Residency Application Advising: Medical Student & Faculty Advisor Perceived Barriers & Expectations.

INTRODUCTION: Given the rapidly changing landscape of residency applications, many medical students struggle to identify guidance from faculty advisors. Additionally, faculty advisors may find it difficult to maintain up-to-date knowledge on changes such as the new supplemental application. These gaps could potentially lead to inequitable advising. The objective of this study was to identify both students' and faculty's perceived barriers and expectations for residency application advising. METHODS: Anonymous surveys were administered to both fourth-year medical students and faculty advisors at a single institution within 2 mo of the residency application deadline. Survey questions assessed student and faculty barriers to establishing the advisor-advisee relationships, as well as expectations of the advisor role. Surveys were analyzed using descriptive statistics. RESULTS: We identified that the majority of students (57%) did not have a faculty advisor within weeks of the application deadline, and an equal amount felt that finding an advisor was either somewhat difficult or extremely difficult. Of all the students, 60% felt their biggest barrier was not knowing how to find an advisor. Though faculty felt equipped to advise students, 75% of faculty in the participating specialties had advising concerns regarding the supplemental application or were unaware of the changes. CONCLUSIONS: We identified gaps in the residency application advising process from both student and faculty perspectives. Future work involves increasing awareness of the resources and opportunities available to students to improve advising relationships. Standardized training tools and resources for faculty will result in more consistent and reliable faculty advising.

Modulation of Chromatin by Noncoding RNA.

Noncoding RNAs (ncRNAs) are remarkably powerful, flexible, and pervasive cellular regulators. The involvement of these molecules in virtually all aspects of eukaryotic chromatin function is notable. Long and short ncRNAs play broadly complementary roles in these processes. Short ncRNAs underlie a programmable system of chromatin modification that silences mobile elements, identifies boundaries, and initiates the formation of constitutive heterochromatin in yeast. In contrast, long noncoding RNAs (lncRNAs) enforce developmentally appropriate expression and switch gene expression programs. lncRNAs accomplish this through diverse mechanisms, but often by modulating the activity or localization of chromatin regulatory complexes. Both long and short ncRNAs play key roles in organization of complex genomes of higher eukaryotes, and their coordinated actions appear to underlie some of the more dramatic examples of epigenetic regulation. This review contrasts well-studied examples of chromatin regulation by RNA and introduces examples of coordination between these systems.

Effectiveness of KTP lasers in tooth bleaching, by comparing tooth color change after bleaching with KTP, Nd:YAG, Er:YAG, and diode laser system: A systematic review.

This systematic review evaluated the role of Potassium-titanyl-phosphate (KTP) lasers in dental bleaching by comparing tooth color change and rise in intrapulpal temperature after bleaching with KTP, Neodymium-doped yttrium aluminum garnet (Nd:YAG), Er:YAG, and diode laser system. Following were the inclusion criteria: in vitro studies in English available in full text. Articles published between 2000 and 2021 were selected. The search for was conducted on PubMed, Cochrane library/CENTRAL, Wiley online library, ProQuest, Science Direct, and Hand searching/specialized registers. Keywords were used: "Lasers" [Mesh] and "Tooth bleaching" [Mesh] using Boolean operators. A total of four articles fulfilled the inclusion criteria. The quality assessment of studies included was undertaken independently as part of data extraction process. KTP lasers demonstrated more effectiveness in attaining color change in stained teeth and showed the lowest rise in intrapulpal temperature. Based on the data obtained in the present review, the choice of bleaching treatment is directly related to the type of discoloration, activation of the bleaching agent, and esthetic requirement. Although all bleaching procedures were effective in color change, the KTP laser showed better results when compared to other laser activation. The bleaching treatment protocol is directly related to the type of discoloration, activation of the bleaching agent, and esthetic requirement. It has been demonstrated that a faster change in color can be obtained when bleaching is performed in combination with a light source, i.e., power bleaching aiming for a more in-depth change of color.

Enhancing precision: A predictive model for 177Lu-DOTATATE treatment response in neuroendocrine tumors using quantitative 68Ga-DOTATATE PET and clinicopathological biomarkers.

Purpose: This study aims to elucidate the role of quantitative SSTR-PET metrics and clinicopathological biomarkers in the progression-free survival (PFS) and overall survival (OS) of neuroendocrine tumors (NETs) treated with peptide receptor radionuclide therapy (PRRT). Methods: A retrospective analysis including 91 NET patients (M47/F44; age 66 years, range 34-90 years) who completed four cycles of standard 177Lu-DOTATATE was conducted. SSTR-avid tumors were segmented from pretherapy SSTR-PET images using a semiautomatic workflow with the tumors labeled based on the anatomical regions. Multiple image-based features including total and organ-specific tumor volume and SSTR density along with clinicopathological biomarkers including Ki-67, chromogranin A (CgA) and alkaline phosphatase (ALP) were analyzed with respect to the PRRT response. Results: The median OS was 39.4 months (95% CI: 33.1-NA months), while the median PFS was 23.9 months (95% CI: 19.3-32.4 months). Total SSTR-avid tumor volume (HR = 3.6; P = 0.07) and bone tumor volume (HR = 1.5; P = 0.003) were associated with shorter OS. Also, total tumor volume (HR = 4.3; P = 0.01), liver tumor volume (HR = 1.8; P = 0.05) and bone tumor volume (HR = 1.4; P = 0.01) were associated with shorter PFS. Furthermore, the presence of large lesion volume with low SSTR uptake was correlated with worse OS (HR = 1.4; P = 0.03) and PFS (HR = 1.5; P = 0.003). Among the biomarkers, elevated baseline CgA and ALP showed a negative association with both OS (CgA: HR = 4.9; P = 0.003, ALP: HR = 52.6; P = 0.004) and PFS (CgA: HR = 4.2; P = 0.002, ALP: HR = 9.4; P = 0.06). Similarly, number of prior systemic treatments was associated with shorter OS (HR = 1.4; P = 0.003) and PFS (HR = 1.2; P = 0.05). Additionally, tumors originating from the midgut primary site demonstrated longer PFS, compared to the pancreas (HR = 1.6; P = 0.16), and those categorized as unknown primary (HR = 3.0; P = 0.002). Conclusion: Image-based features such as SSTR-avid tumor volume, bone tumor involvement, and the presence of large tumors with low SSTR expression demonstrated significant predictive value for PFS, suggesting potential clinical utility in NETs management. Moreover, elevated CgA and ALP, along with an increased number of prior systemic treatments, emerged as significant factors associated with worse PRRT outcomes.

ALCAM-mediated cDC1 CD8 T cells interactions are suppressed in advanced lung tumors.

Conventional type 1 dendritic cells (cDC1) are critical regulators of anti-tumoral T-cell responses. The structure and abundance of intercellular contacts between cDC1 and CD8 T cells in cancer tissues is important to determine the outcome of the T-cell response. However, the molecular determinants controlling the stability of cDC1-CD8 interactions during cancer progression remain poorly investigated. Here, we generated a genetic model of non-small cell lung cancer crossed to a fluorescent cDC1 reporter (KP-XCR1venus) to allow the detection of cDC1-CD8T cell clusters in tumor tissues across tumor stages. We found that cDC1-CD8 clusters are abundant and productive at the early stages of tumor development but progressively diminish in advanced tumors. Transcriptional profiling and flow cytometry identified the adhesion molecule ALCAM/CD166 (Activated Leukocyte Cell Adhesion Molecule, ligand of CD6) as highly expressed by lung cDC1 and significantly downregulated in advanced tumors. Analysis of human datasets indicated that ALCAM is downregulated in non-small cell lung cancer and its expression correlates to better prognosis. Mechanistically, triggering ALCAM on lung cDC1 induces cytoskeletal remodeling and contact formation whereas its blockade prevents T-cell activation. Together, our results indicate that ALCAM is important to stabilize cDC1-CD8 interactions at early tumor stages, while its loss in advanced tumors contributes to immune evasion.

Tim4 enables large peritoneal macrophages to cross-present tumor antigens at early stages of tumorigenesis.

Receptors controlling the cross-presentation of tumor antigens by macrophage subsets in cancer tissues are poorly explored. Here, we show that TIM4+ large peritoneal macrophages efficiently capture and cross-present tumor-associated antigens at early stages of peritoneal infiltration by ovarian cancer cells. The phosphatidylserine (PS) receptor TIM4 promotes maximal uptake of dead cells or PS-coated artificial targets and triggers inflammatory and metabolic gene programs in combination with cytoskeletal remodeling and upregulation of transcriptional signatures related to antigen processing. At the cellular level, TIM4-mediated engulfment induces nucleation of F-actin around nascent phagosomes, delaying the recruitment of vacuolar ATPase, acidification, and cargo degradation. In vivo, TIM4 deletion blunts induction of early anti-tumoral effector CD8 T cells and accelerates the progression of ovarian tumors. We conclude that TIM4-mediated uptake drives the formation of specialized phagosomes that prolong the integrity of ingested antigens and facilitate cross-presentation, contributing to immune surveillance of the peritoneum.

Dendritic cell-targeted therapy expands CD8 T cell responses to bona-fide neoantigens in lung tumors.

Cross-presentation by type 1 DCs (cDC1) is critical to induce and sustain antitumoral CD8 T cell responses to model antigens, in various tumor settings. However, the impact of cross-presenting cDC1 and the potential of DC-based therapies in tumors carrying varied levels of bona-fide neoantigens (neoAgs) remain unclear. Here we develop a hypermutated model of non-small cell lung cancer in female mice, encoding genuine MHC-I neoepitopes to study neoAgs-specific CD8 T cell responses in spontaneous settings and upon Flt3L + αCD40 (DC-therapy). We find that cDC1 are required to generate broad CD8 responses against a range of diverse neoAgs. DC-therapy promotes immunogenicity of weaker neoAgs and strongly inhibits the growth of high tumor-mutational burden (TMB) tumors. In contrast, low TMB tumors respond poorly to DC-therapy, generating mild CD8 T cell responses that are not sufficient to block progression. scRNA transcriptional analysis, immune profiling and functional assays unveil the changes induced by DC-therapy in lung tissues, which comprise accumulation of cDC1 with increased immunostimulatory properties and less exhausted effector CD8 T cells. We conclude that boosting cDC1 activity is critical to broaden the diversity of anti-tumoral CD8 T cell responses and to leverage neoAgs content for therapeutic advantage.

Reattachment of fractured anterior teeth-determining fracture strength using different techniques: an in vitro study.

AIM: The aim of this in vitro study was to evaluate and compare the shear bond strength of teeth reattached with sixth generation dentin bonding agent: Xeno III and microhybrid resin composite: Esthet-X, using three different techniques: (1) Simple reattachment, (2) overcontour and (3) internal dentinal groove. METHODOLOGY: A total of 70 human maxillary central incisors were selected and divided into four groups as follows. Group I: Control group comprised of 10 samples. Group II: Simple reattachment, group III: Overcontour and group IV: Internal dentinal groove. Groups II, III and IV comprised of 20 samples each. The teeth in three study groups were sectioned using a diamond disk and the fragment was reattached with Esthet-X and Xeno III using three different techniques. Specimens were stored in tap water for 24 hours and shear bond strength was determined using universal testing machine using a knife edge chisel (0.5 mm in cross-section) at a crosshead speed of 1 mm/minute. RESULTS: The results of this study showed following mean value of fracture strength in Kgf: Group I: Control-27.71; group II: Simple reattachment-9.78; group III: Overcontour-24.41; group IV: Internal dentinal groove-23.83. CONCLUSION: The overcontour technique had the highest strength recovery while the simple reattachment had the lowest. CLINICAL SIGNIFICANCE: The overcontour technique provided strength recovery almost similar to intact teeth emphasizing that tooth preparation influenced fracture resistance.

Free fatty acid receptor 4 responds to endogenous fatty acids to protect the heart from pressure overload.

AIMS: Free fatty acid receptor 4 (Ffar4) is a G-protein-coupled receptor for endogenous medium-/long-chain fatty acids that attenuates metabolic disease and inflammation. However, the function of Ffar4 in the heart is unclear. Given its putative beneficial role, we hypothesized that Ffar4 would protect the heart from pathologic stress. METHODS AND RESULTS: In mice lacking Ffar4 (Ffar4KO), we found that Ffar4 is required for an adaptive response to pressure overload induced by transverse aortic constriction (TAC), identifying a novel cardioprotective function for Ffar4. Following TAC, remodelling was worsened in Ffar4KO hearts, with greater hypertrophy and contractile dysfunction. Transcriptome analysis 3-day post-TAC identified transcriptional deficits in genes associated with cytoplasmic phospholipase A2α signalling and oxylipin synthesis and the reduction of oxidative stress in Ffar4KO myocytes. In cultured adult cardiac myocytes, Ffar4 induced the production of the eicosapentaenoic acid (EPA)-derived, pro-resolving oxylipin 18-hydroxyeicosapentaenoic acid (18-HEPE). Furthermore, the activation of Ffar4 attenuated cardiac myocyte death from oxidative stress, while 18-HEPE rescued Ffar4KO myocytes. Systemically, Ffar4 maintained pro-resolving oxylipins and attenuated autoxidation basally, and increased pro-inflammatory and pro-resolving oxylipins, including 18-HEPE, in high-density lipoproteins post-TAC. In humans, Ffar4 expression decreased in heart failure, while the signalling-deficient Ffar4 R270H polymorphism correlated with eccentric remodelling in a large clinical cohort paralleling changes observed in Ffar4KO mice post-TAC. CONCLUSION: Our data indicate that Ffar4 in cardiac myocytes responds to endogenous fatty acids, reducing oxidative injury, and protecting the heart from pathologic stress, with significant translational implications for targeting Ffar4 in cardiovascular disease.

Linguistic history and language diversity in India: Views and counterviews.

This paper addresses the theme of the seminar from the perspective of historical linguistics. It introduces the construct of 'language family' and then proceeds to a discussion of contact and the dynamics of linguistic exchange among the main language families of India over several millennia. Some prevalent hypotheses to explain the creation of India as a linguistic area are presented. The 'substratum view' is critically assessed. Evidence from historical linguistics in support of two dominant hypotheses - 'the Aryan migration view''and 'the out-of-India hypothesis' - is presented and briefly assessed. In conclusion, it is observed that the current understanding in historical linguistics favours the Aryan migration view though the 'substratum view' is questionable.