Risk factors associated with heatwave mortality in Chinese adults over 65 years.

Aging populations are susceptible to heat-related mortality because of physiological factors and comorbidities. However, the understanding of individual vulnerabilities in the aging population is incomplete. In the Chinese Longitudinal Healthy Longevity Survey, we assessed daily heatwave exposure individually for 13,527 participants (median age = 89 years) and 3,249 summer mortalities during follow-up from 2008 to 2018. The mortality risk during heatwave days according to relative temperature is approximately doubled (hazard ratio (HR) range = 1.78-1.98). We found that heatwave mortality risks were increased for individuals with functional declines in mobility (HR range = 2.32-3.20), dependency in activities of daily living (HR range = 2.22-3.27), cognitive impairment (HR = 2.22) and social isolation reflected by having nobody to ask for help during difficulties (HR range = 2.14-10.21). Contrary to current understanding, older age was not predictive of heatwave mortality risk after accounting for individual functional declines; no statistical differences were detected according to sex. Beyond age as a risk factor, our findings emphasize that functional aging is an underlying factor in enhancing heatwave resilience. Assessment of functional decline and implementing care strategies are crucial for targeted prevention of mortality during heatwaves.

NLRP3 Inflammasome-dependent Pathway is Involved in the Pathogenesis of Polycystic Ovary Syndrome.

Accumulating evidence has shown that inflammation is a key process in polycystic ovary syndrome (PCOS). Nucleotide-binding oligomerization domain-, leucine-rich repeat-, and pyrin domain-containing 3 (NLRP3) inflammasomes play an essential role in inflammation. We investigated the expression of NLRP3 inflammasome in PCOS and its underlying mechanisms. Human granulosa cells (GCs) were isolated from patients with PCOS and control women who underwent in vitro fertilization and embryo transfer. Ovarian specimens were collected from mice with polycystic ovarian changes induced by a high-fat diet and letrozole. RNA sequencing (RNA-Seq) was performed on a granulosa cell line (KGN) overexpressing NLRP3. Polymerase chain reaction (PCR) was performed to quantify the differentially expressed genes of interest. NLRP3 and caspase-1 expression was significantly higher in GCs from patients with PCOS than in GCs from the control group. Increased NLRP3 and caspase-1 expression was also detected by immunohistochemistry in the GCs of a mouse model of polycystic ovarian changes. The serum IL-18 concentration in PCOS-like mice was significantly higher than that in control mice. Following NLRP3 overexpression in KGN cells, the genes involved in N-glycan processing, steroidogenesis, oocyte maturation, autophagy, and apoptosis were upregulated. The RT-qPCR results revealed that the expression levels of GANAB, ALG-5, HSD3B2, ULK1, PTK2B, and Casp7 in KGN cells after NLRP3 overexpression were significantly higher than those in control cells, which was consistent with the RNA-Seq results. Taken together, the NLRP3 inflammasome-dependent pathway is involved in the pathogenesis of PCOS not only by mediating pyroptosis, but also by regulating glycan synthesis, sex hormone synthesis, autophagy, and apoptosis in GCs.

A novel heterozygous ERCC6 variant identified in a Chinese family with non-syndromic primary ovarian insufficiency.

BACKGROUND: Premature ovarian insufficiency (POI) is a clinical syndrome occurring in women before 40 with decreased ovarian function. Up to 25% of POI cases result from genetic factors that remain largely unknown. The Excision repair cross-complementing, group 6 (ERCC6) variant has been found to cause POI, which is hardly ever diagnosed in adolescents. METHODS: Whole-exome sequencing was performed on a 19-year-old proband with non-syndromic POI and her parents. Sanger sequencing was used to confirm the identified variant. The effect of the variant on the protein was analyzed in silico and Swiss-MODEL. RESULTS: A novel heterozygous missense variant, c.2444G > A (p. GLy815Asp) of ERCC6 was identified in the proband who inherited the variant from her father. The variant was confirmed in another POI patient from the pedigree and was absent in the proband's mother and sister who presented normally. In silico analysis predicted this variant was deleterious. Swiss-Model revealed that the mutant amino acid formed multiple H-bonds with adjacent residues, which may lead to a dysfunction of ERCC6 protein. CONCLUSION: We firstly diagnosed an adolescent POI case associated with a novel heterozygous ERCC6 variant. The results expanded the variants spectrum of ERCC6 and provided guidance for POI diagnosis and genetic counselling.

[Clinical and genetic analysis of a Chinese pedigree affected with Dyggve-Melchior-Clausen syndrome due to a novel frameshift variant of DYM gene].

OBJECTIVE: To explore the genetic basis of a Chinese pedigree affected with Dyggve-Melchior-Clausen syndrome. METHODS: Whole exome sequencing and Sanger sequencing were carried out to detect potential pathogenic variants associated with the syndrome. The function of candidate variant was verified by Western blotting. RESULTS: A novel homozygous variant, c.1222delG of the DYM gene was detected in the two affected siblings, for which both parents were heterozygous carriers. The variant has caused replacement of Asp by Met at amino acid 408 and generate a premature stop codon p.Asp408Metfs*10. Western blotting confirmed that the variant can result in degradation of the mutant DYM protein, suggesting that it is a loss of function variant. CONCLUSION: The homozygous c.1222delG frameshift variant of the DYM probably underlay the Dyggve-Melchior-Clausen syndrome in the two affected siblings. Above findings has enabled clinical diagnosis and genetic counseling for the family.

Mechanisms of catapol inhibiting differentiation and glycolysis of Thl7 cells through MiR-143-3p / 中国药理学通报

Aim To investigate the mechanism of eata- pol (CAT) inhibiting differentiation and glyeolysis of Thl7 eel Is through miR-143-3p.Method The peripheral hloorl CD4 ∗ T eells of HA patients were obtained to deteet the expression of miR-143-3p and the mRNA levels of key glycolytic enzymes, ineluding glucose transporter 1 ( Glutl ) , hexokinase 2 ( HK2 ) , pyruvate kinase 2 (PKM2) , laetate dehydrogenase A ( LDHA).The differentiation of Thl7 eells was induced in vitro, and the ShRNA/lentivirus was applied to achieve the overexpression or knockdown of miR- 143-3 p.Un-transfected eells were divided into control group and CAT group (20, 40, 80 mg • L 1 ) , and transfected eells were divided into four groups: negative control group, miR-143-3p inhibitor group, miR- 143-3p mimies group, miR-143-3p inhibitor + CAT group.The percentage of Thl7 eells was deteeted by flow cytometry, and the level of IL-17A was detected by EL1SA.Quantitative real-time PCR was used to detect the mRNA expression of miR-143-3p and key glycolytic enzymes, and the levels of pyruvate and lactate were also detected.Results The mRNA expression of miR-143-3p in RA peripheral blood CD4 ∗ T cells was negatively correlated with disease severity ( DAS28 ) , transcription factor ROR-yt, and the key glycolytic enzymes Glutl/HK2/LDHA.Compared with negative control group, the down-expression of miR-143-3p markedly elevated the mRNA expression of ROR-yt, Glutl, HK2, LDHA, and the levels of IL-17A, pyruvate, lactate.Catalpol groups significantly up-regula- ted the expression of miR-143-3p, decreased the mRNA expression of HK2/LDHA and the levels of pvru- vate/lactate, and inhibited Thl7 cells differentiation.Compared with miR - 1 4 3 - 3 p inhibitor group , catapol could significantly inhibit the abnormal up-regulated of HK2/LDHA mRNA relative expression, pyruvate/lactate levels and the abnormal differentiation of Thl7 eells.Conclusion MiR-143-3p inhibits the differentiation and glycolysis of Thl7 cells.Catalpol could sup-press the glycolysis and differentiation of Thl7 eells by regulating mill-143-3p.

A novel homozygous variant in CANT1 causes Desbuquois dysplasia type 1 in a Chinese family and review of literatures.

Desbuquois dysplasia (DBQD) is a severe chondrodysplasia characterized by short stature, retarded development, multiple joint dislocations, and a distinct radiological appearance of the proximal femur. Pathogenic variants in the calcium-activated nucleotidase 1 (CANT1) or xylosyltransferase 1 (XYLT1) gene have been previously reported to cause DBQD. Here we present a 12-year-old boy manifesting the typical features of DBQD type 1 caused by a homozygous intronic variant c.836-9G>A of CANT1. To our knowledge, this is the first DBQD case described in China revealing that a CANT1 variant was also responsible for DBQD in the Chinese population and further emphasizing the role of CANT1 variants in the etiology of DBQD type 1. Our finding provides certainty for the DBQD clinical diagnosis of this patient and expands the spectrum of known DBQD genetic risk factors. On the basis of this study, amniocentesis-based prenatal diagnosis or preimplantation genetic diagnosis (PGD)-based assisted reproduction could be a helpful aristogenesis strategy to avoid the birth of a DBQD affected child.

Occurrence, Distribution and Risk Assessment of Mercury in Multimedia of Soil-Dust-Plants in Shanghai, China.

The urban environment is a complex ecosystem influenced by strong human disturbances in multi-environmental media, so it is necessary to analyze urban environmental pollutants through the comprehensive analysis of different media. Soil, road dust, foliar dust, and camphor leaves from 32 sample sites in Shanghai were collected for the analysis of mercury contamination in soil-road dust-leaves-foliar dust systems. Mercury concentrations in surface soils in Shanghai were the highest, followed by road dust, foliar dust, and leaves, successively. The spatial distribution of mercury in the four environmental media presented different distribution patterns. Except for the significant correlation between mercury concentrations in road dust and mercury concentrations in leaves (r = 0.56, p < 0.001), there was no significant correlation between the other groups in the four media. Besides this, there was no significant correlation between mercury concentrations and land types. The LUR (Land use regression) model was used to assess the impact of urbanization factors on mercury distribution in the environment. The results showed that soil mercury was affected by factories and residential areas. Foliar dust mercury was affected by road density and power plants. Leaf mercury was affected by power plants and road dust mercury was affected by public service areas. The highest average HI (Hazard index) value of mercury in Shanghai was found in road dust, followed by surface soil and foliar dust. The HI values for children were much higher than those for adults. However, the HI values of mercury exposure in all sampling sites were less than one, suggesting a lower health risk level. The microscopic mechanism of mercury in different environmental media was suggested to be studied further in order to learn the quantitative effects of urbanization factors on mercury concentrations.

Robotic-assisted partial nephrectomy with sequential clamping of segmental renal arteries for multiple ipsilateral renal tumors: initial outcomes.

BACKGROUND: To assess the technical feasibility and outcomes of robotic-assisted partial nephrectomy (RPN) with sequential segmental renal artery (SRA) clamping for multiple ipsilateral renal tumors (MIRTs). METHODS: From April 2016 to February 2018, consecutive eleven cases successfully underwent RPN with sequential SRA clamping under the guidance of dual-source computed tomography (DSCT). RESULTS: Ten cases had two lesions and two cases had three at the ipsilateral kidneys. The mean size and the mean R.E.N.A.L score for the dominant lesion of single case were 3.3 cm and 5.7, respectively. Twenty-two lesions (84.6%) had one target SRA and four (15.4%) had two target SRAs. Satisfactory ischemic areas were achieved by sequentially clamping two (81.8%) or three (18.2%) target SRAs with mean clamping time of 18.8 (15.0-27.0) min for single lesion, and the mean of total clamping time for single case was 37.5 (32.0-52.0) min. Only the complications of grade 1-2 were found and no positive surgical margin was discovered. The mean follow-up time was 5.4 months and no local recurrence or metastasis was found. The mean postoperative eGFR was 71.2 ml/minute/1.73m2 that was only an insignificant reduction (9.3%) compared with the preoperative baseline. CONCLUSION: This novel nephron-sparing technique, RPN with sequential SRA clamping, represents a good alternative for selected patients with MIRTs. With the guidance of DSCT and skilled robotic experience, this technique is feasible and can maximize renal function preservation. Large-scale multicenter clinical studies are still needed to further prove these initial outcomes.

Trends in clinical features and survival of oral cavity cancer: fifty years of experience with 3,362 consecutive cases from a single institution.

BACKGROUND: Global data demonstrate minimal improvement in the survival rate for oral cavity cancer (OCC) patients. We wished to know whether or not clinical features and survival rate have changed over time for OCC patients receiving initial treatment and follow-up at a large cancer center in China. METHODS: Clinical features and survival data were collected on patients diagnosed during the successive decades of 1960-1969 (n=253), 1970-1979 (n=497), 1980-1989 (n= 659), 1990-1999 (n=793), and 2000-2009 (n=1,160) at the Sun Yat-sen University Cancer Center. RESULTS: Over time, the overall 5-year survival rate for OCC patients was 52.0%. According to tumor localization, this rate was 71.4% for lip cancer, 56.3% for oral tongue cancer, and 42.7% for other parts of the oral cavity. From the 1960s to the 2000s, the 5-year survival rate steadily improved from 47.8% to 55.6% (P<0.001). Survival steadily decreased with age and was higher for women than for men in the 3 most recent decades. The survival rate for male patients was constant over time, while the rate for female patients improved dramatically. Obvious trends in clinical features over time included the following: increasing age of patients, increasing proportions of localized disease at diagnosis, decreasing proportions of diagnoses of lip cancer, decreasing proportions of diagnoses of squamous cell carcinoma, and decreasing proportions of non-surgical treatment approaches. CONCLUSION: The survival rate has steadily improved for OCC patients at this cancer center.

Rs12976445 Polymorphism Is Associated with Post-Ablation Recurrence of Atrial Fibrillation by Modulating the Expression of MicroRNA-125a and Interleukin-6R.

BACKGROUND This study aimed to identify the relationship between miR-125a polymorphism rs12976445 and the post-ablation recurrence of atrial fibrillation (AF), as well as to explore the underlying mechanism of miR-125a in AF recurrence. MATERIAL AND METHODS Microarray analysis was performed to search for miRNAs potentially involved in the regulation of AF recurrence, while real-time PCR (polymerase chain reaction) and Western blot analyses were carried out to study the expression of miR-125a (microRNA-125a), IL-6R (interleukin-6 receptor), and IL-16 (interleukin-16) in different experimental groups, so as to understand the regulatory relationships among miR-125a, IL-6R, and IL-16. Subsequently, a logistic regression analysis was utilized to investigate the survival status of recurrent AF in subjects harboring different genotypes of rs12976445. RESULTS The subjects in the GG and GC/CC groups of miR-125a polymorphism rs12976445 showed no obvious difference regarding all demographic characteristics that were collected in this study. In addition, 19 miRNAs were identified as potentially involved in the regulation of AF recurrence. Among these miRNAs, 6 were upregulated and 13 were downregulated in the group with early recurrence. According to real-time PCR results, the expression of miR-125a was dramatically upregulated in LRAF (late recurrence of atrial fibrillation) as well as in subjects harboring the GG genotype. On the contrary, the level of IL-6R mRNA was dramatically downregulated in LRAF and subjects harboring the GG genotype. Furthermore, IL-6R was confirmed as a candidate target of miR-125a by a luciferase reporter assay. CONCLUSIONS MicroRNA-125a polymorphism rs12976445 plays a role in AF recurrence via the regulation of IL-6R.

Analysis of CARD10 and CARD11 somatic mutations in patients with ovarian endometriosis.

Endometriosis is a complex and heterogeneous pre-malignant inflammatory disease harboring multiple gene mutations. Previous studies have suggested that caspase recruitment domain family member (CARD)10 and CARD11 mutations may exist in endometriosis. In the present study, a collection of endometriotic lesions and paired peripheral blood from 101 patients with ovarian endometriosis were obtained, and the entire coding sequences of the CARD10 and CARD11 genes were sequenced. Evolutionary conservation analysis and online prediction programs were applied to analyze the disease-causing potential of the identified mutations. A total of 4 novel somatic mutations were identified in 4 out of the 101 (4.0%) samples: 2 in-frame deletions in CARD10 (c.785_790delAGGAGA, p.K272_E273delKE; c.785_802delAGGAGAAGGAGAAGGAGA, p.K272_V277delKEPDNV) and 2 heterozygous missense mutations in CARD11 (c.49G>T, p.D17Y; c.160G>C, p.E54Q). The sample with CARD10 p.K272_E273delKE deletion was obtained from a 47-year-old patient who was also diagnosed with uterine leiomyoma, while the CARD10 p.K272_V277delKEPDNV-mutated sample was from a 43-year-old patient exhibiting a decreased blood eosinophil granulocyte ratio (0.3%) and an elevated serum creatine kinase level (314 U/l). The patient with the CARD11 p.D17Y mutation was 38 years old and exhibited an increased level of cancer antigen 125 (45.4 U/ml), while the patient with the CARD11 p.E54Q mutation was 46 years old and exhibited no other gynecological conditions. Evolutionary conservation analysis and online prediction programs suggested that these mutations may be disease-causing. In summary, 4 novel somatic mutations in the CARD10 and CARD11 genes were identified from amongst 101 cases of ovarian endometriosis for the first time, these mutations may serve active roles in the development of ovarian endometriosis.

Testis Tumor of Ovarian Epithelial Type: A Rare Case.

Ovarian epithelial type tumors of the testis have been a rare clinical entity. Its awareness and management remain a clinical challenge. We described the case of an 18-year-old, obese male patient who presented with scrotal enlargement. He underwent eversion of tunica vaginalis and resection of epididymal mass. The histology of the resected sample showed an ovarian epithelial type borderline tumor. We believe our case helps to strengthen awareness and management of this rare disease.

Rapid determination of carbendazim in complex matrices by electrospray ionization mass spectrometry with syringe filter needle.

The determination of pesticide residues is an indispensable task in controlling food safety and environment protection. Carbendazim is one of the extensive uses of pesticides in the agricultural industry. In this study, a simple method utilizing syringe filter has been applied as electrospray ionization emitter for mass spectrometric identification and quantification of carbendazim in complex matrices including soil, natural water, and fruit juice samples, which contain many insoluble materials. With online syringe filter of the complex samples, most of insoluble materials such as soil were excluded in spray ionization process due to the filter effect, and analytes were subsequently sprayed out from syringe needle for mass spectrometric detection. The pore sizes of filters and diameters of syringe needles also were investigated. The analytical performances, including the linear range (1-200 ng·mL-1 ), limit of detection (0.2-0.6 ng·mL-1 , S/N > 3), limit of quantitation (3.5-8.6 ng·mL-1 , S/N > 10), reproducibility (6.4%-12.5%, n = 6), and recoveries (72.1%-91.0%, n = 6) were well acceptable for direct analysis of raw samples. Matrix effect for detection of carbendazim in soil samples also was experimentally investigated. This study demonstrated that syringe filter needle coupled with electrospray ionization mass spectrometry is a simple, efficient, and sensitive method for detection of pesticide residues in water, soil, and fruit juice for risk assessment.

Bisphenol A deteriorates egg quality through HDAC7 suppression.

Bisphenol A (BPA), a synthetic substance of endocrine disrupter, widely distributes in environment and can affect the health of ovarian follicles, thereby impacting the fertilization ability and pregnancy rate. However, the underlying mechanisms regarding how BPA disrupts the egg quality have not been fully revealed. In this study, we determine that BPA treated female mice display the decreasing HDAC7 expression in ovary and eggs compared to control. Moreover, the global levels of H3K9 and H4K16 acetylation abnormally increase after BPA treatment and recover partially upon HDAC7 compensation. Collectively, our study reveals that BPA deteriorates egg quality through HDAC7 suppression.

ATF4 regulates CCL2 expression to promote endometrial cancer growth by controlling macrophage infiltration.

Activating transcription factor 4 (ATF4), an endoplasmic reticulum stress-inducible transcription factor, plays important roles in cancer progression and resistance to therapy. However, no report is available about its roles in endometrial cancer (EC). In this study, we found that ATF4 is commonly expressed in EC cell lines. Loss-of-function studies in two EC cell lines showed that ATF4 knockdown suppresses tumor growth of EC in vivo without influencing cell proliferation in vitro. And xenograft tumors derived from ATF4-knockdown cells had reduced M2 macrophage infiltration. In clinical specimens, ATF4-high expressing tumors indeed contained more macrophage infiltration compared to those with lower ATF4 expression. Moreover, we identified that ATF4-mediated chemokine CCL2 expression ultimately results in macrophage infiltration and tumor growth of EC. Taken together, our findings suggest that ATF4 contributes to tumor growth of EC by promoting CCL2 and subsequent recruitment of macrophage, and that ATF4/CCL2 axis might be a potential therapeutic target for EC.

Downregulation of DNA methyltransferase 3 alpha promotes cell proliferation and invasion of ectopic endometrial stromal cells in adenomyosis.

Adenomyosis is a common benign gynecological condition in female reproductive tract and the detailed molecular etiology remains largely elusive. Previous studies implicated that deregulated expression of DNA (cytosine-5)-methyltransferase 3A (DNMT3A), a de novo DNA methyltransferase, might be involved in the pathogenesis of adenomyosis. Meanwhile, ectopic endometrial stromal cells (EESCs) were suggested to play crucial roles in adenomyosis. Herein, we evaluated the expression of DNMT3A protein in 36 ectopic endometriums with adenomyosis and 37 eutopic endometriums in controls with Western blotting (WB) or immunohistochemistry (IHC), we found that the expression of DNMT3A was significantly decreased in the ectopic endometriums and EESCs in adenomyosis relative to that of eutopic endometriums and EESCs in control samples, respectively. In addition, our functional assays revealed that overexpression of DNMT3A suppressed cell proliferation and invasion, while knockdown of DNMT3A enhanced cell proliferation and invasion in EESCs. Taken together, our results suggested that DNMT3A expression was decreased in ectopic endometriums and EESCs in adenomyosis, and we provided the first evidence that decreased DNMT3A expression in EESCs facilitated the development of adenomyosis via enhanced cell growth and invasion.

[Sperm DNA fragmentation index and the success rate of IVF/ICSI].

Sperm DNA fragmentation index (DFI) refers to the percentage of DNA strand breaks in the total sperm. Many studies suggest that elevated DFI can lead to male infertility and early spontaneous abortion. High-DFI patients are more likely to fail in assisted reproduction and preliminary treatment or prevention methods have been developed for this population. This review focuses on the impact of DFI on clinical pregnancy outcomes and progress in the studies of its treatment.

ERα inhibits epithelial-mesenchymal transition by suppressing Bmi1 in breast cancer.

In human breast cancer, estrogen receptor-α (ERα) suppresses epithelial-mesenchymal transition (EMT) and stemness, two crucial parameters for tumor metastasis; however, the underlying mechanism by which ERα regulates these two processes remains largely unknown. Bmi1, the polycomb group protein B lymphoma Mo-MLV insertion region 1 homolog, regulates EMT transition, maintains the self-renewal capacity of stem cells, and is frequently overexpressed in human cancers. In the present study, ERα upregulated the expression of the epithelial marker, E-cadherin, in breast cancer cells through the transcriptional down-regulation of Bmi1. Furthermore, ERα overexpression suppressed the migration, invasion, and EMT of breast cancer cells. Notably, overexpression of ERα significantly decreased the CD44high/CD24low cell population and inhibited the capacity for mammosphere formation in ERα-negative breast cancer cells. In addition, overexpression of Bmi1 attenuated the ERα-mediated suppression of EMT and cell stemness. Immunohistochemistry revealed an inverse association of ERα and Bmi1 expression in human breast cancer tissue. Taken together, our findings suggest that ERα inhibits EMT and stemness through the downregulation of Bmi1.