Structural basis for distinct roles of SMAD2 and SMAD3 in FOXH1 pioneer-directed TGF-ß signaling.

TGF-ß receptors phosphorylate SMAD2 and SMAD3 transcription factors, which then form heterotrimeric complexes with SMAD4 and cooperate with context-specific transcription factors to activate target genes. Here we provide biochemical and structural evidence showing that binding of SMAD2 to DNA depends on the conformation of the E3 insert, a structural element unique to SMAD2 and previously thought to render SMAD2 unable to bind DNA. Based on this finding, we further delineate TGF-ß signal transduction by defining distinct roles for SMAD2 and SMAD3 with the forkhead pioneer factor FOXH1 as a partner in the regulation of differentiation genes in mouse mesendoderm precursors. FOXH1 is prebound to target sites in these loci and recruits SMAD3 independently of TGF-ß signals, whereas SMAD2 remains predominantly cytoplasmic in the basal state and set to bind SMAD4 and join SMAD3:FOXH1 at target promoters in response to Nodal TGF-ß signals. The results support a model in which signal-independent binding of SMAD3 and FOXH1 prime mesendoderm differentiation gene promoters for activation, and signal-driven SMAD2:SMAD4 binds to promoters that are preloaded with SMAD3:FOXH1 to activate transcription.

Phen-Gen: combining phenotype and genotype to analyze rare disorders.

We introduce Phen-Gen, a method that combines patients' disease symptoms and sequencing data with prior domain knowledge to identify the causative genes for rare disorders. Simulations revealed that the causal variant was ranked first in 88% of cases when it was a coding variant-a 52% advantage over a genotype-only approach-and Phen-Gen outperformed other existing prediction methods by 13-58%. If disease etiology was unknown, the causal variant was assigned the top rank in 71% of simulations. Phen-Gen is available at http://phen-gen.org/.

Novel Use of Drug-Coated Balloon Angioplasty to Treat Pulmonary Vein Stenosis.

Pulmonary vein stenosis is challenging to treat due to high rate of recurrence. Multiple interventions exist but are limited by high rates of restenosis. One theory for the high rate of recurrence is vascular inflammation. Drug-coated balloon angioplasty has been used to limit restenosis caused by inhibiting inflammation in pulmonary vein stenosis.

Recurrent Annular Thrombosis and Embolism Following Mitral Valve Repair.

A patient without evident systemic thrombophilia developed recurrent ischemic stroke following surgical mitral valve repair. Thromboembolism proved resistant to anticoagulation; however, following explantation of the prosthesis, she became asymptomatic with normal valve function. We postulate that an unusual reaction to prosthetic material was the source of thromboembolism.

A Subjective Assessment of Chemotherapy Drug-Induced Taste and Smell Alteration in Non-head and Neck Cancer Patients: A Questionnaire-Based Cross-Sectional Study.

OBJECTIVE: This study aimed to evaluate alterations in taste and smell perceptions among non-head and neck cancer patients receiving chemotherapy, aiming to identify factors influencing these changes. METHODS: A cohort of 70 non-head and neck cancer patients undergoing one to four cycles or more than four cycles, over a six-month period, from oncology outpatient clinics was recruited. Participants completed structured taste and smell questionnaires with assistance from interviewers. Demographic data, recurrence history, chemotherapy cycles, drug regimens, and taste and smell perceptions were analyzed using descriptive statistics and chi-square tests. RESULTS: The mean age of participants was 46.5 years, with a predominance of females (81.4%) and breast cancer cases (42.9%). Taste changes were more prevalent (62.9%) than smell changes (32.9%) post chemotherapy, particularly among those on combination drug regimens. Salty taste alterations were the most common (30.0%), followed by sweet taste (22.9%) and sour/bitter tastes (14.3%). Moreover, 38.57% of patients reported experiencing dysgeusia, while 30% noted the occurrence of parosmia post chemotherapy. CONCLUSION: Chemotherapy-induced alterations in taste and smell significantly impact the quality of life and nutritional status of cancer patients. Despite often being overlooked, these changes warrant increased attention in oncological practice to inform treatment decisions and enhance symptom management, particularly in palliative care settings. Further research is needed to explore the implications of chemosensory alterations on patient outcomes and treatment strategies.

Barriers to Follow Up Care in the South Asian Immigrant Population at High Risk of Acute Coronary Syndrome at Elmhurst Hospital Center.

We studied South Asian immigrant patients who did not return to Elmhurst Hospital Center (EHC) after emergent cardiac catheterization in order to propose interventions to improve follow up care. We identified 74 eligible patients, interviewed 30 about follow up practices, and analyzed findings. Most patients are Bangladeshi and 77% preferred a foreign language. Some were visiting the US during the admission without intent to follow up. Half were dissatisfied with EHC providers, complications, and inadequate care at follow up appointments. Some patients were unaware of scheduled appointments or the necessity of follow up. Most follow with private providers due to language accessibility, availability, and proximity. We found that language barriers contribute to loss to follow up and the true loss to follow up rate is lower than reported at EHC. This can inform practices at hospitals with immigrant populations, minimize resource waste, and improve quality of care.

Overcoming challenges to removing inappropriate penicillin allergy labels: A quality improvement report.

Over 3 months, we provided monthly education to internal medicine residents and distributed resources regarding penicillin-allergy history taking. Allergy information in the electronic record was updated more often during the intervention compared to the period before the intervention (16.1% vs 10.9%; P = .02). Education and interdepartmental collaboration have the potential to affect provider behavior.

Author Correction: Pericyte-like spreading by disseminated cancer cells activates YAP and MRTF for metastatic colonization.

In the version of this Article originally published, the authors inadvertently included the term 'pericytic mimicry' in relation to ref. 54. This has now been corrected by inserting an additional reference at position 51 and amending the text in the Discussion relating to 'pericytic mimicry', ref. 54 and pericyte-like spreading. The original refs 51-70 have also been renumbered. Furthermore, Fig. 8l has been amended to remove the term 'pericyte mimicry' that the authors had included inadvertently during figure preparation. These corrections have been made in the online versions of the Article.

Pericyte-like spreading by disseminated cancer cells activates YAP and MRTF for metastatic colonization.

Metastatic seeding by disseminated cancer cells principally occurs in perivascular niches. Here, we show that mechanotransduction signalling triggered by the pericyte-like spreading of disseminated cancer cells on host tissue capillaries is critical for metastatic colonization. Disseminated cancer cells employ L1CAM (cell adhesion molecule L1) to spread on capillaries and activate the mechanotransduction effectors YAP (Yes-associated protein) and MRTF (myocardin-related transcription factor). This spreading is robust enough to displace resident pericytes, which also use L1CAM for perivascular spreading. L1CAM activates YAP by engaging ß1 integrin and ILK (integrin-linked kinase). L1CAM and YAP signalling enables the outgrowth of metastasis-initiating cells both immediately following their infiltration of target organs and after they exit from a period of latency. Our results identify an important step in the initiation of metastatic colonization, define its molecular constituents and provide an explanation for the widespread association of L1CAM with metastatic relapse in the clinic.

MicroRNA signature and function in retinal neovascularization.

Ischemic retinopathies are clinically well-defined chronic microvascular complications characterized by gradually progressive alterations in the retinal microvasculature and a compensatory aberrant neovascularization of the eye. The subsequent metabolic deficiencies result in structural and functional alterations in the retina which is highly susceptible to injurious stimuli such as diabetes, trauma, hyperoxia, inflammation, aging and dysplipidemia. Emerging evidence indicates that an effective therapy may require targeting multiple components of the angiogenic pathway. Conceptually, mircoRNA (miRNA)-based therapy provides the rationale basis for an effective antiangiogenic treatment. miRNAs are an evolutionarily conserved family of short RNAs, each regulating the expression of multiple protein-coding genes. The activity of specific miRNAs is important for vascular cell signaling and blood vessel formation and function. Recently, important progress has been made in mapping the miRNA-gene target network and miRNA-mediated gene expression control. Here we highlight the latest findings on angiogenic and antiangiogenic miRNAs and their targets as well as potential implications in ocular neovascular diseases. Emphasis is placed on how specific vascular-enriched miRNAs regulate cell responses to various cues by targeting several factors, receptors and/or signaling molecules in order to maintain either vascular function or dysfunction. Further improvement of our knowledge in not only miRNA specificity, turnover, and transport but also how miRNA sequences and functions can be altered will enhance the therapeutic utility of such molecules.