highly enriched in therapy-resistant and recurrent medulloblastomas. Depletion of mitotic Olig2+ progenitors or Olig2 ablation impeded tumor initiation. Genomic profiling revealed that OLIG2 modulates chromatin landscapes and activates oncogenic networks including HIPPO-YAP/TAZ and AURORA-A/MYCN pathways. Co-targeting these oncogenic pathways induced tumor growth arrest. Together, our results indicate that glial lineage-associated OLIG2+ progenitors are tumor-initiating cells during medulloblastoma tumorigenesis and relapse, suggesting OLIG2-driven oncogenic networks as potential therapeutic targets.

RevDate: 2019-09-01

Balkus JE, Carter KA, RS McClelland (2019)

Lessons from Suppressive Therapy and Periodic Presumptive Treatment for Bacterial Vaginosis.

Current infectious disease reports, 21(10):34 pii:10.1007/s11908-019-0688-3.

PURPOSE OF REVIEW: Suppressive therapy and periodic presumptive treatment (PPT) are distinct but related strategies that have been used to reduce the incidence of bacterial vaginosis (BV). Here, we review clinical trial evidence of the effectiveness of suppressive therapy and PPT to reduce BV, and discuss their roles for women who frequently experience symptomatic or asymptomatic BV.

RECENT FINDINGS: Among women who were recently and successfully treated for symptomatic BV, suppressive therapy with twice-weekly metronidazole gel for 16 weeks reduces the likelihood of recurrent symptomatic BV and is currently recommended by the Centers for Disease Control and Prevention for prevention of recurrent BV. The premise of PPT is to provide regimens used to treat BV at regular intervals to reduce the overall frequency of BV, regardless of symptoms. Three PPT trials were conducted using different routes (oral or intravaginal), doses, and frequencies of administration. Each trial demonstrated a significant reduction in BV over the course 12 months, ranging from a 10 to 45% decrease. PPT regimens that substantially reduce the frequency of BV over time could be evaluated in clinical trials to assess whether a reduced frequency of BV leads to subsequent reductions in BV-associated sequelae. While both suppressive therapy and PPT reduce BV, their impact wanes following cessation of the regimen. Given the high prevalence of BV globally and burden of adverse reproductive health outcomes among women with BV, there is a critical need for more effective treatments that produce durable shifts in the microbiota towards vaginal health.

RevDate: 2019-09-01

Sabloff M, Chhabra S, Wang T, et al (2019)

Comparison of high doses of total body irradiation in myeloablative conditioning prior to hematopoietic cell transplantation.

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(19)30526-9 [Epub ahead of print].

Malignancy relapse is the most common cause of treatment failure among recipients of hematopoietic cell transplantation (HCT). Conditioning dose intensity can reduce disease relapse, but it is offset by toxicities. Improvements in radiotherapy techniques and supportive care may translate to better outcomes with higher irradiation doses in the modern era. This study compares outcomes of recipients of increasing doses of high dose total body irradiation (TBI) divided into intermediate high dose (IH 13-13.75 Gy) and high dose (HD 14 Gy) to standard dose (SD 12Gy) with cyclophosphamide (Cy). A total of 2,721 patients ages of 18 to 60 with hematologic malignancies receiving HCT from 2001 to 2013 were included. Cumulative incidence of non-relapse mortality (NRM) at 5 years was 28% (95% Cumulative Incidence [CI] 25-30%), 32% (95%CI 29-36%) and 34% (95%CI 28-39%) for SD, IH and HD, respectively (p=0.02). Patients receiving IH-TBI had a 25% higher risk of NRM compared to SD-TBI (12 Gy) (p=0.007). Corresponding cumulative incidence of relapse was 36% (95%CI 34-38%), 32% (95%CI 29-36%) and 26% (95%CI 21-31%) (p=0.001). Hazard ratio for mortality compared to SD were 1.06 (95% 0.94-1.19, p=0.36) for IH and 0.89 (95% CI 0.76-1.05, p=0.17) for HD. The study demonstrates that despite improvements in supportive care, myeloablative conditioning using higher doses of TBI (with Cy) leads to worse non-relapse mortality and offers no survival benefit over SD, despite reducing disease relapse.

RevDate: 2019-09-01

Gaudinski MR, Houser KV, Doria-Rose NA, et al (2019)

Safety and pharmacokinetics of broadly neutralising human monoclonal antibody VRC07-523LS in healthy adults: a phase 1 dose-escalation clinical trial.

The lancet. HIV pii:S2352-3018(19)30181-X [Epub ahead of print].

BACKGROUND: Human monoclonal antibodies that potently and broadly neutralise HIV-1 are under development to prevent and treat HIV-1 infection. In this phase 1 clinical trial we aimed to determine the safety, tolerability, and pharmacokinetic profile of the broadly neutralising monoclonal antibody VRC07-523LS, an engineered variant of VRC01 that targets the CD4 binding site of the HIV-1 envelope protein.

METHODS: This phase 1, open-label, dose-escalation clinical trial was done at the National Institutes of Health Clinical Center in Bethesda, MD, USA. Individuals were recruited from the greater Washington, DC, area by IRB-approved written and electronic media. We enrolled healthy, HIV-1-negative adults aged 18-50 years. Inclusion criteria were good general health, measured through clinical laboratory tests, medical history, and physical examination. Participants self-selected into one of seven open groups during enrolment without randomisation. Four groups received a single intravenous dose of 1, 5, 20, or 40 mg/kg of VRC07-523LS, and one group received a single 5 mg/kg subcutaneous dose. Two groups received three doses of either 20 mg/kg intravenous VRC07-523LS, or 5 mg/kg subcutaneous VRC07-523LS at 12-week intervals. The primary outcome was the safety and tolerability of VRC07-523LS, assessed by dose, route, and number of administrations. This study is registered with ClinicalTrials.gov, NCT03015181.

FINDINGS: Between Feb 21, 2017, and September 13, 2017, we enrolled 26 participants, including 11 (42%) men and 15 (58%) women. Two (8%) participants withdrew from the study early: one participant in group 1 enrolled in the study but never received VRC07-523LS, and one participant in group 6 chose to withdraw after a single administration. One (4%) participant in group 7 received only one of the three scheduled administrations. 17 participants received intravenous administrations and 8 participants received subcutaneous administrations. VRC07-523LS was safe and well tolerated, we observed no serious adverse events or dose-limiting toxic effects. All reported local and systemic reactogenicity was mild to moderate in severity. The most commonly reported symptoms following intravenous administration were malaise or myalgia in three (18%) participants and headache or chills in two (12%) participants. The most commonly reported symptoms following subcutaneous administration were pain and tenderness in four participants (50%) and malaise or headache in three (38%) participants.

INTERPRETATION: Safe and well tolerated, VRC07-523LS is a strong and practical candidate for inclusion in HIV-1 prevention and therapeutic strategies. The results from this trial also indicate that an HIV-1 broadly neutralising monoclonal antibody engineered for improved pharmacokinetic and neutralisation properties can be safe for clinical use.

FUNDING: National Institutes of Health.

RevDate: 2019-08-31

Chan DSM, Abar L, Cariolou M, et al (2019)

World Cancer Research Fund International: Continuous Update Project-systematic literature review and meta-analysis of observational cohort studies on physical activity, sedentary behavior, adiposity, and weight change and breast cancer risk.

Cancer causes & control : CCC pii:10.1007/s10552-019-01223-w [Epub ahead of print].

PURPOSE: The purpose of the present study was to systematically review the complex associations between energy balance-related factors and breast cancer risk, for which previous evidence has suggested different associations in the life course of women and by hormone receptor (HR) status of the tumor.

METHODS: Relevant publications on adulthood physical activity, sedentary behavior, body mass index (BMI), waist and hip circumferences, waist-to-hip ratio, and weight change and pre- and postmenopausal breast cancer risk were identified in PubMed up to 30 April 2017. Random-effects meta-analyses were conducted to summarize the relative risks across studies.

RESULTS: One hundred and twenty-six observational cohort studies comprising over 22,900 premenopausal and 103,000 postmenopausal breast cancer cases were meta-analyzed. Higher physical activity was inversely associated with both pre- and postmenopausal breast cancers, whereas increased sitting time was positively associated with postmenopausal breast cancer. Although higher early adult BMI (ages 18-30 years) was inversely associated with pre- and postmenopausal breast cancers, adult weight gain and greater body adiposity increased breast cancer risk in postmenopausal women, and the increased risk was evident for HR+ but not HR- breast cancers, and among never but not current users of postmenopausal hormones. The evidence was less consistent in premenopausal women. There were no associations with adult weight gain, inverse associations with adult BMI (study baseline) and hip circumference, and non-significant associations with waist circumference and waist-to-hip ratio that were reverted to positive associations on average in studies accounting for BMI. No significant associations were observed for HR-defined premenopausal breast cancers.

CONCLUSION: Better understanding on the impact of these factors on pre- and postmenopausal breast cancers and their subtypes along the life course is needed.

RevDate: 2019-08-31

Dietz AC, Seidel K, Leisenring WM, et al (2019)

Solid organ transplantation after treatment for childhood cancer: a retrospective cohort analysis from the Childhood Cancer Survivor Study.

The Lancet. Oncology pii:S1470-2045(19)30418-8 [Epub ahead of print].

BACKGROUND: Serious chronic medical conditions occur in childhood cancer survivors. We aimed to investigate incidence of and risk factors for end-organ damage resulting in registration on a waiting list for or receiving a solid organ transplantation and 5-year survival following these procedures.

METHODS: The Childhood Cancer Survivor Study (CCSS) is a retrospective cohort of individuals who survived at least 5 years after childhood cancer diagnosed at younger than 21 years of age, between Jan 1, 1970, and Dec 31, 1986, at one of 25 institutions in the USA. We linked data from CCSS participants treated in the USA diagnosed between Jan 1, 1970, and Dec 31, 1986 (without solid organ transplantation before cohort entry) to the Organ Procurement and Transplantation Network-a database of all US organ transplants. Eligible participants had been diagnosed with leukaemia, lymphoma, malignant CNS tumours, neuroblastoma, Wilms' tumours, and bone and soft tissue sarcomas. The two primary endpoints for each type of organ transplant were date of first registration of a transplant candidate on the waiting list for an organ and the date of the first transplant received. We also calculated the cumulative incidence of being placed on a waiting list or receiving a solid organ transplantation, hazard ratios (HRs) for identified risk factors, and 5-year survival following transplantation.

FINDINGS: Of 13 318 eligible survivors, 100 had 103 solid organ transplantations (50 kidney, 37 heart, nine liver, seven lung) and 67 were registered on a waiting list without receiving a transplant (21 kidney, 25 heart, 15 liver, six lung). At 35 years after cancer diagnosis, the cumulative incidence of transplantation or being on a waiting list was 0·54% (95% CI 0·40-0·67) for kidney transplantation, 0·49% (0·36-0·62) for heart, 0·19% (0·10-0·27) for liver, and 0·10% (0·04-0·16) for lung. Risk factors for kidney transplantation were unilateral nephrectomy (HR 4·2, 95% CI 2·3-7·7), ifosfamide (24·9, 7·4-83·5), total body irradiation (6·9, 2·3-21·1), and mean kidney radiation of greater than 15 Gy (>15-20 Gy, 3·6 [1·5-8·5]; >20 Gy 4·6 [1·1-19·6]); for heart transplantation, anthracycline and mean heart radiation of greater than 20 Gy (dose-dependent, both p<0·0001); for liver transplantation, dactinomycin (3·8, 1·3-11·3) and methotrexate (3·3, 1·0-10·2); for lung transplantation, carmustine (12·3, 3·1-48·9) and mean lung radiation of greater than 10 Gy (15·6, 2·6-92·7). 5-year overall survival after solid organ transplantation was 93·5% (95% CI 81·0-97·9) for kidney transplantation, 80·6% (63·6-90·3) for heart, 27·8% (4·4-59·1) for liver, and 34·3% (4·8-68·6) for lung.

INTERPRETATION: Solid organ transplantation is uncommon in ageing childhood cancer survivors. Organ-specific exposures were associated with increased solid organ transplantation incidence. Survival outcomes showed that solid organ transplantation should be considered for 5-year childhood cancer survivors with severe end-organ failure.

FUNDING: US National Institute of Health, American Lebanese Syrian Associated Charities, US Health Resources and Services Administration.

RevDate: 2019-08-30

Snyder JM, Snider TA, Ciol MA, et al (2019)

Validation of a geropathology grading system for aging mouse studies.

GeroScience pii:10.1007/s11357-019-00088-w [Epub ahead of print].

An understanding of early-onset mechanisms underlying age-related changes can be obtained by evaluating changes that precede frailty and end of life using histological characterization of age-related lesions. Histopathology-based information as a component of aging studies in mice can complement and add context to molecular, cellular, and physiologic data, but there is a lack of information regarding scoring criteria and lesion grading guidelines. This report describes the validation of a grading system, designated as the geropathology grading platform (GGP), which generated a composite lesion score (CLS) for comparison of histological lesion scores in tissues from aging mice. To assess reproducibility of the scoring system, multiple veterinary pathologists independently scored the same slides from the heart, lung, liver, and kidney from two different strains (C57BL/6 and CB6F1) of male mice at 8, 16, 24, and 32 months of age. There was moderate to high agreement between pathologists, particularly when agreement within a 1-point range was considered. CLS for all organs was significantly higher in older versus younger mice, suggesting that the GGP was reliable for detecting age-related pathology in mice. The overall results suggest that the GGP guidelines reliably distinguish between younger and older mice and may therefore be accurate in distinguishing between experimental groups of mice with more, or less, age-related pathology.

RevDate: 2019-08-30

Dörk T, Peterlongo P, Mannermaa A, et al (2019)

Two truncating variants in FANCC and breast cancer risk.

Scientific reports, 9(1):12524 pii:10.1038/s41598-019-48804-y.

Fanconi anemia (FA) is a genetically heterogeneous disorder with 22 disease-causing genes reported to date. In some FA genes, monoallelic mutations have been found to be associated with breast cancer risk, while the risk associations of others remain unknown. The gene for FA type C, FANCC, has been proposed as a breast cancer susceptibility gene based on epidemiological and sequencing studies. We used the Oncoarray project to genotype two truncating FANCC variants (p.R185X and p.R548X) in 64,760 breast cancer cases and 49,793 controls of European descent. FANCC mutations were observed in 25 cases (14 with p.R185X, 11 with p.R548X) and 26 controls (18 with p.R185X, 8 with p.R548X). There was no evidence of an association with the risk of breast cancer, neither overall (odds ratio 0.77, 95%CI 0.44-1.33, p = 0.4) nor by histology, hormone receptor status, age or family history. We conclude that the breast cancer risk association of these two FANCC variants, if any, is much smaller than for BRCA1, BRCA2 or PALB2 mutations. If this applies to all truncating variants in FANCC it would suggest there are differences between FA genes in their roles on breast cancer risk and demonstrates the merit of large consortia for clarifying risk associations of rare variants.

RevDate: 2019-09-05

Schoenherr RM, Huang D, Voytovich UJ, et al (2019)

A dataset describing a suite of novel antibody reagents for the RAS signaling network.

Scientific data, 6(1):160 pii:10.1038/s41597-019-0166-7.

RAS genes are frequently mutated in cancer and have for decades eluded effective therapeutic attack. The National Cancer Institute's RAS Initiative has a focus on understanding pathways and discovering therapies for RAS-driven cancers. Part of these efforts is the generation of novel reagents to enable the quantification of RAS network proteins. Here we present a dataset describing the development, validation (following consensus principles developed by the broader research community), and distribution of 104 monoclonal antibodies (mAbs) enabling detection of 27 phosphopeptides and 69 unmodified peptides from 20 proteins in the RAS network. The dataset characterizes the utility of the antibodies in a variety of applications, including Western blotting, immunoprecipitation, protein array, immunohistochemistry, and targeted mass spectrometry. All antibodies and characterization data are publicly available through the CPTAC Antibody Portal, Panorama Public Repository, and/or PRIDE databases. These reagents will aid researchers in discerning pathways and measuring expression changes in the RAS signaling network.

RevDate: 2019-08-30

Ward KN, Hill JA, Hubacek P, et al (2019)

Guidelines from the 2017 European Conference on Infections in Leukaemia for management of HHV-6 infection in patients with hematological malignancies and after hematopoietic stem cell transplantation.

Haematologica pii:haematol.2019.223073 [Epub ahead of print].

HHV-6B encephalitis is an important cause of morbidity and mortality after allogeneic hematopoietic stem cell transplant. Guidelines for the management of HHV-6 infections in patients with hematological malignancies or post-transplant were prepared a decade ago but there have been no other guidelines since then despite significant advances in the understanding of HHV-6 encephalitis, its therapy, and other aspects of HHV-6 disease in this patient population. Revised guidelines prepared at the 2017 European Conference on Infections in Leukaemia covering diagnosis, preventative strategies and management of HHV-6 disease are now presented.

RevDate: 2019-08-29

Di Meo A, Batruch I, Brown MD, et al (2019)

Searching for Prognostic Biomarkers for Small Renal Masses in the Urinary Proteome.

International journal of cancer [Epub ahead of print].

Renal cell carcinoma (RCC) is frequently diagnosed incidentally as an early-stage small renal mass (SRM; pT1a, ≤ 4 cm). Overtreatment of patients with benign or clinically indolent SRMs is increasingly common and has resulted in a recent shift in treatment recommendations. There are currently no available biomarkers that can accurately predict clinical behaviour. Therefore, we set out to identify early biomarkers of RCC progression. We employed a quantitative label-free LC-MS/MS proteomics approach and targeted parallel-reaction monitoring to identify and validate early, non-invasive urinary biomarkers for RCC-SRMs. In total, we evaluated 115 urine samples, including 33 renal oncocytoma (≤ 4 cm) cases, 30 progressive and 26 non-progressive clear cell RCC-SRM cases, in addition to 26 healthy controls. We identified six proteins which displayed significantly elevated expression in clear cell RCC-SRMs (ccRCC-SRMs) relative to healthy controls. Proteins C12ORF49 and EHD4 showed significantly elevated expression in ccRCC-SRMs compared to renal oncocytoma (≤ 4 cm). Additionally, proteins EPS8L2, CHMP2A, PDCD6IP, CNDP2, and CEACAM1 displayed significantly elevated expression in progressive relative to non-progressive ccRCC-SRMs. A two-protein signature (EPS8L2 and CCT6A) showed significant discriminatory ability (AUC: 0.81, 95% CI: 0.70 to 0.93) in distinguishing progressive from non-progressive ccRCC-SRMs. Patients (stage I-IV) with EPS8L2 and CCT6A mRNA alterations showed significantly shorter overall survival (OS; p = 1.407 x 10-6) compared to patients with no alterations. Our in-depth proteomic analysis identified novel biomarkers for early-stage RCC-SRMs. Pretreatment characterization of urinary proteins may provide insight into early RCC progression and could potentially help assign patients to appropriate management strategies. This article is protected by copyright. All rights reserved.

RevDate: 2019-08-29

Yaghmaie M, CC Yeung (2019)

Molecular Mechanisms of Resistance to Tyrosine Kinase Inhibitors.

Current hematologic malignancy reports pii:10.1007/s11899-019-00543-7 [Epub ahead of print].

PURPOSE OF REVIEW: Chronic myeloid leukemia (CML) patients with constitutive activity of BCR-ABL1 oncoprotein frequently derive significant clinical benefits from tyrosine kinase inhibitors (TKIs). Point mutations in the ABL1 kinase domain (KD) are an important mechanism of TKI resistance in CML. In this review, we present molecular mechanisms of TKI resistance paying particular attention to drug resistance which allows for a survival advantage in CML.

RECENT FINDINGS: Sensitive disease monitoring is a required standard of care for management of CML. Screening of these mutations fail to explain 20-40% of resistant cases where activation of different survival pathways must be the main reason for resistance. Eliminating TKI resistance appears to be the most successful therapeutic way to decrease leukemic disease burden and potentiate cure. Advances on novel strategies for identifying and confronting drug resistance are rapidly altering management of CML that are resistant to TKI and expanding the landscape of available therapies.

RevDate: 2019-08-29

Nagana Gowda GA, D Raftery (2019)

Analysis of Coenzymes and Antioxidants in Tissue and Blood Using 1D 1H NMR Spectroscopy.

Methods in molecular biology (Clifton, N.J.), 2037:97-110.

Cellular coenzymes including coenzyme A (CoA), acetyl coenzyme A (acetyl-CoA), coenzymes of redox reactions and of energy, and antioxidants mediate biochemical reactions fundamental to the functioning of all living cells. The redox coenzymes include NAD+ (oxidized nicotinamide adenine dinucleotide), NADH (reduced nicotinamide adenine dinucleotide), NADP+ (oxidized nicotinamide adenine dinucleotide phosphate), and NADPH (reduced nicotinamide adenine dinucleotide phosphate); the energy coenzymes include ATP (adenosine triphosphate), ADP (adenosine diphosphate), and AMP (adenosine monophosphate); and the antioxidants include GSSG (oxidized glutathione) and GSH (reduced glutathione). Their measurement is important to better understand cellular metabolism. Recent advances have pushed the limit of metabolite quantitation using NMR methods to an unprecedented level, which offer a new avenue for analysis of the coenzymes and antioxidants. Unlike the conventional enzyme assays, which need separate protocols for analysis, a simple 1D 1H NMR experiment enables analysis of all these molecular species in one step. In this chapter, we describe protocols for their identification and quantitation in tissue and whole blood using NMR spectroscopy.

RevDate: 2019-08-29

Nagana Gowda GA, D Raftery (2019)

Analysis of Plasma, Serum, and Whole Blood Metabolites Using 1H NMR Spectroscopy.

Methods in molecular biology (Clifton, N.J.), 2037:17-34.

Blood is the most widely used biological specimen in the metabolomics field. With its unique characteristics of high reproducibility and excellent quantitation, NMR spectroscopy offers immense benefits for the analysis of blood metabolites. In the metabolomics field, intact blood serum and plasma have been widely used for many years. However, such analysis has met with challenges arising from the deleterious effects of the abundant proteins in serum and plasma. Recent advances have led to the development of improved NMR methods that involve removal of protein before analysis. In particular, protein removal by precipitation using methanol alone or using a mixture of methanol and chloroform was shown to be an optimal method for metabolite recovery and for producing highly resolved NMR spectra. This has led to the absolute quantitation of nearly 70 metabolites in serum and plasma and nearly 80 in whole blood. In this chapter, we describe protocols for the analysis of blood serum, blood plasma, and whole blood metabolites using 1D 1H NMR spectroscopy methods.

RevDate: 2019-08-29

Nagana Gowda GA, D Raftery (2019)

Overview of NMR Spectroscopy-Based Metabolomics: Opportunities and Challenges.

Methods in molecular biology (Clifton, N.J.), 2037:3-14.

The fast-growing field of metabolomics is impacting numerous areas of basic and life sciences. In metabolomics, analytical methods play a pivotal role, and nuclear magnetic resonance (NMR) and mass spectrometry (MS) have proven to be the most suitable and powerful methods. Although NMR exhibits lower sensitivity and resolution compared to MS, NMR's numerous important characteristics far outweigh its limitations. Some of its characteristics include excellent reproducibility and quantitative accuracy, the capability to analyze intact biospecimens, an unparalleled ability to identify unknown metabolites, the ability to trace in-cell and in-organelle metabolism in real time, and the capacity to trace metabolic pathways atom by atom using 2H, 13C, or 15N isotopes. Each of these characteristics has been exploited extensively in numerous studies. In parallel, the field has witnessed significant progress in instrumentation, methods development, databases, and automation that are focused on higher throughput and alleviating the limitations of NMR, in particular, resolution and sensitivity. Despite the advances, however, the high complexity of biological mixtures combined with the limitations in sensitivity and resolution continues to pose major challenges. These challenges need to be dealt with effectively to better realize the potential of metabolomics, in general. As a result, multifaceted efforts continue to focus on addressing the challenges as well as reaping the benefits of NMR-based metabolomics. This chapter highlights the current status with emphasis on the opportunities and challenges in NMR-based metabolomics.

RevDate: 2019-09-01

Fong Y (2019)

Fast Bootstrap Confidence Intervals for Continuous Threshold Linear Regression.

Journal of computational and graphical statistics : a joint publication of American Statistical Association, Institute of Mathematical Statistics, Interface Foundation of North America, 28(2):466-470.

Continuous threshold regression is a common type of nonlinear regression that is attractive to many practitioners for its easy interpretability. More widespread adoption of thresh-old regression faces two challenges: (i) the computational complexity of fitting threshold regression models and (ii) obtaining correct coverage of confidence intervals under model misspecification. Both challenges result from the non-smooth and non-convex nature of the threshold regression model likelihood function. In this paper we first show that these two issues together make the ideal approach for making model-robust inference in continuous threshold linear regression an impractical one. The need for a faster way of fitting continuous threshold linear models motivated us to develop a fast grid search method. The new method, based on the simple yet powerful dynamic programming principle, improves the performance by several orders of magnitude.

RevDate: 2019-09-03

Lee Y, Sun D, Ori APS, et al (2019)

Epigenome-wide association study of leukocyte telomere length.

Aging, 11(16):5876-5894.

Telomere length is associated with age-related diseases and is highly heritable. It is unclear, however, to what extent epigenetic modifications are associated with leukocyte telomere length (LTL). In this study, we conducted a large-scale epigenome-wide association study (EWAS) of LTL using seven large cohorts (n=5,713) - the Framingham Heart Study, the Jackson Heart Study, the Women's Health Initiative, the Bogalusa Heart Study, the Lothian Birth Cohorts of 1921 and 1936, and the Longitudinal Study of Aging Danish Twins. Our stratified analysis suggests that EWAS findings for women of African ancestry may be distinct from those of three other groups: males of African ancestry, and males and females of European ancestry. Using a meta-analysis framework, we identified DNA methylation (DNAm) levels at 823 CpG sites to be significantly associated (P<1E-7) with LTL after adjusting for age, sex, ethnicity, and imputed white blood cell counts. Functional enrichment analyses revealed that these CpG sites are near genes that play a role in circadian rhythm, blood coagulation, and wound healing. Weighted correlation network analysis identified four co-methylation modules associated with LTL, age, and blood cell counts. Overall, this study reveals highly significant relationships between two hallmarks of aging: telomere biology and epigenetic changes.

RevDate: 2019-08-28

Lau N, Yi-Frazier JP, Bona K, et al (2019)

Distress and resilience among adolescents and young adults with cancer and their mothers: An exploratory analysis.

Journal of psychosocial oncology [Epub ahead of print].

The aim of this analysis was to explore intra-family longitudinal relationships in psychosocial well-being among adolescent and young adults (AYAs, Mage = 17, SD = 2.1) with cancer and their mothers using data from a multi-site, prospective, survey-based study. AYA-mother dyads (n = 14 dyads) completed validated patient reported outcome (PRO) measures of self-perceived resilience [Connor-Davidson resilience scale (CD-RISC-10)] and distress [Kessler-6 psychological distress scale (K6)] at baseline (14-60 days following diagnosis) and follow-up (3-6 months later). Higher AYA distress predicted better maternal resilience, whereas higher maternal distress predicted worse AYA resilience. Thus, processes of resilience between AYAs and their mothers may differ.

RevDate: 2019-08-28

Hibbitts E, Chi YY, Hawkins DS, et al (2019)

Refinement of risk stratification for childhood rhabdomyosarcoma using FOXO1 fusion status in addition to established clinical outcome predictors: A report from the Children's Oncology Group.

Cancer medicine [Epub ahead of print].

BACKGROUND: Previous studies of the prognostic importance of FOXO1 fusion status in patients with rhabdomyosarcoma (RMS) have had conflicting results. We re-examined risk stratification by adding FOXO1 status to traditional clinical prognostic factors in children with localized or metastatic RMS.

METHODS: Data from six COG clinical trials (D9602, D9802, D9803, ARST0331, ARTS0431, ARST0531; two studies each for low-, intermediate- and high-risk patients) accruing previously untreated patients with RMS from 1997 to 2013 yielded 1727 evaluable patients. Survival tree regression for event-free survival (EFS) was conducted to recursively select prognostic factors for branching and split. Factors included were age, FOXO1, clinical group, histology, nodal status, number of metastatic sites, primary site, sex, tumor size, and presence of metastases in bone/bone marrow, soft tissue, effusions, lung, distant lymph nodes, and other sites. Definition and outcome of the proposed risk groups were compared to existing systems and cross-validated results.

RESULTS: The 5-year EFS and overall survival (OS) for evaluable patients were 69% and 79%, respectively. Extent of disease (localized versus metastatic) was the first split (EFS 73% vs 30%; OS 84% vs. 42%). FOXO1 status (positive vs negative) was significant in the second split both for localized (EFS 52% vs 78%; OS 65% vs 88%) and metastatic disease (EFS 6% vs 46%; OS 19% vs 58%).

CONCLUSIONS: After metastatic status, FOXO1 status is the most important prognostic factor in patients with RMS and improves risk stratification of patients with localized RMS. Our findings support incorporation of FOXO1 status in risk stratified clinical trials.

RevDate: 2019-08-31

Karaesmen E, Hahn T, Dile AJ, et al (2019)

Multiple functional variants in the IL1RL1 region are pretransplant markers for risk of GVHD and infection deaths.

Blood advances, 3(16):2512-2524.

Graft-versus-host disease (GVHD) and infections are the 2 main causes of death without relapse after allogeneic hematopoietic cell transplantation (HCT). Elevated soluble serum simulation-2 (sST2), the product of IL1RL1 in plasma/serum post-HCT, is a validated GVHD biomarker. Hundreds of SNPs at 2q12.1 have been shown to be strongly associated with sST2 concentrations in healthy populations. We therefore hypothesized that the donor genetic variants in IL1RL1 correlate with sST2 protein levels associated with patient survival outcomes after HCT. We used DISCOVeRY-BMT (Determining the Influence of Susceptibility Conveying Variants Related to 1-Year Mortality after Blood and Marrow Transplantation), a genomic study of >3000 donor-recipient pairs, to inform our hypothesis. We first measured pre-HCT plasma/serum sST2 levels in a subset of DISCOVeRY-BMT donors (n = 757) and tested the association of donor sST2 levels with donor single nucleotide polymorphisms (SNPs) in the 2q12.1 region. Donor SNPs associated with sST2 levels were then tested for association with recipient death caused by acute GVHD (aGVHD)-, infection-, and transplant-related mortality in cohorts 1 and 2. Meta-analyses of cohorts 1 and 2 were performed using fixed-effects inverse variance weighting, and P values were corrected for multiple comparisons. Donor risk alleles in rs22441131 (Pmeta = .00026) and rs2310241 (Pmeta = .00033) increased the cumulative incidence of aGVHD death up to fourfold and were associated with high sST2 levels. Donor risk alleles at rs4851601 (Pmeta = 9.7 × 10-7), rs13019803 (Pmeta = 8.9 × 10-6), and rs13015714 (Pmeta = 5.3 × 10-4) increased cumulative incidence of infection death to almost sevenfold and were associated with low sST2 levels. These functional variants are biomarkers of infection or aGVHD death and could facilitate donor selection, prophylaxis, and a conditioning regimen to reduce post-HCT mortality.

RevDate: 2019-08-27

Chow SC, J Zheng (2019)

The use of 95% CI or 90% CI for drug product development - a controversial issue?.

Journal of biopharmaceutical statistics [Epub ahead of print].

For review and approval of drug products, a 95% confidence interval approach for evaluation of new drugs is commonly used, while a 90% confidence interval approach is considered for assessment of generic drugs and biosimilar products. In the past decade, FDA has been challenged for adopting different standards (i.e., 5% type-I error rate for new drugs and 10% type-I error rate for generics/biosimilars) for regulatory submissions of drugs and biologics. This note intends to clarify the confusion by pointing out the fundamental differences between (i) the concepts of point hypotheses and interval hypotheses, and (ii) the concepts of interval hypotheses testing and confidence interval approach. In general, the method of interval hypotheses testing is not equivalent to the confidence interval approach although they may be operationally equivalent under certain conditions.

RevDate: 2019-08-27

Zheng J, Yin D, Yuan M, et al (2019)

Simultaneous confidence interval methods for analytical similarity assessment.

Journal of biopharmaceutical statistics [Epub ahead of print].

In analytical similarity assessment of a biosimilar product, key quality attributes of the test and reference products need to be shown statistically similar. When there were multiple references, similarity among the reference products is also required. We proposed a simultaneous confidence approach based on the fiducial inference theory as an alternative to the pairwise comparison method. Three versions with two types of simultaneous confidence intervals for each version were proposed based on different assumptions of the population variance. We conducted extensive simulation studies to compare the performance of our proposed method and the pairwise method, and provided examples to illustrate the concern of using pairwise method.

RevDate: 2019-09-01

Lee JM, Eguia R, Zost SJ, et al (2019)

Mapping person-to-person variation in viral mutations that escape polyclonal serum targeting influenza hemagglutinin.

eLife, 8: pii:49324.

A longstanding question is how influenza virus evolves to escape human immunity, which is polyclonal and can target many distinct epitopes. Here, we map how all amino-acid mutations to influenza's major surface protein affect viral neutralization by polyclonal human sera. The serum of some individuals is so focused that it selects single mutations that reduce viral neutralization by over an order of magnitude. However, different viral mutations escape the sera of different individuals. This individual-to-individual variation in viral escape mutations is not present among ferrets that have been infected just once with a defined viral strain. Our results show how different single mutations help influenza virus escape the immunity of different members of the human population, a phenomenon that could shape viral evolution and disease susceptibility.

RevDate: 2019-08-27

Fabian K, Molina Y, Kemp CG, et al (2019)

Internalized HIV-Related Stigma and Breast Health Beliefs Among African-American Women Receiving Care for HIV in the USA.

Journal of racial and ethnic health disparities pii:10.1007/s40615-019-00632-6 [Epub ahead of print].

OBJECTIVES: African-American women suffer disproportionately from HIV, breast cancer, and other illnesses. Little is known about the relationship between internalized HIV-related stigma and health beliefs related to other illnesses, including breast cancer. Our study examined (1) the relationship between internalized HIV-related stigma and breast health beliefs over time and (2) the moderating effects of participating in a stigma reduction intervention and/or social support.

METHODS: Data from 239 African-American women receiving care for HIV in Chicago, IL, or Birmingham, AL, enrolled in the Unity randomized controlled trial, were used in this secondary analysis. Threat of breast cancer was measured in terms of perceived susceptibility, fear, and adverse consequences as well as an overall perceived threat of breast cancer. We used multivariate models with generalized estimating equations to examine the relationship between internalized HIV-related stigma and breast health beliefs across three time points (baseline, immediately post-workshop, and at 12-month follow-up) and to examine if the study arm (HIV stigma reduction vs. breast cancer education) or social support moderated the relationship.

RESULTS: Internalized HIV-related stigma was associated with greater overall perceived threat (p < 0.001), susceptibility (p = 0.03), fear (p < 0.001), and perceived adverse consequences (p < 0.001) of breast cancer. These associations remained consistent across study arms and across all levels of social support.

CONCLUSIONS: Future studies that examine co-morbid health conditions among African-American women living with HIV should consider the impact of HIV-related stigma on attitudes and beliefs related to co-morbid conditions.

RevDate: 2019-08-26

Hill JA, Vande Vusse LK, Xie H, et al (2019)

Human Herpesvirus 6B and Lower Respiratory Tract Disease After Hematopoietic Cell Transplantation.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology [Epub ahead of print].

PURPOSE: Human herpesvirus 6B (HHV-6B) DNA is frequently detected in bronchoalveolar lavage fluid (BALF) from immunocompromised subjects with lower respiratory tract disease (LRTD). Whether HHV-6B is a pulmonary pathogen is unclear.

METHODS: We tested BALF for HHV-6B DNA using polymerase chain reaction in allogeneic hematopoietic cell transplantation (HCT) recipients who underwent a BAL for evaluation of LRTD from 1992 to 2015. We used multivariable proportional hazards models to evaluate the association of HHV-6B+ BALF with overall mortality, death from respiratory failure, and the effect of anti-HHV-6B antivirals on these outcomes. We used branched-chain RNA in situ hybridization to detect HHV-6 messenger RNA (U41 and U57 transcripts) in lung tissue.

RESULTS: We detected HHV-6B+ BALF from 147 of 553 (27%) individuals. Subjects with HHV-6B+ BALF, with or without copathogens, had significantly increased risk of overall mortality (adjusted hazard ratio [aHR], 2.18; 95% CI, 1.41-3.39) and death from respiratory failure (aHR, 2.50; 95% CI, 1.56-4.01) compared with subjects with HHV-6B- BALF. Subjects with HHV-6B+ BALF who received antivirals within 3 days pre-BAL had an approximately 1 log10 lower median HHV-6B BALF viral load, as well as a lower risk of overall mortality (aHR, 0.42; 95% CI, 0.16-1.10), compared with subjects with HHV-6B+ BALF not receiving antivirals. We detected intraparenchymal HHV-6 gene expression by RNA in situ hybridization in lung tissue in all three tested subjects with HHV-6B+ BALF and sufficient tissue RNA preservation.

CONCLUSION: These data provide evidence that HHV-6B detection in BALF is associated with higher mortality in allogeneic hematopoietic cell transplantation recipients with LRTD. Definitive evidence of causation will require a randomized prevention or treatment trial.

RevDate: 2019-08-30

Butera NM, Li S, Evenson KR, et al (2019)

Hot Deck Multiple Imputation for Handling Missing Accelerometer Data.

Statistics in biosciences, 11(2):422-448.

Missing data due to non-wear are common in accelerometer studies measuring physical activity and sedentary behavior. Accelerometer output are high-dimensional time-series data that are episodic and often highly skewed, presenting unique challenges for handling missing data. Common methods for missing accelerometry either are ad-hoc, require restrictive parametric assumptions, or do not appropriately impute bouts. This study developed a flexible hot deck multiple imputation (MI; i.e., "replacing" missing data with observed values) procedure to handle missing accelerometry. For each missing segment of accelerometry, "donor pools" contained observed segments from either the same or different participants, and 10 imputed segments were randomly drawn from the donor pool according to selection weights, where the donor pool and selection weight depended on variables associated with non-wear and/or accelerometer-based measures. A simulation study of 2,550 women compared hot deck MI to two standard methods in the field: available case (AC) analysis (i.e., analyzing all observed accelerometry with no restriction on wear time or number of days) and complete case (CC) analysis (i.e., analyzing only participants that wore the accelerometer for ≥10 hours for 4-7 days). This was repeated using accelerometry from the entire 24-hour day and daytime (10am- 8pm) only, and data were missing at random. For the entire 24-hour day, MI produced less bias and better 95% confidence interval (CI) coverage than AC and CC. For the daytime only, MI produced less bias and better 95% CI coverage than AC; CC produced similar bias and 95% CI coverage, but longer 95% CIs than MI.

RevDate: 2019-08-26

Bard AM, Main D, Roe E, et al (2019)

To change or not to change? Veterinarian and farmer perceptions of relational factors influencing the enactment of veterinary advice on dairy farms in the United Kingdom.

Journal of dairy science pii:S0022-0302(19)30718-0 [Epub ahead of print].

Achieving herd health and welfare improvement increasingly relies on cattle veterinarians to train and advise farmers, placing veterinary interactions at the heart of knowledge exchange. Cattle veterinarians recognize their influence and the need to be proactive advisors but struggle with acting upon this awareness in daily practice, reporting a need to enhance their advisory approach to inspire farmer behavior change. Understanding how veterinarian-farmer interactions positively or negatively influence the enactment of change on farm is therefore essential to support the cattle veterinary profession. This paper adopts a qualitative approach to conceptualize how and under what circumstances veterinary advice has the potential to support and inspire farmer engagement with behavior change on the UK dairy farm. Fourteen UK dairy farms were recruited to take part in a qualitative study involving research observation of a typical advisory consultation between veterinarian and farmer (n = 14) followed by separate, in-depth interviews with the farmer(s) and their respective veterinarian. Interview data were organized using a template coding method and analyzed thematically. While accuracy of veterinary advisory content was valued, it was a relational context of trust, shared veterinarian-farmer understanding, and meaningful interpretation of advice at a local (farmer) level that was most likely to enact change. Critically, these relational factors were reported to work together synergistically; a trusting relationship was an essential, but not necessarily sufficient, component to create a culture of change. Findings suggest that cattle veterinarians may benefit from tailoring advisory services to the farmer's specific world view, facilitated by a shared understanding of the farmer's immediate and long-term motivational drivers. In consequence, cattle veterinarians seeking to positively engage farmers in advisory interactions could consider a focus on farmer priorities, motivations, and goals as paramount to frame and inform advisory messages. This explicit collaborative communication encourages the selection of appropriate and timely veterinary expertise, leading to better integration and adoption of advice on farm given enhanced advisory relevance for farmers' unique circumstances. This farmer-centered approach, involving active co-creation of plans between individuals, is critical for engagement and commitment when tackling complex problems.

RevDate: 2019-08-25

Jain T, Bar M, Kansagra AJ, et al (2019)

Utilization of Chimeric Antigen Receptor (CAR) T Cell Therapy in Clinical Practice for Relapsed/Refractory Aggressive B cell non-Hodgkin Lymphoma: An Expert Panel Opinion from the American Society for Transplantation and Cellular Therapy.

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(19)30529-4 [Epub ahead of print].

Axicabtagene ciloleucel (YESCARTA®, Kite Pharma, a Gilead Company) and tisagenlecleucel (KYMRIAH®, Novartis Pharmaceuticals Corp.) are two CD19-directed chimeric antigen receptor T cell (CD19 CAR T) products that are currently approved by the U.S. Food and Drug Administration, the European Medicines Agency, Health Canada, Ministry of Health, Labor and Welfare (Japan) and Therapeutic Goods Administration (Australia) for treatment of specific subtypes of relapsed/ refractory aggressive B cell non-Hodgkin lymphoma (NHL). While this approval has been transformative in the use of cellular immunotherapy in lymphoma, there are concerns regarding appropriate utilization of this novel therapy, as well as short- and long-term toxicities. To address these issues, representatives of American Society of Transplantation and Cellular Therapy (ASTCT) convened to recognize and address key issues surrounding the clinical application of CD19 CAR T cell therapy in B cell lymphomas, in collaboration with worldwide experts and members of International Society of Cell and Gene Therapy (ISCT), American Society of Hematology (ASH), Foundation for the Accreditation of Cellular Therapy (FACT) and European Society for Blood and Marrow Transplantation (EBMT). The aim of this article is to provide consensus opinion from experts in the fields of hematopoietic cell transplantation, cellular immunotherapy, and lymphoma regarding key clinical questions pertinent to the utilization of CD19 CAR T for the treatment of NHL. As the clinical practice using CAR T cells grows worldwide, we anticipate that this guidance will be relevant for hematology/oncology physicians who care for patients with lymphomas.

RevDate: 2019-08-25

DeFilipp Z, Advani AS, Bachanova V, et al (2019)

Hematopoietic Cell Transplantation in the Treatment of Adult Acute Lymphoblastic Leukemia: Updated 2019 Evidence-Based Review from the American Society for Transplantation and Cellular Therapy.

Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation pii:S1083-8791(19)30528-2 [Epub ahead of print].

The role of hematopoietic cell transplantation (HCT) for adults with acute lymphoblastic leukemia (ALL) is reviewed and critically evaluated in this systematic evidence-based review. Specific criteria were used for searching the published literature and for grading the quality and strength of the evidence and the strength of the recommendations. A panel of ALL experts developed consensus on the treatment recommendations based upon the evidence. Allogeneic HCT offers a survival benefit in selected patients with ALL and this review summarizes the standard indications as well as the areas of controversy. There is now greater experience with pediatric-inspired chemotherapy regimens that has transformed upfront therapy for adult ALL, resulting in higher remission rates and overall survival. This in turn has increased the equipoise around decision-making for ALL in first complete remission (CR1) when there is no measurable residual disease (MRD) at the end of induction and/or consolidation. Randomized studies are needed for adults with ALL to compare allogeneic HCT in CR1 with pediatric-inspired chemotherapy alone. Studies to assess indications for transplant in the evolving landscape of MRD assessments and novel targeted and immune therapeutics remain important areas of investigation.

RevDate: 2019-09-05

Pivot X, Pegram M, Cortes J, et al (2019)

Three-year follow-up from a phase 3 study of SB3 (a trastuzumab biosimilar) versus reference trastuzumab in the neoadjuvant setting for human epidermal growth factor receptor 2-positive breast cancer.

European journal of cancer (Oxford, England : 1990), 120:1-9 pii:S0959-8049(19)30423-X [Epub ahead of print].

BACKGROUND: We assessed long-term cardiac safety and efficacy in patients with human epidermal growth factor receptor 2-positive early breast cancer treated with a trastuzumab biosimilar (SB3) or its reference product, trastuzumab (TRZ), in a phase 3 study.

METHODS: Patients who completed the phase 3 study could be enrolled in this extension study. The outcomes included the incidence of symptomatic congestive heart failure (CHF), asymptomatic significant left ventricular ejection fraction (LVEF) decrease, incidence of other cardiac events, event-free survival (EFS), and overall survival. In post hoc analysis, the Cox proportional hazards regression model was used to assess factors associated with EFS.

RESULTS: A total of 367 patients were enrolled in the study (SB3, n = 186; TRZ, n = 181). The median follow-up duration from the main study enrolment was 40.8 and 40.5 months for SB3 and TRZ, respectively. During the two-year follow-up after adjuvant therapy, incidence of asymptomatic significant LVEF decrease was rare (SB3, n = 1; TRZ, n = 2), with all patients recovering with LVEF ≥ 50%, and no cases of symptomatic CHF or other cardiac events were reported. At 3 years, the EFS was 91.9% with SB3 and 85.2% with TRZ. The number of patients with events was 17 (9.1%) with SB3 and 31 (17.1%) with TRZ [hazard ratio: 0.47, 95% confidence interval: 0.26-0.87]. Antibody-dependent cell-mediated cytotoxicity (ADCC) activity and the breast pathologic complete response rate were the factors associated with EFS.

CONCLUSION: Cardiotoxicity was rare in this extension study. EFS was higher with SB3 versus TRZ, with post hoc analysis suggesting that a downward drift in ADCC activity was a contributing factor.

NCT02771795 (EudraCT 2015-005663-17).

RevDate: 2019-08-26

Zhao YQ, Zeng D, Tangen CM, et al (2019)

Robustifying Trial-Derived Optimal Treatment Rules for A Target Population.

Electronic journal of statistics, 13(1):1717-1743.

Treatment rules based on individual patient characteristics that are easy to interpret and disseminate are important in clinical practice. Properly planned and conducted randomized clinical trials are used to construct individualized treatment rules. However, it is often a concern that trial participants lack representativeness, so it limits the applicability of the derived rules to a target population. In this work, we use data from a single trial study to propose a two-stage procedure to derive a robust and parsimonious rule to maximize the benefit in the target population. The procedure allows a wide range of possible covariate distributions in the target population, with minimal assumptions on the first two moments of the covariate distribution. The practical utility and favorable performance of the methodology are demonstrated using extensive simulations and a real data application.

RevDate: 2019-08-26

Zhao YQ, Laber EB, Ning Y, et al (2019)

Efficient augmentation and relaxation learning for individualized treatment rules using observational data.

Journal of machine learning research : JMLR, 20:.

Individualized treatment rules aim to identify if, when, which, and to whom treatment should be applied. A globally aging population, rising healthcare costs, and increased access to patient-level data have created an urgent need for high-quality estimators of individualized treatment rules that can be applied to observational data. A recent and promising line of research for estimating individualized treatment rules recasts the problem of estimating an optimal treatment rule as a weighted classification problem. We consider a class of estimators for optimal treatment rules that are analogous to convex large-margin classifiers. The proposed class applies to observational data and is doubly-robust in the sense that correct specification of either a propensity or outcome model leads to consistent estimation of the optimal individualized treatment rule. Using techniques from semiparametric efficiency theory, we derive rates of convergence for the proposed estimators and use these rates to characterize the bias-variance trade-off for estimating individualized treatment rules with classification-based methods. Simulation experiments informed by these results demonstrate that it is possible to construct new estimators within the proposed framework that significantly outperform existing ones. We illustrate the proposed methods using data from a labor training program and a study of inflammatory bowel syndrome.

RevDate: 2019-08-25

Lee SM, Miao J, Wu R, et al (2019)

A comparison of nurses' and physicians' perception of cancer treatment burden based on reported adverse events.

Health and quality of life outcomes, 17(1):146 pii:10.1186/s12955-019-1210-1.

BACKGROUND: Cancer treatments are associated with a multitude of adverse events (AEs). While both nurses and physicians are involved in patient care delivery and AE assessment, very few studies have examined the differences between nurses' and physicians' reporting and perception of AEs. An approach was recently proposed to assess treatment burden based on reported AEs from the physician's perspective. In this paper, we use this approach to evaluate nurses' perception of burden, and compare nurses' and physicians' assessment of the overall and relative burden of AEs.

METHODS: AE records for 334 cancer patients from a randomized clinical trial conducted by the SWOG Cancer Research Network were evaluated by 14 nurses at Columbia University Medical Center. Two nurses were randomly selected to assign a burden score from 0 to 10 based on their impression of the global burden of the captured AEs. These nurses did not interact directly with the patients. Scores were compared to previously obtained physicians scores using paired T-test and Kappa statistic. Severity scores for individual AEs were obtained using mixed-effects models with nurses assessments, and were qualitatively compared to physicians'.

RESULTS: Given the same AEs, nurses' and physicians' perception of the burden of AEs differed. While nurses generally perceived the overall burden of AEs to be only slightly worse compared to physicians (mean average VAS score of 5.44 versus 5.14), there was poor agreement in the perception of AEs that were in mild to severe range. The percent agreement for a moderate or worse AE was 64% with a Kappa of 0.34. Nurses also assigned higher severity scores to symptomatic AEs compared to physicians (p < 0.05), such as gastrointestinal (4.77 versus 4.14), hemorrhage (5.07 versus 4.14), and pain (5.17 versus 4.14).

CONCLUSIONS: These differences in the perception of burden of AEs can lead to different treatment decisions and symptom management strategies. Thus, having provider consistency, training, or a collaborative approach in follow-up care between nurses and physicians is important to ensure continuity in care delivery. Moreover, estimating overall burden from both physicians' and nurses' perspective, and comparing them may be useful for deciding when collaborations are warranted.

RevDate: 2019-08-22

Dimitrov D, Moore JR, Wood D, et al (2019)

Predicted effectiveness of daily and non-daily PrEP for MSM based on sex and pill-taking patterns from HPTN 067/ADAPT.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America pii:5553311 [Epub ahead of print].

BACKGROUND: HPTN 067/ADAPT evaluated the feasibility of daily and non-daily HIV pre-exposure prophylaxis (PrEP) regimens among high-risk populations, including men who have sex with men (MSM) and transgender women, in Bangkok, Thailand and Harlem, New York, U.S. We used a mathematical model to predict the efficacy and effectiveness of different dosing regimens.

METHODS: An individual-based mathematical model was used to simulate annual HIV incidence among MSM cohorts. PrEP efficacy for covered sex acts, as defined in the HPTN 067/ADAPT protocol, was estimated using subgroup efficacy estimates from the iPrEx trial. Effectiveness was estimated by comparison of the HIV incidence with and without PrEP use.

RESULTS: We estimated that PrEP was highly protective (85%-96% efficacy across regimens and sites) for fully covered acts. PrEP was more protective for partially covered acts in Bangkok (71%-88% efficacy) than in Harlem (62%-81% efficacy). Our model projects 80%, 62%, and 68% effectiveness of daily, time-driven, and event-driven PrEP for MSM in Harlem compared with 90%, 85% and 79% for MSM in Bangkok. Halving the efficacy for partially covered acts decreases effectiveness by 8-9 percentage points in Harlem and by 5-9 percentage points in Bangkok across regimens.

CONCLUSIONS: Our analysis suggests that PrEP was more effective among MSM in Thailand than in the U.S. as a result of more fully covered sex acts and more pills taken around partially covered acts. Overall, non-daily PrEP was less effective than daily PrEP, especially in the U.S. where the sex act coverage associated with daily use was substantially higher.

RevDate: 2019-08-22

Lee C, Lee SJ, S Haneuse (2019)

Time-to-event analysis when the event is defined on a finite time interval.

Statistical methods in medical research [Epub ahead of print].

Acute graft-versus-host disease (GVHD) is a frequent complication following hematopoietic cell transplantation (HCT). Research on risk factors for acute GVHD has tended to ignore two important clinical issues. First, post-transplant mortality is high. In our motivating data, 100-day post-HCT mortality was 15.4%. Second, acute GVHD in its classic form is only diagnosed within 100 days of the transplant; beyond 100 days, a patient may be diagnosed with late onset acute or chronic GVHD. Standard modeling of time-to-event outcomes, however, generally conceive of patients being able to experience the event at any point on the time scale. In this paper, we propose a novel multi-state model that simultaneously: (i) accounts for mortality through joint modeling of acute GVHD and death, and (ii) explicitly acknowledges the finite time interval during which the event of interest can take place. The observed data likelihood is derived, with estimation and inference via maximum likelihood. Additionally, we provide methods for estimating the absolute risk of acute GVHD and death simultaneously. The proposed framework is compared via comprehensive simulations to a number of alternative approaches that each acknowledge some but not all aspects of acute GVHD, and illustrated with an analysis of HCT data that motivated this work.

RevDate: 2019-08-22

Jain RK, Grivas P, SK Pal (2019)

Non-invasive diagnosis and monitoring of urothelial bladder cancer: are we there yet?.

BJU international, 124(3):361-362.

RevDate: 2019-08-22

Kordelas L, Görgens A, Radtke S, et al (2019)

Allogeneic transplantation of peripheral blood stem cell grafts results in a massive decrease of primitive hematopoietic progenitor frequencies in reconstituted bone marrows.

Bone marrow transplantation pii:10.1038/s41409-019-0645-7 [Epub ahead of print].

The success of allogeneic hematopoietic stem cell transplantation (alloSCT) is indicated by the reconstitution of the peripheral blood system of patients after alloSCT and the engraftment of hematopoietic stem and progenitor cells (HSPCs) into their bone marrow (BM). The number of CD34+ cells is commonly used as surrogate for the content of hematopoietic stem cells in the grafts. During the last decade, several antigens (including CD133, CD45RA, CD38, and CD10) were identified allowing discrimination of different HSPC subpopulations within the human CD34+ cell compartment. Although such studies increased our understanding of early human hematopoiesis tremendously, hardly any study dissected the CD34+ compartment in the alloSCT setting. Consequently, we comprehensively analyzed the CD34+ compartment in G-CSF-stimulated peripheral blood stem cell grafts of allogeneic donors, in BM samples of the respective recipients 4 weeks after alloSCT, and in BM samples of healthy donors. We demonstrate that alloSCT is associated with a dramatic shift from primitive to more mature HSPC types. Upon investigating whether the composition of engrafted CD34+ cells has any impact on the incidence and severity of graft-versus-host disease, we did not find any correlation. However, more detailed analyses of the CD34+ compartment may elucidate associations with other transplantation-related complications.

RevDate: 2019-08-30

Li SS, Gilbert PB, Carpp LN, et al (2019)

Fc gamma receptor polymorphisms modulated the vaccine effect on HIV-1 risk in the HVTN 505 HIV vaccine trial.

Journal of virology pii:JVI.02041-18 [Epub ahead of print].

HVTN 505 was a phase 2b efficacy trial of a DNA/recombinant adenovirus 5 (rAd5) HIV vaccine regimen. Although the trial was stopped early for lack of overall efficacy, later correlates of risk and sieve analyses generated the hypothesis that the DNA/rAd5 vaccine regimen protected some vaccinees from HIV infection, yet enhanced HIV infection risk for others. Here we assessed whether and how host Fc gamma receptor (FcγR) genetic variations influenced the DNA/rAd5 vaccine regimen's effect on HIV infection risk. We found that vaccine receipt significantly increased HIV acquisition compared with placebo receipt among participants carrying the FCGR2C-TATA haplotype (comprising minor alleles of four FCGR2C single nucleotide polymorphism (SNP) sites) (HR=9.79, p=0.035) but not among participants without the haplotype (HR=0.86, p=0.67); the interaction of vaccine and haplotype effect was significant (p=0.034). Similarly, vaccine receipt increased HIV acquisition compared with placebo receipt among participants carrying the FCGR3B-AGA haplotype (comprising minor alleles of the 3 FCGR3B SNPs) (HR=2.78, p=0.058) but not among participants without the haplotype (HR=0.73, p=0.44); again, the interaction of vaccine and haplotype was significant (p-value=0.047). The FCGR3B-AGA haplotype also influenced whether a combined Env-specific CD8+ T-cell polyfunctionality score and IgG response correlated significantly with HIV risk; an FCGR2A SNP and two FCGR2B SNPs influenced whether anti-gp140 antibody-dependent cellular phagocytosis correlated significantly with HIV risk. These results provide further evidence that Fc gamma receptor genetic variations may modulate HIV vaccine effects and immune function after HIV vaccination.IMPORTANCE By analyzing data from the HVTN 505 efficacy trial of a DNA/recombinant adenovirus 5 (rAd5) vaccine regimen, we found that host genetics, specifically Fc gamma receptor genetic variations, influenced whether receiving the DNA/rAd5 regimen was beneficial, neutral, or detrimental to an individual with respect to HIV-1 acquisition risk. Moreover, Fc gamma receptor genetic variations influenced immune responses to the DNA/rAd5 vaccine regimen. Thus, Fc gamma receptor genetic variations should be considered in the analysis of future HIV vaccine trials and the development of HIV vaccines.

RevDate: 2019-08-22

Starr K, Greninger AL, Makhsous N, et al (2019)

Comparison of Three Adenovirus Quantitative PCR Assays with ATCC Reference Strains and Clinical Samples.

Journal of clinical microbiology pii:JCM.00735-19 [Epub ahead of print].

Adenoviruses (AdV) have been associated with a variety of human diseases and are recognized as causing significant morbidity and mortality in immunocompromised or transplant patients. Quantification of AdV DNA in plasma is notoriously difficult due to the genetic diversity of the 71 different serotypes identified to date. There is no WHO standard available to harmonize quantitative data so results between labs vary widely. In this study we compared an laboratory-developed multiplex PCR assay with primers and probes specific for each group (A-G) and subgroup E4 (Octaplex) to one with a single primer and probe set (Jothikumar, 2005) and one utilizing bisulfite pre-treatment of DNA to reduce variation prior to amplification (Genetic Signatures). Our Octaplex assay detected all low copy-number clinical samples while the other two assays had subsets of samples that did not amplify. The Jothikumar assay failed to efficiently amplify 3 of the high copy number cultured strains, while the Genetic Signatures (GS) 3base™ assay had a positive bias, resulting in higher copies/mL (> 0.5 log10) for all culture fluids tested. All three assays resulted in end-point detection of the available 51 AdV types. Using two different materials to generate a standard curve revealed that the OctaplexTaqMan assay and the Jothikumar assay both consistently gave adenovirus levels lower than the commercial platform for AdV culture fluids, but not patient samples. This study highlights the differences in detection of AdV between laboratories that can be attributed to both the PCR method as well as the reference material used for quantitation.

RevDate: 2019-08-22

Dvinge H, Guenthoer J, Porter PL, et al (2019)

RNA components of the spliceosome regulate tissue- and cancer-specific alternative splicing.

Genome research pii:gr.246678.118 [Epub ahead of print].

Alternative splicing of pre-mRNAs plays a pivotal role during the establishment and maintenance of human cell types. Characterizing the trans-acting regulatory proteins that control alternative splicing in both healthy and malignant cells has therefore been the focus of much research. Recent work has established that even core protein components of the spliceosome, which are required for splicing to proceed, can nonetheless contribute to splicing regulation by modulating splice site choice. We here demonstrate that the RNA components of the spliceosome likewise influence alternative splicing decisions and contribute to the establishment of global splicing programs. Although these small nuclear RNAs (snRNAs), termed U1, U2, U4, U5, and U6 snRNA, are present in equal stoichiometry within the spliceosome, we found that their relative levels vary by an order of magnitude during development, across tissues, and between normal and malignant cells. Physiologically relevant perturbation of individual snRNAs drove widespread gene-specific differences in alternative splicing, but not transcriptome-wide splicing failure. Genes that were particularly sensitive to variations in snRNA abundance in a breast cancer cell line model were likewise preferentially mis-spliced within a clinically diverse cohort of invasive breast ductal carcinomas. As aberrant mRNA splicing is prevalent in many solid and liquid tumors, we propose that a full understanding of dysregulated pre-mRNA processing in cancers requires study of the RNA as well as protein components of the splicing machinery.

RevDate: 2019-08-21

Holmberg LA, Green D, Libby E, et al (2019)

Bortezomib and Vorinostat Therapy as Maintenance Therapy after Autologous Transplant for Multiple Myeloma.

Acta haematologica pii:000501298 [Epub ahead of print].

BACKGROUND: In multiple myeloma (MM), relapse is a frequent complication after autologous hematopoietic stem cell transplant (ASCT). To reduce the risk of relapse, additional therapy has been added post-ASCT. In a nontransplant relapse setting, the combination of intravenous bortezomib and oral vorinostat (BV) was studied and showed efficacy. Therefore, it was reasonable to study this combination therapy post-ASCT.

PATIENTS AND METHODS: We report on BV given post-ASCT. All 30 patients underwent conditioning for ASCT with high-dose melphalan. After recovery from the acute transplant-related toxicity, BV therapy was started and given for a total of 12 (28-day) cycles.

RESULTS: The most common toxicities were hematological, gastrointestinal (diarrhea and nausea), fatigue, and peripheral neuropathy. The median follow-up for BV patients is 7.8 (range: 6.12-9.03) years. After BV therapy, 18 patients (60%) are alive, and 9 (30%) are alive without disease progression.

CONCLUSIONS: BV can be given post-ASCT with an acceptable toxicity profile and produces reasonable disease-free and overall survival rates. A randomized study comparing the BV regimen to single-agent lenalidomide or bortezomib is needed.

RevDate: 2019-08-21

Navarro SL, Tarkhan A, Shojaie A, et al (2019)

Plasma metabolomics profiles suggest beneficial effects of a low-glycemic load dietary pattern on inflammation and energy metabolism.

The American journal of clinical nutrition pii:5552380 [Epub ahead of print].

BACKGROUND: Low-glycemic load dietary patterns, characterized by consumption of whole grains, legumes, fruits, and vegetables, are associated with reduced risk of several chronic diseases.

METHODS: Using samples from a randomized, controlled, crossover feeding trial, we evaluated the effects on metabolic profiles of a low-glycemic whole-grain dietary pattern (WG) compared with a dietary pattern high in refined grains and added sugars (RG) for 28 d. LC-MS-based targeted metabolomics analysis was performed on fasting plasma samples from 80 healthy participants (n = 40 men, n = 40 women) aged 18-45 y. Linear mixed models were used to evaluate differences in response between diets for individual metabolites. Kyoto Encyclopedia of Genes and Genomes (KEGG)-defined pathways and 2 novel data-driven analyses were conducted to consider differences at the pathway level.

RESULTS: There were 121 metabolites with detectable signal in >98% of all plasma samples. Eighteen metabolites were significantly different between diets at day 28 [false discovery rate (FDR) < 0.05]. Inositol, hydroxyphenylpyruvate, citrulline, ornithine, 13-hydroxyoctadecadienoic acid, glutamine, and oxaloacetate were higher after the WG diet than after the RG diet, whereas melatonin, betaine, creatine, acetylcholine, aspartate, hydroxyproline, methylhistidine, tryptophan, cystamine, carnitine, and trimethylamine were lower. Analyses using KEGG-defined pathways revealed statistically significant differences in tryptophan metabolism between diets, with kynurenine and melatonin positively associated with serum C-reactive protein concentrations. Novel data-driven methods at the metabolite and network levels found correlations among metabolites involved in branched-chain amino acid (BCAA) degradation, trimethylamine-N-oxide production, and β oxidation of fatty acids (FDR < 0.1) that differed between diets, with more favorable metabolic profiles detected after the WG diet. Higher BCAAs and trimethylamine were positively associated with homeostasis model assessment-insulin resistance.

CONCLUSIONS: These exploratory metabolomics results support beneficial effects of a low-glycemic load dietary pattern characterized by whole grains, legumes, fruits, and vegetables, compared with a diet high in refined grains and added sugars on inflammation and energy metabolism pathways. This trial was registered at clinicaltrials.gov as NCT00622661.

RevDate: 2019-08-21

Chou CK, CJ Turtle (2019)

Insight into mechanisms associated with cytokine release syndrome and neurotoxicity after CD19 CAR-T cell immunotherapy.

Bone marrow transplantation, 54(Suppl 2):780-784.

Adoptive immunotherapy with CD19-targeted chimeric antigen receptor (CAR)-T cells has been successful in producing durable remissions in some patients with relapsed or refractory B cell malignancies. Despite the efficacy of CAR-T cell therapy, significant toxicities can occur. Cytokine release syndrome (CRS) and neurotoxicity are the most common toxicities and can range from self-limited fever to life threatening organ damage and death. Understanding the mechanisms underlying these toxicities can help guide and improve outcomes. In this review we describe CRS and neurotoxicity in patients with B cell malignancies treated with CD19 CAR-T cells in pivotal trials, and also provide insight into potential mechanisms associated with these toxicities based on studies conducted in a phase 1/2 clinical trial at the Fred Hutchinson Cancer Research Center.

RevDate: 2019-08-27

Dembitz V, Tomic B, Kodvanj I, et al (2019)

The ribonucleoside AICAr induces differentiation of myeloid leukemia by activating the ATR/Chk1 kinase via pyrimidine depletion.

The Journal of biological chemistry pii:RA119.009396 [Epub ahead of print].

Metabolic pathways play important roles in proliferation and differentiation of malignant cells. 5-Aminoimidazole-4-carboxamide ribonucleoside (AICAr), a precursor in purine biosynthesis and a well-established activator of AMP-activated protein kinase (AMPK), induces widespread metabolic alterations and is commonly used for dissecting the role of metabolism in cancer. We have previously reported that AICAr promotes differentiation and inhibits proliferation of myeloid leukemia cells. Here, using metabolic assays, immunoblotting, flow cytometry analyses, and siRNA-mediated gene silencing in leukemia cell lines, we show that AICAr-mediated differentiation was independent of the known metabolic effects of AMPK, including glucose consumption, but instead depends on the activation of the DNA damage-associated enzyme checkpoint kinase 1 (Chk1) induced by pyrimidine depletion. LC/MS/MS metabolomics analysis revealed that AICAr increases orotate levels and decreases uridine monophosphate (UMP) levels, consistent with inhibition of UMP synthesis at a step downstream of dihydroorotate dehydrogenase (DHODH). AICAr and the DHODH inhibitor brequinar had similar effects on differentiation markers and S-phase arrest, and genetic or pharmacological Chk1 inactivation abrogated both of these effects. Our results delineate an AMPK-independent effect of AICAr on myeloid leukemia differentiation that involves perturbation of pyrimidine biosynthesis and activation of the DNA damage response network.

RevDate: 2019-09-04

Yang W, Lampe PD, Kensel-Hammes P, et al (2019)

Connexin 43 Functions as a Positive Regulator of Stem Cell Differentiation into Definitive Endoderm and Pancreatic Progenitors.

iScience, 19:450-460 pii:S2589-0042(19)30260-3 [Epub ahead of print].

Efficient stem cell differentiation into pancreatic islet cells is of critical importance for the development of cell replacement therapies for diabetes. Here, we identify the expression pattern of connexin 43 (Cx43), a gap junction (GJ) channel protein, in human embryonic stem cell (hESC)-derived definitive endoderm (DE) and primitive gut tube cells, representing early lineages for posterior foregut (PF), pancreatic progenitors (PP), pancreatic endocrine progenitors (PE), and islet cells. As the function of GJ channels is dependent on their gating status, we tested the impact of supplementing hESC-derived PP cell cultures with AAP10, a peptide that promotes Cx43 GJ channel opening. We found that this treatment promotes the expression of DE markers FoxA2 and Sox17, leads to a more efficient derivation of DE, and improves the yield of PF, PP, and PE cells. These results demonstrate a functional involvement of GJ channels in the differentiation of embryonic stem cells into pancreatic cell lineages.

RevDate: 2019-08-23

Angenendt L, Röllig C, Montesinos P, et al (2019)

Chromosomal Abnormalities and Prognosis in NPM1-Mutated Acute Myeloid Leukemia: A Pooled Analysis of Individual Patient Data From Nine International Cohorts.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology [Epub ahead of print].

PURPOSE: Nucleophosmin 1 (NPM1) mutations are associated with a favorable prognosis in acute myeloid leukemia (AML) when an internal tandem duplication (ITD) in the fms-related tyrosine kinase 3 gene (FLT3) is absent (FLT3-ITDneg) or present with a low allelic ratio (FLT3-ITDlow). The 2017 European LeukemiaNet guidelines assume this is true regardless of accompanying cytogenetic abnormalities. We investigated the validity of this assumption.

METHODS: We analyzed associations between karyotype and outcome in intensively treated patients with NPM1mut/FLT3-ITDneg/low AML who were prospectively enrolled in registry databases from nine international study groups or treatment centers.

RESULTS: Among 2,426 patients with NPM1mut/FLT3-ITDneg/low AML, 2,000 (82.4%) had a normal and 426 (17.6%) had an abnormal karyotype, including 329 patients (13.6%) with intermediate and 83 patients (3.4%) with adverse-risk chromosomal abnormalities. In patients with NPM1mut/FLT3-ITDneg/low AML, adverse cytogenetics were associated with lower complete remission rates (87.7%, 86.0%, and 66.3% for normal, aberrant intermediate, and adverse karyotype, respectively; P < .001), inferior 5-year overall (52.4%, 44.8%, 19.5%, respectively; P < .001) and event-free survival (40.6%, 36.0%, 18.1%, respectively; P < .001), and a higher 5-year cumulative incidence of relapse (43.6%, 44.2%, 51.9%, respectively; P = .0012). These associations remained in multivariable mixed-effects regression analyses adjusted for known clinicopathologic risk factors (P < .001 for all end points). In patients with adverse-risk chromosomal aberrations, we found no significant influence of the NPM1 mutational status on outcome.

CONCLUSION: Karyotype abnormalities are significantly associated with outcome in NPM1mut/FLT3-ITDneg/low AML. When adverse-risk cytogenetics are present, patients with NPM1mut share the same unfavorable prognosis as patients with NPM1 wild type and should be classified and treated accordingly. Thus, cytogenetic risk predominates over molecular risk in NPM1mut/FLT3-ITDneg/low AML.

RevDate: 2019-08-22

Cao D, Xu H, Xu X, et al (2019)

High tumor mutation burden predicts better efficacy of immunotherapy: a pooled analysis of 103078 cancer patients.

Oncoimmunology, 8(9):e1629258 pii:1629258.

The relation between tumor mutation burden (TMB) and outcome of cancer patients receiving immunotherapy has been reported. This study aimed to evaluate the prognostic role of TMB in cancer patients receiving immunotherapy. Databases including Embase, PubMed, and the Cochrane library were systematically searched to identify potentially eligible studies until Sep 2018 without language limitation. Studies assessing high versus low TMB in predicting survival of various cancer patients were selected. The pooled analyses were conducted using hazard ratio (HR) of high versus low TMB for overall survival (OS) and progression-free survival (PFS), and the odds ratio (OR) for overall response rate (ORR). The primary endpoint was OS. Secondary outcomes were PFS and ORR. A total of 45 studies consisting of 103078 cancer patients were included. The combined results showed that high TMB was associated with better OS (HR = 0.40; 95% confidence interval (CI):0.30-0.53; p< .00001), PFS (HR = 0.37; 95% CI: 0.26-0.53; p< .00001) and ORR (OR = 4.62; 95%CI: 2.90-7.34; p< .0001) when treated with immunotherapy. In studying patients with high TMB, these patients had improved OS (HR = 0.69; 95%CI: 0.47-1.03; p= .07) when comparing immunotherapy to chemotherapy. Subgroup analyses suggested that the prognostic role of TMB was independent of cancer types and TMB detection methods (all p< .05). Our findings suggest that high TMB is associated with better survival in cancer patients receiving immunotherapy. For cancer patients with high TMB, immunotherapy could be considered.

RevDate: 2019-08-23

Müller NF, Dudas G, T Stadler (2019)

Inferring time-dependent migration and coalescence patterns from genetic sequence and predictor data in structured populations.

Virus evolution, 5(2):vez030 pii:vez030.

Population dynamics can be inferred from genetic sequence data by using phylodynamic methods. These methods typically quantify the dynamics in unstructured populations or assume migration rates and effective population sizes to be constant through time in structured populations. When considering rates to vary through time in structured populations, the number of parameters to infer increases rapidly and the available data might not be sufficient to inform these. Additionally, it is often of interest to know what predicts these parameters rather than knowing the parameters themselves. Here, we introduce a method to infer the predictors for time-varying migration rates and effective population sizes by using a generalized linear model (GLM) approach under the marginal approximation of the structured coalescent. Using simulations, we show that our approach is able to reliably infer the model parameters and its predictors from phylogenetic trees. Furthermore, when simulating trees under the structured coalescent, we show that our new approach outperforms the discrete trait GLM model. We then apply our framework to a previously described Ebola virus dataset, where we infer the parameters and its predictors from genome sequences while accounting for phylogenetic uncertainty. We infer weekly cases to be the strongest predictor for effective population size and geographic distance the strongest predictor for migration. This approach is implemented as part of the BEAST2 package MASCOT, which allows us to jointly infer population dynamics, i.e. the parameters and predictors, within structured populations, the phylogenetic tree, and evolutionary parameters.

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ESP Quick Facts

ESP Origins

In the early 1990's, Robert Robbins was a faculty member at Johns Hopkins, where he directed the informatics core of GDB — the human gene-mapping database of the international human genome project. To share papers with colleagues around the world, he set up a small paper-sharing section on his personal web page. This small project evolved into The Electronic Scholarly Publishing Project.

ESP Support

In 1995, Robbins became the VP/IT of the Fred Hutchinson Cancer Research Center in Seattle, WA. Soon after arriving in Seattle, Robbins secured funding, through the ELSI component of the US Human Genome Project, to create the original ESP.ORG web site, with the formal goal of providing free, world-wide access to the literature of classical genetics.

ESP Rationale

Although the methods of molecular biology can seem almost magical to the uninitiated, the original techniques of classical genetics are readily appreciated by one and all: cross individuals that differ in some inherited trait, collect all of the progeny, score their attributes, and propose mechanisms to explain the patterns of inheritance observed.

ESP Goal

In reading the early works of classical genetics, one is drawn, almost inexorably, into ever more complex models, until molecular explanations begin to seem both necessary and natural. At that point, the tools for understanding genome research are at hand. Assisting readers reach this point was the original goal of The Electronic Scholarly Publishing Project.

ESP Usage

Usage of the site grew rapidly and has remained high. Faculty began to use the site for their assigned readings. Other on-line publishers, ranging from The New York Times to Nature referenced ESP materials in their own publications. Nobel laureates (e.g., Joshua Lederberg) regularly used the site and even wrote to suggest changes and improvements.

ESP Content

When the site began, no journals were making their early content available in digital format. As a result, ESP was obliged to digitize classic literature before it could be made available. For many important papers — such as Mendel's original paper or the first genetic map — ESP had to produce entirely new typeset versions of the works, if they were to be available in a high-quality format.

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Early support from the DOE component of the Human Genome Project was critically important for getting the ESP project on a firm foundation. Since that funding ended (nearly 20 years ago), the project has been operated as a purely volunteer effort. Anyone wishing to assist in these efforts should send an email to Robbins.

ESP Plans

With the development of methods for adding typeset side notes to PDF files, the ESP project now plans to add annotated versions of some classical papers to its holdings. We also plan to add new reference and pedagogical material. We have already started providing regularly updated, comprehensive bibliographies to the ESP.ORG site.

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Cancer is the generic name for more than 100 diseases in which cells begin to grow and divide in an uncontrolled manner. Usually, when cells get too old or damaged, they die and new cells take their place. Cancer begins when genetic changes impair this orderly process so that some cells start to grow uncontrollably. The Emperor of All Maladies is a "biography" of cancer — from its first documented appearances thousands of years ago through the epic battles in the twentieth century to cure, control, and conquer it to a radical new understanding of its essence. This is a must read book for anyone with an interest in cancer. R. Robbins

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Papers in Classical Genetics

The ESP began as an effort to share a handful of key papers from the early days of classical genetics. Now the collection has grown to include hundreds of papers, in full-text format.

Digital Books

Along with papers on classical genetics, ESP offers a collection of full-text digital books, including many works by Darwin (and even a collection of poetry — Chicago Poems by Carl Sandburg).

Timelines

ESP now offers a much improved and expanded collection of timelines, designed to give the user choice over subject matter and dates.

Biographies

Biographical information about many key scientists.

Selected Bibliographies

Bibliographies on several topics of potential interest to the ESP community are now being automatically maintained and generated on the ESP site.

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