Genomic variants within chromosome 14q32.32 regulate bone mass through MARK3 signaling in osteoblasts

Bone mineral density (BMD) is a highly heritable predictor of osteoporotic fracture. GWAS have identified hundreds of loci influencing BMD, but few have been functionally analyzed. In this study, we show that SNPs within a BMD locus on chromosome 14q32.32 alter splicing and expression of PAR-1a/microtubule affinity regulating kinase 3 (MARK3), a conserved serine/threonine kinase known to regulate bioenergetics, cell division, and polarity. Mice lacking Mark3 either globally or selectively in osteoblasts have increased bone mass at maturity. RNA profiling from Mark3-deficient osteoblasts suggested changes in the expression of components of the Notch signaling pathway. Mark3-deficient osteoblasts exhibited greater matrix mineralization compared with controls that was accompanied by reduced Jag1/Hes1 expression and diminished downstream JNK signaling. Overexpression of Jag1 in Mark3-deficient osteoblasts both in vitro and in vivo normalized mineralization capacity and bone mass, respectively. Together, these findings reveal a mechanism whereby genetically regulated alterations in Mark3 expression perturb cell signaling in osteoblasts to influence bone mass.     

3-D Ultrasound Imaging Reliability of Measuring Dysplasia Metrics in Infants

Developmental dysplasia of the hip is a hip abnormality that ranges from mild acetabular dysplasia to irreducible femoral head dislocations. While 2-D B-mode ultrasound (US)-based dysplasia metrics or disease metrics are currently used clinically to diagnose developmental dysplasia of the hip, such estimates suffer from high inter-exam variability. In this work, we propose and evaluate 3-D US-derived dysplasia metrics that are automatically computed and demonstrate that these automatically derived dysplasia metrics are considerably more reproducible. The key features of our automatic method are (i) a random forest-based learning technique to remove regions across the coronal axis that do not contain bone structures necessary for dysplasia-metric extraction, thereby reducing outliers; (ii) a bone segmentation method that uses rotation-invariant and intensity-invariant filters, thus remaining robust to signal dropout and varying bone morphology; (iii) a novel slice-based learning and 3-D reconstruction strategy to estimate a probability map of the hypoechoic femoral head in the US volume; and (iv) formulae for calculating the 3-D US-derived dysplasia metrics. We validate our proposed method on real clinical data acquired from 40 infant hip examinations. Results show a considerable (around 70%) reduction in variability in two key 3-D US-derived dysplasia metrics compared with their 2-D counterparts.     

Aging attenuates the ovarian circadian rhythm

ObjectiveTo study the effect of aging on ovarian circadian rhythm.DesignHuman and animal study.SettingUniversity hospital and research laboratory.Patients/animalsHuman granulosa cells were obtained by follicular aspiration from women undergoing in vitro fertilization (IVF), and ovarian and liver tissues were obtained from female C57BL/6 mice.Intervention(s)None.Main outcome measure(s)Expression of circadian genes in young and older human granulosa cells and circadian rhythm in ovaries and livers of young and older mice.Result(s)All examined circadian clock genes in human granulosa cells showed a downward trend in expression with aging, and their mRNA expression levels were negatively correlated with age (P < 0.05). Older patients (≥ 40 years of age) had significantly reduced serum anti-Müllerian hormone (AMH) levels. Except for Rev-erbα, all other examined circadian clock genes were positively correlated with the level of AMH (P < 0.05). The circadian rhythm in the ovaries of older mice (8 months) was changed significantly relative to that in ovaries of young mice (12 weeks), although the circadian rhythm in the livers of older mice was basically consistent with that of young mice.Conclusion(s)Lower ovarian reserve in older women is partially due to ovarian circadian dysrhythmia as a result of aging.Electronic supplementary materialThe online version of this article (10.1007/s10815-020-01943-y) contains supplementary material, which is available to authorized users.     

Safety and feasibility of laparoscopic living donor right hepatectomy for adult liver transplantation: a meta-analysis

BackgroundLaparoscopic living donor right hepatectomy (LDRH) was a controversial topic due to its unknown safety and feasibility.MethodsPubMed, EMBASE and Cochrane Library databases were searched for studies comparing LDRH with open living donor right hepatectomy (ODRH), which were published between the date of database establishment and June 2020. Revman5.3 was used for statistical analysis.ResultsFourteen studies were included. For the donors, there was no significant difference in warm ischemic time, hospital stay, graft weight, hepatic arterial anomalies (HAA), hepatic vein anomalies (HVA), portal vein anomalies (PVA), biliary anomalies, bleeding, wound infection, severe complication rate and readmission rate. The estimated blood loss, incidence of complication, intra-abdominal fluid rate in the LDRH group were significantly lower than those in the ODRH group, while the operation time, time to remove liver in the LDRH group were significantly higher than those in the ODRH group. For the recipients, there was no significant difference in complication rate, bleeding, HAA, PVA, biliary anomalies, graft failure and mortality. The HVA rate in the LDRH group was significantly higher than that in the ODRH group.ConclusionLDRH is safe and feasible for adult living donor liver transplantation compared with ODRH and it can reduce intraoperative bleeding and postoperative complication in donors, which requires further verification by more multi-center comparative studies with large sample and high quality.     

基于网络药理学和临床试验探讨前列消汤对ⅢA型前列腺炎IL-17与Foxp3表达影响研究＊

目的 基于网络药理学进行前列消汤治疗慢性前列腺炎的预测，同时采用临床试验进行验证，证明前列消汤对ⅢA型前列腺炎患者的临床疗效及对前列腺液（Expressed Prostatic Secretion， EPS）中白细胞介素17（interleukin 17， IL-17）及双头叉转录因子p3（Forkhead box p3， Foxp3）表达的影响。方法 采用网络信息学分析方法，筛选出前列消汤在ⅢA型前列腺炎治疗中发挥疗效的主要作用靶点，采用临床随机非盲法，将符合纳入标准的80例ⅢA型前列腺炎湿热下注证患者随机分为观察组和对照组各40例，观察组口服自拟前列消汤，对照组口服银花泌炎灵片。观察治疗前后两组的症状及证候评分情况、前列腺按摩液以及其IL17、Foxp3表达的差异。取40例正常男性前列腺液为正常对照。结果 网络药理学分析结果提示IL17信号通路为前列消汤治疗慢性前列腺炎的重要通路之一，临床试验结果提示经治疗后观察组有效率达89.19%，较对照组的73.68%为优（P < 0.05）。两组患者服药后的临床表现、前列腺按摩液WBC、症状及证候评分均存在明显改善。观察组和对照组IL-17水平较治疗前下降，Foxp3表达较治疗前升高（P < 0.05）。观察组对降低IL-17表达和提升Foxp3表达上较对照组差异更大（P < 0.05）。观察组治疗后与正常组IL-17和Foxp3水平比较差异较小（P > 0.05）。结论 网络药理学能一定程度上预测中药作用于疾病的相应靶点，前列消汤对ⅢA型前列腺炎湿热下注证患者的临床症状有明显改善作用，并能降低IL-17表达，对Foxp3表达有提升作用，在总有效率和对细胞因子的影响上较银花泌炎灵片组明显。     

腹腔镜精准肝切除术治疗原发性肝癌的临床效果

目的探究腹腔镜精准肝切除术治疗原发性肝癌的临床效果。方法选择2019年1月—2020年6月期间在医院接受腹腔镜肝切除术治疗的80例原发性肝癌患者作为实验分析对象,依据手术治疗方案的不同将患者分为腹腔镜常规肝切除组(对照组)40例和腹腔镜精准肝切除组(观察组)40例,对两组患者手术各项指标、手术前后肝功能指标改善情况及术后并发症发生率进行对比分析。结果观察组患者手术时间明显长于对照组,组间比较进行t检验,差异具有统计学意义(P<0.05);观察组患者术中出血量及术中输血量均少于对照组患者,术后恢复时间明显短于对照组患者,组间比较进行t检验,差异具有统计学意义(P<0.05);术后,两组患者ALT、AST、ALB及TBIL水平均显著降低,组内比较进行t检验,差异具有统计学意义(P<0.05),观察组患者ALT、AST、ALB及TBIL水平降低幅度显著大于对照组患者,组间比较进行t检验,差异具有统计学意义(P<0.05);观察组患者术后并发症发生率为10.00%,对照组患者术后并发症发生率为27.50%,组间比较进行χ2检验,差异具有统计学意义(χ2=4.021;P=0.045)。结论与腹腔镜常规肝切除术比较,腹腔镜精准肝切除术操作精细,手术时间相对较长,患者术中出血量更少,术后恢复时间更短,能够最大限度保护患者的肝脏,减低患者术后并发症发生率,提高手术治疗效果,改善患者预后。     

Breast cancer management pathways during the COVID-19 pandemic: outcomes from the UK ‘Alert Level 4’ phase of the B-MaP-C study

Background The B-MaP-C study aimed to determine alterations to breast cancer (BC) management during the peak transmission period of the UK COVID-19 pandemic and the potential impact of these treatment decisions.Methods This was a national cohort study of patients with early BC undergoing multidisciplinary team (MDT)-guided treatment recommendations during the pandemic, designated ‘standard’ or ‘COVID-altered’, in the preoperative, operative and post-operative setting.Findings Of 3776 patients (from 64 UK units) in the study, 2246 (59%) had ‘COVID-altered’ management. ‘Bridging’ endocrine therapy was used (n = 951) where theatre capacity was reduced. There was increasing access to COVID-19 low-risk theatres during the study period (59%). In line with national guidance, immediate breast reconstruction was avoided (n = 299). Where adjuvant chemotherapy was omitted (n = 81), the median benefit was only 3% (IQR 2–9%) using ‘NHS Predict’. There was the rapid adoption of new evidence-based hypofractionated radiotherapy (n = 781, from 46 units). Only 14 patients (1%) tested positive for SARS-CoV-2 during their treatment journey.Conclusions The majority of ‘COVID-altered’ management decisions were largely in line with pre-COVID evidence-based guidelines, implying that breast cancer survival outcomes are unlikely to be negatively impacted by the pandemic. However, in this study, the potential impact of delays to BC presentation or diagnosis remains unknown.Subject terms: Breast cancer, Surgical oncology, Health care economics, Quality of life, Health policy