Development of an engineered extracellular vesicles-based vaccine platform for combined delivery of mRNA and protein to induce functional immunity.

mRNA incorporated in lipid nanoparticles (LNPs) became a new class of vaccine modality for induction of immunity against COVID-19 and ushered in a new era in vaccine development. Here, we report a novel, easy-to-execute, and cost effective engineered extracellular vesicles (EVs)-based combined mRNA and protein vaccine platform (EV vaccine) and explore its utility in proof-of-concept immunity studies in the settings of cancer and infectious disease. As a first example, we engineered EVs, natural nanoparticle carriers shed by all cells, to contain ovalbumin mRNA and protein (EV vaccine) to serve as cancer vaccine against ovalbumin-expressing melanoma tumors.

Type I conventional dendritic cells facilitate immunotherapy in pancreatic cancer.

Inflammation and tissue damage associated with pancreatitis can precede or occur concurrently with pancreatic ductal adenocarcinoma (PDAC). We demonstrate that in PDAC coupled with pancreatitis (ptPDAC), antigen-presenting type I conventional dendritic cells (cDC1s) are specifically activated. Immune checkpoint blockade therapy (iCBT) leads to cytotoxic CD8 T cell activation and elimination of ptPDAC with restoration of life span even upon PDAC rechallenge.

Mouse Models to Evaluate the Functional Role of the Tumor Microenvironment in Cancer Progression and Therapy Responses.

The tumor microenvironment (TME) is a complex ecosystem of both cellular and noncellular components that functions to impact the evolution of cancer. Various aspects of the TME have been targeted for the control of cancer; however, TME composition is dynamic, with the overall abundance of immune cells, endothelial cells (ECs), fibroblasts, and extracellular matrix (ECM) as well as subsets of TME components changing at different stages of progression and in response to therapy. To effectively treat cancer, an understanding of the functional role of the TME is needed.

Elimination of oncogenic KRAS in genetic mouse models eradicates pancreatic cancer by inducing FAS-dependent apoptosis by CD8 T cells.

Oncogenic KRAS (KRAS) is critical for the initiation and maintenance of pancreatic ductal adenocarcinoma (PDAC) and is a known repressor of tumor immunity. Conditional elimination of KRAS in genetic mouse models of PDAC leads to the reactivation of FAS, CD8 T cell-mediated apoptosis, and complete eradication of tumors. KRAS elimination recruits activated CD4 and CD8 T cells and promotes the activation of antigen-presenting cells.

KRAS inhibition reprograms the microenvironment of early and advanced pancreatic cancer to promote FAS-mediated killing by CD8 T cells.

The KRAS mutation is present in nearly half of pancreatic adenocarcinomas (PDAC). We investigated the effects of inhibiting the KRAS mutant protein with MRTX1133, a non-covalent small molecule inhibitor of KRAS, on early and advanced PDAC and its influence on the tumor microenvironment. Employing 16 different models of KRAS-driven PDAC, we demonstrate that MRTX1133 reverses early PDAC growth, increases intratumoral CD8 effector T cells, decreases myeloid infiltration, and reprograms cancer-associated fibroblasts.

Outcomes of neonatal critical congenital heart disease: results of a prospective registry-based study from South India.

Objectives: Congenital heart disease (CHD) is now a leading contributor of infant and neonatal mortality in many low/middle-income countries including India. We established a prospective neonatal heart disease registry in Kerala to understand presentation of CHD, proportion of newborns with critical defects who receive timely intervention, outcomes at 1 month, predictors of mortality and barriers to timely management.

Methods: The congenital heart disease registry for newborns (≤28 days) in Kerala (CHRONIK) was a prospective hospital-based registry involving 47 hospitals from 1 June 2018 to 31 May 2019.

Study of atrial arrhythmias after surgical or device closure of atrial septal defect.

Background Device closure of atrial septal defect (ASD) has emerged as a treatment modality for the past 3 decades and has changed the natural history of ASD compared to that of surgical closure. Early intervention in ASD retards the geometrical and electrical remodelling of the atrium that contributes to the development of atrial tachyarrhythmias. We studied the incidence of atrial arrhythmias in patients undergoing surgical and device closure of ASD.

Evaluation of ELISA BP180 and BP230 Autoantibodies in Blister Fluid and Serum in the Diagnosis of Bullous Pemphigoid.

Bullous pemphigoid (BP) is a chronic subepidermal immunobullous disorder. Studies have demonstrated the presence of antibasement membrane zone antibodies (BP180 & BP230) in the blister fluid using enzyme-linked immunosorbent assay (ELISA). To detect and compare BP 180 and BP 230 autoantibodies in the blister fluid and serum of patients with BP by ELISA method.

Antigen-presenting type-I conventional dendritic cells facilitate curative checkpoint blockade immunotherapy in pancreatic cancer.

Inflammation and tissue damage associated with pancreatitis can precede or occur concurrently with pancreatic ductal adenocarcinoma (PDAC). We demonstrate that in PDAC coupled with pancreatitis (ptPDAC), antigen-presenting type-I conventional dendritic cells (cDC1s) are specifically activated. Immune checkpoint blockade therapy (iCBT) leads to cytotoxic CD8 T cell activation and eradication of ptPDAC with restoration of lifespan even upon PDAC re-challenge.

Oncogenic Kras specific non-covalent inhibitor reprograms tumor microenvironment to prevent and reverse early pre-neoplastic pancreatic lesions and in combination with immunotherapy regresses advanced PDAC in a CD8 T cells dependent manner.

Pancreatic ductal adenocarcinoma (PDAC) is associated with mutations in Kras, a known oncogenic driver of PDAC; and the mutation is present in nearly half of PDAC patients. Recently, a non-covalent small molecule inhibitor (MRTX1133) was identified with specificity to the Kras mutant protein. Here we explore the impact of Kras inhibition by MRTX1133 on advanced PDAC and its influence on the tumor microenvironment.

Uncloaking cell-impermeant gold nanorods via tumor microenvironmental cathepsin B facilitates cancer cell penetration and potent radiosensitization.

Major impediments to conveyance of intravenously administered drugs to tumors are biofouling, opsonization, and rapid clearance from the circulation by macrophages and reticuloendothelial phagocytes. Cloaking nanoparticles with stealth epilayers partly overcomes these hurdles but it also foils interactions with tumor cells. Here, we describe the synthesis, characterization, and validation of smart gold nanorods (GNRs) that spontaneously transform from inert passengers in the blood stream to active cell-penetrating nanoparticles within tumors to potently sensitize tumors to radiation therapy.

Oncogenic collagen I homotrimers from cancer cells bind to α3β1 integrin and impact tumor microbiome and immunity to promote pancreatic cancer.

In contrast to normal type I collagen (Col1) heterotrimer (α1/α2/α1) produced by fibroblasts, pancreatic cancer cells specifically produce unique Col1 homotrimer (α1/α1/α1). Col1 homotrimer results from epigenetic suppression of the Col1a2 gene and promotes oncogenic signaling, cancer cell proliferation, tumor organoid formation, and growth via α3β1 integrin on cancer cells, associated with tumor microbiome enriched in anaerobic Bacteroidales in hypoxic and immunosuppressive tumors. Deletion of Col1 homotrimers increases overall survival of mice with pancreatic ductal adenocarcinoma (PDAC), associated with reprograming of the tumor microbiome with increased microaerophilic Campylobacterales, which can be reversed with broad-spectrum antibiotics.

Confounders and co-interventions identified in non-randomized studies of interventions.

Objectives: To identify potential confounders and co-interventions systematically to optimise control of confounding for three non-randomized studies of interventions (NRSI) designed to quantify bleeding in populations exposed to different dual antiplatelet therapy (DAPT).

Study Design And Setting: Systematic review, interviews, and surveys with clinicians. We searched Ovid Medline, Ovid Embase, and the Cochrane Library to identify randomized-controlled trials and cohort studies of DAPT interventions.

Impact of paramedic education on door-to-balloon times and appropriate use of the primary PCI pathway in ST-elevation myocardial infarction.

Objective: Evidence supports improved outcomes and reduced mortality with rapid reperfusion through primary percutaneous coronary intervention (PPCI) for ST-elevation myocardial infarction (STEMI). UK national audit data (Myocardial Ischaemia National Audit Project [MINAP]) demonstrates minor improvements in door-to-balloon times (DTB) of <90 min but increasing call-to-balloon times (CTB). We evaluate the effect of a regional Cardiologist delivered paramedic education programme (PEP) on DTB times and appropriate use of the PPCI pathway.

Antiproliferative, apoptotic, and antimutagenic properties of stem bark and seed fractions of (Roxb.).

Aims: The aim was to compare the anticancer and antimutagenic potency of Polyalthia cerasoides seeds and stem bark.

Aim Of The Study: The aim of this study was to investigate the antiproliferative, apoptotic, antioxidation to DNA, and antimutagenic activity of alcoholic (PS-1 and PS-3) and petroleum ether (PS-2 and PS-4) stem bark and seed fractions of P. cerasoides.

The Impact of Calcium on Chronic Total Occlusion Management.

Coronary artery calcification is prevalent in chronic total occlusions (CTO), particularly in those of longer duration and post-coronary artery bypass. The presence of calcium predicts lower procedural success rates and a higher risk of complications of CTO percutaneous coronary intervention. Adjunctive imaging, including pre-procedural computed tomography and intracoronary imaging, are useful to understand the distribution and morphology of the calcium.

Factors Influencing Stent Failure in Chronic Total Occlusion Coronary Intervention.

Stent failure remains one of the greatest challenges for interventional cardiologists. Despite the evolution to superior second- and third-generation drug-eluting stent designs, increasing use of intracoronary imaging and the adoption of more potent antiplatelet regimens, registries continue to demonstrate a prevalence of stent failure or target lesion revascularisation of 15-20%. Predisposition to stent failure is consistent across both chronic total occlusion (CTO) and non-CTO populations and includes patient-, lesion- and procedure-related factors.

Aggregation induced emission based active conjugated imidazole luminogens for visualization of latent fingerprints and multiple anticounterfeiting applications.

Aggregation-induced emission based organic heterocyclic luminogens bearing conjugated electronic structures showed much attention due to its excellent fluorescence in aggregation state. In this communication, a novel conjugated blue light emitting imidazole molecule is synthesized by one pot multicomponent reaction route is reported for the first time. The prepared molecule exhibits a strong fluorescence in aggregation state with exceptional properties, such as high purity, inexpensive, eco-friendly, large scale production, high photostability, etc.

Transitioning to online learning in higher education: Influence of Awareness of COVID-19 and Self-Efficacy on Perceived Net Benefits and Intention.

The COVID-19 pandemic has disrupted existing educational systems worldwide. Due to lockdowns in several countries, the educational institutions have been directed by governments to move towards online learning. The challenge for educational institutions and faculty members is to assess the influence of various factors that would enable adoption of online learning by students in higher education.

Intravascular lithotripsy for treatment of calcific coronary lesions in ST elevation myocardial infarction.

Aims: To describe the utility and safety of intravascular lithotripsy (IVL) in the setting of primary percutaneous coronary intervention (PCI) for ST elevation myocardial infarction (STEMI).

Methods And Results: We performed a retrospective analysis, across six UK sites of all patients in whom IVL was used for coronary calcium modification of the culprit lesion during primary PCI for STEMI. The 72 patients were included.