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PURPOSE: We investigated the effect of metformin and lifestyle intervention on metabolic, inflammatory, and steroid biomarkers of breast cancer (BC) recurrence risk in two intervention trials among BC survivors with overweight or obesity. METHODS: Baseline and follow-up serum samples collected during the two trials were analyzed and data pooled. The USA trial (Reach for Health) included postmenopausal BC survivors (n = 333) randomly assigned to 6-month metformin vs placebo and lifestyle intervention (LSI) vs control (2 × 2 factorial design). The Italian trial (MetBreCS) included BC survivors (n = 40) randomized to 12-month metformin vs placebo. Insulin resistance (HOMA-IR), adipokines, cytokines, and steroids were measured. RESULTS: Metformin compared to placebo showed a favorable decrease in leptin (- 8.8 vs - 3.5 ng/mL; p

Matteo Frigerio,1 Andrea Morciano,2 Marta Barba,1 Michele Carlo Schiavi,3 Alice Cola,1 Elena Cavaliere,4 Carlo Rappa,5 Mauro Cervigni6 On behalf of the “Young Commission” of the Italian Association of Urological Gynecology and Pelvic Floor (AIUG)1Fondazione IRCCS San Gerardo dei Tintori, Monza, Italy; 2Department of Gynecology and Obstetrics, Panico Pelvic Floor Center, Pia Fondazione “Cardinale G. Panico”, Tricase, Italy; 3Department of Gynaecology and Obstetrics, “Sandro Pertini” Hospital, Roma, Italy; 4Department of Gynecology and Obstetric B, Ospedale Della Donna E Del Bambino, Verona, Italy; 5Centro PelviCare “Clinica Villa Angela”, Napoli, Italy; 6Department of Urology, Università “la Sapienza”, ICOT, Latina, ItalyCorrespondence: Marta Barba, Fondazione IRCCS San Gerardo dei Tintori, via G.B. Pergolesi, 33, Monza, 20900, Italy, Tel +0392339434, Email m.barba8792@gmail.comPurpose: Surgical repair is considered the mainstay of genital prolapse management. Several procedures are available both by vaginal and abdominal route, with and without mesh augmentation. The Italian UroGynecology Association (AIUG) promoted this survey with the aim of evaluating current variations in the surgical management of various types of prolapse in different clinical settings and to compare practice amongst practitioners working in high- and medium/low-volume centers.Participants and Methods: The questionnaire examined four contentious areas of contemporary prolapse management. The questionnaire was emailed to the AIUG gynecologist members in Italy in 2023.Results: A total of 104 complete responses were received, resulting in a 6.9% response rate. Native-tissue repair represents the preferred option in most scenarios and was proposed by 76%, 68.3%, 94.2%, and 52.9% of practitioners in the case of primary anterior, uterovaginal, posterior, and vault prolapse respectively. The use of vaginal mesh in these scenarios is very limited. Native tissue repairs in case of recurrent anterior, posterior, or apical recurrent prolapse would be performed only by 37.5%, 47.1%, and 28% of surgeons respectively. In these cases, the use of mesh - by vaginal and abdominal route - increased significantly.Conclusion: This survey showed that in Italy surgical management of genital prolapse is very heterogeneous. Native-tissue repair remains the preferred option, but practitioners tend to lose confidence in mesh-free procedures in case of prolapse recurrence. Despite mesh kits recalls and recommendations, the use of transvaginal implants is still considered an option for prolapse repair.Keywords: pelvic floor, pelvic organ prolapse, survey, surgery, management, urogynecology

Abstract Lynch syndrome is rarely associated with rectal cancer (RC) and thus, metachronous RC has been scarcely investigated. This study aimed to analyze the mucosal immune microenvironment in sporadic and metachronous RC. We analyzed the mucosal immune microenvironment in the 25 metachronous RCs present in the IMMUNOREACT 1 and 2 multicentre observational studies (624 patients). A panel of immune markers was retrospectively investigated at immunohistochemistry: CD3, CD4, CD8, CD8b, Tbet, FoxP3, PD-L1, MSH6, and PMS2 and CD80. Single-cell suspensions were subjected to flow-cytometry to determine the proportion of epithelial cells (pan-cytokeratin) acting as antigen-presenting cells (expressing CD80, CD86, HLA-ABC) and the proportion of activated CD8 + T cells (CD8 + positive for CD28, CD38), inhibitory T cells (CD3 + CTLA-4+) of activated CD4 + T helper cells (CD4 + CD25+) and activated T regulatory cells (CD4 + CD25 + FoxP3+). No mismatch repair gene deficiencies were observed in the patients. The previous history of colorectal adenoma was significantly more frequent in metachronous RC. In healthy epithelial cells, HLA-ABC expression was significantly higher in patients with metachronous RC. In therapy-naïve metachronous RC patients, a significantly lower level of circulating lymphocytes and CD3 + T-cell infiltration in the healthy mucosa surrounding the RC was observed compared to patients with non-metachronous cancer. Our study supports the hypothesis that metachronous RC can occur in a cancerization field in patients with weak systemic and local immune systems. The peculiar site of RC makes the mismatch-repair genes deficiency in metachronous cancer onset less relevant.

Abstract Histone H3-mutant gliomas are deadly brain tumors characterized by a dysregulated epigenome and stalled differentiation. In contrast to the extensive datasets available on tumor cells, limited information exists on their tumor microenvironment (TME), particularly the immune infiltrate. Here, we characterize the immune TME of H3.3K27M and G34R/V-mutant gliomas, and multiple H3.3K27M mouse models, using transcriptomic, proteomic and spatial single-cell approaches. Resolution of immune lineages indicates high infiltration of H3-mutant gliomas with diverse myeloid populations, high-level expression of immune checkpoint markers, and scarce lymphoid cells, findings uniformly reproduced in all H3.3K27M mouse models tested. We show these myeloid populations communicate with H3-mutant cells, mediating immunosuppression and sustaining tumor formation and maintenance. Dual inhibition of myeloid cells and immune checkpoint pathways show significant therapeutic benefits in pre-clinical syngeneic mouse models. Our findings provide a valuable characterization of the TME of oncohistone-mutant gliomas, and insight into the means for modulating the myeloid infiltrate for the benefit of patients.

The 21st century has seen a dramatic rise in experiential learning research and practice. After the previous century, where research on subjective experience was for the most part excluded from academic journals, there is today a resurgence of scholarly research on experience and experiential learning. Yet, how do we know when a given educational experience is experiential? We argue that there is something more to experiential learning than just having an experience. That "something more" is a process of experiencing, a process whereby the learner deeply engages with an experience and is fully present. Through research conducted from an international sample of learners who based response to their lived experience outside of the classroom, we extend findings from Stock & Kolb (2021) and introduce a revised version of the Experiencing Scale based on the discovery of the overarching importance of the role of presence and its ramifications for the experiencing process. Our analysis here suggests that when learning is experiential, it is characterized by active participation, sensory engagement, deep involvement, alert/aware attention and being fully present in the here-and-now.

Research development in higher education is a service-delivery system. In any service field, when choosing appropriate services, practitioners should reach for 'evidence-based practices.' Limited empirical research has addressed the preferences of research faculty regarding research support services. In this project, we sought to provide research development professionals with critical knowledge related to decision making and strategic utilization of resources and in choosing client-centered grant-related services for faculty. The specific research question or objective of this study was to answer, "What factors are perceived by faculty to be barriers or facilitators to grants activity based on extant literature?" This systematic literature review on faculty perceptions of barriers and facilitators to grant activity used an eight-step systematic literature review methodology. The findings describe the characteristics, methodological attributes, and the methodological quality of the articles. Additionally, the integration of the findings revealed eight main factors that faculty perceived to be important for facilitating or hindering grant activity. Three main emerging factors or core categories appeared to be most important across all barriers or facilitators to faculty grant activity. Research development professionals need to be able to provide evidence-based and client-centered research support services. This review provides the factors that faculty view as being most important to grant activity and recommendations for management. Implementing effective client-centered research support services is critical for the success of faculty grant activity.

Abstract Genetically-encoded dopamine (DA) sensors enable high-resolution imaging of DA release, but their ability to detect a wide range of extracellular DA levels, especially tonic versus phasic DA release, is limited by their intrinsic affinity. Here we show that a human-selective dopamine receptor positive allosteric modulator (PAM) can be used to boost sensor affinity on-demand. The PAM enhances DA detection sensitivity across experimental preparations (in vitro, ex vivo and in vivo) via one-photon or two-photon imaging. In vivo photometry-based detection of optogenetically-evoked DA release revealed that DETQ administration produces a stable 31 minutes window of potentiation without effects on animal behavior. The use of the PAM revealed region-specific and metabolic state-dependent differences in tonic DA levels and enhanced single-trial detection of behavior-evoked phasic DA release in cortex and striatum. Our chemogenetic strategy can potently and flexibly tune DA imaging sensitivity and reveal multi-modal (tonic/phasic) DA signaling across preparations and imaging approaches.