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Purpose: Immune checkpoint inhibitors are a standard treatment option for many patients with cancer and are most frequently used to treat lung cancer. Chronic obstructive pulmonary disease (COPD) is the most common comorbidity of patients with lung cancer. As the cancer-specific survival of patients with lung cancer continues to increase with modern treatments, it is critical to optimize comorbidities to improve overall survival. This literature review aimed to summarize current research on the impact of COPD upon immunotherapy outcomes., Methods: A comprehensive search was conducted in the PubMed database using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Inclusion criteria focused on peer-reviewed articles published between 2010 and 2024 that addressed COPD, cancer, and immune checkpoint inhibitors. The study team screened the studies for relevance and then synthesized them narratively., Results: This review identified 37 studies that met the inclusion criteria. Findings suggest that COPD is predictive of improved efficacy but slightly worse toxicity from immune checkpoint inhibitor therapy. The chronic inflammation of COPD leads to immune exhaustion including the overexpression of immune checkpoints on T-cells. Particularly within "hot" tumors that have higher concentrations of tumor-infiltrating lymphocytes, the COPD-related increase in programmed cell death protein 1 (PD-1) signaling likely creates sensitivity to immune checkpoint inhibitors. However, COPD can also lead to respiratory dysfunction, debility, and interstitial lung disease; each of which increases the severity of immune-related adverse events., Conclusion: COPD is a critical comorbidity that has a significant impact on many patients with cancer who receive treatment with immune checkpoint inhibitors. Future research is needed to design interventions to optimize COPD care in this high-risk patient population., Competing Interests: Dr Jill Ohar reports grants from Teva, grants from Boehringer Ingelheim, grants from Mylan, personal fees from Astra Zeca, personal fees from Chiesi, personal fees from Boehringer Ingelheim, personal fees from Verona, outside the submitted work. The authors report no other conflicts of interest in this work., (© 2024 Lycan Jr et al.)

Background For over a decade, the number of residency applications has surged, a trend known as "application inflation." COVID-19 further intensified this trend, leading the Association of American Medical Colleges (AAMC) to address the issue by introducing a supplemental application in the 2021-2022 cycle, allowing programs to identify applicants with a connection to their program or geographic region. For the 2022-2023 cycle, the number of program signals increased from five to seven. The impact of the supplemental application and the increase in signals on the likelihood of an applicant matching with a program has yet to be evaluated. Methods This retrospective cohort study evaluated the impact of program signaling and geographic preference on the matching likelihood in our internal medicine residency program. Data from MyERAS® and the Supplemental Application for 640 applicants who applied to our large, urban, university-based program in the Southeastern United States during the 2020-2021 and 2022-2023 application cycles were included. Using univariate and multivariate analysis, we examined the correlation between program signal, geographic preference, and final match location. Results Applicants who sent a program signal had nearly three-fold higher odds of matching with our program. Geographic preference was numerically but not statistically associated with higher odds of matching. Both signaling a preference for matching with a program in an urban environment and couples matching correlated with decreased odds of matching with our program. Geography was an important predictor of match location as residing in our AAMC geographic region, our four-state area, and our specific state had increased odds of matching with our program. Conclusions Signaling our program was associated with increased odds of matching with our program. Geographic preferences were less predictive of a match with our program; however, they did predict the likelihood of a match at a program within that region. Future studies are needed to ensure external validity., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Wake Forest University Health Sciences Institutional Review Board issued approval IRB00096304. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Norton et al.)

Background: Metabolic syndrome (MetS) has been associated with increased risk for Alzheimer's disease and related dementias (ADRD). Understanding the association of MetS risk factors to processing speed and executive function in the pre-clinical stages of ADRD in under-represented groups would offer insight on potential mechanisms through which MetS associates with ADRD risk., Objective: Examine association of MetS features and processing speed and executive function across three racial groups., Methods: Cognitively unimpaired adults from the Wisconsin Alzheimer's Disease Research Center and the Wisconsin Registry for Alzheimer's Disease Prevention completed blood-draws and neuropsychological testing. Six cognitive outcomes were assessed in association to MetS risk factors: Trailmaking Tests A and B, Animal Fluency, Digit Symbol, and composite scores for Processing Speed and Executive Function. Linear mixed effect models were used to assess the relationship between MetS risk factor count and longitudinal cognitive performance across three racialized groups., Results: Participant sample sizes varied by outcome analyzed (N = 714-1,088). African American and Native American groups exhibited higher rates of MetS than non-Hispanic Whites. MetS was associated with processing speed and executive function across all racialized groups. Three-way interaction by racialized group was limited to one cognitive outcome: Trailmaking Test A., Conclusion: Metabolic dysfunction incrementally affects cognitive trajectory, with generally similar associations across racial groups. Since racialized groups exhibit higher levels of both MetS and ADRD, MetS may represent a driving factor for increased ADRD risk experience by racialized group and an important and modifiable target through which to reduce risk of ADRD.

Introduction: Batch differences in cerebrospinal fluid (CSF) biomarker measurement can introduce bias into analyses for Alzheimer's disease studies. We evaluated and adjusted for batch differences using statistical methods., Methods: A total of 792 CSF samples from 528 participants were assayed in three batches for 12 biomarkers and 3 biomarker ratios. Batch differences were assessed using Bland-Altman plot, paired t test, Pitman-Morgan test, and linear regression. Generalized linear models were applied to convert CSF values between batches., Results: We found statistically significant batch differences for all biomarkers and ratios, except that neurofilament light was comparable between batches 1 and 2. The conversion models generally had high R 2 except for converting P-tau between batches 1 and 3., Discussion: Between-batch conversion allows harmonized CSF values to be used in the same analysis. Such method may be applied to adjust for other sources of variability in measuring CSF or other types of biomarkers., Competing Interests: Dr. Cynthia Carlsson receives grant support from NIH/Lilly, NIH, Veterans Affairs, and Bader Philanthropies. Dr. Sterling Johnson previously served on the advisory board for Roche Diagnostics. Dr. Sanjay Asthana serves as a site PI for pharmaceutical trials funded by Merck Pharmaceuticals, Lundbeck, NIH/UCSD, EISAI, and Genentech Inc. Dr. Richard Chappell serves on data safety monitoring boards for Axsome Pharmaceuticals and TGR Pharmaceuticals and has recently had a speaking engagement at Merck, Inc. Dr. Henrik Zetterberg has served at scientific advisory boards for Denali, Roche Diagnostics, Wave, Samumed, and CogRx; has given lectures in symposia sponsored by Fujirebio, Alzecure, and Biogen; and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program. Dr. Kaj Blennow has served as a consultant or on advisory boards for Abcam, Axon, Biogen, Lilly, MagQu, Novartis, and Roche Diagnostics, and is a co‐founder of Brain Biomarker Solutions in Gothenburg AB (BBS), which is a part of the GU Ventures Incubator Program., (© 2021 The Authors. Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring published by Wiley Periodicals, LLC on behalf of Alzheimer's Association.)

Background: To fully characterize the risk for dementia associated with cigarette smoking, studies must consider competing risks that hinder the observation of dementia or modify the chance that dementia occurs (i.e., death). Extant research examining the competing risks fails to account for the occurrence of death following dementia, limiting our understanding of the relation between smoking and dementia., Objective: Examine the impact of smoking status, lifetime smoking exposure, and duration of abstinence on incident dementia, death following dementia, and death without dementia., Methods: Multi-state models estimated hazard ratios (HR) for 95% confidence interval (CI) of 10,681 cognitively healthy adults for transition from baseline to dementia, baseline to death, and dementia to death based on smoking status, lifetime cigarette exposure, and abstinence duration., Results: Compared to never smokers, current smokers had increased risk of dementia (HR = 1.66; 95% CI 1.18- 2.32; p = 0.004), and death from baseline (HR = 2.98; 95% CI 2.24- 3.98; p < 0.001) and incident dementia (HR = 1.88; 95% CI 1.08- 3.27; p = 0.03). Pack years increased risk of death from baseline (HR = 1.01; 95% CI 1.00- 1.01; p < 0.001), but not dementia risk (HR = 1.00; 95% CI 1.00- 1.00; p = 0.78) or death following dementia (HR = 1.01; 95% CI 1.00- 1.01; p = 0.05). Recent quitters (quit < 10 years), compared to never smokers, had increased risk of death after baseline (HR = 2.31; 95% CI 1.55- 3.43; p < 0.001), but not dementia (HR = 1.17; 95% CI 0.73- 1.88; p = 0.52) or death following dementia (HR = 1.01; 95% CI 0.42- 2.41; p = 0.99)., Conclusion: Current smoking increases the risk for dementia and death, but dementia is better attributed to smoking recency than lifetime exposure. Smoking cessation at any age might reduce these risks for cognitively healthy individuals.

Background: Foxp3 + regulatory T cells (Tregs) play essential roles in immune homeostasis and repair of damaged lung tissue. We hypothesized that patients whose lung injury resolves quickly, as measured by time to liberation from mechanical ventilation, have a higher percentage of Tregs amongst CD4 + T cells in either airway, bronchoalveolar lavage (BAL) or peripheral blood samples., Methods: We prospectively enrolled patients with ARDS requiring mechanical ventilation and collected serial samples, the first within 72 h of ARDS diagnosis (day 0) and the second 48-96 h later (day 3). We analyzed immune cell populations and cytokines in BAL, tracheal aspirates and peripheral blood, as well as cytokines in plasma, obtained at the time of bronchoscopy. The study cohort was divided into fast resolvers (FR; n = 8) and slow resolvers (SR; n = 5), based on the median number of days until first extubation for all participants (n = 13). The primary measure was the percentage of CD4 + T cells that were Tregs., Results: The BAL of FR contained more Tregs than SR. This finding did not extend to Tregs in tracheal aspirates or blood. BAL Tregs expressed more of the full-length FOXP3 than a splice variant missing exon 2 compared to Tregs in simultaneously obtained peripheral blood., Conclusion: Tregs are present in the bronchoalveolar space during ARDS. A greater percentage of CD4 + cells were Tregs in the BAL of FR than SR. Tregs may play a role in the resolution of ARDS, and enhancing their numbers or functions may be a therapeutic target.

Yongey Mingyur Rinpoche (YMR) is a Tibetan Buddhist monk, and renowned meditation practitioner and teacher who has spent an extraordinary number of hours of his life meditating. The brain-aging profile of this expert meditator in comparison to a control population was examined using a machine learning framework, which estimates "brain-age" from brain imaging. YMR's brain-aging rate appeared slower than that of controls suggesting early maturation and delayed aging. At 41 years, his brain resembled that of a 33-year-old. Specific regional changes did not differentiate YMR from controls, suggesting that the brain-aging differences may arise from coordinated changes spread throughout the gray matter.

Recovery from acute lung injury (ALI) is an active process. Foxp3+ Tregs contribute to recovery from ALI through modulating immune responses and enhancing alveolar epithelial proliferation and tissue repair. The current study investigates Treg transcriptional profiles during resolution of ALI in mice. Tregs from either lung or splenic tissue were isolated from uninjured mice or mice recovering from ALI and then examined for differential gene expression between these conditions. In mice with ALI, Tregs isolated from the lungs had hundreds of differentially expressed transcripts compared with those from the spleen, indicating that organ specificity and microenvironment are critical in Treg function. These regulated transcripts suggest which intracellular signaling pathways modulate Treg behavior. Interestingly, several transcripts having no prior recognized function in Tregs were differentially expressed by lung Tregs during resolution. Further investigation into 2 identified transcripts, Mmp12 and Sik1, revealed that Treg-specific expression of each plays a role in Treg-promoted ALI resolution. This study provides potentially novel information describing the signals that may expand resident Tregs, recruit or retain them to the lung during ALI, and modulate their function. The results provide insight into both tissue- and immune microenvironment-specific transcriptional differences through which Tregs direct their effects.

Objectives: Prior research has identified numerous genetic (including sex), education, health, and lifestyle factors that predict cognitive decline. Traditional model selection approaches (e.g., backward or stepwise selection) attempt to find one model that best fits the observed data, risking interpretations that only the selected predictors are important. In reality, several predictor combinations may fit similarly well but result in different conclusions (e.g., about size and significance of parameter estimates). In this study, we describe an alternative method, Information-Theoretic (IT) model averaging, and apply it to characterize a set of complex interactions in a longitudinal study on cognitive decline., Methods: Here, we used longitudinal cognitive data from 1256 late-middle aged adults from the Wisconsin Registry for Alzheimer's Prevention study to examine the effects of sex, apolipoprotein E (APOE) ɛ4 allele (non-modifiable factors), and literacy achievement (modifiable) on cognitive decline. For each outcome, we applied IT model averaging to a set of models with different combinations of interactions among sex, APOE, literacy, and age., Results: For a list-learning test, model-averaged results showed better performance for women versus men, with faster decline among men; increased literacy was associated with better performance, particularly among men. APOE had less of an association with cognitive performance in this age range (∼40-70 years)., Conclusions: These results illustrate the utility of the IT approach and point to literacy as a potential modifier of cognitive decline. Whether the protective effect of literacy is due to educational attainment or intrinsic verbal intellectual ability is the topic of ongoing work. (JINS, 2019, 25, 119-133).

Background & Aims: Colonoscopy may have a greater protective effect for distal colorectal cancer (CRC) than proximal CRC. Serrated polyps are frequently located in the proximal colon, can be missed during colonoscopy, and may progress to CRC. We investigated the prevalence and endoscopist detection rates of proximal serrated polyps in a large cohort of average risk patients undergoing screening colonoscopy., Methods: Screening colonoscopies performed by 15 attending gastroenterologists at 2 academic endoscopy units between 2000 and 2009 were reviewed. Serrated polyps included hyperplastic polyps, sessile serrated adenomas, and traditional serrated adenomas. Endoscopist-level detection rates for adenomas and serrated polyps were calculated. Pearson correlation coefficients were calculated to evaluate the associations of adenoma and proximal serrated polyp detection rates. Logistic regression was used to compare endoscopists' detection rates., Results: A total of 11,049 polyps were detected in 6681 colonoscopies (adenomas: 5637, 51%; serrated: 3984, 36%; proximal serrated: 1238, 11%). The proportion of colonoscopies with at least one proximal serrated polyp was 13% (range 1%-18%). Proximal serrated polyp detection rates per colonoscopy ranged from 0.01 to 0.26. Adenoma and proximal serrated polyp detection rates per colonoscopy were strongly correlated (R = 0.76, P = .0005). The odds of detecting at least one proximal serrated polyp for individual endoscopists ranged from 0.05 to 0.67 compared to the highest level detector. Endoscopist (P < .0001), but not patient age (P = .76) or gender (P = .95), was associated with proximal serrated polyp detection., Conclusions: In an average-risk screening cohort, the detection of proximal serrated polyps was highly variable and endoscopist dependent. A significant proportion of proximal serrated polyps may be missed during colonoscopy. High-quality colonoscopy is important for the detection and resection of all polyps with neoplastic potential., (Copyright © 2011 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Metastatic melanoma is one of the deadliest of skin cancers and is increasing in incidence. Since current treatment regimens are ineffective at controlling and/or curing the disease, novel approaches, such as immunotherapy, for treating this malignant disease are being explored. In this review, we discuss potential melanoma antigens (Ags) and their role in utilizing the HLA class II pathway to elicit tumor Ag-specific CD4+ T cell responses in order to effectively induce long-lasting CD8+ antitumor memory. We also discuss the role of endolysosomal cathepsins and Gamma-Interferon-inducible Lysosomal Thiol reductase (GILT) in Ag processing and presentation, and at enhancing CD4+ T cell recognition of melanoma cells. This review also summarizes our current knowledge on GILT and highlights a novel mechanism of GILT-mediated immune responses against melanoma cells. At the end, we propose a strategy employing GILT in the development of a potential whole cell vaccine for combating metastatic melanoma.

Multiple endocrine neoplasia type 2A (MEN2A) is predisposed by mutations in the RET proto-oncogene. Low expression of the cyclin-dependent kinase inhibitor (CDKI) p27(Kip1) is present in thyroid tumors, and recent evidence demonstrates p27 downregulation by the active RET mutant, RET/PTC1, found in papillary thyroid carcinoma. This implicates decreased p27 activity as an important event during thyroid tumorigenesis. However, p27(-/-) mice develop MEN-like tumors only in combination with loss of another CDKI, p18(Ink4c). This suggests that p18 and p27 functionally collaborate in suppression of tumorigenesis, that loss of both is critical in the development of MEN tumors and that both p18 and p27 are regulated by RET. We report that induction of the constitutively active MEN2A-specific RET mutant, RET2A(C634R), correlates with reduced p18/p27, and elevated cyclin D protein levels, leading to increased CDK activity, increased pRb phosphorylation and proliferation under growth arrest conditions. Mechanistically, RET2A represses p18/p27 mRNA levels while elevating cyclin D1 mRNA levels. RET2A expression also correlates with decreased p27 protein stability. RET2A-mediated regulation of p18 and p27, but not of cyclins D1 and D2, requires functional mitogen-activated protein kinase signaling. Additionally, RET2A-dependent p18 repression is required and sufficient to increase cell proliferation. Perhaps most significantly, MEN2A adrenal tumors also display these changes in cell cycle expression profile, demonstrating the biological relevance of our cell culture studies. Our results demonstrate for the first time that RET2A regulates p18, and suggest that loss of not only p27 but also of p18 expression is a key step in MEN tumorigenesis.