Artificial intelligence-based prognostic model accurately predicts the survival of patients with diffuse large B-cell lymphomas: analysis of a large cohort in China.

BACKGROUND: Diffuse large B-cell lymphomas (DLBCLs) display high molecular heterogeneity, but the International Prognostic Index (IPI) considers only clinical indicators and has not been updated to include molecular data. Therefore, we developed a widely applicable novel scoring system with molecular indicators screened by artificial intelligence (AI) that achieves accurate prognostic stratification and promotes individualized treatments. METHODS: We retrospectively enrolled a cohort of 401 patients with DLBCL from our hospital, covering the period from January 2015 to January 2019. We included 22 variables in our analysis and assigned them weights using the random survival forest method to establish a new predictive model combining bidirectional long-short term memory (Bi-LSTM) and logistic hazard techniques. We compared the predictive performance of our "molecular-contained prognostic model" (McPM) and the IPI. In addition, we developed a simplified version of the McPM (sMcPM) to enhance its practical applicability in clinical settings. We also demonstrated the improved risk stratification capabilities of the sMcPM. RESULTS: Our McPM showed superior predictive accuracy, as indicated by its high C-index and low integrated Brier score (IBS), for both overall survival (OS) and progression-free survival (PFS). The overall performance of the McPM was also better than that of the IPI based on receiver operating characteristic (ROC) curve fitting. We selected five key indicators, including extranodal involvement sites, lactate dehydrogenase (LDH), MYC gene status, absolute monocyte count (AMC), and platelet count (PLT) to establish the sMcPM, which is more suitable for clinical applications. The sMcPM showed similar OS results (P < 0.0001 for both) to the IPI and significantly better PFS stratification results (P < 0.0001 for sMcPM vs. P = 0.44 for IPI). CONCLUSIONS: Our new McPM, including both clinical and molecular variables, showed superior overall stratification performance to the IPI, rendering it more suitable for the molecular era. Moreover, our sMcPM may become a widely used and effective stratification tool to guide individual precision treatments and drive new drug development.

Effect of dietary intake of advanced glycation end products on biomarkers of type 2 diabetes: a systematic review and meta-analysis.

Thermal treatment of food may undergo Maillard reactions and produce harmful substances, e.g., advanced glycation end products (AGEs). Current studies show different results about the effects of dietary AGE intake on the biomarkers of type 2 diabetes mellitus (T2DM). Therefore, this work conducted a systematic review and meta-analysis to explore the effect of dietary AGE intake on the biomarkers of T2DM, the available evidence, and the bias of this evidence. This meta-analysis focused on the association between high AGE intake and fasting plasma glucose, fasting plasma insulin, HbA1c, and HOMA-IR. Thirteen parallel studies and 4 randomized crossover studies were finally included. In the pooled analysis, fasting glucose (SMD: 0.98; 95% CI: 0.23, 1.73; p = .011), fasting insulin (SMD: 1.44; 95% CI: 0.63, 2.25; p < .01), and HOMA-IR (SMD: 1.47; 95% CI: 0.59, 2.34; p < .01) significantly increased after dietary intake with high AGEs. In the subgroup analyses, high-AGE diets and healthy participants were associated with changes in the biomarkers of T2DM. Taken together, the intake of high dietary AGE was related to the development of T2DM.

GPR41 deficiency aggravates type 1 diabetes in streptozotocin-treated mice by promoting dendritic cell maturation.

Disturbances in intestinal immune homeostasis predispose susceptible individuals to type 1 diabetes (T1D). G-protein-coupled receptor 41 (GPR41) is a receptor for short-chain fatty acids (SCFAs) mainly produced by gut microbiota, which plays key roles in maintaining intestinal homeostasis. In this study, we investigated the role of GPR41 in the progression of T1D. In non-obese diabetic (NOD) mice, we found that aberrant reduction of GPR41 expression in the pancreas and colons was associated with the development of T1D. GPR41-deficient (Gpr41-/-) mice displayed significantly exacerbated streptozotocin (STZ)-induced T1D compared to wild-type mice. Furthermore, Gpr41-/- mice showed enhanced gut immune dysregulation and increased migration of gut-primed IFN-γ+ T cells to the pancreas. In bone marrow-derived dendritic cells from Gpr41-/- mice, the expression of suppressor of cytokine signaling 3 (SOCS) was significantly inhibited, while the phosphorylation of STAT3 was significantly increased, thus promoting dendritic cell (DC) maturation. Furthermore, adoptive transfer of bone marrow-derived dendritic cells (BMDC) from Gpr41-/- mice accelerated T1D in irradiated NOD mice. We conclude that GPR41 is essential for maintaining intestinal and pancreatic immune homeostasis and acts as a negative regulator of DC maturation in T1D. GPR41 may be a potential therapeutic target for T1D.

Retinal ganglion cell complex thickness in subjects with diabetes mellitus and uncontrolled hypertension in China.

PURPOSE: To assess the interactive relationship between blood pressure status and diabetic mellitus (DM) with ganglion cell complex (GCC) thickness in elderly individuals in rural China. METHODS: Participants aged 50 years and older in a rural area of Daxing District, Beijing, were recruited in this study from October 2018 to November 2018. All subjects underwent a comprehensive systemic and ocular examination. Blood pressure status was graded as normotension, controlled hypertension and uncontrolled hypertension according to blood pressure measurements and the use of any medication for hypertension treatment. GCC parameters were measured by spectral-domain optical coherence tomography (SD-OCT). Generalized linear models (GLM) adjusted for related potential confounders were used to assess the interaction between DM and blood pressure status. RESULTS: Among 1415 screened subjects (2830 eyes), a total of 1117 eyes were enrolled in the final analysis. GLM analysis showed a significant interactive relationship between DM with uncontrolled hypertension status (ß = 3.868, p = 0.011). GCC thickness would decrease 0.255 µm per year as the age increased (ß=-0.255, p < 0.001). In a subgroup of 574 subjects with uncontrolled hypertension, DM was associated with an increased average of GCC thickness (ß = 1.929, p = 0.022). CONCLUSIONS: The present results revealed a significant interactive relationship between blood pressure status and DM. The average GCC thickness increased in individuals with DM combined with uncontrolled hypertension, which should be considered in the measurement of GCC. Further studies are warranted to explore ganglion cells changes as a non-invasive method to detect neuron alterations in individuals with DM and uncontrolled hypertension. TRAIL REGISTRATION: The registration number of the present trial in the Chinese Clinical Trial Registry is ChiCTR2000037944.

CUL4B enhances the malignant phenotype of esophageal squamous cell carcinoma by suppressing TGFBR3 expression.

Cullin 4B (CUL4B), which acts as a scaffold protein in CUL4B-RING ubiquitin ligase complexes (CRL4B), is frequently overexpressed in cancer and represses tumor suppressors through epigenetic mechanisms. However, the expression and function of CUL4B in esophageal squamous cell carcinoma (ESCC) have not been well illustrated. In this study, we show that upregulation of CUL4B in ESCC cells enhances proliferation, invasion and cisplatin (CDDP)-resistance, while knockdown of CUL4B significantly represses the malignant activities. Mechanistically, we demonstrate that CUL4B promotes proliferation and migration of ESCC cells through inhibiting expression of transforming growth factor beta receptor III (TGFBR3). CRL4B complex binds to the promoter of TGFBR3, and represses its transcription by catalyzing monoubiquitination at H2AK119 and coordinating with PRC2 and HDAC complexes. Taken together, our findings establish a critical role for the CUL4B/TGFBR3 axis in the regulation of ESCC malignancy.

Rps6ka2 enhances iMSC chondrogenic differentiation to attenuate knee osteoarthritis through articular cartilage regeneration in mice.

Articular cartilage (AC) is most susceptible to degeneration in knee osteoarthritis (OA); however, the existing treatments for OA do not target the core link of the pathogenesis-"decreased tissue cell function activity and extracellular matrix (ECM) metabolic disorders" for effective intervention. iMSC hold lower heterogeneity and great promise in biological research and clinical applications. Rps6ka2 may play an important role in the iMSC to treat OA. In this study, the CRISPR/Cas9 gene editing Rps6ka2-/- iMSC were obtained. Effect of Rps6ka2 on iMSC proliferation and chondrogenic differentiation was evaluated in vitro. An OA model was constructed in mice by surgical destabilization of medial meniscus (DMM). The Rps6ka2-/- iMSC and iMSC were injected into the articular cavity twice-weekly for 8 weeks. In vitro experiments showed that Rps6ka2 could promote iMSC proliferation and chondrogenic differentiation. In vivo results further confirmed that Rps6ka2 could improve iMSC viability to promote ECM production to attenuate OA in mice.

Hsp90 is a potential risk factor for ovarian cancer prognosis: an evidence of a Chinese clinical center.

BACKGROUND: The potential treatment effects of heat shock protein 90 (Hsp90) inhibitors in ovarian cancer (OC) are controversial. This research aims to investigate the relationship between the level of Hsp90 in peripheral blood and the prognosis of OC patients, as well as the clinicopathological indicators. MATERIALS AND METHODS: We retrospectively collected the clinicopathological indicators of OC patients who were admitted to the Department of Obstetrics and Gynecology of the First Affiliated Hospital of Anhui Medical University from 2017 to 2022. Hsp90 level in patient blood was detected by enzyme-linked immunosorbent assay, and the correlation between Hsp90 level and OC prognosis was systematically investigated. Kaplan-Meier method was used to draw the survival curve, and the average survival time and survival rate were calculated. The log-rank test and Cox model were used for univariate survival analysis, and the Cox proportional hazards model was applied for multivariate survival analysis. Based on the TCGA dataset of OC obtained by cBioPortal, Pearson's correlation coefficients between Hsp90 level values and other mRNA expression values were calculated to further conduct bioinformatics analysis. GSEA and GSVA analysis were also conducted for gene functional enrichment. The expression of Hsp90 in OC tissues were evaluated and compared by Immunohistochemical staining. RESULTS: According to the established screening criteria, 106 patients were selected. The enzyme-linked immunosorbent assay results showed that 50.94% OC patients with abnormal Hsp90 level. According to the outcome of Kaplan-Meier curves, the results revealed that the abnormal level of Hsp90 was suggested to poor prognosis (P = 0.001) of OC patients. Furthermore, the result of multivariate Cox proportional hazards regression model analysis also predicted that abnormal Hsp90 level (HR = 2.838, 95%CI = 1.139-7.069, P = 0.025) was linked to poor prognosis, which could be an independent prognostic factor for the prognosis of OC patients. Moreover, top 100 genes screened by Pearson's value associated with Hsp90, indicating that Hsp90 participated in the regulation of ATF5 target genes, PRAGC1A target genes and BANP target genes and also enriched in the metabolic processes of cell response to DNA damage stimulus, response to heat and protein folding. CONCLUSION: Hsp90 level is positively associated with OC mortality and is a potential prognostic indicator of OC.

G protein coupled receptor 41 regulates fibroblast activation in pulmonary fibrosis via Gαi/o and downstream Smad2/3 and ERK1/2 phosphorylation.

Pulmonary fibrosis is a progressive and fatal fibrotic lung disease with mysterious pathogenesis and limited effective therapies. G protein-coupled receptors (GPRs) participate in a variety of physiologic functions, and several GPRs have critical fibrosis-promoting or -inhibiting roles in pulmonary fibrosis. Here, we explored the role of GPR41 in the pathobiology of pulmonary fibrosis. We found that GPR41 expression was elevated in lung tissues of mice with bleomycin-induced pulmonary fibrosis and lung fibroblasts treated with transforming growth factor-ß1 (TGF-ß1). Knockout of GPR41 attenuated pulmonary fibrosis in mice, as evidenced by improved lung morphology, decreased lung weight and collagen secretion, and down-regulated α-SMA, collagen type I alpha and fibronectin expression in lungs. Additionally, GPR41 knockout inhibited the differentiation of fibroblasts to myofibroblasts, and decreased myofibroblast migration. By further mechanistic analysis, we demonstrated that GPR41 regulated TGF-ß1-induced fibroblast-to-myofibroblast differentiation and Smad2/3 and ERK1/2 phosphorylation via its Gαi/o subunit but not Gßγ subunit. Together, our data indicate that GPR41 is involved in pulmonary fibroblast activation and fibrosis, and GPR41 represents a potential therapeutic target for pulmonary fibrosis.

Identification of exosomal mRNA, lncRNA and circRNA signatures in an osteoarthritis synovial fluid-exosomal study.

AIMS: Osteoarthritis (OA) is a common degenerative disease that is pathologically characterized by destruction of the joint matrix and reduction of articular chondrocytes, resulting in joint deformity and motor dysfunction. However, the molecular mechanisms governing this pathology have not been elucidated to date. METHODS: In this study, we determined the expression levels of lncRNAs, circRNAs, and mRNAs extracted from synovial exosomes of OA and control patients. A network of circRNA/lncRNA-miRNA-mRNA interactions was established using MiRanda and TargetScan software to explore OA pathogenesis. The exosomal lncRNA, circRNA and mRNA expression profiles of the OA and control groups were analysed using LC human competing endogenous RNA (ceRNA) microarrays. The differentially expressed genes were analysed to determine their potential roles in the pathogenesis of OA by bioinformatic analysis. RESULTS: There were 52 mRNAs, 196 lncRNAs and 98 circRNAs differentially expressed in synovial exosomes between osteoarthritis synovial and the control group. The final ceRNA network of lncRNAs and circRNAs exhibited a complex interaction between ncRNA and mRNA related to OA pathological mechanisms. An intersection analysis of the ceRNA network showed that 22 miRNAs, 45 lncRNAs, and 34 circRNAs enriched in the PI3K/Akt and autophagy pathways correlated with 7 mRNAs and may play important roles in OA pathological mechanisms. CONCLUSION: Our work analysed mRNA/lncRNA/circRNA expression and displayed the ceRNA network of lncRNAs and circRNAs to profile the pathogenesis of OA in synovial exosomes. The results of this study may help to elucidate the pathogenesis of OA and may provide important references for further research attempting to identify more effective targets for the diagnosis and therapy of OA.

Adriamycin induces cardiac fibrosis in mice via PRMT5-mediated cardiac fibroblast activation.

Long-term treatment with adriamycin (ADR) is associated with higher incidences of cumulative cardiotoxicity manifest as heart failure. ADR-induced cardiomyopathy is characterized by extensive fibrosis that is caused by cardiac fibroblast activation. To date, however, no specific treatment is available to alleviate ADR-induced cardiotoxicity. Protein arginine methyltransferase 5 (PRMT5), a major enzyme responsible for methylation of arginine, regulates numerous cellular processes such as cell differentiation. In the present study we investigated the role of PRMT5 in cardiac fibrosis. Mice were administered ADR (3 mg/kg, i.p., every 2 days) for 2 weeks. We showed that aberrant PRMT5 expression was largely co-localized with α-SMA-positive activated cardiac fibroblasts in ADR-injected mice and in ADR-treated cardiac fibroblasts in vitro. PRMT5-overexpression exacerbated, whereas PRMT5 knockdown alleviated ADR-induced cardiac fibrosis in vivo and TGF-ß1-induced cardiac fibroblast activation in vitro. We demonstrated that PRMT5-overexpression enhanced methylated-Smad3 levels in vivo and in vitro. Pretreatment with a specific PRMT5 inhibitor EPZ015666 (5 nM) or overexpression of a catalytically inactive mutant of PRMT5, PRMT5(E444Q), reduced PRMT5-induced methylation of Smad3, thus suppressing PRMT5-mediated cardiac fibroblast activation in vitro. Furthermore, ADR activated cardiac fibroblasts was depending on autocrine TGF-ß1. Taken together, our results demonstrate that PRMT5 promotes ADR-induced cardiac fibrosis via activating cardiac fibroblasts, suggesting that it may be a potential therapeutic target of ADR-caused cardiotoxicity.

Targeted therapy using engineered extracellular vesicles: principles and strategies for membrane modification.

Extracellular vesicles (EVs) are 30-150 nm membrane-bound vesicles naturally secreted by cells and play important roles in intercellular communication by delivering regulatory molecules such as proteins, lipids, nucleic acids and metabolites to recipient cells. As natural nano-carriers, EVs possess desirable properties such as high biocompatibility, biological barrier permeability, low toxicity, and low immunogenicity, making them potential therapeutic delivery vehicles. EVs derived from specific cells have inherent targeting capacity towards specific cell types, which is yet not satisfactory enough for targeted therapy development and needs to be improved. Surface modifications endow EVs with targeting abilities, significantly improving their therapeutic efficiency. Herein, we first briefly introduce the biogenesis, composition, uptake and function of EVs, and review the cargo loading approaches for EVs. Then, we summarize the recent advances in surface engineering strategies of EVs, focusing on the applications of engineered EVs for targeted therapy. Altogether, EVs hold great promise for targeted delivery of various cargos, and targeted modifications show promising effects on multiple diseases.

Factors associated with severe corneal endothelial damage following acute primary angle closure in Chinese subjects.

PURPOSE: To investigate the corneal endothelial damage caused by acute primary angle closure (APAC) and related risk factors for severe corneal endothelial cell damage in Chinese subjects. METHODS: In this multicentre retrospective study, 160 Chinese patients (171 eyes) diagnosed with APAC were recruited. Endothelial cell density (ECD) and morphological changes short after APAC were studied. Univariate regression and multivariate regression were used to identify risk factors associated with the extent of ECD reduction, including age, gender, education level, patients' location, systemic diseases, APAC duration (hours), highest recorded intraocular pressure (IOP), and presenting IOP. Factors associated with the probability of severe corneal damage (ECD lower than 1000/mm2) were analysed based on a linear function. RESULTS: After one APAC episode, 12.28% eyes had ECD lower than 1000/mm2, 30.41% had ECD between 1000 and 2000/mm2, and 57.31% had ECD more than 2000/mm2. Attack duration was the only factor associated with severe endothelial damage (p < 0.0001). If the attack were to be subsided within 15.0 h, possibility of ECD lower than 1000/mm2 could be controlled under 1%. CONCLUSION: Shortly after the abortion of APAC, 12.28% patients experienced severe endothelial cell damage with ECD less than 1000/mm2. The only factor associated with severe ECD decrease was attack duration. Immediate and effective treatment is pivotal for preserving corneal endothelial function in APAC patients.

Effects of biochar on rice yield, grain quality and starch viscosity attributes.

BACKGROUND: Biochar can play a key role in improving paddy soil and productivity. However, there is limited information on the effects of biochar on rice quality and starch gelatinization. In this study, four rice straw biochar dosage treatments (0, 20, 40 and 60 g kg-1 ; CK, C20, C40 and C60, respectively) were set up to investigate rice yield components, rice processing, appearance and cooking quality, and starch gelatinization. RESULTS: Addition of biochar increased the effective panicle, grain number per panicle and seed setting rate. However, it decreased the 1000-grain weight, resulting in an increase in yield. In 2019, all the biochar treatments improved the head rice rate (9.13-11.42%), whereas in 2020 only the C20 treatment improved. Low biochar dosage had little effect on grain appearance. High biochar dosage significantly decreased the chalky rice rate by 21.47% and chalkiness by 19.44% in 2019. However, it significantly increased the chalky rice rate and chalkiness by 118.95% and 85.45% in 2020, respectively. Biochar significantly lowered the amylose content except for the C20 and C40 treatments in 2020, and the gel consistency. The C40 and C60 treatments significantly increased the peak and breakdown viscosities and decreased the setback viscosity compared with CK. Correlation analysis showed that starch gelatinization characteristics were significantly correlated with the head rice rate, chalky rate and amylose content. CONCLUSION: A lower biochar dosage can improve the yield and milled rice rate and maintain a higher quality of appearance, whereas a higher biochar dosage can significantly improve starch gelatinization. © 2023 Society of Chemical Industry.

A conserved clathrin-coated vesicle component, OsSCYL2, regulates plant innate immunity in rice.

Clathrin-mediated vesicle trafficking (CMVT) is a fundamental process in all eukaryotic species, and indispensable to organism's growth and development. Recently, it has been suggested that CMVT also plays important roles in the regulation of plant immunity. However, the molecular link between CMVT and plant immunity is largely unknown. SCY1-LIKE2 (SCYL2) is evolutionally conserved among the eukaryote species. Loss-of-function of SCYL2 in Arabidopsis led to severe growth defects. Here, we show that mutation of OsSCYL2 in rice gave rise to a novel phenotype-hypersensitive response-like (HR) cell death in a light-dependent manner. Although mutants of OsSCYL2 showed additional defects in the photosynthetic system, they exhibited enhanced resistance to bacterial pathogens. Subcellular localisation showed that OsSCYL2 localized at Golgi, trans-Golgi network and prevacuolar compartment. OsSCYL2 interacted with OsSPL28, subunit of a clathrin-associated adaptor protein that is known to regulate HR-like cell death in rice. We further showed that OsSCYL2-OsSPL28 interaction is mediated by OsCHC1. Collectively, we characterized a novel component of the CMVT pathway in the regulation of plant immunity. Our work also revealed unidentified new functions of the very conserved SCYL2. It thus may provide new breeding targets to achieve both high yield and enhanced resistance in crops.

Opportunities and challenges of polyphenols and polysaccharides for type 1 diabetes intervention.

Type 1 diabetes (T1D) is an autoimmune disorder characterized by the destruction of insulin-producing pancreatic ß cell. It contributes to high mortality, frequent diabetic complications, poor quality of life in patients and also puts a significant economic burden on health care systems. Therefore, the development of new therapeutic strategies is urgently needed. Recently, certain dietary compounds with potential applications in food industry, particularly polyphenols and polysaccharides, have gained increasing attention with their prominent anti-diabetic effects on T1D by modulating ß cell function, the gut microbiota and/or the immune system. In this review, we critically discuss the recent findings of several dietary polyphenols and polysaccharides with the potential to protect against T1D and the underlying anti-diabetic mechanisms. More importantly, we highlight the current trends, major issues, and future directions of industrial production of polyphenols- and polysaccharides-based functional foods for preventing or delaying T1D.

Deep muscularis propria tumor invasion without lymph node metastasis as a unique subclassification of stage IB gastric cancer: a retrospective study.

BACKGROUND: The prognosis difference based on the depth of tumor muscularis propria invasion in gastric cancer (GC) was still debated, and therapy strategy for stage IB GC patient required further investigation. METHODS: A total of 380 patients with pT2 GC after radical surgery were retrospectively analyzed, including 185 in superficial muscularis propria (sMP) group and 195 in deep muscularis propria (dMP) group. RESULTS: The overall survival (OS) was significantly better for patients in sMP group than for patients in dMP group (P = 0.007). In multivariate analysis, depth of tumor invasion, pN stage, age, primary location, positive expression of p53, elevated maximal LDH, elevated initial CA19-9 and AFP level were independent prognostic factors for OS. The sMP group had a significantly better OS than dMP group (P = 0.014) in pN0 stage. After further stratification, the survival outcomes were not significantly different between deep muscularis propria tumor invasion without lymph node metastasis (dMPN0) group (stage IB) and superficial muscularis propria tumor invasion with stage 1-2 lymph node metastasis (sMPN1-2) group (stage II) (P = 0.100). Patients with adjuvant chemotherapy had a statistically better survival than those without in dMPN0 group (P = 0.045) and dMPN0 patients with adjuvant chemotherapy had better OS than sMPN1-2 patients (P = 0.015). In addition, greater postoperative survival could be observed in sMPN0 patients than dMPN0 patients in p53-positive group (P = 0.002), and similar OS could be seen between dMPN0 patients with p53-positive and T2N1-2 patients (P = 0.872). CONCLUSION: As a unique subclassification of stage IB GC, appropriate adjuvant chemotherapy should be considered for patients with dMPN0 stage. In addition, positive expression of p53, elevated LDH could be potential factors in identifying the different prognoses for stage IB GC patients.

CUL4B renders breast cancer cells tamoxifen-resistant via miR-32-5p/ER-α36 axis.

Tamoxifen (TAM) resistance is a significant clinical challenge in endocrine therapies for estrogen receptor (ER)-positive breast cancer patients. Cullin 4B (CUL4B), which acts as a scaffold protein in CUL4B-RING ubiquitin ligase complexes (CRL4B), is frequently overexpressed in cancer and represses tumor suppressors through diverse epigenetic mechanisms. However, the role and the underlying mechanisms of CUL4B in regulating drug resistance remain unknown. Here, we showed that CUL4B promotes TAM resistance in breast cancer cells through a miR-32-5p/ER-α36 axis. We found that upregulation of CUL4B correlated with decreased TAM sensitivity of breast cancer cells, and knockdown of CUL4B or expression of a dominant-negative CUL4B mutant restored the response to TAM in TAM-resistant MCF7-TAMR and T47D-TAMR cells. Mechanistically, we demonstrated that CUL4B renders breast cancer cells TAM-resistant by upregulating ER-α36 expression, which was mediated by downregulation of miR-32-5p. We further showed that CRL4B epigenetically represses the transcription of miR-32-5p by catalyzing monoubiquitination at H2AK119 and coordinating with PRC2 and HDAC complexes to promote trimethylation at H3K27 at the promoter of miR-32-5p. Pharmacologic or genetic inhibition of CRL4B/PRC2/HDAC complexes significantly increased TAM sensitivity in breast cancer cells in vitro and in vivo. Taken together, our findings thus establish a critical role for the CUL4B-miR-32-5p-ER-α36 axis in the regulation of TAM resistance and have important therapeutic implications for combined application of TAM and the inhibitors of CRL4B/PRC2/HDAC complex in breast cancer treatment. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Association between fluoroquinolone exposure and children's growth and development: A multisite biomonitoring-based study in northern China.

BACKGROUND: Although animal experiments found that antibiotic exposure during early life increased adiposity, limited human epidemiological evidence is available for the effects of veterinary antibiotic exposure on children's growth and development. OBJECTIVE: This study was conducted to examine the body burden of fluoroquinolones in northern Chinese children and assess its association with growth and development. METHODS: After recruiting 233 children aged 0-15 years from 12 different sites in northern China in 2020, we measured urinary concentrations of 5 respective fluoroquinolones (fleroxacin, ofloxacin, norfloxacin, ciprofloxacin, and enrofloxacin) by high performance liquid chromatography. Categories of children's growth and development were identified based on the Z score of body mass index. The health risks of individual and combined antibiotic exposure were estimated by the hazard quotient (HQ) and hazard index (HI), respectively. The association between children's growth and development with antibiotic concentrations was evaluated via multiple logistic regression analysis. RESULTS: In total, 4 antibiotics, fleroxacin, ofloxacin, ciprofloxacin, and enrofloxacin, were found in urine samples of northern Chinese children at an overall frequency of 57.08%. Due to diet and economic differences, antibiotic concentrations in urine samples differed by study area, and the highest concentrations were found in Tianjin, Henan, and Beijing. The percentage of the participants with HQ > 1 caused by ciprofloxacin exposure was 20.61%, and the HI values in 23.18% of samples exceeded 1, suggesting potential health risks. The odds ratio (95% confidence interval) of overweight or obesity risk of tertile 2 of enrofloxacin was 3.01 (1.12, 8.11), indicating an increase in overweight or obesity risk for children with middle-concentration enrofloxacin exposure. CONCLUSION: This is the first study to show a positive association of enrofloxacin internal exposure with overweight or obesity risk in children, demonstrating that more attention should be given to the usage and disposal of fluoroquinolones to safeguard children's health.

Retina Vascular Structures near the Optic Disc and in the Macula in Primary Angle-Closure Suspects.

INTRODUCTION: The main aim of this article was to study the retinal peripapillary and macular vascular structures in eyes with primary angle-closure suspects (PACS) using optical coherence tomography angiography (OCTA). METHODS: In this cross-sectional study, control and PACS subjects were recruited from a community screening. Only one eye per subject was used for analysis. All participants underwent a questionnaire survey, physical and ophthalmic examinations, ocular biometry measurements, and OCTA. We compared basic demographics and vessel structure parameters between control and PACS eyes. Univariate and multivariate linear regression analyses were performed to investigate factors associated with vascular parameters in both groups. RESULTS: Data from 254 subjects including 155 PACS and 99 controls were analyzed. In the peripapillary region, PACS eyes showed similar retina nerve fiber layer (RNFL) and vessel densities (VDs) including and excluding large vessels compared to control eyes. Compared to control eyes, all macular OCTA parameters showed significant differences in PACS eyes, including decreased superficial VD (p = 0.006) and deep VD (p = 0.004), larger fovea avascular zone (FAZ) area (p = 0.006), and longer FAZ perimeter (p = 0.004). Gender (p = 0.039), age (p < 0.001), and Garway-Heath superior hemisphere RNFL (p < 0.001) were risk factors influencing optic disc VD excluding large vessels. Axial length was the major factor affecting macula superficial and deep VDs (p = 0.004 and 0.001 respectively), while PACS was an independent factor associated with larger FAZ perimeter (p = 0.046). CONCLUSION: While PACS and control eyes have comparable RNFL and vascular structure around the optic nerve head, macular vascular structures are significantly different.

Transcriptomic, proteomic, and physiological comparative analyses of flooding mitigation of the damage induced by low-temperature stress in direct seeded early indica rice at the seedling stage.

BACKGROUND: Low temperature (LT) often occurs at the seedling stage in the early rice-growing season, especially for direct seeded early-season indica rice, and using flooding irrigation can mitigate LT damage in rice seedlings. The molecular mechanism by which flooding mitigates the damage induced by LT stress has not been fully elucidated. Thus, LT stress at 8 °C, LT accompanied by flooding (LTF) and CK (control) treatments were established for 3 days to determine the transcriptomic, proteomic and physiological response in direct seeded rice seedlings at the seedling stage. RESULTS: LT damaged chloroplasts, and thylakoid lamellae, and increased osmiophilic bodies and starch grains compared to CK, but LTF alleviated the damage to chloroplast structure caused by LT. The physiological characteristics of treated plants showed that compared with LT, LTF significantly increased the contents of rubisco, chlorophyll, PEPCK, ATP and GA3 but significantly decreased soluble protein, MDA and ABA contents. 4D-label-free quantitative proteomic profiling showed that photosynthesis-responsive proteins, such as phytochrome, as well as chlorophyll and the tricarboxylic acid cycle were significantly downregulated in LT/CK and LTF/CK comparison groups. However, compared with LT, phytochrome, chlorophyllide oxygenase activity and the glucan branching enzyme in LTF were significantly upregulated in rice leaves. Transcriptomic and proteomic studies identified 72,818 transcripts and 5639 proteins, and 4983 genes that were identified at both the transcriptome and proteome levels. Differentially expressed genes (DEGs) and differentially expressed proteins (DEPs) were significantly enriched in glycine, serine and threonine metabolism, biosynthesis of secondary metabolites, glycolysis/gluconeogenesis and metabolic pathways. CONCLUSION: Through transcriptomic, proteomic and physiological analyses, we determined that a variety of metabolic pathway changes were induced by LT and LTF. GO and KEGG enrichment analyses demonstrated that DEGs and DEPs were associated with photosynthesis pathways, antioxidant enzymes and energy metabolism pathway-related proteins. Our study provided new insights for efforts to reduce the damage to direct seeded rice caused by low-temperature stress and provided a breeding target for low temperature flooding-resistant cultivars. Further analysis of translational regulation and metabolites may help to elucidate the molecular mechanisms by which flooding mitigates low-temperature stress in direct seeded early indica rice at the seedling stage.