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Abstract Background Mesenchymal stem/stromal cells (MSCs) can regenerate tissues through engraftment and differentiation but also via paracrine signalling via extracellular vesicles (EVs). Fetal-derived MSCs (fMSCs) have been shown, both in vitro and in animal studies, to be more efficient than adult MSC (aMSCs) in generating bone and muscle but the underlying reason for this difference has not yet been clearly elucidated. In this study, we aimed to systematically investigate the differences between fetal and adult MSCs and MSC-derived EVs at the phenotypic, RNA, and protein levels. Methods We carried out a detailed and comparative characterization of culture-expanded fetal liver derived MSCs (fMSCs) and adult bone marrow derived MSCs (aMSCs) phenotypically, and the MSCs and MSC-derived EVs were analysed using transcriptomics and proteomics approaches with RNA Sequencing and Mass Spectrometry. Results Fetal MSCs were smaller, exhibited increased proliferation and colony-forming capacity, delayed onset of senescence, and demonstrated superior osteoblast differentiation capability compared to their adult counterparts. Gene Ontology analysis revealed that fMSCs displayed upregulated gene sets such as “Positive regulation of stem cell populations”, “Maintenance of stemness” and “Muscle cell development/contraction/Myogenesis” in comparison to aMSCs. Conversely, aMSCs displayed upregulated gene sets such as “Complement cascade”, “Adipogenesis”, “Extracellular matrix glycoproteins” and “Cellular metabolism”, and on the protein level, “Epithelial cell differentiation” pathways. Signalling entropy analysis suggested that fMSCs exhibit higher signalling promiscuity and hence, higher potency than aMSCs. Gene ontology comparisons revealed that fetal MSC-derived EVs (fEVs) were enriched for “Collagen fibril organization”, “Protein folding”, and “Response to transforming growth factor beta” compared to adult MSC-derived EVs (aEVs), whereas no significant difference in protein expression in aEVs compared to fEVs could be detected. Conclusions This study provides detailed and systematic insight into the differences between fMSCs and aMSCs, and MSC-derived EVs. The key finding across phenotypic, transcriptomic and proteomic levels is that fMSCs exhibit higher potency than aMSCs, meaning they are in a more undifferentiated state. Additionally, fMSCs and fMSC-derived EVs may possess greater bone forming capacity compared to aMSCs. Therefore, using fMSCs may lead to better treatment efficacy, especially in musculoskeletal diseases.

Evidence-based practice in educational development includes leveraging data to iteratively refine center for teaching and learning (CTL) services. However, CTL data collection is often limited to counts and satisfaction surveys rather than direct measures of outcomes. To directly assess impacts of consultations on course and syllabus design, we analyzed 94 clients' syllabi (32 faculty, 62 graduate students and postdocs) before and after consultations. Faculty and non-faculty clients demonstrated significant change following consultations (6% and 10% gains in syllabus rubric scores, representing 50% and 31% of possible gains and effect sizes of 0.73 and 1.04 standard deviations, respectively). We compared faculty clients to quasi-experimental control groups that did not receive consultations. Syllabi from non-clients scored lower and did not demonstrate similar changes across semesters. Attendance at a CTL seminar on course and syllabus design did not explain variation in clients' syllabi. We discuss implications for assessment of CTL services and how we leveraged formative assessments to inform and iteratively refine our educational development practices.

Abstract Hereditary alpha-tryptasemia (HαT) is an autosomal dominant disorder estimated to affect 5% of the population. High baseline tryptase level is a consistent finding, but there is a great variability of clinic manifestations, including no symptoms at all. We describe a case of HαT in a 5 years 8 months old girl manifesting with idiopathic anaphylaxis and elevated baseline tryptase level. As more cases of HαT are described, a better understanding of the clinical phenotype will be acquired.

Abstract Background Cancer-associated fibroblasts (CAFs) are considered to play a fundamental role in pancreatic ductal adenocarcinoma (PDAC) progression and chemoresistance. Patient-derived organoids have demonstrated great potential as tumor avatars for drug response prediction in PDAC, yet they disregard the influence of stromal components on chemosensitivity. Methods We established direct three-dimensional (3D) co-cultures of primary PDAC organoids and patient-matched CAFs to investigate the effect of the fibroblastic compartment on sensitivity to gemcitabine, 5-fluorouracil and paclitaxel treatments using an image-based drug assay. Single-cell RNA sequencing was performed for three organoid/CAF pairs in mono- and co-culture to uncover transcriptional changes induced by tumor-stroma interaction. Results Upon co-culture with CAFs, we observed increased proliferation and reduced chemotherapy-induced cell death of PDAC organoids. Single-cell RNA sequencing data evidenced induction of a pro-inflammatory phenotype in CAFs in co-cultures. Organoids showed increased expression of genes associated with epithelial-to-mesenchymal transition (EMT) in co-cultures and several potential receptor-ligand interactions related to EMT were identified, supporting a key role of CAF-driven induction of EMT in PDAC chemoresistance. Conclusions Our results demonstrate the potential of personalized PDAC co-cultures models not only for drug response profiling but also for unraveling the molecular mechanisms involved in the chemoresistance-supporting role of the tumor stroma.

Background: There has been an increasing number of Canadian medical graduates who have gone unmatched in the residency selection process. Medical students have been engaging in extracurricular activities outside the formal curriculum which may help to distinguish themselves from their peers in the selection process. To understand how competitiveness in residency selection shapes applicant demographic characteristics and behaviours, this study set out to explore the demographic characteristics and prevalence of reported extra-curricular activities by applicants to Canadian Otolaryngology – Head & Neck Surgery (OTL-HNS) residency across time. Methods: A retrospective, descriptive study reviewed specific sections of the curriculum vitae (CV) of applicants to OTL-HNS programs in Canada. These sections were self-reported, and included research productivity, involvement in volunteer and leadership activities, membership in associations, and honours or awards granted. Data was quantified and analyzed descriptively. Results: Between 2013 to 2017, a total of 267 applicants reported a median of 12.6 research publications, 9.6 volunteer activities, six leadership activities, six association memberships and 9.8 honours/awards. Applicants were younger over time, with proportions of applicants over 30 years old decreasing from 56% in 2013 to 9% in 2017. Conclusion: Applicants to Canadian OTL-HNS residency programs are reporting consistently high numbers of extracurricular activities and were of increasingly younger ages. Medical students are investing significant time and energy to pursue these activities which are above and beyond the formal curriculum, possibly contributing to decreased diversity in applicants for competitive residencies, increasing the likelihood of misrepresentation in residency applications, and likely contributing to medical student burnout.

Summary: Although dietary fructose is associated with an elevated risk for pancreatic cancer, the underlying mechanisms remain elusive. Here, we report that ketohexokinase (KHK), the rate-limiting enzyme of fructose metabolism, is a driver of PDAC development. We demonstrate that fructose triggers KHK and induces fructolytic gene expression in mouse and human PDAC. Genetic inactivation of KhkC enhances the survival of KPC-driven PDAC even in the absence of high fructose diet. Furthermore, it decreases the viability, migratory capability, and growth of KPC cells in a cell autonomous manner. Mechanistically, we demonstrate that genetic ablation of KHKC strongly impairs the activation of KRAS-MAPK pathway and of rpS6, a downstream target of mTORC signaling. Moreover, overexpression of KHKC in KPC cells enhances the downstream KRAS pathway and cell viability. Our data provide new insights into the role of KHK in PDAC progression and imply that inhibiting KHK could have profound implications for pancreatic cancer therapy.

Our experiment demonstrates that LED-pumping through luminescent concentrator enables sufficient pump power for viable alexandrite amplifier gain. In 10 passes we obtain a gain of 19 with 10 W output power, for 50 µs pulses at 20 Hz and 760 nm.

Objectives: The oral cavity commonly displays mucosal lichenoid lesions and salivary gland dysfunction, which are considered different chronic Graft-versus-Host Disease (cGVHD) pathophysiology’s. However, diagnostics of salivary gland (sg-)cGVHD are limited. The objectives of the current study are to evaluate the minor salivary gland (MSG) histo-immunopathological profiles post allogenic hematopoietic cell transplantation based on sg-cGVHD criteria. Design: Histopathology was characterized according to two published grading strategies. Firstly, the National Institute of Health (NIH) assessed peri-ductal/acinar infiltration, exocytosis, damage, and fibrosis, and a points-based grading scheme was established (0–16 points, Grade (G) 0 to IV). Second, a modified Sjögren’s Syndrome focus-score with parenchymal damage was also adapted, (0–10 points, Score 0 to 2). 146 MSG biopsies from 79 patients were compared, using the histopathological specific criteria for sg-cGVHD pathology. Quantitative immunohistochemistry for T-cells (CD4, CD8), B-cells (CD19, CD20), monocytic cells (CD68) and dendritic cells (CD1a) were also assessed. Results: The large-scale cohort validated the use of both grading schemes. GIII-GIV and score 2 signified a histopathological diagnosis of “likely” sg-cGVHD. Immunopathological severity was associated with increased T-cells (CD4 and CD8) and monocytic (CD68) infiltrate, with minimal involvement of B-cells (CD19 and CD20), and Langerhans cells (CD1a). Conclusions: Both schemes were verified as being suitable for histological grading to improve assessment and diagnosis of sg-cGVHD. The NIH cGVHD grading appears to be more beneficial for research purposes, including final diagnostics of “no/inactive”, “possible” or “likely” cGVHD. The study highlights the intricacies of sg-cGVHD pathology; and the need for standardized assessment to improve patient management associated to sg-cGVHD.

Objective: Retention to complete follow-up surveys in extensive longitudinal epidemiological cohort studies is vital yet challenging. All of Us developed pilot interventions to improve response rates for follow-up surveys. Study design and setting: The pilot interventions occurred from April 27, 2020, to August 3, 2020. The three arms were: (1) telephone appointment [staff members calling participants offering appointments to complete surveys over phone] (2) postal [mail reminder to complete surveys through U.S. Postal Service], and (3) combination of telephone appointment and postal. Controls received digital-only reminders [program-level digital recontact via email or through the participant portal]. Study sites chose their study arm and participants were not randomized. Results: A total of 50 sites piloted interventions with 17,593 participants, while 47,832 participants comprised controls during the same period. Of all participants, 6,828 (10.4%) completed any follow-up surveys (1448: telephone; 522: postal; 486: combination; 4372: controls). Follow-up survey completions were 24% higher in the telephone appointment arm than in controls in bivariate analyses. When controlling for confounders, telephone appointment and combination arms increased rates of completion similarly compared to controls, while the postal arm had no significant effect (odds ratio [95% Confidence Interval], telephone appointment:2.01[1.81–2.23]; combination:1.91[1.66–2.20]; postal:0.92[0.79–1.07]). Although the effects of the telephone appointment and combination arms were similar, differential effects were observed across sub-populations. Conclusion: Telephone appointments appeared to be the most successful intervention in our study. Lessons learned about retention interventions, and improvement in follow-up survey completion rates provide generalizable knowledge for similar cohort studies and demonstrate the potential value of precision reminders and engagement with sub-populations of a cohort. [ABSTRACT FROM AUTHOR]

The preparation of enantioenriched diarylmethanol derivatives is described using nickel‐catalyzed electrochemical cross‐couplings between various alkyl/aryl aldehydes and aryl iodides. Performed in an electrochemical cell equipped with an iron anode and a nickel cathode, this electrocatalytic variant led to the scalemic targeted products in the presence of 2,2‐bis((4 R,5S)‐4,5‐diphenyl‐4,5‐dihydrooxazol‐2‐yl)acetonitrile (L2), as enantiopure cyano‐bis(oxazoline) ligand. X‐ray structure analysis of a pre‐catalyst, for instance the [Ni(II)(L2)2] complex, with L2 as an anionic bisoxazolinate ligand, confirms the chemical formulation of one nickel surrounded by two ligands. The redox behavior of the new Ni complexes generated in situ was first assessed by cyclic voltammetry showing a redox wave at ca. −1.5 V that can be assigned to the two‐electron reduction of the Ni(II) center to the Ni(0) state. Oxidative addition between the electrogenerated Ni(0) complex and aryl iodide was evidenced. An intense current was observed in presence of a mixture of the two substrates pertaining an electrocatalytic process. Interestingly, we found that the sacrificial iron anode plays a crucial role in the catalytic mechanism. [ABSTRACT FROM AUTHOR]

nema

Introduction Evidence suggests that minorities tend to under-utilize mental health services, and may face specific barriers and facilitators towards recovery. One community which remains particularly under-researched in the Western World are Haredi Jews — a diverse group of individuals characterized by a shared devotion to traditional Talmudic and Halakhah teachings and observances. Objectives The overarching aim of this study is to document and analyze barriers and facilitators towards recovery and mental health service utilization among Haredi Jews with a history of mental distress. Specific objectives include: (i) eliciting and understanding participants’ mental health knowledge, beliefs, behaviours & attitudes; (ii) exploring their pathways and barriers to mental health care, especially examining the role of religiosity, religious community and rabbinical advice; and (iii) investigating their experience within the official mental health care system. Methods To gain an in-depth understanding, we conducted a qualitative study. This involved semi-structured interviews with 24 participants who (i) identified as Haredi Jews; (ii) had used mental health services; and (iii) were 18+ years of age. It also included interviews with several key stakeholders, for example local Rabbis and other community leaders. Data was analyzed using thematic analysis techniques. Results Participants typically had experienced mild to moderate mental distress, and tended to view mental health services in a positive light, mainly expressing satisfaction with services received. The analysis revealed three important facilitators and three important barriers to recovery. Facilitators comprised of (i) high levels of social support within the community, including specific well-being support groups; (ii) a positive relationship and connection with G-d, considered to provide guidance and support during troubled times; and (iii) the presence of many bridges and resources within the local Haredi community, including community-run health services, and Rabbis who encouraged mental health care utilization where appropriate. Barriers comprised of (i) stigma related to marriageability of self and offspring, inhibiting disclosure and mental health care use; (ii) acknowledged lack of awareness and knowledge about mental health, mental illness, treatments, and therapies; and (iii) generic health service issues, including long waitlists, limited availability and lack of appropriate therapists. Conclusions Study participants tended to have positive views of psychiatric services, and utilized different health care and community-based resources to help foster recovery. However, ongoing issues of stigma and low levels of mental health literacy may inhibit mental health care use and recovery. This implies a need for religiously-informed and community-grounded mental health literacy campaigns among Haredi Jewish communities. Disclosure of Interest None Declared

Pancreatic tumors are frequently divided into basal and classical subtypes. Here, the authors use single cell sequencing to investigate organoids derived from pancreatic cancer tissue and find a hierarchy of distinct cell states, and classical and basal cells existing within the same tumor.