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69 [5.73, 37.65]. Furthermore, the aberrant expression rates of β-catenin in high-grade and invasive bladder neoplasm tissues were greater than those in low-grade and non-muscle-invasive bladder tissues (P less then 0.05), and the combined ORs were 0.31 [0.23, 0.43] and 0.21 [0.15, 0.29]. Finally, we found through meta-analysis that the higher the expression level of β-catenin, the shorter was the progression-free survival (PFS) of patients with BC (P less then 0.05), and the combined OR was 2.74 [1.22, 6.14]. The present study suggests that the abnormal expression of β-catenin is associated with aggressive behavior and poor prognosis of BC, and β-catenin may be a molecular marker of the malignant degree and poor prognosis of BC.Tracking DNA double strand break (DSB) repair is paramount for the understanding and therapeutic development of various diseases including cancers. Herein, we describe a multiplexed bioluminescent repair reporter (BLRR) for non-invasive monitoring of DSB repair pathways in living cells and animals. The BLRR approach employs secreted Gaussia and Vargula luciferases to simultaneously detect homology-directed repair (HDR) and non-homologous end joining (NHEJ), respectively. BLRR data are consistent with next-generation sequencing results for reporting HDR (R2 = 0.9722) and NHEJ (R2 = 0.919) events. Moreover, BLRR analysis allows longitudinal tracking of HDR and NHEJ activities in cells, and enables detection of DSB repairs in xenografted tumours in vivo. Using the BLRR system, we observed a significant difference in the efficiency of CRISPR/Cas9-mediated editing with guide RNAs only 1-10 bp apart. Moreover, BLRR analysis detected altered dynamics for DSB repair induced by small-molecule modulators. Finally, we discovered HDR-suppressing functions of anticancer cardiac glycosides in human glioblastomas and glioma cancer stem-like cells via inhibition of DNA repair protein RAD51 homolog 1 (RAD51). The BLRR method provides a highly sensitive platform to simultaneously and longitudinally track HDR and NHEJ dynamics that is sufficiently versatile for elucidating the physiology and therapeutic development of DSB repair.
Primary colorectal cancer (PCRC) is a common digestive tract cancer in the elderly. However, the treatment effect of PCRC is still limited, and the long-term survival rate is low. Therefore, further exploring the pathogenesis of PCRC, and searching for specific molecular targets for diagnosis are the development trends of precise medical treatment, which have important clinical significance.
The public data were downloaded from Gene Expression Omnibus (GEO) database. Verification for repeatability of intra-group data was performed by Pearson's correlation test and principal component analysis. Differentially expressed genes (DEGs) between normal and PCRC were identified, and the protein-protein interaction (PPI) network was constructed. Significant module and hub genes were found in the PPI network. A total of 192 PCRC patients were recruited between 2010 and 2019 from the Fourth Hospital of Hebei Medical University. RT-PCR was used to measure the relative expression of CLCA4 and MS4A12. Furthermore, the study explored the effect of expression of CLCA4 and MS4A12 for overall survival.
A total of 53 DEGs were identified between PCRC and normal colorectal tissues. Ten hub genes concerned to PCRC were screened, namely CLCA4, GUCA2A, GCG, SST, MS4A12, PLP1, CHGA, PYY, VIP, and GUCA2B. The PCRC patients with low expression of CLCA4 and MS4A12 has a worse overall survival than high expression of CLCA4 and MS4A12 (P<0.05).
The research of DEGs in PCRC (53 DEGs, 10 hub genes, especially CLCA4 and MS4A12) and related signaling pathways is conducive to the differential analysis of the molecular mechanism of PCRC.
The research of DEGs in PCRC (53 DEGs, 10 hub genes, especially CLCA4 and MS4A12) and related signaling pathways is conducive to the differential analysis of the molecular mechanism of PCRC.FANCJ, a DNA helicase and interacting partner of the tumor suppressor BRCA1, is crucial for the repair of DNA interstrand crosslinks (ICL), a highly toxic lesion that leads to chromosomal instability and perturbs normal transcription. In diploid cells, FANCJ is believed to operate in homologous recombination (HR) repair of DNA double-strand breaks (DSB); however, its precise role and molecular mechanism is poorly understood. Moreover, compensatory mechanisms of ICL resistance when FANCJ is deficient have not been explored. In this work, we conducted a siRNA screen to identify genes of the DNA damage response/DNA repair regime that when acutely depleted sensitize FANCJ CRISPR knockout cells to a low concentration of the DNA cross-linking agent mitomycin C (MMC). One of the top hits from the screen was RAP80, a protein that recruits repair machinery to broken DNA ends and regulates DNA end-processing. Concomitant loss of FANCJ and RAP80 not only accentuates DNA damage levels in human cells but also adversely affects the cell cycle checkpoint, resulting in profound chromosomal instability. Genetic complementation experiments demonstrated that both FANCJ's catalytic activity and interaction with BRCA1 are important for ICL resistance when RAP80 is deficient. The elevated RPA and RAD51 foci in cells co-deficient of FANCJ and RAP80 exposed to MMC are attributed to single-stranded DNA created by Mre11 and CtIP nucleases. Altogether, our cell-based findings together with biochemical studies suggest a critical function of FANCJ to suppress incompletely processed and toxic joint DNA molecules during repair of ICL-induced DNA damage.
Persons with Alzheimer's disease (AD) are at higher risk of hip fractures (HFs) than general older population and have worse prognosis after HF. Hospital stays after HF have shortened along time. We investigated the association between length of hospital stay after HF and mortality after discharge among persons with AD.
The MEDALZ cohort includes all Finnish community dwellers who received clinically verified AD diagnosis in 2005-2011 (N = 70 718). Patients who experienced first HF after AD diagnosis in 2005‒2015 (n = 6999) were selected. Length of hospital stay for HF was measured as a sum of the consecutive days spent in hospital after HF until discharge. Outcome was defined as death within 30 days after hospital discharge.
Mean of overall length of hospital stay after a HF decreased from 52.6 (SD 62.9) days in 2005 to 19.6 (SD 23.1) days in 2015. learn more Shortest treatment decile (1‒4 days) had the highest risk of death within 30 days after discharge (adjusted hazard ratio [aHR] 2.76; 95% confidence interval [CI] 1.
