Cyclooxygenase/lipoxygenase shunting lowers the anti-cancer effect of cyclooxygenase-2 inhibition in colorectal cancer cells

BACKGROUND: Arachidonic acid metabolite, generated by cyclooxygenase (COX), is implicated in the colorectal cancer (CRC) pathogenesis. Inhibiting COX may therefore have anti-carcinogenic effects. Results from use of non-steroidal anti-inflammatory drugs inhibiting only COX have been conflicting. It has been postulated that this might result from the shunting of arachidonic acid metabolism to the 5-lipoxygenase (5-LOX) pathway. Cancer cell viability is promoted by 5-LOX through several mechanisms that are similar to those of cyclooxygenase-2 (COX-2). Expression of 5-LOX is upregulated in colorectal adenoma and cancer. The aim of this study was to investigate the shunting of arachidonic acid metabolism to the 5-LOX pathway by cyclooxygenase inhibition and to determine if this process antagonizes the anti-cancer effect in colorectal cancer cells. METHODS: Three colorectal cancer cell lines (HCA7, HT-29 & LoVo) expressing 5-LOX and different levels of COX-2 expression were used. The effects of aspirin (a non-selective COX inhibitor) and rofecoxib (COX-2 selective) on prostaglandin E(2) (PGE(2)) and leukotriene B(4) (LTB(4)) secretion were quantified by ELISA. Proliferation and viability were studied by quantifying double-stranded DNA (dsDNA) content and metabolic activity. Apoptosis was determined by annexin V and propidium iodide staining using confocal microscopy, and caspase-3/7 activity by fluorescent substrate assay. RESULTS: COX inhibitors suppressed PGE(2) production but enhanced LTB(4) secretion in COX-2 expressing cell lines (P <0.001). The level of COX-2 expression in colorectal cancer cells did not significantly influence the anti-proliferative and pro-apoptotic effects of COX inhibitors due to the shunting mechanism. CONCLUSIONS: This study provides evidence of shunting between COX and 5-LOX pathways in the presence of unilateral inhibition, and may explain the conflicting anti-carcinogenic effects reported with use of COX inhibitors

An empirical study to understand the effectiveness and scope of Blockchain Technology in Indian Public sector

The Blockchain is a distributed database that is maintained as Blocks and contains all transactions or digital occurrences. These are the records of transactions that take place between parties.Blockchain blocks are kept as blocks and shared among participants. Each Block is examined, validated, and saved by the parties who are a part of the system/network, each brick is unique and contains the details of a single transaction as well as the transaction\u27s hash key. The study offers insights to researchers about the opportunity threat and future use of blockchain in the public sector

Circular dichroism of designed peptide helices and β-hairpins: analysis of trp- and tyr-rich peptides

VCD versus ECD spectroscopy. Peptides rich in aromatic residues yield anomalous far-UV electronic circular dichroism (ECD) spectra that preclude secondary structure assignment. The utility of vibrational circular dichroism (VCD) in conformation analysis is demonstrated by using a set of well-defined peptide helices and hairpins containing proximal aromatic residues

Factors associated with preterm delivery and low birth weight: a study from rural Maharashtra, India

Background: Although preterm delivery and low birth weight (LBW) have been studied in India, findings may not be generalisable to rural areas such as the Marathwada region of Maharashtra state. There is limited information available on maternal and child health indicators from this region. We aimed to present some local estimates of preterm delivery and LBW in the Osmanabad district of Marathwada and assess available maternal risk factors. Methods: The study used routinely collected data on all in-hospital births in the maternity department of Halo Medical Foundation’s hospital from 1 (st )January 2008 to 31 (st )December 2014. Multivariable logistic regression analysis provided odds ratios (OR) with 95% confidence intervals (CI) for preterm delivery and LBW according to each maternal risk factor. Results: We analysed 655 live births, of which 6.1% were preterm deliveries. Of the full term births (N=615), 13.8% were LBW (<2.5 kilograms at birth). The odds of preterm delivery were three times higher (OR=3.23, 95% CI 1.36 to 7.65) and the odds of LBW were double (OR=2.03, 95% CI 1.14 to 3.60) among women <22 years of age compared with older women. The odds of both preterm delivery and LBW were reduced in multigravida compared with primigravida women regardless of age. Anaemia (Hb<11g/dl), which was prevalent in 91% of women tested, was not significantly related to these birth outcomes. Conclusions: The odds of preterm delivery and LBW were much higher in mothers under 22 years of age in this rural Indian population. Future studies should explore other related risk factors and the reasons for poor birth outcomes in younger mothers in this population, to inform the design of appropriate public health policies that address this issue

An empirical study to understand the effectiveness and scope of Blockchain Technology in Indian Public sector

The Blockchain is a distributed database that is maintained as Blocks and contains all transactions or digital occurrences. These are the records of transactions that take place between parties.Blockchain blocks are kept as blocks and shared among participants. Each Block is examined, validated, and saved by the parties who are a part of the system/network, each brick is unique and contains the details of a single transaction as well as the transaction\u27s hash key. The study offers insights to researchers about the opportunity threat and future use of blockchain in the public sector

Cholesterol accessibility at the ciliary membrane controls hedgehog signaling

Previously we proposed that transmission of the hedgehog signal across the plasma membrane by Smoothened is triggered by its interaction with cholesterol (Luchetti et al., 2016). But how is cholesterol, an abundant lipid, regulated tightly enough to control a signaling system that can cause birth defects and cancer? Using toxin-based sensors that distinguish between distinct pools of cholesterol, we find that Smoothened activation and Hedgehog signaling are driven by a biochemically-defined, small fraction of membrane cholesterol, termed accessible cholesterol. Increasing cholesterol accessibility by depletion of sphingomyelin, which sequesters cholesterol in complexes, amplifies Hedgehog signaling. Hedgehog ligands increase cholesterol accessibility in the membrane of the primary cilium by inactivating the transporter-like protein Patched 1. Trapping this accessible cholesterol blocks Hedgehog signal transmission across the membrane. Our work shows that the organization of cholesterol in the ciliary membrane can be modified by extracellular ligands to control the activity of cilia-localized signaling proteins

Clinical Outcomes With a Repositionable Self-Expanding Transcatheter Aortic Valve Prosthesis: The International FORWARD Study

Background Clinical outcomes in large patient populations from real-world clinical practice with a next-generation self-expanding transcatheter aortic valve are lacking. Objectives This study sought to document the clinical and device performance outcomes of transcatheter aortic valve replacement (TAVR) with a next-generation, self-expanding transcatheter heart valve (THV) system in patients with severe symptomatic aortic stenosis (AS) in routine clinical practice. Methods The FORWARD (CoreValve Evolut R FORWARD) study is a prospective, single-arm, multinational, multicenter, observational study. An independent clinical events committee adjudicated safety endpoints based on Valve Academic Research Consortium-2 definitions. An independent echocardiographic core laboratory evaluated all echocardiograms. From January 2016 to December 2016, TAVR with the next-generation self-expanding THV was attempted in 1,038 patients with symptomatic, severe AS at 53 centers on 4 continents. Results Mean age was 81.8 ± 6.2 years, 64.9% were women, the mean Society of Thoracic Surgeons Predicted Risk of Mortality was 5.5 ± 4.5%, and 33.9% of patients were deemed frail. The repositioning feature of the THV was applied in 25.8% of patients. A single valve was implanted in the proper anatomic location in 98.9% of patients. The mean aortic valve gradient was 8.5 ± 5.6 mm Hg, and moderate or severe aortic regurgitation was 1.9% at discharge. All-cause mortality was 1.9%, and disabling stroke occurred in 1.8% at 30 days. The expected-to-observed early surgical mortality ratio was 0.35. A pacemaker was implanted in 17.5% of patients. Conclusions TAVR using the next-generation THV is clinically safe and effective for treating older patients with severe AS at increased operative risk. (CoreValve Evolut R FORWARD Study [FORWARD]; NCT02592369

Global, regional, and national burden of disorders affecting the nervous system, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND: Disorders affecting the nervous system are diverse and include neurodevelopmental disorders, late-life neurodegeneration, and newly emergent conditions, such as cognitive impairment following COVID-19. Previous publications from the Global Burden of Disease, Injuries, and Risk Factor Study estimated the burden of 15 neurological conditions in 2015 and 2016, but these analyses did not include neurodevelopmental disorders, as defined by the International Classification of Diseases (ICD)-11, or a subset of cases of congenital, neonatal, and infectious conditions that cause neurological damage. Here, we estimate nervous system health loss caused by 37 unique conditions and their associated risk factors globally, regionally, and nationally from 1990 to 2021. METHODS: We estimated mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs), with corresponding 95% uncertainty intervals (UIs), by age and sex in 204 countries and territories, from 1990 to 2021. We included morbidity and deaths due to neurological conditions, for which health loss is directly due to damage to the CNS or peripheral nervous system. We also isolated neurological health loss from conditions for which nervous system morbidity is a consequence, but not the primary feature, including a subset of congenital conditions (ie, chromosomal anomalies and congenital birth defects), neonatal conditions (ie, jaundice, preterm birth, and sepsis), infectious diseases (ie, COVID-19, cystic echinococcosis, malaria, syphilis, and Zika virus disease), and diabetic neuropathy. By conducting a sequela-level analysis of the health outcomes for these conditions, only cases where nervous system damage occurred were included, and YLDs were recalculated to isolate the non-fatal burden directly attributable to nervous system health loss. A comorbidity correction was used to calculate total prevalence of all conditions that affect the nervous system combined. FINDINGS: Globally, the 37 conditions affecting the nervous system were collectively ranked as the leading group cause of DALYs in 2021 (443 million, 95% UI 378–521), affecting 3·40 billion (3·20–3·62) individuals (43·1%, 40·5–45·9 of the global population); global DALY counts attributed to these conditions increased by 18·2% (8·7–26·7) between 1990 and 2021. Age-standardised rates of deaths per 100 000 people attributed to these conditions decreased from 1990 to 2021 by 33·6% (27·6–38·8), and age-standardised rates of DALYs attributed to these conditions decreased by 27·0% (21·5–32·4). Age-standardised prevalence was almost stable, with a change of 1·5% (0·7–2·4). The ten conditions with the highest age-standardised DALYs in 2021 were stroke, neonatal encephalopathy, migraine, Alzheimer's disease and other dementias, diabetic neuropathy, meningitis, epilepsy, neurological complications due to preterm birth, autism spectrum disorder, and nervous system cancer. INTERPRETATION: As the leading cause of overall disease burden in the world, with increasing global DALY counts, effective prevention, treatment, and rehabilitation strategies for disorders affecting the nervous system are needed