HIT

A dual-targeting approach is predicted to yield better cancer therapy outcomes. Consequently, a series of coumarin-based thiazoles ( 5a - h , 6 , and 7a - e ) were designed and constructed as potential carbonic anhydrase (CA) and VEGFR-2 suppressors. The inhibitory actions of the target compounds were assessed against CA isoforms IX and VEGFR-2. The assay results showed that coumarin-based thiazoles 5a , 5d , and 5e can effectively inhibit both targets. 5a , 5d , and 5e cytotoxic effects were tested on pancreatic, breast, and prostate cancer cells (PANC1, MCF7, and PC3)...

UNLABELLED: Alpha-particle radionuclide-antibody conjugates are being clinically evaluated against solid tumors even when they moderately express the targeted markers. At this limit of lower tumor-absorbed doses, to maintain efficacy, the few(er) intratumorally delivered alpha-particles need to traverse/hit as many different cancer cells as possible. We complement antibody-radioconjugate therapies with a separate nanocarrier delivering a fraction of the same total injected radioactivity to tumor regions geographically different than those affected by targeting antibodies; these carrier-cocktails collectively distribute the alpha-particle emitters better...

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is the most common neurobehavioral disorder. Treatments for ADHD include pharmacological and nonpharmacological therapy. However, pharmacological treatments have side effects such as poor appetite, sleep disturbance, and headache. Moreover, nonpharmacological treatments are not effective in ameliorating core symptoms and are time-consuming. Hence, developing an alternative and effective treatment without (or with fewer) side effects is crucial...

OBJECTIVE: To examine the benefits and harms of structured outdoor physical activity (PA) for people living with one or more somatic or mental diseases. METHODS: We identified articles from inception until Marts 2023 in MEDLINE, EMBASE, CINAHL and CENTRAL and citation tracking in Web of Science. We included randomized controlled trials (RCTs) and observational studies examining structured outdoor PA reporting physical function, health-related quality of life (HRQOL), pain or mental outcomes...

Animal welfare encompasses the overall well-being of an animal, spanning both its physical and mental health, assessable through potential measurements. It stands in contrast to mistreatment, which involves actions, direct or indirect, that endanger an animal's well-being. This study sought to appraise the factors influencing the Brazilian population's understanding of dog welfare and mistreatment. The survey questions were adapted from the Animal Welfare Examination Protocol, utilized by veterinarians to evaluate suspected passive abuse cases in dogs...

It was in 2019 that the world experienced the devastation caused by SARS-COV-2, contributing to a large number of deaths. This contagious virus not only challenged the health care system but has also hit the economy very badly. There has been a lot of research on effective vaccine development, and there has been some success in the same, but no effective antiviral drugs are available in the market. No doubt vaccination can prevent the disease, but it doesn't have the potential to cure an infected person, for which there is a dire need to develop some effective drug...

The molecular recognition of saccharides by synthetic hosts has become an appealing but elusive task in the last decades. Herein, we combine Dynamic Combinatorial Chemistry (DCC) for the rapid self-assembly and screening of virtual libraries of receptors, with the use of ITC and NMR to validate the hits and molecular modelling to understand the binding mechanisms. We discovered a minimalistic receptor, 1F ( N -benzyl-L-phenylalanine), with considerable affinity for fructose ( K a = 1762 M-1 ) and remarkable selectivity (>50-fold) over other common monosaccharides...

INTRODUCTION: Continuous recognition tasks (CRTs) assess episodic memory (EM), the central functional disturbance in Alzheimer's disease and several related disorders. The online MemTrax computerized CRT provides a platform for screening and assessment that is engaging and can be repeated frequently. MemTrax presents complex visual stimuli, which require complex involvement of the lateral and medial temporal lobes and can be completed in less than 2 min. Results include number of correct recognitions (HITs), recognition failures (MISSes = 1-HITs), correct rejections (CRs), false alarms (FAs = 1-CRs), total correct (TC = HITs + CRs), and response times (RTs) for each HIT and FA...

INTRODUCTION: High-flow priapism is rare, uncontrolled arterial inflow, preceded by penile or perineal trauma and arterial-lacunar fistula. There are several ways to treat high-flow priapism, i.e., conservative management, the use of ice packs, mechanical decompression, surgery, and super-selective arterial embolization. Embolization is currently widely accepted in patients who fail from conservative management. This study aimed to report the use of Gelfoam and microcoil embolization in recurrent high-flow priapism compared to PVA embolization...

Nod-like receptor protein 3 (NLRP-3), is an intracellular sensor that is involved in inflammasome activation, and the aberrant expression of NLRP3 is responsible for diabetes mellitus, its complications, and many other inflammatory diseases. NLRP3 is considered a promising drug target for novel drug design. Here, a pharmacophore model was generated from the most potent inhibitor, and its validation was performed by the Gunner-Henry scoring method. The validated pharmacophore was used to screen selected compounds databases...

Over the last years, new evidence has accumulated on multiple aspects of diagnosis and management of cerebral venous and dural sinus thrombosis (CVT) including identification of new risk factors, studies on interventional treatment as well as treatment with direct oral anticoagulants. Based on the GRADE questions of the European Stroke Organization guideline on this topic, the new German guideline on CVT is a consensus between expert representatives of Austria, Germany and Switzerland. New recommendations include:• CVT occurring in the first weeks after SARS-CoV-2 vaccination with vector vaccines may be associated with severe thrombocytopenia, indicating the presence of a prothrombotic immunogenic cause (Vaccine-induced immune thrombotic thrombocytopenia; VITT)...

BACKGROUND: Multidrug-resistant tuberculosis (particularly resistant to pyrazinoic acid) is a life-threatening chronic pulmonary disease. Running a marketed regime specifically targets the ribosomal protein subunit-1 (RpsA) and stops trans-translation in the non-mutant bacterium, responsible for the lysis of bacterial cells. However, in the strains of mutant bacteria, this regime has failed in curing TB and killing pathogens, which may only because of the ala438 deletion, which inhibit the binding of pyrazinoic acid to the RpsA active site...

BACKGROUND: Nutritional deficiencies (ND) continue to threaten the lives of millions of people around the world, with children being the worst hit. Nevertheless, no systematic study of the epidemiological features of child ND has been conducted so far. Therefore, we aimed to comprehensively assess the burden of pediatric ND. METHODS: We analyzed data on pediatric ND between 1990 and 2019 from the Global Burden of Disease study (GBD) 2019 at the global, regional, and national levels...

DNA methyl transferases (DNMTs) are one of the crucial epigenetic modulators associated with a wide variety of cancer conditions. Among the DNMT isoforms, DNMT1 is correlated with bladder, pancreatic, and breast cancer, as well as acute myeloid leukemia and esophagus squamous cell carcinoma. Therefore, the inhibition of DNMT1 could be an attractive target for combating cancers and other metabolic disorders. The disadvantages of the existing nucleoside and non-nucleoside DNMT1 inhibitors are the main motive for the discovery of novel promising inhibitors...

177 Lu-PSMA therapy is an effective treatment in patients with metastatic castration-resistant prostate cancer. SUVmean is a valuable screening biomarker to assess the suitability for 177 Lu-PSMA therapy but requires quantitative software. This study aims to develop a simple, clinically applicable prostate-specific membrane antigen PET/CT score that encompasses the elements of SUVmean without requiring additional quantification. Methods: Datasets from ethics-approved trials of patients with metastatic castration-resistant prostate cancer after androgen receptor signaling inhibition and taxane chemotherapy (or unfit for taxane), who were treated with 177 Lu-PSMA-617 and 177 Lu-PSMA I&T with a pretreatment screening with 68 Ga-PSMA-11 PET/CT, and clinical outcome data, including a prostate-specific antigen (PSA) 50% response rate (PSA50), PSA progression-free survival (PSA-PFS), and overall survival (OS), were included...

OBJECTIVES: Heparin-induced thrombocytopenia is a known complication of heparin exposure with potentially life-threatening sequelae. Direct thrombin inhibitors can be substituted for heparin in patients with heparin-induced thrombocytopenia that require anticoagulation. However, the use of direct thrombin inhibitors as a substitute for heparin has not been widely reported in the neuroendovascular literature. MATERIALS AND METHODS: Here we report the first use of the direct thrombin inhibitor bivalirudin in a neuroendovascular procedure as a substitute for heparin in a patient with a ruptured pseudoaneurysm and heparin-induced thrombocytopenia, and review the literature on the use of bivalirudin and argatroban for such patients...

Hepatitis B virus (HBV) capsid assembly modulators (CAMs) represent a promising therapeutic approach for the treatment of HBV infection. In this study, the hit compound CDI (IC50  = 2.46 ± 0.33 μM) was identified by screening of an in-house compound library. And then novel potent benzimidazole derivatives were designed and synthesized as core assembly modulators, and their antiviral effects were evaluated in vitro and in vivo biological experiments. The results indicated that compound 26f displayed the most optimized modulator of HBV capsid assembly (IC50  = 0...

Brazil counts among the countries the hardest hit by the Covid-19 pandemic. A great deal has been said about the negative role played by President Bolsonaro's denialism, but relatively few studies have attempted to measure precisely what impact it actually had on the pandemic. Our paper conducts econometric estimates based on observational data at municipal level to quantitatively assess the 'Bolsonaro effect' over time from March 2020 to December 2022. To our knowledge, this paper presents the most comprehensive investigation of Bolsonaro's influence in the spread of the pandemic from two angles: considering Covid-19 mortality and two key transmission mitigation channels (social distancing and vaccination); and exploring the full pandemic cycle (2020-2022) and its dynamics over time...

The rise of pyrazinamide (PZA)-resistant strains of Mycobacterium tuberculosis (MTB) poses a major challenge to conventional tuberculosis (TB) treatments. PZA, a cornerstone of TB therapy, must be activated by the mycobacterial enzyme pyrazinamidase (PZase) to convert its active form, pyrazinoic acid, which targets the ribosomal protein S1. Resistance, often associated with mutations in the RpsA protein, complicates treatment and highlights a critical gap in the understanding of structural dynamics and mechanisms of resistance, particularly in the context of the G97D mutation...

Introduction: The significance of automated drug design using virtual generative models has steadily grown in recent years. While deep learning-driven solutions have received growing attention, only a few modern AI-assisted generative chemistry platforms have demonstrated the ability to produce valuable structures. At the same time, virtual fragment-based drug design, which was previously less popular due to the high computational costs, has become more attractive with the development of new chemoinformatic techniques and powerful computing technologies...