Targeting eIF4G1-dependent translation in melanoma.

Elevated expression of components of eIF4F translation initiation complex has been documented in cancer, resulting in enhanced translation of mRNAs encoding pro-tumorigenic factors, including oncogenic proteins. We previously identified SBI-756, a small molecule that interferes with the eIF4F assembly and overcomes melanoma resistance to BRAF inhibitors. SBI-756 enhanced anti-tumor immunity in pancreatic cancer and was effective in the treatment of diffuse large B cell lymphoma.

The Emotional Intelligence of the GPT-4 Large Language Model.

Background: Advanced AI models such as the large language model GPT-4 demonstrate sophisticated intellectual capabilities, sometimes exceeding human intellectual performance. However, the emotional competency of these models, along with their underlying mechanisms, has not been sufficiently evaluated.

Objective: Our research aimed to explore different emotional intelligence domains in GPT-4 according to the Mayer-Salovey-Caruso model.

Structure-activity relationships of thiadiazole agonists of the human secretin receptor.

Agonists of the secretin receptor have potential applications for diseases of the cardiovascular, gastrointestinal, and metabolic systems, yet no clinically-active non-peptidyl agonists of this receptor have yet been developed. In the current work, we have identified a new small molecule lead compound with this pharmacological profile. We have prepared and characterized a systematic structure-activity series around this thiadiazole scaffold to better understand the molecular determinants of its activity.

Structural Basis for Substrate Binding, Catalysis and Inhibition of Breast Cancer Target Mitochondrial Creatine Kinase by Covalent Inhibitor via Cryo-EM.

Mitochondrial creatine kinases are key players in maintaining energy homeostasis in cells by working in conjunction with cytosolic creatine kinases for energy transport from mitochondria to cytoplasm. High levels of MtCK observed in Her2+ breast cancer and inhibition of breast cancer cell growth by substrate analog, cyclocreatine, indicate dependence of cancer cells on the 'energy shuttle' for cell growth and survival. Hence, understanding the key mechanistic features of creatine kinases and their inhibition plays an important role in the development of cancer therapeutics.

The role of psychological characteristics of the personality of patients with colorectal cancer in the timeliness of diagnosis verification and prognosis of disease outcome.

Objective: Colorectal cancer (CRC) has become the third most commonly diagnosed type of cancer in the world. Based on the risk factors for colorectal cancer (behavior, lifestyle), it is important to better understand the behavioral and psychological characteristics of the individual associated with timely seeking medical help, coping with the extreme situation of diagnosis, and the course of the disease. This determined the purpose of the study: identify the psychological characteristics of patients with colorectal cancer associated with the stage of diagnosis verification and the prognosis of disease outcome.

Melanoma-intrinsic NR2F6 activity regulates antitumor immunity.

Nuclear receptors (NRs) are implicated in the regulation of tumors and immune cells. We identify a tumor-intrinsic function of the orphan NR, NR2F6, regulating antitumor immunity. NR2F6 was selected from 48 candidate NRs based on an expression pattern in melanoma patient specimens (i.

Mechanism of Action and Structure-Activity Relationships of Tetracyclic Small Molecules Acting as Universal Positive Allosteric Modulators of the Cholecystokinin Receptor.

As part of an ongoing effort to develop a drug targeting the type 1 cholecystokinin receptor (CCK1R) to help prevent and/or treat obesity, we recently performed a high throughput screening effort of small molecules seeking candidates that enhanced the action of the natural agonist, CCK, thus acting as positive allosteric modulators without exhibiting intrinsic agonist action. Such probes would be expected to act in a temporally finite way to enhance CCK action to induce satiety during and after a meal and potentially even modulate activity at the CCK1R in a high cholesterol environment present in some obese patients. The current work focuses on the best scaffold, representing tetracyclic molecules identified through high throughput screening we previously reported.

[The psychological and environment risk factors of development of breast cancer in women residing in industrial megalopolis and rural locality].

The breast cancer hold leading position in the structure of oncological morbidity of women worldwide. The purpose of the study is to analyze contribution of psychological and environmental factors to risk of development of breast cancer in women residing in industrial metropolis and rural locality. The actuality of the study is conditioned by acquisition of new knowledge about risk factors of breast cancer.

Responses to Wildfire and Prescribed Fire Smoke: A Survey of a Medically Vulnerable Adult Population in the Wildland-Urban Interface, Mariposa County, California.

California plans to substantially increase the use of prescribed fire to reduce risk of catastrophic wildfires. Although for a beneficial purpose, prescribed fire smoke may still pose a health concern, especially among sensitive populations. We sought to understand community health experience, adaptive capacity, and attitudes regarding wildland and prescribed fire smoke to inform public health guidance.

Psychological predictors of favorable and unfavorable disease course of prostate cancer: results of a pilot study.

Objective: The statistical data on the incidence and mortality rates from prostate cancer leave gaps in understanding the causal risk factors for the unfavorable course of the disease determined the relevance of this work, determined the purpose of the study: to identify psychological predictors of favorable and unfavorable courses of prostate cancer.

Patients And Methods: Basic beliefs, coping, quality of life, level of subjective control, resilience, life orientation, as well as socio-demographic characteristics were analyzed in 124 men with different courses of the disease. Firstly, the psychological characteristics of men with prostate cancer with a favorable or unfavorable course were compared, and secondly, psychological predictors were identified and their contribution to the course of prostate cancer was assessed.

NRF2 mediates melanoma addiction to GCDH by modulating apoptotic signalling.

Tumour dependency on specific metabolic signals has been demonstrated and often guided numerous therapeutic approaches. We identify melanoma addiction to the mitochondrial protein glutaryl-CoA dehydrogenase (GCDH), which functions in lysine metabolism and controls protein glutarylation. GCDH knockdown induced cell death programmes in melanoma cells, an activity blocked by inhibition of the upstream lysine catabolism enzyme DHTKD1.

Screening for positive allosteric modulators of cholecystokinin type 1 receptor potentially useful for management of obesity.

Obesity has become a prevailing health burden globally and particularly in the US. It is associated with many health problems, including cardiovascular disease, diabetes and poorer mental health. Hence, there is a high demand to find safe and effective therapeutics for sustainable weight loss.

Discovery of a Positive Allosteric Modulator of Cholecystokinin Action at CCK1R in Normal and Elevated Cholesterol.

Drugs useful in prevention/treatment of obesity could improve health. Cholecystokinin (CCK) is a key regulator of appetite, working through the type 1 CCK receptor (CCK1R); however, full agonists have not stimulated more weight loss than dieting. We proposed an alternate strategy to target this receptor, while reducing likelihood of side effects and/or toxicity.

Magnetic Properties of Bacterial Magnetosomes Produced by SO-1.

In this study, the magnetic properties of magnetosomes isolated from lyophilized magnetotactic bacteria SO-1 were assessed for the first time. The shape and size of magnetosomes and cell fragments were studied by electron microscopy and dynamic light scattering techniques. Phase and elemental composition were analyzed by X-ray and electron diffraction and Raman spectroscopy.

Discovery of 1-[2-(1-methyl-1H-pyrazol-5-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-yl]-3-(pyridin-4-ylmethyl)urea as a potent NAMPT (nicotinamide phosphoribosyltransferase) activator with attenuated CYP inhibition.

Nicotinamide phosphoribosyltransferase (NAMPT) catalyzes the rate-limiting step of the NAD salvage pathway. Since NAD plays a pivotal role in many biological processes including metabolism and aging, activation of NAMPT is an attractive therapeutic target for treatment of diverse array of diseases. Herein, we report the continued optimization of novel urea-containing derivatives which were identified as potent NAMPT activators.

Optimization of a urea-containing series of nicotinamide phosphoribosyltransferase (NAMPT) activators.

NAD is a crucial cellular factor that plays multifaceted roles in wide ranging biological processes. Low levels of NAD have been linked to numerous diseases including metabolic disorders, cardiovascular disease, neurodegeneration, and muscle wasting disorders. A novel strategy to boost NAD is to activate nicotinamide phosphoribosyltransferase (NAMPT), the putative rate-limiting step in the NAD salvage pathway.

Discovery of small molecule positive allosteric modulators of the secretin receptor.

The secretin receptor (SCTR) is a prototypic Class B1 G protein-coupled receptor (GPCR) that represents a key target for the development of therapeutics for the treatment of cardiovascular, gastrointestinal, and metabolic disorders. However, no non-peptidic molecules targeting this receptor have yet been disclosed. Using a high-throughput screening campaign directed at SCTR to identify small molecule modulators, we have identified three structurally related scaffolds positively modulating SCTRs.

Serine-Threonine Kinase TAO3-Mediated Trafficking of Endosomes Containing the Invadopodia Scaffold TKS5α Promotes Cancer Invasion and Tumor Growth.

Invadopodia are actin-based proteolytic membrane protrusions required for invasive behavior and tumor growth. In this study, we used our high-content screening assay to identify kinases whose activity affects invadopodia formation. Among the top hits selected for further analysis was TAO3, an STE20-like kinase of the GCK subfamily.

Development of a Testing Funnel for Identification of Small-Molecule Modulators Targeting Secretin Receptors.

The secretin receptor (SCTR), a prototypical class B G protein-coupled receptor (GPCR), exerts its effects mainly by activating Gαs proteins upon binding of its endogenous peptide ligand secretin. SCTRs can be found in a variety of tissues and organs across species, including the pancreas, stomach, liver, heart, lung, colon, kidney, and brain. Beyond that, modulation of SCTR-mediated signaling has therapeutic potential for the treatment of multiple diseases, such as heart failure, obesity, and diabetes.

A cellular target engagement assay for the characterization of SHP2 (PTPN11) phosphatase inhibitors.

The nonreceptor protein-tyrosine phosphatase (PTP) SHP2 is encoded by the proto-oncogene and is a ubiquitously expressed key regulator of cell signaling, acting on a number of cellular processes and components, including the Ras/Raf/Erk, PI3K/Akt, and JAK/STAT pathways and immune checkpoint receptors. Aberrant SHP2 activity has been implicated in all phases of tumor initiation, progression, and metastasis. Gain-of-function mutations drive oncogenesis in several leukemias and cause developmental disorders with increased risk of malignancy such as Noonan syndrome.

Molecular Inhibitor of QSOX1 Suppresses Tumor Growth .

Quiescin sulfhydryl oxidase 1 (QSOX1) is an enzyme overexpressed by many different tumor types. QSOX1 catalyzes the formation of disulfide bonds in proteins. Because short hairpin knockdowns (KD) of QSOX1 have been shown to suppress tumor growth and invasion and , we hypothesized that chemical compounds inhibiting QSOX1 enzymatic activity would also suppress tumor growth, invasion, and metastasis.

Boosting NAD with a small molecule that activates NAMPT.

Pharmacological strategies that boost intracellular NAD are highly coveted for their therapeutic potential. One approach is activation of nicotinamide phosphoribosyltransferase (NAMPT) to increase production of nicotinamide mononucleotide (NMN), the predominant NAD precursor in mammalian cells. A high-throughput screen for NAMPT activators and hit-to-lead campaign yielded SBI-797812, a compound that is structurally similar to active-site directed NAMPT inhibitors and blocks binding of these inhibitors to NAMPT.

Novel Antimycobacterial Compounds Suppress NAD Biogenesis by Targeting a Unique Pocket of NaMN Adenylyltransferase.

Conventional treatments to combat the tuberculosis (TB) epidemic are falling short, thus encouraging the search for novel antitubercular drugs acting on unexplored molecular targets. Several whole-cell phenotypic screenings have delivered bioactive compounds with potent antitubercular activity. However, their cellular target and mechanism of action remain largely unknown.

Identification and characterization of small molecule inhibitors of the ubiquitin ligases Siah1/2 in melanoma and prostate cancer cells.

Inhibition of ubiquitin ligases with small molecule remains a very challenging task, given the lack of catalytic activity of the target and the requirement of disruption of its interactions with other proteins. Siah1/2, which are E3 ubiquitin ligases, are implicated in melanoma and prostate cancer and represent high-value drug targets. We utilized three independent screening approaches in our efforts to identify small-molecule Siah1/2 inhibitors: Affinity Selection-Mass Spectrometry, a protein thermal shift-based assay and an in silico based screen.