Bayesian consensus clustering for multivariate longitudinal data

In clinical and epidemiological studies, there is a growing interest in studying the heterogeneity among patients based on longitudinal characteristics to identify subtypes of the study population. Compared to clustering a single longitudinal marker, simultaneously clustering multiple longitudinal markers allow additional information to be incorporated into the clustering process, which reveals co-existing longitudinal patterns and generates deeper biological insight. In the current study, we propose a Bayesian consensus clustering (BCC) model for multivariate longitudinal data. Instead of arriving at a single overall clustering, the proposed model allows each marker to follow marker-specific local clustering and these local clusterings are aggregated to find a global (consensus) clustering. To estimate the posterior distribution of model parameters, a Gibbs sampling algorithm is proposed. We apply our proposed model to the primary biliary cirrhosis study to identify patient subtypes that may be associated with their prognosis. We also perform simulation studies to compare the clustering performance between the proposed model and existing models under several scenarios. The results demonstrate that the proposed BCC model serves as a useful tool for clustering multivariate longitudinal data.     

SHR‐A1403, a novel c‐mesenchymal‐epithelial transition factor (c‐Met) antibody‐drug conjugate,overcomes AZD9291 resistance in non‐small cell lung cancer cells overexpressing c‐Met

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) have been used as the first‐line treatment of non‐small cell lung cancers (NSCLC) harboring EGFR‐activating mutations, but acquired resistance is ubiquitous and needs to be solved urgently. Here, we introduce an effective approach for overcoming resistance to the EGFR‐TKI, AZD9291, in NSCLC cells using SHR‐A1403, a novel c‐mesenchymal‐epithelial transition factor (c‐Met)‐targeting antibody‐drug conjugate (ADC) consisting of an anti‐c‐Met monoclonal antibody (c‐Met mAb) conjugated to a microtubule inhibitor. Resistant cells were established by exposing HCC827 to increasing concentrations of EGFR‐TKI. c‐Met was found to be overexpressed in most resistant cells. AZD9291 resistance was partially restored by combination of AZD9291 and crizotinib only in resistant cells overexpressing phospho‐c‐Met, which synergistically inhibited c‐Met‐mediated phosphorylation of the downstream targets ERK1/2 and AKT. In resistant cells overexpressing c‐Met, neither crizotinib nor c‐Met mAb was able to overcome AZD9291 resistance. In contrast, SHR‐A1403 strongly inhibited proliferation of AZD9291‐resistant HCC827 overexpressing c‐Met, regardless of the levels of c‐Met phosphorylation. SHR‐A1403 bound to resistant cells overexpressing c‐Met was internalized into cells and released associated microtubule inhibitor, resulting in cell‐killing activity that was dependent on c‐Met expression levels only, irrespective of the involvement of c‐Met or EGFR signaling in AZD9291 resistance. Consistent with its activity in vitro, SHR‐A1403 significantly inhibited the growth of AZD9291‐resistant HCC827 tumors and caused tumor regression in vivo. Thus, our findings show that SHR‐A1403 efficiently overcomes AZD9291 resistance in cells overexpressing c‐Met, and further indicate that c‐Met expression level is a biomarker predictive of SHR‐A1403 efficacy.     

NET1 Enhances Proliferation and Chemoresistance in Acute Lymphoblastic Leukemia Cells

Acute lymphoblastic leukemia (ALL) is the most prevalent of pediatric cancers. Neuroepithelial cell-transforming 1 (NET1) has been associated with malignancy in a number of cancers, but the role of NET1 in ALL development is unclear. In the present study, we investigated the effect of NET1 gene in ALL cell proliferation and chemoresistance. We analyzed GEO microarray data comparing bone marrow expression profiles of pediatric B-cell ALL samples and those of age-matched controls. MTT and colony formation assays were performed to analyze cell proliferation. ELISA assays, Western blot analyses, and TUNEL staining were used to detect chemoresistance. We confirmed that NET1 was targeted by miR-206 using Western blot and luciferase reporter assays. We identified NET1 gene as one of the most significantly elevated genes in pediatric B-ALL. MTT and colony formation assays demonstrated that NET1 overexpression increases B-ALL cell proliferation in Nalm-6 cells. ELISA assays, Western blot analyses, and TUNEL staining showed that NET1 contributes to ALL cell doxorubicin resistance, whereas NET1 inhibition reduces resistance. Using the TargetScan database, we found that several microRNAs (miRNAs) were predicted to target NET1, including microRNA-206 (miR- 206), which has been shown to regulate cancer development. To determine whether miR-206 targets NET1 in vitro, we transfected Nalm-6 cells with miR-206 or its inhibitor miR-206-in. Western blot assays showed that miR-206 inhibits NET1 expression and miR-206-in increases NET1 expression. Luciferase assays using wild-type or mutant 3 -untranslated region (3 -UTR) of NET1 confirmed these findings. We ultimately found that miR-206 inhibits B-ALL cell proliferation and chemoresistance induced by NET1. Taken together, our results provide the first evidence that NET1 enhances proliferation and chemoresistance in B-ALL cells and that miR-206 regulates these effects by targeting NET1. This study therefore not only contributes to a greater understanding of the molecular mechanisms underlying B-ALL progression but also opens the possibility for developing curative interventions.     

未来提高胰腺癌临床诊治效果的十大方向

胰腺癌是恶性程度极高的消化系统肿瘤。近10年来, 由于治疗理念的更新和有效治疗方案的普及, 其治疗效果有所提高。然而, 胰腺癌总体疗效仍不尽如人意, 患者5年生存率仍仅为10%左右。如何进一步提高胰腺癌诊治水平, 是未来肿瘤学研究和临床实践的头等大事。作者团队基于既往临床和科研经验, 针对胰腺癌早期预防、早诊早治、分子分型、精准治疗、新药开发、方案联合、手术技术和策略改变、模型建立和数据库开发、传统中医药的创新和治疗理念的突破等, 提出十大热点和未来方向供大家参考。期待未来十年中, 胰腺癌诊治研究有突破性进展, 真正做到"可防可控"。     

治疗性腹腔镜胃癌腹主动脉旁淋巴结清扫术的操作技巧及临床意义

目的探讨治疗性腹腔镜胃癌腹主动脉旁淋巴结清扫术的安全性和有效性。方法回顾性分析2017年1月至2018年12月就诊广东省中医院胃肠外科实施治疗性腹腔镜胃癌腹主动脉旁淋巴结术的6例病人基线资料、术中及术后短期结果。结果6例病人术前经影像学评估均存在第16组淋巴结转移,无其他远处转移,经转化治疗后,均达到部分缓解并顺利完成腹腔镜胃癌D2根治并腹主动脉旁淋巴结清扫术,术中1例因合并胰腺侵犯而联合行胰体尾+脾切除术,无中转开腹、腹腔出血、脏器损伤等并发症发生;中位手术时长482.5(445,510)min;中位淋巴结清扫总数、腹主动脉旁淋巴结(para-aortic lymph nodes,PALN)清扫总数及PALN阳性数目分别为50(16,80)枚、18(3,31)枚、3.5(0,15)枚,其中5例PALN病理阳性,1例阴性;术后1例出现胰瘘,1例胸腔积液,1例腹泻,Clavien-Dindo分级均为2级,经对症治疗后均好转出院;术后中位住院时间17(6,30)天,术后30天内无二次手术及死亡发生;中位随访时间13.25(10~18)月,3例病人因肿瘤复发死亡,术后存活时间10~18月,余3例均未见肿瘤复发转移。结论治疗性腹腔镜腹主动脉旁淋巴结清扫术在技术上是可行的,对于胃癌合并PALN转移的患者。     

The elevation of the mucosal flap without additional anterior canal wall incisions for repairing anterior perforations using endoscopic cartilage tympanoplasty

European Archives of Oto-Rhino-Laryngology -