Novel role for CRK adaptor proteins as essential components of SRC/FAK signaling for epithelial–mesenchymal transition and colorectal cancer aggressiveness

Epithelial–mesenchymal transition (EMT) is a cell plasticity process required for metastasis and chemoresistance of carcinoma cells. We report a crucial role of the signal adaptor proteins CRK and CRKL in promoting EMT and tumor aggressiveness, as well as resistance against chemotherapy in colorectal and pancreatic carcinoma. Genetic loss of either CRKL or CRK partially counteracted EMT in three independent cancer cell lines. Strikingly, complete loss of the CRK family shifted cells strongly toward the epithelial phenotype. Cells exhibited greatly increased E-cadherin and grew as large, densely packed clusters, completely lacked invasiveness and the ability to undergo EMT induced by cytokines or genetic activation of SRC. Furthermore, CRK family-deficiency significantly reduced cell survival, proliferation and chemoresistance, as well as ERK1/2 phosphorylation and c-MYC protein levels. In accordance, MYC-target gene expression was identified as novel hallmark process positively regulated by CRK family proteins. Mechanistically, CRK proteins were identified as pivotal amplifiers of SRC/FAK signaling at focal adhesions, mediated through a novel positive feedback loop depending on RAP1. Expression of the CRK family and the EMT regulator ZEB1 was significantly correlated in samples from colorectal cancer patients, especially in invasive regions. Further, high expression of CRK family genes was significantly associated with reduced survival in locally advanced colorectal cancer, as well as in pan-cancer datasets from the TCGA project. Thus, CRK family adaptor proteins are promising therapeutic targets to counteract EMT, chemoresistance, metastasis formation and minimal residual disease. As proof of concept, CRK family-mediated oncogenic signaling was successfully inhibited by a peptide-based inhibitor.     

Estimated pulse wave velocity (ePWV) as a potential gatekeeper for MRI-assessed PWV: a linear and deep neural network based approach in 2254 participants of the Netherlands Epidemiology of Obesity study

The International Journal of Cardiovascular Imaging - Pulse wave velocity (PWV) assessed by magnetic resonance imaging (MRI) is a prognostic marker for cardiovascular events. Prediction modelling...     

Molecular characterization of human prostate carcinoma cell lines

BACKGROUND: This study presents a comprehensive survey and characterization of available prostate carcinoma cell lines, most of which have been widely used but are incompletely characterized. METHODS: A total of 21 cell lines were investigated, including three "classical" (DU 145, LNCaP, and PC-3) and 18 "non-classical" lines (1013L, 22Rv1, ALVA-55, ALVA-101, ARCaP, CWR-R1, DuCaP, DuPro-1, LAPC-4, MDA PCa 1, MDA PCa 2a, MDA PCa 2b, NCI-H660, PC-346C, PC-93, PSK-1, UM-SCP-1, and VCaP). Cytogenetics, DNA profiling, expression of basal, luminal, and neuroendocrine differentiation markers, and mutation analyses of the TP53 and androgen receptor (AR) genes were performed. RESULTS: Based on cytogenetics and DNA profiling analyses, out of the 18 "non-classical" lines, six were confirmed to be unique, eight (in four pairs) were confirmed to be related in origin, and four lines were identified as cross-contaminants. Of this latter group, PC-93 was found to be a derivative of HeLa, whereas DuPro-1, ALVA-55, and ALVA-101 were derivatives of PC-3. The 17 genuine prostate cell lines expressed keratin 8 (K8) and K18. Nine showed AR expression, of which five harbored mutations in the AR gene. Prostate-specific antigen and DD3 were exclusively detected in AR expressing cell lines. Seven lines expressed the basal cell marker K5, three of these lines showed co-expression of AR. CONCLUSIONS: This study defines a collection of 17 genuine prostate carcinoma cell lines. This collection, although small, constitutes a variety of different types and stages of prostate cancer, while it also partly reflects the heterogeneous nature of this malignancy.     

新型青光眼引流装置——Paul青光眼植入物在印度尼西亚人群中应用的早期经验

目的：探究Paul青光眼植入物(PGI)在短期随访期间的安全性和有效性，分享新型房水引流装置在印度尼西亚人群中应用的首次经验。

方法：回顾性分析2022-04/2022-12期间使用PGI植入物的患者21例22眼，随访至少2mo。主要结局指标为手术失败，定义为眼压(IOP)超过21mmHg，或连续2次就诊较基线水平降低小于20%，需行其他青光眼手术或移除植入物。

结果：纳入患者的随访时间为2-6mo，平均IOP降低52.27±22.94%(9-90)%，总体成功率为59%，有青光眼手术史和未接受过青光眼手术的患者手术完全成功率分别为50%和59%。并发症有复视(2例)、早期低眼压(1例)、前房积血(1例)及引流管暴露(2例)。

结论：植入PGI的完全成功率为57%。未发生严重术后并发症，低眼压术后早期消退1例。