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Background: Recent withdrawals of major drugs have highlighted the critical importance of drug safety surveillance in the postmarketing phase. Limitations of spontaneous report data have led drug safety professionals to pursue alternative postmarketing surveillance approaches based on healthcare administrative claims data. These data are typically analysed by comparing the adverse event rates associated with a drug of interest to those of a single comparable reference drug.Objective: The aim of this study was to determine whether adverse event detection can be improved by incorporating information from multiple reference drugs. We developed a pharmacological network model that implemented this approach and evaluated its performance.Methods: We studied whether adverse event detection can be improved by incorporating information from multiple reference drugs, and describe two approaches for doing so. The first, reported previously, combines a set of related drugs into a single reference cohort. The second is a novel pharmacoepidemiological network model, which integrates multiple pair-wise comparisons across an entire set of related drugs into a unified consensus safety score for each drug. We also implemented a single reference drug approach for comparison with both multi-drug approaches. All approaches were applied within a sequential analysis framework, incorporating new information as it became available and addressing the issue of multiple testing over time. We evaluated all these approaches using statin (HMG-CoA reductase inhibitors) safety data from a large healthcare insurer in the US covering April 2000 through March 2005.Results: We found that both multiple reference drug approaches offer earlier detection (6-13 months) than the single reference drug approach, without triggering additional false positives.Conclusions: Such combined approaches have the potential to be used with existing healthcare databases to improve the surveillance of therapeutics in the postmarketing phase over single-comparator methods. The proposed network approach also provides an integrated visualization framework enabling decision makers to understand the key high-level safety relationships amongst a group of related drugs. [ABSTRACT FROM AUTHOR]

The multifunctional bioactive materials were prepared from Enteromorpha prolifera by enzyme-assisted extraction using four proteases and seven carbohydrases, and the biological activities of the enzyme-assisted extracts were evaluated as antioxidant, anti-acetylcholinesterase (AChE) and anti-inflammatory effect as the measures of inhibition of lipopolysaccharide (LPS)-induced nitric oxide (NO) production in RAW264.7 cells. The enzyme-assisted extracts were rich in polyphenols in the range 124 ± 4.2 to 844 ± 9.1 mg/100 g and flavonoids in the range 453 ± 6.0 to 675 ± 5.2 mg/100 g, and Protamex and Viscozyme extracts, which were rich in polyphenols and flavonoids, showed the highest 2,2-diphenyl-1-picrylhydrazyl scavenging, hydrogen peroxide scavenging, ferrous ion chelating and reducing power. Flavourzyme extract (89.92%) and Promozyme extract (93.64%) showed the highest AChE inhibitory activities at the concentration of 1.0 mg/ml. All enzyme-assisted extracts showed no cytotoxic effect on RAW264.7 cells at the tested concentration and significantly inhibited the LPS-induced NO production in RAW264.7 cells. [ABSTRACT FROM AUTHOR]

AIM OF THE STUDY: Gastrodia elata (GE) Blume (Orchidaceae) has been traditionally used as a folk medicine in Oriental countries since centuries for their variety of therapeutic benefits. This study is an attempt to investigate the protective effects of GE extract against MPP(+)-induced cytotoxicity in human dopaminergic SH-SY5Y cells and explore the neuroprotective mechanisms involved. MATERIALS AND METHODS: Human dopaminergic SH-SY5Y cells were used to demonstrate the protective effects of GE against multiple parameters such as MPP(+)-induced cell viability, oxidative damage, expression of Bcl-2 and Bax, caspase-3 and poly(ADP-ribose) polymerase proteolysis. RESULTS: GE effectively attenuated the cytotoxicity and improved cell viability in a dose-dependent manner. GE was effective in inhibiting both, the increased production of reactive oxygen species (ROS) and increase in Bax/Bcl-2 ratio, cleaved caspase-3 and PARP proteolysis. CONCLUSION: Data from this study suggests the protective effects of GE on MPP(+)-induced cytotoxicity in dopaminergic cells, which may be ascribed to its significant anti-oxidative and anti-apoptotic properties, thus, GE might prove to be a valuable therapeutic agent for the treatment of various neurodegenerative diseases including progressive Parkinson's disease (PD). [ABSTRACT FROM AUTHOR]

Objective: The goal of this study was to compare the impact of using a lower thoracic (LT) versus upper lumbar (UL) level as the upper instrumented vertebra (UIV) on clinical and radiographic outcomes following minimally invasive surgery for adult spinal deformity., Methods: A multicenter retrospective study design was used. Inclusion criteria were age ≥ 18 years, and one of the following: coronal Cobb angle > 20°, sagittal vertical axis > 50 mm, pelvic tilt > 20°, pelvic incidence-lumbar lordosis mismatch > 10°. Patients were treated with circumferential or hybrid minimally invasive techniques at ≥ 3 spinal levels and had a 2-year minimum follow-up. They were then divided into 2 groups depending on whether the UIV was in the UL region, defined as a UIV location of L1-2, or the LT region, defined as T10-12., Results: A total of 114 of 223 patients met the inclusion criteria (68 LT and 46 UL). The UL group was older (67.5 vs 62.3 years; p = 0.015). Preoperative spinopelvic parameters were similar, except for sacral slope, which was higher in the UL group (30.5° vs 26.5°; p < 0.001). The percentage of patients with fixation crossing the lumbosacral junction was also similar (70.6% vs 67.4%; p = 0.717). Postoperative lumbar lordosis (42.5° vs 35.5°; p = 0.01) and change in coronal Cobb angle (-23.2° vs -9.6°; p < 0.001) were greater in the LT group, but other changes in postoperative spinopelvic parameters and changes in health-related quality-of-life scores were similar between groups. Reoperation rates were lower in the UL group (17.4% vs 36.8%; p = 0.025), largely associated with fewer radiographic failures (UL = 10.9% vs LT = 26.5%; p = 0.042); however, overall complication rates were not significantly different (UL = 43.5% vs LT = 60.3%; p = 0.077)., Conclusions: Selecting a UL vertebra for UIV in minimally invasive surgical correction of adult spinal deformity results in lower reoperation rates compared to extending fixation to the LT region. This choice also correlates with shorter operating room times and reduced estimated blood loss. Although extending fixation to the LT region is associated with slightly greater lumbar lordosis and a greater change in the coronal Cobb angle, clinical outcomes were similar between the LT and UL groups for UIV.

Atherosclerotic cardiovascular disease (ASCVD) and consequent acute coronary syndromes (ACS) are substantial contributors to morbidity and mortality across Europe. Fortunately, as much as two thirds of this disease's burden is modifiable, in particular by lipid-lowering therapy (LLT). Current guidelines are based on the sound premise that, with respect to low-density lipoprotein cholesterol (LDL-C), "lower is better for longer", and recent data have strongly emphasised the need for also "the earlier the better". In addition to statins, which have been available for several decades, ezetimibe, bempedoic acid (also as fixed dose combinations), and modulators of proprotein convertase subtilisin/kexin type 9 (PCSK9 inhibitors and inclisiran) are additionally very effective approaches to LLT, especially for those at very high and extremely high cardiovascular risk. In real life, however, clinical practice goals are still not met in a substantial proportion of patients (even in 70%). However, with the options we have available, we should render lipid disorders a rare disease. In April 2021, the International Lipid Expert Panel (ILEP) published its first position paper on the optimal use of LLT in post-ACS patients, which complemented the existing guidelines on the management of lipids in patients following ACS, which defined a group of "extremely high-risk" individuals and outlined scenarios where upfront combination therapy should be considered to improve access and adherence to LLT and, consequently, the therapy's effectiveness. These updated recommendations build on the previous work, considering developments in the evidential underpinning of combination LLT, ongoing education on the role of lipid disorder therapy, and changes in the availability of lipid-lowering drugs. Our aim is to provide a guide to address this unmet clinical need, to provide clear practical advice, whilst acknowledging the need for patient-centred care, and accounting for often large differences in the availability of LLTs between countries., Competing Interests: Declarations. Funding: No external funding was used in the preparation of this article. Conflict of interest: Dr. Banach has received research grant(s)/support from Amgen, Daiichi-Sankyo, Mylan/Viatris, and Sanofi, and has received honoraria and/or served as a consultant for Adamed, Amgen, Daiichi-Sankyo, Esperion, Kogen, KRKA, Lilly, MSD, Mylan/Viatris, NewAmsterdam Pharma, Novartis, Novo Nordisk, Polfarmex, Polpharma, Sanofi-Regeneron, Servier, Teva, and Zentiva. Dr. Reiner has received honoraria from Sanofi and Novartis. Dr. Cicero has received personal fees from Mylan-Viatris, Sharper, and Servier. Dr. Dyrbuś has received fee for scientific activities from Novartis, Sanofi-Aventis, and Amgen. Dr. Fedacko has received a consultancy fee from Sanofi, Amgen and Novo Nordisk, and a research grant from Pfizer. Dr. Fras has received grants and fees for scientific activities from Amgen, Krka, Novartis, Swix BioPharma, and Viatris. Dr. Gaita has received honoraria from Amgen, AstraZeneca, Bayer, Berlin Chemie, Biofarm, Boehringer Ingelheim, Galenica, GSK, Gedeon Richter, Krka, MSD, Novartis, Novo Nordisk, Pfizer, Sanofi, Servier, Terapia, Vifor Pharma, and Zentiva. Dr. Gierlotka reports honoraria from Sanofi, Novartis, Bayer, Amgen, Novo Nordisk, AstraZeneca, Servier. Dr. Gouni-Berthold has served as consultant and received honoraria from Akcea, Amgen, Daiichi-Sankyo, Novartis, Sanofi-Regeneron, Ultragenyx, and Amarin. Dr. Jankowski has received a research grant from Sanofi and has served as a consultant for Novartis, Servier, and Zentiva. Dr. Járai has served as a consultant for and received honoraria from Bayer, Berlin-Chemie, Boehringer Ingelheim, Egis, MSD, Novartis (Sandoz), Novo Nordisk, Pfizer, Richter Gedeon, Sanofi, Servier, and Teva. Dr. Latkovskis has given talks, attended conferences, received consultancy fees, and/or participated in trials sponsored by Abbott Laboratories, Amgen, AstraZeneca, Berlin-Chemie/Menarini, Bayer, Boehringer Ingelheim, GlaxoSmithKline, Grindex, KRKA, MSD, Mylan, Novartis, Novo Nordisk, Pfizer, Sanofi, Servier Laboratories, Siemens Laboratories, and Zentiva. Dr. Magda has received consultation fees from Novartis, Sanofi, and Servier. Dr. Margetic has received a fee for scientific activities from Novartis and Sanofi. Dr. Ostadal has received honoraria from Getinge, Abiomed, Edwards, Fresenius/Xenios, AstraZeneca, Bayer, Boehringer Ingelheim, Amgen, Sanofi, Servier, Novartis, Pfizer, AOP, and GSK. Dr Paragh has received lectures fees from Hungarian branches of Novartis, Richter Gedeon, and Sandoz. Dr. Paneni has received honoraria from Novo Nordisk. Dr. Pećin has received grants and fees for scientific activities from Amgen, Bayer, Novartis, and Sanofi. Dr. Pella has received grant support and honoraria from Sanofi, Amgen, MSD, Servier, Novartis, and Pfizer. Dr. Postadzhiyan reports fees for educational activities from Amgen, AstraZeneca, KRKA, Novartis, Servier, Teva, and Zentiva. Dr. Stoian has given lectures, received honoraria and research support, and participated in conferences, advisory boards, and clinical trials sponsored by pharmaceutical companies, from AstraZeneca, Amgen, Boehringer Ingelheim, Coca-Cola, Eli Lilly, Merck, Medtronic, MSD, Medochemie, Novo Nordisk, Novartis, Roche Diagnostics, Servier, Sandoz, and Sanofi. Dr. Trbusic has received a fee for scientific activities from Novartis and Sanofi. Dr. Udroiu has received a fee for scientific activities from AstraZeneca and Pfizer. Dr. Viigimaa reports fees for educational activities from Amgen, AstraZeneca, Novartis, Novo Nordisk, Menarini, Servier, and Swixx BioPharma. Dr. Vinereanu has received research grants and expert fees from Amgen, Sanofi, Novartis, and Servier. Dr. Vlachopoulos has received grants and fees for scientific activities from Amgen, Sanofi, and MSD. Dr. Vrablik has received personal fees from Abbott, Amgen, AstraZeneca, BMS, Genzyme, KRKA, MSD Idea, Novartis, Pfizer, and Sanofi-Regeneron. Dr. Vulic has received a fee for scientific activities from Sanofi. Dr. Penson owns four shares in AstraZeneca PLC and has received honoraria from Amgen and Sanofi and travel/accommodation reimbursement for events sponsored by AKCEA, Amgen, AMRYT, Link Medical, Mylan, and Napp. All other authors declare that they have no potential conflicts of interest that might be relevant to the contents of this article. Authors’ contributions: Dr. Banach: Conceptualisation; data curation; methodology; project administration; supervision; validation; visualisation; writing, reviewing, and editing; revisions; preparing the final version of the paper. Dr. Penson: Data curation; investigation; methodology; validation; visualisation; first draft preparation; reviewing and editing. Dr Surma: data curation, visualisation, draft figures preparations; reviewing and editing. Drs. Reiner, Bajraktari, Bielecka-Dabrowa, Bunc, Bytyçi, Ceska, Cicero, Dudek, Dyrbuś, Fedacko, Fras, Gaita, Gavish, Gierlotka, Gil, Gouni-Berthold, Jankowski, Járai, Jóźwiak, Katsiki, Latkovskis, Magda, Margetic, Margoczy, Mitchenko, Durak-Nalbantic, Ostadal, Paragh, Petrulioniene, Paneni, Pećin, Pella, Postadzhiyan, Stoian, Trbusic, Udroiu, Viigimaa, Vinereanu, Vlachopoulos, Vrablik, and Vulic: Investigation, methodology; validation; writing, reviewing, and editing; final revisions and approval. Data availability statement: Data sharing is not applicable to this article as no datasets were generated for this article. Ethics approval: Not applicable. Code availability: Not applicable. Consent to participate: Not applicable. Consent for publication: Not applicable., (© 2024. The Author(s).)

Background: The PARP inhibitor (PARPi) olaparib is approved for homologous recombination repair (HRR) gene-altered metastatic castration-resistant prostate cancer (mCRPC). However, there is significant heterogeneity in response to PARPi in patients with mCRPC. Better clinical biomarkers are needed to identify patients likely to benefit from PARPi., Methods: Patients with prostate adenocarcinoma and panel sequencing at Dana-Farber Cancer Institute were identified. Mutational signature analysis was performed using SigMA to characterize tumors as HRR deficient (HRD). The validity of SigMA to identify patients likely to benefit from olaparib was compared to the current FDA label (presence of a deleterious alteration in one of 14 HRR genes)., Results: 546 patients were identified, of which 34% were HRD. Among patients with HRR gene alterations, only patients with BRCA2 two-copy loss (2CL) were more likely to be HRD compared to patients without HRR gene alterations (74% vs 31%; P = 9.1 × 10 -7 ). 28 patients with mCRPC received olaparib, of which 13 were HRD and 9 had BRCA2 2CL. SigMA improved upon the current FDA label for predicting PSA50 (sensitivity: 100% vs 90%; specificity: 83% vs 44%; PPV: 77% vs 47%; NPV: 100% vs 89%) and rPFS > 6 months (sensitivity: both 92%; specificity: 93% vs 53%; PPV: 92% vs 63%; NPV: 93% vs 89%). On multivariate analysis, incorporating prognostic clinical factors and HR gene alterations, SigMA-predicted HRD independently associated with improved PSA-PFS (HR = 0.086, p = 0.00082) and rPFS (HR = 0.078, p = 0.0070)., Conclusions: SigMA-predicted HRD may better identify patients likely to benefit from olaparib as compared to the current FDA label. Larger studies are needed for further validation., (© 2024 Wiley Periodicals LLC.)

Germline mutations modulate the risk of developing schizophrenia (SCZ). Much less is known about the role of mosaic somatic mutations in the context of SCZ. Deep (239×) whole-genome sequencing (WGS) of brain neurons from 61 SCZ cases and 25 controls postmortem identified mutations occurring during prenatal neurogenesis. SCZ cases showed increased somatic variants in open chromatin, with increased mosaic CpG transversions (CpG>GpG) and T>G mutations at transcription factor binding sites (TFBSs) overlapping open chromatin, a result not seen in controls. Some of these variants alter gene expression, including SCZ risk genes and genes involved in neurodevelopment. Although these mutational processes can reflect a difference in factors indirectly involved in disease, increased somatic mutations at developmental TFBSs could also potentially contribute to SCZ.

Since human neurons are postmitotic and long-lived, the regulation of their genomic content is crucial. Normal neuronal function is uniquely dependent on gene dosage, with diverse genome copy number alterations (CNA) associated with neurodevelopmental and neuropsychiatric conditions 1-3 . In this study, we evaluated the landscape of CNA arising in normal human brains, focusing on prenatal and perinatal ages. We surveyed ∼5,897 CNA in >1,200 single neurons from human postmortem brain of individuals without a neurological diagnosis, ranging in age from gestational week (GW) 14 to 90 years old. Using Tn5-based single-cell whole-genome amplification (scWGA) and informatic advances to validate CNAs in single neurons, we determined that a striking proportion of neurons (up to 45%) in human prenatal cortex showed aberrant genomes, characterized by large-scale CNAs in multiple chromosomes, which reduces significantly during the perinatal period (p<0.1). Furthermore, we identified micronuclei in the developing cortex, reflecting genetic instability reminiscent of that described in early embryonic development 4-6 . The scale of CNA appeared to alter the trajectory of neuronal elimination, as subchromosomal CNAs were more slowly eliminated, over the course of a lifetime. CNAs were depleted for dosage-sensitive genes and genes involved in neurodevelopmental disorders (p<.05), and thus represent genomic quality control mechanisms that eliminate selectively those neurons with CNA involving critical genes. Perinatal elimination of defective neuronal genomes may in turn reflect a developmental landmark essential for normal cognitive function.

Background: Hepatocellular carcinoma (HCC) with portal vein invasion (PVI) is considered an advanced stage with a poor prognosis. Although current guidelines recommend systemic treatment for HCC with PVI, surgical resection could produce acceptable outcomes in selected patients. This study aimed to identify the clinical significance of surgical resection for HCC with PVI patients using a large-scale nationwide registry., Methods: This retrospective, multicenter, observational cohort analyzed data from the Korean Primary Liver Cancer Registry. A total of 16,781 patients who were newly diagnosed with HCC between 2008 and 2018 were enrolled in this study. Patients with worse Child-Turcotte-Pugh scores (≥7) or performance status (≥2) were excluded. Among them, 998 patients who received treatment for HCC with PVI were included in the analysis and were divided into two groups: resection group of 151 (15.1%) and palliative group of 847 (84.9%) who received transarterial and systemic therapy according to the treatment intent. After matching the number and size of the tumors and model for end-stage liver disease (MELD) score between the groups, the final study cohort for analysis comprised 151 (26.6%) patients in the resection group and 417 (73.4%) in the palliative group. The primary endpoints were overall survival (OS) and cancer-specific survival (CSS)., Results: The number and maximum size of HCC did not differ between the resection and palliative groups after matching [1 (range, 1-5) vs. 1 (range, 1-6), P=0.11 and 5.5 (range, 1.2-20.6) vs. 6.0 (range, 1.0-20.5) cm, P=0.24, respectively]. Tumor markers, including alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II), also did not differ between the groups (P=0.29 and P=0.36, respectively). The 5-year OS and CSS rates of the resection and palliative groups were 44.8% and 17.4% (P<0.001) and 47.7% and 18.6% (P<0.001), respectively. Multivariate analysis showed that palliative treatment intent was the most significant risk factor for OS and CSS [odds ratio (OR) =2.24; 95% confidence interval (CI): 1.66-3.02; P<0.001 and OR =2.29; 95% CI: 1.68-3.12; P<0.001, respectively]., Conclusions: Surgical resection could significantly improve OS and CSS in selected HCC with PVI patients who have preserved liver function and performance status., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://hbsn.amegroups.com/article/view/10.21037/hbsn-23-578/coif). The authors have no conflicts of interest to declare., (2024 AME Publishing Company. All rights reserved.)

Accurate detection of homologous recombination deficiency (HRD) in cancer patients is paramount in clinical applications, as HRD confers sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. With the advances in genome sequencing technology, mutational profiling on a genome-wide scale has become readily accessible, and our knowledge of the genomic consequences of HRD has been greatly expanded and refined. Here, we review the recent advances in HRD detection methods. We examine the copy number and structural alterations that often accompany the genome instability that results from HRD, describe the advantages of mutational signature-based methods that do not rely on specific gene mutations, and review some of the existing algorithms used for HRD detection. We also discuss the choice of sequencing platforms (panel, exome, or whole-genome) and catalog the HRD detection assays used in key PARP inhibitor trials.

Background: Although advancements in desensitization protocols have led to increased ABO-incompatible (ABOi) living-donor liver transplantation (LDLT), a higher biliary complication rate remains a problem. This study evaluated the effect of baseline anti-ABO antibody titers before desensitization on biliary complications after ABOi LDLT. Methods: The study cohort comprised 116 patients in the ABO-compatible group (ABOc), 29 in the ABOi with the low titer (<1:128) group (ABOi-L), and 14 in the high titer (≥1:128) group (ABOi-H). Results: Biliary complications occurred more frequently in the ABOi-H group than in the ABOi-L and ABOc groups (7 [50.0%] vs. 8 [27.6%] and 24 [20.7%], respectively, p = 0.041). Biliary complication-free survival was significantly worse in the ABOi-H group than in the other groups ( p = 0.043). Diffuse intrahepatic biliary strictures occurred more frequently in the ABOi-H group than in the other groups ( p = 0.005). Multivariable analysis revealed that the high anti-ABO antibody titer (≥1:128) is an independent risk factor for biliary complications (hazard ratio 3.943 [1.635-9.506]; p = 0.002). Conclusions: A high baseline anti-ABO antibody titer (≥1:128), female sex, and hepatic artery complications are significant risk factors for biliary complications.

Objective: Endovascular aortic aneurysm repair (EVAR) is the primary treatment for abdominal aortic aneurysms, constituting 70%-80% of interventions. Despite initial benefits, long-term studies show increased mortality. Using nationwide data, this study assesses outcomes of EVAR, open aortic repair (OAR), and EVAR explantation (EE) in Korea, while exploring characteristics of late open conversion, including the rising EE incidence., Methods: Employing the National Health Insurance Service database, covering health-related data for nearly 50 million Koreans, the study spanned from 2002 to 2020. Patients with AAA diagnoses (I71.3 or I71.4) were categorized into OAR, EVAR, and EE groups based on procedural codes. Statistical analyses, including t-tests, Fisher's exact tests, Cox proportional hazard models, and multivariate Cox regression, assessed baseline characteristics, mortality risks, and factors within the EE group., Results: The analysis encompassed 26,195 patients, with 66.19% in the EVAR group, 31.87% in the OAR group, and 1.94% in the EE group. EVAR cases steadily increased from 2002 to 2018. Survival rates favored EVAR, followed by OAR and EE. 30-day survival was lower in EE than EVAR. Multivariate analysis for EE revealed no risk factors for 30-days survival but identified age, chronic kidney disease, high Charlson Comorbidity Index scores, and less than 6 months since EVAR as risk factors for overall mortality., Conclusion: Rising EE trends with increased EVAR adoption, particularly evident in the Korean dataset, underscore inferior outcomes. This highlights the critical need for strategic initial treatment decisions and timely interventions to enhance overall results and mitigate the unfavorable EE incidence., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Whole chromosome and arm-level copy number alterations occur at high frequencies in tumors, but their selective advantages, if any, are poorly understood. Here, utilizing unbiased whole chromosome genetic screens combined with in vitro evolution to generate arm- and subarm-level events, we iteratively selected the fittest karyotypes from aneuploidized human renal and mammary epithelial cells. Proliferation-based karyotype selection in these epithelial lines modeled tissue-specific tumor aneuploidy patterns in patient cohorts in the absence of driver mutations. Hi-C-based translocation mapping revealed that arm-level events usually emerged in multiples of two via centromeric translocations and occurred more frequently in tetraploids than diploids, contributing to the increased diversity in evolving tetraploid populations. Isogenic clonal lineages enabled elucidation of pro-tumorigenic mechanisms associated with common copy number alterations, revealing Notch signaling potentiation as a driver of 1q gain in breast cancer. We propose that intrinsic, tissue-specific proliferative effects underlie tumor copy number patterns in cancer., (© 2024. The Author(s).)

Purpose: The number of older patients who need vascular access for end-stage renal disease is rapidly increasing. However, determining the optimal vascular access for older patients is difficult. We aimed to compare the outcomes of radiocephalic (RC) and brachiocephalic (BC) arteriovenous fistula (AVF) in patients aged >80 years., Methods: This study included 94 patients undergoing hemodialysis who underwent the procedure for the first time between 2013 and 2019 in Korea University Guro Hospital. The primary outcomes were primary patency (PP) and cumulative patency (CP). The secondary outcome was maturation failure and death with functional vascular access., Results: Of the 94 patients (mean age, 83.9 ± 2.97 years), 66 (70.2%) and 28 (29.8%) patients belonged to the RC and BC AVF groups, respectively. One-year PP was worse in the RC AVF group than in the BC AVF group (59.6% vs. 87.4%, p  = 0.013). However, no significant difference was observed in 1-year CP between the groups (87.4% vs. 91.2%, p  = 0.441). The unassisted maturation rate was higher in the BC AVF group than in the RC AVF group (74.2% vs. 96.4%, p  = 0.011). During follow-up (649 ± 612 days), only 6 (6.4%) patients required secondary fistula placement. Eighteen patients (19.1%), all of whom had functional AVF, died., Conclusion: BC AVF showed better PP and a smaller number of interventions than RC AVF in octogenarians. Therefore, BC AVF could be a primary choice of vascular access in the octogenarian patient. However, further research is warranted to confirm these findings., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Characterizing somatic mutations in the brain is important for disentangling the complex mechanisms of aging, yet little is known about mutational patterns in different brain cell types. Here, we performed whole-genome sequencing (WGS) of 86 single oligodendrocytes, 20 mixed glia, and 56 single neurons from neurotypical individuals spanning 0.4-104 years of age and identified >92,000 somatic single-nucleotide variants (sSNVs) and small insertions/deletions (indels). Although both cell types accumulate somatic mutations linearly with age, oligodendrocytes accumulated sSNVs 81% faster than neurons and indels 28% slower than neurons. Correlation of mutations with single-nucleus RNA profiles and chromatin accessibility from the same brains revealed that oligodendrocyte mutations are enriched in inactive genomic regions and are distributed across the genome similarly to mutations in brain cancers. In contrast, neuronal mutations are enriched in open, transcriptionally active chromatin. These stark differences suggest an assortment of active mutagenic processes in oligodendrocytes and neurons., Competing Interests: Declaration of interests J.G. is now a Merck Research Laboratories (MRL) employee, and no work related to this manuscript was performed at MRL. P.J.P. is a member of the scientific advisory board for Bioskryb Genomics, Inc., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction/background: Immune checkpoint inhibitors (ICIs) have limited efficacy in prostate cancer (PCa). Better biomarkers are needed to predict responses to ICIs. We sought to demonstrate that a panel-based mutational signature identifies mismatch repair (MMR) deficient (MMRd) PCa and is a biomarker of response to pembrolizumab., Patients and Methods: Clinico-genomic data was obtained for 2664 patients with PCa sequenced at Dana-Farber Cancer Institute (DFCI) and Memorial Sloan Kettering (MSK). Clinical outcomes were collected for patients with metastatic castration-resistant PCa (mCRPC) treated with pembrolizumab at DFCI. SigMA was used to characterize tumors as MMRd or MMR proficient (MMRp). The concordance between MMRd with microsatellite instability (MSI-H) was assessed. Radiographic progression-free survival (rPFS) and overall survival (OS) were collected for patients treated with pembrolizumab. Event-time distributions were estimated using Kaplan-Meier methodology., Results: Across both cohorts, 100% (DFCI: 12/12; MSK: 43/43) of MSI-H tumors were MMRd. However, 14% (2/14) and 9.1% (6/66) of MMRd tumors in the DFCI and MSK cohorts respectively were microsatellite stable (MSS), and 26% (17/66) were MSI-indeterminate in the MSK cohort. Among patients treated with pembrolizumab, those with MMRd (n = 5) versus MMRp (n = 14) mCRPC experienced markedly improved rPFS (HR = 0.088, 95% CI: 0.011-0.70; P = .0064) and OS (HR = 0.11, 95% CI: 0.014-0.80; P = .010) from start of treatment. Four patients with MMRd experienced remissions of >= 2.5 years., Conclusion: SigMA detects additional cases of MMRd as compared to MSI testing in PCa and identifies patients likely to experience durable response to pembrolizumab., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The Brain Imaging Data Structure (BIDS) is a community-driven standard for the organization of data and metadata from a growing range of neuroscience modalities. This paper is meant as a history of how the standard has developed and grown over time. We outline the principles behind the project, the mechanisms by which it has been extended, and some of the challenges being addressed as it evolves. We also discuss the lessons learned through the project, with the aim of enabling researchers in other domains to learn from the success of BIDS., Competing Interests: Gaia Rizzo is an employee of Invicro. No other authors have competing interests to declare., (© 2024 Massachusetts Institute of Technology. Published under a Creative Commons Attribution 4.0 International (CC BY 4.0) license.)

In all terrestrial vertebrates, the parathyroid glands are critical regulators of calcium homeostasis and the sole source of parathyroid hormone (PTH). Hyperparathyroidism and hypoparathyroidism are clinically important disorders affecting multiple organs. However, our knowledge regarding regulatory mechanisms governing the parathyroids has remained limited. Here, we present the comprehensive maps of the chromatin landscape of the human parathyroid glands, identifying active regulatory elements and chromatin interactions. These data allow us to define regulatory circuits and previously unidentified genes that play crucial roles in parathyroid biology. We experimentally validate candidate parathyroid-specific enhancers and demonstrate their integration with GWAS SNPs for parathyroid-related diseases and traits. For instance, we observe reduced activity of a parathyroid-specific enhancer of the Calcium Sensing Receptor gene, which contains a risk allele associated with higher PTH levels compared to the wildtype allele. Our datasets provide a valuable resource for unraveling the mechanisms governing parathyroid gland regulation in health and disease., (© 2024. The Author(s).)

Mutational signature analysis is a recent computational approach for interpreting somatic mutations in the genome. Its application to cancer data has enhanced our understanding of mutational forces driving tumorigenesis and demonstrated its potential to inform prognosis and treatment decisions. However, methodological challenges remain for discovering new signatures and assigning proper weights to existing signatures, thereby hindering broader clinical applications. Here we present Mutational Signature Calculator (MuSiCal), a rigorous analytical framework with algorithms that solve major problems in the standard workflow. Our simulation studies demonstrate that MuSiCal outperforms state-of-the-art algorithms for both signature discovery and assignment. By reanalyzing more than 2,700 cancer genomes, we provide an improved catalog of signatures and their assignments, discover nine indel signatures absent in the current catalog, resolve long-standing issues with the ambiguous 'flat' signatures and give insights into signatures with unknown etiologies. We expect MuSiCal and the improved catalog to be a step towards establishing best practices for mutational signature analysis., (© 2024. The Author(s).)

Hair dermal papilla cells (hDPCs) play a crucial role in hair growth and regeneration, and their function is influenced by nutrient and oxygen supply. A microenvironment with significantly low oxygen (O 2 ) levels, known as anoxic conditions (<0.2%) due to oxygen deficiency, hinders hDPC promotion and retards hair regrowth. Here, a nanoemulsion (NE) based on perfluorooctyl bromide (PFOB), a member of the perfluorocarbon family, is presented to provide a sustainable O 2 supply and maintain physical stability in vitro . The PFOB-NE has been shown to continuously release oxygen for 36 h, increasing and maintaining the O 2 concentration in the anoxic microenvironment of up to 0.8%. This sustainable O 2 supply using PFOB-NE has promoted hDPC growth and also induced a complex cascade of effects. These effects encompass regulation via inhibiting lactate accumulation caused via oxygen deficiency, increasing lactate dehydrogenase activity, and promoting the expression of genes, such as the hypoxia-inducible factor 1 family and NADPH oxidase 4 under anoxic conditions. Sustained O 2 supply is shown to enhance human hair organ elongation approximately four times compared to the control under anoxic conditions. In conclusion, the perfluorocarbon-based NE containing oxygen proves to be an important strategic tool for improving hair growth and alleviating hair loss.