Global, regional, and national burden of neurological disorders during 1990-2015 : a systematic analysis for the Global Burden of Disease Study 2015

Background Comparable data on the global and country-specific burden of neurological disorders and their trends are crucial for health-care planning and resource allocation. The Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study provides such information but does not routinely aggregate results that are of interest to clinicians specialising in neurological conditions. In this systematic analysis, we quantified the global disease burden due to neurological disorders in 2015 and its relationship with country development level. Methods We estimated global and country-specific prevalence, mortality, disability-adjusted life-years (DALYs), years of life lost (YLLs), and years lived with disability (YLDs) for various neurological disorders that in the GBD classification have been previously spread across multiple disease groupings. The more inclusive grouping of neurological disorders included stroke, meningitis, encephalitis, tetanus, Alzheimer's disease and other dementias, Parkinson's disease, epilepsy, multiple sclerosis, motor neuron disease, migraine, tension-type headache, medication overuse headache, brain and nervous system cancers, and a residual category of other neurological disorders. We also analysed results based on the Socio-demographic Index (SDI), a compound measure of income per capita, education, and fertility, to identify patterns associated with development and how countries fare against expected outcomes relative to their level of development. Findings Neurological disorders ranked as the leading cause group of DALYs in 2015 (250.7 [95% uncertainty interval (UI) 229.1 to 274.7] million, comprising 10.2% of global DALYs) and the second-leading cause group of deaths (9.4 [9.1 to 9.7] million], comprising 16.8% of global deaths). The most prevalent neurological disorders were tensiontype headache (1505 9 [UI 1337.3 to 1681.6 million cases]), migraine (958.8 [872.1 to 1055.6] million), medication overuse headache (58.5 [50.8 to 67.4 million]), and Alzheimer's disease and other dementias (46.0 [40.2 to 52.7 million]). Between 1990 and 2015, the number of deaths from neurological disorders increased by 36.7%, and the number of DALYs by 7.4%. These increases occurred despite decreases in age-standardised rates of death and DALYs of 26.1% and 29.7%, respectively; stroke and communicable neurological disorders were responsible for most of these decreases. Communicable neurological disorders were the largest cause of DALYs in countries with low SDI. Stroke rates were highest at middle levels of SDI and lowest at the highest SDI. Most of the changes in DALY rates of neurological disorders with development were driven by changes in YLLs. Interpretation Neurological disorders are an important cause of disability and death worldwide. Globally, the burden of neurological disorders has increased substantially over the past 25 years because of expanding population numbers and ageing, despite substantial decreases in mortality rates from stroke and communicable neurological disorders. The number of patients who will need care by clinicians with expertise in neurological conditions will continue to grow in coming decades. Policy makers and health-care providers should be aware of these trends to provide adequate services.Peer reviewe

BMI1, stem cell factor acting as novel serum-biomarker for Caucasian and African-American prostate cancer.

Lack of reliable predictive biomarkers is a stumbling block in the management of prostate cancer (CaP). Prostate-specific antigen (PSA) widely used in clinics has several caveats as a CaP biomarker. African-American CaP patients have poor prognosis than Caucasians, and notably the serum-PSA does not perform well in this group. Further, some men with low serum-PSA remain unnoticed for CaP until they develop disease. Thus, there is a need to identify a reliable diagnostic and predictive biomarker of CaP. Here, we show that BMI1 stem-cell protein is secretory and could be explored for biomarker use in CaP patients.Semi-quantitative analysis of BMI1 was performed in prostatic tissues of TRAMP (autochthonous transgenic mouse model), human CaP patients, and in cell-based models representing normal and different CaP phenotypes in African-American and Caucasian men, by employing immunohistochemistry, immunoblotting and Slot-blotting. Quantitative analysis of BMI1 and PSA were performed in blood and culture-media of siRNA-transfected and non-transfected cells by employing ELISA. BMI1 protein is (i) secreted by CaP cells, (ii) increased in the apical region of epithelial cells and stromal region in prostatic tumors, and (iii) detected in human blood. BMI1 is detectable in blood of CaP patients in an order of increasing tumor stage, exhibit a positive correlation with serum-PSA and importantly is detectable in patients which exhibit low serum-PSA. The clinical significance of BMI1 as a biomarker could be ascertained from observation that CaP cells secrete this protein in higher levels than cells representative of benign prostatic hyperplasia (BPH).BMI1 could be developed as a dual bio-marker (serum and biopsy) for the diagnosis and prognosis of CaP in Caucasian and African-American men. Though compelling these data warrant further investigation in a cohort of African-American patients

DataSheet1_Computational insights into the stereo-selectivity of catechins for the inhibition of the cancer therapeutic target EGFR kinase.pdf

The epidermal growth factor receptor (EGFR) plays a crucial role in regulating cellular growth and survival, and its dysregulation is implicated in various cancers, making it a prime target for cancer therapy. Natural compounds known as catechins have garnered attention as promising anticancer agents. These compounds exert their anticancer effects through diverse mechanisms, primarily by inhibiting receptor tyrosine kinases (RTKs), a protein family that includes the notable member EGFR. Catechins, characterized by two chiral centers and stereoisomerism, demonstrate variations in chemical and physical properties due to differences in the spatial orientation of atoms. Although previous studies have explored the membrane fluidity effects and transport across cellular membranes, the stereo-selectivity of catechins concerning EGFR kinase inhibition remains unexplored. In this study, we investigated the stereo-selectivity of catechins in inhibiting EGFR kinase, both in its wild-type and in the prevalent L858R mutant. Computational analyses indicated that all stereoisomers, including the extensively studied catechin (−)-EGCG, effectively bound within the ATP-binding site, potentially inhibiting EGFR kinase activity. Notably, gallated catechins emerged as superior EGFR inhibitors to their non-gallated counterparts, revealing intriguing binding trends. The top four stereoisomers exhibiting high dock scores and binding energies with wild-type EGFR comprise (−)-CG (−)-GCG (+)-CG, and (−)-EGCG. To assess dynamic behavior and stability, molecular dynamics simulations over 100 ns were conducted for the top-ranked catechin (−)-CG and the widely investigated catechin (−)-EGCG with EGFR kinase. This study enhances our understanding of how the stereoisomeric nature of a drug influences inhibitory potential, providing insights that could guide the selection of specific stereoisomers for improved efficacy inexisting drugs.</p

BMI1 Polycomb Group Protein Acts as a Master Switch for Growth and Death of Tumor Cells: Regulates TCF4-Transcriptional Factor-Induced BCL2 Signaling

<div><p>For advanced prostate cancer (CaP), the progression of tumors to the state of chemoresistance and paucity of knowledge about the mechanism of chemoresistance are major stumbling blocks in the management of this disease. Here, we provide compelling evidence that BMI1 polycomb group protein and a stem cell factor plays a crucial role in determining the fate of tumors vis-à-vis chemotherapy. We show that progressive increase in the levels of BMI1 occurs during the progression of CaP disease in humans. We show that BMI1-rich tumor cells are non-responsive to chemotherapy whereas BMI1-silenced tumor cells are responsive to therapy. By employing microarray, ChIP, immunoblot and Luciferase reporter assays, we identified a unique mechanism through which BMI1 rescues tumor cells from chemotherapy. We found that BMI1 regulates (i) activity of TCF4 transcriptional factor and (ii) binding of TCF4 to the promoter region of anti-apoptotic <i>BCL2</i> gene. Notably, an increased TCF4 occupancy on <i>BCL2</i> gene was observed in prostatic tissues exhibiting high BMI1 levels. Using tumor cells other than CaP, we also showed that regulation of TCF4-mediated BCL2 by BMI1 is universal. It is noteworthy that forced expression of BMI1 was observed to drive normal cells to hyperproliferative mode. We show that targeting BMI1 improves the outcome of docetaxel therapy in animal models bearing chemoresistant prostatic tumors. We suggest that BMI1 could be exploited as a potential molecular target for therapeutics to treat chemoresistant tumors.</p></div

(A–B) BMI1 induces TCF4 binding to promoter region of <i>BCL2</i> gene. (C) TCF4 occupancy on <i>BCL2</i> is elevated in malignant prostatic tissues. (D) BMI1 confers chemoresistance to tumors in a mouse model.

<p><b>(A–B)</b> Histogram represents effect of BMI1 expression on TCF4-occupancy on promoter regions of <i>BCL2</i> in PC-3 and HT29 cells as assessed by ChIP assay. <b>(C–D)</b> immunoblot and histogram represents the BMI1 protein expression, and TCF4-occupancy on <i>BCl2 gene</i> in normal and malignant human prostate tissues as assessed by immunoblotting and ChIP assays. Equal loading of proteins was confirmed by ß-actin for immunoblotting. (A–B, D). Each bar represents mean ± SE of three independent experiments. <b>(E–F)</b> The line graph represents average volume of BMI1-overexpressing and BMI1-suppressed tumors as a function of time vis-à-vis docetaxel therapy on in nude mice. <b>(G–H)</b> The line graph shows the number of mice with tumor volumes <1000 mm³ for indicated weeks. Data is represented as mean±SE; * indicates p<0.05.</p

BMI1 protein levels in prostatic tumor tissues of humans and TRAMP transgenic mice.

<p>(<b>A</b>) Photomicrographs represent immunostaining of BMI1 in prostatic tissues of transgenic TRAMP mice. Arrows indicate staining for BMI1. Magnification ×40. (<b>Bi</b>) Photomicrographs show BMI1-positive neoplastic and non-neoplastic regions of prostatic specimens of CaP patients as assessed by immunostaining. Arrows indicate staining for BMI1. Magnification ×40. (<b>Bii</b>) Box plots for BMI1 protein based on score pertain to immunostaining pattern in normal and CaP specimens in stromal region.*, P<0.05; black bar in box, median values.</p

BMI1 confers chemoresistance to tumor cells.

<p>Rate of proliferation and apoptosis in cells were determined by 3[H]thymidine uptake and flow cytometery respectively. <b>(A–D)</b> Histograms represents the rate of proliferation in <b>(A–B)</b> LNCaP and <b>(C–D)</b> PC3 cells harboring varied BMI1 levels and treated with chemotherapeutic agents. Vehicle treated cells served as control. <b>(Ei and Fi)</b> immunoblots represent the levels of BMI1, Cyclin-D1 and BCL2 proteins in docetaxel-resistant, and BMI1-silenced docetaxel-resistant cells. (Eii and Fii) Histograms showing the rate of proliferation in docetaxel-resistant, and BMI1-silenced docetaxel-resistant cells. For immunoblot analyses (Figure Ei and Fi), equal loading of proteins was confirmed by ß-actin. (A–D, Eii and Fii) Each bar represents mean ± SE of three independent experiments, * represents P<0.05. <b>(G–H)</b> represents quantitative estimation of apoptosis in BMI1-silencing chemoresistant cells. The lower right quadrant of the FL1/FL2 plot (Annexin V-FITC) represent early apoptosis and the upper right quadrant (labeled with AnnexinV-FITC and PI) represent late apoptosis.</p

Secretory BMI1 is correlated with its intracellular levels in prostatic tumor cells and is independent of androgen.

<p>(<b>A–F</b>) Figure represents the effect of (A–<b>C</b>) BMI1-silencing and (<b>D–F</b>) BM11-overexpression on the level of secreted BMI1 protein in conditional media of different cells as assessed by ELISA assay. Equal loading of protein was confirmed by reprobing immunoblots for β-actin. Each bar in the histogram represents mean ± SE of 3 independent experiments, *represents P<0.05. (<b>Gi</b>) Figure represents the level of BMI1 protein in androgen (R1881) treated and non-treated CaP cells as assessed by immunoblot analysis. Equal loading of protein was confirmed by reprobing immunoblot for β-actin. (<b>Gii</b>) Histogram showing the densitometry analysis of immunoblots of BMI1. *, P<0.05; black bar in gray box, median values.</p