Multiple sclerosis (MS) is a multifactorial demyelinating disease characterized by neurodegenerative events and autoimmune response against myelin component. Citrullination or deimination, a post-translational modification of protein-bound arginine into citrulline, catalyzed by Ca(2+) dependent peptidylarginine deiminase enzyme (PAD), plays an essential role in physiological processes include gene expression regulation, apoptosis and the plasticity of the central nervous system, while aberrant citrullination can generate new epitopes, thus involving in the initiation and/or progression of autoimmune disorder like MS. Myelin basic protein (MBP) is the major myelin protein and is generally considered to maintain the stability of the myelin sheath. This review describes the MBP citrullination and its consequence, as well as offering further support for the "inside-out" hypothesis that MS is primarily a neurodegenerative disease with secondary inflammatory demyelination. In addition, it discusses the role of MBP citrullination in the immune inflammation and explores the potential of inhibition of PAD enzymes as a therapeutic strategy for the disease.

The main purpose of this study was to build a prediction model for patients with contralateral breast cancer (CBC) using competing risks methodology. The aim is to help clinicians predict the probability of CBC in breast cancer (BC) survivors.We reviewed data from the Surveillance, Epidemiology, and End Results database of 434,065 patients with BC. Eligible patients were used to quantify the association between the development of CBC and multiple characteristics of BC patients using competing risk models. A nomogram was also created to facilitate clinical visualization and analysis. Finally, the stability of the model was verified using concordance index and calibration plots, and decision curve analysis was used to evaluate the clinical utility of the model by calculating the net benefit.Four hundred thirty-four thousand sixty-five patients were identified, of whom 6944 (1.6%) developed CBC in the 10 years followup. The 10-year cumulative risk of developing CBC was 2.69%. According to a multivariate competing risk model, older patients with invasive lobular carcinoma who had undergone unilateral BC surgery, and whose tumor was better differentiated, of smaller size and ER-negative/PR-positive, had a higher risk of CBC. The calibration plots illustrated an acceptable correlation between the prediction by nomogram and actual observation, as the calibration curve was closed to the 45°diagonal line. The concordance index for the nomogram was 0.65, which indicated it was well calibrated for individual risk of CBC. Decision curve analysis produced a wide range of risk thresholds under which the model we built would yield a net benefit.BC survivors remain at high risk of developing CBC. Patients with CBC have a worse clinical prognosis compared to those with unilateral BC. We built a predictive model for the risk of developing CBC based on a large data cohort to help clinicians identify patients at high risk, which can then help them plan individualized surveillance and treatment. Abbreviations: AAPC = average annual percentage change, APC = annual percentage change, BC = breast cancer, BCM = breast-conserving mastectomy, CBC = contralateral breast cancer, C-index = concordance index, CPM = contralateral prophylactic mastectomy, IDC = invasive ductal carcinoma, ILC = invasive lobular carcinoma, PBC = primary breast cancer, SEER = Surveillance, Epidemiology, and End Results Program, ULM = unilateral mastectomy.

Drug resistance is the leading cause for rapid progression and relapse in small‐cell lung cancer (SCLC) patients. Thus overcoming drug resistance still remains to be urgently resolved during SCLC treatment. Here, we found p62/SQSTM1 was enriched in SCLC spheroids, a subpopulation possessing cancer stem‐like properties, which is responsible for cancer relapse and metastasis. Subsequent functional assays in vitro showed that short hairpin RNA (shRNA)‐mediated p62 knockdown increased sensitivity of SCLC cell lines to cisplatin (DDP), whereas lentivirus‐mediated p62 ectopic overexpression diminished DDP‐induced cytotoxicity in both NCI‐H446 and NCI‐H1688 cell lines. Moreover, ectopic p62 overexpression promoted DDP resistance of NCI‐H446 cells‐derived tumor xenografts in immunodeficient mice in vivo, as indicated by accelerated tumor growth rate and reduced fluorescent activity of cleaved caspase‐3. Gene expression profiling analysis revealed that p62 was positively correlated with neuronal precursor cell‐expressed, developmentally downregulated gene 9 (NEDD9) expression level. Consistently, NEDD9 messenger RNA (mRNA) level was decreased upon p62 suppression by small interfering RNA (siRNA) and increased with p62 transient overexpression in SCLC cell lines, suggesting that p62 positively regulated NEDD9 mRNA. Depletion of NEDD9 by siRNA, to a large extent, reversed p62‐overexpressed SCLC cells to DDP‐induced cytotoxicity, implying NEDD9 might act as a downstream target which was in charge of p62‐mediated DDP resistance. Taken together, our findings uncovered a previously unknown role of p62 in the regulation of SCLC drug resistance, assigning p62 as an attractive target for SCLC treatment.

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