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Abstract Background Learning environment in any medical school is found to be important in determining students' academic success. This study was undertaken to compare the perceptions of first year and clinical phase students regarding the learning environment at Melaka Manipal Medical College (MMMC) (Manipal Campus) and also to identify the gender wise differences in their perceptions. Methods In the present study, the Dundee Ready Education Environment Measure (DREEM) inventory was used. DREEM was originally developed at Dundee and has been validated as a universal diagnostic inventory for assessing the quality of educational environment. In the present study, DREEM was administered to undergraduate medical students of first year (n = 118) and clinical phase (n = 108) and the scores were compared using a nonparametric test. Results Among the two batches, first year students were found to be more satisfied with the learning environment at MMMC (as indicated by their higher DREEM score) compared to the clinical batch students. Gender wise, there was not much difference in the students' perceptions. Conclusion The present study revealed that both groups of students perceived the learning environment positively. Nevertheless, the study also revealed problematic areas of learning environment in our medical school which enabled us to adopt some remedial measures.

Competing Interests: Competing interests: The authors declare no competing interests.

Cancer metastasis remains the most lethal characteristic of tumors mediating the majority of cancer-related deaths. Identifying key molecules responsible for metastasis, understanding their biological functions and therapeutically targeting these molecules is therefore of tremendous value. Metastasis Associated in Colon Cancer 1 (MACC1), a gene first described in 2009, is such a key driver of metastatic processes, initiating cellular proliferation, migration, invasion, and metastasis in vitro and in vivo. Since its discovery, the value of MACC1 as a prognostic biomarker has been confirmed in over 20 cancer entities. Additionally, several therapeutic strategies targeting MACC1 and its pro-metastatic functions have been developed. In this review, we will provide a comprehensive overview on MACC1, from its clinical relevance, towards its structure and role in signaling cascades as well as molecular networks. We will highlight specific biological consequences of MACC1 expression, such as an increase in stem cell properties, its immune-modulatory effects and induced therapy resistance. Lastly, we will explore various strategies interfering with MACC1 expression and/or its functions. Conclusively, this review underlines the importance of understanding the role of individual molecules in mediating metastasis., Competing Interests: Declarations. Ethics approval and consent to participate: N.A. Consent for publication: All authors have read and agreed to the published version of the manuscript. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

In multiple sclerosis (MS), persisting disability can occur independent of relapse activity or development of new central nervous system (CNS) inflammatory lesions, termed chronic progression. This process occurs early and it is mostly driven by cells within the CNS. One promising strategy to control progression of MS is the inhibition of the enzyme Bruton's tyrosine kinase (BTK), which is centrally involved in the activation of both B cells and myeloid cells, such as macrophages and microglia. The benefit of BTK inhibition by evobrutinib was shown as we observed reduced pro-inflammatory activation of microglia when treating chronic experimental autoimmune encephalomyelitis (EAE) or following the adoptive transfer of activated T cells. Additionally, in a model of toxic demyelination, evobrutinib-mediated BTK inhibition promoted the clearance of myelin debris by microglia, leading to an accelerated remyelination. These findings highlight that BTK inhibition has the potential to counteract underlying chronic progression of MS., (© 2024. The Author(s).)

Metastasis remains the most critical factor limiting patient survival and the most challenging part of cancer-targeted therapy. Identifying the causal drivers of metastasis and characterizing their properties in various key aspects of cancer biology is essential for the development of novel metastasis-targeting approaches. Metastasis-associated in colon cancer 1 (MACC1) is a prognostic and predictive biomarker that is now recognized in more than 20 cancer entities. Although MACC1 can already be linked with many hallmarks of cancer, one key process-the facilitation of immune evasion-remains poorly understood. In this review, we explore the direct and indirect links between MACC1 and the mechanisms of immune escape. Therein, we highlight the signaling pathways and secreted factors influenced by MACC1 as well as their effects on the infiltration and anti-tumor function of immune cells.

Importance: Currently, disease-modifying therapies for multiple sclerosis (MS) use 4 mechanisms of action: immune modulation, suppressing immune cell proliferation, inhibiting immune cell migration, or cellular depletion. Over the last decades, the repertoire substantially increased because of the conceptual progress that not only T cells but also B cells play an important pathogenic role in MS, fostered by the empirical success of B cell-depleting antibodies against the surface molecule CD20. Notwithstanding this advance, a continuous absence of B cells may harbor safety risks, such as a decline in the endogenous production of immunoglobulins. Accordingly, novel B cell-directed MS therapies are in development, such as inhibitors targeting Bruton tyrosine kinase (BTK)., Observations: BTK is centrally involved in the B cell receptor-mediated activation of B cells, one key requirement in the development of autoreactive B cells, but also in the activation of myeloid cells, such as macrophages and microglia. Various compounds in development differ in their binding mode, selectivity and specificity, relative inhibitory concentration, and potential to enter the central nervous system. The latter may be important in assessing whether BTK inhibition is a promising strategy to control inflammatory circuits within the brain, the key process that is assumed to drive MS progression. Accordingly, clinical trials using BTK inhibitors are currently conducted in patients with relapsing-remitting MS as well as progressive MS, so far generating encouraging data regarding efficacy and safety., Conclusions and Relevance: While the novel approach of targeting BTK is highly promising, several questions remain unanswered, such as the long-term effects of using BTK inhibitors in the treatment of inflammatory CNS disease. Potential changes in circulating antibody levels should be evaluated and compared with B cell depletion. Also important is the potential of BTK inhibitors to enter the CNS, which depends on the given compound. Remaining questions involve where BTK inhibitors fit in the landscape of MS therapeutics. A comparative analysis of their distinct properties is necessary to identify which inhibitors may be used in relapsing vs progressive forms of MS as well as to clarify which agent may be most suitable for sequential use after anti-CD20 treatment.

In multiple sclerosis (MS) persisting disability can derive from acute relapses or, alternatively, from slow and steady deterioration, termed chronic progression. Emerging data suggest that the latter process occurs largely independent from relapse activity or development of new central nervous system (CNS) inflammatory lesions. Pathophysiologically, acute relapses develop as a consequence of de novo CNS infiltration of immune cells, while MS progression appears to be driven by a CNS-trapped inflammatory circuit between CNS-established hematopoietic cells as well as CNS-resident cells, such as microglia, astrocytes, and oligodendrocytes. Within the last decades, powerful therapies have been developed to control relapse activity in MS. All of these agents were primarily designed to systemically target the peripheral immune system and/or to prevent CNS infiltration of immune cells. Based on the above described dichotomy of MS pathophysiology, it is understandable that these agents only exert minor effects on progression and that novel targets within the CNS have to be utilized to control MS progression independent of relapse activity. In this regard, one promising strategy may be the inhibition of the enzyme Bruton's tyrosine kinase (BTK), which is centrally involved in the activation of B cells as well as myeloid cells, such as macrophages and microglia. In this review, we discuss where and to what extent BTK is involved in the immunological and molecular cascades driving MS progression. We furthermore summarize all mechanistic, preclinical, and clinical data on the various BTK inhibitors (evobrutinib, tolebrutinib, fenebrutinib, remibrutinib, orelabrutinib, BIIB091) that are currently in development for treatment of MS, with a particular focus on the potential ability of either drug to control MS progression., (© 2022. The Author(s).)

The origin and function of CD20 + T cells are poorly understood. Here, we characterized CD20 + T cells in mice and humans and investigated how they are affected by anti-CD20 antibody treatment. We report that murine CD20 + T cells are unable to endogenously express the B cell lineage marker CD20; the development of CD20 + T cells in rodents requires the presence of CD20-expressing B cells. Our results demonstrated that both murine and human T cells acquire CD20 from B cells via trogocytosis while being activated by an antigen-presenting B cell. In patients with multiple sclerosis (MS) and mice with experimental autoimmune encephalomyelitis (EAE), expression of CD20 on T cells is associated with an up-regulation of activation markers, proinflammatory cytokines, and adhesion molecules, suggesting high pathogenic potential. Supporting this hypothesis, CD20 + T cells expand during active EAE in rodents; furthermore, adoptive transfer of CD20 + T cells into EAE-diseased mice worsened histological and clinical severity. Of direct therapeutic relevance, we demonstrate that the exclusive therapeutic elimination of CD20 + T cells effectively ameliorates EAE, independent of B cells. The results support the hypothesis that CD20 + T cells arise upon B cell-T cell interaction and that depletion of CD20 + T cells might contribute to the success of anti-CD20 antibody therapies in MS and other inflammatory disorders.

B cell depletion via anti-CD20 antibodies is a highly effective treatment for multiple sclerosis (MS). However, little is known about the maturation/activation stage of the returning B cell population after treatment cessation and the wider effects on other immune cells. In the present study, 15 relapsing-remitting MS patients receiving 1,000 mg of rituximab were included. B, T, and myeloid cells were analyzed before anti-CD20 administration and in different time intervals thereafter over a period of 24 mo. In comparison to the phenotype before anti-CD20 treatment, the reappearing B cell pool revealed a less mature and more activated phenotype: 1) reappearing B cells were significantly enriched in transitional (before: 10.1 ± 1.9%, after: 58.8 ± 5.2%) and mature naive phenotypes (before: 45.5 ± 3.1%, after: 25.1 ± 3.5%); 2) the frequency of memory B cells was reduced (before: 36.7 ± 3.1%, after: 8.9 ± 1.7%); and 3) reappearing B cells showed an enhanced expression of activation markers CD25 (before: 2.1 ± 0.4%, after: 9.3 ± 2.1%) and CD69 (before: 5.9 ± 1.0%, after: 21.4 ± 3.0%), and expressed significantly higher levels of costimulatory CD40 and CD86. T cells showed 1) a persistent increase in naive (CD4 + : before: 11.8 ± 1.3%, after: 18.4 ± 3.4%; CD8 + : before: 12.5 ± 1.4%, after: 16.5 ± 2.3%) and 2) a decrease in terminally differentiated subsets (CD4 + : before: 47.3 ± 3.2%, after: 34.4 ± 3.7%; CD8 + : before: 53.7 ± 2.1%, after: 49.1 ± 2.7%)., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)

Anti-CD20-mediated B-cell depletion effectively reduces acute multiple sclerosis (MS) flares. Recent data shows that antibody-mediated extinction of B cells as a lasting immune suppression, harbors the risk of developing humoral deficiencies over time. Accordingly, more selective, durable and reversible B-cell-directed MS therapies are needed. We here tested inhibition of Bruton's tyrosine kinase (BTK), an enzyme centrally involved in B-cell receptor signaling, as the most promising approach in this direction. Using mouse models of MS, we determined that evobrutinib, the first BTK inhibiting molecule being developed, dose-dependently inhibited antigen-triggered activation and maturation of B cells as well as their release of pro-inflammatory cytokines. Most importantly, evobrutinib treatment functionally impaired the capacity of B cells to act as antigen-presenting cells for the development of encephalitogenic T cells, resulting in a significantly reduced disease severity in mice. In contrast to anti-CD20, BTK inhibition silenced this key property of B cells in MS without impairing their frequency or functional integrity. In conjunction with a recent phase II trial reporting that evobrutinib is safe and effective in MS, our mechanistic data highlight therapeutic BTK inhibition as a landmark towards selectively interfering with MS-driving B-cell properties.

Introduction: B cells have increasingly come under the spotlight as mediators of inflammatory central nervous system (CNS) demyelinating diseases such as multiple sclerosis (MS). B cell depletion via the targeting of the surface molecule CD20 has proven to be highly effective; however, continuous absence of an integral component of the immune system may cause safety concerns over time. Declining humoral competence and potential immune system impairments are key issues, and moreover, unselective removal of B cells reduces immune system control functions which should preferably be maintained in inflammatory CNS disease., Areas Covered: This paper illuminates the novel approach of specific interference with B cell signaling by targeting Bruton´s tyrosine kinase (BTK). We discuss the role of BTK within the B cell receptor (BCR) signaling cascade and BTK inhibition as a promising strategy to control inflammatory CNS disease which crucially excludes immune-cell depletion. We searched PubMed or clinicaltrials.gov for the terms 'BTK inhibition' or 'Bruton´s Tyrosine Kinase' or 'anti-CD20' and 'Multiple Sclerosis'., Expert Opinion: BTK inhibition has shown effectiveness in preclinical models of CNS disease and MS clinical trials. Further studies are necessary to differentiate this approach from B cell depletion and to position it in the armamentarium of therapeutics.

The exact cause of multiple sclerosis (MS) is unknown; however, it is considered to be an inflammatory disease of the central nervous system (CNS) triggered by a combination of both environmental and genetic factors. Vitamin D deficiency is also discussed as a possible disease-promoting factor in MS, as low vitamin D status is associated with increased formation of CNS lesions, elevated number of relapses and accelerated disease progression. However, it remains unclear whether this association is causal and related and most importantly, whether vitamin D supplementation in MS is of direct therapeutic benefit. Recently, we could show that in a murine model of MS, administration of a moderate vitamin D dose was of clinical benefit, while excessive vitamin D supplementation had a negative effect on disease severity. Of note, disease exacerbation was associated with high-dose vitamin D caused secondary hypercalcemia. Mechanistically dissecting this outcome, we found that hypercalcemia independent of vitamin D similarly triggered activation of disease-perpetuating T cells. These findings caution that vitamin D should be supplemented in a controlled and moderate manner in patients with MS and concomitantly highlight calcium as a novel potential MS risk factor by itself. In this review, we will summarize the current evidence from animal and clinical studies aiming to assess whether vitamin D may be of benefit in patients with MS. Furthermore, we will discuss any possible secondary effects of vitamin D with a particular focus on the role of calcium on immune cells and in the pathogenesis of CNS demyelinating disease., (Copyright © 2020 Häusler, Torke and Weber.)

Poor vitamin D status is associated with a higher relapse rate and earlier disability in multiple sclerosis. Based on these associations, patients with multiple sclerosis are frequently supplemented with the vitamin D precursor cholecalciferol, although it is unclear whether this regimen is of therapeutic benefit. To model consequences of this common practice, mice were fed for more than 3 months with a low, medium or high dose of cholecalciferol, representative of vitamin D deficiency, modest and disproportionally high supplementation, respectively, in patients with multiple sclerosis. Compared to vitamin D-deprived mice, its moderate supplementation reduced the severity of subsequent experimental autoimmune encephalomyelitis, which was associated with an expansion of regulatory T cells. Direct exposure of murine or human T cells to vitamin D metabolites inhibited their activation. In contrast, mice with 25-(OH) vitamin D levels above 200 nmol/l developed fulminant experimental autoimmune encephalomyelitis with massive CNS infiltration of activated myeloid cells, Th1 and Th17 cells. When dissecting this unexpected outcome, we observed that high, but not medium dose vitamin D had caused mild hypercalcaemia, which rendered T cells more prone to pro-inflammatory activation. Exposing murine or human T cells to equivalent calcium concentrations in vitro enhanced its influx, triggering activation, upregulation of pro-inflammatory gene products and enhanced transmigration across a blood-brain barrier model. These findings suggest that vitamin D at moderate levels may exert a direct regulatory effect, while continuous high dose vitamin D treatment could trigger multiple sclerosis disease activity by raising mean levels of T-cell excitatory calcium., (© The Author(s) (2019). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

The anti-CD20 antibody ocrelizumab, approved for treatment of multiple sclerosis, leads to rapid elimination of B cells from the blood. The extent of B cell depletion and kinetics of their recovery in different immune compartments is largely unknown. Here, we studied how anti-CD20 treatment influences B cells in bone marrow, blood, lymph nodes, and spleen in models of experimental autoimmune encephalomyelitis (EAE). Anti-CD20 reduced mature B cells in all compartments examined, although a subpopulation of antigen-experienced B cells persisted in splenic follicles. Upon treatment cessation, CD20 + B cells simultaneously repopulated in bone marrow and spleen before their reappearance in blood. In EAE induced by native myelin oligodendrocyte glycoprotein (MOG), a model in which B cells are activated, B cell recovery was characterized by expansion of mature, differentiated cells containing a high frequency of myelin-reactive B cells with restricted B cell receptor gene diversity. Those B cells served as efficient antigen-presenting cells (APCs) for activation of myelin-specific T cells. In MOG peptide-induced EAE, a purely T cell-mediated model that does not require B cells, in contrast, reconstituting B cells exhibited a naive phenotype without efficient APC capacity. Our results demonstrate that distinct subpopulations of B cells differ in their sensitivity to anti-CD20 treatment and suggest that differentiated B cells persisting in secondary lymphoid organs contribute to the recovering B cell pool., Competing Interests: The authors declare no conflict of interest., (Copyright © 2018 the Author(s). Published by PNAS.)

The present study reports perceptions of first-year undergraduate medical students ( n = 120), regarding modified directed self-learning (DSL) sessions in physiology. Students were provided with prereading assignments (faculty developed PowerPoint slides containing diagrams with incomplete labeling/flowcharts with missing steps) pertaining to the DSL topic 1 wk before the scheduled small-group DSL presentations. During DSL presentation sessions, which were facilitated by teachers, a few students individually presented learning objectives in the specified topic. Apart from that, students discussed answers for the questions in the prereading assignment. Students were also given an opportunity to use technology to support DSL, by way of involving them in Pecha Kucha (PK) talks. The impact of the modified DSL method was determined by requesting students to respond to a validated questionnaire. Frequency analysis of the responses revealed that >60% of students were positive about the modified DSL sessions improving their DSL, presentation, collaborative learning, and information retrieving skills. Students agreed that PK talks helped them to learn how to organize content (65%), present concise information (65.8%), and apply creativity (72.5%). Even though small in number, there were comments that the prereading assignments were useful for learning. The present study revealed that, even though students actively participated in modified DSL sessions, their perceptions on satisfaction and usefulness of the same toward achievement of various skills were not encouraging. The study generated significant results, which implies that undergraduate medical students should be oriented on the relevance of active learning strategies in their future studies.

In the pathogenesis of central nervous system (CNS) demyelinating disorders, antigen-specific B cells are implicated to act as potent antigen-presenting cells (APC), eliciting waves of inflammatory CNS infiltration. Here, we provide the first evidence that CNS-reactive antibodies (Ab) are similarly capable of initiating an encephalitogenic immune response by targeting endogenous CNS antigen to otherwise inert myeloid APC. In a transgenic mouse model, constitutive production of Ab against myelin oligodendrocyte glycoprotein (MOG) was sufficient to promote spontaneous experimental autoimmune encephalomyelitis (EAE) in the absence of B cells, when mice endogenously contained MOG-recognizing T cells. Adoptive transfer studies corroborated that anti-MOG Ab triggered activation and expansion of peripheral MOG-specific T cells in an Fc-dependent manner, subsequently causing EAE. To evaluate the underlying mechanism, anti-MOG Ab were added to a co-culture of myeloid APC and MOG-specific T cells. At otherwise undetected concentrations, anti-MOG Ab enabled Fc-mediated APC recognition of intact MOG; internalized, processed and presented MOG activated naïve T cells to differentiate in an encephalitogenic manner. In a series of translational experiments, anti-MOG Ab from two patients with an acute flare of CNS inflammation likewise facilitated detection of human MOG. Jointly, these observations highlight Ab-mediated opsonization of endogenous CNS auto-antigen as a novel disease- and/or relapse-triggering mechanism in CNS demyelinating disorders.

Background: The undergraduate curriculum at our institution is divided system-wise into four blocks, each block ending with theory and objective structured practical examination (OSPE). The OSPE in Physiology consists of 12 stations, and a conventional minimum score to qualify is 50%. We aimed to incorporate standard setting using the modified Angoff method in OSPE to differentiate the competent from the non-competent student and to explore the possibility of introducing standard setting in Physiology OSPE at our institution., Methods: Experts rated the OSPE using the modified Angoff method to obtain the standard set cut-off in two of the four blocks. We assessed the OSPE marks of 110 first year medical students. Chi-square test was used to compare the number of students who scored less than standard set cut-off and conventional cut-off; correlation coefficient was used to assess the relation between OSPE and theory marks in both blocks. Feedback was obtained from the experts., Results: The standard set was 62% and 67% for blocks II and III, respectively. The use of standard set cut-off resulted in 16.3% (n=18) and 22.7% (n=25) students being declared unsuccessful in blocks II and III, respectively. Comparison between the number, who scored less than standard set and conventional cut-off was statistically significant (p=0.001). The correlation coefficient was 0.65 (p=0.003) and 0.52 (p<0.001) in blocks II and III, respectively. The experts welcomed the idea of standard setting., Conclusion: Standard setting helped in differentiating the competent from the non-competent student, indicating that standard setting enhances the quality of OSPE as an assessment tool.

The present study aimed to provide undergraduate medical students at Melaka Manipal Medical College (Manipal Campus), Manipal University, in Karnataka, India, an opportunity to apply their knowledge in cardiovascular concepts to real-life situations. A group activity named "Heart Shots" was implemented for a batch of first-year undergraduate students (n = 105) at the end of a block (teaching unit). Students were divided into 10 groups each having 10-11 students. They were requested to make a video/PowerPoint presentation about the application of cardiovascular principles to real-life situations. The presentation was required to be of only pictures/photos and no text material, with a maximum duration of 7 min. More than 95% of students considered that the activity helped them to apply their knowledge in cardiovascular concepts to real-life situations and understand the relevance of physiology in medicine and to revise the topic. More than 90% of students agreed that the activity helped them to apply their creativity in improving their knowledge and to establish a link between concepts rather than learning them as isolated facts. Based on the feedback, we conclude that the activity was student centered and that it facilitated learning., (Copyright © 2015 The American Physiological Society.)

Background: Learning environment in any medical school is found to be important in determining students' academic success. This study was undertaken to compare the perceptions of first year and clinical phase students regarding the learning environment at Melaka Manipal Medical College (MMMC) (Manipal Campus) and also to identify the gender wise differences in their perceptions., Methods: In the present study, the Dundee Ready Education Environment Measure (DREEM) inventory was used. DREEM was originally developed at Dundee and has been validated as a universal diagnostic inventory for assessing the quality of educational environment. In the present study, DREEM was administered to undergraduate medical students of first year (n = 118) and clinical phase (n = 108) and the scores were compared using a nonparametric test., Results: Among the two batches, first year students were found to be more satisfied with the learning environment at MMMC (as indicated by their higher DREEM score) compared to the clinical batch students. Gender wise, there was not much difference in the students' perceptions., Conclusion: The present study revealed that both groups of students perceived the learning environment positively. Nevertheless, the study also revealed problematic areas of learning environment in our medical school which enabled us to adopt some remedial measures.

Assessment is the process by which the teacher and the student gain knowledge about student progress. Assessment systems should aim at evaluating the desired learning outcomes. In Melaka Manipal Medical College, (Manipal Campus), Manipal, India, the TEMM model (consisting of 4 assessment methods: Triple Jump Test, essay incorporating critical thinking questions, Multistation Integrated Practical Examination, and multiple choice questions) was introduced to 30 refresher students in the fourth block of the academic year. At the end of the block, a questionnaire was distributed to ask the students to rank the different assessments in the order of their preference with respect to seven items. Analysis of the results showed that not a single type of assessment was ranked highest for all the seven items, proving the earlier observation that a single assessment does not fulfill all aspects of assessment and that there is a need for an evaluating system with multiple ways of assessment.

Medicine is an applied science, interpreting evidence and applying it to real life by using clinical reasoning skills and experience. COPT (clinically oriented physiology teaching) was incorporated in physiology instruction aiming to relate the study of physiology to real-life problems, to generate enthusiasm and motivation for learning, and to demonstrate the vocational relevance of physiology among students by integrating clinical experience with teaching. COPT consisted of two elements: 1) critical-thinking questions (CTQ) and 2) clinical case studies. After a few topics were taught, CTQ and case studies were given as an assignment. Answers were discussed in the next class. Two exams, each of which contained CTQ and recall questions, were conducted, one before (exam 1) and one after (exam 2) the implementation of COPT. Analysis of student performance in the examinations revealed that the students did better in exam 2 (P < 0.0001). Feedback from students indicated that this method was useful and challenging.