The circular RNA Rap1b promotes Hoxa5 transcription by recruiting Kat7 and leading to increased Fam3a expression, which inhibits neuronal apoptosis in acute ischemic stroke.

Circular RNAs can regulate the development and progression of ischemic cerebral disease. However, it remains unclear whether they play a role in acute ischemic stroke. To investigate the role of the circular RNA Rap1b (circRap1b) in acute ischemic stroke, in this study we established an in vitro model of acute ischemia and hypoxia by subjecting HT22 cells to oxygen and glucose deprivation and a mouse model of acute ischemia and hypoxia by occluding the right carotid artery. We found that circRap1b expression was remarkably down-regulated in the hippocampal tissue of the mouse model and in the HT22 cell model. In addition, Hoxa5 expression was strongly up-regulated in response to circRap1b overexpression. Hoxa5 expression was low in the hippocampus of a mouse model of acute ischemia and in HT22-AIS cells, and inhibited HT22-AIS cell apoptosis. Importantly, we found that circRap1b promoted Hoxa5 transcription by recruiting the acetyltransferase Kat7 to induce H3K14ac modification in the Hoxa5 promoter region. Hoxa5 regulated neuronal apoptosis by activating transcription of Fam3a, a neuronal apoptosis-related protein. These results suggest that circRap1b regulates Hoxa5 transcription and expression, and subsequently Fam3a expression, ultimately inhibiting cell apoptosis. Lastly, we explored the potential clinical relevance of circRap1b and Hoxa5 in vivo. Taken together, these findings demonstrate the mechanism by which circRap1b inhibits neuronal apoptosis in acute ischemic stroke.

Comprehensive multimodal management of borderline resectable pancreatic cancer: Current status and progress.

Borderline resectable pancreatic cancer (BRPC) is a complex clinical entity with specific biological features. Criteria for resectability need to be assessed in combination with tumor anatomy and oncology. Neoadjuvant therapy (NAT) for BRPC patients is associated with additional survival benefits. Research is currently focused on exploring the optimal NAT regimen and more reliable ways of assessing response to NAT. More attention to management standards during NAT, including biliary drainage and nutritional support, is needed. Surgery remains the cornerstone of BRPC treatment and multidisciplinary teams can help to evaluate whether patients are suitable for surgery and provide individualized management during the perioperative period, including NAT responsiveness and the selection of surgical timing.

Research trends and hotspots of neoadjuvant therapy in pancreatic cancer: a bibliometric analysis based on the Web of Science Core Collection.

Neoadjuvant therapy (NAT) for pancreatic cancer (PC) has achieved certain results. This article was aimed to analyze the trends in NAT in PC over the past 20 years using bibliometric analysis and visualization tools to guide researchers in exploring future research hotspots. Articles related to NAT for PC were retrieved from the Web of Science Core Collection for the period 2002-2021. The information was analyzed and visualized using VOSviewer, Citespace, Microsoft Excel and R software. The number of articles per year has continued to increase over the past 20 years. Of the 1,598 eligible articles, the highest number was from the United States (760), and an analysis of institutions indicated that the University of Texas System (150) had the highest number of articles. Matthew H. G. Katz had the highest number of citations and the highest H-index. "Pancreatic cancer" (981), "Resection" (623), "Cancer" (553), "Neoadjuvant therapy" (509) and "Survival" (484) were the top five ranked keywords. Combined with the keywords-cluster analysis and citation burst analysis, current research hotspots were the optimal NAT regimen, NAT response assessment, NAT for resectable PC and management of complications. NAT has received increasing attention in the field of PC over the past 20 years, but greater collaboration between countries and additional multicenter randomized clinical trials are needed. Overall, we have revealed current research hotspots and provided valuable information for the choice of future research directions.

Efficacy of exenatide on weight loss, metabolic parameters and pregnancy in overweight/obese polycystic ovary syndrome.

CONTEXT: Weight loss remains one of the most important arms in obese patients with polycystic ovary syndrome (PCOS). Further studies are needed to identify the best treatment. OBJECTIVE: To evaluate the effects of exenatide (EXE) on reproductive and metabolic function in overweight/obese (OW/OB) PCOS. DESIGN: This is a 24-week open-label prospective, randomized, clinical study. PATIENTS AND MEASUREMENTS: This study randomized 176 OW/OB women diagnosed with PCOS to receive either EXE 10 µg BID (n = 88) or metformin (MET) 1000 mg BID (n = 88) for the first 12 weeks. Then all patients were treated with MET alone during the second 12 weeks. We observed metabolic parameters at 0 and 12 weeks, and then tracked the rate of pregnancy during the second 12 weeks. RESULTS: After the first 12 weeks of intervention, compared with MET, subjects who received EXE had significantly decreased weight (4.29 ± 1.29 kg vs 2.28 ± 0.55 kg, P < .001) and total fat% (4.67 ± 0.09% vs 1.11 ± 0.32%, P < .001), improved the homeostasis model of assessment for insulin resistance (1.30 ± 0.58 vs 0.59 ± 0.12, P < .001) and increased the menstrual frequency ratio (0.62 ± 0.12 vs 0.37 ± 0.01, P < .001). During the second 12 weeks, the rate of natural pregnancy of EXE-treated patients was significantly higher than MET-treated patients (43.60% vs 18.70%, P < .05). CONCLUSIONS: Short-term EXE therapy was linked to significant weight loss and central adiposity reduction, which may further explain the improvements in insulin resistance, inflammatory marker and menstrual cycle, which may contribute to increasing pregnancy rates in OW/OB women with PCOS.

Serum levels of nesfatin-1 are increased in gestational diabetes mellitus.

OBJECTIVE: To analyze the concentrations of nesfatin-1 in maternal and cord serum, to evaluate the expression of nesfatin-1 in subcutaneous adipose tissue (SAT) from pregnant women with gestational diabetes mellitus (GDM) and those with normal glucose tolerance (NGT). METHODS: We studied a total of 50 GDM and 50 NGT subjects. The clinical features, serum nesfatin-1, homeostasis model assessment of insulin resistance (HOMA-IR), lipid profiles were measured at the third trimester of pregnancy. The expression of nesfatin-1 in the SAT was determined by western blot. RESULTS: Compared with the NGT group, the GDM group showed greater levels of serum nesfatin-1, adipocyte fatty acid binding protein (AFABP), and leptin; a greater level of cord blood nesfatin-1; and a higher level of expression in SAT (p < 0.05 or p < 0.01). Fasting insulin (FI) (b = 0.317, p= 0.022) and body mass index (BMI) before delivery (b = 0.367, p=0.008) were independently associated with serum nesfatin-1. Nesfatin-1 was the independent risk factor for GDM. CONCLUSIONS: The GDM group had higher levels of maternal serum and cord blood nesfatin-1, and greater nesfatin-1 expression in SAT. Nesfatin-1 is closely related to obesity and IR in pregnancy.

Changes in serum adipocyte fatty acid-binding protein in women with gestational diabetes mellitus and normal pregnant women during mid- and late pregnancy.

AIMS/INTRODUCTION: To observe the longitudinal changes in serum adipocyte fatty acid-binding protein (AFABP), carbohydrate, and lipid metabolism parameters in women with and without gestational diabetes mellitus (GDM) during mid- and late pregnancy periods, as well as to identify whether there is any association between AFABP and development of GDM. MATERIALS AND METHODS: A total of 40 GDM and 240 normal glucose tolerance participants were enrolled at 24-28 weeks and completed the study. The clinical features, serum AFABP, other adipocytokines (leptin, adiponectin, retinol-binding protein 4), homeostasis model assessment of insulin resistance, and lipid profiles were measured in the second and third trimesters of pregnancy. RESULTS: Compared with the normal glucose tolerance group, the GDM group showed greater levels of AFABP, leptin and retinol-binding protein 4; and a decreased level of adiponectin (P < 0.05 or P < 0.01) during mid- and late pregnancy periods. Prepregnancy body mass index was the independent factor impacting serum AFABP levels in the second (ß = 0.567, P = 0.004) and third trimesters (ß = 0.619, P = 0.001). Furthermore, GDM was independently associated with AFABP concentrations in multiple regression analysis in the second and third trimester (all P < 0.01). Serum AFABP, leptin and retinol-binding protein 4 are risk factors for GDM; adiponectin is a protective factor for GDM (P < 0.05 or P < 0.01). CONCLUSIONS: The GDM group had a higher level of AFABP during mid- and late stages of pregnancy; prepregnancy body mass index and GDM were the independent factors with respect to serum AFABP. AFABP might be closely related to obesity, insulin resistance and leptin resistance in pregnancy, and is a major risk factor for GDM.

Identification of p27/KIP1 expression level as a candidate biomarker of response to rapalogs therapy in human cancer.

Rapamycin analogs temsirolimus and everolimus have been approved for the treatment of advanced renal cancer and are being tested in a wide spectrum of human tumors. However, objective response rates with rapalogs in clinical trials were modest and variable. Identification of biomarkers capable of predicting response to rapalogs is of increasing interest. We analyzed pairwise Pearson correlation coefficients (r) between rapalogs activity and gene expression profile for each NCI-60 cell line. p27 showed the highest positive correlation among 9,706 gene probes tested. At cellular levels, breast cancer MCF-7, T47D, and BT-474 cells, expressing high levels of p27, were sensitive to rapalogs, whereas the cells expressed low levels of p27, such as MDA-MB-231, MDA-MB-468, and MDA-MB-435 cells, exhibited resistance to rapalogs. Mechanistic study indicated that this correlation is likely determined by the basal level of p27 regardless of the phosphorylation or redistribution of p27 upon rapalogs treatment, which may provide a putative threshold to block G1/S transition. Consistently, down-regulation of p27 by siRNA conferred MCF-7 and BT-474 cells insensitive to rapalogs. Moreover, a significant positive correlation between p27 gene expression and rapamycin anti-tumor activity was also observed in mice bearing different human cancer cell xenografts. In conclusion, p27 expression level is positively correlated with the anticancer activity of rapalogs in vitro and in vivo. We propose p27 expression level may be also a candidate predictive biomarker for patient selection for rapalogs-based therapy, which requires clinical validation in a series of patients treated with rapalogs.

3D structure modeling of cytochrome P450 2C19 and its implication for personalized drug design.

Cytochrome P450 2C19 (CYP2C19) is a member of the cytochrome P-450 enzyme superfamily and plays an important role in the metabolism of drugs. In order to gain insights for developing personalized drugs, the 3D (dimensional) structure of CYP2C19 has been developed based on the crystal structure of CYP2C9 (PDB code 1R90), and its structure-activity relationship with the ligands of CEC, Fluvoxamine, Lescol, and Ticlopidine investigated through the structure-activity relationship approach. By means of a series of docking studies, the binding pockets of CYP2C19 for the four compounds are explicitly defined that will be very useful for conducting mutagenesis studies, providing insights into personalization of drug treatments and stimulating novel strategies for finding desired personalized drugs.