Oocyte maturation arrest produced by TUBB8 mutations: impact of genetic disorders in infertility treatment

Abstract

Oocyte maturation defect is a challenging situation in the management of infertility, the etiology may be related to endocrine causes, protocols used in ovarian stimulation, oocyte intrinsic defects or procedures in embryology laboratory. We report three Mexican females in treatment for primary infertility with non-mature oocytes after ovary stimulation and oocyte capture in whom a genetic diagnosis of TUBB8-oocyte maturation defect was revealed by exome sequencing. Two couples achieved pregnancies though oocyte donation after establishing the genetic etiology. Our results expand the role of TUBB8-disorders in patients of non-Asian ethnicity. Oocyte maturation defects of monogenic origin are a growing group of disorders that endocrinologists and reproductive medicine specialists should be aware in order to provide referral to genetics for establish a correct and opportune diagnosis.     

Ginsenoside Rg1 prevents acetaminophen-induced oxidative stress and apoptosis via Nrf2/ARE signaling pathway

Inappropriate use of acetaminophen (APAP) can lead to morbidity and mortality secondary to hepatic necrosis. Ginsenoside Rg1 is a major active ingredient in processed Panax ginseng, which is proved to elicit biological effects. We hypothesized the beneficial effect of Rg1 on APAP-mediated hepatotoxicity was through Nrf2/ARE pathway. The study was conducted in cells and mice, comparing the actions of Rg1. Rg1 significantly improved cell survival rates and promoted the expression of antioxidant proteins. Meanwhile, Rg1 reduced the excessive ROS and the occurrence of cell apoptosis, which were related to Nrf2/ARE pathway. Expression of Nrf2 has a certain cell specificity.

     

股骨转子间骨折的稳定性重建概念演化与研究进展

目的总结近年来股骨转子间骨折在稳定性重建方面的概念演化与研究进展。方法查阅国内外相关文献并结合自身经验，从股骨转子间骨折的解剖特点、稳定型骨折与不稳定型骨折分类、稳定性复位与不稳定性复位、术中加压初始稳定与术后滑动二次稳定、内固定术后稳定性评估、早期下地站立负重等方面进行总结分析。结果股骨转子间骨折发生于股骨颈干骺端转换区，具有天然的内翻不稳定倾向。骨折复位质量是影响后续内固定物安放的最重要前提因素。判断骨折复位质量有对线和对位两方面，对线采用 Garden 指数；在对位方面，随着皮质对位理念（正性、中性、负性）的提出，特别强调前内侧皮质的相互砥住支撑（解剖、正性），是获得骨折稳定性复位的关键，而不再强调后内侧小转子骨块的作用。术后影像学的稳定性评分为早期下地站立负重提供了量化指标。但术中的前内侧皮质支撑复位，在术后头颈骨块滑动获得二次稳定的过程中，仍有皮质对位丢失现象，需研究其危险因素和防范措施。结论股骨转子间骨折在取得良好对线的基础上，只要获得了前内侧皮质的相互砥住和支撑，并用内固定器械维持住，就获得了术后稳定性。术后稳定性评分优良者，可以安全地早期下地负重、站立行走活动。     

Efficacy and safety of pembrolizumab for the treatment of advanced biliary cancer: Results from the KEYNOTE-158 and KEYNOTE-028 studies

We present data from patients with advanced biliary tract cancer (BTC) receiving pembrolizumab in the KEYNOTE-158 (NCT02628067; phase 2) and KEYNOTE-028 (NCT02054806; phase 1b) studies. Eligible patients aged ≥18 years from both studies had histologically/cytologically confirmed incurable BTC that progressed after standard treatment regimen(s), measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, Eastern Cooperative Oncology Group performance status 0/1, and no prior immunotherapy. Programmed death ligand 1 (PD-L1)-positive tumors were required for eligibility in KEYNOTE-028 only. Patients received pembrolizumab 200 mg every three weeks (KEYNOTE-158) or 10 mg/kg every two weeks (KEYNOTE-028) for ≤2 years. Primary efficacy endpoint was objective response rate (ORR) by RECIST v1.1. Response assessed by independent central review is reported. KEYNOTE-158 enrolled 104 patients and KEYNOTE-028 enrolled 24 patients. Median (range) follow-up was 7.5 months (0.6-34.3) in KEYNOTE-158 and 5.7 months (0.6-55.4) in KEYNOTE-028. In KEYNOTE-158, ORR was 5.8% (6/104; 95% CI, 2.1%-12.1%); median duration of response (DOR) was not reached (NR) (range, 6.2-26.6+ months). Median (95% CI) OS and PFS were 7.4 (5.5-9.6) and 2.0 (1.9-2.1) months. Among PD-L1-expressers (n = 61) and PD-L1-nonexpressers (n = 34), respectively, ORR was 6.6% (4/61) and 2.9% (1/34). In KEYNOTE-028, ORR was 13.0% (3/23; 95% CI, 2.8%-33.6%); median DOR was NR (range, 21.5-53.2+ months). Median (95% CI) OS and PFS were 5.7 (3.1-9.8) and 1.8 (1.4-3.1) months. Grade 3 to 5 treatment-related adverse events occurred in 13.5% of patients in KEYNOTE-158 (no grade 4; grade 5 renal failure, n = 1) and 16.7% in KEYNOTE-028 (no grade 4/5). In summary, pembrolizumab provides durable antitumor activity in 6% to 13% of patients with advanced BTC, regardless of PD-L1 expression, and has manageable toxicity.     

新生儿肺炎PCT和炎性因子水平表达及其意义

目的研究新生儿肺炎(NP)患儿血清高敏C反应蛋白(hs-CRP)、降钙素原(PCT)、白细胞介素-6(IL-6)水平表达及其意义。方法选取2017年1月-2018年2月韶关市曲江区妇幼保健计划生育服务中心诊治的NP患儿80例,按细菌感染情况分为观察1组和观察2组,各40例。选择同期40例健康新生儿作为对照组。测定并比较三组的hs-CRP、PCT和IL-6水平。结果观察1组血清PCT、hs-CRP和IL-6水平明显高于观察2组和对照组,差异均有统计学意义(P<0.05)。观察1组血清PCT、hs-CRP和1L-6检测阳性率明显高于观察2组和对照组,差异均有统计学意义(P<0.05),且观察1组血清PCT、hs-CRP和1L-6诊断NP的敏感度均明显高于观察2组,差异均有统计学意义(P<0.05);观察组各指标特异度与观察2组比较差异无统计学意义(P>0.05)。结论血清hs-CRP、PCT、IL-6水平可作为NP患儿的辅助鉴别指标,为抗生素的合理使用和疗效提供依据。     

Effect of stromal cell-derived factor-1/CXCR4 axis in neural stem cell transplantation for Parkinson’s disease

Previous studies have shown that neural stem cell transplantation has the potential to treat Parkinson’s disease,but its specific mechanism of action is still unclear.Stromal cell-derived factor-1 and its receptor,chemokine receptor 4(CXCR4),are important regulators of cell migration.We speculated that the CXCR4/stromal cell-derived factor 1 axis may be involved in the therapeutic effect of neural stem cell transplantation in the treatment of Parkinson’s disease.A Parkinson’s disease rat model was injected with 6-hydroxydopamine via the right ascending nigrostriatal dopaminergic pathway,and then treated with 5μL of neural stem cell suspension(1.5×104/L)in the right substantia nigra.Rats were intraperitoneally injected once daily for 3 days with 1.25 mL/kg of the CXCR4 antagonist AMD3100 to observe changes after neural stem cell transplantation.Parkinson-like behavior in rats was detected using apomorphine-induced rotation.Immunofluorescence staining was used to determine the immunoreactivity of tyrosine hydroxylase,CXCR4,and stromal cell-derived factor-1 in the brain.Using quantitative real-time polymerase chain reaction,the mRNA expression of stromal cell-derived factor-1 and CXCR4 in the right substantia nigra were measured.In addition,western blot assays were performed to analyze the protein expression of stromal cell-derived factor-1 and CXCR4.Our results demonstrated that neural stem cell transplantation noticeably reduced apomorphine-induced rotation,increased the mRNA and protein expression of stromal cell-derived factor-1 and CXCR4 in the right substantia nigra,and enhanced the immunoreactivity of tyrosine hydroxylase,CXCR4,and stromal cell-derived factor-1 in the brain.Injection of AMD3100 inhibited the aforementioned effects.These findings suggest that the stromal cell-derived factor-1/CXCR4 axis may play a significant role in the therapeutic effect of neural stem cell transplantation in a rat model of Parkinson’s disease.This study was approved by the Animal Care and Use Committee of Kunming Medical University,China(approval No.SYXKK2015-0002)on April 1,2014.     

Interleukin 1 alpha (IL1A) polymorphisms and risk of endometriosis in Iranian population: a case-control study

Abstract

Endometriosis is one of the most common gynecological diseases and a major cause of pain and infertility. It is influenced by genetic, epigenetic, and environmental factors. Recently, genome-wide association studies have revealed a strong association between IL1A single nucleotide polymorphisms (SNPs) and increased risk of endometriosis in Japanese women. The aim of the present study was to evaluate the association of three IL1A SNPs, rs17561, rs1304037, and rs2856836 with the risk of endometriosis in Iranian population. Totally, 105 women with diagnosis of endometriosis and 102 healthy women as control group were included. Three SNPs of the IL1A, rs17561?G/T, rs1304037 A/G, and rs2856836 T/C, were genotyped by PCR and RFLP. The rs2856836?TC genotype was significantly higher (p?=?.002; OR?=?3.1, 95% CI: 1.5–6.5) in the patients (28.1%) than the control group (12.7%). The rs2856836?CC genotype was significantly higher (p?=?.047; OR?=?2.3, 95% CI: 1.0–5.3) in the patients (17.5%) than the control group (10.8%). The rs2856836 C allele was significantly higher (p?=?.001; OR?=?2.2, 95% CI: 1.4–3.6) in the patients (31.6%) than the control group (17.2%). The IL1A rs2856836 T/C SNP was associated with susceptibility to endometriosis and the rs2856836 C allele may increase the risk of endometriosis in Iranian women.     

归脾丸加减对围绝经期功血患者免疫功能的影响

目的:探究归脾丸加减对围绝经期功血患者免疫功能、白细胞介素2(IL-2)、可溶性白细胞介素-2受体(sIL-2R)的影响。方法:选取2019年3月至2018年6月山东省济南市中西医结合医院收治的符合纳入条件的围绝经期功血患者118例作为研究对象,按照就诊顺序编号随机分为对照组和观察组,每组59例。对照组常规西医治疗,观察组加用归脾丸加减治疗,均治疗3个月。观察2组治疗前、完成治疗后T淋巴细胞亚群、IL-2、sIL-2R、凝血功能、子宫内膜厚度、激素水平、症状积分变化;完成治疗后统计治疗过程中的不良反应。结果:1)完成治疗后,2组CD3+、CD4+、CD4+/CD8+、IL-2较治疗前均显著升高,CD8+、sIL-2R则显著下降(P<0.05);完成治疗后观察组CD8+、sIL-2R显著低于于对照组,余均高于对照组(P<0.05)。2)完成治疗后2组凝血酶原时间(PT)、活化部分凝血活酶时间(APTT)、凝血酶时间(TT)、子宫内膜厚度较治疗前均显著下降(P<0.05),完成治疗后观察组以上指标均显著低于对照组(P<0.05)。3)完成治疗后2组黄体生成素(LH)、促排卵生成素(FSH)、雌二醇(E2)、孕酮(P)、血管内皮生长因子(VEGF)、碱性成纤维细胞生长因子(bFGF)较治疗前均显著下降(P<0.05),完成治疗后观察组以上指标均显著低于对照组(P<0.05)。4)完成治疗后2组月经周期、阴道出血量、阴道出血天数、神疲乏力积分较治疗前均显著下降(P<0.05),完成治疗后观察组以上指标均显著低于对照组(P<0.05)。5)完成治疗后观察组胃肠道反应、体质量增加、肝功能异常、乳房胀痛发生率均显著低于对照组,2组比较差异有统计学意义(P<0.05)。结论:归脾丸加减能提高围绝经期功血患者免疫功能,抑制IL-2、sIL-2R,改善凝血功能,从而改善症状,提高疗效。     

CyclinA1 Promoter Methylation in Self-Sampling Test

Background: Self sampled HPV testing is a cervical cancer screening method . However, cytology in self-sampled specimen cannot be used as a triage test.  Therefore, other methods for triage should be considered. CyclinA1 (CCNA1) promoter methylation has strong association with cervical precancerous and cancerous lesion. The objective of this study was to compare the diagnostic value of CCNA1 and self-sampled specimen for detecting high-grade cervical intraepithelial lesions or worse (CIN2+). Materials and Methods: A cross sectional study was conducted. Women with abnormal cytology or positive for high risk HPV (hrHPV) indicated for colposcopic examination were enrolled.  Self-collected sampling for hrHPV DNA (SS-HPV) and CCNA1 were performed. hrHPV DNA testing was done by Cobas 4800 method. CCNA1 promoter methylation was detected by CCNA1 duplex methylation specific PCR. Histopathologic result as CIN2+ obtaining from colposcopic directed biopsy or excisional procedure  was considered as positive a gold standard. The results of hrHPV and CCNA1 were reported as positive or negative. Sensitivity specificity, positive predictive value, and negative predictive value of SS-HPV and CCNA1 were calculated by comparing the results with the gold standard. Results: Two hundreds and eighty women were recruited. High-grade cervical lesions and cervical cancer (CIN2+) were diagnosed in 21.8% (61 cases) of the patients. The most common type of hrHPV was non 16, 18 subtype, followed by HPV16 and 18. CCNA1 was positive in 13 patients out of whom, twelve were CIN2+. Sensitivity of CCNA1 was 19.7 % and its  specificity and accuracy were 99.5% and 82.14%, respectively.  The sensitivity of SS-HPV was 70.5%, and its  specificity and accuracy were 39.2% and 43.3%, respectively. Conclusion:  Due to high specificity and positive predictive value of CCNA1, it can be used as alarming sign of having high-grade cervical intraepithelial lesions, especially in patient who has positive hrHPV DNA test based on self-collected sampling.