Twisted Epithelial-to-Mesenchymal Transition Promotes Progression of Surviving Bladder Cancer T24 Cells with hTERT-Dysfunction

Human cancer cells maintain telomeres to protect cells from senescence through telomerase activity (TA) or alternative lengthening of telomeres (ALT) in different cell types. Moreover, cellular senescence can be bypassed by Epithelial-to-mesenchymal transition (EMT) during cancer progression in diverse solid tumors. However, it has not been elucidated the characteristics of telomere maintenance and progression ability after long-term culture in bladder cancer T24 cells with hTERT dysfunction.In this study, by using a dominant negative mutant human telomerase reverse transcriptase (hTERT) vector to inhibit TA in bladder cancer T24 cells, we observed the appearance of long phenotype of telomere length and the ALT-associated PML body (APB) complex after the 27(th) passage, indicating the occurrence of ALT-like pathway in surviving T24/DN868A cells with telomerase inhibition. Meanwhile, telomerase inhibition resulted in significant EMT as shown by change in cellular morphology concomitant with variation of EMT markers. Consistently, the surviving T24/DN868A cells showed increased progression ability in vitro and in vivo. In addition, we found Twist was activated to mediate EMT in surviving T24/DN868A samples.Taken together, our findings indicate that bladder cancer T24 cells may undergo the telomerase-to-ALT-like conversion and promote cancer progression at advanced stages through promoting EMT, thus providing novel possible insight into the mechanism of resistance to telomerase inhibitors in cancer treatment

Psychometric properties of the Children’s Revised Impact of Events Scale (CRIES) with Bangladeshi children and adolescents

Identification of possible cases suffering post-traumatic stress disorder (PTSD) is important, especially in developing countries where traumatic events are typically prevalent. The Children’s Revised Impact of Events Scale is a reliable and valid measure that has two brief versions (13 items and 8 items) to assess reactions to traumatic events among young people. The current study evaluated the psychometric properties of both versions of the CRIES in a sample of 1,342 children and adolescents aged 9–17 years (M = 12.3 years, SD = 2.12) recruited from six districts of Bangladesh. A sub-group of 120 children from four schools was re-tested on the measures within 3.5 weeks. Confirmatory factor analysis supported factor structures similar to those found in other studies for both versions of the CRIES. Multiple group confirmatory factor analysis showed gender and age-group differences within the sample, supporting established age and gender differences in prevalence of PTSD symptoms. Analyses also indicated moderate to excellent internal consistency and test-retest reliability and clear discriminant and convergent validity. These data support use of both the CRIES-13 and CRIES-8 to provide quick and psychometrically sound assessment of symptoms of PTSD among children and adolescents from Bangla-speaking communities

A rapid VEGF-gene-sequence photoluminescence detector for osteoarthritis

Osteoarthritis (OA) has become a serious problem to the human society for years due to its high economic burden, disability, pain, and severe impact on the patient’s lifestyle. The importance of current clinical imaging modalities in the assessment of the onset and progression of OA is well recognized by clinicians, but these modalities can only detect OA in the II stage with significant structural deterioration and clinical symptoms. Blood vessel formation induced by vascular endothelial growth factor (VEGF) occurs in the early stage and throughout the entire course of OA, enables VEGF relating gene sequence to act as a biomarker in the field of early diagnosis and monitoring of the disease. Here in, a facile rapid detection of VEGF relating ssDNA sequence was developed, in which manganese-based zeolitic imidazolate framework nanoparticles (Mn-ZIF-NPs) were synthesized by a simple coprecipitation strategy, followed by the introduction and surficial absorption of probe ssDNAs and the CRISPR/Cas12a system components. Furthermore, fluorescence experiments demonstrated that the biosensor displayed a low detection limit of 2.49 nM, a good linear response to the target ssDNA ranging from 10 nM to 500 nM, and the ability of distinguishing single nucleotide polymorphism. This finding opens a new window for the feasible and rapid detection of ssDNA molecules for the early diagnose of OA

Woods and Russell, Hill, and the emergence of medical statistics

In 1937, Austin Bradford Hill wrote Principles of Medical Statistics (Lancet: London, 1937) that became renowned throughout the world and is widely associated with the birth of modern medical statistics. Some 6 years earlier Hilda Mary Woods and William Thomas Russell, colleagues of Hill at the London School of Hygiene and Tropical Medicine, wrote a similar book An Introduction to Medical Statistics (PS King and Son: London, 1931) that is little known today. We trace the origins of these two books from the foundations of early demography and vital statistics, and make a detailed examination of some of their chapters. It is clear that these texts mark a watershed in the history of medical statistics that demarcates the vital statistics of the nineteenth and early twentieth centuries from the modern discipline. Moreover, we consider that the book by Woods and Russell is of some importance in the development of medical statistics and we describe and acknowledge their place in the history of this discipline. Copyright © 2010 John Wiley & Sons, Ltd

Targeting the BRD4/FOXO3a/CDK6 Axis Sensitizes AKT Inhibition in Luminal Breast Cancer

BRD4 assembles transcriptional machinery at gene super-enhancer regions and governs the expression of genes that are critical for cancer progression. However, it remains unclear whether BRD4-mediated gene transcription is required for tumor cells to develop drug resistance. Our data show that prolonged treatment of luminal breast cancer cells with AKT inhibitors induces FOXO3a dephosphorylation, nuclear translocation, and disrupts its association with SirT6, eventually leading to FOXO3a acetylation as well as BRD4 recognition. Acetylated FOXO3a recognizes the BD2 domain of BRD4, recruits the BRD4/RNAPII complex to the CDK6 gene promoter, and induces its transcription. Pharmacological inhibition of either BRD4/FOXO3a association or CDK6 significantly overcomes the resistance of luminal breast cancer cells to AKT inhibitors in vitro and in vivo. Our study reports the involvement of BRD4/FOXO3a/CDK6 axis in AKTi resistance and provides potential therapeutic strategies for treating resistant breast cancer