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Objectives Long-term exposure to ambient fine particles (PM(2.5)) has been shown to increase mortality. Variables measured on the same spatial scales of air pollution may confound associations, and so the authors' objectives were to evaluate the associations between PM(2.5) and individual-level measures of smoking, obesity and sociodemographic status. The authors present an approach to evaluate the impact that uncontrolled confounding from smoking may have on associations between PM(2.5) and mortality. Methods Individual-level behavioural and sociodemographic data were obtained from a 2003 national survey of 122548 Canadians. Estimates of ground-level PM(2.5) at a resolution of 10x10 km between 2001 and 2006 were derived from satellite remote sensing. Exposures were assigned to the residence of the participants at the time of the survey. Differences in the prevalence of smoking across concentrations of PM(2.5) and RRs drawn from the literature were used to model the bias on rate ratios. Results Participants in areas with higher concentrations of PM(2.5) had a higher income and educational attainment, smoked less and were more likely immigrants. Smoking had a negative confounding effect on the associations between PM(2.5) and mortality. To compensate for this bias, for a 10 [mu]g/m(3) increase in PM(2.5), mortality from lung cancer and heart disease in the referent exposure group needed to be increased by 6.9% and 3.2%, respectively. Conclusions Associations were found between sociodemographic and lifestyle characteristics and PM(2.5) at a resolution of 10x10 km. The authors present a model to adjust for uncontrolled confounding of smoking that can be readily adapted to exposures measured at different spatial resolutions. [ABSTRACT FROM AUTHOR]

In the first 6.5 years of Operation Iraqi Freedom (OIF), U.S. military casualties exceeded 3,400 hostile deaths, 800 nonhostile deaths (due to disease, nonbattle injury, and other causes), and over 31,000 troops wounded in action. Casualty rates in Iraq have been considerably lower that during the Vietnam conflict, and a greater proportion of troops wounded in Iraq survive their wounds. Before the surge in troop levels that began in early 2007, the survival rate was 90.4% in Iraq as compared to 86.5% in Vietnam. Wounded-in-action rates increased during the first few months of the surge, but declined below presurge levels after the number of U.S. brigades in Iraq climbed from 15 to its maximum level of 20. Wounds during the surge were somewhat more lethal than previously, but because there were fewer wounding incidents the net effect was a reduction in the hostile death rate. [ABSTRACT FROM AUTHOR]

The present article challenges the ways in which ethical guidelines are implemented in reviewing the design and conduct of research involving human participants in observational studies in Canada. Fieldwork procedures should be designed in such a way as to be valid scientifically but also acceptable in terms of local ethical considerations, such as confidentiality of participant's identity and information, and other social norms. To set the stage, I present briefly essential information regarding the valid design and conduct of observational epidemiologic studies. As an example of the difficulties encountered in implementing these procedures, I present my experience in gaining ethical approval for a population-based, case-control study of environmental causes of postmenopausal breast cancer. [ABSTRACT FROM AUTHOR]

BACKGROUND: Practice guidelines for breast cancer emphasize the importance of establishing an accurate diagnosis using a minimum number of procedures and selecting optimal treatment regimens. Understanding the determinants of waiting time is essential to develop optimum interventions to reduce delay. OBJECTIVES: The purpose of this study is to estimate the extent to which variability in 1) the number of procedures before surgery and 2) waiting time from initial procedure to surgery are explainable by factors related to the woman, to the provider, and to the care setting. RESEARCH DESIGN: Records of physicians' fee-for-service claims were obtained for 23,370 women undergoing breast cancer surgery in Quebec between 1992 and 1997. Multilevel logistic regression was used to determine predictors of having multiple procedures before surgery. Hierarchical linear regression models were used to identify predictors of waiting time, separately for women with lymph node involvement and without this involvement. RESULTS: Overall, 23% of the women had 3 or more procedures before surgery with significant variation found across hospitals and surgeons. Number of procedures was a strong predictor of waiting time. Waiting time also varied by stage, age, comorbidity, a history of benign disease, surgical setting, calendar time, month of initial procedure, and hospital teaching status. CONCLUSION: Although variability in waiting time was more strongly influenced by the characteristics of the women rather than by physician- or hospital-related factors, most variation remained unexplained by the factors included in this study. To reduce overall waiting time, strategies would need to be systemically applied. [ABSTRACT FROM AUTHOR]

Purpose: We used Poisson regression methods to examine the relation between temporal changes in the levels of fine particulate air pollution (PM(2.5)) and the risk of mortality among participants of the Harvard Six Cities longitudinal study.Methods: Our analyses were based on 1430 deaths that occurred between 1974 and 1991 in a cohort that accumulated 105,714 person-years of follow-up. For each city, indices of PM(2.5) were derived using daily samples. Individual level data were collected on several risk factors including: smoking, education, body mass index (BMI), and occupational exposure to dusts. Time-dependent indices of PM(2.5) were created across 13 calendar periods (< 1979, 1979, 1980, em leader, 1989, >/= 1990) to explore whether recent or chronic exposures were more important predictors of mortality.Results: The relative risk (RR) of mortality calculated using Poisson regression based on average city-specific exposures that remained constant during follow-up was 1.31 [95% confidence interval (CI) = 1.12-1.52] per 18.6 microg/m(3) of PM(2.5). This result was similar to the risk calculated using the Cox model (RR = 1.26, 95% CI = 1.08-1.46). The RR of mortality was attenuated when the Poisson regression model included a time-dependent estimate of exposure (RR = 1.19, 95% CI = 1.04-1.36). There was little variation in RR across time-dependent indices of PM(2.5).Conclusions: The attenuated risk of mortality that was observed with a time-dependent index of PM(2.5) is due to the combined influence of city-specific variations in mortality rates and decreasing levels of air pollution that occurred during follow-up. The RR of mortality associated with PM(2.5) did not depend on when exposure occurred in relation to death, possibly because of little variation between the time-dependent city-specific exposure indices. [ABSTRACT FROM AUTHOR]

α-synuclein accumulation is recognized as a prominent feature in the majority of Parkinson's disease cases and also occurs in a broad range of neurodegenerative disorders including Alzheimer's disease. It has been shown that α-synuclein can spread from a donor cell to neighboring cells and thus propagate cellular damage, antagonizing the effectiveness of therapies such as transplantation of fetal or iPSC derived dopaminergic cells. As we and others previously have shown, insufficient lysosomal function due to genetic mutations or targeted disruption of cathepsin D can cause α-synuclein accumulation. We here investigated whether overexpression of cathepsin D or knockout (KO) of the transcriptional suppressor of lysosomal biogenesis ZKSCAN3 can attenuate propagation of α-synuclein aggregation and cell death. We examined dopaminergic neurodegeneration in the substantia nigra using stereology of tyrosine hydroxylase-immunoreactive cells 4 months and 6 months after intrastriatal injection of α-synuclein preformed fibrils or monomeric α-synuclein control in control, central nervous system (CNS)-cathepsin D overexpressing and CNS-specific ZKSCAN3 KO mice. We also examined pS129-α-synuclein aggregates in the substantia nigra, cortex, amygdala and striatum. The extent of dopaminergic neurodegeneration and pS129-α-synuclein aggregation in the brains of CNS-specific ZKSCAN3 knockout mice and CNS-cathepsin D overexpressing mice was similar to that observed in wild-type mice. Our results indicate that neither enhancing cathepsin D expression nor disrupting ZKSCAN3 in the CNS is sufficient to attenuate pS129-α-synuclein aggregate accumulation or dopaminergic neurodegeneration.

Aim: To independently confirm that the 40-gene expression profile (40-GEP) test can identify patients with high-risk cutaneous squamous cell carcinoma who are more or less likely to benefit from adjuvant radiation therapy (ART). Materials & methods: Primary cutaneous squamous cell carcinoma tumors from two academic centers received retrospective 40-GEP testing and were analyzed for 5-year metastasis-free survival and projected time to event. Results: Random sampling of matched patient pairs ( n  = 52 ART-treated; 371 no ART) showed a median 50% decrease in 5-year progression rate for ART-treated patients (vs no ART) with 40-GEP Class 2B. Class 2A was associated with a modest ART benefit, but not Class 1. Conclusion: The 40-GEP identified patients most likely to benefit from ART (Class 2B) and those that can consider deferring treatment (Class 1).

Abstract: Comparing studies of molecular ancillary diagnostic tests for difficult-to-diagnose cutaneous melanocytic neoplasms presents a methodological challenge, given the disparate ways accuracy metrics are calculated. A recent report by Boothby-Shoemaker et al investigating the real-world accuracy of the 23-gene expression profile (23-GEP) test highlights this methodological difficulty, reporting lower accuracy than previously observed. However, their calculation method-with indeterminate test results defined as either false positive or false negative-was different than those used in previous studies. We corrected for these differences and recalculated their reported accuracy metrics in the same manner as the previous studies to enable appropriate comparison with previously published reports. This corrected analysis showed a sensitivity of 92.1% (95% confidence interval [CI], 82.1%-100%) and specificity of 94.4% (91.6%-96.9%). We then compared these results directly to previous studies with >25 benign and >25 malignant cases with outcomes and/or concordant histopathological diagnosis by ≥3 dermatopathologists. All studies assessed had enrollment imbalances of benign versus malignant patients (0.8-7.0 ratio), so balanced cohorts were resampled according to the lowest common denominator to calculate point estimates and CIs for accuracy metrics. Overall, we found no statistically significant differences in the ranges of 23-GEP sensitivity, 90.4%-96.3% (95% CI, 80.8%-100%), specificity, 87.3%-96.2% (78.2%-100%), positive predictive value, 88.5%-96.1% (81.5%-100%), or negative predictive value, 91.1%-96.3% (83.6%-100%) between previous studies and the cohort from Boothby-Shoemaker et al with this unified methodological approach. Rigorous standardization of calculation methods is necessary when the goal is direct cross-study comparability., Competing Interests: E. Marks has served as a consultant for Castle Biosciences, Inc. C. J. Cockerell has served as a consultant and advisory board member for Castle Biosciences, Inc. J. H. Rogers, J. J. Siegel, B. H. Russell, and M. S. Goldberg are employees and shareholders of Castle Biosciences, Inc., the current laboratory where the 23-gene expression profile test is performed. The remaining authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Histopathological examination is adequate for the diagnosis of most cutaneous melanocytic neoplasms. However, there is a subset that is either difficult to definitively diagnose or would have diagnostic disagreement upon review by multiple dermatopathologists if a more exhaustive review was performed., Methods: Melanocytic lesions underwent an independent, blinded diagnostic histopathological review of hematoxylin and eosin-stained sections. Each lesion was reviewed by three to six dermatopathologists and categorized as benign, malignant, or unknown malignant potential (UMP). Diagnoses were grouped as concordant (all the same designation); opposing (received benign and malignant designations); majority (single designation with the highest number of diagnoses, no benign/malignant opposing designations); and non-definitive (equal number of non-opposing designations [i.e., benign/UMP or malignant/UMP]). Lesions with equivocal designations (concordant or majority UMP, opposing, majority, and non-definitive) were utilized in a patient treatment model of projected surgical treatment discrepancies., Results: In total, 3317 cases were reviewed, and 23.8% of lesions received equivocal diagnoses. Of these, 7.3% were majority benign, 4.8% were majority malignant, 2.7% were majority UMP, 0.5% were concordant UMP, 6.9% were opposing, and 1.6% were non-definitive. Patient treatment models of those with equivocal lesions (n = 788) revealed a potential of overall surgical treatment variations ranging from 18% to 72%, with the highest variation amongst lesions with opposing, non-definitive, or majority UMP (40%-72%) diagnoses., Conclusion: Histopathologic review in this large cohort demonstrated substantial diagnostic variation, with 23.8% of cases receiving equivocal diagnoses. We identified diagnostic ambiguity even in lesions where a definitive diagnosis was previously rendered by a single real-world dermatopathologist. The combined clinical impact of diagnostic discordance or a final diagnosis of UMP is highlighted by high diagnosis-dependent treatment variation in the patient treatment model, which could be underreported in a real-world setting, where review by more than one to two dermatopathologists is relatively rare., (© 2024 Castle Biosciences, Inc and The Authors. Journal of Cutaneous Pathology published by John Wiley & Sons Ltd.)

Background: Parkinson's disease is a progressive neurodegenerative disorder with multifactorial causes, among which genetic risk factors play a part. The RAB GTPases are regulators and substrates of LRRK2, and variants in the LRRK2 gene are important risk factors for Parkinson's disease. We aimed to explore genetic variability in RAB GTPases within cases of familial Parkinson's disease., Methods: We did whole-exome sequencing in probands from families in Canada and Tunisia with Parkinson's disease without a genetic cause, who were recruited from the Centre for Applied Neurogenetics (Vancouver, BC, Canada), an international consortium that includes people with Parkinson's disease from 36 sites in 24 countries. 61 RAB GTPases were genetically screened, and candidate variants were genotyped in relatives of the probands to assess disease segregation by linkage analysis. Genotyping was also done to assess variant frequencies in individuals with idiopathic Parkinson's disease and controls, matched for age and sex, who were also from the Centre for Applied Neurogenetics but unrelated to the probands or each other. All participants were aged 18 years or older. The sequencing and genotyping findings were validated by case-control association analyses using bioinformatic data obtained from publicly available clinicogenomic databases (AMP-PD, GP2, and 100 000 Genomes Project) and a private German clinical diagnostic database (University of Tübingen). Clinical and pathological findings were summarised and haplotypes were determined. In-vitro studies were done to investigate protein interactions and enzyme activities., Findings: Between June 1, 2010, and May 31, 2017, 130 probands from Canada and Tunisia (47 [36%] female and 83 [64%] male; mean age 72·7 years [SD 11·7; range 38-96]; 109 White European ancestry, 18 north African, two east Asian, and one Hispanic] underwent whole-exome sequencing. 15 variants in RAB GTPase genes were identified, of which the RAB32 variant c.213C>G (Ser71Arg) cosegregated with autosomal dominant Parkinson's disease in three families (nine affected individuals; non-parametric linkage Z score=1·95; p=0·03). 2604 unrelated individuals with Parkinson's disease and 344 matched controls were additionally genotyped, and five more people originating from five countries (Canada, Italy, Poland, Turkey, and Tunisia) were identified with the RAB32 variant. From the database searches, in which 6043 individuals with Parkinson's disease and 62 549 controls were included, another eight individuals were identified with the RAB32 variant from four countries (Canada, Germany, UK, and USA). Overall, the association of RAB32 c.213C>G (Ser71Arg) with Parkinson's disease was significant (odds ratio [OR] 13·17, 95% CI 2·15-87·23; p=0·0055; I 2 =99·96%). In the people who had the variant, Parkinson's disease presented at age 54·6 years (SD 12·75, range 31-81, n=16), and two-thirds had a family history of parkinsonism. RAB32 Ser71Arg heterozygotes shared a common haplotype, although penetrance was incomplete. Findings in one individual at autopsy showed sparse neurofibrillary tangle pathology in the midbrain and thalamus, without Lewy body pathology. In functional studies, RAB32 Arg71 activated LRRK2 kinase to a level greater than RAB32 Ser71., Interpretation: RAB32 Ser71Arg is a novel genetic risk factor for Parkinson's disease, with reduced penetrance. The variant was found in individuals with Parkinson's disease from multiple ethnic groups, with the same haplotype. In-vitro assays show that RAB32 Arg71 activates LRRK2 kinase, which indicates that genetically distinct causes of familial parkinsonism share the same mechanism. The discovery of RAB32 Ser71Arg also suggests several genetically inherited causes of Parkinson's disease originated to control intracellular immunity. This shared aetiology should be considered in future translational research, while the global epidemiology of RAB32 Ser71Arg needs to be assessed to inform genetic counselling., Funding: National Institutes of Health, the Canada Excellence Research Chairs program, Aligning Science Across Parkinson's, the Michael J Fox Foundation for Parkinson's Research, and the UK Medical Research Council., Competing Interests: Declaration of interests AR receives unrestricted research support from the Dr Ali Rajput Endowment for Parkinson's Disease and Movement Disorders; in the past 2 years AR has received honoraria from Quebec Consortium for Drug Discovery–Brain Canada and Ipsen Biopharmaceuticals Canada. MSG reports grants from National Institutes of Health (NIH)–National Institute of Neurological Disorders and Stroke (NINDS) and the Michael J Fox Foundation for Parkinson's Research. AJS has received fees from Neurocrine (Chair, Data and Safety Monitoring Board [DSMB]), AskBio (Member, DSMB) and Capsida (advisor), receives a stipend from the International Parkinson's and Movement Disorders Society (Editor-in-Chief, Movement Disorders) and grant funding from Michael J Fox Foundation, Weston Brain Institute, and Brain Canada. ZG-O received consultancy fees from Bial Biotec, Bial, Capsida, Handl Therapeutics, Idorsia, Neuron23, Ono Therapeutics, Prevail Therapeutics, UCB, and Vanqua. He reports grants from the Michael J Fox Foundation for Parkinson's Research, The Weston Family Foundation, The Silverstein Foundation, NIH, and the Canadian Consortium on Neurodegeneration in Aging. HRM is employed by University College Londn. In the last 12 months he reports paid consultancy from Roche, Aprinoia, AI Therapeutics, and Amylyx; lecture fees or honoraria from BMJ, Kyowa Kirin, Movement Disorders Society; and research grants from Parkinson's UK, Cure Parkinson's Trust, PSP Association, Medical Research Council, and Michael J Fox Foundation. HRM is a co-applicant on a patent application related to C9ORF72: method for diagnosing a neurodegenerative disease (PCT/GB2012/052140). MJF reports US patents associated with LRRK2 mutations and mouse models (8409809 and 8455243), and methods of treating neurodegenerative disease (20110092565). SA-C has received honoraria from Merz, and grant funding from the Pacific Parkinson's Research Institute, the Weston Family Foundation, Parkinson Canada, Canadian Institutes of Health Research (CIHR), the VGH and UBC Hospital Foundation, Rick's Heart Foundation, and the Jack and Darlene Poole Foundation. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Aim: Cutaneous melanocytic neoplasms with diagnostic and/or clinical ambiguity pose patient management challenges. Methods: Six randomized case scenarios with diagnostic/clinical uncertainty were described with/without a benign or malignant diagnostic gene expression profile (GEP) result. Results: Clinical impact was assessed by reporting the mean increase/decrease of management changes normalized to baseline (n = 32 dermatologists). Benign GEP results prompted clinicians to decrease surgical margins (84.2%). Malignant GEP results escalated surgical excision recommendations (100%). A majority (72.2%) reduced and nearly all (98.9%) increased follow-up frequency for benign or malignant GEP results, respectively. There was an overall increase in management plan confidence with GEP results. Conclusion: Diagnostic GEP tests help guide clinical decision-making in a variety of diagnostically ambiguous or clinicopathologically discordant scenarios., Competing Interests: The authors have no competing interests or relevant affiliations with any organization or entity with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties., (© 2024 The Authors.)

The ubiquitin kinase-ligase pair PINK1-PRKN recognizes and transiently labels damaged mitochondria with ubiquitin phosphorylated at Ser65 (p-S65-Ub) to mediate their selective degradation (mitophagy). Complete loss of PINK1 or PRKN function unequivocally leads to early-onset Parkinson disease, but it is debated whether impairments in mitophagy contribute to disease later in life. While the pathway has been extensively studied in cell culture upon acute and massive mitochondrial stress, basal levels of activation under endogenous conditions and especially in vivo in the brain remain undetermined. Using rodent samples, patient-derived cells, and isogenic neurons, we here identified age-dependent, brain region-, and cell type-specific effects and determined expression levels and extent of basal and maximal activation of PINK1 and PRKN. Our work highlights the importance of defining critical risk and therapeutically relevant levels of PINK1-PRKN signaling which will further improve diagnosis and prognosis and will lead to better stratification of patients for future clinical trials.

Background: Empirical decisions to select therapies for psoriasis (PSO) and atopic dermatitis (AD) can lead to delays in disease control and increased health care costs. However, routine molecular testing for AD and PSO are lacking., Objective: To examine (1) how clinicians choose systemic therapies for patients with PSO and AD without molecular testing and (2) to determine how often the current approach leads to patients switching medications., Methods: A 20-question survey designed to assess clinician strategies for systemic treatment of AD and PSO was made available to attendees of a national dermatology conference in 2022., Results: Clinicians participating in the survey (265/414, 64% response rate) ranked "reported efficacy" as the most important factor governing treatment choice ( P  < .001). However, 62% (165/265) of clinicians estimated that 2 or more systemic medications were typically required to achieve efficacy. Over 90% (239/265) of respondents would or would likely find a molecular test to guide therapeutic selection useful., Limitations: To facilitate ease of recall, questions focused on systemic therapies as a whole and not individual therapies., Conclusion: Clinicians want a molecular test to help determine the most efficacious drug for individual patients., Competing Interests: Dr Brownstone received a stipend paid for by Castle Biosciences, Inc. Dr Farberg is a consultant for Castle Biosciences, Inc and on the advisory board for Amgen, Boehringer Ingelheim, Eli Lilly, Galderma, Incyte, Janssen, Novartis, Ortho Dermatologics, Pfizer, and Sun Pharma. Drs Quick, Siegel, Hurton, and Goldberg are employees and option and stockholders for Castle Biosciences, Inc. Dr Lio reports research grants/funding from AbbVie, AOBiome, Eczema Foundation, National Eczema Association; is on the speaker's bureau for AbbVie, Eli Lilly, Galderma, Hyphens Pharma, Incyte, La Roche-Posay/L’Oreal, MyOR Diagnostics, ParentMD, Pfizer, Pierre-Fabre Dermatologie, and Regeneron/Sanofi Genzyme; reports consulting/advisory boards for AbbVie, Almirall, Amyris, Arbonne, ASLAN, Bodewell, Boston Skin Science, Bristol-Myers Squibb, Burt’s Bees, Castle Biosciences, Codex Labs, Concerto Biosci, Dermavant, Dermira, DermVeda, Eli Lilly, Galderma, IntraDerm, Janssen, Johnson & Johnson, Kaleido Biosci, Kimberly Clark, LEO Pharma, Lipidor, L’Oreal, Menlo Therapeutics, Merck, Micreos, MyOR Diagnostics, Regeneron/Sanofi Genzyme, Sibel Health, Skinfix, Sonica, Theraplex, UCB, Unilever, Verrica, and Yobee Care; reports stock options with LearnSkin/Learn Health, Medable, Micreos, Modernizing Medicine, and Yobee Care. In addition, Dr Lio has a patent pending for a Theraplex product with royalties paid and is a Board member and Scientific Advisory Committee Member of the National Eczema Association. Author Litchman has no conflicts of interest to declare., (© 2024 by the American Academy of Dermatology, Inc. Published by Elsevier Inc.)

Introduction: The validated 40-gene expression profile (40-GEP) test independently stratifies risk of regional or distant metastasis for cutaneous squamous cell carcinoma (cSCC) tumors with high-risk clinicopathologic features. This study evaluated the stratification of risk by the 40-GEP test in a large cohort of tumors with one or more high-risk factors and in clinically relevant subgroups, including tumors within National Comprehensive Cancer Network (NCCN) high- and very-high-risk groups, lower-stage BWH T1 and T2a tumors, and patients > 65 years old., Methods: This multicenter (n = 58) performance study of the 40-GEP included 897 patients. Kaplan-Meier analyses were performed to assess risk stratification profiles for 40-GEP Class 1 (low), Class 2A (higher) and Class 2B (highest) risk groups, while nested Cox regression models were used to compare risk prediction of clinicopathologic risk classification systems versus risk classification systems in combination with 40-GEP., Results: Patients classified as 40-GEP Class 1, Class 2A, or Class 2B had significantly different metastatic risk profiles (p < 0.0001). Integrating 40-GEP results into models with individual clinicopathologic risk factors or risk classification systems (Brigham and Women's Hospital, American Joint Committee on Cancer Staging Manual, 8th Edition) and NCCN demonstrated significant improvement in accuracy for prediction of metastatic events (ANOVA for model deviance, p < 0.0001 for all models)., Conclusion: The 40-GEP test demonstrates accurate, independent, clinically actionable stratification of metastatic risk and improves predictive accuracy when integrated into risk classification systems. The improved accuracy of risk assessment when including tumor biology via the 40-GEP test ensures more risk-aligned, personalized patient management decisions., (© 2024. The Author(s).)

Ancillary tests such as immunohistochemistry (IHC) and gene expression profile (GEP) testing may be needed to arrive at a definitive diagnosis for some atypical melanocytic neoplasms. A 34-year-old male with a family history of melanoma presented with a large, heterogeneous melanocytic lesion on the cheek. Histopathological review of two biopsies revealed an atypical intradermal melanocytic proliferation with spitzoid features without ulceration or regression. Scattered mitotic figures were identified. In addition to performing SOX10 IHC, PRAME and HMB45 staining highlighted weak, patchy positivity that was stronger in superficial, pleomorphic melanocytes (Ki-67, 5-7% mitotic rate). Based on these concerning but ambiguous IHC results and lingering concern for melanoma reiterated by other consulting dermatopathologists, the 23-GEP was requested for both specimens, which both returned a malignant result. The inconclusive histopathological features of malignancy were resolved by 23-GEP testing, facilitating a final diagnosis of malignant melanoma (pT3a, 2.5 mm Breslow depth, Clark's level IV).

Background: Breast cancer is the most diagnosed cancer among women and recognized risk factors explain 25%-47% of cases. Organic solvents are used widely in the workplace and exposure may increase the risk of developing breast cancer, yet there are insufficient data to confirm this hypothesis. We sought to determine whether past occupational exposures to selected organic solvents were associated with the incidence of invasive breast cancer in postmenopausal women in Montréal, Canada., Methods: From a population-based case-control study (2008-2011), using in-depth interviews we elicited information on risk factors and lifetime occupational histories. Industrial hygienists and chemists translated job descriptions into specific chemical and physical exposures. We assessed 11 individual solvents and four solvent groups. Unconditional logistic regression was used to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for metrics of past exposures to selected solvents. Exposure metrics included any previous exposure, average frequency in hours per week, duration in years, and average cumulative concentration weighted by hours per workweek exposed., Results: We enrolled 695 cases and 608 controls. We found increased ORs for average cumulative concentration of exposure to mononuclear aromatic hydrocarbons (OR: 1.52, 95% CI: 1.04, 2.28), chlorinated alkanes (OR: 2.42, 95% CI: 1.23, 5.68), toluene (OR: 1.59, 95% CI: 1.02, 2.59), and a group of organic solvents with reactive metabolites (OR: 1.53, 95% CI: 1.08, 2.24). Positive associations were found across all exposure metrics and were higher among women with estrogen-positive/progesterone-negative tumors., Conclusion: Our findings suggest occupational exposure to certain organic solvents may increase the risk of incident postmenopausal breast cancer., (© 2023 The Authors. American Journal of Industrial Medicine Published by Wiley Periodicals LLC.)

Light-at-night triggers the decline of pineal gland melatonin biosynthesis and secretion and is an IARC-classified probable breast-cancer risk factor. We applied a large-scale molecular epidemiology approach to shed light on the putative role of melatonin in breast cancer. We investigated associations between breast-cancer risk and polymorphisms at genes of melatonin biosynthesis/signaling using a study population of 44,405 women from the Breast Cancer Association Consortium (22,992 cases, 21,413 population-based controls). Genotype data of 97 candidate single nucleotide polymorphisms (SNPs) at 18 defined gene regions were investigated for breast-cancer risk effects. We calculated adjusted odds ratios (ORs) and 95% confidence intervals (CI) by logistic regression for the main-effect analysis as well as stratified analyses by estrogen- and progesterone-receptor (ER, PR) status. SNP-SNP interactions were analyzed via a two-step procedure based on logic regression. The Bayesian false-discovery probability (BFDP) was used for all analyses to account for multiple testing. Noteworthy associations (BFDP < 0.8) included 10 linked SNPs in tryptophan hydroxylase 2 (TPH2) (e.g. rs1386492: OR = 1.07, 95% CI 1.02-1.12), and a SNP in the mitogen-activated protein kinase 8 (MAPK8) (rs10857561: OR = 1.11, 95% CI 1.04-1.18). The SNP-SNP interaction analysis revealed noteworthy interaction terms with TPH2- and MAPK-related SNPs (e.g. rs1386483 R ∧ rs1473473 D ∧ rs3729931 D : OR = 1.20, 95% CI 1.09-1.32). In line with the light-at-night hypothesis that links shift work with elevated breast-cancer risks our results point to SNPs in TPH2 and MAPK-genes that may impact the intricate network of circadian regulation., (© 2023. The Author(s).)

Parkinson's disease (PD) is the most common neurodegenerative movement disorder. There are no available therapeutics that slow or halt the progressive loss of dopamine-producing neurons, which underlies the primary clinical symptoms. Currently approved PD drugs can provide symptomatic relief by increasing brain dopamine content or activity; however, the alleviation is temporary, and the effectiveness diminishes with the inevitable progression of neurodegeneration. Discovery and development of disease-modifying neuroprotective therapies has been hampered by insufficient understanding of the root cause of PD-related neurodegeneration. The etiology of PD involves a combination of genetic and environmental factors. Although a single cause has yet to emerge, genetic, cell biological and neuropathological evidence implicates mitochondrial dysfunction and protein aggregation. Postmortem PD brains show pathognomonic Lewy body intraneuronal inclusions composed of aggregated α-synuclein, indicative of failure to degrade misfolded protein. Mutations in the genes that code for α-synuclein, as well as the E3 ubiquitin ligase Parkin, cause rare inherited forms of PD. While many ubiquitin ligases label proteins with ubiquitin chains to mark proteins for degradation by the proteasome, Parkin has been shown to mark dysfunctional mitochondria for degradation by mitophagy. The ubiquitin proteasome system participates in several aspects of the cell's response to mitochondrial damage, affording numerous therapeutic opportunities to augment mitophagy and potentially stop PD progression. This review examines the role and therapeutic potential of such UPS modulators, exemplified by both ubiquitinating and deubiquitinating enzymes., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

MacroH2A has established tumour suppressive functions in melanoma and other cancers, but an unappreciated role in the tumour microenvironment. Using an autochthonous, immunocompetent mouse model of melanoma, we demonstrate that mice devoid of macroH2A variants exhibit increased tumour burden compared with wild-type counterparts. MacroH2A-deficient tumours accumulate immunosuppressive monocytes and are depleted of functional cytotoxic T cells, characteristics consistent with a compromised anti-tumour response. Single cell and spatial transcriptomics identify increased dedifferentiation along the neural crest lineage of the tumour compartment and increased frequency and activation of cancer-associated fibroblasts following macroH2A loss. Mechanistically, macroH2A-deficient cancer-associated fibroblasts display increased myeloid chemoattractant activity as a consequence of hyperinducible expression of inflammatory genes, which is enforced by increased chromatin looping of their promoters to enhancers that gain H3K27ac. In summary, we reveal a tumour suppressive role for macroH2A variants through the regulation of chromatin architecture in the tumour stroma with potential implications for human melanoma., (© 2023. The Author(s).)

Lyme disease (LD) is the most common vector-borne illness in the USA. Incidence is related to specific environmental conditions such as temperature, metrics of land cover, and vertebrate species diversity. To determine whether greenness, as measured by the Normalized Difference Vegetation Index (NDVI), and other selected indices of land cover were associated with the incidence of LD in the northeastern USA for the years 2000-2018, we conducted an ecological analysis of incidence rates of LD in counties of 15 "high" incidence states and the District of Columbia for 2000-2018. Annual counts of LD by county were obtained from the US Centers for Disease Control and values of NDVI were acquired from the Moderate Resolution Imaging Spectroradiometer instrument aboard Terra and Aqua Satellites. County-specific values of human population density, area of land and water were obtained from the US Census. Using quasi-Poisson regression, multivariable associations were estimated between the incidence of LD, NDVI, land cover variables, human population density, and calendar year. We found that LD incidence increased by 7.1% per year (95% confidence interval: 6.8-8.2%). Land cover variables showed complex non-linear associations with incidence: average county-specific NDVI showed a "u-shaped" association, the standard deviation of NDVI showed a monotonic upward relationship, population density showed a decreasing trend, areas of land and water showed "n-shaped" relationships. We found an interaction between average and standard deviation of NDVI, with the highest average NDVI category; increased standard deviation of NDVI showed the greatest increase in rates. These associations cannot be interpreted as causal but indicate that certain patterns of land cover may have the potential to increase exposure to infected ticks and thereby may contribute indirectly to increased rates of LD. Public health interventions could make use of these results in informing people where risks may be high., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

Ubiquitin phosphorylation by the mitochondrial protein kinase PTEN-induced kinase 1 (PINK1), upon mitochondrial depolarization, is an important intermediate step in the recycling of damaged mitochondria via mitophagy. As mutations in PINK1 can cause early-onset Parkinson's disease (PD), there has been a growing interest in small-molecule activators of PINK1-mediated mitophagy as potential PD treatments. Herein, we show that N 6 -substituted adenosines, such as N 6 -(2-furanylmethyl)adenosine (known as kinetin riboside) and N 6 -benzyladenosine, activate PINK1 in HeLa cells and induce PINK1-dependent mitophagy in primary mouse fibroblasts. Interestingly, pre-treatment of HeLa cells and astrocytes with these compounds inhibited elevated ubiquitin phosphorylation that is induced by established mitochondrial depolarizing agents, carbonyl cyanide m -chlorophenyl-hydrazine and niclosamide. Together, this highlights N 6 -substituted adenosines as progenitor PINK1 activators that could potentially be developed, in the future, as treatments for aged and sporadic PD patients who have elevated phosphorylated ubiquitin levels in the brain.

Purpose: The DecisionDx-Melanoma 31-gene expression profile (31-GEP) test is validated to classify cutaneous malignant melanoma (CM) patient risk of recurrence, metastasis, or death as low (class 1A), intermediate (class 1B/2A), or high (class 2B). This study aimed to examine the effect of 31-GEP testing on survival outcomes and confirm the prognostic ability of the 31-GEP at the population level., Methods: Patients with stage I-III CM with a clinical 31-GEP result between 2016 and 2018 were linked to data from 17 SEER registries (n = 4,687) following registries' operation procedures for linkages. Melanoma-specific survival (MSS) and overall survival (OS) differences by 31-GEP risk category were examined using Kaplan-Meier analysis and the log-rank test. Crude and adjusted hazard ratios (HRs) were calculated using Cox regression model to evaluate variables associated with survival. 31-GEP tested patients were propensity score-matched to a cohort of non-31-GEP tested patients from the SEER database. Robustness of the effect of 31-GEP testing was assessed using resampling., Results: Patients with a 31-GEP class 1A result had higher 3-year MSS and OS than patients with a class 1B/2A or class 2B result (MSS: 99.7% v 97.1% v 89.6%, P < .001; OS: 96.6% v 90.2% v 79.4%, P < .001). A class 2B result was an independent predictor of MSS (HR, 7.00; 95% CI, 2.70 to 18.00) and OS (HR, 2.39; 95% CI, 1.54 to 3.70). 31-GEP testing was associated with a 29% lower MSS mortality (HR, 0.71; 95% CI, 0.53 to 0.94) and 17% lower overall mortality (HR, 0.83; 95% CI, 0.70 to 0.99) relative to untested patients., Conclusion: In a population-based, clinically tested melanoma cohort, the 31-GEP stratified patients by their risk of dying from melanoma.