In vivo assessment of a single adenine mutation in 5'UTR of Endothelin-1 gene in paediatric cases with severe pulmonary hypertension: an observational study.

Objective: Endothelin-1 plays an important role in the pathogenesis of severe pulmonary hypertension. The + 139 'A', adenine insertion variant in 5'UTR of edn1 gene has been reported to be associated with increased expression of Endothelin-1 in vitro. The aim of present study was to explore the association of this variant with the circulating levels of Endothelin-1 in vivo using archived DNA and plasma samples from 38 paediatric congenital heart disease (cyanotic and acyanotic) patients with severe pulmonary hypertension.

The Small Molecule BC-2059 Inhibits Wingless/Integrated (Wnt)-Dependent Gene Transcription in Cancer through Disruption of the Transducin -Like 1--Catenin Protein Complex.

The central role of -catenin in the Wnt pathway makes it an attractive therapeutic target for cancers driven by aberrant Wnt signaling. We recently developed a small-molecule inhibitor, BC-2059, that promotes apoptosis by disrupting the -catenin/transducin -like 1 (TBL1) complex through an unknown mechanism of action. In this study, we show that BC-2059 directly interacts with high affinity for TBL1 when in complex with -catenin.

Tumor- and osteoclast-derived NRP2 in prostate cancer bone metastases.

Understanding the role of neuropilin 2 (NRP2) in prostate cancer cells as well as in the bone microenvironment is pivotal in the development of an effective targeted therapy for the treatment of prostate cancer bone metastasis. We observed a significant upregulation of NRP2 in prostate cancer cells metastasized to bone. Here, we report that targeting NRP2 in cancer cells can enhance taxane-based chemotherapy with a better therapeutic outcome in bone metastasis, implicating NRP2 as a promising therapeutic target.

Modeling pancreatic cancer in mice for experimental therapeutics.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy that is characterized by early metastasis, low resectability, high recurrence, and therapy resistance. The experimental mouse models have played a central role in understanding the pathobiology of PDAC and in the preclinical evaluation of various therapeutic modalities. Different mouse models with targetable pathological hallmarks have been developed and employed to address the unique challenges associated with PDAC progression, metastasis, and stromal heterogeneity.

Role of phosphodiesterase 1 in the pathophysiology of diseases and potential therapeutic opportunities.

Cyclic nucleotide phosphodiesterases (PDEs) are superfamily of enzymes that regulate the spatial and temporal relationship of second messenger signaling in the cellular system. Among the 11 different families of PDEs, phosphodiesterase 1 (PDE1) sub-family of enzymes hydrolyze both 3',5'-cyclic adenosine monophosphate (cAMP) and 3',5'-cyclic guanosine monophosphate (cGMP) in a mutually competitive manner. The catalytic activity of PDE1 is stimulated by their binding to Ca/calmodulin (CaM), resulting in the integration of Ca and cyclic nucleotide-mediated signaling in various diseases.

Dual blockade of EGFR and CDK4/6 delays head and neck squamous cell carcinoma progression by inducing metabolic rewiring.

Despite preclinical success, monotherapies targeting EGFR or cyclin D1-CDK4/6 in Head and Neck squamous cell carcinoma (HNSCC) have shown a limited clinical outcome. Here, we aimed to determine the combined effect of palbociclib (CDK4/6) and afatinib (panEGFR) inhibitors as an effective strategy to target HNSCC. Using TCGA-HNSCC co-expression analysis, we found that patients with high EGFR and cyclin D1 expression showed enrichment of gene clusters associated with cell-growth, glycolysis, and epithelial to mesenchymal transition processes.

Mucins reprogram stemness, metabolism and promote chemoresistance during cancer progression.

Mucins are high-molecular-weight glycoproteins dysregulated in aggressive cancers. The role of mucins in disease progression, tumor proliferation, and chemotherapy resistance has been studied extensively. This article provides a comprehensive review of mucin's function as a physical barrier and the implication of mucin overexpression in impeded drug delivery to solid tumors.

Amyloid Precursor-like Protein 2 Expression Increases during Pancreatic Cancer Development and Shortens the Survival of a Spontaneous Mouse Model of Pancreatic Cancer.

In the United States, pancreatic cancer is a major cause of cancer-related deaths. Although substantial efforts have been made to understand pancreatic cancer biology and improve therapeutic efficacy, patients still face a bleak chance of survival. A greater understanding of pancreatic cancer development and the identification of novel treatment targets are desperately needed.

ST6GalNAc-I promotes lung cancer metastasis by altering MUC5AC sialylation.

Lung cancer (LC) is the leading cause of cancer-related mortality. However, the molecular mechanisms associated with the development of metastasis are poorly understood. Understanding the biology of LC metastasis is critical to unveil the molecular mechanisms for designing targeted therapies.

Power Doppler sonography - A supplement to hysteroscopy in abnormal uterine bleeding: Redefining diagnostic strategies.

Background: Abnormal Uterine Bleeding (AUB) is a very frequent cause of gynecological visits in women of all age groups. Ultrasound pelvis with or without endometrial sampling have been conventionally used to make diagnosis. Power Doppler is a comparatively recent modality which can be used to screen patients who will need endometrial biopsy/ curretage.

RNA-based therapies: A cog in the wheel of lung cancer defense.

Lung cancer (LC) is a heterogeneous disease consisting mainly of two subtypes, non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC), and remains the leading cause of death worldwide. Despite recent advances in therapies, the overall 5-year survival rate of LC remains less than 20%. The efficacy of current therapeutic approaches is compromised by inherent or acquired drug-resistance and severe off-target effects.

Which one restores in vivo knee kinematics effectively-medial or lateral pivot?

Introduction: Total knee arthroplasty (TKA) usually provides good pain relief and improved function but has generally been unable to fully restore normal knee kinematics. Does Medial or Lateral Pivot TKA designs guide us to native knee kinematics needs to be elucidated?

Methods: Kinematic assessment of 13 knees with Medial Pivot TKA and 13 knees with Lateral Pivot TKA was done. The subjects were asked to perform step-up and weight bearing deep knee bend exercise under fluoroscopy for kinematic assessment.

Persons with Co-Existing Neurological Disorders: Risk Analysis, Considerations and Management in COVID-19 Pandemic.

Increasing reports of neurological symptoms in COVID-19 patient's warrant clinicians to adopt and define the standardized diagnostic and managing protocols in order to investigate the linkage of neurological symptoms in COVID-19. Encephalitis, anosmia, acute cerebrovascular disease and ageusia are some of the emerging neurological manifestations which are reported in several cohort studies on hospitalized patients with COVID-19. Although the COVID-19 pandemic is primarily associated with infection of the respiratory tract system, but measures like lockdown and restricted physical movements to control the spread of this infection will certainly have neurobehavioural implications.

Plexin-B3 Regulates Cellular Motility, Invasiveness, and Metastasis in Pancreatic Cancer.

The Plexins family of proteins are well-characterized transmembrane receptors of semaphorins, axon guidance cue molecules, that mediate the cell attraction or repelling effects for such cues. Plexins and their ligands are involved in numerous cellular activities, such as motility, invasion, and adhesion to the basement membrane. The detachment of cells and the gain in motility and invasion are hallmarks of the cancer metastasis cascade, thus generating interest in exploring the role of plexins in cancer metastasis.

COVID-19 pandemic: from origins to outcomes. A comprehensive review of viral pathogenesis, clinical manifestations, diagnostic evaluation, and management.

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), the causative pathogen for the COVID-19, first emerged in Wuhan, China, in December 2019 and by March 2020, it was declared a pandemic. COVID-19 pandemic has overburdened healthcare systems in most countries and has led to massive economic losses. SARS-CoV-2 transmission typically occurs by respiratory droplets.

Radiofrequency Ablation of Parathyroid Adenomas: Safety and Efficacy in a Study of 10 Patients.

Purpose: To evaluate safety and effectiveness of ultrasound-guided percutaneous radiofrequency ablation of parathyroid adenoma in surgically unfit patients with hypercalcemia because of hyperparathyroidism.

Materials And Methods: A retrospective review of hospital records from Jan 2012 to Dec 2018 revealed 10 patients, who had undergone ablation for solitary parathyroid adenoma. All 10 patients suffered from hyperparathyroidism because of parathyroid adenoma, resulting in hypercalcemia.

Recent advances in organoid development and applications in disease modeling.

An improved understanding of stem cell niches, organogenesis, and disease models has paved the way for developing a three-dimensional (3D) organoid culture system. Organoid cultures can be derived from primary tissues (single cells or tissue subunits), adult stem cells (ASCs), induced pluripotent stem cells (iPSCs), or embryonic stem cells (ESCs). As a significant technological breakthrough, 3D organoid models offer a promising approach for understanding the complexities of human diseases ranging from the mechanistic investigation of disease pathogenesis to therapy.

New sulphonamide pyrolidine carboxamide derivatives: Synthesis, molecular docking, antiplasmodial and antioxidant activities.

Carboxamides bearing sulphonamide functionality have been shown to exhibit significant lethal effect on Plasmodium falciparum, the causative agent of human malaria. Here we report the synthesis of thirty-two new drug-like sulphonamide pyrolidine carboxamide derivatives and their antiplasmodial and antioxidant capabilities. In addition, molecular docking was used to check their binding affinities for homology modelled P.

Synthesis and Assessment of Fused β-Carboline Derivatives as Kappa Opioid Receptor Agonists.

The synthesis of 5-formyl-6-aryl-6H-indolo[3,2,1-de][1,5] naphthyridine-2-carboxylates by reaction between 1-formyl-9H-β-carbolines and cinnamaldehydes in the presence of pyrrolidine in water with microwave irradiation is described. Pharmacophoric modification of the formyl group offered several new fused β-carboline derivatives, which were investigated for their κ-opioid receptor (KOR) agonistic activity. Two compounds 4 a and 4 c produced appreciable agonist activity on KOR with EC values of 46±19 and 134±9 nM, respectively.

Proteasomal Regulation of Mammalian SPT16 in Controlling Transcription.

FACT (cilitates hromatin ranscription), an essential and evolutionarily conserved heterodimer from yeast to humans, controls transcription and is found to be upregulated in various cancers. However, the basis for such upregulation is not clearly understood. Our recent results deciphering a new ubiquitin-proteasome system regulation of the FACT subunit SPT16 in orchestrating transcription in yeast hint at the involvement of the proteasome in controlling FACT in humans, with a link to cancer.

Antileishmanial assessment of isoxazole derivatives against .

A chemical library comprising substituted 3-nitroisoxazoles and 3-aminoisoxazoles was prepared and screened for their antileishmanial activity against . As compared to Miltefosine, the standard drug used in bioassays, several compounds displayed remarkably better inhibition of the promastigote and amastigote stages of parasites. The evaluation of a few compounds in a golden hamster model showed significant reduction of the parasite load post treatment the intraperitoneal route by several compounds.