High triiodothyronine levels induce myocardial hypertrophy via BAFF overexpression.

Activated B cells contribute to heart diseases, and inhibition of B-cell activating factor (BAFF) expression is an effective therapeutic target for heart diseases. Whether activated B cells participate in the development and progression of hyperthyroid heart disease, and what induces B cells activation in hyperthyroidism are unknown. The present study aimed to determine the roles of BAFF overexpression induced by high concentrations of triiodothyronine (T3) in the pathogenesis of hyperthyroid heart disease. Female C57BL/6J mice were subcutaneously injected with T3 for 6 weeks, and BAFF expression was inhibited using shRNA. Protein and mRNA expression of BAFF in mouse heart tissues evaluated via immunohistochemistry, western blotting and polymerase chain reaction (PCR). Proportions of B cells in mouse cardiac tissue lymphocytes were quantified via flow cytometry. Morphology and left ventricle function were assessed using pathological sections and echocardiography, respectively. Here, we demonstrate that compared with the control group, the proportion of myocardial B cells was larger in the T3 group; immunohistochemistry, western blotting and PCR analyses revealed increased protein and mRNA expression levels of TNF-α and BAFF in heart tissues of the T3 group. Compared with the normal controls group, in the T3 group, the diameter of myocardial cells and some echocardiographic values significantly increased and hypertrophy and structural disorder were noticeable. Our results revealed that elevated levels of circulating T3 can promote the expression of BAFF in myocardial cells and can lead to B-cell activation, an elevated inflammatory response and ventricular remodelling.

Circ_SNX27 regulates hepatocellular carcinoma development via miR-637/FGFR1 axis.

BACKGROUND: Circular RNAs (circRNAs) serve as critical regulatory factors in cancer development. Nonetheless, the potential regulatory mechanism of circRNA sorting nexin 27 (circ_SNX27) in hepatocellular carcinoma (HCC) is still unknown. METHODS: The circ_SNX27, microRNA-637 (miR-637), and fibroblast growth factor receptor 1 (FGFR1) levels were quantified by quantitative real-time polymerase chain reaction and western blot analysis. Next, function experiments were conducted using in vitro assays and in vivo senograft study. The relationship between miR-637 with circ_SNX27 or FGFR1 was uncovered by dual-luciferase reporter and RNA pull-down assays. RESULTS: The circ_SNX27 and FGFR1 levels were up-regulated, but miR-637 content was reduced in HCC. Circ_SNX27 down-regulation inhibited HCC cell proliferation, motility, and invasion and promoted apoptosis in vitro, as well as weakened tumor growth in vivo. Circ_SNX27 served as a sponge of miR-637 to promote FGFR1 expression. MiR-637 reduction abolished the restrained effect of circ_SNX27 absence on HCC cell development. Moreover, miR-637 curbed HCC cell malignant phenotype by regulating FGFR1. CONCLUSION: Circ_SNX27 contributed to HCC development via miR-637/FGFR1 axis, offering a new idea for the treatment of HCC.

Paternal origin of Tungusic-speaking populations: Insights from the updated phylogenetic tree of Y-chromosome haplogroup C2a-M86.

OBJECTIVES: Haplogroup C2a-M48 is the predominant paternal lineage of Tungusic-speaking populations, one of the largest population groups in Siberia. Up until now, the origins and dispersal of Tungusic-speaking populations have remained unclear. In this study, the demographic history of Tungusic-speaking populations was explored using the phylogenetic analysis of haplogroup C2a-M86, the major subbranch of C2a-M48. MATERIALS AND METHODS: In total, 18 newly generated Y chromosome sequences from C2a-M48 males and 20 previously available Y-chromosome sequences from this haplogroup were analyzed. A highly revised phylogenetic tree of haplogroup C2a-M86 with age estimates was reconstructed. Frequencies of this lineage in the literature were collected and a comprehensive analysis of this lineage in 13 022 individuals from 245 populations in Eurasia was performed. RESULTS: The distribution map of C2a-M48 indicated the most probable area of origin and diffusion route of this paternal lineage in North Eurasia. Most C2a-M86 samples from Tungusic-speaking populations belonged to the sublineage C2a-F5484, which emerged about 3300 years ago. We identified six unique sublineages corresponding to the Manchu, Evenks, Evens, Oroqen, and Daurpopulations; these sublineages diverged gradually over the past 1900 years. Notably, we observed a clear north-south dichotomous structure for sublineages derived from C2a-F5484, consistent with the internal north-south divergence of Tungusic languages and ethnic groups. CONCLUSIONS: We identified the important founding paternal haplogroup, C2a-F5484, for Tungusic-speaking populations as well as numerous unique subgroups of this haplogroup. We propose that the timeframe for the divergence of C2a-F5484 corresponds with the early differentiation of ancestral Tungusic-speaking populations.

Can patients manage toileting after reverse total shoulder arthroplasty? A systematic review.

PURPOSE: A major concern for patients undergoing reverse total shoulder arthroplasty (RTSA) is managing toileting after surgery. The goals of this systematic review of RTSA studies were to determine the following: (1) the percentage of patients who can manage toileting, (2) their degree of difficulty with toileting, and (3) the percentage of patients who can manage toileting after bilateral versus unilateral RTSA. METHODS: Medline, EMBASE, Google Scholar, and the Cochrane Central Register of Controlled Trials were searched for studies reporting the ability to manage toileting after RTSA. Six studies with at least 12 months of follow-up were included, yielding 183 patients (105 unilateral RTSA, 78 bilateral RTSA). We pooled patient data and calculated the weighted mean proportion of patients able to manage toileting, those who reported difficulty, and those able to manage toileting after unilateral versus bilateral RTSA. Statistical significance was set at P < 0.05. RESULTS: Most patients (92%; 95% confidence interval, 87-95%) were able to manage toileting after RTSA. Some degree of difficulty with toileting was reported for 20% of all shoulders. Almost all patients with bilateral RTSA were able to manage toileting with at least one arm (weighted mean proportion 97%; 95% confidence interval, 88-99%). There was no significant difference in the proportion of patients able to manage toileting after unilateral versus bilateral RTSA (P = 0.08). Only 3% of all papers published on the clinical results of RTSA by June 2017 reported upon toileting after the procedure. CONCLUSIONS: With the available evidence, most patients were able to manage toileting after RTSA, although one-fifth reported some degree of difficulty. Ability to manage toileting was similar after unilateral versus bilateral RTSA. In the future, this variable should be a standard question after shoulder arthroplasty. LEVEL OF EVIDENCE: IV.

Glutamine attenuates obstructive cholestasis in rats via farnesoid X receptor-mediated regulation of Bsep and Mrp2.

To investigate the protective effect of glutamine (Gln) against obstructive cholestasis in association with farnesoid X receptor (FXR) activation, an obstructive cholestasis model was established in male Sprague-Dawley rats by bile duct ligation (BDL). Serum biomarkers and hematoxylin plus eosin staining were used to identify the degree of hepatic injury in the rats with obstructive cholestasis after Gln treatment. Immunohistochemistry, real-time PCR, Western blot, cultured primary rat hepatocytes with FXR knockdown, and dual-luciferase reporter assay were performed to elucidate the mechanisms underlying Gln hepatoprotection. We found that Gln treatment protected against obstructive cholestasis induced by BDL through reducing hepatocyte injury. Upregulation of the hepatic efflux transporters small heterodimer partner (Shp), bile salt export pump (Bsep), and multidrug resistance-associated protein 2 (Mrp2), and inhibition of the hepatic uptake transporter Na+/taurocholate cotransporting polypeptide (Ntcp) and the bile acid synthesis enzyme cholesterol 7α-hydroxylase (Cyp7a1) expression were observed in rats with BDL treated with Gln in vivo. Furthermore, the regulatory effect of Gln on Bsep and Mrp2 expression was abrogated after FXR knockdown in rat primary cultured hepatocytes. Luciferase assay HepG2 cells also illustrated FXR was a direct target for Gln treatment. In conclusion, the regulation of Bsep and Mrp2 expression mediated by FXR might be an important mechanism for Gln against obstructive cholestasis.

Robust evidence for five new Graves' disease risk loci from a staged genome-wide association analysis.

Graves' disease (GD), characterized by autoantibodies targeting antigens specifically expressed in thyroid tissues causing hyperthyroidism, is triggered by a combination of genetic and environmental factors. However, only a few loci for GD risk were confirmed in the various ethnic groups, and additional genetic determinants have to be detected. In this study, we carried out a three-stage study in 9529 patients with GD and 9984 controls to identify new risk loci for GD and found genome-wide significant associations in the overall populations for five novel susceptibility loci: the GPR174-ITM2A at Xq21.1, C1QTNF6-RAC2 at 22q12.3-13.1, SLAMF6 at 1q23.2, ABO at 9q34.2 and an intergenic region harboring two non-coding RNAs at 14q32.2 and one previous indefinite locus, TG at 8q24.22 (Pcombined < 5 × 10(-8)). The genotypes of corresponding variants at 14q32.2 and 8q24.22 were correlated with the expression levels of C14orf64 and a TG transcript skipping exon 46, respectively. This study increased the number of GD loci with compelling evidence and indicated that non-coding RNAs might be potentially involved in the pathogenesis of GD.

Application of multidisciplinary team-based integrated traditional Chinese medicine and Western medicine in rotator cuff injury patients undergoing arthroscopic surgery.

BACKGROUND: Arthroscopic rotator cuff repair is a common surgical treatment for rotator cuff injuries (RCIs). Although this procedure has certain clinical advantages, it requires rehabilitation management interventions to ensure therapeutic efficacy. AIM: To investigate the effect of integrated traditional Chinese medicine and Western medicine (TCM-WM) under the multidisciplinary team (MDT) model on the postoperative recovery of patients undergoing arthroscopic surgery for RCIs. METHODS: This study enrolled 100 patients who underwent arthroscopic rotator cuff repair for RCIs at the Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine between June 2021 and May 2024. They were divided into a control group (n = 48) that received routine rehabilitation treatment and an experimental group (n = 52) that received TCM-WM under the MDT model (e.g., acupuncture, TCM traumatology and orthopedics, and rehabilitation). The results of the Constant-Murley Shoulder Score (CMS), Visual Analogue Scale (VAS), Shoulder Pain and Disability Index (SPADI), muscular strength evaluation, and shoulder range of motion (ROM) assessments were analyzed. RESULTS: After treatment, the experimental group showed significantly higher CMS scores in terms of pain, functional activity, shoulder joint mobility, and muscular strength than the baseline and those of the control group. The experimental group also exhibited significantly lower VAS and SPADI scores than the baseline and those of the control group. In addition, the experimental group showed significantly enhanced muscular strength (forward flexor and external and internal rotator muscles) and shoulder ROM (forward flexion, abduction, and lateral abduction) after treatment compared with the control group. CONCLUSION: TCM-WM under the MDT model improved shoulder joint function, relieved postoperative pain, promoted postoperative functional recovery, and facilitated the recovery of muscular strength and shoulder ROM in patients with RCIs who underwent arthroscopic rotator cuff repair.

Treatment of a femoral neck fracture combined with ipsilateral femoral head and intertrochanteric fractures: A case report.

BACKGROUND: This article presents a rare case of a complex hip fracture involving the ipsilateral femoral neck, trochanter, and femoral head, that was accompanied by hip dislocation. Currently, there is no established standard treatment method for this specific type of fracture. Therefore, it is crucial to comprehensively consider factors such as patient age, fracture type, and degree of displacement to achieve a successful outcome. CASE SUMMARY: A 38-year-old man sustained a comminuted fracture of his right hip as a result of a car accident. The injuries included a fracture of the femoral head, a fracture of the femoral neck, an intertrochanteric fracture of the femur, and a posterior dislocation of the hip on the same side. We opted for a treatment approach combining the use of a proximal femoral locking plate, cannulated screws, and Kirschner wires. Following the surgery, we developed an individualized rehabilitation program to restore patient limb function. CONCLUSION: For this complex fracture, we selected appropriate internal fixation and formulated individualized rehabilitation, which ultimately achieved good results.

Single-Cell RNA Sequencing Analysis of Steroidogenesis and Spermatogenesis Impairment in the Testis of db/db Mice.

Objective: The mechanism of steroidogenesis and spermatogenesis impairment in men with type 2 diabetes remains unclear. We aimed to explore the local changes of steroidogenesis and spermatogenesis in the testis of db/db mice. Research Design and Methods. We performed single-cell RNA sequencing analysis in the testis of db/db and C57BL/6J mice. The differentially expressed genes were then confirmed by real-time PCR. The histopathological characteristics of testis in db/db mice and C57BL/6J control were also performed. Results: The 20-week-old db/db mice had significantly higher blood glucose and body weight (both p < 0.001). The serum testosterone levels (4.4 ± 0.8 vs. 9.8 ± 0.7 ng/ml, p=0.001) and weight of the testis (0.16 ± 0.01 vs. 0.24 ± 0.01 g, p < 0.001) were significantly lower in db/db mice than that in C57BL/6J controls. db/db mice had a lower cross-sectional area of seminiferous tubules and thickness of the cell layer (both p < 0.05). The numbers of Sertoli cells and Leydig cells decreased in db/db mice (both p < 0.01). Single-cell RNA sequencing analysis showed that compared with the control group, the percentage of spermatogonia was significantly higher in the db/db mouse (p < 0.001), while the proportions of spermatocytes, round and elongating spermatids, and sperms were all lower in the db/db mouse (p all < 0.001). The most differentially expressed genes were found in round spermatids (n = 86), which were not found in spermatogonia, spermatocyte, and sperm. Igfbp5 was the most significantly decreased gene in Leydig cells of the db/db mouse, while the expression of Cd74, H2-Aa, and H2-Eb1 was elevated. Ccl7 and Ptgds were the most significantly increased and decreased genes in Sertoli cells of the db/db mouse. Conclusions: The present study indicates spermiogenesis and steroidogenesis defects in db/db mice. The mechanism of steroidogenesis impairment in the testis of db/db mice deserves further investigation.

Altered activation patterns of the sensory-motor cortex in patients with knee osteoarthritis during knee isokinetic movement at different speeds.

Background: Abnormal brain activation patterns in patients with knee osteoarthritis (KOA) at rest have been revealed, but it is unclear how brain activation patterns change during movement. This study aimed to investigate the alterations in brain activation patterns in KOA patients during knee isokinetic movement, and the correlation between cortical activity changes and pain severity and dysfunction. Methods: Eighteen patients with KOA and 18 healthy controls (HC) were recruited, and to performed the knee isokinetic test with three speeds. Functional near-infrared spectroscopy (fNIRS) was used to detect the cerebral cortex hemodynamics changes of primary somatosensory (S1), primary motor (M1) and somatosensory association cortex (SAC) in the region of interest (ROI) during movement. Then, we evaluated potential correlations between M1, S1 and SAC values and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and visual analog scale (VAS) scores. Results: The results showed that peak torque of knee extension in KOA patients was significantly smaller than that in HC. For HC, unilateral knee movement activated bilateral ROIs. The contralateral activation was dominant, showing the phenomenon of high contralateral activation. For KOA patients, there were no statistical difference in the activation level between the left and right of the cerebral cortex, with both sides showing lower activation levels compared to HC. Further analysis found that the contralateral M1, S1, and SAC of the affected knee in KOA patients were significantly lower than those in HC, while no difference was found on the ipsilateral side. Moreover, during isokinetic movement at 180°/s, VAS score in KOA patients was negatively correlated with the activation level of the contralateral S1 and M1 values, and WOMAC was negatively correlated with the activation level of the contralateral M1 value. Conclusion: Contralateral activation of the sensorimotor cortex exists during unilateral knee movement, but in KOA patients, this contralateral cortical activation is suppressed. Furthermore, the clinical pain and dysfunction in KOA patients are associated with activation levels of specific brain regions. These findings can provide a better understanding of KOA brain science and are expected to contribute to the development of central intervention for the disease.

Matrix metallopeptidase 9 contributes to the beginning of plaque and is a potential biomarker for the early identification of atherosclerosis in asymptomatic patients with diabetes.

Aims: To determine the roles of matrix metallopeptidase-9 (MMP9) on human coronary artery smooth muscle cells (HCASMCs) in vitro, early beginning of atherosclerosis in vivo in diabetic mice, and drug naïve patients with diabetes. Methods: Active human MMP9 (act-hMMP9) was added to HCASMCs and the expressions of MCP-1, ICAM-1, and VCAM-1 were measured. Act-hMMP9 (n=16) or placebo (n=15) was administered to diabetic KK.Cg-Ay/J (KK) mice. Carotid artery inflammation and atherosclerosis measurements were made at 2 and 10 weeks after treatment. An observational study of newly diagnosed drug naïve patients with type 2 diabetes mellitus (T2DM n=234) and healthy matched controls (n=41) was performed and patients had ultrasound of carotid arteries and some had coronary computed tomography angiogram for the assessment of atherosclerosis. Serum MMP9 was measured and its correlation with carotid artery or coronary artery plaques was determined. Results: In vitro, act-hMMP9 increased gene and protein expressions of MCP-1, ICAM-1, VCAM-1, and enhanced macrophage adhesion. Exogenous act-hMMP9 increased inflammation and initiated atherosclerosis in KK mice at 2 and 10 weeks: increased vessel wall thickness, lipid accumulation, and Galectin-3+ macrophage infiltration into the carotid arteries. In newly diagnosed T2DM patients, serum MMP9 correlated with carotid artery plaque size with a possible threshold cutoff point. In addition, serum MMP9 correlated with number of mixed plaques and grade of lumen stenosis in coronary arteries of patients with drug naïve T2DM. Conclusion: MMP9 may contribute to the initiation of atherosclerosis and may be a potential biomarker for the early identification of atherosclerosis in patients with diabetes. Clinical trial registration: https://clinicaltrials.gov, identifier NCT04424706.

Dense mapping of IL2RA shows no association with Graves' disease in Chinese Han population.

OBJECTIVE: Associations between IL2RA and various autoimmune diseases have been reported in Caucasians. We investigated whether genetic polymorphisms at the IL2RA locus were associated with Graves' disease (GD) in the Chinese Han population. DESIGN: We performed a genome-wide association study (GWAS) in 1 536 GD patients and 1 516 controls. The 1000 Genomes Project data were adopted as references for imputation analysis. After forward and conditional logistic regressions, we found that rs11256313 was the major risk variant in the CD25/IL2RA region. Thus, we further genotyped rs11256313 in a replication cohort with 3 694 GD patients and 3 510 controls using ABI 7900HT TaqMan Real-Time PCR System. RESULTS: Nine single nucleotide polymorphisms (SNPs) in the IL2RA block were nominally associated with GD in our GWAS (0·01 < P < 0·05). After imputation analysis, 13 imputed SNPs in the IL2RA block were weakly associated with GD (P ≤ 0·05). Logistic regression analysis suggested that the imputed rs11256313 could represent the IL2RA block (P = 0·003). However, we failed to replicate the association of rs11256313 in a larger cohort (P = 0·145). A subphenotype analysis of rs11256313 on thyroid hormone receptor antibody (TRAb) and gender showed that there was no association in any of the subphenotype groups (P > 0·05). CONCLUSIONS: The results suggested that common genetic polymorphisms at IL2RA do not exert a significant genetic effect on the development of GD in the Chinese Han population. Previously reported associations between CD25/IL2RA and autoimmune diseases including GD in Caucasians again imply that heterogeneity exists in different ethnic populations.

A meta-analysis of internal mammary lymph node metastasis in breast cancer patients.

BACKGROUND: Knowing the status of the internal mammary lymph (IML) nodes is important for accurate staging and appropriate selection of subsequent treatment in breast cancer. We conducted a meta-analysis to clarify the rate of IML node metastasis in breast cancer patients and discussed the importance of this finding. METHODS: We retrieved articles from the literature that reported positive rates of IML node metastasis in breast cancer patients. The quality of the selected articles was assessed using the 'Methodological Index for Non-Randomized Studies'. The heterogeneity was tested, and publication bias was assessed using a funnel plot. Finally, the positive rate of IML node metastasis in breast cancer patients was calculated using the random-effects model. RESULTS: 15 articles met the inclusion criteria and a total of 4,248 patients were included in the analysis. Heterogeneity across the studies was statistically significant (p = 0.014); thus, the random-effects model was used and the calculated positive rate of IML node metastasis was 23% (95% confidence interval (CI), 0.21-0.25). CONCLUSIONS: Approximately 23% of the breast cancer patients had IML node metastases, for which the prognosis is generally poor. Accurate staging and integrated treatment are necessary to improve the survival of these patients.

[The association between vitamin D deficiency and diabetic nephropathy in type 2 diabetic patients].

OBJECTIVE: To evaluate the association between vitamin D deficiency and diabetic nephropathy in type 2 diabetic patients. METHODS: A total of 594 patients with type 2 diabetes were enrolled from the inpatients of the Nanjing Medical University Affiliated Nanjing Hospital. Fasting serum lipid profile, 25-hydroxycalciferol vitamin D and urinary albumin excretion rate were investigated. The relationship between nephropathy and vitamin D deficiency ( < 20 µg/L) or insufficiency (20-<30 µg/L) was analyzed. RESULTS: Nephropathy was found in 177 subjects (29.8%) with albuminuria in 141 and proteinuria in 36 subjects. Vitamin D deficiency was found in 180 subjects and insufficiency in 157 subjects. The proportion of vitamin D deficiency was higher in the individuals with nephropathy than those without nephropathy (36.2% vs 27.8%, P < 0.05). The urinary albumin excretion rate was significantly higher in the patients with vitamin D deficiency than those with normal vitamin D concentration [(123.0 ± 299.2) mg/24h vs (47.6 ± 97.1) mg/24h, P < 0.01]. The prevalence of nephropathy was higher in the patients with vitamin D deficiency than those with normal vitamin D concentration (35.6% vs 26.1%, P < 0.05), while the prevalence of proteinuria was higher in patients with vitamin D deficiency (12.2% vs 3.1%, P < 0.01). Logistic regression analysis demonstrated that vitamin D deficiency was associated with nephropathy (OR 1.57, 95%CI 1.04-2.37), even after the adjustment for age, gender, hypertension, dyslipidemia, smoking status, use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (OR 1.78, 95%CI 1.12-2.81). The Vitamin D concentration was significantly negatively correlated with urinary albumin excretion rate (r = -1.783, P < 0.001). CONCLUSIONS: Type 2 diabetic patients have a high prevalence of vitamin D deficiency. Vitamin D deficiency is independently associated with diabetic nephropathy.

Metformin induces pyroptosis in leptin receptor-defective hepatocytes via overactivation of the AMPK axis.

Metformin is the biguanide of hepatic insulin sensitizer for patients with non-alcohol fatty liver disease (NAFLD). Findings regarding its efficacy in restoring blood lipids and liver histology have been contradictory. In this study, we explore metformin's preventive effects on NAFLD in leptin-insensitive individuals. We used liver tissue, serum exosomes and isolated hepatocytes from high-fat diet (HFD)-induced Zucker diabetic fatty (ZDF) rats and leptin receptor (Lepr) knockout rats to investigate the correlation between hepatic Lepr defective and liver damage caused by metformin. Through immunostaining, RT-PCR and glucose uptake monitoring, we showed that metformin treatment activates adenosine monophosphate (AMP)-activated protein kinase (AMPK) and its downstream cytochrome C oxidase (CCO). This leads to overactivation of glucose catabolism-related genes, excessive energy repertoire consumption, and subsequent hepatocyte pyroptosis. Single-cell RNA sequencing further confirmed the hyper-activation of glucose catabolism after metformin treatment. Altogether, we showed that functional Lepr is necessary for metformin treatment to be effective, and that long-term metformin treatment might promote NAFLD progression in leptin-insensitive individuals. This provides important insight into the clinical application of metformin.

Functional study of an aberrant splicing variant of the human luteinizing hormone (LH) receptor.

The luteinizing hormone receptor (LHR) is a member of a subfamily of G protein-coupled receptors that is characterized by its alternative splicing. In a previous study, we identified a splice site mutation of intron 6 (IVS6-3C>A) in a patient suffering from Leydig cell hypoplasia, which leads to aberrant splicing of LHR mRNA. In vitro expression analysis confirmed that this mutation results in the skipping of exon 7 in the mature mRNA of the LHR gene. In this study, we determined the impact of IVS6-3C>A on the RNA secondary structure and function of LHR-Del7. The three-dimensional structure of the leucine-rich repeats in LHR was predicted by molecular modeling. Radioactive ligand-binding assays verified that LHR-Del7 has no binding affinity for hCG. Furthermore, we detected negligible cAMP production in cells transfected with LHR-Del7. Cells co-expressing LHR-WT and LHR-Del7 were able to generate cAMP in response to hCG, but there was no significant difference between cells transfected with LHR-WT/vector and LHR-WT/LHR-Del7, although the variant was able to localize to cell surface, similar to wild-type receptor. These results indicated that LHR-Del7 does not have a dominant negative effect on LHR-WT cell surface expression, and although the pathological splicing variant LHR-Del7 was able to localize to cell membranes it failed to bind hCG and had no effect on wild-type LHR.

Insights into Circulating Tumor Cell Clusters: A Barometer for Treatment Effects and Prognosis for Prostate Cancer Patients.

Prostate cancer (PCa) exhibits high cellular heterogeneity across patients. Therefore, there is an urgent need for more real-time and accurate detection methods, in both prognosis and treatment in clinical settings. Circulating tumor cell (CTC) clusters, a population of tumor cells and non-malignant cells in the blood of patients with tumors, are a promising non-invasive tool for screening PCa progression and identifying potential benefit groups. CTC clusters are associated with tumor metastasis and possess stem-like characteristics, which are likely attributable to epithelial-mesenchymal transition (EMT). Additionally, these biological properties of CTC clusters, particularly androgen receptor V7, have indicated the potential to reflect curative effects, guide treatment modalities, and predict prognosis in PCa patients. Here, we discuss the role of CTC clusters in the mechanisms underlying PCa metastasis and clinical applications, with the aim of informing more appropriate clinical decisions, and ultimately, improving the overall survival of PCa patients.

Spatio-temporal trajectory evolution and cause analysis of air pollution in Chengdu, China.

This study comprehensively analyzed air pollution in Chengdu (CD), a megacity in southwest China, evaluated the Variation Characteristics of air quality during 2015-2018, and conducted Random Forest classification of air pollution data of 2017. The classification results showed three pollution periods: severe (December, January and February), ozone (May‒August), and slight (March and November). These features were combined with potential source contribution function (PSCF), concentration weighted trajectory (CWT) and backward trajectory model (HYSPLIT) for simulating spatio-temporal trajectory of air polluted during each pollution periods. The results show that PM2.5 mainly comes from CD and surrounding cities, and some may be from India, Myanmar and Chongqing; PM10 mainly comes from CD and surrounding cities and some may be from India and Myanmar; NO2 mainly comes from CD and surrounding cities and cities and Some of the pollution may come from the input of India, Myanmar, Chongqing and Inner Mongolia; O3 mainly comes from the urban agglomeration of Sichuan Basin and some areas from Chongqing, Sichuan Liangshan and Yunnan Guizhou. Combined with the meteorological data of temperature, relative humidity and wind speed, aerosol optical depth, planetary boundary layer height and thermal anomaly data, the Monthly, daily and hourly spatio-temporal characteristics and the possible occurred cause of the main air pollution during each pollution period in CD were revealed detail. The research in this paper is critical for pollution control and prevention and provides a scientific basis for studying the spatio-temporal characteristics and sources of pollution in megacities in terrain such as basins and mountains.Implications: Air pollution has a significant impact on human and ecological health. In 2013, Chengdu was one of the five cities with the most serious PM2.5 pollution in the world. In the previous study of air pollution in Chengdu, it was only for a short period of pollution. It is impossible to fully understand the spatio-temporal trajectory and cause of air pollution. Chengdu is surrounded by mountains, and the meteorological conditions have been stagnant for a long time. The research on the spatio-temporal evolution of the main air pollution trajectories in each pollution period in Chengdu is particularly important. Quantifying the pollution trajectory and air pollution concentration is helpful to fully understand the air quality in Chengdu. The comprehensive analysis of multi-source data such as air pollution and meteorology has focused on strengthening the in-depth research on the transmission law of air pollution, the spatio-temporal change trend of air pollution, the sources of air pollution and the causes of air pollution, so as to help people fully understand the sources and causes of pollution in Chengdu. Aiming at the trajectory law, causes and occurrence time of air pollution, it is conducive for the government to formulate corresponding policies, carry out regional emission reduction and joint prevention and control, improve air quality and minimize the harm of air pollution to the public.

Thymosin beta-4 improves endothelial function and reparative potency of diabetic endothelial cells differentiated from patient induced pluripotent stem cells.

BACKGROUND: Prior studies show that signature phenotypes of diabetic human induced pluripotent stem cells derived endothelial cells (dia-hiPSC-ECs) are disrupted glycine homeostasis, increased senescence, impaired mitochondrial function and angiogenic potential as compared with healthy hiPSC-ECs. In the current study, we aimed to assess the role of thymosin ß-4 (Tb-4) on endothelial function using dia-hiPSC-ECs as disease model of endothelial dysfunction. METHODS AND RESULTS: Using dia-hiPSC-ECs as models of endothelial dysfunction, we determined the effect of Tb-4 on cell proliferation, senescence, cyto-protection, protein expression of intercellular adhesion molecule-1 (ICAM-1), secretion of endothelin-1 and MMP-1, mitochondrial membrane potential, and cyto-protection in vitro and angiogenic potential for treatment of ischemic limb disease in a mouse model of type 2 diabetes mellitus (T2DM) in vivo. We found that 600 ng/mL Tb4 significantly up-regulated AKT activity and Bcl-XL protein expression, enhanced dia-hiPSC-EC viability and proliferation, limited senescence, reduced endothelin-1 and MMP-1 secretion, and improved reparative potency of dia-hiPSC-ECs for treatment of ischemic limb disease in mice with T2DM. However, Tb4 had no effect on improving mitochondrial membrane potential and glycine homeostasis and reducing intercellular adhesion molecule-1 protein expression in dia-hiPSC-ECs. CONCLUSIONS: Tb-4 improves endothelial dysfunction through enhancing hiPSC-EC viability, reducing senescence and endothelin-1 production, and improves angiogenic potency in diabetes.

Real-Time Flash Glucose Monitoring Had Better Effects on Daily Glycemic Control Compared With Retrospective Flash Glucose Monitoring in Patients With Type 2 Diabetes on Premix Insulin Therapy.

Background and Aims: To compare the effects of real-time and retrospective flash glucose monitoring (FGM) on daily glycemic control and lifestyle in patients with type 2 diabetes on premix insulin therapy. Methods and Results: A total of 172 patients using premix insulin, with HbA1c ≥ 7.0% (56 mmol/mol), or the time below the target (TBR) ≥ 4%, or the coefficient of variation (CV) ≥36% during the screening period, were randomly assigned to retrospective FGM (n = 89) or real-time FGM group (n = 83). Another two retrospective or real-time 14-day FGMs were performed respectively, 1 month apart. Both groups received educations and medication adjustment after each FGM. Time in range (3.9~10.0 mmol/l, TIR) increased significantly after 3 months in the real-time FGM group (6.5%) compared with the retrospective FGM group (-1.1%) (p = 0.014). HbA1c decreased in both groups (both p < 0.01). Real-time FGMs increased daily exercise time compared with the retrospective group (p = 0.002). Conclusions: Real-time FGM with visible blood glucose improves daily glycemic control and diabetes self-care behaviors better than retrospective FGM in patients with type 2 diabetes on premix insulin therapy. Clinical Trial Registration: https://clinicaltrials.gov/NCT04847219.