Cellular heterogeneity and dynamics of the human uterus in healthy premenopausal women.

The human uterus is a complex and dynamic organ whose lining grows, remodels, and regenerates every menstrual cycle or upon tissue damage. Here, we applied single-cell RNA sequencing to profile more the 50,000 uterine cells from both the endometrium and myometrium of five healthy premenopausal individuals, and jointly analyzed the data with a previously published dataset from 15 subjects. The resulting normal uterus cell atlas contains more than 167K cells, representing the lymphatic endothelium, blood endothelium, stromal, ciliated epithelium, unciliated epithelium, and immune cell populations. Focused analyses within each major cell type and comparisons with subtype labels from prior studies allowed us to document supporting evidence, resolve naming conflicts, and propose a consensus annotation system of 39 subtypes. We release their gene expression centroids, differentially expressed genes, and messenger Ribonucleic Acid (mRNA) patterns of literature-based markers as a shared community resource. We identify multiple potential progenitor cells: compartment-wide progenitors for each major cell type and potential cross-lineage multipotent stromal progenitors that may replenish the epithelial, stromal, and endothelial compartments. Furthermore, many cell types and subtypes exhibit shifts in cell number and transcriptomes across different phases of the menstrual cycle. Finally, comparisons between premenopausal, postpartum, and postmenopausal samples revealed substantial alterations in tissue composition, particularly in the proportions of stromal, endothelial, and immune cells. The cell taxonomy and molecular markers we report here are expected to inform studies of both basic biology of uterine function and its disorders.

Selective inhibition of the BD2 bromodomain of BET proteins in prostate cancer.

Proteins of the bromodomain and extra-terminal (BET) domain family are epigenetic readers that bind acetylated histones through their bromodomains to regulate gene transcription. Dual-bromodomain BET inhibitors (DbBi) that bind with similar affinities to the first (BD1) and second (BD2) bromodomains of BRD2, BRD3, BRD4 and BRDt have displayed modest clinical activity in monotherapy cancer trials. A reduced number of thrombocytes in the blood (thrombocytopenia) as well as symptoms of gastrointestinal toxicity are dose-limiting adverse events for some types of DbBi1-5. Given that similar haematological and gastrointestinal defects were observed after genetic silencing of Brd4 in mice6, the platelet and gastrointestinal toxicities may represent on-target activities associated with BET inhibition. The two individual bromodomains in BET family proteins may have distinct functions7-9 and different cellular phenotypes after pharmacological inhibition of one or both bromodomains have been reported10,11, suggesting that selectively targeting one of the bromodomains may result in a different efficacy and tolerability profile compared with DbBi. Available compounds that are selective to individual domains lack sufficient potency and the pharmacokinetics properties that are required for in vivo efficacy and tolerability assessment10-13. Here we carried out a medicinal chemistry campaign that led to the discovery of ABBV-744, a highly potent and selective inhibitor of the BD2 domain of BET family proteins with drug-like properties. In contrast to the broad range of cell growth inhibition induced by DbBi, the antiproliferative activity of ABBV-744 was largely, but not exclusively, restricted to cell lines of acute myeloid leukaemia and prostate cancer that expressed the full-length androgen receptor (AR). ABBV-744 retained robust activity in prostate cancer xenografts, and showed fewer platelet and gastrointestinal toxicities than the DbBi ABBV-07514. Analyses of RNA expression and chromatin immunoprecipitation followed by sequencing revealed that ABBV-744 displaced BRD4 from AR-containing super-enhancers and inhibited AR-dependent transcription, with less impact on global transcription compared with ABBV-075. These results underscore the potential value of selectively targeting the BD2 domain of BET family proteins for cancer therapy.

High sugar diet promotes tumor progression paradoxically through aberrant upregulation of pepck1.

High dietary sugar (HDS), a contemporary dietary concern due to excessive intake of added sugars and carbohydrates, escalates the risk of metabolic disorders and concomitant cancers. However, the molecular mechanisms underlying HDS-induced cancer progression are not completely understood. We found that phosphoenolpyruvate carboxykinase 1 (PEPCK1), a pivotal enzyme in gluconeogenesis, is paradoxically upregulated in tumors by HDS, but not by normal dietary sugar (NDS), during tumor progression. Targeted knockdown of pepck1, but not pepck2, specifically in tumor tissue in Drosophila in vivo, not only attenuates HDS-induced tumor growth but also significantly improves the survival of Ras/Src tumor-bearing animals fed HDS. Interestingly, HP1a-mediated heterochromatin interacts directly with the pepck1 gene and downregulates pepck1 gene expression in wild-type Drosophila. Mechanistically, we demonstrated that, under HDS conditions, pepck1 knockdown reduces both wingless and TOR signaling, decreases evasion of apoptosis, reduces genome instability, and suppresses glucose uptake and trehalose levels in tumor cells in vivo. Moreover, rational pharmacological inhibition of PEPCK1, using hydrazinium sulfate, greatly improves the survival of tumor-bearing animals with pepck1 knockdown under HDS. This study is the first to show that elevated levels of dietary sugar induce aberrant upregulation of PEPCK1, which promotes tumor progression through altered cell signaling, evasion of apoptosis, genome instability, and reprogramming of carbohydrate metabolism. These findings contribute to our understanding of the complex relationship between diet and cancer at the molecular, cellular, and organismal levels and reveal PEPCK1 as a potential target for the prevention and treatment of cancers associated with metabolic disorders.

Heterogeneity of State Stroke Center Certification and Designation Processes.

BACKGROUND: Stroke centers are critical for the timely diagnosis and treatment of acute stroke and have been associated with improved treatment and outcomes; however, variability exists in the definitions and processes used to certify and designate these centers. Our study categorizes state stroke center certification and designation processes and provides examples of state processes across the United States, specifically in states with independent designation processes that do not rely on national certification. METHODS: In this cross-sectional study from September 2022 to April 2023, we used peer-reviewed literature, primary source documents from states, and communication with state officials in all 50 states to capture each state's process for stroke center certification and designation. We categorized this information and outlined examples of processes in each category. RESULTS: Our cross-sectional study of state-level stroke center certification and designation processes across states reveals significant heterogeneity in the terminology used to describe state processes and the processes themselves. We identify 3 main categories of state processes: No State Certification or Designation Process (category A; n=12), State Designation Reliant on National Certification Only (category B; n=24), and State Has Option for Self-Certification or Independent Designation (category C; n=14). Furthermore, we describe 3 subcategories of self-certification or independent state designation processes: State Relies on Self-Certification or Independent Designation for Acute Stroke Ready Hospital or Equivalent (category C1; n=3), State Has Hybrid Model for Acute Stroke Ready Hospital or Equivalent (category C2; n=5), and State Has Hybrid Model for Primary Stroke Center and Above (category C3; n=6). CONCLUSIONS: Our study found significant heterogeneity in state-level processes. A better understanding of how these differences may impact the rigor of each process and clinical performance of stroke centers is worthy of further investigation.

Assessing the predictive value of intraductal carcinoma of the prostate (IDC-P) in determining abiraterone efficacy for metastatic hormone-sensitive prostate cancer (mHSPC) patients.

BACKGROUND: This study explored the value of intraductal carcinoma of the prostate (IDC-P) in predicting the efficacy of abiraterone treatment in metastatic hormone-sensitive prostate cancer (mHSPC) patients. METHODS: A retrospective study of 925 patients who underwent prostate biopsies to detect IDC-P was conducted, with participants divided into two cohorts. The first cohort of 165 mHSPC patients receiving abiraterone treatment was analyzed to compare therapeutic effectiveness between IDC-P positive and negative cases. Utilizing propensity score matching (PSM) to reduce bias, outcomes such as PSA response, progression-free survival (PSA-PFS), radiographic progression-free survival (rPFS), and overall survival were assessed. Additionally, the second cohort of 760 mHSPC patients compared the efficacy of abiraterone with conventional hormone therapy, focusing on differences between IDC-P positive and negative individuals. RESULTS: After PSM, our first cohort included 108 patients with similar baseline characteristics. Among them, 50% (54/108) were diagnosed with IDC-P, with 22.2% (12/54) having IDC-P pattern 1 and 77.8% (42/54) with IDC-P pattern 2. While no notable difference was seen in PSA responses between IDC-P positive and negative patients, IDC-P presence linked to worse clinical outcomes (PSA-PFS: 18.6 months vs. not reached [NR], p = 0.009; rPFS: 23.6 months vs. NR, p = 0.020). Further analysis showed comparable outcomes for IDC-P pattern 1 but significantly worse prognosis for IDC-P pattern 2 (PSA-PFS: 18.6 months vs. NR, p = 0.002; rPFS: 22.4 months vs. NR, p = 0.010). Subgroup analysis revealed IDC-P pattern 2 consistently predicted poorer outcomes across patient subgroups. Remarkably, both IDC-P positive and negative patients gained more from androgen deprivation therapy with abiraterone than conventional treatment, with IDC-P negative patients showing a more significant survival advantage, supported by better hazard ratios (0.47 and 0.66). CONCLUSION: This study found that IDC-P, especially pattern 2, predicts poor prognosis in mHSPC patients on abiraterone therapy. Also, abiraterone's advantage over hormone therapy is reduced in cases with IDC-P compared to those without.

Bortezomib in relapsed/refractory immune thrombotic thrombocytopenic purpura: A single-centre retrospective cohort and systematic literature review.

Immune thrombotic thrombocytopenic purpura (iTTP) is a rare and life-threatening haematological condition. Initial treatment involves plasma exchange (PLEX), corticosteroids, caplacizumab and rituximab. In relapsed and refractory cases despite initial treatments, further immune-modulating therapy includes the proteasome inhibitor, bortezomib. Evidence for bortezomib in this setting is limited to case reports and case series. We report our experience and perform a systematic review of the literature. We identified 21 publications with 28 unique patients in addition to our cohort of eight patients treated with bortezomib. The median age of patients was 44 years (IQR: 27-53) and 69% female. They were usually in an initial, refractory presentation of iTTP where they had received PLEX, corticosteroids, rituximab and another line of therapy. After bortezomib administration, 72% of patients had a complete response, with 85% maintaining a durable response without relapse at the last follow-up.

Efficacy of Single-Agent Chemotherapy in Endocrine Therapy-Refractory Metastatic Invasive Lobular Carcinoma.

BACKGROUND: Hormone receptor (HR)-positive, HER2-negative metastatic invasive lobular breast cancer (mILC) is distinct from invasive ductal cancer (IDC) in clinicopathologic and molecular characteristics, impacting its response to systemic therapy. While endocrine therapy (ET) combined with targeted therapies has shown efficacy in ET-sensitive mILC, data on chemotherapy in ET-refractory mILC remain limited. We investigated the efficacy of single-agent capecitabine (CAP) versus taxanes (TAX) in ET-refractory HR+ HER2-negative patients with mILC. MATERIALS AND METHODS: Using data from the MD Anderson prospectively collected breast cancer database, we identified patients with HR+ HER2-negative mILC who received prior ET and first-time chemotherapy in the metastatic setting. We compared outcomes between 173 CAP-treated and 96 TAX-treated patients. RESULTS: CAP-treated patients had significantly better median progression-free survival (PFS) than TAX-treated patients (8.8 vs 5.0 months, HR 0.63, P < .001). Overall survival (OS) did not differ significantly between the groups (42.7 vs 36.6 months for CAP vs TAX, respectively, HR 0.84, P = .241). Multivariate analyses for PFS and OS revealed better outcomes in subjects with fewer metastatic sites and those exposed to more lines of ET. Additionally, Black patients showed worse OS outcomes compared to White patients (HR 2.46; P = .001). CONCLUSION: In ET-refractory HR+ HER2-negative mILC, single-agent CAP demonstrated superior PFS compared to TAX. Our findings highlight the potential benefit of CAP in this patient subset, warranting further investigation through prospective trials.

Simultaneous SERS Sensing of Cysteine and Homocysteine in Blood Based on the CBT-Cys Click Reaction: Toward Precisive Diagnosis of Schizophrenia.

At present, there is a lack of sufficiently specific laboratory diagnostic indicators for schizophrenia. Serum homocysteine (Hcy) levels have been found to be related to schizophrenia. Cysteine (Cys) is a demethylation product in the metabolism of Hcy, and they always coexist with highly similar structures in vivo. There are few reports on the use of Cys as a diagnostic biomarker for schizophrenia in collaboration with Hcy, mainly because the rapid, economical, accurate, and high-throughput simultaneous detection of Cys and Hcy in serum is highly challenging. Herein, a click reaction-based surface-enhanced Raman spectroscopy (SERS) sensor was developed for simultaneous and selective detection of Cys and Hcy. Through the efficient and specific CBT-Cys click reaction between the probe containing cyan benzothiazole and Cys/Hcy, the tiny methylene difference between the molecular structures of Cys and Hcy was converted into the difference between the ring skeletons of the corresponding products that could be identified by plasmonic silver nanoparticle enhanced molecular fingerprint spectroscopy to realize discriminative detection. Furthermore, the SERS sensor was successfully applied to the detection in related patient serum samples, and it was found that the combined analysis of Cys and Hcy can improve the diagnostic accuracy of schizophrenia compared to a single indicator.

Outcomes of older adults with early-stage triple-negative breast cancer (TNBC) receiving chemotherapy: a single-institution experience.

BACKGROUND: Despite lower chemotherapy use in older triple-negative breast cancer (TNBC) patients, their outcomes match younger counterparts. We compared outcomes in early-stage TNBC patients by age receiving chemotherapy at a major cancer center with a national TNBC database. METHODS: Retrospective study using institutional data on stage I-III TNBC (ER/PR < 10%) women with neoadjuvant/adjuvant chemotherapy. Based on their ages at diagnosis, patients were stratified into four categories: ≤40, 41-59, 60-69, and ≥ 70 years. Demographic and clinical characteristics recorded included race, disease stage, ER/PR positivity, treatment regimen, lymphatic or vascular invasion (LVI), histologic grade, Ki-67 level, body mass index (BMI), and pathologic complete response (pCR) following neoadjuvant treatment and are summarized using descriptive statistics. The primary endpoints were overall survival (OS), disease-free survival (DFS), and distant disease-free survival (DDFS); all were estimated using the Kaplan-Meier method. Both univariate and multivariate (MV) Cox regressions were applied to evaluate the impact of important covariates on these time-to-event endpoints. RESULTS: Of the 2336 patients studied, 492 (21.1%) were ≤ 40 years old, 1239 (53.1%) were 41-59, 461 (19.7%) were 60-69, and 144 (6.2%) were ≥ 70. In the univariate regression model of OS/DFS/DDFS, age ≥ 70 was significantly associated with worse OS (p = 0.0217); other factors associated with worse OS were non-anthracycline-based chemotherapy, higher tumor stage, and neoadjuvant chemotherapy. The multivariate Cox regression model, adjusted for race and stage, showed no significant effects of age on OS; however, patients ≥ 70 years old who received non-anthracycline treatment combinations had worse DFS (hazard ratio = 0.349 vs. 1.049, p = 0.0293) and DDFS (hazard ratio = 0.317 vs. 1.016, p = 0.0251) than patients ≤ 40 years old. DFS from MV model after adjusting for age, race, and disease stage, the hazard ratio between anthracycline + taxane treatments and anthracycline + other treatments in patients ≥ 70 years old was statistically significantly lower than in patients ≤ 40 years old (hazard ratios [HRs] = 0.349 vs. 1.049, p = 0.0293). CONCLUSIONS: Our findings indicate that outcomes such as DFS are less favorable in older compared to younger patients with early-stage TNBC, primarily in those who did not receive an anthracycline based chemotherapy regimen.

MRI Tumor Regression Response to Neoadjuvant Chemotherapy Alone without Radiation for Rectal Adenocarcinoma.

Background Neoadjuvant chemotherapy (NCT) is gaining acceptance for the management of locally advanced rectal cancer (LARC) in patients without negative prognostic factors. However, the value of MRI in evaluating tumor response after NCT remains unclear. Purpose To investigate the accuracy of MRI in assessing pathologic complete response in participants with LARC who underwent surgery after NCT without radiation. Materials and Methods A retrospective imaging substudy was conducted within two consecutive prospective clinical trials: the expanded phase II trial (from December 2017 to May 2021) and the COPEC trial (comparison of tumor response to two or four cycles of neoadjuvant chemotherapy alone, ongoing from August 2021). All included participants received four cycles of capecitabine combined with oxaliplatin (or CAPOX) before surgery. Three radiologists who were blinded to the clinicopathologic data independently evaluated the tumor response using five methods, namely, MR tumor regression grade (MR-TRG) alone, diffusion-weighted imaging (DWI) alone, DWI-modified MR-TRG (DWImodMR-TRG), MRI complete response, and radiologic neoadjuvant response score. With pathologic assessment serving as the reference standard, the positive and negative predictive values, sensitivity, specificity, and area under the receiver operating characteristic curve (AUC) were determined to evaluate the accuracy and performance of these models. The AUCs of the models were compared using the DeLong test. Results A total of 224 participants were included, comprising 119 from the expanded phase II trial (median age, 61 years [IQR, 53-67]; 89 male) and 105 from the COPEC trial (median age, 59 years [IQR, 53-67]; 65 male). MR-TRG, DWI, DWImodMR-TRG, MRI complete response, and the radiologic neoadjuvant response score were associated with pathologic complete response. DWImodMR-TRG achieved the highest AUC of 0.90 (95% CI: 0.85, 0.95), with a specificity of 89% (162 of 182) and a negative predictive value of 93% (162 of 174). Conclusion MRI-based models were accurate for determining pathologic complete response in participants with LARC following NCT. DWI improved the predictive performance of MRI-based assessment. © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Santiago and Shur in this issue.

Abundant Edge Active Sites-Modified High-Crystalline g-C3N5 for Hydrogen Peroxide Production from Pure-Water via a Quasi-Homogeneous Photocatalytic Process.

Ultrathin carbon nitride pioneered a paradigm that facilitates effective charge separation and acceleration of rapid charge migration. Nevertheless, the dissociation process confronts a disruption owing to the proclivity of carbon nitride to reaggregate, thereby impeding the optimal utilization of active sites. In response to this exigency, the adoption of a synthesis methodology featuring alkaline potassium salt-assisted molten salt synthesis is advocated in this work, aiming to craft a nitrogenated graphitic carbon nitride (g-C3N5) photocatalyst characterized by thin layer and hydrophilicity, which not only amplifies the degree of crystallization of g-C3N5 but also introduces a plethora of abundant edge active sites, engendering a quasi-homogeneous photocatalytic system. Under visible light irradiation, the ultra-high H2O2 production rate of this modified high-crystalline g-C3N5 in pure water attains 151.14 µm h-1. This groundbreaking study offers a novel perspective for the innovative design of highly efficient photocatalysts with a quasi-homogeneous photocatalytic system.

Increased plasma lipocalin-2 levels are associated with nonmotor symptoms and neuroimaging features in patients with Parkinson's disease.

Lipocalin-2 (LCN2) is essential for the regulation of neuroinflammation and cellular uptake of iron. This study aimed to evaluate plasma LCN2 levels and explore their correlation with clinical and neuroimaging features in Parkinson's disease (PD) patients. Enzyme-linked immunosorbent assay (ELISA) was used to measure plasma LCN2 levels in 120 subjects. Evaluation of motor symptoms and nonmotor symptoms in PD patients was assessed by the associated scales. Voxel-based morphometry (VBM) was used to evaluate brain volume alterations, and quantitative susceptibility mapping (QSM) was used to quantitatively analyze brain iron deposition in 46 PD patients. Plasma LCN2 levels were significantly higher in PD patients than those in healthy controls. LCN2 levels were negatively correlated with Montreal Cognitive Assessment (MoCA) scores, total brain gray matter volume (GMV), and GMV/total intracranial volume (TIV) ratio, but positively correlated with Hamilton Anxiety Rating Scale (HAMD) scores and mean QSM values of the bilateral substantial nigra (SN). Receiver operating characteristic (ROC) curves confirmed that plasma LCN2 levels had good predictive accuracy for PD. The results suggest that plasma LCN2 levels have potential as a biomarker for the diagnosis of PD. LCN2 may be a therapeutic target for neuroinflammation and brain iron deposition.

sB7-H4 is a diagnostic biomarker in epithelial ovarian cancer and correlates to platinum resistance.

Ovarian cancer, with its high mortality rate among gynecological cancers, is often diagnosed late due to the lack of early diagnostic symptoms and biomarkers. The tumor immune microenvironment has become a focal point in cancer diagnostic and therapeutic research. Among these, B7-H4, a checkpoint protein, plays a crucial role in immune regulation and tumor suppression, contributing to immune evasion within the tumor microenvironment. This study aims to identify the concentration of soluble B7-H4(sB7-H4) in the plasma of patients with ovarian cancer and to evaluate its clinical significance. Through a comprehensive analysis involving enzyme-linked immunosorbent assay, immunohistochemistry, and multicolor immunofluorescence, we quantified sB7-H4 levels in patient plasma and ascites, correlating these findings with tissue expression and clinical outcomes. Results indicated a strong association between high sB7-H4 levels and advanced disease, surgical outcomes, lymphatic metastasis, and platinum resistance. When compared with traditional biomarkers CA125 and HE4, sB7-H4, especially in conjunction with these markers, enhances the diagnostic accuracy for epithelial ovarian cancer, offering insights into disease progression and therapeutic efficacy. This comprehensive analysis suggests that sB7-H4 is a promising biomarker for EOC, providing valuable insights into diagnosis, stage differentiation, treatment effectiveness, and prognosis.

Potential drug targets for gastroesophageal reflux disease and Barrett's esophagus identified through Mendelian randomization analysis.

Gastroesophageal reflux disease (GERD) is a prevalent chronic ailment, and present therapeutic approaches are not always effective. This study aimed to find new drug targets for GERD and Barrett's esophagus (BE). We obtained genetic instruments for GERD, BE, and 2004 plasma proteins from recently published genome-wide association studies (GWAS), and Mendelian randomization (MR) was employed to explore potential drug targets. We further winnowed down MR-prioritized proteins through replication, reverse causality testing, colocalization analysis, phenotype scanning, and Phenome-wide MR. Furthermore, we constructed a protein-protein interaction network, unveiling potential associations among candidate proteins. Simultaneously, we acquired mRNA expression quantitative trait loci (eQTL) data from another GWAS encompassing four different tissues to identify additional drug targets. Meanwhile, we searched drug databases to evaluate these targets. Under Bonferroni correction (P < 4.8 × 10-5), we identified 11 plasma proteins significantly associated with GERD. Among these, 7 are protective proteins (MSP, GPX1, ERBB3, BT3A3, ANTR2, CCM2, and DECR2), while 4 are detrimental proteins (TMEM106B, DUSP13, C1-INH, and LINGO1). Ultimately, C1-INH and DECR2 successfully passed the screening process and exhibited similar directional causal effects on BE. Further analysis of eQTLs highlighted 4 potential drug targets, including EDEM3, PBX3, MEIS1-AS3, and NME7. The search of drug databases further supported our conclusions. Our study indicated that the plasma proteins C1-INH and DECR2, along with 4 genes (EDEM3, PBX3, MEIS1-AS3, and NME7), may represent potential drug targets for GERD and BE, warranting further investigation.

In chronic spontaneous urticaria, increased Galectin-9 expression on basophils and eosinophils is linked to high disease activity, endotype-specific markers, and response to omalizumab treatment.

BACKGROUND: Galectin-9 (Gal-9) has been implicated in allergic and autoimmune diseases, but its role and relevance in chronic spontaneous urticaria (CSU) are unclear. OBJECTIVES: To characterize the role and relevance of Gal-9 in the pathogenesis of CSU. METHODS: We assessed 60 CSU patients for their expression of Gal-9 on circulating eosinophils and basophils as well as T cell expression of the Gal-9 receptor TIM-3, compared them with 26 healthy controls (HCs), and explored possible links with disease features including disease activity (urticaria activity score, UAS), total IgE, basophil activation test (BAT), and response to omalizumab treatment. We also investigated potential drivers of Gal-9 expression by eosinophils and basophils. RESULTS: Our CSU patients had markedly increased rates of circulating Gal-9+ eosinophils and basophils and high numbers of lesional Gal-9+ cells. High rates of blood Gal-9+ eosinophils/basophils were linked to high disease activity, IgE levels, and BAT negativity. Serum levels of TNF-α were positively correlated with circulating Gal-9+ eosinophils/basophils, and TNF-α markedly upregulated Gal-9 on eosinophils. CSU patients who responded to omalizumab treatment had more Gal-9+ eosinophils/basophils than non-responders, and omalizumab reduced blood levels of Gal-9+ eosinophils/basophils in responders. Gal-9+ eosinophils/basophils were negatively correlated with TIM-3+TH17 cells. CONCLUSION: Our findings demonstrate a previously unrecognized involvement of the Gal-9/TIM-3 pathway in the pathogenesis CSU and call for studies that explore its relevance.

Exploring the Cellular Impact of Size-Segregated Cigarette Aerosols: Insights into Indoor Particulate Matter Toxicity and Potential Therapeutic Interventions.

Exposure to anthropogenic aerosols has been associated with a variety of adverse health effects, increased morbidity, and premature death. Although cigarette smoke poses one of the most significant public health threats, the cellular toxicity of particulate matter contained in cigarette smoke has not been systematically interrogated in a size-segregated manner. In this study, we employed a refined particle size classification to collect cigarette aerosols, enabling a comprehensive assessment and comparison of the impacts exerted by cigarette aerosol extract (CAE) on SH-SY5Y, HEK293T, and A549 cells. Exposure to CAE reduced cell viability in a dose-dependent manner, with organic components having a greater impact and SH-SY5Y cells displaying lower tolerance compared to HEK293T and A549 cells. Moreover, CAE was found to cause increased oxidative stress, mitochondrial dysfunction, and increased levels of apoptosis, pyroptosis, and autophagy, leading to increased cell death. Furthermore, we found that rutin, a phytocompound with antioxidant potential, could reduce intracellular reactive oxygen species and protect against CAE-triggered cell death. These findings underscore the therapeutic potential of antioxidant drugs in mitigating the adverse effects of cigarette aerosol exposure for better public health outcomes.

Assessment of Lung Nodule Detection and Lung CT Screening Reporting and Data System Classification Using Zero Echo Time Pulmonary MRI.

BACKGROUND: The detection rate of lung nodules has increased considerably with CT as the primary method of examination, and the repeated CT examinations at 3 months, 6 months or annually, based on nodule characteristics, have increased the radiation exposure of patients. So, it is urgent to explore a radiation-free MRI examination method that can effectively address the challenges posed by low proton density and magnetic field inhomogeneities. PURPOSE: To evaluate the potential of zero echo time (ZTE) MRI in lung nodule detection and lung CT screening reporting and data system (lung-RADS) classification, and to explore the value of ZTE-MRI in the assessment of lung nodules. STUDY TYPE: Prospective. POPULATION: 54 patients, including 21 men and 33 women. FIELD STRENGTH/SEQUENCE: Chest CT using a 16-slice scanner and ZTE-MRI at 3.0T based on fast gradient echo. ASSESSMENT: Nodule type (ground-glass nodules, part-solid nodules, and solid nodules), lung-RADS classification, and nodule diameter (manual measurement) on CT and ZTE-MRI images were recorded. STATISTICAL TESTS: The percent of concordant cases, Kappa value, intraclass correlation coefficient (ICC), Wilcoxon signed-rank test, Spearman's correlation, and Bland-Altman. The p-value <0.05 is considered significant. RESULTS: A total of 54 patients (age, 54.8 ± 11.9 years; 21 men) with 63 nodules were enrolled. Compared with CT, the total nodule detection rate of ZTE-MRI was 85.7%. The intermodality agreement of ZTE-MRI and CT lung nodules type evaluation was substantial (Kappa = 0.761), and the intermodality agreement of ZTE-MRI and CT lung-RADS classification was moderate (Kappa = 0.592). The diameter measurements between ZTE-MRI and CT showed no significant difference and demonstrated a high degree of interobserver (ICC = 0.997-0.999) and intermodality (ICC = 0.956-0.985) agreements. DATA CONCLUSION: The measurement of nodule diameter by pulmonary ZTE-MRI is similar to that by CT, but the ability of lung-RADS to classify nodes from MRI images still requires further research. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

How do we manage hyperhemolysis syndrome.

BACKGROUND: Hyperhemolysis syndrome (HHS) is a catastrophic anemia characterized by destruction of both donor and patient red blood cells (RBC). HHS occurs after transfusion and can cause significant morbidity and mortality. Given the difficulty in diagnosing and managing this process, we provide a detailed overview of our treatment protocol. STUDY DESIGN AND METHODS: Members of the Transfusion Medicine and Hematology faculty at our institution collaborated in an iterative process to produce a consensus approach to patients with HHS. RESULTS: We present diagnostic criteria for HHS: recent transfusion within past 7 days (up to 21 days), rapid hemoglobin decline to below the pretransfusion level (usually hemoglobin drop >25% from pretransfusion), a significant decrease in HbA% (in patients with sickle cell disease or beta thalassemia), low or decreasing reticulocyte count in a patient with worsening anemia, and laboratory evidence of hemolysis. We also describe an in-depth approach to management focusing on optimizing hematopoiesis while dampening the immune response. CONCLUSION: We provide a comprehensive approach to the diagnosis and management of HHS based on contemporary literature and clinical experience designed to optimize outcomes for patients.

Clinical and pathological characteristics of OPDM4 patients in advanced disease.

INTRODUCTION/AIMS: Oculopharyngodistal myopathy type 4 (OPDM4) arises from a CGG repeat expansion in the 5' UTR of the RILPL1 gene. Reported cases of OPDM4 have been limited. The aim of this study was to investigate the clinical and myopathological characteristics of OPDM4 patients with advanced disease. METHODS: We assessed a total of 8 affected and 12 unaffected individuals in an OPDM4 family with autosomal dominant inheritance. Muscle biopsy tissue from the proband underwent histological, enzyme histochemical, and immunohistochemical stains, and electron microscopy analysis. Whole exome sequencing and repeat primer PCR (RP-PCR) were conducted to investigate underlying variants. RESULTS: OPDM4 patients displayed a progressive disease course. Most experienced lower limb weakness and diminished walking ability in their 20s and 30s, followed by ptosis, ophthalmoplegia, swallowing difficulties, and dysarthria in their 30s to 50s, By their 50s to 70s, they became non-ambulatory. Muscle magnetic resonance imaging (MRI) of the proband in advanced disease revealed severe fatty infiltration of pelvic girdle and lower limb muscles. Biopsied muscle tissue exhibited advanced changes typified by adipose connective tissue replacement and the presence of multiple eosinophilic and p62-positive intranuclear inclusions. Immunopositivity for the intranuclear inclusions was observed with anti-glycine antibody and laboratory-made polyA-R1 antibody. RP-PCR unveiled an abnormal CGG repeat expansion in the 5' UTR of the RILPL1 gene. DISCUSSION: The clinical and radiological features in this family broaden the phenotypic spectrum of OPDM4. The presence of intranuclear inclusions in the proliferative adipose connective tissues of muscle biopsy specimens holds diagnostic significance for OPDM4 in advanced disease.

Electronic and Atomic Structural Properties Associated with Enhanced Photodegradation Activity in Mo-Doped TiO2 Nanoparticles.

The efficacy and structural evolution of Mo-doped titania nanoparticles (MTNPs) as advanced photocatalysts for degrading methyl blue (MB) are investigated by X-ray absorption spectroscopy (XAS). The 3 wt % MTNP, characterized by uniform size and anatase structure, exhibits higher efficiency. The spectral analyses unveiled structural variations in the TiO6 octahedral structure and revealed an active site of the distorted square pyramidal structure symmetry (C4v). The in situ XAS spectra illustrate that MTNPs, particularly at 3 wt % doping, effectively enhanced the hole carriers in Ti 3d orbitals with a charge transfer to Mo 4d orbitals and impeded electron-hole pair merging, significantly enhancing the photodegradation under light illumination. This study deepens our understanding of the crucial role of Mo doping in optimizing TiO2 nanoparticle performance for efficient environmental remediation, showcasing the potential of MTNPs as sustainable photocatalytic materials.