Effect of Intraperitoneal Local Anesthetics in Laparoscopic Bariatric Surgery: A Meta-Analysis of Randomized Controlled Trials.

OBJECTIVE: The effectiveness of intraperitoneal local anesthesia (IPLA) has been confirmed in other fields, but its use in bariatric surgery remains debatable. This study aimed to evaluate the analgesic effect of IPLA in bariatric surgery. METHODS: PubMed, Web of Science, Embase, and the Cochrane Library were searched from inception to February 2022. All randomized controlled trials (RCTs) assessing IPLA's analgesic effect in bariatric surgery were included in this study. Pain-related indicators were the outcome. RESULTS: Ten RCTs with 979 patients were included. Postoperative pain scores were significantly lower in IPLA group. Subgroup analysis demonstrated that IPLA was associated with lower pain scores in 6 h and at 24 h compared to the control group, without significant differences at 8, 12, and 48 h. Meanwhile, IPLA reduced the dose of opioids taken postoperatively. Additionally, there were no differences in adverse events between the two groups. As far as the number of postoperative analgesics used and hospital stays were concerned, our results did not show statistical differences between the two groups. CONCLUSION: IPLA can reduce postoperative pain safely and effectively, particularly during the early postoperative stage.

Guidelines on the treatment with integrated traditional Chinese medicine and western medicine for severe coronavirus disease 2019.

Severe Coronavirus Disease 2019 (COVID-19) is characterized by numerous complications, complex disease, and high mortality, making its treatment a top priority in the treatment of COVID-19. Integrated traditional Chinese medicine (TCM) and western medicine played an important role in the prevention, treatment, and rehabilitation of COVID-19 during the epidemic. However, currently there are no evidence-based guidelines for the integrated treatment of severe COVID-19 with TCM and western medicine. Therefore, it is important to develop an evidence-based guideline on the treatment of severe COVID-19 with integrated TCM and western medicine, in order to provide clinical guidance and decision basis for healthcare professionals, public health personnel, and scientific researchers involved in the diagnosis, treatment, and care of COVID-19 patients. We developed and completed the guideline by referring to the standardization process of the "WHO handbook for guideline development", the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system, and the Reporting Items for Practice Guidelines in Healthcare (RIGHT).

Akap1 deficiency exacerbates diabetic cardiomyopathy in mice by NDUFS1-mediated mitochondrial dysfunction and apoptosis.

AIMS/HYPOTHESIS: Diabetic cardiomyopathy, characterised by increased oxidative damage and mitochondrial dysfunction, contributes to the increased risk of heart failure in individuals with diabetes. Considering that A-kinase anchoring protein 121 (AKAP1) is localised in the mitochondrial outer membrane and plays key roles in the regulation of mitochondrial function, this study aimed to investigate the role of AKAP1 in diabetic cardiomyopathy and explore its underlying mechanisms. METHODS: Loss- and gain-of-function approaches were used to investigate the role of AKAP1 in diabetic cardiomyopathy. Streptozotocin (STZ) was injected into Akap1-knockout (Akap1-KO) mice and their wild-type (WT) littermates to induce diabetes. In addition, primary neonatal cardiomyocytes treated with high glucose were used as a cell model of diabetes. Cardiac function was assessed with echocardiography. Akap1 overexpression was conducted by injecting adeno-associated virus 9 carrying Akap1 (AAV9-Akap1). LC-MS/MS analysis and functional experiments were used to explore underlying molecular mechanisms. RESULTS: AKAP1 was downregulated in the hearts of STZ-induced diabetic mouse models. Akap1-KO significantly aggravated cardiac dysfunction in the STZ-treated diabetic mice when compared with WT diabetic littermates, as evidenced by the left ventricular ejection fraction (LVEF; STZ-treated WT mice [WT/STZ] vs STZ-treated Akap1-KO mice [KO/STZ], 51.6% vs 41.6%). Mechanistically, Akap1 deficiency impaired mitochondrial respiratory function characterised by reduced ATP production. Additionally, Akap1 deficiency increased cardiomyocyte apoptosis via enhanced mitochondrial reactive oxygen species (ROS) production. Furthermore, immunoprecipitation and mass spectrometry analysis indicated that AKAP1 interacted with the NADH-ubiquinone oxidoreductase 75 kDa subunit (NDUFS1). Specifically, Akap1 deficiency inhibited complex I activity by preventing translocation of NDUFS1 from the cytosol to mitochondria. Akap1 deficiency was also related to decreased ATP production and enhanced mitochondrial ROS-related apoptosis. In contrast, restoration of AKAP1 expression in the hearts of STZ-treated diabetic mice promoted translocation of NDUFS1 to mitochondria and alleviated diabetic cardiomyopathy in the LVEF (WT/STZ injected with adeno-associated virus carrying gfp [AAV9-gfp] vs WT/STZ AAV9-Akap1, 52.4% vs 59.6%; KO/STZ AAV9-gfp vs KO/STZ AAV9-Akap1, 42.2% vs 57.6%). CONCLUSIONS/INTERPRETATION: Our study provides the first evidence that Akap1 deficiency exacerbates diabetic cardiomyopathy by impeding mitochondrial translocation of NDUFS1 to induce mitochondrial dysfunction and cardiomyocyte apoptosis. Our findings suggest that Akap1 upregulation has therapeutic potential for myocardial injury in individuals with diabetes.

Berberine, a Traditional Chinese Medicine, Reduces Inflammation in Adipose Tissue, Polarizes M2 Macrophages, and Increases Energy Expenditure in Mice Fed a High-Fat Diet.

BACKGROUND The uncoupling protein 1 (UCP1) gene has a role in mitochondrial energy expenditure in brown adipose tissue. This study aimed to investigate the effects of berberine, a benzylisoquinoline alkaloid used in traditional Chinese medicine, on energy expenditure, expression of the UCP1 gene, the cell stress protein inositol-requiring enzyme 1α (IRE1α), apoptosis genes, and macrophage phenotype (M1 and M2) in white and brown adipose tissue in an obese mouse model fed a high-fat diet. MATERIAL AND METHODS Four-week-old C57BL/6J male mice (n=20) were divided into a high-fat diet group, a normal diet group, a group treated with berberine at 100 mg/kg/d in 0.9% normal saline, and a non-treated group. Whole-body fat mass, blood glucose, insulin resistance, and oxygen expenditure during physical activity were measured. After 16 weeks, the mice were euthanized for examination of liver and adipose tissue. The expression of pro-inflammatory cytokines, apoptosis genes, thermogenic genes (including UCP1), and IRE1α, were investigated using immunohistochemistry, Western blot, and quantitative reverse transcription polymerase chain reaction (qRT-PCR), in white and brown adipose tissue. Magnetic cell sorting harvested M1 and M2 macrophages in adipose tissue. Clodronate liposomes were used to inhibit macrophage recruitment. RESULTS Berberine treatment in mice fed a high-fat diet increased energy metabolism, glucose tolerance, and expression of UCP1, and reduced expression of pro-inflammatory cytokines, macrophage recruitment, and resulted in M2 macrophage polarization in white adipose tissue. Polarized M2 macrophages showed reduced expression of apoptotic genes and IRE1α. CONCLUSIONS Berberine improved metabolic function in a mouse model fed a high-fat diet.

Adipose tissue levels of polybrominated diphenyl ethers and breast cancer risk in Chinese women: A case-control study.

Polybrominated diphenyl ethers (PBDEs) are suspected to be associated with breast cancer risk because of their estrogenic potencies. Epidemiological studies of PBDEs and breast cancer are scarce. Our study aimed to estimate the association between adipose-tissue PBDE concentrations and breast cancer risk. A total of 209 breast cancer cases and 165 controls were recruited from hospitals between January 2014 and May 2016 in Shantou, Chaoshan area, China. Concentrations of 14 PBDE congeners were measured in adipose tissues obtained from the breast for cases and the abdomen/breast for controls during surgery. Demographic and clinicopathologic characteristics were obtained from medical records. Breast cancer risk as well as clinicopathologic characteristics were evaluated by adipose-tissue PBDE level. Odds ratios (ORs) and 95% confidence intervals (95% CIs) for breast cancer risk associated with levels of PBDE congeners were estimated from logistic regression models for all cases and stratified by estrogen receptor (ER) status. Level of total PBDEs (∑PBDE) and most individual PBDE congeners were higher in breast cancer cases than controls (median ∑PBDE, 94.99 vs 73.72 ng/g lipid). In the adjusted univariate model for all cases, breast cancer risk was increased with both 2nd and 3rd tertiles versus the 1st tertile of BDE-47 level (OR 2.05 [95% CI 1.08-3.92]; 5.47 [2.96-10.11]) and BDE-209 level (2.48 [1.30-4.73]; 4.72 [2.52-8.83]) with trend (both P < 0.001) and with the 3rd tertile of BDE-28 level (2.83 [1.63-4.92]), BDE-99 (3.22 [1.85-5.60]), BDE-100 (5.45 [2.90-10.23]), BDE-138 (2.40 [1.37-4.20]), BDE-153 (1.74 [1.02-2.97]), BDE-154 (1.84 [1.05-3.22]), and ∑PBDE levels (1.83 [1.07-3.14]) but decreased with the 3rd tertile of BDE-71 level (0.38 [0.22-0.65]) with trend (all P < 0.01). After stratifying by ER-positive or -negative status, the adjusted results were similar for ER-positive patients except for BDE-153 and BDE-154, with no statistical significance. In the multivariate model for all cases, age, menarche age, BDE-47, 71, 99, 100, 183 and 209 were independent factors associated with breast-cancer risk. ∑PBDE and most individual PBDE congeners investigated were positively associated with breast cancer risk in women from the Chaoshan area, China. PBDE may play a role in the occurrence and development of breast cancer.

Subchorionic hematoma: Research status and pathogenesis (Review).

Subchorionic hematoma (SCH) is a hematoma in which blood accumulates between the chorion and decidua basalis due to the separation of the chorion and decidua basalis. It is common in patients with threatened abortion in early pregnancy and is mainly detected by ultrasound. SCH mainly manifests as an hypoechoic or anechoic crescent-shaped fluid dark area on ultrasound images. Although there are numerous studies on SCH, its pathogenesis and etiology remain unclear, and its influence on pregnancy outcomes is also controversial; there are also no uniform clinical treatment guidelines. Current studies suggest that the occurrence of SCH may be related to several factors, such as abnormal coagulation function, autoimmune factors of pregnant women, assisted reproduction, drug use during pregnancy and reproductive tract infection; however, its exact etiology remains unclear. Some studies suggest that SCH is associated with adverse pregnancy outcomes such as miscarriage, preterm birth, preeclampsia and fetal growth restriction, although other studies have found that SCH does not increase the risk of adverse pregnancy outcomes. Therefore, the present review mainly discusses the pathogenesis, etiology and treatment of SCH in an aim to provide a reference for the clinical treatment of this condition in pregnant women.

Analysis of risk factors and pregnancy outcomes in pregnant women with subchorionic hematoma.

Subchorionic hemorrhage (SCH) or hematoma is one of the abnormal ultrasonic manifestations. At present, there are few studies on the pathogenesis of SCH, and its underlying mechanism is still unclear. It may be related to abnormal placenta formation and implantation, autoimmune dysfunction, and coagulation dysfunction. As a unique complication of pregnancy, SCH has a controversial effect on pregnancy outcome. The aim of the present study was to explore the possible etiology of SCH, especially its association with autoimmune dysfunctions, as well as the pregnancy outcomes of SCH patients. This retrospective cohort study was conducted at the Third Affiliated Hospital of Zhengzhou University. Patients with a singleton pregnancy of ≤14 weeks gestation from June 2021 to June 2022 were included. Patients with SCH detected by ultrasound were selected as the study group, while patients without SCH during the same period were chosen as the control group. Immunological indicators and pregnancy outcomes were primarily compared between the 2 groups. The decrease in protein S activity and antithrombin-III levels, the increase in homocysteine levels, and the presence of autoantibodies (such as lupus anticoagulant, anticardiolipin antibody, and antinuclear antibody spectrum) were found to be risk factors for SCH. SCH in the first trimester was associated with higher rates of premature rupture of membranes (13.5% vs 3.8%) and miscarriage (14.4% vs 6.4%). However, there were no significant differences in the rates of placental abruption, fetal distress, cesarean section, neonatal birth weight, and gestational age. The incidence of miscarriage was also significantly higher in patients with subchorionic hematoma (SCH) who tested positive for autoantibodies (28.2% vs 7.6%). There were no significant differences in other clinical characteristics and pregnancy outcomes between patients with SCH who had positive autoantibodies and those who did not. The occurrence of SCH may be related to maternal immune abnormalities. SCH may increase the risk of premature rupture of membranes and abortion. However, there is no correlation between the presence or absence of SCH and neonatal outcomes.

Jieduquyuziyin prescription alleviates SLE complicated by atherosclerosis via promoting cholesterol efflux and suppressing TLR9/MyD88 activation.

ETHNOPHARMACOLOGICAL RELEVANCE: Jieduquyuziyin prescription (JP), as a traditional Chinese medicine formula, is extensively applied to treat systemic lupus erythematosus (SLE). Its prescription is based on clinical practice and an evidence-based application of traditional medicines. It is approved by use in Chinese hospitals as a clinical prescription that can be directly used. AIM OF THE STUDY: The study aims to elucidate JP's efficacy on lupus-like disease combined with atherosclerosis and to explore its mechanism. MATERIALS AND METHODS: To conduct in vivo experiments, we established a model of lupus-like disease with atherosclerosis in ApoE-/- mice fed a high-fat diet and injected intraperitoneally with pristane. In addition, oxidized low-density lipoprotein (ox-LDL) and a TLR9 agonist (CpG-ODN2395) were utilized to examine the mechanism of JP on SLE combined with AS in RAW264.7 macrophages in vitro. RESULTS: Results indicated that JP reduced hair loss and levels of the spleen index, maintained stable body weight, alleviated kidney damage in mice, and reduced the expression levels of urinary protein, autoantibodies, and inflammatory factors in serum. Furthermore, JP is effective at alleviating the lupus-like symptoms observed in mice. In mice, JP inhibited aortic plaque deposition, stimulated lipid metabolism, and increased the expression of genes that regulate cholesterol efflux, including ATP-binding cassette transporter A1 (ABCA1), ATP-binding cassette subfamily G member 1 (ABCG1), scavenger receptor class B type I (SR-BI), and peroxisome proliferator-activated receptor γ (PPAR-γ). In vivo, JP inhibited the expression of the Toll-like receptor 9 (TLR9)-induced signaling pathway, which links TLR9/MyD88/NF-kB to the expression of subsequent inflammatory factors. Furthermore, JP inhibited the expression of TLR9 and MyD88 in vitro. In addition, the JP treatment effectively reduced foam cell formation in RAW264.7 macrophages by increasing the expression of ABCA1/G1, PPAR-γ and SR-BI. CONCLUSIONS: JP played a therapeutic role in ApoE-/- mice with pristane-induced lupus-like diseases and AS, possibly through inhibition of TLR9/MyD88 signaling and promotion of cholesterol efflux.

Long-Term Outcomes of Neoadjuvant Chemotherapy in Locally Advanced Gastric Cancer/Esophagogastric Junction Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: Neoadjuvant chemotherapy (NAC) has been defined as any preoperative chemotherapy scheme aiming to reduce tumor staging and to control preoperative micrometastasis, which has been extensively used as a treatment for resectable gastric cancer. However, its effect on the long-term survival of patients with locally advanced gastric cancer (AGC) or esophagogastric junction cancer (EGC) remains unknown. OBJECTIVE: This study aimed at investigating the long-term efficacy of NAC in locally AGC/EGC. METHODS: The following databases were searched for articles published from their inception to April 2020: PubMed, Web of Science, EBSCO, and Cochrane library. The primary outcomes were overall survival (OS) and progression-free survival (PFS). RESULTS: A total of 19 articles were included in this meta-analysis, with a total of 4,446 patients. The results showed that NAC increased the patients' 3-year OS (HR: 0.56, 95% CI, 0.21 - 0.91, p < 0.001), 3-year PFS (HR: 0.76, 95% CI, 0.66 - 0.87, p < 0.001), 5-year OS (HR: 0.71, 95% CI, 0.64 - 0.78, p < 0.001), and 5-year PFS (HR: 0.70, 95% CI, 0.61 - 0.79, p < 0.001). Besides, subgroup analysis showed that Asian countries have benefited significantly from NAC (HR: 0.65, 95% CI, 0.55 - 0.74, p < 0.001), and other countries have also benefited (HR: 0.79, 95% CI, 0.68 - 0.89, p < 0.001). CONCLUSION: Compared with adjuvant chemotherapy and surgery alone, NAC can improve the long-term survival outcomes (OS and PFS) of patients with resectable AGC or EGC.

Qinghao-Biejia Herb Pair Alleviates Pristane-Induced Lupus-Like Disease and Associated Renal and Aortic Lesions in ApoE-/- Mice.

Backgroud: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease involving multiple systems with a high prevalence of nephritis and atherosclerosis. Jieduquyuziyin prescription is a famous prescription with immune modulating and inflammation controlling effects, which is efficacious in the treatment of SLE. The most critical herbs in this prescription are Qinghao and Biejia. The aim of this study was to evaluate the therapeutic effect of Qinghao-Biejia herb hair (QB) on mice with SLE combined with atherosclerosis. Materials and Methods: The effect of QB (identification using UPLC-TOF-MS) was assessed in female ApoE-/- mice intraperitoneally injected with 0.5 ml of pristane. Serum autoantibodies and lipid metabolic parameters were tested every 4 weeks, and spleen index, serum inflammatory biomarkers, renal injury, and aortic injury were observed after 16 weeks. The expression of signaling pathway in kidney tissues was observed by RT-qPCR and Western blot. Results: The mice of QB-treated group exhibited a significant reduced serum autoantibodies level, urine protein, and renal immune complex deposition. QB treatment reduced the levels of inflammatory cytokines and improved the renal pathological changes. In addition, there was a reduction in aortic atheromatous plaque and some improvement in dyslipidemia. Moreover, QB suppressed the expression of HMGB1, TLR4, and MyD88 to some extent. Conclusion: The present study implied that QB has clear efficacy for the treatment of SLE combined with atherosclerosis, and that inhibition of the HMGB1/TLR4 signaling pathway may be one of the therapeutic targets of QB for SLE combined with atherosclerosis.

AKAP1 Deficiency Attenuates Diet-Induced Obesity and Insulin Resistance by Promoting Fatty Acid Oxidation and Thermogenesis in Brown Adipocytes.

Altering the balance between energy intake and expenditure is a major strategy for treating obesity. Nonetheless, despite the progression in antiobesity drugs on appetite suppression, therapies aimed at increasing energy expenditure are limited. Here, knockout ofAKAP1, a signaling hub on outer mitochondrial membrane, renders mice resistant to diet-induced obesity.AKAP1 knockout significantly enhances energy expenditure and thermogenesis in brown adipose tissues (BATs) of obese mice. Restoring AKAP1 expression in BAT clearly reverses the beneficial antiobesity effect in AKAP1-/- mice. Mechanistically, AKAP1 remarkably decreases fatty acid ß-oxidation (FAO) by phosphorylating ACSL1 to inhibit its activity in a protein-kinase-A-dependent manner and thus inhibits thermogenesis in brown adipocytes. Importantly, AKAP1 peptide inhibitor effectively alleviates diet-induced obesity and insulin resistance. Altogether, the findings demonstrate that AKAP1 functions as a brake of FAO to promote diet-induced obesity, which may be used as a potential therapeutic target for obesity.

Risk of breast cancer and adipose tissue concentrations of polychlorinated biphenyls and organochlorine pesticides: a hospital-based case-control study in Chinese women.

Polychlorinated biphenyls (PCBs), dichlorodiphenyltrichloroethane (DDT), and dichlorodiphenyldichloroethylene (DDE) are suspected to be associated with breast cancer risk, but the results are controversial. This study was performed to evaluate the associations between adipose tissue PCB, DDT, and DDE concentrations and breast cancer risk. Two hundred and nine pathologically diagnosed breast cancer cases and 165 controls were recruited from three local hospitals in Shantou city, China, from 2014 to 2016. Concentrations of 7 PCB congeners, p,p'-DDT, and p,p'-DDE were measured in adipose tissues obtained from the breast for cases and the breast/abdomen for controls during surgery. Clinicopathologic information and demographic characteristics were collected from medical records. PCBs, p,p'-DDT, and p,p'-DDE concentrations in adipose tissues were compared between cases and controls. Multivariate logistic regression model was used to analyze the risk of breast cancer by PCBs, p,p'-DDT, and p,p'-DDE concentrations in adipose tissues. Breast cancer cases have relatively higher menarche age, higher breastfeeding and postmenopausal proportion than controls. Levels of PCB-52, PCB-101, PCB-118, PCB-138, PCB-153, PCB-180, total PCBs (∑PCBs), and p,p'-DDE were relatively higher in breast cancer cases than controls. Breast cancer risk was increased in the third tertile of PCB-101, PCB-118, PCB-138, PCB-153, PCB-180, ∑PCBs, and p,p'-DDE as compared with the first tertile in both adjusted and unadjusted logistic regression models (odds ratios [ORs] were from 1.58 to 7.88); and increased linearly across categories of PCB-118 and p,p'-DDE in unadjusted model, and PCB-118 and PCB-153 in the adjusted model with trend (all P < 0.01). While breast cancer risk was declined in the second tertile of PCB-28, PCB-52, and PCB-101 in both unadjusted and adjusted models, also second tertile of p,p'-DDT and third tertile of PCB-28 in the adjusted models. This study suggests associations between the exposure of PCBs, p,p'-DDT, and p,p'-DDE and breast cancer risk. Based on adjusted models, PCB-118, PCB-138, PCB-153, PCB-180, ∑PCBs, and p,p'-DDE exposures increase breast cancer risk at current exposure levels, despite existing inconsistent even inverse results in PCB-28, PCB-52, PCB-101, and p,p'-DDT. More epidemiological studies are still needed to verify these findings in different populations.

Interactome Analyses implicated CAMK2A in the genetic predisposition and pharmacological mechanism of Bipolar Disorder.

Bipolar disorder (BPD) is a severe mental illness characterized by fluctuations in mood states, behaviors and energy levels. Growing evidence suggests that genes associated with specific illnesses tend to interact together and encode a tight protein-protein interaction (PPI) network, providing valuable information for understanding their pathogenesis. To gain insights into the genetic and physiological foundation of BPD, we conduct the physical PPI analysis of 184 BPD risk genes distilled from genome-wide association studies and exome sequencing studies. We have identified several hub genes (CAMK2A, HSP90AA1 and PLCG1) among those risk genes, and observed significant enrichment of the BPD risk genes in certain pathways such as calcium signaling, oxytocin signaling and circadian entrainment. Furthermore, while none of the 184 genetic risk genes are "well established" BPD drug targets, our PPI analysis showed that αCaMKII (encoded by CAMK2A) had direct physical PPIs with targets (HRH1, SCN5A and CACNA1E) of clinically used anti-manic BPD drugs, such as carbamazepine. We thus speculated that αCaMKII might be involved in the cellular pharmacological actions of those drugs. Using cultured rat primary cortical neurons, we found that carbamazepine treatment induced phosphorylation of αCaMKII in dose-dependent manners. Intriguingly, previous study showed that CAMK2A heterozygous knockout (CAMK2A+/-) mice exhibited infradian oscillation of locomotor activities that can be rescued by carbamazepine. Our data, in combination with previous studies, provide convergent evidence for the involvement of CAMK2A in the risk of BPD.

Further Evidence of an Association between NCAN rs1064395 and Bipolar Disorder.

Genome-wide association studies suggest that rs1064395 in the neurocan gene (NCAN) is a potential risk factor for bipolar disorder (BPD), and further replication analyses in larger independent samples are needed. We herein analyzed rs1064395 in a Han Chinese sample of 1,146 BPD cases and 2,031 controls, followed by a meta-analysis of BPD samples from worldwide populations including a total of 15,318 cases and 91,990 controls. The meta-analysis found that rs1064395 showed a genome-wide significant association with BPD (p = 4.92 × 10-9, OR = 1.126 for the A allele), although it did not reach the significance level in the Han Chinese sample (p = 0.415, OR = 1.070 for the A allele). We also examined the association between the single nucleotide polymorphisms and major depressive disorder (MDD) given the presumed genetic overlap between BPD and MDD, and rs1064395 was also associated with MDD (p = 0.0068, OR = 1.067 for the A allele) in a meta-analysis of 14,543 cases and 14,856 controls. Our data provide further evidence for the involvement of NCAN in the genetic susceptibility to BPD and also implicate its broader role in major mood disorders.

Replicated associations of FADS1, MAD1L1, and a rare variant at 10q26.13 with bipolar disorder in Chinese population.

Genetic analyses of psychiatric illnesses, such as bipolar disorder (BPD), have revealed essential information regarding the underlying pathological mechanisms. While such studies in populations of European ancestry have achieved prominent success, understanding the genetic risk factors of these illnesses (especially BPD) in Chinese population remains an urgent task. Given the lack of genome-wide association study (GWAS) of BPD in Chinese population from Mainland China, replicating the previously reported GWAS hits in distinct populations will provide valuable information for future GWAS analysis in Han Chinese. In the present study, we have recruited 1146 BPD cases and 1956 controls from Mainland China for genetic analyses, as well as 65 Han Chinese brain amygdala tissues for mRNA expression analyses. Using this clinical sample, one of the largest Han Chinese BPD samples till now, we have conducted replication analyses of 21 single nucleotide polymorphisms (SNPs) extracted from previous GWAS of distinct populations. Among the 21 tested SNPs, 16 showed the same direction of allelic effects in our samples compared with previous studies; 6 SNPs achieved nominal significance (p < 0.05) at one-tailed test, and 2 additional SNPs showed marginal significance (p < 0.10). Aside from replicating previously reported BPD risk SNPs, we herein also report several intriguing findings: (1) the SNP rs174576 was associated with BPD in our Chinese sample and in the overall global meta-analysis, and was significantly correlated with FADS1 mRNA in diverse public RNA-seq datasets as well as our in house collected Chinese amygdala samples; (2) two (partially) independent SNPs in MAD1L1 were both significantly associated with BPD in our Chinese sample, which was also supported by haplotype analysis; (3) a rare SNP rs78089757 in 10q26.13 region was a genome-wide significant variant for BPD in East Asians, and this SNP was near monomorphic in Europeans. In sum, these results confirmed several significant BPD risk genes. We hope this Chinese BPD case-control sample and the current brain amygdala tissues (with continuous increasing sample size in the near future) will provide helpful resources in elucidating the genetic and molecular basis of BPD in this major world population.

Efficacy and safety of endocrine monotherapy as first-line treatment for hormone-sensitive advanced breast cancer: A network meta-analysis.

BACKGROUND: Endocrine therapy was recommended as the preferred first-line treatment for hormone receptor-positive (HR+, i.e., ER+ and/or PgR+), human epidermal growth factor receptor-2-negative (HER2-) postmenopausal advanced breast cancer (ABC), but which endocrine monotherapy is optimal lacks consensus. We aimed to identify the optimal endocrine monotherapy with a network meta-analysis. METHODS: We performed a network meta-analysis for a comprehensive analysis of 6 first-line endocrine monotherapies (letrozole, anastrozole, exemestane, tamoxifen, fulvestrant 250 mg and 500 mg) for HR+ HER2- metastatic or locally advanced breast cancer in postmenopausal patients. The main outcomes were objective response rate (ORR), time to progression (TTP), and progression-free survival (PFS). Secondary outcomes were adverse events. RESULTS: We identified 27 articles of 8 randomized controlled trials including 3492 patients in the network meta-analysis. For ORR, the treatments ranked in descending order of effectiveness were letrozole > exemestane > anastrozole > fulvestrant 500 mg > tamoxifen > fulvestrant 250 mg. For TTP/PFS, the order was fulvestrant 500 mg > letrozole > anastrozole > exemestane > tamoxifen > fulvestrant 250 mg. We directly compared adverse events and found that tamoxifen produced more hot flash events than fulvestrant 250 mg. CONCLUSIONS: Fulvestrant 500 mg and letrozole might be optimal first-line endocrine monotherapy choices for HR+ HER2- ABC because of efficacious ORR and TTP/PFS, with a favorable tolerability profile. However, direct comparisons among endocrine monotherapies in the first-line therapy setting are still required to robustly demonstrate any differences among these endocrine agents. Clinical choices should also depend on the specific disease situation and duration of endocrine therapy.

Blood cadmium levels associated with short distant metastasis-free survival time in invasive breast cancer.

Distant metastasis is strongly associated with poor prognosis of breast cancer. Cadmium (Cd) exposure was previously found associated with breast cancer incidence. We explored the associations of blood cadmium levels (BCLs) and clinicopathologic characteristics with invasive breast cancer distant metastasis. Blood samples were collected and analyzed for BCLs by graphite-furnace atomic absorption spectrometry. Clinicopathologic characteristics, including basic clinical information and tumor characteristics, were obtained from medical records. Breast cancer distant metastasis-free survival (DMFS) time was calculated at follow-up. The associations of BCLs and clinicopathologic characteristics with DMFS time were examined by Kaplan-Meier method and Cox regression analysis, and associations between BCLs and tumor characteristics were also explored. Blood Cd level was positively associated with distant metastasis, clinical stage, BMI, and age. On univariate analysis, older age at diagnosis, family history of breast cancer, high N classification and clinical stage, positivity for human epidermal growth factor receptor 2, and high BCLs were associated with short DMFS time. On multivariate analysis model, older age at diagnosis, family history of breast cancer, high N classification, and BCLs were predictors for breast cancer distant metastasis. BCLs were a risk factor for short DMFS time of invasive breast cancer. BCLs and some clinicopathologic factors affect breast cancer distant metastasis, which needs further epidemiological and experimental studies to confirm.

Association of breast adipose tissue levels of polychlorinated biphenyls and breast cancer development in women from Chaoshan, China.

Polychlorinated biphenyls (PCBs) are implied to be potential risk factors for breast cancer in wildlife and in in vivo and in vitro studies. Epidemiological studies revealed some individual or groups of PCB congeners associated with breast cancer risk, but consistent conclusions are scarce. This study aimed to explore the association between PCB exposure and breast cancer development. Breast adipose tissues were collected, and seven PCB congeners were analyzed by gas chromatography-mass spectrometry (GC-MS). Demographic characteristics, basic clinical data, and pathological diagnosis information were obtained from medical records. The differences in PCB exposure levels among different groups and indices were compared, and the correlation among PCB congeners was evaluated. The order of congener profile by molar concentration was PCB-153 > PCB-138 > PCB-180 > PCB-118 > PCB-101 > PCB-52 > PCB-28. ∑PCB level differed by occupation and residence and was significantly higher at 55-59-year-old group than at the other age groups. ∑PCB level was higher in postmenopausal than in premenopausal women. Decreasing ∑PCB levels were related with increasing parity among women with progesterone receptor (PR)-positive breast tumors. With increased clinical stage, the ∑PCB level increased significantly. ∑PCB level did not differ by tumor-node-metastasis classification and PR or human epidermal growth factor receptor 2 (HER2) expression but did differ by estrogen receptor (ER) expression (P = 0.04) without a regularly increasing trend in breast adipose tissue. These results suggest a potential association between PCB exposure and breast cancer development. Further in vitro and in vivo studies are needed to confirm these findings and explain the underlying mechanisms. Graphical Abstract Total PCBs level among different clinical stages in breast cancer patients.