Reproductive Risk Factor Patterns in Caribbean Women With Breast Cancer Across 4 Generations.

Importance: Breast cancer (BC) is commonly diagnosed among Caribbean women. Shifts in reproductive patterns modify the incidence of BC diagnosis and age at BC diagnosis in population-based studies; however, reproductive patterns in Caribbean women remain understudied. Objective: To describe the temporal trends in reproductive patterns and age at BC diagnosis in Caribbean-born women. Design, Setting, and Participants: A cross-sectional observational study-the Caribbean Women's Cancer Study-was conducted, with data on reproductive patterns known to affect BC risk collected in The Bahamas, Barbados, Cayman Islands, Dominica, Haiti, Jamaica, and Trinidad and Tobago. Participants were recruited prospectively. The sample included women born in Caribbean countries and diagnosed with invasive BC and/or ovarian cancer from June 1, 2010, to June 30, 2018, and was divided into 4 birth cohorts (born before 1950, 1950-1959, 1960-1969, and in or after 1970). Data were analyzed between August 1, 2023, and July 31, 2024. Exposures: Receipt of a BC diagnosis and birth in a Caribbean country. Main Outcomes and Measures: Change in reproductive patterns between birth cohorts, including age at BC diagnosis, family history of cancer, age at first pregnancy, number of pregnancies, number of full-term pregnancies, number of siblings, age at menarche and menopause, estrogen receptor status, and germline pathogenic/likely pathogenic variants. Results: Of 1015 participants diagnosed with BC and ovarian cancer, 995 women (mean [SD] age, 46.6 [10.8] years; 605 [81.8%] Afro-Caribbean, 98 [13.2%] East Indian, 22 [3.0%] White, and 12 [1.6%] >1 race) received a diagnosis of invasive BC. Comparison from older to younger birth cohorts (presented in the order of born before 1950, 1950-1959, 1960-1969 and in or after 1970) showed an increased proportion of women experiencing menarche at age 12 years or younger (33.0% vs 47.3% vs 45.5% vs 57.9%; P < .001), women with no pregnancies (6.8% vs 6.8% vs 10.5% vs 22.8%; P < .001), and nulliparous women (8.6% vs 9.2% vs 13.9% vs 27.6%; P < .001). Younger age at BC diagnosis was observed in women experiencing menarche at age 12 years or younger (mean [SD], 45.0 [10.5] years) vs 15 years or older (mean [SD], 49.1 [11.2] years) and in nulliparous women (mean [SD], 42.1 [11.2] years) vs 3 or more full-term pregnancies (mean [SD], 49.9 [10.6] years; P < .001). For every year of first pregnancy delay, women had a 4% increased chance of being diagnosed with estrogen receptor-positive tumors (odds ratio, 1.04; 95% CI, 1.01-1.08; P = .02). Conclusions and Relevance: In this cross-sectional study, between each 10-year birth cohort, women diagnosed with BC had a lower age at menarche, number of pregnancies, and number of full-term pregnancies. These findings suggest that interventions targeting other BC risk factors need to be implemented.

Proteogenomic analysis integrated with electronic health records data reveals disease-associated variants in Black Americans.

BACKGROUND: Most genome wide association studies (GWAS) of plasma proteomics have focused on White individuals of European ancestry, limiting biological insight from other ancestry enriched protein quantitative loci (pQTL). METHODS: We conducted a discovery GWAS of ~3,000 plasma proteins measured by the antibody based Olink platform in 1,054 Black adults from the Jackson Heart Study (JHS), and validated our findings in the Multi-Ethnic Study of Atherosclerosis (MESA). The genetic architecture of identified pQTLs were further explored through fine mapping and admixture association analysis. Finally, using our pQTL findings, we performed a phenome wide association study (PheWAS) across two large multi-ethnic electronic health record (EHR) systems in All of Us and BioMe. RESULTS: We identified 1002 pQTLs for 925 proteins. Fine mapping and admixture analyses suggested allelic heterogeneity of the plasma proteome across diverse populations. We identified associations for variants enriched in African ancestry, many in diseases that lack precise biomarkers, including cis-pQTLs for Cathepsin L (CTSL) and Siglec-9 that were linked with sarcoidosis and non-Hodgkin's lymphoma, respectively. We found concordant associations across clinical diagnoses and laboratory measurements, elucidating disease pathways, including a cis-pQTL associated with circulating CD58, white blood cell count, and multiple sclerosis. CONCLUSIONS: Our findings emphasize the value of leveraging diverse populations to enhance biological insights from proteomics GWAS, and we have made this resource readily available as an interactive web portal.

Cardiac Hepatoma: An Unlikely Cause of Malignant Cardiac Metastatic Disease.

Cardiac hepatoma is an extremely rare presentation of tumor metastasis. We present a case of an 80-year-old male who presented with symptoms of heart failure and was subsequently diagnosed with cardiac metastatic tumors. This case report highlights the diagnostic challenges and management options associated with this rare entity.

Morphologic Spectrum of HPV-associated Sinonasal Carcinomas.

BACKGROUND: High-risk human papillomavirus (HR-HPV) infection has been increasingly recognized as a risk factor for sinonasal tract carcinomas. However the prevalence and prognostic significance of HPV-associated sinonasal carcinomas is not well known due to limited studies and inconsistency in HPV testing modalities in literatures. Morphologically, HPV-associated sinonasal carcinomas encompass a diverse group of tumors. HPV-associated sinonasal adenocarcinoma has not been reported. The purpose of this study was to determine the prevalence, morphologic spectrum and prognostic implication of HPV-associated sinonasal carcinomas. METHODS: This cohort included 153 sinonasal carcinomas. Tissue microarrays were constructed. P16 immunohistochemistry and HR-HPV E6/7 in-situ Hybridization (ISH) were performed. Carcinomas were deemed HPV-associated based on a positive ISH testing. Clinicopathologic data was collected. RESULTS: 28/153 (18%) sinonasal carcinomas were HPV-associated. HPV-associated carcinomas consisted of 26 (93%) squamous cell carcinomas and variants, 1 (3.5%) HPV-related multiphenotypic sinonasal carcinoma and 1 (3.5%) adenocarcinoma. The HPV-associated adenocarcinoma closely resembled HPV-associated endocervical adenocarcinoma morphologically. HPV-associated carcinomas occurred in 8 (29%) women and 20 (71%) men with a median age of 66 years old. HPV-associated carcinomas were predominantly located at nasal cavity. A trend toward improved overall survival and progression free survival in HPV-associated carcinomas patients was observed, yet without statistical significance. CONCLUSION: Our study identifies a novel HPV-associated sinonasal adenocarcinoma subtype, highlights the broad morphologic spectrum of HPV-associated sinonasal carcinomas, and supports routine p16 testing during pathology practice regardless of tumor subtype followed by a confirmatory HR-HPV testing. This practice is critical for studying the clinical behavior of HPV-associated sinonasal carcinomas.

Effect of General Surgery Resident Participation in Thoracic Surgery on Oncologic Outcomes: An Observational Cohort Study.

Background: Despite increasing sub-specialization, general surgeons continue to perform oncologic thoracic surgeries. Our objective was to determine whether general surgery resident participation in thoracic surgery affects surgical quality or oncologic outcomes. We hypothesized that patient outcomes with and without resident participation would be similar. Methods: We retrospectively reviewed the electronic health records of patients with stage 0-IV lung cancer undergoing oncologic pulmonary resection at BLINDED FOR REVIEW during an 11-year period (2012-2022). Patients younger than 18 years or older than 85 years were excluded, as were those who had incomplete follow-up data or were unregistered in our institutional cancer registry. Patients were divided into groups based on whether residents or staff surgeons completed >50% of the critical portions of the operation. We compared 30-day morbidity outcomes, overall survival (OS), and disease-free survival (DFS). Results: Three hundred thirteen patients met inclusion criteria. Demographic and clinical characteristics were similar between groups, as were types of surgical resection and median operative times. A statistical difference was found in the distribution of surgical approach. The odds of morbidity were 65% higher in the Staff group (OR=1.65; 95% CI, 1.007-2.71). Resident participation was not significantly associated with OS or DFS (P =.32 and P =.54, respectively). Discussion: General surgery resident involvement in lung cancer operations is not associated with longer operative times but is associated with a higher likelihood of a thoracotomy. General surgery resident involvement was associated with decreased postoperative morbidity and did not significantly affect OS or DFS.

Generalized genetic liability to substance use disorders.

Lifetime and temporal co-occurrence of substance use disorders (SUDs) is common and compared with individual SUDs is characterized by greater severity, additional psychiatric comorbidities, and worse outcomes. Here, we review evidence for the role of generalized genetic liability to various SUDs. Coaggregation of SUDs has familial contributions, with twin studies suggesting a strong contribution of additive genetic influences undergirding use disorders for a variety of substances (including alcohol, nicotine, cannabis, and others). GWAS have documented similarly large genetic correlations between alcohol, cannabis, and opioid use disorders. Extending these findings, recent studies have identified multiple genomic loci that contribute to common risk for these SUDs and problematic tobacco use, implicating dopaminergic regulatory and neuronal development mechanisms in the pathophysiology of generalized SUD genetic liability, with certain signals demonstrating cross-species and translational validity. Overlap with genetic signals for other externalizing behaviors, while substantial, does not explain the entirety of the generalized genetic signal for SUD. Polygenic scores (PGS) derived from the generalized genetic liability to SUDs outperform PGS for individual SUDs in prediction of serious mental health and medical comorbidities. Going forward, it will be important to further elucidate the etiology of generalized SUD genetic liability by incorporating additional SUDs, evaluating clinical presentation across the lifespan, and increasing the granularity of investigation (e.g., specific transdiagnostic criteria) to ultimately improve the nosology, prevention, and treatment of SUDs.

Determinants of mosaic chromosomal alteration fitness.

Clonal hematopoiesis (CH) is characterized by the acquisition of a somatic mutation in a hematopoietic stem cell that results in a clonal expansion. These driver mutations can be single nucleotide variants in cancer driver genes or larger structural rearrangements called mosaic chromosomal alterations (mCAs). The factors that influence the variations in mCA fitness and ultimately result in different clonal expansion rates are not well understood. We used the Passenger-Approximated Clonal Expansion Rate (PACER) method to estimate clonal expansion rate as PACER scores for 6,381 individuals in the NHLBI TOPMed cohort with gain, loss, and copy-neutral loss of heterozygosity mCAs. Our mCA fitness estimates, derived by aggregating per-individual PACER scores, were correlated (R2 = 0.49) with an alternative approach that estimated fitness of mCAs in the UK Biobank using population-level distributions of clonal fraction. Among individuals with JAK2 V617F clonal hematopoiesis of indeterminate potential or mCAs affecting the JAK2 gene on chromosome 9, PACER score was strongly correlated with erythrocyte count. In a cross-sectional analysis, genome-wide association study of estimates of mCA expansion rate identified a TCL1A locus variant associated with mCA clonal expansion rate, with suggestive variants in NRIP1 and TERT.

Reactivity of amino acids and short peptide sequences: identifying bioactive compounds via DFT calculations.

Bioactive peptides are short amino acid sequences that play important roles in various physiological processes, including antioxidant and protective effects. These compounds can be obtained through protein hydrolysis and have a wide range of potential applications in a variety of areas. However, despite the potential of these compounds, more in-depth knowledge is still necessary to better understand details regarding their chemical reactivity and electronic properties. In this study, we used molecular modeling techniques to investigate the electronic structure of isolated amino acids (AA) and short peptide sequences. Details on the relative alignments between the frontier electronic levels, local chemical reactivity and donor-acceptor properties of the 20 primary amino acids and some di- and tripeptides were evaluated in the framework of the density functional theory (DFT). Our results suggest that the electronic properties of isolated amino acids can be used to interpret the reactivity of short sequences. We found that aromatic and charged amino acids, as well as Methionine, play a key role in determining the local reactivity of peptides, in agreement with experimental data. Our analyses also allowed us to identify the influence of the relative position of AA and terminations on the local reactivity of the sequences, which can guide experimental studies and help to propose/evaluate possible mechanisms of action. In summary, our data indicate that the position of active sites of polypeptides can be predicted from short sequences, providing a promising strategy for the synthesis and bioprospection of new optimized compounds.

Thermally Robust Solvent-Free Liquid Polyplexes for Heat-Shock Protection and Long-Term Room Temperature Storage of Therapeutic Nucleic Acids.

Nucleic acid therapeutics have attracted recent attention as promising preventative solutions for a broad range of diseases. Nonviral delivery vectors, such as cationic polymers, improve the cellular uptake of nucleic acids without suffering the drawbacks of viral delivery vectors. However, these delivery systems are faced with a major challenge for worldwide deployment, as their poor thermal stability elicits the need for cold chain transportation. Here, we demonstrate a biomaterial strategy to drastically improve the thermal stability of DNA polyplexes. Importantly, we demonstrate long-term room temperature storage with a transfection efficiency maintained for at least 9 months. Additionally, extreme heat shock studies show retained luciferase expression after heat treatment at 70 °C. We therefore provide a proof of concept for a platform biotechnology that could provide long-term room temperature storage for temperature-sensitive nucleic acid therapeutics, eliminating the need for the cold chain, which in turn would reduce the cost of distributing life-saving therapeutics worldwide.

A randomized trial to compare smooth monofilament suture vs. barbed suture using the three-layer continuous closure technique in canine ovariohysterectomy in a high-quality high-volume spay/neuter clinic.

The primary objective of this study was to compare time efficiency and complication rates between smooth monofilament suture (SMS) and barbed suture (BS) using the three-layer continuous incisional closure pattern after ovariohysterectomy in a high-quality high-volume spay/neuter clinic. The study was designed as a randomized controlled trial enrolling 71 adult female dogs. Dogs were randomly assigned to SMS or BS treatments. The effect of closure with BS or SMS on closure time was tested through multilevel, multivariable linear regression in a generalized linear mixed model. Body condition score, weight, and pre-closure incision length were tested as covariates. Surgeon was included in the model as a random effect. Pre-closure incision length (p = 0.01) and method (p ≤ 0.0001) were associated with closure time. Adjusting for pre-closure incision length, the average time for closure with SMS was 6.5 min (range 3.70-10.31 min), and the average time for closure with BS was 4.91 min (range 3.05-8.05 min). Accounting for the closure method, the closure time increased by 39 s for each additional centimeter of incision length. BS was more efficient than SMS when performing the three-layer continuous suture pattern. No short-term telemedicine-assessed complications were noted with either treatment method. BS can improve efficiency in surgical closures, especially considering large volumes of animals, and appears to have a similar short-term, telemedicine-assessed complication rate when compared to SMS.

Improved corneal clarity following lamellar keratectomy for corneal lipidosis in a canine with ocular manifestations of hypothyroidism.

OBJECTIVE: To report the corneal clarity outcome following lamellar keratectomy of arcus lipoides corneae secondary to canine hypothyroidism and report a unique retinal manifestation of systemic disease. ANIMAL STUDIED: Four-year-old spayed female Sheepdog-Poodle canine. PROCEDURE: Lamellar keratectomy OD. RESULTS: Bilateral severe arcus lipoides corneae was noted in the initial presentation. Bilateral, symmetric, and multifocal bullous retinal detachments were observed at subsequent visits. Biochemical testing revealed hyperlipidemia presumed to be associated with primary acquired thyroiditis. Corneal clarity and visual behaviors were significantly improved following unilateral lamellar keratectomy with no evidence of recurrence within the year following surgery. Bilateral retinal detachments and hyperlipidemia resolved months after initiation of thyroxine supplementation. Corneal lipidosis in the untreated eye remained static. CONCLUSIONS: Lamellar keratectomy is a viable surgical option for the treatment of arcus lipoides corneae. Hypothyroidism should be considered a differential diagnosis for spontaneous, bilateral, multifocal, and serous retinal detachments.

A genetic association study of circulating coagulation factor VIII and von Willebrand factor levels.

ABSTRACT: Coagulation factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are critical to coagulation and platelet aggregation. We leveraged whole-genome sequence data from the Trans-Omics for Precision Medicine (TOPMed) program along with TOPMed-based imputation of genotypes in additional samples to identify genetic associations with circulating FVIII and VWF levels in a single-variant meta-analysis, including up to 45 289 participants. Gene-based aggregate tests were implemented in TOPMed. We identified 3 candidate causal genes and tested their functional effect on FVIII release from human liver endothelial cells (HLECs) and VWF release from human umbilical vein endothelial cells. Mendelian randomization was also performed to provide evidence for causal associations of FVIII and VWF with thrombotic outcomes. We identified associations (P < 5 × 10-9) at 7 new loci for FVIII (ST3GAL4, CLEC4M, B3GNT2, ASGR1, F12, KNG1, and TREM1/NCR2) and 1 for VWF (B3GNT2). VWF, ABO, and STAB2 were associated with FVIII and VWF in gene-based analyses. Multiphenotype analysis of FVIII and VWF identified another 3 new loci, including PDIA3. Silencing of B3GNT2 and the previously reported CD36 gene decreased release of FVIII by HLECs, whereas silencing of B3GNT2, CD36, and PDIA3 decreased release of VWF by HVECs. Mendelian randomization supports causal association of higher FVIII and VWF with increased risk of thrombotic outcomes. Seven new loci were identified for FVIII and 1 for VWF, with evidence supporting causal associations of FVIII and VWF with thrombotic outcomes. B3GNT2, CD36, and PDIA3 modulate the release of FVIII and/or VWF in vitro.

Smoking-associated Electrocardiographic Abnormalities Predict Cardiovascular Mortality: Insights from NHANES.

Background­: Smoking is associated with arrhythmia and sudden cardiac death, but the biological mechanisms remain unclear. Abnormal electrocardiogram (ECG) durations of ventricular repolarization (QT interval), atrial depolarization (P wave), and atrioventricular depolarization (PR interval and segment), predict cardiac arrhythmia and mortality. Objectives­: To elucidate how smoking affects cardiac excitation, we assessed in a nationally representative sample (NHANES III) associations between cotinine, abnormalities in P duration, PR interval, PR segment, rate-corrected QT (QTc), QRS duration, and JT interval, and long-term mortality. Methods­: We analyzed data from 5,633 adults using survey-weighted multinomial logistic regression to estimate associations between tobacco use (>15 ng/ml serum cotinine) and short (<5th percentile) or long (>95th percentile) ECG intervals, relative to reference (5 - 95th percentile). Results­: After adjustment for demographics, risk factors, and conduction-altering medications, smoking was associated with a higher odds of short PR interval, PR segment, and QRS, and long JT. Broader ECG effects of smoking were also assessed by survey-weighted linear regression of continuous cotinine and ECG intervals, which revealed cotinine inversely associated with PR segment and QTc. Over a 22-year follow-up, many ECG abnormalities predicted cardiovascular mortality in smokers, including long JT, QRS, and QTc, and short QRS. Conclusions­: Smoking increases likelihood for rapid atrioventricular conduction, rapid ventricular depolarization, and slow ventricular repolarization. The ventricular electrophysiologic abnormalities associated with smoking also predict cardiovascular mortality in smokers; however, traditional ECG measures of cardiac risk like QTc can overlook these ventricular defects and their independent predictive value in smokers.

L-cysteine ethylester reverses the adverse effects of morphine on breathing and arterial blood-gas chemistry while minimally affecting antinociception in unanesthetized rats.

L-cysteine ethylester (L-CYSee) is a membrane-permeable analogue of L-cysteine with a variety of pharmacological effects. The purpose of this study was to determine the effects of L-CYSee on morphine-induced changes in ventilation, arterial-blood gas (ABG) chemistry, Alveolar-arterial (A-a) gradient (i.e., a measure of the index of alveolar gas-exchange), antinociception and sedation in male Sprague Dawley rats. An injection of morphine (10 mg/kg, IV) produced adverse effects on breathing, including sustained decreases in minute ventilation. L-CYSee (500 µmol/kg, IV) given 15 min later immediately reversed the actions of morphine. Another injection of L-CYSee (500 µmol/kg, IV) after 15 min elicited more pronounced excitatory ventilatory responses. L-CYSee (250 or 500 µmol/kg, IV) elicited a rapid and prolonged reversal of the actions of morphine (10 mg/kg, IV) on ABG chemistry (pH, pCO2, pO2, sO2) and A-a gradient. L-serine ethylester (an oxygen atom replaces the sulfur; 500 µmol/kg, IV), was ineffective in all studies. L-CYSee (500 µmol/kg, IV) did not alter morphine (10 mg/kg, IV)-induced sedation, but slightly reduced the overall duration of morphine (5 or 10 mg/kg, IV)-induced analgesia. In summary, L-CYSee rapidly overcame the effects of morphine on breathing and alveolar gas-exchange, while not affecting morphine sedation or early-stage analgesia. The mechanisms by which L-CYSee modulates morphine depression of breathing are unknown, but appear to require thiol-dependent processes.

Nicotine Formulation Influences the Autonomic and Arrhythmogenic Effects of Electronic Cigarettes.

INTRODUCTION: Evidence is mounting that electronic cigarette (e-cig) use induces cardiac sympathetic dominance and electrical dysfunction conducive to arrhythmias and dependent upon nicotine. A variety of nicotine types and concentrations are available in e-cigs, but their relative cardiovascular effects remain unclear. Here we examine how different nicotine forms (racemic, free-base, and salt) and concentrations influence e-cig-evoked cardiac dysfunction and arrhythmogenesis and provide a mechanism for nicotine-salt-induced autonomic imbalance. METHODS: ECG-telemetered C57BL/6J mice were exposed to filtered air (FA) or e-cig aerosols from propylene glycol and vegetable glycerin solvents either without nicotine (vehicle) or with increasing nicotine concentrations (1%, 2.5%, and 5%) for three 9-min puff sessions per concentration. Spontaneous ventricular premature beat (VPB) incidence rates, heart rate, and heart rate variability (HRV) were compared between treatments. Subsequently, to test the role of ß1-adrenergic activation in e-cig-induced cardiac effects, mice were pretreated with atenolol and exposed to either FA or 2.5% nicotine salt. RESULTS: During puffing and washout phases, ≥ 2.5% racemic nicotine reduced heart rate and increased HRV relative to FA and vehicle controls, indicating parasympathetic dominance. Relative to both controls, 5% nicotine salt elevated heart rate and decreased HRV during washout, suggesting sympathetic dominance, and also increased VPB frequency. Atenolol abolished e-cig-induced elevations in heart rate and declines in HRV during washout, indicating e-cig-evoked sympathetic dominance is mediated by ß1-adrenergic stimulation. CONCLUSIONS: Our findings suggest that inhalation of e-cig aerosols from nicotine salt-containing e-liquids could increase the cardiovascular risks of vaping by inducing sympathetic dominance and cardiac arrhythmias. IMPLICATIONS: Exposure to e-cig aerosols containing commercially relevant concentrations of nicotine salts may increase nicotine delivery and impair cardiac function by eliciting ß1-adrenoceptor-mediated sympathoexcitation and provoking ventricular arrhythmias. If confirmed in humans, our work suggests that regulatory targeting of nicotine salts through minimum pH standards or limits on acid additives in e-liquids may mitigate the public health risks of vaping.

Deleterious heteroplasmic mitochondrial mutations are associated with an increased risk of overall and cancer-specific mortality.

Mitochondria carry their own circular genome and disruption of the mitochondrial genome is associated with various aging-related diseases. Unlike the nuclear genome, mitochondrial DNA (mtDNA) can be present at 1000 s to 10,000 s copies in somatic cells and variants may exist in a state of heteroplasmy, where only a fraction of the DNA molecules harbors a particular variant. We quantify mtDNA heteroplasmy in 194,871 participants in the UK Biobank and find that heteroplasmy is associated with a 1.5-fold increased risk of all-cause mortality. Additionally, we functionally characterize mtDNA single nucleotide variants (SNVs) using a constraint-based score, mitochondrial local constraint score sum (MSS) and find it associated with all-cause mortality, and with the prevalence and incidence of cancer and cancer-related mortality, particularly leukemia. These results indicate that mitochondria may have a functional role in certain cancers, and mitochondrial heteroplasmic SNVs may serve as a prognostic marker for cancer, especially for leukemia.

Clonal Hematopoiesis of Indeterminate Potential (CHIP) and Incident Type 2 Diabetes Risk.

OBJECTIVE: Clonal hematopoiesis of indeterminate potential (CHIP) is an aging-related accumulation of somatic mutations in hematopoietic stem cells, leading to clonal expansion. CHIP presence has been implicated in atherosclerotic coronary heart disease (CHD) and all-cause mortality, but its association with incident type 2 diabetes (T2D) is unknown. We hypothesized that CHIP is associated with elevated risk of T2D. RESEARCH DESIGN AND METHODS: CHIP was derived from whole-genome sequencing of blood DNA in the National Heart, Lung, and Blood Institute Trans-Omics for Precision Medicine (TOPMed) prospective cohorts. We performed analysis for 17,637 participants from six cohorts, without prior T2D, cardiovascular disease, or cancer. We evaluated baseline CHIP versus no CHIP prevalence with incident T2D, including associations with DNMT3A, TET2, ASXL1, JAK2, and TP53 variants. We estimated multivariable-adjusted hazard ratios (HRs) and 95% CIs with adjustment for age, sex, BMI, smoking, alcohol, education, self-reported race/ethnicity, and combined cohorts' estimates via fixed-effects meta-analysis. RESULTS: Mean (SD) age was 63.4 (11.5) years, 76% were female, and CHIP prevalence was 6.0% (n = 1,055) at baseline. T2D was diagnosed in n = 2,467 over mean follow-up of 9.8 years. Participants with CHIP had 23% (CI 1.04, 1.45) higher risk of T2D than those with no CHIP. Specifically, higher risk was for TET2 (HR 1.48; CI 1.05, 2.08) and ASXL1 (HR 1.76; CI 1.03, 2.99) mutations; DNMT3A was nonsignificant (HR 1.15; CI 0.93, 1.43). Statistical power was limited for JAK2 and TP53 analyses. CONCLUSIONS: CHIP was associated with higher incidence of T2D. CHIP mutations located on genes implicated in CHD and mortality were also related to T2D, suggesting shared aging-related pathology.

A pilot study of volumetric and density tumor analysis of ACC patients treated with vorinostat in a phase II clinical trial.

Rationale and objectives: Adenoid cystic carcinoma (ACC) is a rare salivary gland cancer. The vast majority of clinical trials evaluating systemic therapy efficacy in solid tumors use the Response Evaluation Criteria in Solid Tumors (RECIST) to measure response that is limited to 2 dimensional only evaluations, not taking volume or density into account. The indolent behavior ACC represents a challenge toward an appropriate evaluation of therapy response. Objectives: 1) To describe and contrast volumetric and density changes at each time-point, including changes noted from baseline to best response, to currently used 2 dimensional-only criteria (RECIST) and 2) To report the coefficient of variation in volume measurement among three reviewers on a subset of ACC patients. Materials and methods: We retrospectively assessed a cohort of 18 prospectively treated patients with ACC in a phase 2 trial with vorinostat using a volumetric (viable tumor volume, VTV) and density criteria. Three independent and blinded observers segmented target lesions across a sample of randomly selected computed tomography (CT) exams to examine inter-observer variation. Results: We found that the average coefficient of variation among observers for all target lesions was 16.1%, with lung lesions displaying a smaller variation at 14.0% (p-value >0.17). We describe examples of decrease in volume and density in several lesions despite stable disease by RECIST. Conclusion: This pilot study demonstrates that two-dimensional criteria such as RECIST may not be the best criteria to assess response to therapy, especially with evolving tools within picture archiving and communication system (PACS) that can assess volumetric size, density and texture, however, this should be prospectively studied.

WNTinib is a multi-kinase inhibitor with specificity against ß-catenin mutant hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. ß-Catenin (CTNNB1)-mutated HCC represents 30% of cases of the disease with no precision therapeutics available. Using chemical libraries derived from clinical multi-kinase inhibitor (KI) scaffolds, we screened HCC organoids to identify WNTinib, a KI with exquisite selectivity in CTNNB1-mutated human and murine models, including patient samples. Multiomic and target engagement analyses, combined with rescue experiments and in vitro and in vivo efficacy studies, revealed that WNTinib is superior to clinical KIs and inhibits KIT/mitogen-activated protein kinase (MAPK) signaling at multiple nodes. Moreover, we demonstrate that reduced engagement on BRAF and p38α kinases by WNTinib relative to several multi-KIs is necessary to avoid compensatory feedback signaling-providing a durable and selective transcriptional repression of mutant ß-catenin/Wnt targets through nuclear translocation of the EZH2 transcriptional repressor. Our studies uncover a previously unknown mechanism to harness the KIT/MAPK/EZH2 pathway to potently and selectively antagonize CTNNB1-mutant HCC with an unprecedented wide therapeutic index.

Intra-racial disaggregation reveals associations between nativity and overall survival in women with endometrial cancer.

OBJECTIVE: Prior studies have demonstrated survival differences between Black women with endometrial cancer (EC) born in the US and Caribbean. Our objective was to determine if country of birth influences EC overall survival (OS) in disaggregated subpopulations of Black women. METHODS: Using the Florida Cancer Data System, women with EC diagnosed from 1981 to 2017 were identified. Demographic and clinical information were abstracted. Women who self-identified as Black and born in the US (USB), Jamaica (JBB), or Haiti (HBB) were included. Statistical analyses were performed using chi-square, Cox proportional hazards models, and Kaplan-Meier methods with significance set at p < 0.05. RESULTS: 3817 women met the inclusion criteria. Compared to USB, JBB and HBB had more high-grade histologies, more advanced stage disease, had a greater proportion of uninsured or Medicaid insured, and had a higher proportion of women who received chemotherapy (all p < 0.05). In multivariate analyses, age (HR 1.03 [1.02-1.05]), regional stage (HR 1.52 [1.22-1.89]), distant stage (HR 3.73 [2.84-4.89]), lymphovascular space invasion (HR 1.96 [1.61-2.39]), receipt of surgery (HR 0.47 [0.29-0.75]), and receipt of chemotherapy (HR 0.77 [0.62-0.95]) were independently associated with OS. Compared to USB, Haitian nativity was an independent negative predictor of OS when evaluating all histologies together (HR 1.54 [1.18-2.00]) and for endometrioid EC specifically (HR 1.77 [1.10-2.83]). Among women with serous EC, HBB had markedly worse median OS (18.5 months [13.4-46.5]) relative to USB (29.9 months [26.3-35.9]) and JBB (41.0 months, [34.1-82.6], p = 0.013). CONCLUSION: Country of birth is associated with endometrial cancer survival in Black women, with HBB demonstrating worse outcomes.