Citations

AbstractBackgroundGenetic variations have emerged as crucial players in the etiology of Alzheimer’s disease (AD), and they serve for a better understanding of the disease mechanisms; yet the specific roles of these genetic variants remain uncertain. Animal models with reminiscent disease pathology could uncover previously uncharacterized roles of these genes. Therefore, we generated zebrafish models for AD variants to analyze the in depth molecular and biological functions of these variants.MethodUsing CRISPR/Cas9, we generated a knockout model for abca7, orthologous to human ABCA7. We performed single cell transcriptomics and analyzed the altered genes and molecular pathways in zebrafish. We leveraged data from multiethnic AD cohorts at Mayo Clinic and Columbia University, to perform genetic association studies, co‐expression analyses, in silico interaction mapping, family based variant segregation analyses and epigenetic association studies, and the functional and histological studies in zebrafish.ResultThe abca7± zebrafish reduced astroglial proliferation, synaptic integrity, and microglial response after Aβ42 toxicity. We found that the abca7 loss‐of‐function (LOF) reduced neuropeptide Y (npy) expression as well as Brain‐derived neurotrophic factor (bdnf) and Nerve growth factor receptor (ngfr). Human brain analysis showed reduced NPY in AD, regulatory interaction between NPY and BDNF, genetic variants in NPY associated with AD, and segregation of variants in ABCA7, BDNF and NGFR in families. ABCA7 variants altered the epigenetic codes in NPY, BDNF, and NGFR promoter regions. Human results paralleled with zebrafish findings to indicate an evolutionarily conserved disease mechanism through ABCA7‐NPY signalling axis. NPY administration to zebrafish rescued the phenotypes in abca7 knockout, suggesting a true biological relevance.ConclusionOur results demonstrate a previously unknown link between ABCA7 and NPY in regulation of synaptic integrity and neurogenesis in AD. We propose that ABCA7‐dependent NPY is a resilience factor in vertebrate brains, and this reserve mechanism is impaired in AD.

Purpose of review Peyronie's disease characterizes a condition in which there is angular curvature of the penis. We know that the most patients with Peyronie's disease will not have spontaneous resolution of their penile curvature. As such, patients who desire treatment can elect for either surgical or nonsurgical therapy. Herein, we discuss the contemporary nonsurgical management options for Peyronie's disease. Recent findings Nonsurgical management options for Peyronie's disease include oral therapy, intra-lesional injections, and penile traction therapy. At the time of this review, there is essentially no high-level evidence demonstrating any benefit for oral therapy. Penile traction therapy has evolved over the past decade with second-generation devices demonstrating strong efficacy and more convenient treatment regimens. Intra-lesional options include collagenase Clostridium histolyticum (CCH), verapamil, and interferon alpha-2b. The IMPRESS trial garnered the strongest level of evidence (two randomized, double-blind, placebo-controlled trials) to support the safety and efficacy of CCH. Verapamil is an option supported by several urological societies; however, the evidence supporting its efficacy is inconsistent between several notable series and randomized studies. IFN alpha 2b can produce modest improvement in curvature, however, is not available for use in North America. Summary Herein, we will discuss notable advances in nonsurgical management of Peyronie's disease.

DEK::AFF2 fusion nonkeratinizing squamous cell carcinoma (NKSCC) is an emerging entity in the sinonasal tract, temporal bone, and skull base. However, the clinical behavior of these tumors has not been well studied. Here, we report the largest cohort of DEK::AFF2 carcinomas to determine if morphology, mitotic rate, and/or Ki-67 IHC are associated with patient outcomes, including a comparison with high-risk human papillomavirus (HPV)-associated and independent patients. We solicited cases of molecularly or AFF2 immunohistochemistry (IHC) proven DEK::AFF2 SCC from surgical pathologists to collect patient demographic, clinical, and outcome data. Using representative H&E slides, we characterized the morphology and counted mitoses. Ki-67 immunohistochemistry was performed. We also compared the DEK::AFF2 survival rates to those in a cohort of AFF2 IHC-negative HPV-associated and HPV-independent SCC. DEK::AFF2 carcinomas most commonly arose in the nasal cavity (13/30, 43%), and the average number of recurrences was 1.8 (range: 0 to 10). At the last follow-up, most patients were disease free (19/30, 63%) or were alive with disease (9/30, 30%). There was an average mitotic rate of 2 per 2 mm2 (range: 0 to 9) and Ki-67 proliferation rate of 26% (range: 3% to 60%). Local recurrence was common, but morphology, mitotic activity, and Ki-67 index were not associated with recurrence or survival. On Kaplan-Meier survival analysis, DEK::AFF2 patients had lower disease-free survival but otherwise had similar outcomes to conventional SCC patients. Our multi-institutional study shows that local recurrence is common in DEK::AFF2 fusion nonkeratinizing SCC patients, but patients have survival rates similar to conventional SCC. Despite showing a range of different features and proliferation rates, traditional grading by morphology, mitotic rate, and/or Ki-67 activity does not seem to be predictive of outcome.

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) has surged as a major cause of liver transplants in the United States. Existing studies have presented conflicting findings regarding the association between liver characteristics (specifically steatosis and fibrosis) and mortality. This study investigates the relationship between the controlled attenuation parameter (CAP) and liver stiffness measurement (LSM) via vibration-controlled transient elastography (VCTE) and all-cause mortality in MASLD patients. Methods: Using the NHANES 2017-2018 database, 3821 individuals representing the United States population with MASLD underwent VCTE for liver stiffness measurement. Exclusion criteria were applied, eliminating ineligible cases, incomplete examinations, underage individuals, and those with hepatitis B or C, along with significant alcohol consumption history. Cox proportional hazard models assessed the hazard ratio (HR) for all-cause mortality in CAP and LSM. Cox regression analysis with interaction terms was employed for deeper exploration. Results: The study unveiled a strong, independent correlation between LSM and all-cause mortality. However, the CAP failed to demonstrate a significant association with mortality in both univariate and adjusted analyses, contrary to recent findings. The analysis underscores the importance of accurately measuring liver stiffness via VCTE in predicting adverse outcomes in MASLD patients, emphasizing the pivotal role of fibrosis in assessing mortality risk. Conclusion: This study reaffirms the robust link between liver fibrosis (measured through VCTE) and mortality among MASLD individuals. The absence of a significant association between steatosis (indicated by CAP) and mortality challenges recent research, urging further comprehensive investigations with larger cohorts to delineate steatosis’ precise impact on MASLD-related mortality.

Abstract As the healthcare burden caused by an increasingly aging population rapidly rises, a pressing need exists for innovative geroscience research that can elucidate aging mechanisms and precipitate the development of therapeutic interventions to support healthy aging. The Fifth Annual Midwest Aging Consortium Aging Research symposium, held from April 28 to 30, 2024, was hosted by The Ohio State University in Columbus, Ohio, and featured presentations from investigators across the Midwestern United States. This report summarizes the research presented at the symposium, whose topics included cellular senescence and the aging brain, metabolism and metabolic interventions, nutrition, redox mechanisms and biomarkers, and stress mechanisms. Abstract presentations and short talks highlighted early-stage and young investigators, whereas 2 keynote presentations anchored the symposium. Overall, this symposium showed the robustness of aging research in the Midwest and underscored the advantages of a collaborative approach to geroscience research.

Abstract Introduction Incorporation of mammographic density to breast cancer risk models could improve risk stratification to tailor screening and prevention strategies according to risk. Robust evaluation of the value of adding mammographic density to models with comprehensive information on questionnaire-based risk factors and polygenic risk score is needed to determine its effectiveness in improving risk stratification of such models. Methods We used the Individualized Coherent Absolute Risk Estimator (iCARE) tool for risk model building and validation to incorporate density to a previously validated literature-based model with questionnaire-based risk factors and a 313-variant polygenic risk score (PRS). The model was evaluated for calibration and discrimination in three prospective cohorts of European-ancestry women (1,468 cases, 19,104 controls): US-based Nurses’ Health Study (NHS I and II) and Mayo Mammography Health Study (MMHS); and Sweden-based Karolinska Mammography Project for Risk Prediction of Breast Cancer (KARMA) study. Analyses were done separately for women younger (NHS II, KARMA) and older than 50 years (NHS I, MMHS, KARMA). Improvements in terms of risk stratification and reclassification proportions were assessed among European-ancestry women aged 50–70 years in US and Sweden. Results For women younger and older than 50 years, the model with questionnaire-based risk factors, PRS and density was generally well calibrated across risk with some evidence of miscalibration at the extremes of the risk distribution. Incorporation of density led to modest improvements risk discrimination beyond the model with questionnaire-based risk factors and PRS: the area under the curve (AUC) among younger women was 67.0% (95% CI: 63.5–70.6%) vs. 65.6% (95% CI: 61.9–69.3%) for models with and without density; and 66.1% (95% CI 64.4–67.8%) vs. 65.5% (95% CI: 63.8–67.2%) among older women. The model with density identified 18.4% of US women 50–70 years old ≥ 3% 5-year predicted risk (threshold used for recommending risk-reducing medication in the US), with 42.4% of future cases expected to occur in this group. At this threshold, 7.9% of US women were reclassified by adding density to the model, resulting in the identification of 2.8% of additional future cases. The model with density identified 10.3% of Swedish women ≥ 3% 5-year predicted risk, with 29.4% of future cases expected to occur in this group. At this threshold, 5.3% of women were reclassified with the addition of density, leading to the identification of an additional 4.4% of future cases. Conclusion Integrating density with questionnaire-based risk factors and PRS could potentially identify more women of European-ancestry with elevated risk of breast cancer in the United States and Sweden. Further investigations of the integrated model in non-European ancestry populations are needed prior to considering clinical applications.

Abstract Aims We aimed to perform a retrospective cohort study using the Centers for Disease Control and Prevention’s (CDC’s) Wide-Ranging Online Data for Epidemiologic Research (WONDER) database to analyse the trends in cardiovascular disease (CVD)–related mortality in patients with myeloproliferative neoplasms (MPNs) from 1999 to 2020. Methods and results We analysed the death certificate data from the CDC WONDER database from 1999 to 2020 for CVD with co-morbid myeloproliferative disorders in the US population. Age-adjusted mortality rates (AAMRs) and 95% confidence intervals (CIs) were computed per 1 million population by standardizing crude mortality rates to the 2000 US census population. To assess annual national mortality trends, we employed the Joinpoint regression model, calculating the annual per cent change in AAMR and corresponding 95% CIs. A total of 15 269 deaths related to CVD occurred in patients with co-morbid MPNs from 1999 to 2020. Overall, there was a decreasing trend in CVD-related AAMRs throughout these years. Males contributed to 51% of total deaths, and their AAMR was persistently higher than women throughout the study. Non-Hispanic (NH) Whites had the highest overall AAMR, followed by NH Blacks, NH American Indians or Alaska Natives, Hispanics or Latinos, and NH Asian or Pacific Islanders. Conclusion Our findings indicate a significant decline with notable gender, racial/ethnic, and regional differences in CVD-related mortality among patients with MPN over the past two decades. We emphasize the importance of a collaborative approach between oncologists and cardiologists in managing these patients, highlighting the potential benefits of integrating cardio-oncology services to enhance patient outcomes.

Background: The joint College of American Pathologists/American College of Medical Genetics and Genomics Cytogenetics Committee works to ensure the competency and proficiency of clinical cytogenetic testing laboratories through proficiency testing (PT) programs for various clinical tests offered by such laboratories, including the evaluation of cytogenetic abnormalities in solid tumors. Methods: Review and analyze 25 years (1999–2023) of solid tumor chromosome analysis PT results, utilizing G-banded karyograms. A retrospective review of results from 1999 to 2023 was performed, identifying the challenges addressing solid tumors. The chromosomal abnormalities and overall performance were evaluated. Results: A total of 21 solid tumor challenges were administered during the period 1999–2018. No solid tumor challenges were administered during the period 2019–2023. Challenges consisted of metaphase images and accompanying clinical history for the evaluation of numerical and/or structural abnormalities. All 21 cases reached 80% grading consensus for abnormality recognition. However, five cases (24%) failed to reach consensus for nomenclature reporting by participating laboratories. These cases illustrate errors in reporting chromosomal abnormalities, including whole-arm translocations and those involving sex chromosomes. In addition, they highlight the challenges with differentiation of terminal and interstitial deletions, difficulties in identifying correct breakpoints, and omission of brackets in neoplastic cases. Conclusions: This comprehensive 25-year review demonstrates the exceptional proficiency of cytogenetic laboratories in accurately identifying chromosome abnormalities in solid tumors, while also highlighting the challenges of reporting specific types of chromosomal abnormalities.