Impact of Mechanical and Architectural Signals in the Tumor Microenvironment on Melanoma.

Compared to sun-exposed melanomas, acral melanomas are genetically diverse and occur in areas with low sun exposure and high mechanical loads. During metastatic growth, melanomas invade from the epidermis to the dermis layers through dense tumor stroma and are exposed to fibrillar collagen architectures and mechanical stresses. However, the role of these signals during acral melanoma pathogenesis is not well understood.

LZTR1 is a melanoma oncogene that promotes invasion and suppresses apoptosis.

Leucine zipper like transcription regulator 1 (LZTR1) is amplified in acral melanomas, is required for melanocytes and melanoma cell proliferation, and it induces anchorage-independent growth, by yet unknown mechanisms. We therefore performed comprehensive studies to identify its activity in melanomas employing proximity biotinylation and co-immunoprecipitation combined with LC-MS/MS proteomics and molecular characterization. The results show that LZTR1 regulates the ubiquitin proteasome system in melanoma cells and also associates with actin-related proteins and actin cytoskeleton organization.

Effect of lemborexant on sleep parameters and architecture in adult and elderly participants with mild-to-severe obstructive sleep apnea.

Objective: To evaluate sleep parameters and architecture in a post hoc analysis of participants with untreated obstructive sleep apnea (OSA) who received lemborexant (LEM) 10 mg (LEM10), a competitive dual orexin-receptor antagonist approved for the treatment of adults with insomnia.

Methods: Study E2006-A001-102 (Study 102; NCT03471871) and Study E2006-A001-113 (Study 113; NCT04647383) were multicenter, randomized, double-blind, placebo (PBO)-controlled, 2-period cross-over studies in participants with mild OSA (apnea-hypopnea index [AHI] ≥5 to <15 events/hour) and moderate (AHI ≥15 to <30 events/hour) or severe OSA (AHI ≥30 events/hour), respectively. Participants were randomized to 1 of 2 treatment sequences (Sequence A: PBO/LEM10; Sequence B: LEM10/PBO) consisting of 8 nights of treatment (LEM10 or PBO), with each treatment period separated by a ≥14-day washout period.

Monomethyl auristatin E and paclitaxel use different mechanisms to alter intracellular calcium signaling.

Antibody-drug conjugates (ADCs) are a promising class of targeted cancer therapies that deliver cytotoxic agents to cancer cells. Although designed to reduce side effects, ADCs utilizing a microtubule-targeting agent, exemplified by monomethyl auristatin E (MMAE), as the drug cargo, frequently induce chemotherapy-induced peripheral neuropathy (CIPN) at rates comparable to taxanes like paclitaxel (PTX). Despite their clinical success, ADC-associated neurotoxicity remains a significant challenge, necessitating a deeper mechanistic understanding and potential neuroprotective strategies.

Epidermal Stem Cells Control Periderm Injury Repair via Matrix-Driven Specialization of Intercellular Junctions.

Epidermal stem cells interact with the extracellular matrix (ECM) to regulate their differentiation and maintain skin architecture. Here, we demonstrate a novel role for basal epidermal stem cells (BECs)-ECM interaction in regulating adhesion molecules expressed by the periderm-the superficial epidermal cells (SECs) of the embryonic bilayered skin. Using the developing zebrafish fin fold, we identify BECs form distinct regions of collagen-versus laminin-enriched basement membranes through integrin-mediated adhesions.

Advanced tissue-engineered pulsatile conduit using human induced pluripotent stem cell-derived cardiomyocytes.

Single ventricle congenital heart defects (SVCHDs) are life-threatening defects that can lead to severe circulation issues and increased stress on the heart. Without prompt treatment, these defects can prove fatal in infancy. Fontan surgery is a conventional treatment for SVCHDs, which reroutes oxygen-poor blood directly to the lungs, bypassing the non-functioning ventricle.

Application of instant assembly of collagen to bioprint cardiac tissues.

Advancing cardiac tissue engineering requires innovative fabrication techniques, including 3D bioprinting and tissue maturation, to enable the generation of new muscle for repairing or replacing damaged heart tissue. Recent advances in tissue engineering have highlighted the need for rapid, high-resolution bioprinting methods that preserve cell viability and maintain structural fidelity. Traditional collagen-based bioinks gel slowly, limiting their use in bioprinting.

Instant assembly of collagen for tissue engineering and bioprinting.

Engineering functional cellular tissue components holds great promise in regenerative medicine. Collagen I, a key scaffolding material in bodily tissues, presents challenges in controlling its assembly kinetics in a biocompatible manner in vitro, restricting its use as a primary scaffold or adhesive in cellular biofabrication. Here we report a collagen fabrication method termed as tunable rapid assembly of collagenous elements that leverages macromolecular crowding to achieve the instant assembly of unmodified collagen.

Involvement of long non-coding RNA (lncRNA) MALAT1 in shear stress regulated adipocyte differentiation.

Adipocyte differentiation plays an important role in bone remodeling due to secretory factors that can directly modulate osteoblast and osteoclast, thus affecting overall bone mass and skeletal integrity. Excessive adipocyte differentiation within the bone marrow microenvironment can lead to decreased bone mass, eventually causing osteoporosis. The mechanical microenvironment of bone marrow, including fluid shear, maintains the balance of adipocyte and osteoblast differentiation during bone remodeling.

Adaptation to Volumetric Compression Drives an Apoptosis-Resistant and Invasive Phenotype in Liver Cancer.

Unlabelled: Physical constraints like compression influence cancer cell invasion and transcriptional dynamics in various tumors. Liver cancer is characterized by the rapid proliferation of tumor cells within a densely packed tissue matrix, subjecting the cancer cells to crowding and compression. The highly dysregulated mechanical environment highlights the need to elucidate the broader impact of compression on liver cancer development and evolution.

Arthroscopic bone grafting in scaphoid fracture nonunion: Is it a universal solution?

Since 1997, arthroscopic bone grafting has offered hand surgeons a solution to the riddle of scaphoid fracture nonunion. The intended merit of an arthroscopic approach for scaphoid fracture nonunion management lies in its minimal invasiveness, which preserves the tenuous vascularity of the scaphoid, poses minimal disturbance to carpal ligaments, and allows comprehensive evaluation in diagnostic uncertainty. What does the evidence tell us about its outcomes and limitations compared to open techniques? Level III evidence suggests that arthroscopic bone graft yields similar union rates and potentially earlier time to union compared to open bone graft, at an average union rate of 96 % and union time of 13.

Macromolecular crowding-based biofabrication utilizing unmodified extracellular matrix bioinks.

The extracellular matrix (ECM) is the body's natural cell-scaffolding material, and its structure and content are often imitated for applications in tissue engineering and regenerative medicine to promote biocompatibility. One approach toward biomimicking natural ECMs is to utilize decellularized extracellular matrices (dECMs), which involve removing cellular components from native tissues to preserve natural components. Solubilizing dECMs to produce bioinks therefore holds high potential for 3D biofabrication and bioprinting of bioactive scaffolds and tissues.

Management of Insomnia in the General Hospital.

The Psychiatric Consultation Service at Massachusetts General Hospital sees medical and surgical inpatients with comorbid psychiatric symptoms and conditions. During their twice-weekly rounds, Dr Stern and other members of the Consultation Service discuss diagnosis and management of hospitalized patients with complex medical or surgical problems who also demonstrate psychiatric symptoms or conditions. These discussions have given rise to rounds reports that will prove useful for clinicians practicing at the interface of medicine and psychiatry.

Fully biologic endothelialized-tissue-engineered vascular conduits provide antithrombotic function and graft patency.

Tissue-engineered vascular conduits (TEVCs), often made by seeding autologous bone marrow cells onto biodegradable polymeric scaffolds, hold promise toward treating single-ventricle congenital heart defects (SVCHDs). However, the clinical adoption of TEVCs has been hindered by a high incidence of graft stenosis in prior TEVC clinical trials. Herein, we developed endothelialized TEVCs by coating the luminal surface of decellularized human umbilical arteries with human induced pluripotent stem cell (hiPSC)-derived endothelial cells (ECs), followed by shear stress training, in flow bioreactors.

Viscosity regulates cell spreading and cell-extracellular matrix interactions.

Fluid viscosity and osmolarity are among some of the underappreciated mechanical stimuli that cells can detect. Abnormal changes of multiple fluidic factors such as viscosity and osmolarity have been linked with diseases such as cystic fibrosis, cancer, and coronary heart disease. Changes in viscosity have been recently suggested as a regulator of cell locomotion.

Delphi consensus recommendations for the management of chronic insomnia in Canada.

Objective: The lack of current Canadian practice guidelines for the management of insomnia poses a challenge for healthcare providers (HCP) in selecting the appropriate treatment options. This study aimed to establish expert consensus recommendations for the management of chronic insomnia in Canada.

Composition Of The Committee: Sixteen multidisciplinary experts in sleep medicine and insomnia across Canada developed consensus recommendations based on their knowledge of the literature and their practical experience.

Poor Sleep is Common in Treatment-Resistant Late-life Depression and Associated With Poorer Antidepressant Response: Findings From the OPTIMUM Clinical Trial.

Background: Adults with treatment-resistant late-life depression (TRLLD) have high rates of sleep problems; however, little is known about the occurrence and change in sleep during pharmacotherapy of TRLLD. This analysis examined: (1) the occurrence of insufficient sleep among adults with TRLLD; (2) how sleep changed during pharmacotherapy; and (3) whether treatment outcomes differed among participants with persistent insufficient sleep, worsened sleep, improved sleep, or persistent sufficient sleep.

Methods: Secondary analysis of data from 634 participants age 60+ years in the OPTIMUM clinical trial for TRLLD.

Optimization of Vascularized Intestinal Organoid Model.

Vasculature is crucial for maintaining organ homeostasis and metabolism. Although 3D organoids can mimic organ structures and patterns, they still lack vascular systems, limiting the recapitulation of physiological complexities. Although vascularization of organoids has been demonstrated by mixing Matrigel in fibrin, how the mixed gel niche affects endothelial cells (ECs) and organoids remains unclear.

Protocol for isolating and identifying small extracellular vesicles derived from human umbilical cord mesenchymal stem cells.

Small extracellular vesicles (sEVs) are lipid bilayer-enclosed particles secreted by living cells. Here, we present a protocol for the collection and isolation of sEVs derived from human umbilical cord mesenchymal stem cells (hucMSCs). We describe steps for characterizing their morphology and integrity by transmission electron microscopy (TEM) and size distribution using nanoparticle tracking analysis (NTA) and an atomic force microscope (AFM).