Targeting Glioma Stem Cells by Functional Inhibition of a Prosurvival OncomiR-138 in Malignant Gliomas

SummaryMalignant gliomas are the most aggressive forms of brain tumors, associated with high rates of morbidity and mortality. Recurrence and tumorigenesis are attributed to a subpopulation of tumor-initiating glioma stem cells (GSCs) that are intrinsically resistant to therapy. Initiation and progression of gliomas have been linked to alterations in microRNA expression. Here, we report the identification of microRNA-138 (miR-138) as a molecular signature of GSCs and demonstrate a vital role for miR-138 in promoting growth and survival of bona fide tumor-initiating cells with self-renewal potential. Sequence-specific functional inhibition of miR-138 prevents tumorsphere formation in vitro and impedes tumorigenesis in vivo. We delineate the components of the miR-138 regulatory network by loss-of-function analysis to identify specific regulators of apoptosis. Finally, the higher expression of miR-138 in GSCs compared to non-neoplastic tissue and association with tumor recurrence and survival highlights the clinical significance of miR-138 as a prognostic biomarker and a therapeutic target for treatment of malignant gliomas

A highly efficient green synthesis of 1, 8-dioxo-octahydroxanthenes

SmCl3 (20 mol%) has been used as an efficient catalyst for reaction between aromatic aldehydes and 5,5-dimethyl-1,3-cyclohexanedione at 120°C to give 1,8-dioxo-octahydroxanthene derivatives in high yield. The same reaction in water, at room temperature gave only the open chain analogue of 1,8-dioxo-octahydroxanthene. Use of eco-friendly green Lewis acid, readily available catalyst and easy isolation of the product makes this a convenient method for the synthesis of either of the products

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Dietary non-coding RNAs from plants: Fairy tale or treasure?

The past two decades have witnessed soaring interest in the field of non-coding RNAs, largely attributed by its regulatory role in controlling two third of human transcriptional output. Though, there are several classes of non-coding RNAs found in nature, microRNAs takes the central stage because of their pleiotropic roles. In particular, extracellular microRNAs are gaining traction due to their relative stability and bio availability. Extracellular microRNAs has been shown to occur in all living organisms, including dietary plants. Some of the recent reports suggest that these dietary microRNAs pass through the gut, enter systemic circulation and exert biological effects on animal physiology. However, evidences against this hypothesis are also presented in literature and hence this area has been strongly debated. In this review, I will briefly summarise the evidences accumulated for and against this hypothesis and discuss potential implications of such findings in human health. Keywords: Dietary non-coding RNAs, microRNAs and edible nanoparticle

Computer simulation of intracranial hemodynamics during the induction phase of anesthesia

The induction of general anesthesia is associated with severe hemodynamic compromises which, in turn, may cause acute elevation of intracranial pressure (ICP). Quantitative assessment of cerebrovascular responses arising from multiple mechanical and pharmacological interventions occurring in a short time interval require a large number of human studies which are difficult to perform. The purpose of this project is to evaluate the effect of various stimuli on the intracranial hemodynamics during induction using a mathematical model of cerebrovascular circulation. A five compartmental model of the cerebrovascular system is used for our simulation. Autoregulation is modeled by adjusting arterial-arteriolar resistance in order to change the flow towards its control value. The effect of thiopental on cerebrovascular circulation is simulated by a variable arteriolar resistance which is functionally dependent on the thiopental concentration. Thiopental concentration, in turn, is predicted by a three compartmental pharmacokinetic model. The simulation program was written in TUTSIM dynamic simulation language for an IBM compatible PC. The presented computer simulation permits development of an optimal drug administration schedule to control ICP during various phases of anesthesia. It was demonstrated that if the time interval between the administration of a drug and intubation is more than 2 minutes, an additional dose of thiopental is required to prevent elevation of ICP during laryngoscopy

Carcinoma Cells Reprogram a Wound-healing Switch to Promote Metastasis

Wound healing is a dynamic event where barrier disruption is transient and miR-198/FSTL1 molecular switch orchestrate wound re-epithelialization. However, epithelial carcinomas maintain a prolonged wound-healing phase to promote malignant transformation. Delineating the molecular mechanism we demonstrate, how epidermal growth factor (EGF) hijacks the wound-healing switch to promote metastasis of carcinoma

Performance, emission and combustion characteristics of a branched higher mass, C3 alcohol (isopropanol) blends fuelled medium duty MPFI SI engine

With growing concerns about environmental pollution caused by automobiles, biofuels containing oxygen – also known as oxygenates – are being researched very rigorously. In this article, we have inspected the use of isopropanol/gasoline blends, as fuel in a 4 – cylinder Spark Ignition engine with Multi-Point Fuel Injection System. Isopropanol was mixed with Unleaded Gasoline in proportions of 10, 20 and 30% by volume (IPA10, IPA20 and IPA30). It is found that with the use of isopropanol/gasoline blends in Spark Ignition Engine, Brake Thermal Efficiency and NOx emissions increased whereas carbon monoxide and hydrocarbon emissions decreased. When the spark timing was retarded by 2 degrees, it was found that isopropanol/gasoline blends emitted lower NOx emissions than those at original spark timing. Isopropanol blends also increased the in-cylinder pressure values and heat release rate values