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Single-nucleus analysis allows robust cell-type classification and helps to establish relationships between chromatin accessibility and cell-type-specific gene expression. Here, using samples from 92 women of several genetic ancestries, we developed a comprehensive chromatin accessibility and gene expression atlas of the breast tissue. Integrated analysis revealed ten distinct cell types, including three major epithelial subtypes (luminal hormone sensing, luminal adaptive secretory precursor (LASP) and basal-myoepithelial), two endothelial and adipocyte subtypes, fibroblasts, T cells, and macrophages. In addition to the known cell identity genes FOXA1 (luminal hormone sensing), EHF and ELF5 (LASP), TP63 and KRT14 (basal-myoepithelial), epithelial subtypes displayed several uncharacterized markers and inferred gene regulatory networks. By integrating breast epithelial cell gene expression signatures with spatial transcriptomics, we identified gene expression and signaling differences between lobular and ductal epithelial cells and age-associated changes in signaling networks. LASP cells and fibroblasts showed genetic ancestry-dependent variability. An estrogen receptor-positive subpopulation of LASP cells with alveolar progenitor cell state was enriched in women of Indigenous American ancestry. Fibroblasts from breast tissues of women of African and European ancestry clustered differently, with accompanying gene expression differences. Collectively, these data provide a vital resource for further exploring genetic ancestry-dependent variability in healthy breast biology., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Background: Despite evidence indicating the dominance of cell-of-origin signatures in molecular tumor patterns, translating these genome-wide patterns into actionable insights has been challenging. This study introduces breast cancer cell-of-origin signatures that offer significant prognostic value across all breast cancer subtypes and various clinical cohorts, compared to previously developed genomic signatures., Methods: We previously reported that triple hormone receptor (THR) co-expression patterns of androgen (AR), estrogen (ER), and vitamin D (VDR) receptors are maintained at the protein level in human breast cancers. Here, we developed corresponding mRNA signatures (THR-50 and THR-70) based on these patterns to categorize breast tumors by their THR expression levels. The THR mRNA signatures were evaluated across 56 breast cancer datasets (5040 patients) using Kaplan-Meier survival analysis, Cox proportional hazard regression, and unsupervised clustering., Results: The THR signatures effectively predict both overall and progression-free survival across all evaluated datasets, independent of subtype, grade, or treatment status, suggesting improvement over existing prognostic signatures. Furthermore, they delineate three distinct ER-positive breast cancer subtypes with significant survival in differences-expanding on the conventional two subtypes. Additionally, coupling THR-70 with an immune signature identifies a predominantly ER-negative breast cancer subgroup with a highly favorable prognosis, comparable to ER-positive cases, as well as an ER-negative subgroup with notably poor outcome, characterized by a 15-fold shorter survival., Conclusions: The THR cell-of-origin signature introduces a novel dimension to breast cancer biology, potentially serving as a robust foundation for integrating additional prognostic biomarkers. These signatures offer utility as a prognostic index for stratifying existing breast cancer subtypes and for de novo classification of breast cancer cases. Moreover, THR signatures may also hold promise in predicting hormone treatment responses targeting AR and/or VDR., (© 2024. The Author(s).)

Most cells in solid tumors are exposed to oxygen levels between 0.5% and 5%. We developed an approach that allows collection, processing, and evaluation of cancer and non-cancer cells under physioxia, while preventing exposure to ambient air. This aided comparison of baseline and drug-induced changes in signaling pathways under physioxia and ambient oxygen. Using tumor cells from transgenic models of breast cancer and cells from breast tissues of clinically breast cancer-free women, we demonstrate oxygen-dependent differences in cell preference for epidermal growth factor receptor (EGFR) or platelet-derived growth factor receptor beta (PDGFRβ) signaling. Physioxia caused PDGFRβ-mediated activation of AKT and extracellular regulated kinase (ERK) that reduced sensitivity to EGFR and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) inhibition and maintained PDGFRβ+ epithelial-mesenchymal hybrid cells with potential cancer stem cell (CSC) properties. Cells in ambient air displayed differential EGFR activation and were more sensitive to targeted therapies. Our data emphasize the importance of oxygen considerations in preclinical cancer research to identify effective drug targets and develop combination therapy regimens., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Breast cancer (BC) is the most common cancer among women with high morbidity and mortality. Therefore, new research is still needed for biomarker detection. GSE101124 and GSE182471 datasets were obtained from the Gene Expression Omnibus (GEO) database to evaluate differentially expressed circular RNAs (circRNAs). The Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) databases were used to identify the significantly dysregulated microRNAs (miRNAs) and genes considering the Prediction Analysis of Microarray classification (PAM50). The circRNA-miRNA-mRNA relationship was investigated using the Cancer-Specific CircRNA, miRDB, miRTarBase, and miRWalk databases. The circRNA-miRNA-mRNA regulatory network was annotated using Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway database. The protein-protein interaction network was constructed by the STRING database and visualized by the Cytoscape tool. Then, raw miRNA data and genes were filtered using some selection criteria according to a specific expression level in PAM50 subgroups. A bottleneck method was utilized to obtain highly interacted hub genes using cytoHubba Cytoscape plugin. The Disease-Free Survival and Overall Survival analysis were performed for these hub genes, which are detected within the miRNA and circRNA axis in our study. We identified three circRNAs, three miRNAs, and eighteen candidate target genes that may play an important role in BC. In addition, it has been determined that these molecules can be useful in the classification of BC, especially in determining the basal-like breast cancer (BLBC) subtype. We conclude that hsa_circ_0000515/miR-486-5p/SDC1 axis may be an important biomarker candidate in distinguishing patients in the BLBC subgroup of BC., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Erdogan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

A central role for vitamin D (VD) in immune modulation has recently been recognized linking VD insufficiency to autoimmune disorders that commonly exhibit sex-associated differences. Similar to other autoimmune diseases, there is a higher incidence of multiple sclerosis (MS) in women, but a poorer prognosis in men, often characterized by a more rapid progression. Although sex hormones are most likely involved, this phenomenon is still poorly understood. Oxidative stress, modulated by VD serum levels as well as sex hormones, may act as a contributing factor to demyelination and axonal damage in both MS and the corresponding preclinical models. In this study, we analyzed sex-associated differences and VD effects utilizing an animal model that recapitulates histopathological features of the progressive MS phase (PMS). In contrast to relapsing-remitting MS (RRMS), PMS has been poorly investigated in this context. Male ( n = 50) and female ( n = 46) Dark Agouti rats received either VD (400 IU per week; VD + ) or standard rodent food without extra VD (VD - ) from weaning onwards. Myelination, microglial activation, apoptotic cell death and neuronal viability were assessed using immunohistochemical markers in brain tissue. Additionally, we also used two different histological markers against oxidized lipids along with colorimetric methods to measure protective polyphenols (PP) and total antioxidative capacity (TAC) in serum. Neurofilament light chain serum levels (sNfL) were analyzed using single-molecule array (SIMOA) analysis. We found significant differences between female and male animals. Female rats exhibited a better TAC and higher amounts of PP. Additionally, females showed higher myelin preservation, lower microglial activation and better neuronal survival while showing more apoptotic cells than male rats. We even found a delay in reaching the peak of the disease in females. Overall, both sexes benefitted from VD supplementation, represented by significantly less cortical, neuroaxonal and oxidative damage. Unexpectedly, male rats had an even higher overall benefit, most likely due to differences in oxidative capacity and defense systems.

Single-cell transcriptomics studies have begun to identify breast epithelial cell and stromal cell specific transcriptome differences between BRCA1/2 mutation carriers and non-carriers. We generated a single-cell transcriptome atlas of breast tissues from BRCA1, BRCA2 mutation carriers and compared this single-cell atlas of mutation carriers with our previously described single-cell breast atlas of healthy non-carriers. We observed that BRCA1 but not BRCA2 mutations altered the ratio between basal (basal-myoepithelial), luminal progenitor (luminal adaptive secretory precursor, LASP), and mature luminal (luminal hormone sensing) cells in breast tissues. A unique subcluster of cells within LASP cells is underrepresented in case of BRCA1 and BRCA2 mutation carriers compared with non-carriers. Both BRCA1 and BRCA2 mutations specifically altered transcriptomes in epithelial cells which are an integral part of NFκB, LARP1, and MYC signaling. Signaling pathway alterations in epithelial cells unique to BRCA1 mutations included STAT3, BRD4, SMARCA4, HIF2A/EPAS1, and Inhibin A signaling. BRCA2 mutations were associated with upregulation of IL6, PDK1, FOXO3, and TNFSF11 signaling. These signaling pathway alterations are sufficient to alter sensitivity of BRCA1/BRCA2-mutant breast epithelial cells to transformation as epithelial cells from BRCA1 mutation carriers overexpressing hTERT + PIK3CAH1047R generated adenocarcinomas, whereas similarly modified mutant BRCA2 cells generated basal carcinomas in NSG mice. Thus, our studies provide a high-resolution transcriptome atlas of breast epithelial cells of BRCA1 and BRCA2 mutation carriers and reveal their susceptibility to PIK3CA mutation-driven transformation., Significance: This study provides a single-cell atlas of breast tissues of BRCA1/2 mutation carriers and demonstrates that aberrant signaling due to BRCA1/2 mutations is sufficient to initiate breast cancer by mutant PIK3CA., (© 2024 The Authors; Published by the American Association for Cancer Research.)

Purpose: In this prospective, randomized study, we aimed to compare the global recovery scores and postoperative pain management between US-guided mTLIP block versus QLB after lumbar spine surgery., Methods: 60 patients with ASA score I-II planned for microendoscopic discectomy under general anesthesia were included. We allocated the patients into two groups: the QLB group (n = 30) or the mTLIP group (n = 30). QLB and mTLIP was performed with 30 ml 0.25% bupivacaine in the groups. Paracetamol 1 g IV 3 × 1 was ordered to the patients at the postoperative period. If the NRS score was ≥ 4, 1 mg/kg tramadol IV was administered as rescue analgesia., Results: There was a significant between-group difference in the mean global QoR-40 scores 24 h postsurgery. Both the static and dynamic NRS scores were significantly lower in the postoperative 1-16 h period in the mTLIP group. There was no significant between-group difference in the NRS scores 24 h postsurgery. There was no significant between-group difference in postoperative rescue analgesia consumption. However, the need for rescue analgesia was lower in the postoperative first 5 h in the mTLIP group, and survival probability was higher in the mTLIP group according to Kaplan-Meier survival analysis. There was no significant difference between the groups in the rate of adverse events., Conclusion: mTLIP provided superior analgesia compared to posterior QLB. The QoR-40 scores in the mTLIP group were higher than those in the QLB group., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To compare the efficacy of maxillomandibular advancement (MMA) for patients with obstructive sleep apnea (OSA) with class 2 versus 3 dentofacial deformities (DFDs)., Study Design: Retrospective chart review., Setting: Tertiary sleep surgery center., Methods: Patients with OSA and DFD class 2 versus 3 undergoing MMA at Stanford Sleep Surgery between 2014 and 2021 were matched by preoperative body mass index (BMI), age, and sex. Postoperative outcome was compared with polysomnography measures and patient-reported outcome measures (PROMs)., Results: Twenty-eight matched subjects, 14 in each deformity group were identified and assessed. The mean age (standard deviation) was 34.29 (10.21) and 33.86 (10.23) for classes 2 and 3, respectively. The apnea-hypopnea index (AHI) decreased from 43.42 (28.30) to 9.6 (5.29) (p < .001) and 37.17 (35.77) to 11.81 (15.74) (p = .042) in class 2 and 3 subjects, respectively. The oxygen desaturation index (ODI) changed from 30.48 (24.02) to 6.88 (3.39) (p = .024) and 11.43 (11.40) to 5.44 (7.96) (p = .85) in class 2 and 3 subjects, respectively. The Epworth sleepiness scale changed from 8.93 (5.28) to 3.91 (2.70) (p = .018) and 10.23 (4.38) to 4.22 (3.07) (p = .006) in class 2 and 3 subjects, respectively., Conclusion: Among age, sex, and BMI-matched subjects, MMA is equally effective in both dentofacial class 2 and 3 groups, both objectively and subjectively. Preoperatively, dentofacial class 2 patients with OSA presented with the more severe disease with higher AHI and ODI. Dentofacial class 3 patients with OSA may require additional attention to improve nasal function outcomes., (© 2023 American Academy of Otolaryngology-Head and Neck Surgery Foundation.)

Endometrioma superinfection is a rare clinical entity that may cause diagnostic confusion and can be complicated by rupture, peritonitis, sepsis, and even death. Therefore, early diagnosis is crucial for appropriate patient management. Since clinical findings can be mild or nonspecific, radiological imaging is frequently used for diagnostic purposes. From a radiological perspective, it can be challenging to distinguish the presence of infection in an endometrioma. Complex cyst structure, wall thickening, increased peripheral vascularization, nondependent air bubbles, and surrounding inflammatory changes have been reported as potential US and CT findings suggestive of superinfection. On the other hand, there is a gap in the literature regarding MRI findings. To the best of our knowledge, this is the first case report in the literature to discuss MRI findings and temporal evolution of infected endometriomas. In this case report, we aim to present a patient with bilateral infected endometriomas at different stages, and to discuss the multimodality imaging findings, focusing specifically on the MRI. We defined 2 new MRI findings that may indicate the presence of superinfection in the early period. The first one was the "T1 signal reversal" seen in bilateral endometriomas. The second one, "progressive disappearance of T2 shading," was observed only in the right-sided lesion. These nonenhancing signal changes accompanied by increased lesion sizes during MRI follow-up were thought to represent a transition from blood to pus, and the percutaneous drainage of the right-sided endometrioma microbiologically confirmed our suspicion. In conclusion, MRI can be helpful in the early diagnosis of infected endometrioma due to its high soft tissue resolution. Percutaneous treatment may contribute to patient management as an alternative to surgical drainage., (© 2023 The Authors. Published by Elsevier Inc. on behalf of University of Washington.)

Introduction: To identify new clinical and biologic parameters associated with short-term survival in allogeneic or autologous hematopoietic stem cell transplantation (HSCT) patients who were admitted to the intensive care unit (ICU) during their post-transplant period., Materials and Methods: 40 patients who were admitted to the ICU in our center during their post-transplant period were evaluated retrospectively between Jan 2014 - Jun 2021. Baseline patient characteristics before the transplant, reasons for ICU admissions, laboratory and clinical findings, supportive treatment in ICU and short-term survival were analyzed., Results: We found 8.8% ICU admission rate in all patient group (n = 450). Mortality rate of the patients who were admitted to ICU was 75%. Invasive mechanic ventilation, need for vasopressor, heart rate was significantly different between survivor and non-survivor group (p = 0.001, p = 0.001, p = 0.004). Elevated INR was associated with poor survival on ICU (p = 0.033). APACHE II score was an independent predictor of ICU mortality (p = 0.045)., Conclusion: Despite the recent advances in transplant conditioning protocols, prophylaxis strategies and improvements of management in ICU, overall survival for HSCT patients in ICU is still poor. In this study INR level was described as a new prognostic factor in ICU for first time in the literature., Competing Interests: Conflict of interestAll authors declare no conflict of interest that may have influences either the conduct or the presentation of the research., (© The Author(s), under exclusive licence to Indian Society of Hematology and Blood Transfusion 2022, Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

T cells are integral components of the adaptive immune system, and their responses are mediated by unique T-cell receptors (TCR) that recognize specific antigens from a variety of biological contexts. As a result, analyzing the T-cell repertoire offers a better understanding of immune responses and of diseases like cancer. Next-generation sequencing technologies have greatly enabled the high-throughput analysis of the TCR repertoire. On the basis of our extensive experience in the field from the past decade, we provide an overview of TCR sequencing, from the initial library preparation steps to sequencing and analysis methods and finally to functional validation techniques. With regards to data analysis, we detail important TCR repertoire metrics and present several computational tools for predicting antigen specificity. Finally, we highlight important applications of TCR sequencing and repertoire analysis to understanding tumor biology and developing cancer immunotherapies., (©2022 The Authors; Published by the American Association for Cancer Research.)

Background: Quadratus lumborum block (QLB) is a fascial plane block. There is no randomized study on the efficacy of QLB for lumbar surgery. We evaluated the efficacy of QLB for postoperative pain management and patient satisfaction after lumbar disc herniation surgery (LDHS)., Methods: Sixty patients with ASA score I-II planned for LDHS under general anesthesia were included. We allocated the patients into two groups: the QLB group (n = 30) or the control group (n = 30). QLB was performed with 30 ml 0.25% bupivacaine in the QLB group. Paracetamol 1 g IV 3 × 1 was ordered to the patients at the postoperative period. If the NRS score was ≥ 4, 1 mg/ kg tramadol IV was administered as rescue analgesia., Results: There was a reduction in the median static NRS at 0 h and 2 h with QLB compared to the control group (p < 0.05). There was no difference in the resting NRS at any other time point up to 24 h. The median dynamic NRS was significantly lower at 0, 2, 4, 8, and 16 h in the QLB group (p < 0.05). The need for rescue analgesia was significantly lower in the QLB group. The incidence of nausea was significantly higher in the control group. The postoperative patient satisfaction was significantly higher in the QLB group (p < 0.05)., Conclusion: We found that the QLB is effective for pain control following LDHS., (© 2022. The Author(s).)

Background: The study aimed to describe the epidemiology and outcomes of hospital-acquired bloodstream infections (HABSIs) between COVID-19 and non-COVID-19 critically ill patients., Methods: We used data from the Eurobact II study, a prospective observational multicontinental cohort study on HABSI treated in ICU. For the current analysis, we selected centers that included both COVID-19 and non-COVID-19 critically ill patients. We performed descriptive statistics between COVID-19 and non-COVID-19 in terms of patients' characteristics, source of infection and microorganism distribution. We studied the association between COVID-19 status and mortality using multivariable fragility Cox models., Results: A total of 53 centers from 19 countries over the 5 continents were eligible. Overall, 829 patients (median age 65 years [IQR 55; 74]; male, n = 538 [64.9%]) were treated for a HABSI. Included patients comprised 252 (30.4%) COVID-19 and 577 (69.6%) non-COVID-19 patients. The time interval between hospital admission and HABSI was similar between both groups. Respiratory sources (40.1 vs. 26.0%, p < 0.0001) and primary HABSI (25.4% vs. 17.2%, p = 0.006) were more frequent in COVID-19 patients. COVID-19 patients had more often enterococcal (20.5% vs. 9%) and Acinetobacter spp. (18.8% vs. 13.6%) HABSIs. Bacteremic COVID-19 patients had an increased mortality hazard ratio (HR) versus non-COVID-19 patients (HR 1.91, 95% CI 1.49-2.45)., Conclusions: We showed that the epidemiology of HABSI differed between COVID-19 and non-COVID-19 patients. Enterococcal HABSI predominated in COVID-19 patients. COVID-19 patients with HABSI had elevated risk of mortality. Trial registration ClinicalTrials.org number NCT03937245 . Registered 3 May 2019., (© 2022. The Author(s).)

Background: Colorectal cancer (CRC) consensus molecular subtypes (CMS) have different immunological, stromal cell, and clinicopathological characteristics. Single-cell characterization of CMS subtype tumor microenvironments is required to elucidate mechanisms of tumor and stroma cell contributions to pathogenesis which may advance subtype-specific therapeutic development. We interrogate racially diverse human CRC samples and analyze multiple independent external cohorts for a total of 487,829 single cells enabling high-resolution depiction of the cellular diversity and heterogeneity within the tumor and microenvironmental cells., Results: Tumor cells recapitulate individual CMS subgroups yet exhibit significant intratumoral CMS heterogeneity. Both CMS1 microsatellite instability (MSI-H) CRCs and microsatellite stable (MSS) CRC demonstrate similar pathway activations at the tumor epithelial level. However, CD8+ cytotoxic T cell phenotype infiltration in MSI-H CRCs may explain why these tumors respond to immune checkpoint inhibitors. Cellular transcriptomic profiles in CRC exist in a tumor immune stromal continuum in contrast to discrete subtypes proposed by studies utilizing bulk transcriptomics. We note a dichotomy in tumor microenvironments across CMS subgroups exists by which patients with high cancer-associated fibroblasts (CAFs) and C1Q+TAM content exhibit poor outcomes, providing a higher level of personalization and precision than would distinct subtypes. Additionally, we discover CAF subtypes known to be associated with immunotherapy resistance., Conclusions: Distinct CAFs and C1Q+ TAMs are sufficient to explain CMS predictive ability and a simpler signature based on these cellular phenotypes could stratify CRC patient prognosis with greater precision. Therapeutically targeting specific CAF subtypes and C1Q + TAMs may promote immunotherapy responses in CRC patients., (© 2022. The Author(s).)