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Bibliography on: Publications by FHCRC Researchers

The Electronic Scholarly Publishing Project: Providing world-wide, free access to classic scientific papers and other scholarly materials, since 1993.


ESP: PubMed Auto Bibliography 08 Dec 2023 at 01:48 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: ( fhcrc[Affiliation] OR "fred hutchinson"[Affiliation] OR "Fred Hutchinson Cancer Research"[Affiliation] OR "Fred Hutch"[affiliation] ) NOT pmcbook NOT ispreviousversion

Citations The Papers (from PubMed®)


RevDate: 2023-12-06

Dontchos BN, Lobbes MBI, H Rahbar (2023)

Reply to "Cost-Effectiveness of Breast Cancer Staging Modalities: Is There a Role for MDCT in Low- and Moderate-Income Countries?".

AJR. American journal of roentgenology [Epub ahead of print].

RevDate: 2023-12-06

Hammons L, Haider S, Portuguese AJ, et al (2023)

Chimeric antigen receptor and bispecific T-cell engager therapies in multiple myeloma patients with prior allogeneic transplantation.

British journal of haematology [Epub ahead of print].

Chimeric antigen receptor T-cell (CAR-T) therapy and bispecific T-cell engagers (BsAb) have emerged as promising immunotherapeutic modalities in patients with relapsed and/or refractory multiple myeloma (RRMM). However, there is limited data on the safety and efficacy of CAR-T and BsAb therapies in MM patients with a prior history of allogeneic transplantation (allo-HCT). Thirty-three MM patients with prior allo-HCT received CAR-T (n = 24) or BsAb (n = 9) therapy. CAR-T therapy demonstrated an ORR of 92% (67% ≥ CR), and 73% were MRD negative. BsAb therapy resulted in an ORR of 44% (44% ≥ CR) and 44% MRD negative. Safety analysis showed grade ≥3 AEs in 92% of CAR-T and 56% of BsAb patients. Cytokine release syndrome (CRS) occurred in 83% of CAR-T and 78% of BsAb recipients, while immune effector cell-associated neurotoxicity syndrome (ICANS) was observed in three CAR-T patients. Infections of grade ≥3 were reported in 50% of CAR-T and 44% of BsAb recipients. No exacerbation of graft-versus-host disease occurred except in one BsAb recipient. CAR-T and BsAb therapies appear to be feasible, safe and provide deep and durable responses in MM patients with prior allo-HCT.

RevDate: 2023-12-07

Waters AR, Liu Q, Ji X, et al (2023)

Job lock among survivors of childhood cancer and their spouses post Affordable Care Act implementation: A Childhood Cancer Survivor Study brief report.

Pediatric blood & cancer [Epub ahead of print].

It is unknown how common job lock (i.e., staying at job to maintain health insurance) remains among childhood cancer survivors after Affordable Care Act (ACA) implementation in 2010. We examined prevalence of and factors associated with job lock using a cross-sectional survey from the Childhood Cancer Survivor Study (3503 survivors; 942 siblings). Survivor, spousal, and any survivor/spouse job lock were more frequently reported by survivors than siblings. Survivor job lock/any job lock was associated with older age, low income, severe chronic conditions, and debt/inability to pay debt. Job lock remains more common among survivors than siblings after ACA implementation.

RevDate: 2023-12-05

Petersdorf EW, McKallor C, Malkki M, et al (2023)

HLA Haplotypes and Relapse After Hematopoietic Cell Transplantation.

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

PURPOSE: Recurrence of blood malignancy is the major cause of hematopoietic cell transplant failure. HLA class II molecules play a fundamental role in antitumor responses but the role of class II haplotypes is not known.

METHODS: HLA-DR, -DQ, -DM, and -DO allele variation was determined in 1,629 related haploidentical transplants to study the clinical significance of individual molecules and haplotypes.

RESULTS: Outcome correlated with patient and donor variation for HLA-DRβ residue 86 (Gly/Val), HLA-DQ (G1/G2) heterodimers, and donor HLA-DM (DM11,11/nonDM11,11) molecules, and depended on patient-donor mismatching. Risks of relapse were lower for DRβ-86 GlyGly patients when the donor was GlyVal (hazard ratio [HR], 0.46 [95% CI, 0.30 to 0.68]; P < .001); GlyVal patients benefited from HLA-DRB1-matched donors, whereas no donor was superior to another for ValVal patients. G1G2 patients with G1G2-mismatched donors had lower relapse. Transplantation from donors with DMα residue 184 ArgHis was associated with higher risk of relapse (HR, 1.60 [95% CI, 1.09 to 2.36]; P = .02) relative to ArgArg. Relapse and mortality risks differed across HLA-DR-DQ-DM haplotypes.

CONCLUSION: HLA class II haplotypes may be functional constituents of the transplantation barrier, and their consideration in patients and donors may improve the success of transplantation.

RevDate: 2023-12-05

Jacobson JM, Felber BK, Chen H, et al (2023)

The immunogenicity of an HIV-1 gag conserved element DNA vaccine in people with HIV and receiving antiretroviral therapy.

AIDS (London, England) pii:00002030-990000000-00408 [Epub ahead of print].

OBJECTIVE: The primary objective of the study was to assess the immunogenicity of an HIV-1 Gag conserved element DNA vaccine (p24CE DNA) in people with HIV (PWH) receiving suppressive antiretroviral therapy (ART).

DESIGN: AIDS Clinical Trials Group A5369 was a phase I/IIa, randomized, double-blind, placebo-controlled study of PWH receiving ART with plasma HIV-1 RNA less than 50 copies/ml, current CD4+ T-cell counts greater than 500 cells/μl, and nadir CD4+ T-cell counts greater than 350 cells/μl.

METHODS: The study enrolled 45 participants randomized 2 : 1 : 1 to receive p24CE DNA vaccine at weeks 0 and 4, followed by p24CE DNA admixed with full-length p55Gag DNA vaccine at weeks 12 and 24 (arm A); full-length p55Gag DNA vaccine at weeks 0, 4, 12, and 24 (arm B); or placebo at weeks 0, 4, 12, and 24 (arm c). The active and placebo vaccines were administered by intramuscular electroporation.

RESULTS: There was a modest, but significantly greater increase in the number of conserved elements recognized by CD4+ and/or CD8+ T cells in arm A compared with arm C (P = 0.014). The percentage of participants with an increased number of conserved elements recognized by T cells was also highest in arm A (8/18, 44.4%) vs. arm C (0/10, 0.0%) (P = 0.025). There were no significant differences between treatment groups in the change in magnitude of responses to total conserved elements.

CONCLUSION: A DNA-delivered HIV-1 Gag conserved element vaccine boosted by a combination of this vaccine with a full-length p55Gag DNA vaccine induced a new conserved element-directed cellular immune response in approximately half the treated PWH on ART.

RevDate: 2023-12-06
CmpDate: 2023-12-06

Booth GT, Daza RM, Srivatsan SR, et al (2023)

High-capacity sample multiplexing for single cell chromatin accessibility profiling.

BMC genomics, 24(1):737.

Single-cell chromatin accessibility has emerged as a powerful means of understanding the epigenetic landscape of diverse tissues and cell types, but profiling cells from many independent specimens is challenging and costly. Here we describe a novel approach, sciPlex-ATAC-seq, which uses unmodified DNA oligos as sample-specific nuclear labels, enabling the concurrent profiling of chromatin accessibility within single nuclei from virtually unlimited specimens or experimental conditions. We first demonstrate our method with a chemical epigenomics screen, in which we identify drug-altered distal regulatory sites predictive of compound- and dose-dependent effects on transcription. We then analyze cell type-specific chromatin changes in PBMCs from multiple donors responding to synthetic and allogeneic immune stimulation. We quantify stimulation-altered immune cell compositions and isolate the unique effects of allogeneic stimulation on chromatin accessibility specific to T-lymphocytes. Finally, we observe that impaired global chromatin decondensation often coincides with chemical inhibition of allogeneic T-cell activation.

RevDate: 2023-12-04

Brahma S, S Henikoff (2023)

The BAF chromatin remodeler synergizes with RNA polymerase II and transcription factors to evict nucleosomes.

Nature genetics [Epub ahead of print].

Chromatin accessibility is a hallmark of active transcription and entails ATP-dependent nucleosome remodeling, which is carried out by complexes such as Brahma-associated factor (BAF). However, the mechanistic links between transcription, nucleosome remodeling and chromatin accessibility are unclear. Here, we used a chemical-genetic approach coupled with time-resolved chromatin profiling to dissect the interplay between RNA Polymerase II (RNAPII), BAF and DNA-sequence-specific transcription factors in mouse embryonic stem cells. We show that BAF dynamically unwraps and evicts nucleosomes at accessible chromatin regions, while RNAPII promoter-proximal pausing stabilizes BAF chromatin occupancy and enhances ATP-dependent nucleosome eviction by BAF. We find that although RNAPII and BAF dynamically probe both transcriptionally active and Polycomb-repressed genomic regions, pluripotency transcription factor chromatin binding confers locus specificity for productive chromatin remodeling and nucleosome eviction by BAF. Our study suggests a paradigm for how functional synergy between dynamically acting chromatin factors regulates locus-specific nucleosome organization and chromatin accessibility.

RevDate: 2023-12-04

Barnabas RV, Brown ER, Onono MA, et al (2023)

Durability of single-dose HPV vaccination in young Kenyan women: randomized controlled trial 3-year results.

Nature medicine [Epub ahead of print].

Cervical cancer burden is high where prophylactic vaccination and screening coverage are low. We demonstrated in a multicenter randomized, double-blind, controlled trial that single-dose human papillomavirus (HPV) vaccination had high vaccine efficacy (VE) against persistent infection at 18 months in Kenyan women. Here, we report findings of this trial through 3 years of follow-up. Overall, 2,275 healthy women aged 15-20 years were recruited and randomly assigned to receive bivalent (n = 760), nonavalent (n = 758) or control (n = 757) vaccine. The primary outcome was incident-persistent vaccine type-specific cervical HPV infection. The primary evaluation was superiority analysis in the modified intention-to-treat (mITT) HPV 16/18 and HPV 16/18/31/33/45/52/58 cohorts. The trial met its prespecified end points of vaccine type-specific persistent HPV infection. A total of 75 incident-persistent infections were detected in the HPV 16/18 mITT cohort: 2 in the bivalent group, 1 in the nonavalent group and 72 in the control group. Nonavalent VE was 98.8% (95% CI 91.3-99.8%, P < 0.0001) and bivalent VE was 97.5% (95% CI 90.0-99.4%, P < 0.0001). Overall, 89 persistent infections were detected in the HPV 16/18/31/33/45/52/58 mITT cohort: 5 in the nonavalent group and 84 in the control group; nonavalent VE was 95.5% (95% CI 89.0-98.2%, P < 0.0001). There were no vaccine-related severe adverse events. Three years after vaccination, single-dose HPV vaccination was highly efficacious, safe and conferred durable protection. no. NCT03675256 .

RevDate: 2023-12-04

Giafaglione JM, Crowell PD, Delcourt AML, et al (2023)

Prostate lineage-specific metabolism governs luminal differentiation and response to antiandrogen treatment.

Nature cell biology [Epub ahead of print].

Lineage transitions are a central feature of prostate development, tumourigenesis and treatment resistance. While epigenetic changes are well known to drive prostate lineage transitions, it remains unclear how upstream metabolic signalling contributes to the regulation of prostate epithelial identity. To fill this gap, we developed an approach to perform metabolomics on primary prostate epithelial cells. Using this approach, we discovered that the basal and luminal cells of the prostate exhibit distinct metabolomes and nutrient utilization patterns. Furthermore, basal-to-luminal differentiation is accompanied by increased pyruvate oxidation. We establish the mitochondrial pyruvate carrier and subsequent lactate accumulation as regulators of prostate luminal identity. Inhibition of the mitochondrial pyruvate carrier or supplementation with exogenous lactate results in large-scale chromatin remodelling, influencing both lineage-specific transcription factors and response to antiandrogen treatment. These results establish reciprocal regulation of metabolism and prostate epithelial lineage identity.

RevDate: 2023-12-04

Adams RC, Carter-Cusack D, Llanes GT, et al (2023)

CSF1R inhibition promotes neuroinflammation and behavioural deficits during graft-versus-host disease in mice.

Blood pii:506500 [Epub ahead of print].

Chronic graft-versus-host disease (cGVHD) remains a significant complication of allogeneic hematopoietic stem cell transplantation. Central nervous system (CNS) involvement is becoming increasingly recognised, where brain-infiltrating donor MHC class II+ bone marrow-derived macrophages (BMDM) drive pathology. BMDM are also mediators of cutaneous and pulmonary cGVHD, and clinical trials assessing the efficacy of antibody blockade of colony-stimulating factor 1 receptor (CSF1R) to deplete macrophages are promising. We hypothesised that CSF1R antibody blockade may also be a useful strategy to prevent/treat CNS cGVHD. Increased blood-brain barrier permeability during acute GVHD (aGVHD) facilitated CNS antibody access and microglia depletion by anti-CSF1R treatment. However, CSF1R blockade early post-transplant unexpectedly exacerbated aGVHD neuroinflammation. In established cGVHD, vascular changes and anti-CSF1R efficacy were more limited. Anti-CSF1R-treated mice retained donor BMDM, activated microglia, CD8+ and CD4+ T cells, and local cytokine expression in the brain. These findings were recapitulated in GVHD recipients where CSF1R was conditionally depleted in donor CX3CR1+ BMDM. Notably, inhibition of CSF1R signalling post-transplant failed to reverse GVHD-induced behavioural changes. Moreover, we observed aberrant behaviour in non-GVHD control recipients administered anti-CSF1R blocking antibody and naïve mice lacking CSF1R in CX3CR1+ cells, revealing a novel role for homeostatic microglia and indicating that ongoing clinical trials of CSF1R inhibition should assess neurological adverse events in patients. In contrast, transfer of Ifngr-/- grafts could reduce MHC class II+ BMDM infiltration, resulting in improved neurocognitive function. Our findings highlight unexpected neurological immune toxicity during CSF1R blockade and provide alternative targets for the treatment of cGVHD within the CNS.

RevDate: 2023-12-04

Greenlaw AC, Alavattam KG, T Tsukiyama (2023)

Post-transcriptional regulation shapes the transcriptome of quiescent budding yeast.

Nucleic acids research pii:7458319 [Epub ahead of print].

To facilitate long-term survival, cells must exit the cell cycle and enter quiescence, a reversible non-replicative state. Budding yeast cells reprogram their gene expression during quiescence entry to silence transcription, but how the nascent transcriptome changes in quiescence is unknown. By investigating the nascent transcriptome, we identified over a thousand noncoding RNAs in quiescent and G1 yeast cells, and found noncoding transcription represented a larger portion of the quiescent transcriptome than in G1. Additionally, both mRNA and ncRNA are subject to increased post-transcriptional regulation in quiescence compared to G1. We found that, in quiescence, the nuclear exosome-NNS pathway suppresses over one thousand mRNAs, in addition to canonical noncoding RNAs. RNA sequencing through quiescent entry revealed two distinct time points at which the nuclear exosome controls the abundance of mRNAs involved in protein production, cellular organization, and metabolism, thereby facilitating efficient quiescence entry. Our work identified a previously unknown key biological role for the nuclear exosome-NNS pathway in mRNA regulation and uncovered a novel layer of gene-expression control in quiescence.

RevDate: 2023-12-06

Hollis JA, Chan MC, Malik HS, et al (2023)

Evolutionary origin and structural ligand mimicry by the inserted domain of alpha-integrin proteins.

bioRxiv : the preprint server for biology.

Heterodimeric integrin proteins transmit signals through conformational changes upon ligand binding between their alpha (α) and beta (β) subunits. Early in chordate evolution, some α subunits acquired an "inserted" (I) domain, which expanded their ligand binding capacity but simultaneously obstructed the ancestral ligand-binding pocket. While this would seemingly impede conventional ligand-mediated integrin activation, it was proposed that the I domain itself could serve both as a ligand replacement and an activation trigger. Here, we provide compelling evidence in support of this longstanding hypothesis using high-resolution cryo-electron microscopy structures of two distinct integrin complexes: the ligand-free and E-cadherin-bound states of the αEβ7 integrin with the I domain, as well as the α4β7 integrin lacking the I domain in both a ligand-free state and bound to MadCAM-1. We trace the evolutionary origin of the I domain to an ancestral collagen-collagen interaction domain. Our analyses illuminate how the I domain intrinsically mimics an extrinsic ligand, enabling integrins to undergo the canonical allosteric cascade of conformational activation and dramatically expanding the range of cellular communication mechanisms in vertebrates.

RevDate: 2023-12-04

Amundsen SK, GR Smith (2023)

RecBCD enzyme: mechanistic insights from mutants of a complex helicase-nuclease.

Microbiology and molecular biology reviews : MMBR [Epub ahead of print].

SUMMARYRecBCD enzyme is a multi-functional protein that initiates the major pathway of homologous genetic recombination and DNA double-strand break repair in Escherichia coli. It is also required for high cell viability and aids proper DNA replication. This 330-kDa, three-subunit enzyme is one of the fastest, most processive helicases known and contains a potent nuclease controlled by Chi sites, hotspots of recombination, in DNA. RecBCD undergoes major changes in activity and conformation when, during DNA unwinding, it encounters Chi (5'-GCTGGTGG-3') and nicks DNA nearby. Here, we discuss the multitude of mutations in each subunit that affect one or another activity of RecBCD and its control by Chi. These mutants have given deep insights into how the multiple activities of this complex enzyme are coordinated and how it acts in living cells. Similar studies could help reveal how other complex enzymes are controlled by inter-subunit interactions and conformational changes.

RevDate: 2023-12-04

Nasir A, Hegerova L, Yousaf H, et al (2023)

Digital and manual interfollicular Ki-67 are associated with a progression-free survival in patients with low-grade follicular lymphoma.

American journal of clinical pathology pii:7458183 [Epub ahead of print].

OBJECTIVES: Novel histopathologic prognostic factors are needed to identify patients with follicular lymphoma (FL) at risk of inferior outcomes. Our primary objective was to evaluate the Ki-67 proliferative index in follicular and interfollicular areas in tissue biopsy specimens from patients with newly diagnosed FL and correlate with clinical outcomes. Our secondary objective was to correlate PD-L1 and LAG-3 with clinical outcomes.

METHODS: Seventy cases of low-grade FL from the University of Minnesota were evaluated with Ki-67 immunohistochemical stain. Ki-67 expression as a continuous variable was interpreted digitally and manually in follicular and interfollicular areas. Progression-free survival (PFS) and overall survival (OS) were analyzed by Cox regression, and hazard ratios (HRs) per 10-point increase in Ki-67 were calculated.

RESULTS: Progression-free survival at 4 years was 28% (95% CI, 19%-41%). Interfollicular, but not follicular, Ki-67 was associated with PFS by manual (HR, 1.33; P = .01) and digital (HR, 1.38; P = .02) analysis. Digital and manual Ki-67 were only moderately correlated but demonstrated similar effects on PFS. At 4 years, OS was 90% with no association with follicular or interfollicular Ki-67 proliferation.

CONCLUSIONS: Higher interfollicular Ki-67 by either digital or manual analysis is associated with a poorer PFS in patients with low-grade FL. These results suggest further validation of this marker is warranted to improve pathologic risk stratification at FL diagnosis. PD-L1 and LAG-3 were not associated with PFS or OS.

RevDate: 2023-12-04

Knoerl R, Sannes TS, Giobbie-Hurder A, et al (2023)

Exploring anxiety as an influencing factor of the impact of exercise and mind-body prehabilitation on cognitive functioning among women undergoing breast cancer surgery.

Journal of psychosocial oncology [Epub ahead of print].

OBJECTIVE: The purpose of this secondary analysis was to describe the prevalence of anxiety, depression, and perceived stress among women newly diagnosed with breast cancer and the impact of baseline and changes in anxiety on cognitive functioning following exercise and mind-body prehabilitation interventions.

METHODS: The sample consisted of 49 women with newly diagnosed breast cancer (stages I-III) who planned to undergo breast cancer surgery at two academic cancer centers. Participants were randomized to receive an exercise or mind-body prehabilitation intervention between the time of diagnosis and breast cancer surgery. Participants completed self-report measures of anxiety, depression (HADS), perceived stress, and cognitive functioning (EORTC-QLQ-C30) at study enrollment and prior to surgery (post-intervention). The relationships between change in cognitive functioning and change in anxiety among all participants were estimated using linear regression modeling.

RESULTS: A significant proportion of women with newly diagnosed breast cancer had clinically significant anxiety (34.0%). Greater anxiety was moderately associated with worse cognitive functioning (r = -0.33) at baseline. Linear modeling found that changes in cognitive functioning and anxiety were inversely related: Each one-unit decrease in anxiety was associated with a two-unit improvement in cognitive function (p = .06).

CONCLUSIONS: Anxiety was common in women with newly diagnosed breast cancer and was related to worse cognitive functioning. Assessment of anxiety at the time of diagnosis may allow for earlier anxiety management and subsequent improvement in cognitive functioning.

RevDate: 2023-12-04

Sule KC, Nakamura M, SM Parkhurst (2023)

Nuclear envelope budding: Getting large macromolecular complexes out of the nucleus.

BioEssays : news and reviews in molecular, cellular and developmental biology [Epub ahead of print].

Transport of macromolecules from the nucleus to the cytoplasm is essential for nearly all cellular and developmental events, and when mis-regulated, is associated with diseases, tumor formation/growth, and cancer progression. Nuclear Envelope (NE)-budding is a newly appreciated nuclear export pathway for large macromolecular machineries, including those assembled to allow co-regulation of functionally related components, that bypasses canonical nuclear export through nuclear pores. In this pathway, large macromolecular complexes are enveloped by the inner nuclear membrane, transverse the perinuclear space, and then exit through the outer nuclear membrane to release its contents into the cytoplasm. NE-budding is a conserved process and shares many features with nuclear egress mechanisms used by herpesviruses. Despite its biological importance and clinical relevance, little is yet known about the regulatory and structural machineries that allow NE-budding to occur in any system. Here we summarize what is currently known or proposed for this intriguing nuclear export process.

RevDate: 2023-12-03

Loghavi S, Kanagal-Shamanna R, Khoury JD, et al (2023)


Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc pii:S0893-3952(23)00302-2 [Epub ahead of print].

In this manuscript, we review myeloid neoplasms in the 5[th] edition of the World Health Organization classification of hematolymphoid tumors (WHO-HEM5), focusing on changes from the revised 4[th] edition (WHO-HEM4R). Disease types and subtypes have expanded compared with WHO-HEM4R, mainly because of the expansion in genomic knowledge of these diseases. The revised classification follows a hierarchical structure allowing usage of family (class) level definitions where the defining diagnostic criteria are partially met or a complete investigational workup has not been possible. Overall, the WHO-HEM5 revisions to the classification of myeloid neoplasms includes major updates and revisions with increased emphasis on genetic and molecular drivers of disease. The revised classification is based on a multidisciplinary approach including input from a large body of pathologists, clinician's and geneticists. The most notable changes have been applied to the sections of acute myeloid leukemia and myelodysplastic neoplasms (previously referred to as myelodysplastic syndrome) with incorporation of novel, disease defining genetic changes. In this review we will focus on highlighting the updates in classification of myeloid neoplasms, providing a comparison with WHO-HEM4R and offering guidance on how the new classification can be applied to the diagnosis of myeloid neoplasms in routine practice.

RevDate: 2023-12-01

Zhang X, Irajizad E, Hoffman KL, et al (2023)

Modulating a prebiotic food source influences inflammation and immune-regulating gut microbes and metabolites: insights from the BE GONE trial.

EBioMedicine pii:S2352-3964(23)00439-5 [Epub ahead of print].

BACKGROUND: Accessible prebiotic foods hold strong potential to jointly target gut health and metabolic health in high-risk patients. The BE GONE trial targeted the gut microbiota of obese surveillance patients with a history of colorectal neoplasia through a straightforward bean intervention.

METHODS: This low-risk, non-invasive dietary intervention trial was conducted at MD Anderson Cancer Center (Houston, TX, USA). Following a 4-week equilibration, patients were randomized to continue their usual diet without beans (control) or to add a daily cup of study beans to their usual diet (intervention) with immediate crossover at 8-weeks. Stool and fasting blood were collected every 4 weeks to assess the primary outcome of intra and inter-individual changes in the gut microbiome and in circulating markers and metabolites within 8 weeks. This study was registered on as NCT02843425, recruitment is complete and long-term follow-up continues.

FINDINGS: Of the 55 patients randomized by intervention sequence, 87% completed the 16-week trial, demonstrating an increase on-intervention in diversity [n = 48; linear mixed effect and 95% CI for inverse Simpson index: 0.16 (0.02, 0.30); p = 0.02] and shifts in multiple bacteria indicative of prebiotic efficacy, including increased Faecalibacterium, Eubacterium and Bifidobacterium (all p < 0.05). The circulating metabolome showed parallel shifts in nutrient and microbiome-derived metabolites, including increased pipecolic acid and decreased indole (all p < 0.002) that regressed upon returning to the usual diet. No significant changes were observed in circulating lipoproteins within 8 weeks; however, proteomic biomarkers of intestinal and systemic inflammatory response, fibroblast-growth factor-19 increased, and interleukin-10 receptor-α decreased (p = 0.01).

INTERPRETATION: These findings underscore the prebiotic and potential therapeutic role of beans to enhance the gut microbiome and to regulate host markers associated with metabolic obesity and colorectal cancer, while further emphasizing the need for consistent and sustainable dietary adjustments in high-risk patients.

FUNDING: This study was funded by the American Cancer Society.

RevDate: 2023-12-04
CmpDate: 2023-12-04

Lim FY, Kim SY, Kulkarni KN, et al (2023)

High-frequency home self-collection of capillary blood correlates IFI27 expression kinetics with SARS-CoV-2 viral clearance.

The Journal of clinical investigation, 133(23):.

RevDate: 2023-12-03

Evenson KR, Wen F, Moore CC, et al (2023)

Calibrating Physical Activity and Sedentary Behavior for Hip-Worn Accelerometry in Older Women With Two Epoch Lengths: The Women's Health Initiative Objective Physical Activity and Cardiovascular Health Calibration Study.

Journal for the measurement of physical behaviour, 6(2):156-161.

PURPOSE: The purpose of this study was to develop 60-second epoch accelerometer intensity cutpoints for vertical axis count and vector magnitude (VM) output from hip-worn tri-axial accelerometers among women 60-91 years. We also compared these cutpoints against cutpoints derived by multiplying 15-second epoch cutpoints by four.

METHODS: Two hundred apparently healthy women wore an ActiGraph GT3X+ accelerometer on their hip while performing a variety of laboratory-based activities that were sedentary (watching television, assembling a puzzle), low light (washing/drying dishes), high light (laundry, dust mopping), or MVPA (400-meter walk) intensity. Oxygen uptake was measured using an Oxycon[™] portable calorimeter. Sedentary behavior and physical activity intensity cutpoints for vertical axis and VM counts were derived for 60-second epochs from receiver operating characteristic (ROC) and by multiplying the 15-second cutpoints by four); both were compared to oxygen uptake.

RESULTS: The median age was 74.5 years (interquartile range 70-83). The 60-second epoch cutpoints for vertical counts were 0 sedentary, 1-73 low light, 74-578 high light, and >=579 MVPA. The 60-second epoch cutpoints for VM were 0-88 sedentary, 89-663 low light, 664-1730 high light, and >=1731 MVPA. For both sets of cutpoints, the ROC approach yielded more accurate estimates than the multiplication approach.

CONCLUSION: The derived 60-second epoch cutpoints for vertical counts and VM can be applied to epidemiologic studies to define sedentary behavior and physical activity intensities in older adult populations.

RevDate: 2023-12-04
CmpDate: 2023-12-04

Martin PJ (2023)

A Reflection Inspired by Reflections.

Transplantation and cellular therapy, 29(12):723-724.

RevDate: 2023-11-30

Zhu Q, Yuan C, Dong X, et al (2023)

Bile acid metabolomics identifies chenodeoxycholic acid as a therapeutic agent for pancreatic necrosis.

Cell reports. Medicine pii:S2666-3791(23)00498-6 [Epub ahead of print].

Bile acids are altered and associated with prognosis in patients with acute pancreatitis (AP). Here, we conduct targeted metabolomic analyses to detect bile acids changes in patients during the acute (n = 326) and the recovery (n = 133) phases of AP, as well as in healthy controls (n = 60). Chenodeoxycholic acid (CDCA) decreases in the acute phase, increases in the recovery phase, and is associated with pancreatic necrosis. CDCA and its derivative obeticholic acid exhibit a protective effect against acinar cell injury in vitro and pancreatic necrosis in murine models, and RNA sequencing reveals that the oxidative phosphorylation pathway is mainly involved. Moreover, we find that overexpression of farnesoid X receptor (FXR, CDCA receptor) inhibits pancreatic necrosis, and interfering expression of FXR exhibits an opposite phenotype in mice. Our results possibly suggest that targeting CDCA is a potential strategy for the treatment of acinar cell necrosis in AP, but further verification is needed.

RevDate: 2023-11-30

Tollefson D, Dasgupta S, Setswe G, et al (2023)

Impact of youth lay health workers on HIV service delivery in South Africa: A pragmatic cluster randomized trial of the Youth Health Africa program.

PloS one, 18(11):e0294719.

BACKGROUND: Innovative approaches are needed to increase lay health workers in HIV programs. The Youth Health Africa (YHA) program is a novel approach that places young adults seeking work experience in one-year internships in health facilities to support HIV-related programming (e.g., HIV testing) or administration (e.g., filing).

METHODS: We implemented a pragmatic, randomized trial among 20 facilities in Ngaka Modiri Molema district in North West province from October 2020-August 2021 to assess impact of YHA interns on HIV testing, treatment initiation, and retention in care. The primary outcome was proportion of patients tested for HIV. Secondary outcomes assessed HIV positivity, initiation in care, retention in care, and HIV testing among males and adolescents/young adults. We conducted an intention-to-treat analysis accounting for variations in baseline outcomes between control and intervention facilities using difference-in-difference and controlled time series approaches. We repeated this using as-treated groupings for sensitivity analyses.

RESULTS: Fifty interns were placed in 20 facilities; thirty-four interns remained at 18 facilities through August 2021. Compared to control facilities, intervention facilities had a greater improvement in HIV testing (ΔΔ+5.7%, 95% Confidence Interval (CI): -3.7%-15.1%) and treatment initiation (ΔΔ+10.3%, 95% CI: -27.8-48.5%), but these differences were not statistically significant. There was an immediate increase in HIV testing in intervention facilities after program interns were placed, which was not observed in control facilities; this difference was significant (ΔΔ+8.4%, 95% CI: 0.5-16.4%, p = 0.036). There were no other differences in outcomes observed between intervention and control facilities.

CONCLUSION: This was largely a null trial, but there were signals that program interns may have positive impact on HIV testing and treatment initiation. As implemented in this study, addition of YHA program interns had little impact on facility-based HIV service delivery. A higher number of interns placed per facility may be necessary to affect HIV services.

TRIAL REGISTRATION: Registration: This trial was registered with the ISRCTN (Registration number: ISRCTN67031403) in October 2022.

RevDate: 2023-11-30

Anderson JT, Henikoff S, K Ahmad (2023)

Chromosome-specific maturation of the epigenome in the Drosophila male germline.

eLife, 12: pii:89373.

Spermatogenesis in the Drosophila male germline proceeds through a unique transcriptional program controlled both by germline-specific transcription factors and by testis-specific versions of core transcriptional machinery. This program includes the activation of genes on the heterochromatic Y chromosome, and reduced transcription from the X chromosome, but how expression from these sex chromosomes is regulated has not been defined. To resolve this, we profiled active chromatin features in the testes from wildtype and meiotic arrest mutants and integrate this with single-cell gene expression data from the Fly Cell Atlas. These data assign the timing of promoter activation for genes with germline-enriched expression throughout spermatogenesis, and general alterations of promoter regulation in germline cells. By profiling both active RNA polymerase II and histone modifications in isolated spermatocytes, we detail widespread patterns associated with regulation of the sex chromosomes. Our results demonstrate that the X chromosome is not enriched for silencing histone modifications, implying that sex chromosome inactivation does not occur in the Drosophila male germline. Instead, a lack of dosage compensation in spermatocytes accounts for the reduced expression from this chromosome. Finally, profiling uncovers dramatic ubiquitinylation of histone H2A and lysine-16 acetylation of histone H4 across the Y chromosome in spermatocytes that may contribute to the activation of this heterochromatic chromosome.

RevDate: 2023-12-01

Kim P, Rothberg MB, Nowacki AS, et al (2023)

Derivation and external validation of a prediction model for pneumococcal urinary antigen test positivity in patients with community-acquired pneumonia.

Antimicrobial stewardship & healthcare epidemiology : ASHE, 3(1):e166.

OBJECTIVE: Derive and externally validate a prediction model for pneumococcal urinary antigen test (pUAT) positivity.

METHODS: Retrospective cohort study of adults admitted with community-acquired pneumonia (CAP) to 177 U.S. hospitals in the Premier Database (derivation and internal validation samples) or 12 Cleveland Clinic hospitals (external validation sample). We utilized multivariable logistic regression to predict pUAT positivity in the derivation dataset, followed by model performance evaluation in both validation datasets. Potential predictors included demographics, comorbidities, clinical findings, and markers of disease severity.

RESULTS: Of 198,130 Premier patients admitted with CAP, 27,970 (14.1%) underwent pUAT; 1962 (7.0%) tested positive. The strongest predictors of pUAT positivity were history of pneumococcal infection in the previous year (OR 6.99, 95% CI 4.27-11.46), severe CAP on admission (OR 1.76, 95% CI 1.56-1.98), substance abuse (OR 1.57, 95% CI 1.27-1.93), smoking (OR 1.23, 95% CI 1.09-1.39), and hyponatremia (OR 1.35, 95% CI 1.17-1.55). Negative predictors included IV antibiotic use in past year (OR 0.65, 95% CI 0.52-0.82), congestive heart failure (OR 0.72, 95% CI 0.63-0.83), obesity (OR 0.71, 95% CI 0.60-0.85), and admission from skilled nursing facility (OR 0.60, 95% CI 0.45-0.78). Model c-statistics were 0.60 and 0.67 in the internal and external validation cohorts, respectively. Compared to guideline-recommended testing of severe CAP patients, our model would have detected 23% more cases with 5% fewer tests.

CONCLUSION: Readily available data can identify patients most likely to have a positive pUAT. Our model could be incorporated into automated clinical decision support to improve test efficiency and antimicrobial stewardship.

RevDate: 2023-12-01

Xu Y, Miller CP, Xue J, et al (2023)

Single cell atlas of kidney cancer endothelial cells reveals distinct expression profiles and phenotypes.

Research square.

BACKGROUND: Tumor endothelial cells (TECs) represent the primary interface between the tumor microenvironment and circulating immune cells, however their phenotypes are incompletely understood in highly vascularized clear cell renal cell carcinoma (ccRCC).

METHODS: We purified tumor and matched normal endothelial cells (NECs) from ccRCC specimens and performed single-cell RNA-sequencing to create a reference-quality atlas available as a searchable web resource for gene expression patterns. We established paired primary TECs and NECs cultures for ex vivo functional testing.

RESULTS: TECs from multiple donors shared a common phenotype with increased expression of pathways related to extracellular matrix regulation, cell-cell communication, and insulin-like growth factor signaling that was conserved in comparison to hepatocellular carcinoma associated TECs, suggesting convergent TEC phenotypes between unrelated tumors. Cultured TECs stably maintained a core program of differentially regulated genes, were inherently resistant to apoptosis after vascular endothelial growth factor removal and displayed increased adhesiveness to subsets of immune cells including regulatory T-cells.

CONCLUSIONS: Our studies delineate unique functional and phenotypic properties of TECs, which may provide insights into their interactions with available and emerging therapies. Functional phenotypes of cultured TECs suggest potential mechanisms of resistance to both antiangiogenic and immune-based therapies.

RevDate: 2023-12-01

Saner FAM, Takahashi K, Budden T, et al (2023)

Concurrent RB1 loss and BRCA-deficiency predicts enhanced immunological response and long-term survival in tubo-ovarian high-grade serous carcinoma.

medRxiv : the preprint server for health sciences.

BACKGROUND: Somatic loss of the tumour suppressor RB1 is a common event in tubo-ovarian high-grade serous carcinoma (HGSC), which frequently co-occurs with alterations in homologous recombination DNA repair genes including BRCA1 and BRCA2 (BRCA). We examined whether tumour expression of RB1 was associated with survival across ovarian cancer histotypes (HGSC, endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous carcinoma (LGSC)), and how co-occurrence of germline BRCA pathogenic variants and RB1 loss influences long-term survival in a large series of HGSC.

PATIENTS AND METHODS: RB1 protein expression patterns were classified by immunohistochemistry in epithelial ovarian carcinomas of 7436 patients from 20 studies participating in the Ovarian Tumor Tissue Analysis consortium and assessed for associations with overall survival (OS), accounting for patient age at diagnosis and FIGO stage. We examined RB1 expression and germline BRCA status in a subset of 1134 HGSC, and related genotype to survival, tumour infiltrating CD8+ lymphocyte counts and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cell lines with and without BRCA1 mutations to model co-loss with treatment response. We also performed genomic analyses on 126 primary HGSC to explore the molecular characteristics of concurrent homologous recombination deficiency and RB1 loss.

RESULTS: RB1 protein loss was most frequent in HGSC (16.4%) and was highly correlated with RB1 mRNA expression. RB1 loss was associated with longer OS in HGSC (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.66-0.83, P = 6.8 ×10[-7]), but with poorer prognosis in ENOC (HR 2.17, 95% CI 1.17-4.03, P = 0.0140). Germline BRCA mutations and RB1 loss co-occurred in HGSC (P < 0.0001). Patients with both RB1 loss and germline BRCA mutations had a superior OS (HR 0.38, 95% CI 0.25-0.58, P = 5.2 ×10[-6]) compared to patients with either alteration alone, and their median OS was three times longer than non-carriers whose tumours retained RB1 expression (9.3 years vs. 3.1 years). Enhanced sensitivity to cisplatin (P < 0.01) and paclitaxel (P < 0.05) was seen in BRCA1 mutated cell lines with RB1 knockout. Among 126 patients with whole-genome and transcriptome sequence data, combined RB1 loss and genomic evidence of homologous recombination deficiency was correlated with transcriptional markers of enhanced interferon response, cell cycle deregulation, and reduced epithelial-mesenchymal transition in primary HGSC. CD8+ lymphocytes were most prevalent in BRCA-deficient HGSC with co-loss of RB1.

CONCLUSIONS: Co-occurrence of RB1 loss and BRCA mutation was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.

RevDate: 2023-12-01

Laing KJ, Ford ES, Johnson MJ, et al (2023)

Recruitment of naive CD4+ T cells by the recombinant zoster vaccine correlates with persistent immunity.

The Journal of clinical investigation, 133(23):.

Herpes zoster (HZ) is a substantial problem for people with decreased cell-mediated immunity, including older adults. The first vaccine approved for HZ prevention, the zoster vaccine live (ZVL), which provided limited and short-lived protection, has been supplanted by the superior recombinant zoster vaccine (RZV), which provides robust and durable protection. To understand the mechanisms underlying the differential immunologic characteristics of the 2 vaccines, we used T cell receptor β chain sequencing and peptide-MHC class II tetramer staining to analyze recombinant glycoprotein E-specific (gE-specific) CD4+ T cell clonotypes in RZV and ZVL recipients. Compared with ZVL, RZV expanded more gE-specific CD4+ clonotypes, with greater breadth and higher frequency of public clonotypes. RZV recruited a higher proportion of clonotypes from naive than from memory cells, while ZVL recruited equally from memory and naive compartments. Compared with memory-derived, naive-derived clonotypes were more likely to last 5 or more years after immunization. Moreover, the frequency of tetramer+ persistent clones correlated with the frequency of tetramer+ naive CD4+ prevaccination T cells. We conclude that the ability of RZV to recruit naive CD4+ T cells into the response may contribute to the durability of its effect. The abundance, breadth, and frequency of public clonotypes may further add to its protective effect.

RevDate: 2023-11-29

Stephenson KE, Marcelin JR, Pettifor AE, et al (2023)

Efficacy of Messenger RNA-1273 Against Severe Acute Respiratory Syndrome Coronavirus 2 Acquisition in Young Adults From March to December 2021.

Open forum infectious diseases, 10(11):ofad511.

BACKGROUND: The efficacy of messenger RNA (mRNA)-1273 against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is not well defined, particularly among young adults.

METHODS: Adults aged 18-29 years with no known history of SARS-CoV-2 infection or prior vaccination for coronavirus disease 2019 (COVID-19) were recruited from 44 US sites from 24 March to 13 September 2021 and randomized 1:1 to immediate vaccination (receipt of 2 doses of mRNA-1273 vaccine at months 0 and 1) or the standard of care (receipt of COVID-19 vaccine). Randomized participants were followed up for SARS-CoV-2 infection measured by nasal swab testing and symptomatic COVID-19 measured by nasal swab testing plus symptom assessment and assessed for the primary efficacy outcome. A vaccine-declined observational group was also recruited from 16 June to 8 November 2021 and followed up for SARS-CoV-2 infection as specified for the randomized participants.

RESULTS: The study enrolled 1149 in the randomized arms and 311 in the vaccine-declined group and collected >122 000 nasal swab samples. Based on randomized participants, the efficacy of 2 doses of mRNA-1273 vaccine against SARS-CoV-2 infection was 52.6% (95% confidence interval, -14.1% to 80.3%), with the majority of infections due to the Delta variant. Vaccine efficacy against symptomatic COVID-19 was 71.0% (95% confidence interval, -9.5% to 92.3%). Precision was limited owing to curtailed study enrollment and off-study vaccination censoring. The incidence of SARS-CoV-2 infection in the vaccine-declined group was 1.8 times higher than in the standard-of-care group.

CONCLUSIONS: mRNA-1273 vaccination reduced the incidence of SARS-CoV-2 infection from March to September 2021, but vaccination was only one factor influencing risk.


RevDate: 2023-11-29

Zhong X, Chen S, Xiao H, et al (2023)

Perceived HIV risk and factors associated with condom use among women aged 40 and older: A cross-sectional survey.

International journal of nursing sciences, 10(4):533-539.

OBJECTIVES: A noticeable increase in HIV-positive cases among women, particularly those of middle and old age, has been observed worldwide. This study aimed to describe women's perceived HIV risk, HIV/Acquired Immunodeficiency Syndrome (AIDS) knowledge, attitude, and sexual behaviors to determine factors associated with condom use among these women in Hunan, China.

METHODS: A cross-sectional study was conducted from July 2019 to August 2020 among 958 women aged 40 and older in four regions of Hunan, China. We collected data on sociodemographic characteristics, perceived HIV risk, HIV/AIDS knowledge and attitude, condom use, and sexual behaviors. Univariate and multivariate logistic regression were performed to identify factors related to condom use.

RESULTS: Out of 958 participants, 60.6% perceived no risk of HIV infection, and 46.8% reported they had never used a condom during their past sexual life. Those who were older, had lower monthly household income for family, had not received HIV education in the past year, were unwilling to use condoms, could not determine condom use during sexual activity, and had more negative attitudes towards HIV/AIDS and HIV-positive people were less likely to use condoms in their past sexual behaviors.

CONCLUSIONS: In Hunan Province, most women aged 40 and older perceived themselves as having a low or no risk of HIV infection; their rate of condom use was low, and six factors were associated with condom use. It is imperative to strengthen HIV prevention and control programs among women aged 40 and above, particularly focusing on those who may use condoms infrequently or not at all.

RevDate: 2023-11-29

Dwivedi AK, Gornalusse GG, Siegel DA, et al (2023)

A cohort-based study of host gene expression: tumor suppressor and innate immune/inflammatory pathways associated with the HIV reservoir size.

PLoS pathogens, 19(11):e1011114 pii:PPATHOGENS-D-23-00056 [Epub ahead of print].

The major barrier to an HIV cure is the HIV reservoir: latently-infected cells that persist despite effective antiretroviral therapy (ART). There have been few cohort-based studies evaluating host genomic or transcriptomic predictors of the HIV reservoir. We performed host RNA sequencing and HIV reservoir quantification (total DNA [tDNA], unspliced RNA [usRNA], intact DNA) from peripheral CD4+ T cells from 191 ART-suppressed people with HIV (PWH). After adjusting for nadir CD4+ count, timing of ART initiation, and genetic ancestry, we identified two host genes for which higher expression was significantly associated with smaller total DNA viral reservoir size, P3H3 and NBL1, both known tumor suppressor genes. We then identified 17 host genes for which lower expression was associated with higher residual transcription (HIV usRNA). These included novel associations with membrane channel (KCNJ2, GJB2), inflammasome (IL1A, CSF3, TNFAIP5, TNFAIP6, TNFAIP9, CXCL3, CXCL10), and innate immunity (TLR7) genes (FDR-adjusted q<0.05). Gene set enrichment analyses further identified significant associations of HIV usRNA with TLR4/microbial translocation (q = 0.006), IL-1/NRLP3 inflammasome (q = 0.008), and IL-10 (q = 0.037) signaling. Protein validation assays using ELISA and multiplex cytokine assays supported these observed inverse host gene correlations, with P3H3, IL-10, and TNF-α protein associations achieving statistical significance (p<0.05). Plasma IL-10 was also significantly inversely associated with HIV DNA (p = 0.016). HIV intact DNA was not associated with differential host gene expression, although this may have been due to a large number of undetectable values in our study. To our knowledge, this is the largest host transcriptomic study of the HIV reservoir. Our findings suggest that host gene expression may vary in response to the transcriptionally active reservoir and that changes in cellular proliferation genes may influence the size of the HIV reservoir. These findings add important data to the limited host genetic HIV reservoir studies to date.

RevDate: 2023-11-29

Bussi IL, Neitz AF, Sanchez REA, et al (2023)

Expression of the vesicular GABA transporter within neuromedin S[+] neurons sustains behavioral circadian rhythms.

Proceedings of the National Academy of Sciences of the United States of America, 120(49):e2314857120.

The suprachiasmatic nucleus (SCN) of the hypothalamus is the site of a central circadian clock that orchestrates overt rhythms of physiology and behavior. Circadian timekeeping requires intercellular communication among SCN neurons, and multiple signaling pathways contribute to SCN network coupling. Gamma-aminobutyric acid (GABA) is produced by virtually all SCN neurons, and previous work demonstrates that this transmitter regulates coupling in the adult SCN but is not essential for the nucleus to sustain overt circadian rhythms. Here, we show that the deletion of the gene that codes for the GABA vesicular transporter Vgat from neuromedin-S (NMS)[+] neurons-a subset of neurons critical for SCN function-causes arrhythmia of locomotor activity and sleep. Further, NMS-Vgat deletion impairs intrinsic clock gene rhythms in SCN explants cultured ex vivo. Although vasoactive intestinal polypeptide (VIP) is critical for SCN function, Vgat deletion from VIP-expressing neurons did not lead to circadian arrhythmia in locomotor activity rhythms. Likewise, adult SCN-specific deletion of Vgat led to mild impairment of behavioral rhythms. Our results suggest that while the removal of GABA release from the adult SCN does not affect the pacemaker's ability to sustain overt circadian rhythms, its removal from a critical subset of neurons within the SCN throughout development removes the nucleus ability to sustain circadian rhythms. Our findings support a model in which SCN GABA release is critical for the developmental establishment of intercellular network properties that define the SCN as a central pacemaker.

RevDate: 2023-11-29

Loroña NC, Othus M, Malone KE, et al (2023)

Alcohol, smoking, and risks of breast cancer recurrence and mortality among women with luminal, triple-negative, and HER2-overexpressing breast cancer.

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology pii:731460 [Epub ahead of print].

BACKGROUND: This study evaluates the relationship between smoking, alcohol, and breast cancer outcomes according to molecular subtype.

METHODS: This population-based prospective cohort consisted of 3,876 women aged 20-69 diagnosed with a first primary invasive breast cancer from 2004 through 2015 in the Seattle-Puget Sound region. Breast cancer was categorized into three subtypes based on estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression: luminal (ER+), triple-negative (TN) (ER-/PR-/HER2-), and HER2-overexpressing (H2E) (ER-/HER2+). We fit Cox proportional hazards models to assess the association between alcohol consumption and smoking status at diagnosis and risks of recurrence, breast cancer-specific mortality, and all-cause mortality.

RESULTS: Histories of ever smoking (HR:1.33; 95%CI:1.01-1.74) and current smoking (HR:1.59; 95%CI:1.07-2.35) were associated with greater risk of breast cancer recurrence among TN cases. Smoking was also associated with greater risk of recurrence to bone among all cases and among luminal cases. Elevated risks of breast cancer-specific and all-cause mortality were observed among current smokers across all subtypes. Alcohol use was not positively associated with risk of recurrence or mortality overall; however, TN patients who drank four or more drinks per week had a decreased risk of recurrence (HR:0.71; 95%CI:0.51-0.98) and breast cancer-specific mortality (HR:0.73; 95%CI:0.55-0.97) compared to non-current drinkers.

CONCLUSIONS: Breast cancer patients with a history of smoking at diagnosis have elevated risks of recurrence and mortality.

IMPACT: These findings underscore the need to prioritize smoking cessation among women diagnosed with breast cancer.

RevDate: 2023-11-29

Guo B, Zhao C, He MZ, et al (2023)

Identifying patterns of reported findings on long-term cardiac complications of COVID-19: a systematic review and meta-analysis.

BMC medicine, 21(1):468.

INTRODUCTION: Prior reviews synthesized findings of studies on long-term cardiac complications of COVID-19. However, the reporting and methodological quality of these studies has not been systematically evaluated. Here, we conducted a systematic review and meta-analysis on long-term cardiac complications of COVID-19 and examined patterns of reported findings by study quality and characteristics.

METHODS: We searched for studies examining long-term cardiac complications of COVID-19 that persisted for 4 weeks and over. A customized Newcastle-Ottawa scale (NOS) was used to evaluate the quality of included studies. Meta-analysis was performed to generate prevalence estimates of long-term cardiac complications across studies. Stratified analyses were further conducted to examine the prevalence of each complication by study quality and characteristics. The GRADE approach was used to determine the level of evidence for complications included in the meta-analysis.

RESULTS: A total number of 150 studies describing 57 long-term cardiac complications were included in this review, and 137 studies reporting 17 complications were included in the meta-analysis. Only 25.3% (n = 38) of studies were of high quality based on the NOS quality assessment. Chest pain and arrhythmia were the most widely examined long-term complications. When disregarding study quality and characteristics, summary prevalence estimates for chest and arrhythmia were 9.79% (95% CI 7.24-13.11) and 8.22% (95% CI 6.46-10.40), respectively. However, stratified analyses showed that studies with low-quality scores, small sample sizes, unsystematic sampling methods, and cross-sectional design were more likely to report a higher prevalence of complications. For example, the prevalence of chest pain was 22.17% (95% CI 14.40-32.55), 11.08% (95% CI 8.65-14.09), and 3.89% (95% CI 2.49-6.03) in studies of low, medium, and high quality, respectively. Similar patterns were observed for arrhythmia and other less examined long-term cardiac complications.

CONCLUSION: There is a wide spectrum of long-term cardiac complications of COVID-19. Reported findings from previous studies are strongly related to study quality, sample sizes, sampling methods, and designs, underscoring the need for high-quality epidemiologic studies to characterize these complications and understand their etiology.

RevDate: 2023-11-28

Sui P, Ge G, Chen S, et al (2023)

SRSF2 mutation cooperates with ASXL1 truncated alteration to accelerate leukemogenesis.

Leukemia [Epub ahead of print].

RevDate: 2023-11-28

Huang Y, Zhang L, Karuna S, et al (2023)

Adults on pre-exposure prophylaxis (tenofovir-emtricitabine) have faster clearance of anti-HIV monoclonal antibody VRC01.

Nature communications, 14(1):7813.

Broadly neutralizing monoclonal antibodies (mAbs) are being developed for HIV-1 prevention. Hence, these mAbs and licensed oral pre-exposure prophylaxis (PrEP) (tenofovir-emtricitabine) can be concomitantly administered in clinical trials. In 48 US participants (men and transgender persons who have sex with men) who received the HIV-1 mAb VRC01 and remained HIV-free in an antibody-mediated-prevention trial ( #NCT02716675), we conduct a post-hoc analysis and find that VRC01 clearance is 0.08 L/day faster (p = 0.005), and dose-normalized area-under-the-curve of VRC01 serum concentration over-time is 0.29 day/mL lower (p < 0.001) in PrEP users (n = 24) vs. non-PrEP users (n = 24). Consequently, PrEP users are predicted to have 14% lower VRC01 neutralization-mediated prevention efficacy against circulating HIV-1 strains. VRC01 clearance is positively associated (r = 0.33, p = 0.03) with levels of serum intestinal Fatty Acid Binding protein (I-FABP), a marker of epithelial intestinal permeability, which is elevated upon starting PrEP (p = 0.04) and after months of self-reported use (p = 0.001). These findings have implications for the evaluation of future HIV-1 mAbs and postulate a potential mechanism for mAb clearance in the context of PrEP.

RevDate: 2023-11-28

Ahmad K, Brahma S, S Henikoff (2023)

Epigenetic pioneering by SWI/SNF family remodelers.

Molecular cell pii:S1097-2765(23)00916-4 [Epub ahead of print].

In eukaryotic genomes, transcriptional machinery and nucleosomes compete for binding to DNA sequences; thus, a crucial aspect of gene regulatory element function is to modulate chromatin accessibility for transcription factor (TF) and RNA polymerase binding. Recent structural studies have revealed multiple modes of TF engagement with nucleosomes, but how initial "pioneering" results in steady-state DNA accessibility for further TF binding and RNA polymerase II (RNAPII) engagement has been unclear. Even less well understood is how distant sites of open chromatin interact with one another, such as when developmental enhancers activate promoters to release RNAPII for productive elongation. Here, we review evidence for the centrality of the conserved SWI/SNF family of nucleosome remodeling complexes, both in pioneering and in mediating enhancer-promoter contacts. Consideration of the nucleosome unwrapping and ATP hydrolysis activities of SWI/SNF complexes, together with their architectural features, may reconcile steady-state TF occupancy with rapid TF dynamics observed by live imaging.

RevDate: 2023-11-28

Hughley RW, Matejcic M, Song Z, et al (2023)

Polygenic Risk Score Modifies Prostate Cancer Risk of Pathogenic Variants in Men of African Ancestry.

Cancer research communications pii:731436 [Epub ahead of print].

Prostate cancer risk is influenced by rare and common germline variants. We examined the aggregate association of rare germline pathogenic/likely pathogenic/deleterious (P/LP/D) variants in ATM, BRCA2, PALB2, and NBN with a polygenic risk score (PRS) on prostate cancer risk among 1,796 prostate cancer cases (222 metastatic) and 1,424 controls of African ancestry. Relative to P/LP/D non-carriers at average genetic risk (33-66% of PRS), men with low (0-33%) and high (66-100%) PRS had odds ratios (OR) for overall prostate cancer of 2.08 (95% confidence interval (CI)=0.58 to 7.49) and 18.06 (95% CI=4.24 to 76.84) among P/LP/D carriers and 0.57 (95% CI=0.46 to 0.71) and 3.02 (95% CI=2.53 to 3.60) among non-carriers, respectively. The OR for metastatic prostate cancer was 2.73 (95% CI=0.24 to 30.54) and 28.99 (95% CI=4.39 to 191.43) among P/LP/D carriers and 0.54 (95% CI=0.31 to 0.95) and 3.22 (95% CI=2.20 to 4.73) among non-carriers, for men with low and high PRS, respectively. Lifetime absolute risks of overall prostate cancer increased with PRS (low to high) from 9.8% to 51.5% in P/LP/D carriers and 5.5% to 23.9% in non-carriers. Lifetime absolute risks of metastatic prostate cancer increased with PRS from 1.9% to 18.1% in P/LP/D carriers and 0.3% to 2.2% in non-carriers These findings suggest that assessment of prostate cancer risk for rare variant carriers should include PRS status.

RevDate: 2023-11-28

Cowan AJ, DJ Green (2023)

Unveiling the link between genetic alterations in gamma secretase and BCMA surface density in multiple myeloma.

British journal of haematology [Epub ahead of print].

Cattaneo et al. report a unique case of a multiple myeloma patient with elevated B-cell maturation antigen (BCMA) surface density, potentially due to genetic alterations in the gamma-secretase protease complex-responsible for BCMA cleavage from plasma cells. No mutations in the BCMA gene were detected, but there was partial deletion of PSEN1 and amplification of PSEN2 (components of the gamma-secretase complex), which may explain the lack of response to the gamma-secretase inhibitor DAPT. This case, along with recent published literature, underscores the significance of gamma secretase in modulating BCMA density and the potential impact of its genetic alterations. Commentary on: Cattaneo et al. Genetic defects of gamma-secretase genes in a multiple myeloma patient with high and dysregulated BCMA surface density: A case report. Br J Haematol 2023 (Online ahead of print). doi: 10.1111/bjh.19168.

RevDate: 2023-11-29

Hannon WW, JD Bloom (2023)

dms-viz: Structure-informed visualizations for deep mutational scanning and other mutation-based datasets.

bioRxiv : the preprint server for biology.

Understanding how mutations impact a protein's functions is valuable for many types of biological questions. High-throughput techniques such as deep-mutational scanning (DMS) have greatly expanded the number of mutation-function datasets. For instance, DMS has been used to determine how mutations to viral proteins affect antibody escape (Dadonaite et al. 2023), receptor affinity (Starr et al. 2020), and essential functions such as viral genome transcription and replication (Li et al. 2023). With the growth of sequence databases, in some cases the effects of mutations can also be inferred from phylogenies of natural sequences (Bloom and Neher 2023) (Figure 1). The mutation-based data generated by these approaches is often best understood in the context of a protein's 3D structure; for instance, to assess questions like how mutations that affect antibody escape relate to the physical antibody binding epitope on the protein. However, current approaches for visualizing mutation data in the context of a protein's structure are often cumbersome and require multiple steps and softwares. To streamline the visualization of mutation-associated data in the context of a protein structure, we developed a web-based tool, dms-viz. With dms-viz, users can straightforwardly visualize mutation-based data such as those from DMS experiments in the context of a 3D protein model in an interactive format. See to use dms-viz.

RevDate: 2023-11-29

Freie B, Carroll PA, Varnum-Finney BJ, et al (2023)

A Germline Point Mutation in the MYC-FBW7 Phosphodegron Initiates Hematopoietic Malignancies.

bioRxiv : the preprint server for biology.

Oncogenic activation of MYC in cancers predominantly involves increased transcription rather than coding region mutations. However, MYC-dependent lymphomas frequently contain point mutations in the MYC phospho-degron, including at threonine-58 (T58), where phosphorylation permits binding by the FBW7 ubiquitin ligase triggering MYC degradation. To understand how T58 phosphorylation functions in normal cell physiology, we introduced an alanine mutation at T58 (T58A) into the endogenous c-Myc locus in the mouse germline. While MYC-T58A mice develop normally, lymphomas and myeloid leukemias emerge in ~60% of adult homozygous T58A mice. We find that primitive hematopoietic progenitor cells from MYC-T58A mice exhibit aberrant self-renewal normally associated with hematopoietic stem cells (HSCs) and upregulate a subset of Myc target genes important in maintaining stem/progenitor cell balance. Genomic occupancy by MYC-T58A was increased at all promoters, compared to WT MYC, while genes differentially expressed in a T58A-dependent manner were significantly more proximal to MYC-bound enhancers. MYC-T58A lymphocyte progenitors exhibited metabolic alterations and decreased activation of inflammatory and apoptotic pathways. Our data demonstrate that a single point mutation in Myc is sufficient to produce a profound gain of function in multipotential hematopoietic progenitors associated with self-renewal and initiation of lymphomas and leukemias.

RevDate: 2023-11-29

Jiang D, Rosenlind K, Baxter S, et al (2023)

Evaluating the prevalence of inborn errors of immunity in adults with chronic immune thrombocytopenia or Evans syndrome.

Blood advances, 7(23):7202-7208.

Inborn errors of immunity (IEIs) are monogenic disorders that predispose patients to immune dysregulation, autoimmunity, and infection. Autoimmune cytopenias, such as immune thrombocytopenia (ITP) and Evans syndrome (a combination of ITP and autoimmune hemolytic anemia), are increasingly recognized phenotypes of IEI. Although recent findings suggest that IEIs may commonly underlie pediatric ITP and Evans syndrome, its prevalence in adult patients with these disorders remains undefined. This study sought to estimate the prevalence of underlying IEIs among adults with persistent or chronic ITP or Evans syndrome using a next-generation sequencing panel encompassing >370 genes implicated in IEIs. Forty-four subjects were enrolled from an outpatient adult hematology clinic at a tertiary referral center in the United States, with a median age of 49 years (range, 20-83). Fourteen subjects (31.8%) had secondary ITP, including 8 (18.2%) with Evans syndrome. No cases of IEI were identified despite a high representation of subjects with a personal history of autoimmunity (45.5%) and early onset of disease (median age at diagnosis of 40 years [range, 2-77]), including 20.5% who were initially diagnosed as children. Eight subjects (18.2%) were found to be carriers of pathogenic IEI variants, which, in their heterozygous state, are not disease-causing. One case of TUBB1-related congenital thrombocytopenia was identified. Although systematic screening for IEI has been proposed for pediatric patients with Evans syndrome, findings from this real-world study suggest that inclusion of genetic testing for IEI in the routine work-up of adults with ITP and Evans syndrome has a low diagnostic yield.

RevDate: 2023-11-28

Wang K, Du R, Myall NJ, et al (2023)

BRIEF REPORT: Real-world efficacy and safety of amivantamab for EGFR-mutant non-small cell lung cancer (NSCLC).

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer pii:S1556-0864(23)02376-6 [Epub ahead of print].

BACKGROUND: Amivantamab-vmjw (amivantamab) is a bispecific EGFR/MET antibody approved for patients with advanced non-small cell lung cancer (NSCLC) with EGFR Exon 20 insertion mutations, after prior therapy. However, the benefits and safety of amivantamab in other EGFR-mutation lung cancer, with or without osimertinib, and with concurrent radiation therapy, are less known.

METHODS: We queried the MD Anderson Lung Cancer GEMINI, Fred Hutchinson Cancer Research Center, University of California Davis Comprehensive Cancer Center and Stanford Cancer Center's database for patients with EGFR-mutant NSCLC treated with amivantamab, not on a clinical trial. The data analyzed included initial response, duration of treatment, and concomitant radiation safety in overall population and prespecified subgroups.

RESULTS: Sixty-one patients received amivantamab. Median age was 65 (31 - 81); 72.1% were female and 77% were patients with never smoking history. Median number of prior lines of therapies were four. Based on tumor's EGFR mutation, 39 patients were in the classical mutation cohort; 15 patients in the Exon20 cohort; and 7 patients in the atypical cohort. Thirty-seven patients (58.7%) received amivantamab concomitantly with osimertinib and 25 patients (39.1%) received concomitant radiation. Fifty-four patients were evaluable for response in the overall population; 19 patients (45.2%) had clinical response and disease control rate (DCR) was 64.3%. In the classical mutation cohort of the 33 evaluable patients, twelve (36.4%) had clinical response and DCR was 48.5%. In the atypical mutation cohort, six of the seven patients (85.7%) had clinical response and DCR was 100%. Of the 13 patient evaluable patients in the Exon 20 cohort, five patients (35.7%) had clinical response and DCR was 64.3%. Adverse events reported with amivantamab use were similar as previously described in product labeling. No additional toxicities were noted when amivantamab was given with radiation and/or osimertinib.

CONCLUSION: Our real-world multi-center analysis demonstrated that amivantamab is a potentially effective treatment option for patients with EGFR mutations outside of Exon 20 insertion mutations. The combination of osimertinib with amivantamab is safe and feasible. Radiation therapy also appears safe when administered sequentially or concurrently with amivantamab.

RevDate: 2023-11-28

Eastment MC, Wanje G, Richardson BA, et al (2023)

Results of a cluster randomized trial testing the Systems Analysis and Improvement Approach to increase cervical cancer screening in family planning clinics in Mombasa County, Kenya.

Implementation science : IS, 18(1):66.

BACKGROUND: Cervical cancer is the leading cause of cancer death in Kenyan women. Integrating cervical cancer screening into family planning (FP) clinics is a promising strategy to improve health for reproductive-aged women. The objective of this cluster randomized trial was to test the efficacy of an implementation strategy, the Systems Analysis and Improvement Approach (SAIA), as a tool to increase cervical cancer screening in FP clinics in Mombasa County, Kenya.

METHODS: Twenty FP clinics in Mombasa County were randomized 1:1 to SAIA versus usual procedures. SAIA has five steps: (1) cascade analysis tool to understand the cascade and identify inefficiencies, (2) sequential process flow mapping to identify bottlenecks, (3) develop and implement workflow modifications (micro-interventions) to address identified bottlenecks, (4) assess the micro-intervention in the cascade analysis tool, and (5) repeat the cycle. Prevalence ratios were calculated using Poisson regression with robust standard errors to compare the proportion of visits where women were screened for cervical cancer in SAIA clinics compared to control clinics.

RESULTS: In the primary intent-to-treat analysis in the last quarter of the trial, 2.5% (37/1507) of visits with eligible FP clients at intervention facilities included cervical cancer screening compared to 3.7% (66/1793) in control clinics (prevalence ratio [PR] 0.67, 95% CI 0.45-1.00). When adjusted for having at least one provider trained to perform cervical cancer screening at baseline, there was no significant difference between screening in intervention clinics compared to control clinics (adjusted PR 1.14, 95% CI 0.74-1.75).

CONCLUSIONS: The primary analysis did not show an effect on cervical cancer screening. However, the COVID-19 pandemic and a healthcare worker strike likely impacted SAIA's implementation with significant disruptions in FP care delivery during the trial. While SAIA's data-informed decision-making and clinic-derived solutions are likely important, future work should directly study the mechanisms through which SAIA operates and the influence of contextual factors on implementation.

TRIAL REGISTRATION:, NCT03514459. Registered on April 19, 2018.

RevDate: 2023-11-27

Rafati M, Brown D, Zhou W, et al (2023)

JAK2V617F Mutation and Associated Chromosomal Alterations in Primary and Secondary Myelofibrosis and Post-HCT Outcomes.

Blood advances pii:498482 [Epub ahead of print].

JAK2V617F is the most common driver mutation in primary or secondary myelofibrosis in which allogeneic hematopoietic cell transplantation (HCT) is the only curative treatment. Knowledge of the prognostic utility of JAK2 alterations in the HCT setting is limited. We identified all patients with MF who received HCT between 2000 and 2016 and had a pre-HCT blood sample (N=973) available at the Center of International Blood and Marrow Transplant Research biorepository. PacBio sequencing and SNP-array genotyping were used to identify JAK2V617F mutation and associated mosaic chromosomal alterations (mCAs), respectively. Cox proportional hazard models were used for HCT outcome analyses. Genomic testing was complete for 924 MF patients (634 primary MF [PMF], 135 post-polycythemia vera [PPV-MF], and 155 post-essential thrombocytopenia [PET-MF]). JAK2V617F affected 562 patients (57.6% of PMF, 97% of PPV-MF, and 42.6% of PET-MF). Almost all patients with mCAs involving the JAK2 region (97.9%) were JAK2V617-positive. In PMF, JAK2V617F mutation status, allele burden, or identified mCAs were not associated with disease progression/relapse, non-relapse mortality (NRM), or overall survival. Almost all PPV-MF were JAK2V617F-positive (97%), with no association between HCT outcomes and mutation allele burden or mCAs. In PET-MF, JAK2V617F high mutation allele burden (≥60%) was associated with excess risk of NRM, restricted to transplants received in the era of JAK inhibitors (2013-2016; HR=7.65, 95% CI=2.10-27.82, p=0.002). Yet, allele burden was not associated with post-HCT disease progression/relapse or survival. Our findings support the concept that HCT can mitigate the known negative effect of JAK2V617F in MF patients, particularly for PMF and PPV-MF.

RevDate: 2023-11-27

Plumlee CR, Barrett HW, Shao DE, et al (2023)

Assessing vaccine-mediated protection in an ultra-low dose Mycobacterium tuberculosis murine model.

PLoS pathogens, 19(11):e1011825 pii:PPATHOGENS-D-23-01154 [Epub ahead of print].

Despite widespread immunization with Bacille-Calmette-Guerin (BCG), the only currently licensed tuberculosis (TB) vaccine, TB remains a leading cause of mortality globally. There are many TB vaccine candidates in the developmental pipeline, but the lack of a robust animal model to assess vaccine efficacy has hindered our ability to prioritize candidates for human clinical trials. Here we use a murine ultra-low dose (ULD) Mycobacterium tuberculosis (Mtb) challenge model to assess protection conferred by BCG vaccination. We show that BCG confers a reduction in lung bacterial burdens that is more durable than that observed after conventional dose challenge, curbs Mtb dissemination to the contralateral lung, and, in a small percentage of mice, prevents detectable infection. These findings are consistent with the ability of human BCG vaccination to mediate protection, particularly against disseminated disease, in specific human populations and clinical settings. Overall, our findings demonstrate that the ultra-low dose Mtb infection model can measure distinct parameters of immune protection that cannot be assessed in conventional dose murine infection models and could provide an improved platform for TB vaccine testing.

RevDate: 2023-11-27

Bricker JB, Santiago-Torres M, Mull KE, et al (2023)

Do medications increase the efficacy of digital interventions for smoking cessation? Secondary results from the iCanQuit randomized trial.

Addiction (Abingdon, England) [Epub ahead of print].

BACKGROUND AND AIMS: iCanQuit is a smartphone application (app) proven efficacious for smoking cessation in a Phase III randomized controlled trial (RCT). This study aimed to measure whether medications approved by the US Food and Drug Administration (FDA) for smoking cessation would further enhance the efficacy of iCanQuit, relative to its parent trial comparator-the National Cancer Institute's (NCI's) QuitGuide app.

DESIGN: Secondary analysis of the entire parent trial sample of a two-group (iCanQuit and QuitGuide), stratified, doubled-blind RCT.

SETTING: United States.

PARTICIPANTS: Participants who reported using an FDA-approved cessation medication on their own (n = 619) and those who reported no use of cessation medications (n = 1469).

INTERVENTIONS: Participants were randomized to receive iCanQuit app or NCI's QuitGuide app.

MEASUREMENTS: Use of FDA-approved medications was measured at 3 months post-randomization. Smoking cessation outcomes were measured at 3, 6 and 12 months. The primary outcome was 12-month self-reported 30-day point prevalence abstinence (PPA).

FINDINGS: The data retention rate at the 12-month follow-up was 94.0%. Participants were aged 38.5 years, 71.0% female, 36.6% minority race/ethnicity, 40.6% high school or less education, residing in all 50 US States and smoking 19.2 cigarettes/day. The 29.6% of all participants who used medications were more likely to choose nicotine replacement therapy (NRT; 78.8%) than other cessation medications (i.e. varenicline or bupropion; 18.3 and 10.5%, respectively) and use did not differ by app treatment assignment (all P > 0.05). There was a significant (P = 0.049) interaction between medication use and app treatment assignment on PPA. Specifically, 12-month quit rates were 34% for iCanQuit versus 20% for QuitGuide [odds ratio (OR) = 2.36, 95% confidence interval (CI) = 1.59, 3.49] among participants reporting any medication use, whereas among participants reporting no medication use, quit rates were 28% for iCanQuit versus 22% for QuitGuide (OR = 1.41, 95% CI = 1.09, 1.82). Results were stronger for those using only NRT: 40% quit rates for iCanQuit versus 18% quit rates for QuitGuide (OR = 3.57, 95% CI = 2.20, 5.79).

CONCLUSIONS: The iCanQuit smartphone app for smoking cessation was more efficacious than the QuitGuide smartphone app, regardless of whether participants used medications to aid cessation. Smoking cessation medications, especially nicotine replacement therapy, might enhance the efficacy of the iCanQuit app.

RevDate: 2023-11-25

Elgart M, Zhang Y, Zhang Y, et al (2023)

Anaerobic pathogens associated with OSA may contribute to pathophysiology via amino-acid depletion.

EBioMedicine, 98:104891 pii:S2352-3964(23)00457-7 [Epub ahead of print].

BACKGROUND: The human microbiome is linked to multiple metabolic disorders such as obesity and diabetes. Obstructive sleep apnoea (OSA) is a common sleep disorder with several metabolic risk factors. We investigated the associations between the gut microbiome composition and function, and measures of OSA severity in participants from a prospective community-based cohort study: the Hispanic Community Health Study/Study of Latinos (HCHS/SOL).

METHODS: Bacterial-Wide Association Analysis (BWAS) of gut microbiome measured via metagenomics with OSA measures was performed adjusting for clinical, lifestyle and co-morbidities. This was followed by functional analysis of the OSA-enriched bacteria. We utilized additional metabolomic and transcriptomic associations to suggest possible mechanisms explaining the microbiome effects on OSA.

FINDINGS: Several uncommon anaerobic human pathogens were associated with OSA severity. These belong to the Lachnospira, Actinomyces, Kingella and Eubacterium genera. Functional analysis revealed enrichment in 49 processes including many anaerobic-related ones. Severe OSA was associated with the depletion of the amino acids glycine and glutamine in the blood, yet neither diet nor gene expression revealed any changes in the production or consumption of these amino acids.

INTERPRETATION: We show anaerobic bacterial communities to be a novel component of OSA pathophysiology. These are established in the oxygen-poor environments characteristic of OSA. We hypothesize that these bacteria deplete certain amino acids required for normal human homeostasis and muscle tone, contributing to OSA phenotypes. Future work should test this hypothesis as well as consider diagnostics via anaerobic bacteria detection and possible interventions via antibiotics and amino-acid supplementation.

FUNDING: Described in methods.

RevDate: 2023-11-27

Zhang M, Ceyhan Y, Mei S, et al (2023)

Regulation of EZH2 Expression by INPP4B in Normal Prostate and Primary Prostate Cancer.

Cancers, 15(22):.

The phosphatases INPP4B and PTEN are tumor suppressors that are lost in nearly half of advanced metastatic cancers. The loss of PTEN in prostate epithelium initially leads to an upregulation of several tumor suppressors that slow the progression of prostate cancer in mouse models. We tested whether the loss of INPP4B elicits a similar compensatory response in prostate tissue and whether this response is distinct from the one caused by the loss of PTEN. Knockdown of INPP4B but not PTEN in human prostate cancer cell lines caused a decrease in EZH2 expression. In Inpp4b[-/-] mouse prostate epithelium, EZH2 levels were decreased, as were methylation levels of histone H3. In contrast, Ezh2 levels were increased in the prostates of Pten[-/-] male mice. Contrary to PTEN, there was a positive correlation between INPP4B and EZH2 expression in normal human prostates and early-stage prostate tumors. Analysis of single-cell transcriptomic data demonstrated that a subset of EZH2-positive cells expresses INPP4B or PTEN, but rarely both, consistent with their opposing correlation with EZH2 expression. Unlike PTEN, INPP4B did not affect the levels of SMAD4 protein expression or Pml mRNA expression. Like PTEN, p53 protein expression and phosphorylation of Akt in Inpp4b[-/-] murine prostates were elevated. Taken together, the loss of INPP4B in the prostate leads to overlapping and distinct changes in tumor suppressor and oncogenic downstream signaling.

RevDate: 2023-11-25

Storek J, J Lindsay (2023)

Rituximab for posttransplant lymphoproliferative disorder - therapeutic, preemptive, or prophylactic?.

Bone marrow transplantation [Epub ahead of print].

To minimize mortality due to posttransplant lymphoproliferative disorder (PTLD), the following strategies have been used: (1) Therapy without EBV Monitoring, i.e., administration of rituximab after PTLD diagnosis, usually by biopsy, in the absence of routine Epstein-Barr virus (EBV) DNAemia monitoring, (2) Prompt Therapy, i.e., monitoring EBV DNAemia, searching for PTLD by imaging when the DNAemia has exceeded a pre-specified threshold, and administration of rituximab if the imaging is consistent with PTLD, (3) Preemptive Therapy, i.e., monitoring EBV DNAemia and administration of rituximab when the DNAemia has exceeded a pre-specified threshold, and (4) Prophylaxis, i.e., administration of rituximab to all transplant recipients. The superiority of one of these strategies over the other strategies has not been established. Here we review the pros and cons of each strategy. Preemptive therapy or prophylaxis may currently be preferred for patients who are at a high risk of dying due to PTLD. However, Therapy without EBV Monitoring may be used for both high- and low-risk patients in the future, if effective and relatively non-toxic therapies for rituximab-refractory PTLD (e.g., EBV-specific T cells) have become easily available.

RevDate: 2023-11-24

Prigerson HG, Singer J, C Killikelly (2023)

Prolonged Grief Disorder: Addressing Misconceptions With Evidence.

The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry pii:S1064-7481(23)00469-4 [Epub ahead of print].

There are many misconceptions about Prolonged Grief Disorder (PGD). We show with data that PGD is a diagnosis that applies to a rare few of mourners who are at risk of significant distress and dysfunction. Those mourners who meet criteria for PGD have been shown to benefit from specialized, targeted treatment for it. The case against PGD is empirically unsubstantiated, and the need for scientific examination of effective treatments is warranted.

RevDate: 2023-11-24

Prentice RL (2023)

Diet and Chronic Disease Research in the Women's Health Initiative.

Journal of the Academy of Nutrition and Dietetics pii:S2212-2672(23)01690-8 [Epub ahead of print].

The Women's Health Initiative (WHI) has been a major contributor to diet and chronic disease research among postmenopausal U.S. women, over its 30+ year history (1993- present). The WHI program included full-scale randomized trials of a low-fat dietary pattern high in fruits, vegetables and grains, and of calcium and vitamin D supplementation, each with designated primary and secondary chronic disease outcomes. The history of these trials will be briefly reviewed here, along with principal findings that included evidence for breast cancer-related benefits for each of the two interventions. In recent years WHI investigators have developed an active research program in nutritional biomarker development and in the application of these biomarkers in WHI cohorts, among various other nutritional epidemiology uses of WHI observational study resources. The intake biomarker work, which primarily relies on blood and urine metabolomics profiles, lends support to the low-fat dietary pattern trial results, and supports chronic disease benefits of higher carbohydrate diets more generally, especially through the fiber component of carbohydrate.

RevDate: 2023-11-26

Watson KS, Tossas KY, San Miguel Y, et al (2023)

Mi-CARE: Comparing Three Evidence-Based Interventions to Promote Colorectal Cancer Screening among Ethnic Minorities within Three Different Clinical Contexts.

International journal of environmental research and public health, 20(22):.

Multiple evidence-based interventions (EBIs) have been developed to improve the completion of colorectal cancer (CRC) screening within Federally Qualified Health Centers (FQHCs) and other safety net settings in marginalized communities. Little effort has been made, however, to evaluate their relative effectiveness across different clinical contexts and populations. To this end, we tested the relative effectiveness of three EBIs (mailed birthday cards, lay navigation, and provider-delivered education) among a convenience sample of 1252 patients (aged 50-75 years old, who were due for CRC screening and scheduled for a visit at one of three clinics within a network of Federally Qualified Health Centers (FQHCs) in the United States. To be eligible for the study, patients had to identify as African American (AA) or Latino American (LA). We compared the effects of the three EBIs on CRC screening completion using logistic regression. Overall, 20% of the study population, an increase from a baseline of 13%, completed CRC screening. Clinical demographics appeared to influence the effectiveness of the EBIs. Mailed birthday reminders appeared to be the most effective within the multi-ethnic clinic (p = 0.03), provider-delivered education within the predominantly LA clinic (p = 0.02), and lay navigation within the predominantly AA clinic (p = 0.03). These findings highlight the importance of understanding clinical context when selecting which evidence-based interventions to deploy.

RevDate: 2023-11-24

Vera M, Bukusi E, Achieng P, et al (2023)

"Pharmacies are Everywhere, and You can get it at any Time": Experiences With Pharmacy-Based PrEP Delivery Among Adolescent Girls and Young Women in Kisumu, Kenya.

Journal of the International Association of Providers of AIDS Care, 22:23259582231215882.

INTRODUCTION: Many Kenyan adolescent girls and young women (AGYW) with behaviors associated with HIV acquisition access contraception at retail pharmacies. Offering oral pre-exposure prophylaxis (PrEP) in pharmacies could help reach AGYW with PrEP services.

METHODS: We piloted PrEP delivery at 3 retail pharmacies in Kisumu, Kenya. AGYW purchasing contraception were offered PrEP by nurses with remote prescriber oversight. AGYW who accepted were provided with a free 1-month supply. We conducted in-depth interviews with AGYW 30 days postobtaining PrEP. Transcripts were analyzed to explore experiences of AGYW accessing PrEP at pharmacies.

RESULTS: We conducted 41 interviews. AGYW preferred pharmacies for accessing PrEP and they were willing to pay for PrEP even if available for free at clinics. Reasons for this preference included accessibility, lack of queues, and medication stockouts, privacy, anonymity, autonomy, and high-quality counseling from our study nurses.

CONCLUSIONS: Pharmacies may be an important PrEP access option for this population.

RevDate: 2023-11-23

Chen CC, Tran W, Song K, et al (2023)

Temporal evolution reveals bifurcated lineages in aggressive neuroendocrine small cell prostate cancer trans-differentiation.

Cancer cell pii:S1535-6108(23)00365-3 [Epub ahead of print].

Trans-differentiation from an adenocarcinoma to a small cell neuroendocrine state is associated with therapy resistance in multiple cancer types. To gain insight into the underlying molecular events of the trans-differentiation, we perform a multi-omics time course analysis of a pan-small cell neuroendocrine cancer model (termed PARCB), a forward genetic transformation using human prostate basal cells and identify a shared developmental, arc-like, and entropy-high trajectory among all transformation model replicates. Further mapping with single cell resolution reveals two distinct lineages defined by mutually exclusive expression of ASCL1 or ASCL2. Temporal regulation by groups of transcription factors across developmental stages reveals that cellular reprogramming precedes the induction of neuronal programs. TFAP4 and ASCL1/2 feedback are identified as potential regulators of ASCL1 and ASCL2 expression. Our study provides temporal transcriptional patterns and uncovers pan-tissue parallels between prostate and lung cancers, as well as connections to normal neuroendocrine cell states.

RevDate: 2023-11-24

Koyama M (2023)

A potential tissue-based biomarker in gut GVHD.

Blood, 142(21):1768-1769.

RevDate: 2023-11-24
CmpDate: 2023-11-24

Ferreira M, Redman MW, KL Reckamp (2023)

Moving Toward Rationale Phase 3 Designs for Advanced NSCLC.

Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer, 18(12):1629-1631.

RevDate: 2023-11-21

Malani R, Bhatia A, Warner AB, et al (2023)

Leptomeningeal Carcinomatosis from Solid Tumor Malignancies: Treatment Strategies and Biomarkers.

Seminars in neurology [Epub ahead of print].

Leptomeningeal metastases/diseases (LMDs) are a late-stage complication of solid tumor or hematologic malignancies. LMD is spread of cancer cells to the layers of the leptomeninges (pia and arachnoid maters) and subarachnoid space seen in 3 to 5% of cancer patients. It is a disseminated disease which carries with it significant neurologic morbidity and mortality. Our understanding of disease pathophysiology is currently lacking; however, advances are being made. As our knowledge of disease pathogenesis has improved, treatment strategies have evolved. Mainstays of treatment such as radiotherapy have changed from involved-field radiotherapy strategies to proton craniospinal irradiation which has demonstrated promising results in recent clinical trials. Systemic treatment strategies have also improved from more traditional chemotherapeutics with limited central nervous system (CNS) penetration to more targeted therapies with better CNS tumor response. Many challenges remain from earlier clinical detection of disease through improvement of active treatment options, but we are getting closer to meaningful treatment.

RevDate: 2023-11-23
CmpDate: 2023-11-23

Acenas DV, JA Dudakov (2023)

Feeling at home: Identifying a human thymic epithelial progenitor cell niche.

Developmental cell, 58(22):2411-2412.

T cell development relies on a supportive epithelial microenvironment. Embryonic and postnatal epithelial progenitors have been identified in mice, but not humans. In this issue of Developmental Cell, Raggazzini et al. use scRNAseq, spatial sequencing, and clonogenic assays to identify a putative bipotent TEPC in pediatric human thymic tissue.

RevDate: 2023-11-23

Taber A, Konecny A, Oda SK, et al (2023)

TGF-β broadly modifies rather than specifically suppresses reactivated memory CD8 T cells in a dose-dependent manner.

Proceedings of the National Academy of Sciences of the United States of America, 120(48):e2313228120.

Transforming growth factor β (TGF-β) directly acts on naive, effector, and memory T cells to control cell fate decisions, which was shown using genetic abrogation of TGF-β signaling. TGF-β availability is altered by infections and cancer; however, the dose-dependent effects of TGF-β on memory CD8 T cell (Tmem) reactivation are still poorly defined. We examined how activation and TGF-β signals interact to shape the functional outcome of Tmem reactivation. We found that TGF-β could suppress cytotoxicity in a manner that was inversely proportional to the strength of the activating TCR or proinflammatory signals. In contrast, even high doses of TGF-β had a comparatively modest effect on IFN-γ expression in the context of weak and strong reactivation signals. Since CD8 Tmem may not always receive TGF-β signals concurrently with reactivation, we also explored whether the temporal order of reactivation versus TGF-β signals is of importance. We found that exposure to TGF-β before or after an activation event were both sufficient to reduce cytotoxic effector function. Concurrent ATAC-seq and RNA-seq analysis revealed that TGF-β altered ~10% of the regulatory elements induced by reactivation and also elicited transcriptional changes indicative of broadly modulated functional properties. We confirmed some changes on the protein level and found that TGF-β-induced expression of CCR8 was inversely proportional to the strength of the reactivating TCR signal. Together, our data suggest that TGF-β is not simply suppressing CD8 Tmem but modifies functional and chemotactic properties in context of their reactivation signals and in a dose-dependent manner.

RevDate: 2023-11-20

McEvoy AM, Hippe DS, Lachance K, et al (2023)

Merkel cell carcinoma recurrence risk estimation is improved by integrating factors beyond cancer stage: a multivariable model and web-based calculator.

Journal of the American Academy of Dermatology pii:S0190-9622(23)03220-6 [Epub ahead of print].

BACKGROUND: Merkel cell carcinoma (MCC) recurs in 40% of patients. In addition to stage, factors known to affect recurrence risk include: sex, immunosuppression, unknown primary status, age, site of primary tumor, and time since diagnosis.

PURPOSE: Create a multivariable model and web-based calculator to predict MCC recurrence risk more accurately than stage alone.

METHODS: Data from 618 patients in a prospective cohort were used in a competing risk regression model to estimate recurrence risk using stage and other factors.

RESULTS: In this multivariable model, the most impactful recurrence risk factors were: AJCC stage (p<0.001), immunosuppression (hazard ratio 2.05; p<0.001), male sex (1.59; p=0.003) and unknown primary (0.65; p=0.064). Compared to stage alone, the model improved prognostic accuracy (concordance index for two-year risk, 0.66 vs. 0.70; p<0.001), and modified estimated recurrence risk by up to 4-fold (18% for low-risk stage IIIA vs. 78% for high-risk IIIA over five years).

LIMITATIONS: Lack of an external data set for model validation.

CONCLUSION: / Relevance: As demonstrated by this multivariable model, accurate recurrence risk prediction requires integration of factors beyond stage. An online calculator based on this model (at integrates time since diagnosis and provides new data for optimizing surveillance for MCC patients.

RevDate: 2023-11-23

Leeds BK, Kostello KF, Liu YY, et al (2023)

Mechanical coupling coordinates microtubule growth.

bioRxiv : the preprint server for biology.

During mitosis, kinetochore-attached microtubules form bundles (k-fibers) in which many filaments grow and shorten in near-perfect unison to align and segregate each chromosome. However, individual microtubules grow at intrinsically variable rates, which must be tightly regulated for a k-fiber to behave as a single unit. This exquisite coordination might be achieved biochemically, via selective binding of polymerases and depolymerases, or mechanically, because k-fiber microtubules are coupled through a shared load that influences their growth. Here, we use a novel dual laser trap assay to show that microtubule pairs growing in vitro are coordinated by mechanical coupling. Kinetic analyses show that microtubule growth is interrupted by stochastic, force-dependent pauses and indicate persistent heterogeneity in growth speed during non-pauses. A simple model incorporating both force-dependent pausing and persistent growth speed heterogeneity explains the measured coordination of microtubule pairs without any free fit parameters. Our findings illustrate how microtubule growth may be synchronized during mitosis and provide a basis for modeling k-fiber bundles with three or more microtubules, as found in many eukaryotes.

RevDate: 2023-11-20

Durowoju L, Mathias PC, Bell-Brown A, et al (2023)

Performance of OC-Auto Micro 80 Fecal Immunochemical Test in an Integrated Academic-Community Health System.

Journal of clinical gastroenterology pii:00004836-990000000-00215 [Epub ahead of print].

GOALS: We aimed to determine the performance of the OC-Auto Micro 80 fecal immunochemical test (FIT) in an average-risk population receiving care in an integrated, academic-community health system.

BACKGROUND: The FIT is the most used colorectal cancer (CRC) screening test worldwide. However, many Food and Drug Administration-cleared FIT products have not been evaluated in clinical settings.

STUDY: We performed a retrospective cohort study of patients (50 to 75 y old) in the University of Washington Medicine health care system who were screened for CRC by OC-Auto Micro 80 FIT between March 2016 and September 2021. We used electronic health records to extract patient-level and clinic-level factors, FIT use, colonoscopy, and pathology findings. The primary outcomes were the FIT positivity rate and neoplasms detected at colonoscopy. Secondary outcomes were FIT positivity by sex and safety-net versus non-safety-net clinical settings.

RESULTS: We identified 39,984 FITs completed by 26,384 patients; 2411 (6.0%) had a positive FIT result (>100 ng/mL of hemoglobin in buffer), and 1246 (51.7%) completed a follow-up colonoscopy. The FIT positive rate was 7.0% in men and 5.2% in women (P <0.01). Among those who completed a colonoscopy after an abnormal FIT result, the positive predictive value for CRC, advanced adenoma, and advanced neoplasia was 3.0%, 20.9%, and 23.9%, respectively.

CONCLUSIONS: In a retrospective analysis of a large heterogeneous population, the OC-Auto Micro 80 FIT for CRC screening demonstrated a positivity rate of 6.0% and a positive predictive value for CRC of 3.0%.

RevDate: 2023-11-20

Liu S, Bradley P, W Sun (2023)

Neural network models for sequence-based TCR and HLA association prediction.

PLoS computational biology, 19(11):e1011664 pii:PCOMPBIOL-D-23-00978 [Epub ahead of print].

T cells rely on their T cell receptors (TCRs) to discern foreign antigens presented by human leukocyte antigen (HLA) proteins. The TCRs of an individual contain a record of this individual's past immune activities, such as immune response to infections or vaccines. Mining the TCR data may recover useful information or biomarkers for immune related diseases or conditions. Some TCRs are observed only in the individuals with certain HLA alleles, and thus characterizing TCRs requires a thorough understanding of TCR-HLA associations. The extensive diversity of HLA alleles and the rareness of some HLA alleles present a formidable challenge for this task. Existing methods either treat HLA as a categorical variable or represent an HLA by its alphanumeric name, and have limited ability to generalize to the HLAs that are not seen in the training process. To address this challenge, we propose a neural network-based method named Deep learning Prediction of TCR-HLA association (DePTH) to predict TCR-HLA associations based on their amino acid sequences. We demonstrate that DePTH is capable of making reasonable predictions for TCR-HLA associations, even when neither the HLA nor the TCR have been included in the training dataset. Furthermore, we establish that DePTH can be used to quantify the functional similarities among HLA alleles, and that these HLA similarities are associated with the survival outcomes of cancer patients who received immune checkpoint blockade treatments.

RevDate: 2023-11-20

Carneiro BA, Cavalcante L, Mahalingam D, et al (2023)

Phase 1 study of Elraglusib (9-ING-41), a glycogen synthase kinase-3b inhibitor, as monotherapy or combined with chemotherapy in patients with advanced malignancies.

Clinical cancer research : an official journal of the American Association for Cancer Research pii:730199 [Epub ahead of print].

PURPOSE: The safety, pharmacokinetics and efficacy of elraglusib, a GSK-3b small molecule inhibitor, as monotherapy or combined with chemotherapy, in patients with relapsed or refractory solid tumors or hematologic malignancies was studied.

PATIENTS AND METHODS: Elraglusib (intravenously twice weekly in three-week cycles) monotherapy dose-escalation was followed by dose-escalation with eight chemotherapy regimens (gemcitabine, doxorubicin, lomustine, carboplatin, irinotecan, gemcitabine/nab-paclitaxel, paclitaxel/carboplatin, and pemetrexed/carboplatin) in patients previously exposed to the same chemotherapy.

RESULTS: Patients received monotherapy (n=67) or combination therapy (n=171) elraglusib doses 1-15 mg/kg twice weekly. The initial recommended phase 2 dose (RP2D) of elraglusib was 15 mg/kg twice weekly and was defined, without DLT observation, due to fluid volumes necessary for drug administration. The RP2D was subsequently reduced to 9.3 mg/kg once weekly to reduce elraglusib-associated central/peripheral vascular access catheter blockages. Other common elraglusib-related adverse events (AE) included transient visual changes and fatigue. Grade 3 treatment-emergent AE occurred in 55.2% and 71.3% of patients on monotherapy and combination therapy, respectively. Part 1 monotherapy (n=62) and part 2 combination (n=138) patients were evaluable for response. In part 1, a patient with melanoma had a complete response, and a patient with acute T-cell leukemia/lymphoma had a partial response (PR). In part 2, 7 PRs were observed, and the median progression-free survival and overall survival were 2.1 (95% CI, 2-2.6) and 6.9 (95% CI, 5.7-8.4) months, respectively.

CONCLUSIONS: Elraglusib had a favorable toxicity profile as monotherapy and combined with chemotherapy and was associated with clinical benefit supporting further clinical evaluation in combination with chemotherapy.

RevDate: 2023-11-21

Williamson BD, Gilbert PB, Simon NR, et al (2023)

A general framework for inference on algorithm-agnostic variable importance.

Journal of the American Statistical Association, 118(543):1645-1658.

In many applications, it is of interest to assess the relative contribution of features (or subsets of features) toward the goal of predicting a response - in other words, to gauge the variable importance of features. Most recent work on variable importance assessment has focused on describing the importance of features within the confines of a given prediction algorithm. However, such assessment does not necessarily characterize the prediction potential of features, and may provide a misleading reflection of the intrinsic value of these features. To address this limitation, we propose a general framework for nonparametric inference on interpretable algorithm-agnostic variable importance. We define variable importance as a population-level contrast between the oracle predictiveness of all available features versus all features except those under consideration. We propose a nonparametric efficient estimation procedure that allows the construction of valid confidence intervals, even when machine learning techniques are used. We also outline a valid strategy for testing the null importance hypothesis. Through simulations, we show that our proposal has good operating characteristics, and we illustrate its use with data from a study of an antibody against HIV-1 infection.

RevDate: 2023-11-19

Zhao JL, Antonarakis ES, Cheng HH, et al (2023)

Phase 1b study of enzalutamide plus CC-115, a dual mTORC1/2 and DNA-PK inhibitor, in men with metastatic castration-resistant prostate cancer (mCRPC).

British journal of cancer [Epub ahead of print].

BACKGROUND: CC-115, a dual mTORC1/2 and DNA-PK inhibitor, has promising antitumour activity when combined with androgen receptor (AR) inhibition in pre-clinical models.

METHODS: Phase 1b multicentre trial evaluating enzalutamide with escalating doses of CC-115 in AR inhibitor-naive mCRPC patients (n = 41). Primary endpoints were safety and RP2D. Secondary endpoints included PSA response, time-to-PSA progression, and radiographic progression.

RESULTS: Common adverse effects included rash (31.7% Grades 1-2 (Gr); 31.7% Gr 3), pruritis (43.9% Gr 1-2), diarrhoea (37% Gr 1-2), and hypertension (17% Gr 1-2; 9.8% Gr 3). CC-115 RP2D was 5 mg twice a day. In 40 evaluable patients, 80% achieved ≥50% reduction in PSA (PSA50), and 58% achieved ≥90% reduction in PSA (PSA90) by 12 weeks. Median time-to-PSA progression was 14.7 months and median rPFS was 22.1 months. Stratification by PI3K alterations demonstrated a non-statistically significant trend towards improved PSA50 response (PSA50 of 94% vs. 67%, p = 0.08). Exploratory pre-clinical analysis suggested CC-115 inhibited mTOR pathway strongly, but may be insufficient to inhibit DNA-PK at RP2D.

CONCLUSIONS: The combination of enzalutamide and CC-115 was well tolerated. A non-statistically significant trend towards improved PSA response was observed in patients harbouring PI3K pathway alterations, suggesting potential predictive biomarkers of response to a PI3K/AKT/mTOR pathway inhibitor.


RevDate: 2023-11-20
CmpDate: 2023-11-20

Carson D, S Psutka (2023)

Surgically Feasible? Yes. But Is It the Right Option? It Depends.

International journal of radiation oncology, biology, physics, 117(5):1049.

RevDate: 2023-11-18

Tachiki LML, Hippe DS, Silva KW, et al (2023)

Correction to: Extended duration of treatment using reduced‑frequency dosing of anti‑PD‑1 therapy in patients with advanced melanoma and Merkel cell carcinoma.

RevDate: 2023-11-17

Jiang W, Ronen K, Osborn L, et al (2023)

HIV viral load patterns and risk factors among women in prevention of mother-to-child transmission (PMTCT) programs to inform differentiated service delivery (DSD).

Journal of acquired immune deficiency syndromes (1999) pii:00126334-990000000-00329 [Epub ahead of print].

BACKGROUND: Differentiated service delivery (DSD) approaches decrease frequency of clinic visits for individuals who are stable on antiretroviral therapy (ART). It is unclear how to optimize DSD models for postpartum women living with HIV (PWLH). We evaluated longitudinal HIV viral load (VL) and cofactors, and modelled DSD eligibility with virologic failure (VF) among PWLH in PMTCT programs.

METHODS: This analysis used programmatic data from participants in the Mobile WAChX trial (NCT02400671). Women were assessed for DSD-eligibility using the WHO criteria among general people living with HIV (receiving ART for ≥6 months and having at least one suppressed VL [<1,000 copies/mL] within the past 6 months). Longitudinal VL patterns were summarized using group-based trajectory modelling (GBTM). VF was defined as having a subsequent VL ≥1,000 copies/mL after being assessed as DSD-eligible. Predictors of VF were determined using log-binomial models among DSD-eligible PWLH.

RESULTS: Among 761 women with 3,359 VL results (median 5 VL per woman), a three-trajectory model optimally summarized longitudinal VL, with most (80.8%) women having sustained low probability of unsuppressed VL. Among women who met DSD criteria at 6 months postpartum, most (83.8%) maintained viral suppression until 24 months. Residence in Western Kenya, depression, reported interpersonal abuse, unintended pregnancy, nevirapine-based ART, low-level viremia (VL 200-1,000 copies/mL), and drug resistance were associated with VF among DSD-eligible PWLH.

CONCLUSIONS: Most postpartum women maintained viral suppression from early postpartum to 24 months and may be suitable for DSD referral. Women with depression, drug resistance and detectable VL need enhanced services.

RevDate: 2023-11-17

Lambo S, Trinh DL, Ries RE, et al (2023)

A longitudinal single-cell atlas of treatment response in pediatric AML.

Cancer cell pii:S1535-6108(23)00364-1 [Epub ahead of print].

Pediatric acute myeloid leukemia (pAML) is characterized by heterogeneous cellular composition, driver alterations and prognosis. Characterization of this heterogeneity and how it affects treatment response remains understudied in pediatric patients. We used single-cell RNA sequencing and single-cell ATAC sequencing to profile 28 patients representing different pAML subtypes at diagnosis, remission and relapse. At diagnosis, cellular composition differed between genetic subgroups. Upon relapse, cellular hierarchies transitioned toward a more primitive state regardless of subtype. Primitive cells in the relapsed tumor were distinct compared to cells at diagnosis, with under-representation of myeloid transcriptional programs and over-representation of other lineage programs. In some patients, this was accompanied by the appearance of a B-lymphoid-like hierarchy. Our data thus reveal the emergence of apparent subtype-specific plasticity upon treatment and inform on potentially targetable processes.

RevDate: 2023-11-20

McGraw KE, Schilling K, Glabonjat RA, et al (2023)

Urinary Metal Levels and Coronary Artery Calcification: Longitudinal Evidence in the Multi-Ethnic Study of Atherosclerosis (MESA).

medRxiv : the preprint server for health sciences.

OBJECTIVE: Growing evidence indicates that exposure to metals are risk factors for cardiovascular disease (CVD). We hypothesized that higher urinary levels of metals with prior evidence of an association with CVD, including non-essential (cadmium , tungsten, and uranium) and essential (cobalt, copper, and zinc) metals are associated with baseline and rate of change of coronary artery calcium (CAC) progression, a subclinical marker of atherosclerotic CVD.

METHODS: We analyzed data from 6,418 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) with spot urinary metal levels at baseline (2000-2002) and 1-4 repeated measures of spatially weighted coronary calcium score (SWCS) over a ten-year period. SWCS is a unitless measure of CAC highly correlated to the Agatston score but with numerical values assigned to individuals with Agatston score=0. We used linear mixed effect models to assess the association of baseline urinary metal levels with baseline SWCS, annual change in SWCS, and SWCS over ten years of follow-up. Urinary metals (adjusted to μg/g creatinine) and SWCS were log transformed. Models were progressively adjusted for baseline sociodemographic factors, estimated glomerular filtration rate, lifestyle factors, and clinical factors.

RESULTS: At baseline, the median and interquartile range (25[th], 75[th]) of SWCS was 6.3 (0.7, 58.2). For urinary cadmium, the fully adjusted geometric mean ratio (GMR) (95%Cl) of SWCS comparing the highest to the lowest quartile was 1.51 (1.32, 1.74) at baseline and 1.75 (1.47, 2.07) at ten years of follow-up. For urinary tungsten, uranium, and cobalt the corresponding GMRs at ten years of follow-up were 1.45 (1.23, 1.71), 1.39 (1.17, 1.64), and 1.47 (1.25, 1.74), respectively. For copper and zinc, the association was attenuated with adjustment for clinical risk factors; GMRs at ten years of follow-up before and after adjustment for clinical risk factors were 1.55 (1.30, 1.84) and 1.33 (1.12, 1.58), respectively, for copper and 1.85 (1.56, 2.19) and 1.57 (1.33, 1.85) for zinc.

CONCLUSION: Higher levels of cadmium, tungsten, uranium, cobalt, copper, and zinc, as measured in urine, were associated with subclinical CVD at baseline and at follow-up. These findings support the hypothesis that metals are pro-atherogenic factors.

RevDate: 2023-11-20

Li X, Chen H, Selvaraj MS, et al (2023)

A statistical framework for powerful multi-trait rare variant analysis in large-scale whole-genome sequencing studies.

bioRxiv : the preprint server for biology.

Large-scale whole-genome sequencing (WGS) studies have improved our understanding of the contributions of coding and noncoding rare variants to complex human traits. Leveraging association effect sizes across multiple traits in WGS rare variant association analysis can improve statistical power over single-trait analysis, and also detect pleiotropic genes and regions. Existing multi-trait methods have limited ability to perform rare variant analysis of large-scale WGS data. We propose MultiSTAAR, a statistical framework and computationally-scalable analytical pipeline for functionally-informed multi-trait rare variant analysis in large-scale WGS studies. MultiSTAAR accounts for relatedness, population structure and correlation among phenotypes by jointly analyzing multiple traits, and further empowers rare variant association analysis by incorporating multiple functional annotations. We applied MultiSTAAR to jointly analyze three lipid traits (low-density lipoprotein cholesterol, high-density lipoprotein cholesterol and triglycerides) in 61,861 multi-ethnic samples from the Trans-Omics for Precision Medicine (TOPMed) Program. We discovered new associations with lipid traits missed by single-trait analysis, including rare variants within an enhancer of NIPSNAP3A and an intergenic region on chromosome 1.

RevDate: 2023-11-17

Stromberg KA, Spain T, Tomlin SA, et al (2023)

Evolutionary diversification reveals distinct somatic versus germline cytoskeletal functions of the Arp2 branched actin nucleator protein.

Current biology : CB pii:S0960-9822(23)01456-2 [Epub ahead of print].

Branched actin networks are critical in many cellular processes, including cell motility and division. Arp2, a protein within the seven-membered Arp2/3 complex, is responsible for generating branched actin. Given its essential roles, Arp2 evolves under stringent sequence conservation throughout eukaryotic evolution. We unexpectedly discovered recurrent evolutionary diversification of Arp2 in Drosophila, yielding independently arising paralogs Arp2D in obscura species and Arp2D2 in montium species. Both paralogs are unusually testis-enriched in expression relative to Arp2. We investigated whether their sequence divergence from canonical Arp2 led to functional specialization by replacing Arp2 in D. melanogaster with either Arp2D or Arp2D2. Despite their divergence, we surprisingly found that both complement Arp2's essential function in somatic tissue, suggesting they have preserved the ability to polymerize branched actin even in a non-native species. However, we found that Arp2D- and Arp2D2-expressing males display defects throughout sperm development, with Arp2D resulting in more pronounced deficiencies and subfertility, suggesting the Arp2 paralogs are cross-species incompatible in the testis. We focused on Arp2D and pinpointed two highly diverged structural regions-the D-loop and C terminus-and found that they contribute to germline defects in D. melanogaster sperm development. However, while the Arp2D C terminus is suboptimal in the D. melanogaster testis, it is essential for Arp2D somatic function. Testis cytology of the paralogs' native species revealed striking differences in germline actin structures, indicating unique cytoskeletal requirements. Our findings suggest canonical Arp2 function differs between somatic versus germline contexts, and Arp2 paralogs may have recurrently evolved for species-specialized actin branching in the testis.

RevDate: 2023-11-17

Grivas P, Grande E, Davis ID, et al (2023)

Avelumab first-line maintenance treatment for advanced urothelial carcinoma: review of evidence to guide clinical practice.

ESMO open, 8(6):102050 pii:S2059-7029(23)01291-7 [Epub ahead of print].

The JAVELIN Bladder 100 phase III trial led to the incorporation of avelumab first-line (1L) maintenance treatment into international guidelines as a standard of care for patients with advanced urothelial carcinoma (UC) without progression after 1L platinum-based chemotherapy. JAVELIN Bladder 100 showed that avelumab 1L maintenance significantly prolonged overall survival (OS) and progression-free survival in this population compared with a 'watch-and-wait' approach. The aim of this manuscript is to review clinical studies of avelumab 1L maintenance in patients with advanced UC, including long-term efficacy and safety data from JAVELIN Bladder 100, subgroup analyses in clinically relevant subpopulations, and 'real-world' data obtained outside of clinical trials, providing a comprehensive resource to support patient management. Extended follow-up from JAVELIN Bladder 100 has shown that avelumab provides a long-term efficacy benefit, with a median OS of 23.8 months measured from start of maintenance treatment, and 29.7 months measured from start of 1L chemotherapy. Longer OS was observed across subgroups, including patients who received 1L cisplatin + gemcitabine, patients who received four or six cycles of 1L chemotherapy, and patients with complete response, partial response, or stable disease as best response to 1L induction chemotherapy. No new safety signals were seen in patients who received ≥1 year of avelumab treatment, and toxicity was similar in those who had received cisplatin or carboplatin with gemcitabine. Other clinical datasets, including noninterventional studies conducted in Europe, USA, and Asia, have confirmed the efficacy of avelumab 1L maintenance. Potential subsequent treatment options after avelumab maintenance include antibody-drug conjugates (enfortumab vedotin or sacituzumab govitecan), erdafitinib in biomarker-selected patients, platinum rechallenge in suitable patients, nonplatinum chemotherapy, and clinical trial participation; however, evidence to determine optimal treatment sequences is needed. Ongoing trials of avelumab-based combination regimens as maintenance treatment have the potential to evolve the treatment landscape for patients with advanced UC.

RevDate: 2023-11-17

Kampouri E, Ibrahimi SS, Xie H, et al (2023)

CMV Reactivation and CMV-Specific Cell-Mediated Immunity after Chimeric Antigen Receptor T-Cell Therapy.

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America pii:7425426 [Epub ahead of print].

BACKGROUND: The epidemiology of cytomegalovirus (CMV) after chimeric antigen receptor-modified T-cell immunotherapy (CARTx) is poorly understood due to lack of routine surveillance.

METHODS: We prospectively enrolled 72 adult CMV-seropositive CD19-, CD20-, or BCMA-targeted CARTx-recipients and tested plasma for CMV pre- and weekly up to twelve weeks post-CARTx. We assessed CMV-cell mediated immunity (CMI) pre-, and at week two and four post-CARTx using an interferon-γ release assay quantifying T-cell responses to IE-1 and pp65. We tested pre-CARTx samples to calculate a risk score for cytopenias and infection (CAR-HEMATOTOX). We used Cox regression to evaluate CMV risk factors and evaluated the predictive performance of CMV-CMI for CMV reactivation in receiver operator characteristic curves.

RESULTS: CMV was detected in one patient (1.4%) pre- and 18 patients (25%) post-CARTx for a cumulative incidence of 27% (95% CI, 16.8-38.2). Median CMV viral load was 127 IU/mL (interquartile range (IQR), 61-276), with no end-organ disease observed; five patients received preemptive therapy based on clinical results. CMV-CMI values reached a nadir two weeks post-infusion and recovered to baseline levels by week four. In adjusted models, BCMA-CARTx (versus CD19/CD20) and corticosteroid use for >3 days were significantly associated with CMV reactivation, and possible associations were detected for lower week 2 CMV-CMI and more prior antitumor regimens. The cumulative incidence of CMV reactivation almost doubled when stratified by BCMA CARTx-target and use of corticosteroids for >3 days (46% and 49%, respectively).

CONCLUSIONS: CMV testing could be considered between 2-6 weeks in high-risk CARTx-recipients.

RevDate: 2023-11-17

Chandar AK, Keerthy K, Gupta R, et al (2023)

Patients with Esophageal Adenocarcinoma with prior GERD symptoms are similar to those without GERD: A Cross-sectional Study.

The American journal of gastroenterology pii:00000434-990000000-00945 [Epub ahead of print].

OBJECTIVES: A substantial proportion of esophageal adenocarcinoma (EAC) patients do not report GERD symptoms. This study aimed to compare the risk factor profiles and cancer stage at presentation of EAC patients with and without prior GERD.

METHODS: In this retrospective, cross-sectional study, EAC patients were divided into two cohorts: 1. EAC with prior GERD: patients who reported typical GERD symptoms (heartburn or regurgitation) ≥1 year before cancer diagnosis, and 2. EAC without prior GERD: patients who did not report prior GERD symptoms or reported symptoms within 1 year of their cancer diagnosis. Baseline demographics, risk factors, and cancer stage at presentation were compared between the two cohorts. Additionally, the distribution of patients based on numbers of BE/EAC-associated risk factors (1, 2, 3, 4, 5 or more) was examined in the symptomatic and asymptomatic cohorts.

RESULTS: Over 13 years, 388 EAC patients with prior GERD and 245 EAC patients without prior GERD were recruited. Both groups had similar baseline demographics and risk factors, but EAC patients with prior GERD were more likely to have a history of BE. Asymptomatic patients had more advanced disease. Patients with 3 or more BE/EAC related risk factors formed the largest proportion of patients in both the symptomatic and asymptomatic cohorts.

CONCLUSIONS: Esophageal adenocarcinoma patients with and without prior GERD symptoms are phenotypically similar, suggesting that BE screening efforts to prevent or detect early EAC should not be restricted to just those with GERD.

RevDate: 2023-11-18

Liao SY, Rudoy D, Frank SB, et al (2023)

SND1 binds to ERG and promotes tumor growth in genetic mouse models of prostate cancer.

Nature communications, 14(1):7435.

SND1 and MTDH are known to promote cancer and therapy resistance, but their mechanisms and interactions with other oncogenes remain unclear. Here, we show that oncoprotein ERG interacts with SND1/MTDH complex through SND1's Tudor domain. ERG, an ETS-domain transcription factor, is overexpressed in many prostate cancers. Knocking down SND1 in human prostate epithelial cells, especially those overexpressing ERG, negatively impacts cell proliferation. Transcriptional analysis shows substantial overlap in genes regulated by ERG and SND1. Mechanistically, we show that ERG promotes nuclear localization of SND1/MTDH. Forced nuclear localization of SND1 prominently increases its growth promoting function irrespective of ERG expression. In mice, prostate-specific Snd1 deletion reduces cancer growth and tumor burden in a prostate cancer model (PB-Cre/Pten[flox/flox]/ERG mice), Moreover, we find a significant overlap between prostate transcriptional signatures of ERG and SND1. These findings highlight SND1's crucial role in prostate tumorigenesis, suggesting SND1 as a potential therapeutic target in prostate cancer.

RevDate: 2023-11-17

Park J, Lim F, Prest M, et al (2023)

Quantifying the potential benefits of early detection for pancreatic cancer through a counterfactual simulation modeling analysis.

Scientific reports, 13(1):20028.

The benefits of cancer early detection depend on various factors, including cancer type, screening method performance, stage at diagnosis, and subsequent treatment. Although numerous studies have evaluated the effectiveness of screening interventions for identifying cancer at earlier stages, there is no quantitative analysis that studies the optimal early detection time interval that results in the greatest mortality benefit; such data could serve as a target and benchmark for cancer early detection strategies. In this study, we focus on pancreatic ductal adenocarcinoma (PDAC), a cancer known for its lack of early symptoms. Consequently, it is most often detected at late stages when the 5-year survival rate is only 3%. We developed a PDAC population model that simulates an individual patient's age and stage at diagnosis, while replicating overall US cancer incidence and mortality rates. The model includes "cancer sojourn time," serving as a proxy for the speed of cancer progression, with shorter times indicating rapid progression and longer times indicating slower progression. In our PDAC model, our hypothesis was that earlier cancer detection, potentially through a hypothetical screening intervention in the counterfactual analysis, would yield reduced mortality as compared to a no-screening group. We found that the benefits of early detection, such as increased life-years gained, are greater when the sojourn time is shorter, reaching their maximum when identification is made 4-6 years prior to clinical diagnosis (e.g., when a symptomatic diagnosis is made). However, when early detection occurs even earlier, for example 6-10 years prior to clinical diagnosis, the benefits significantly diminish for shorter sojourn time cancers, and level off for longer sojourn time cancers. Our study clarifies the potential benefits of PDAC early detection that explicitly incorporates individual patient heterogeneity in cancer progression and identifies quantitative benchmarks for future interventions.

RevDate: 2023-11-18

Laha N, Moodie Z, Huang Y, et al (2022)

Improved inference for vaccine-induced immune responses via shape-constrained methods.

Electronic journal of statistics, 16(2):5852-5933.

We study the performance of shape-constrained methods for evaluating immune response profiles from early-phase vaccine trials. The motivating problem for this work involves quantifying and comparing the IgG binding immune responses to the first and second variable loops (V1V2 region) arising in HVTN 097 and HVTN 100 HIV vaccine trials. We consider unimodal and log-concave shape-constrained methods to compare the immune profiles of the two vaccines, which is reasonable because the data support that the underlying densities of the immune responses could have these shapes. To this end, we develop novel shape-constrained tests of stochastic dominance and shape-constrained plug-in estimators of the squared Hellinger distance between two densities. Our techniques are either tuning parameter free, or rely on only one tuning parameter, but their performance is either better (the tests of stochastic dominance) or comparable with the nonparametric methods (the estimators of the squared Hellinger distance). The minimal dependence on tuning parameters is especially desirable in clinical contexts where analyses must be prespecified and reproducible. Our methods are supported by theoretical results and simulation studies.

RevDate: 2023-11-17

Walter RB (2023)

Perspective on measurable residual disease testing in acute myeloid leukemia.

Leukemia [Epub ahead of print].

RevDate: 2023-11-16

Im C, Lu Z, Mostoufi-Moab S, et al (2023)

Development and validation of age-specific risk prediction models for primary ovarian insufficiency in long-term survivors of childhood cancer: a report from the Childhood Cancer Survivor Study and St Jude Lifetime Cohort.

The Lancet. Oncology pii:S1470-2045(23)00510-7 [Epub ahead of print].

BACKGROUND: Female survivors of childhood cancer are at risk for primary ovarian insufficiency (POI), defined as the cessation of gonadal function before the age of 40 years. We aimed to develop and validate models to predict age-specific POI risk among long-term survivors of childhood cancer.

METHODS: To develop models to predict age-specific POI risk for the ages of 21-40 years, we used data from the Childhood Cancer Survivor Study (CCSS). Female survivors aged 18 years or older at their latest follow-up, with self-reported menstrual history information and free of subsequent malignant neoplasms within 5 years of diagnosis, were included. We evaluated models that used algorithms based on statistical or machine learning to consider all predictors, including cancer treatments. Cross-validated prediction performance metrics (eg, area under the receiver operating characteristic curve [AUROC]) were compared to select the best-performing models. For external validation of the models, we used data from 5-year survivors in the St Jude Lifetime Cohort (SJLIFE) with ovarian status clinically ascertained using hormone measurements (menopause defined by follicle stimulating hormone >30 mIU/mL and oestradiol <17 pg/mL) and medical chart or questionnaire review. We also evaluated an SJLIFE-based polygenic risk score for POI among 1985 CCSS survivors with genotype data available.

FINDINGS: 7891 female CCSS survivors (922 with POI) were included in the development of the POI risk prediction model, and 1349 female SJLIFE survivors (101 with POI) were included in the validation study. Median follow-up from cancer diagnosis was 23·7 years (IQR 18·3-30·0) in CCSS and 15·1 years (10·4-22·9) in SJLIFE. Between the ages of 21 and 40 years, POI prevalence increased from 7·9% (95% CI 7·3-8·5) to 18·6% (17·3-20·0) in CCSS and 7·3% (5·8-8·9) to 14·9% (11·6-19·1) in SJLIFE. Age-specific logistic regression models considering ovarian radiation dosimetry or prescribed pelvic and abdominal radiation dose, along with individual chemotherapy predictors, performed well in CCSS. In the SJLIFE validation, the prescribed radiation dose model performed well (AUROC 0·88-0·95), as did a simpler model that considered any exposures to pelvic or abdominal radiotherapy or alkylators (0·82-0·90). Addition of the polygenic risk predictor significantly improved the average positive predictive value (from 0·76 [95% CI 0·63-0·89] to 0·87 [0·80-0·94]; p=0·029) among CCSS survivors treated with ovarian radiation and chemotherapy.

INTERPRETATION: POI risk prediction models using treatment information showed robust prediction performance in adult survivors of childhood cancer.

FUNDING: Canadian Institutes of Health Research, US National Cancer Institute.

RevDate: 2023-11-16

Stecklein SR, Barlow W, Pusztai L, et al (2023)

Dual Prognostic Classification of Triple-Negative Breast Cancer by DNA Damage Immune Response and Homologous Recombination Deficiency.

JCO precision oncology, 7:e2300197.

PURPOSE: Triple-negative breast cancer (TNBC) is a heterogeneous disease. We previously showed that homologous recombination deficiency (HRD) and the DNA damage immune response (DDIR) signature are prognostic in TNBC. We hypothesized that these biomarkers reflect related but not completely interdependent biological processes, that their combined use would be prognostic, and that simultaneous assessment of the immunologic microenvironment and susceptibility to DNA damaging therapies might be able to identify subgroups with distinct therapeutic vulnerabilities.

METHODS: We analyzed the dual DDIR/HRD classification in 341 patients with TNBC treated with adjuvant anthracycline-based chemotherapy on the SWOG S9313 trial and corroborated our findings in The Cancer Genome Atlas breast cancer data set.

RESULTS: DDIR/HRD classification is highly prognostic in TNBC and identifies biologically and immunologically distinct subgroups. Immune-enriched DDIR+/HRD+ TNBCs have the most favorable prognosis, and DDIR+/HRD- and DDIR-/HRD+ TNBCs have favorable intermediate prognosis, despite the latter being immune-depleted. DDIR-/HRD- TNBCs have the worst prognosis and represent an internally heterogeneous group of immune-depleted chemoresistant tumors.

CONCLUSION: Our findings propose DDIR/HRD classification as a potentially clinically relevant approach to categorize tumors on the basis of therapeutic vulnerabilities.

RevDate: 2023-11-16

Aziz Z, Wagner S, Agyekum A, et al (2023)

Cost-Effectiveness of Liquid Biopsy for Colorectal Cancer Screening in Patients Who Are Unscreened.

JAMA network open, 6(11):e2343392 pii:2811942.

IMPORTANCE: Despite recommendations for universal screening, adherence to colorectal cancer screening in the US is approximately 60%. Liquid biopsy tests are in development for cancer early detection, but it is unclear whether they are cost-effective for colorectal cancer screening.

OBJECTIVE: To estimate the cost-effectiveness of liquid biopsy for colorectal cancer screening in the US.

In this economic evaluation, a Markov model was developed to compare no screening and 5 colorectal cancer screening strategies: colonoscopy, liquid biopsy, liquid biopsy following nonadherence to colonoscopy, stool DNA, and fecal immunochemical test. Adherence to first-line screening with colonoscopy, stool DNA, or fecal immunochemical test was assumed to be 60.6%, and adherence for liquid biopsy was assumed to be 100%. For colonoscopy, stool DNA, and fecal immunochemical test, patients who did not adhere to testing were not offered other screening. In colonoscopy-liquid biopsy hybrid, liquid biopsy was second-line screening for those who deferred colonoscopy. Scenario analyses were performed to include the possibility of polyp detection for liquid biopsy.

EXPOSURES: No screening, colonoscopy, fecal immunochemical test, stool DNA, liquid biopsy, and colonoscopy-liquid biopsy hybrid screening.

MAIN OUTCOMES AND MEASURES: Model outcomes included life expectancy, total cost, and incremental cost-effectiveness ratios. A strategy was considered cost-effective if it had an incremental cost-effectiveness ratio less than the US willingness-to-pay threshold of $100 000 per life-year gained.

RESULTS: This study used a simulated cohort of patients aged 45 years with average risk of colorectal cancer. In the base case, colonoscopy was the preferred, or cost-effective, strategy with an incremental cost-effectiveness ratio of $28 071 per life-year gained. Colonoscopy-liquid biopsy hybrid had the greatest gain in life-years gained but had an incremental cost-effectiveness ratio of $377 538. Colonoscopy-liquid biopsy hybrid had a greater gain in life-years if liquid biopsy could detect polyps but remained too costly.

CONCLUSIONS AND RELEVANCE: In this economic evaluation of liquid biopsy for colorectal cancer screening, colonoscopy was a cost-effective strategy for colorectal cancer screening in the general population, and the inclusion of liquid biopsy as a first- or second-line screening strategy was not cost-effective at its current cost and screening performance. Liquid biopsy tests for colorectal cancer screening may become cost-effective if their cost is substantially lowered.

RevDate: 2023-11-17

Nelson AJ, Lopes RD, Hong H, et al (2023)

Cardiovascular Effects of GnRH Antagonists Compared With Agonists in Prostate Cancer: A Systematic Review.

JACC. CardioOncology, 5(5):613-624.

BACKGROUND: Androgen deprivation therapy is the cornerstone of treatment for patients with advanced prostate cancer. Meta-analysis of small, oncology-focused trials suggest gonadotropin-releasing hormone (GnRH) antagonists may be associated with fewer adverse cardiovascular outcomes compared with GnRH agonists.

OBJECTIVES: This study sought to determine whether GnRH antagonists were associated with fewer major adverse cardiovascular events compared with GnRH agonists.

METHODS: Electronic databases were searched for all prospective, randomized trials comparing GnRH antagonists with agonists. The primary outcome was a major adverse cardiovascular event as defined by the following standardized Medical Dictionary for Regulatory Activities terms: "myocardial infarction," "central nervous system hemorrhages and cerebrovascular conditions," and all-cause mortality. Bayesian meta-analysis models with random effects were fitted.

RESULTS: A total of 11 eligible studies of a maximum duration of 3 to 36 months (median = 12 months) enrolling 4,248 participants were included. Only 1 trial used a blinded, adjudicated event process, whereas potential bias persisted in all trials given their open-label design. A total of 152 patients with primary outcome events were observed, 76 of 2,655 (2.9%) in GnRH antagonist-treated participants and 76 of 1,593 (4.8%) in agonist-treated individuals. Compared with GnRH agonists, the pooled OR of GnRH antagonists for the primary endpoint was 0.57 (95% credible interval: 0.37-0.86) and 0.58 (95% credible interval: 0.32-1.08) for all-cause death.

CONCLUSIONS: Despite the addition of the largest, dedicated cardiovascular outcome trial, the volume and quality of available data to definitively answer this question remain suboptimal. Notwithstanding these limitations, the available data suggest that GnRH antagonists are associated with fewer cardiovascular events, and possibly mortality, compared with GnRH agonists.

RevDate: 2023-11-15

Ferar K, Hall TO, Crawford DC, et al (2023)

Author Correction: Genetic variation in the human leukocyte antigen region confers susceptibility to Clostridioides difficile infection.

Scientific reports, 13(1):19972 pii:10.1038/s41598-023-47359-3.

RevDate: 2023-11-17

Saunders LM, Srivatsan SR, Duran M, et al (2023)

Embryo-scale reverse genetics at single-cell resolution.

Nature [Epub ahead of print].

The maturation of single-cell transcriptomic technologies has facilitated the generation of comprehensive cellular atlases from whole embryos[1-4]. A majority of these data, however, has been collected from wild-type embryos without an appreciation for the latent variation that is present in development. Here we present the 'zebrafish single-cell atlas of perturbed embryos': single-cell transcriptomic data from 1,812 individually resolved developing zebrafish embryos, encompassing 19 timepoints, 23 genetic perturbations and a total of 3.2 million cells. The high degree of replication in our study (eight or more embryos per condition) enables us to estimate the variance in cell type abundance organism-wide and to detect perturbation-dependent deviance in cell type composition relative to wild-type embryos. Our approach is sensitive to rare cell types, resolving developmental trajectories and genetic dependencies in the cranial ganglia neurons, a cell population that comprises less than 1% of the embryo. Additionally, time-series profiling of individual mutants identified a group of brachyury-independent cells with strikingly similar transcriptomes to notochord sheath cells, leading to new hypotheses about early origins of the skull. We anticipate that standardized collection of high-resolution, organism-scale single-cell data from large numbers of individual embryos will enable mapping of the genetic dependencies of zebrafish cell types, while also addressing longstanding challenges in developmental genetics, including the cellular and transcriptional plasticity underlying phenotypic diversity across individuals.

RevDate: 2023-11-15

Clasie BM, Letourneau D, Schwarz M, et al (2023)

Proton Therapy Equipment Installation, Upgrades and Building Design.

Practical radiation oncology pii:S1879-8500(23)00297-7 [Epub ahead of print].

RevDate: 2023-11-15

Liu ZS, Sinha S, Bannister M, et al (2023)

R-loop accumulation in spliceosome mutant leukemias confers sensitivity to PARP1 inhibition by triggering transcription-replication conflicts.

Cancer research pii:730129 [Epub ahead of print].

RNA splicing factor (SF) gene mutations are commonly observed in patients with myeloid malignancies. Here we showed that SRSF2- and U2AF1-mutant leukemias are preferentially sensitive to PARP inhibitors (PARPi) despite being proficient in homologous recombination repair. Instead, SF-mutant leukemias exhibited R-loop accumulation that elicited an R-loop associated PARP1 response, rendering cells dependent on PARP1 activity for survival. Consequently, PARPi induced DNA damage and cell death in SF-mutant leukemias in an R-loop dependent manner. PARPi further increased aberrant R-loop levels, causing higher transcription-replication collisions and triggering ATR activation in SF-mutant leukemias. Ultimately, PARPi-induced DNA damage and cell death in SF-mutant leukemias could be enhanced by ATR inhibition. Finally, the level of PARP1 activity at R loops correlated with PARPi sensitivity, suggesting that R-loop associated PARP1 activity could be predictive of PARPi sensitivity in patients harboring SF gene mutations. This study highlights the potential of targeting different R-loop response pathways caused by spliceosome gene mutations as a therapeutic strategy for treating cancer.

RevDate: 2023-11-17

Liang EC, Albittar A, Huang JJ, et al (2023)

Factors associated with long-term outcomes of CD19 CAR T-cell therapy for relapsed/refractory CLL.

Blood advances, 7(22):6990-7005.

High response rates have been reported after CD19-targeted chimeric antigen receptor-modified (CD19 CAR) T-cell therapy for relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL), yet the factors associated with duration of response in this setting are poorly characterized. We analyzed long-term outcomes in 47 patients with R/R CLL and/or Richter transformation treated on our phase 1/2 clinical trial of CD19 CAR T-cell therapy with an updated median follow-up of 79.6 months. Median progression-free survival (PFS) was 8.9 months, and the 6-year PFS was 17.8%. Maximum standardized uptake value (hazard ratio [HR], 1.15; 95% confidence interval [CI], 1.07-1.23; P < .001) and bulky disease (≥5 cm; HR, 2.12; 95% CI, 1.06-4.26; P = .034) before lymphodepletion were associated with shorter PFS. Day +28 complete response by positron emission tomography-computed tomography (HR, 0.13; 95% CI, 0.04-0.40; P < .001), day +28 measurable residual disease (MRD) negativity by multiparameter flow cytometry (HR, 0.08; 95% CI, 0.03-0.22; P < .001), day +28 MRD negativity by next-generation sequencing (HR, 0.21; 95% CI, 0.08-0.51; P < .001), higher peak CD8+ CAR T-cell expansion (HR, 0.49; 95% CI; 0.36-0.68; P < .001), higher peak CD4+ CAR T-cell expansion (HR, 0.47; 95% CI; 0.33-0.69; P < .001), and longer CAR T-cell persistence (HR, 0.56; 95% CI, 0.44-0.72; P < .001) were associated with longer PFS. The 6-year duration of response and overall survival were 26.4% and 31.2%, respectively. CD19 CAR T-cell therapy achieved durable responses with curative potential in a subset of patients with R/R CLL. This trial was registered at as #NCT01865617.

RevDate: 2023-11-15

Lerner SP, McConkey DJ, Tangen CM, et al (2023)

Association of Molecular Subtypes with Pathologic Response, PFS and OS in a Phase II Study of COXEN with Neoadjuvant Chemotherapy for Muscle-Invasive Bladder Cancer.

Clinical cancer research : an official journal of the American Association for Cancer Research pii:730040 [Epub ahead of print].

PURPOSE: The COXEN gene expression model with chemotherapy-specific scores (for DD-MVAC and GC) was developed to identify responders to NAC. We investigated RNA-based molecular subtypes as additional predictive biomarkers for NAC response, PFS, and OS in patients treated in S1314.

EXPERIMENTAL DESIGN: 237 patients were randomized between 4 cycles of ddMVAC (51%) and GC (49%). Based on Affymetrix transcriptomic data, we determined subtypes using 3 classifiers: TCGA (k=5), Consensus (k=6), and MD Anderson (MDA; k=3) and assessed subtype association with path response to NAC and determined associations with COXEN. We also tested whether each classifier contributed additional predictive power when added to a model based on pre-defined stratification factors (PS 0 vs. 1; T2 vs. T3, T4a).

RESULTS: 155 patients had gene expression results, received at least 3 of 4 cycles of NAC and had pT-N response based on RC. TCGA 3 group classifier BS/Neuronal, Lum, Lum infiltrated and GC COXEN score yielded the largest AUCs for pT0 (0.59 p=0.28; 0.60 p=0.18, respectively). For downstaging (
CONCLUSIONS: The Consensus classifier, based in part on the TCGA and MDA classifiers, modestly improved prediction for pathologic downstaging but subtypes were not associated with PFS or OS.

RevDate: 2023-11-15

Dignum T, Burroughs L, Mallhi K, et al (2023)

Dermatologic complications in pediatric patients after hematopoietic stem cell transplantation for sickle cell disease.

Pediatric dermatology [Epub ahead of print].

Dermatologic complications are common following allogeneic hematopoietic stem cell transplantation, but dermatologic complications among pediatric patients undergoing hematopoietic stem cell transplantation for the treatment of sickle cell disease have been poorly characterized. In this case series of 17 patients (<21 years old) with sickle cell disease who underwent hematopoietic stem cell transplantation, 16 (94.1%) experienced one or more dermatologic complications after transplant, with the most common complications including acute or chronic mucocutaneous graft-versus-host disease (GVHD) (34.1% of complications), skin eruptions of unknown origin (15.9% of complications), infections (15.9% of complications), and chemotherapy-related pigmentary changes (11.4% of complications). Patients who developed acute or chronic skin GVHD were significantly older at the time of hematopoietic stem cell transplantation. These findings highlight the need to closely monitor for dermatologic complications in pediatric patients who undergo hematopoietic stem cell transplantation for sickle cell disease and underscore the importance of involving dermatology early on when skin complications occur, although further research with a larger multicenter study could help clarify the risk for dermatologic complications and help identify potential ways to mitigate this risk.

RevDate: 2023-11-15

Paller CJ, Barata PC, Lorentz J, et al (2023)

PROMISE Registry: A prostate cancer registry of outcomes and germline mutations for improved survival and treatment effectiveness.

The Prostate [Epub ahead of print].

BACKGROUND: Recently approved treatments and updates to genetic testing recommendations for prostate cancer have created a need for correlated analyses of patient outcomes data via germline genetic mutation status. Genetic registries address these gaps by identifying candidates for recently approved targeted treatments, expanding clinical trial data examining specific gene mutations, and understanding effects of targeted treatments in the real-world setting.

METHODS: The PROMISE Registry is a 20-year (5-year recruitment, 15-year follow-up), US-wide, prospective genetic registry for prostate cancer patients. Five thousand patients will be screened through an online at-home germline testing to identify and enroll 500 patients with germline mutations, including: pathogenic or likely pathogenic variants and variants of uncertain significance in genes of interest. Patients will be followed for 15 years and clinical data with real time patient reported outcomes will be collected. Eligible patients will enter long-term follow-up (6-month PRO surveys and medical record retrieval). As a virtual study with patient self-enrollment, the PROMISE Registry may fill gaps in genetics services in underserved areas and for patients within sufficient insurance coverage.

RESULTS: The PROMISE Registry opened in May 2021. 2114 patients have enrolled to date across 48 US states and 23 recruiting sites. 202 patients have met criteria for long-term follow-up. PROMISE is on target with the study's goal of 5000 patients screened and 500 patients eligible for long-term follow-up by 2026.

CONCLUSIONS: The PROMISE Registry is a novel, prospective, germline registry that will collect long-term patient outcomes data to address current gaps in understanding resulting from recently FDA-approved treatments and updates to genetic testing recommendations for prostate cancer. Through inclusion of a broad nationwide sample, including underserved patients and those unaffiliated with major academic centers, the PROMISE Registry aims to provide access to germline genetic testing and to collect data to understand disease characteristics and treatment responses across the disease spectrum for prostate cancer with rare germline genetic variants.

RevDate: 2023-11-14

Rodriguez PJ, Heagerty PJ, Clark S, et al (2023)

Using Machine Learning to Leverage Biomarker Change and Predict Colorectal Cancer Recurrence.

JCO clinical cancer informatics, 7:e2300066.

PURPOSE: The risk of colorectal cancer (CRC) recurrence after primary treatment varies across individuals and over time. Using patients' most up-to-date information, including carcinoembryonic antigen (CEA) biomarker profiles, to predict risk could improve personalized decision making.

METHODS: We used electronic health record data from an integrated health system on a cohort of patients diagnosed with American Joint Committee on Cancer stage I-III CRC between 2008 and 2013 (N = 3,970) and monitored until recurrence or end of follow-up. We addressed missingness in recurrence outcomes and longitudinal CEA measures, and engineered CEA features using current and past biomarker values for inclusion in a risk prediction model. We used a discrete time Superlearner model to evaluate various algorithms for predicting recurrence. We evaluated the time-varying discrimination and calibration of the algorithms and assessed the role of individual predictors.

RESULTS: Recurrence was documented in 448 (11.3%) patients. XGBoost with depth = 1 (XGB-D1) predicted recurrence substantially better than all other algorithms at all time points, with AUC ranging from 0.87 (95% CI, 0.86 to 0.88) at 6 months to 0.94 (95% CI, 0.92 to 0.96) at 54 months. The only variable used by XGB-D1 was 6-month change in log CEA. Predicted 1-year risk of recurrence was nearly zero for patients whose log CEA did not increase in the last 6 months, between 12.2% and 34.1% for patients whose log CEA increased between 0.10 and 0.40, and 43.6% for those with a log CEA increase >0.40. Compared with XGB, penalized regression approaches (lasso, ridge, and elastic net) performed poorly, with AUCs ranging from 0.58 to 0.69.

CONCLUSION: A flexible, machine learning approach that incorporated longitudinal CEA information yielded a simple and high-performing model for predicting recurrence on the basis of 6-month change in log CEA.

RevDate: 2023-11-14

Carpenter JS, Larson JC, Hunter MS, et al (2023)

Correlations among Core Outcomes in Menopause-recommended vasomotor symptom outcomes in MsFLASH trials.

Menopause (New York, N.Y.) [Epub ahead of print].

OBJECTIVE: This study aimed to advance understanding of vasomotor symptom (VMS) outcomes measurement using pooled data from three Menopause Strategies Finding Lasting Answers to Symptoms and Health (MsFLASH) trials.

METHODS: Participants self-reported VMS frequency, severity, and bother using daily diaries; completed standardized measures of VMS interference, insomnia severity, and sleep quality/disturbance; and completed four treatment satisfaction items. Analyses included descriptive statistics, Pearson correlations (baseline pooled sample, posttreatment pooled sample, posttreatment placebo only), t tests, and analysis of variance.

RESULTS: Participants were mostly postmenopausal (82.9%) and a mean of 54.5 years old. VMS frequency was fairly correlated with severity, bother, and interference for pooled baseline and placebo posttreatment samples (r values = 0.21-0.39, P values < 0.001) and moderately correlated with severity, bother, and interference for pooled posttreatment (r values = 0.40-0.44, P values < 0.001). VMS severity, bother, and interference were moderately correlated (r values = 0.37-0.48, P values < 0.001), with one exception. VMS severity and bother were strongly correlated (r values = 0.90-0.92, P values < 0.001). VMS interference was moderately correlated with insomnia (r values = 0.45-0.54, P values < 0.001) and fairly to moderately correlated with sleep quality/disturbance (r values = 0.31-0.44, P values < 0.001). Other VMS outcomes were weakly to fairly correlated with insomnia (r values = 0.07-0.33, P values < 0.001 to < 0.05) and sleep quality/disturbance (r values = 0.06-0.26, P values < 0.001 to > 0.05). Greater improvement in VMS and sleep over time was associated with higher treatment satisfaction (P values < 0.001).

CONCLUSIONS: This pooled analysis advances understanding of VMS outcomes measurement and has implications for selecting measures and creating future research.

RevDate: 2023-11-15
CmpDate: 2023-11-15

Walsh CA, Good J, Ismaiel A, et al (2023)

Development and refinement of a novel end-of-life planning website for patients with advanced cancer: a mixed methods approach.

Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer, 31(12):695.

PURPOSE: Despite known benefits of planning for end-of-life, no digital tool exists to help patients with advanced cancer and their loved ones plan for death comprehensively. To address this unmet need, we developed a preliminary version of an innovative website to help patients with advanced cancer prepare for end-of-life tasks.

METHODS: Guided by the Obesity-Related Behavioral Intervention Trials (ORBIT) model for behavioral intervention development, patients with advanced cancer (n = 10) and their caregivers (n = 10) participated in a "Think Aloud" exercise and usability protocols to optimize the end-of-life planning website. The website was iteratively refined throughout the study in collaboration with the partnering company, Peacefully, Inc. Participants also completed the Acceptability E-Scale and System Usability Scale, with a priori benchmarks established for acceptability (scores of ≥ 24 on the Acceptability E-Scale) and usability (scores of ≥ 68 on the System Usability Scale).

RESULTS: Patients (N = 10) and caregivers (N = 10) completed usability testing. Patients were majority female (80%), White (100%), and had a mean age of 58 years. Caregivers (N = 10) were majority male (60%), spouse/partner (90%), White (90%), and had a mean age of 59 years. For patients, a priori hypotheses were met for both acceptability (mean score of 24.7, SD = 4.35) and usability (mean score of 73.8, SD = 6.15). For caregivers, acceptability was just below the cutoff (mean score of 22.9, SD = 4.07) and usability exceeded the cutoff (mean score of 70.0, SD = 8.42). Overall, patients and caregivers reported high levels of satisfaction and found the website helpful, with specific suggestions for changes (e.g., add more information about information security, improve text legibility).

CONCLUSIONS: The findings from this study will inform modifications to optimize an innovative website to support patients with advanced cancer to prepare holistically for end-of-life tasks.

RevDate: 2023-11-14

Clark SE, Marcum ZA, Radich J, et al (2023)

Temporal effect of imatinib adherence on time to remission in chronic myeloid leukemia patients.

Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners [Epub ahead of print].

INTRODUCTION: Adherence to imatinib in chronic myeloid leukemia (CML) patients is estimated to be as low as 70% despite its clinical benefit, and our understanding of the impact of nonadherence in this population is limited. This study presents a novel application of the Alternating Conditional Estimation (ACE) algorithm in newly diagnosed CML patients to map the full dose-response curve (DRC) and determine how the strength of this curve varies over time.

METHODS: We applied the ACE algorithm alongside a backward elimination procedure to detect the presence of time dependence and nonlinearity in the relationship between imatinib adherence and time-to-remission. An extended Cox model allowing for the flexible modeling of identified effects via unpenalized B-splines was subsequently fit and assessed.

RESULTS: The substantial improvement in model fit associated with the extended Cox approach suggests that traditional Cox proportional hazards model assumptions do not hold in this setting. Results indicate that the DRC for imatinib is non-linearly increasing, with an attenuated effect above a 74% adherence rate. The strength of this effect on remission varied over time and was strongest in the initial months of treatment, reaching a peak around 90 days post-initiation (log hazard ratio: 2.12, 95% confidence interval: 1.47 to 2.66).

CONCLUSION: Most patients that achieved remission did so by 4 months (120 days) with consistently high adherence, suggesting that this could be a critical time and duration for realizing treatment benefit and patient monitoring. Findings regarding the relationship between adherence and remission can additionally help guide the design of future studies.

RevDate: 2023-11-13

Schommers P, Kim DS, Schlotz M, et al (2023)

Dynamics and durability of HIV-1 neutralization are determined by viral replication.

Nature medicine [Epub ahead of print].

Human immunodeficiency virus type 1 (HIV-1)-neutralizing antibodies (nAbs) that prevent infection are the main goal of HIV vaccine discovery. But as no nAb-eliciting vaccines are yet available, only data from HIV-1 neutralizers-persons with HIV-1 who naturally develop broad and potent nAbs-can inform about the dynamics and durability of nAb responses in humans, knowledge which is crucial for the design of future HIV-1 vaccine regimens. To address this, we assessed HIV-1-neutralizing immunoglobulin G (IgG) from 2,354 persons with HIV-1 on or off antiretroviral therapy (ART). Infection with non-clade B viruses, CD4[+] T cell counts <200 µl[-1], being off ART and a longer time off ART were independent predictors of a more potent and broad neutralization. In longitudinal analyses, we found nAb half-lives of 9.3 and 16.9 years in individuals with no- or low-level viremia, respectively, and 4.0 years in persons who newly initiated ART. Finally, in a potent HIV-1 neutralizer, we identified lower fractions of serum nAbs and of nAb-encoding memory B cells after ART initiation, suggesting that a decreasing neutralizing serum activity after antigen withdrawal is due to lower levels of nAbs. These results collectively show that HIV-1-neutralizing responses can persist for several years, even at low antigen levels, suggesting that an HIV-1 vaccine may elicit a durable nAb response.

RevDate: 2023-11-13

Cohen MS, ER Brown (2023)

Rebound of COVID-19 With Nirmatrelvir-Ritonavir Antiviral Therapy.

Annals of internal medicine [Epub ahead of print].

RevDate: 2023-11-13

Abrams HR, Chen AW, R Banerjee (2023)

Opportunity Strikes for Reducing Cancer Drug Waste: Bortezomib as an Example of Vial Mis-Sizing in Oncology.

JCO oncology practice [Epub ahead of print].


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.

ESP Help

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

Electronic Scholarly Publishing
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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).


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


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.

ESP Picks from Around the Web (updated 07 JUL 2018 )