Acral melanoma in the Caucasian population: a comprehensive cohort study on epidemiological, clinicopathological, and prognostic features.

Background: Acral melanoma is associated with poor prognosis. Studying the characteristics and prognosis of Caucasian patients is crucial to understand the distinct features of this tumor.

Objectives: To analyze the epidemiological, clinicopathological, and prognostic features of acral melanoma in Caucasian patients.

Design and Discovery of a Potent and Selective Inhibitor of Integrin αvβ1.

Selective inhibition of the RGD (Arg-Gly-Asp) integrin αvβ1 has been recently identified as an attractive therapeutic approach for the treatment of liver fibrosis given its function, target expression, and safety profile. Our identification of a non-RGD small molecule lead followed by focused, systematic changes to the core structure utilizing a crystal structure, modeling, and a tractable synthetic approach resulted in the identification of a potent small molecule exhibiting a remarkable affinity for αvβ1 relative to several other integrin isoforms measured. Azabenzimidazolone demonstrated antifibrotic efficacy in an rat liver fibrosis model and represents a tool compound capable of further exploring the biological consequences of selective αvβ1 inhibition.

Tuft cell-derived acetylcholine promotes epithelial chloride secretion and intestinal helminth clearance.

Epithelial cells secrete chloride to regulate water release at mucosal barriers, supporting both homeostatic hydration and the "weep" response that is critical for type 2 immune defense against parasitic worms (helminths). Epithelial tuft cells in the small intestine sense helminths and release cytokines and lipids to activate type 2 immune cells, but whether they regulate epithelial secretion is unknown. Here, we found that tuft cell activation rapidly induced epithelial chloride secretion in the small intestine.

Determination of asbestos cement rooftop surface composition using regression analysis and hyper-spectral reflectance data in the visible and near-infrared ranges.

The effects of asbestos on human health have spurred numerous studies examining its risks in urban environments. Recent works have shifted towards less-invasive techniques for remote detection and classification of asbestos-cement. In this context, this study combines visible (VIS) and near-infrared (NIR) reflectance data collected in-situ with reference signals from the USGS spectral library, utilizing optimized regression analysis to determine the surface composition of corrugated asbestos-cement rooftops.

The use of bone wax versus dermal regeneration matrix for the reconstruction of scalp defects.

Background: Secondary intention healing is an alternative to consider in large tumors or tumors located in areas of limited skin mobility, such as the scalp. To promote epithelialization, we can use Dermal Regeneration Matrix (DRM) or bone wax.

Objective: This study aimed to compare the efficacy of DRM and bone wax in secondary intention healing of cutaneous scalp tumors in elderly patients with comorbidities.

Impact of bread diet on intestinal dysbiosis and irritable bowel syndrome symptoms in quiescent ulcerative colitis: A pilot study.

Gut microbiota may be involved in the presence of irritable bowel syndrome (IBS)-like symptomatology in ulcerative colitis (UC) patients in remission. Bread is an important source of dietary fiber, and a potential prebiotic. To assess the effect of a bread baked using traditional elaboration, in comparison with using modern elaboration procedures, in changing the gut microbiota and relieving IBS-like symptoms in patients with quiescent ulcerative colitis.

Development of multidisciplinary, evidenced-based protocol recommendations and implementation strategies for anterior lumbar interbody fusion surgery following a literature review.

The anterior lumbar interbody fusion (ALIF) procedure involves several surgical specialties, including general, vascular, and spinal surgery due to its unique approach and anatomy involved. It also carries its own set of complications that differentiate it from posterior lumbar fusion surgeries. The demonstrated benefits of treatment guidelines, such as Enhanced Recovery after Surgery in other surgical procedures, and the lack of current recommendations regarding the anterior approach, underscores the need to develop protocols that specifically address the complexities of ALIF.

Cholesterol Hydroperoxide Co-trafficking in Testosterone-generating Leydig Cells: GPx4 Inhibition of Cytotoxic and Anti-steroidogenic Effects.

Trafficking of intracellular cholesterol (Ch) to and into mitochondria of steroidogenic cells is required for steroid hormone biosynthesis. This trafficking is typically mediated by one or more proteins of the steroidogenic acute regulatory (StAR) family. Our previous studies revealed that 7-OOH, a redox-active cholesterol hydroperoxide, could be co-trafficked with Ch to/into mitochondria of MA-10 Leydig cells, thereby inducing membrane lipid peroxidation (LPO) which impaired progesterone biosynthesis.

Melanoma-specific survival is worse in the elderly: a multicentric cohort study.

We aimed to characterise cutaneous melanoma in the elderly and determine its association with poorer prognosis. We studied a prospective cohort of the melanoma population in Catalonia between 2012 and 2016. We compared young patient group (<75 years old) with elderly patient group (≥75 years old).

Tuft cell-derived acetylcholine regulates epithelial fluid secretion.

Tuft cells are solitary chemosensory epithelial cells that can sense lumenal stimuli at mucosal barriers and secrete effector molecules to regulate the physiology and immune state of their surrounding tissue. In the small intestine, tuft cells detect parasitic worms (helminths) and microbe-derived succinate, and signal to immune cells to trigger a Type 2 immune response that leads to extensive epithelial remodeling spanning several days. Acetylcholine (ACh) from airway tuft cells has been shown to stimulate acute changes in breathing and mucocilliary clearance, but its function in the intestine is unknown.

The discovery of (1R, 3R)-1-(3-chloro-5-fluorophenyl)-3-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinoline-6-carbonitrile, a potent and selective agonist of human transient receptor potential cation channel subfamily m member 5 (TRPM5) and evaluation of as a potential gastrointestinal prokinetic agent.

This publication details the discovery of a series of selective transient receptor potential cation channel subfamily M member 5 (TRPM5) agonists culminating with the identification of the lead compound (1R, 3R)-1-(3-chloro-5-fluorophenyl)-3-(hydroxymethyl)-1,2,3,4-tetrahydroisoquinoline-6-carbonitrile (39). We describe herein our biological rationale for agonism of the target, the examination of the then current literature tool molecules, and finally the process of our discovery starting with a high throughput screening hit through lead development. We also detail the selectivity of the lead compound 39 versus related family members TRPA1, TRPV1, TRPV4, TRPM4 and TRPM8, the drug metabolism and pharmacokinetics (DMPK) profile and in vivo efficacy in a mouse model of gastrointestinal motility.

Correction: Chaparro et al. Incidence, Clinical Characteristics and Management of Inflammatory Bowel Disease in Spain: Large-Scale Epidemiological Study. 2021, , 2885.

The authors wish to make the following corrections to this paper [...

Cognitive load, fatigue and aversive simulator symptoms but not manipulated zeitgebers affect duration perception in virtual reality.

The perceived duration of an interval depends on numerous aspects of the passed event both endogenous, including physiological arousal, level of wakefulness, attention, and surprise, as well as exogenous such as valence, salience, or context in the environment. There is some evidence that "time-giving" cues from the environment (zeitgebers) are coupled with time perception. The movement of the sun on the horizon was demonstrated to affect interval perception in a study conducted by Schatzschneider et al.

Comparison of metabolic effects of mitochondrial dysfunctions in the context of vulnerability to fatigue: computer simulation study.

In recent years, the accumulation of phosphate ions and the increase in acidity have been described as crucial metabolic fatigue-leading factors that disturb muscle fiber contractions. This fact is especially important in the context of mitochondrial dysfunctions in which excessive fatigue is one of the possible symptoms. However, little is known about the precise fatigue-inducing thresholds of work intensity in mitochondrial dysfunctions of various types and at various stages of their severity.

Identification of positive modulators of TRPM5 channel from a high-throughput screen using a fluorescent membrane potential assay.

Transient Receptor Potential Melastatin 5 (TRPM5) is an intracellular calcium-activated cation-selective ion channel expressed in a variety of cell types. Dysfunction of this channel has recently been implied in a range of disease states including diabetes, enteric infections, inflammatory responses, parasitic infection and other pathologies. However, to date, agonists and positive modulators of this channel with sufficient selectivity to enable target validation studies have not been described, limiting the evaluation of TRPM5 biology and its potential as a drug target.

Prebiotic Effect of Bread-Making Process in Inflammatory Bowel Disease Microbiome.

Inflammatory bowel disease (IBD), including its two main categories (Crohn's disease and ulcerative colitis), has been linked both to gut microbiota and to diet. Bread is a daily food that has a potential capacity as a prebiotic. Our aim was to evaluate different bread-making processes and their effect on fecal colonic microbiota in IBD patients.

Discovery of the Bruton's Tyrosine Kinase Inhibitor Clinical Candidate TAK-020 ()-5-(1-((1-Acryloylpyrrolidin-3-yl)oxy)isoquinolin-3-yl)-2,4-dihydro-3-1,2,4-triazol-3-one, by Fragment-Based Drug Design.

This publication details the successful use of FBDD (fragment-based drug discovery) principles in the invention of a novel covalent Bruton's tyrosine kinase inhibitor, which ultimately became the Takeda Pharmaceuticals clinical candidate TAK-020. Described herein are the discovery of the fragment 5-phenyl-2,4-dihydro-3-1,2,4-triazol-3-one, the subsequent optimization of this hit molecule to the candidate, and synthesis and performance in pharmacodynamic and efficacy models along with direct biophysical comparison of TAK-020 with other clinical-level assets and the marketed drug Ibrutinib.

Incidence, Clinical Characteristics and Management of Inflammatory Bowel Disease in Spain: Large-Scale Epidemiological Study.

(1) Aims: To assess the incidence of inflammatory bowel disease (IBD) in Spain, to describe the main epidemiological and clinical characteristics at diagnosis and the evolution of the disease, and to explore the use of drug treatments. (2) Methods: Prospective, population-based nationwide registry. Adult patients diagnosed with IBD-Crohn's disease (CD), ulcerative colitis (UC) or IBD unclassified (IBD-U)-during 2017 in Spain were included and were followed-up for 1 year.

Structures of the TRPM5 channel elucidate mechanisms of activation and inhibition.

The Ca-activated TRPM5 channel plays essential roles in taste perception and insulin secretion. However, the mechanism by which Ca regulates TRPM5 activity remains elusive. We report cryo-EM structures of the zebrafish TRPM5 in an apo closed state, a Ca-bound open state, and an antagonist-bound inhibited state.

Tauroursodeoxycholic Acid (TUDCA)-Lipid Interactions and Antioxidant Properties of TUDCA Studied in Model of Photoreceptor Membranes.

Tauroursodeoxycholic acid (TUDCA), a hydrophilic bile acid containing taurine conjugated with the ursodeoxycholic acid (UDCA), has been known and used from ancient times as a therapeutic compound in traditional Chinese medicine. TUDCA has recently been gaining significant interest as a neuroprotective agent, also exploited in the visual disorders. Among several mechanisms of TUDCA's protective action, its antioxidant activity and stabilizing effect on mitochondrial and plasma membranes are considered.

From High-Throughput Screening to Target Validation: Benzo[]isothiazoles as Potent and Selective Agonists of Human Transient Receptor Potential Cation Channel Subfamily M Member 5 Possessing In Vivo Gastrointestinal Prokinetic Activity in Rodents.

Transient receptor potential cation channel subfamily M member 5 (TRPM5) is a nonselective monovalent cation channel activated by intracellular Ca increase. Within the gastrointestinal system, TRPM5 is expressed in the stoma, small intestine, and colon. In the search for a selective agonist of TRPM5 possessing in vivo gastrointestinal prokinetic activity, a high-throughput screening was performed and compound was identified as a promising hit.