Novel Regulatory Mechanisms and Functions of MUC4 in Pancreatic Cancer

Mucins are high molecular weight glycoproteins and have critical functions in protecting epithelial cells from a myriad of cellular stress. However, mucins are expressed aberrantly under cancer conditions that allow tumors to progress and metastasize. Among many mucins, Mucin 4 (MUC4) serves as one of the top-differentially expressed proteins in pancreatic cancer (PC), however, the precise mechanism responsible for its aberrant expression is still not clear. The evolving view of cancer as an energetic and growing ecosystem underlines an intricate interplay between cancer and its microenvironment. In spite of being recognized as one of the most critical oncogenic proteins in PC, MUC4 regulation in terms of micro-environmental stress has not been determined. In my dissertation research, I have investigated the role of PC microenvironment in the regulation of MUC4. From my studies, I have demonstrated that MUC4 stability is significantly reduced due to hypoxia-mediated induction of reactive oxygen species (ROS), which promotes autophagy by inhibiting pAkt/mTORC1 pathway. Hypoxia-mediated degradation of MUC4 provides necessary metabolites to ensure the survival of highly stressed PC cells. The longstanding model of cancer development involves that presence of cytokines can trigger chronic inflammation and impact tumor development, including PC. In addition to cytokines, bile acids (BA) facilitated chronic inflammation has shown to induce intestinal metaplasia, but their role in PC is still elusive. Elevated levels of BA (p In addition to the regulation, I have pinpointed the novel functional roles of MUC4 in determining the fate of receptor tyrosine kinases (RTKs) in PC. Multiple studies have associated MUC4 overexpression with increased stability of RTKs for sustained proliferation; however, no studies have so far highlighted the implicated mechanism. I have demonstrated that the presence of MUC4 leads to increased internalization and recycling of EGFR and HER2 to the plasma membrane compared to MUC4 silenced PC cells. Mechanistically, the impact of MUC4 on RTKs trafficking is associated with its ability to regulate the activity of RAB5A, which is known to catalyze the rate-limiting step in receptor internalization. Lastly, I have detected the presence of MUC4 in pancreatic cancer associated stellate cells (PaSC). This was an unexpected finding given that MUC4 is normally expressed in the epithelial cells. These results indicate towards the involvement of MUC4 expression in determining the activation status of PaSC and provide us an additional strong rationale to therapeutically target MUC4. Altogether, in my dissertation research, I have elucidated the novel regulatory mechanisms and functions of MUC4 in PC condition

Altered Mucins (MUC) trafficking in benign and malignant conditions.

Mucins are high molecular weight O-glycoproteins that are predominantly expressed at the apical surface of epithelial cells and have wide range of functions. The functional diversity is attributed to their structure that comprises of a peptide chain with unique domains and multiple carbohydrate moieties added during posttranslational modifications. Tumor cells aberrantly overexpress mucins, and thereby promote proliferation, differentiation, motility, invasion and metastasis. Along with their aberrant expression, accumulating evidence suggest the critical role of altered subcellular localization of mucins under pathological conditions due to altered endocytic processes. The mislocalization of mucins and their interactions result in change in the density and activity of important cell membrane proteins (like, receptor tyrosine kinases) to facilitate various signaling, which help cancer cells to proliferate, survive and progress to more aggressive phenotype. In this review article, we summarize studies on mucins trafficking and provide a perspective on its importance to pathological conditions and to answer critical questions including its use for therapeutic interventions

Student centric Integrated Teaching- An Innovative approach in Medical education

Background: Today’s medical education system aims at imbibing new teaching learning methods so as to keep up with the requirements of and to match the international standards. Integration simply means bridging connections between academic knowledge and practical. Apart from having the benefits, there are some limitations, mainly it is teacher-oriented method of teaching than student oriented. In the current study, we have made to introduce a student centric approach for integrated teaching method. Aim: To analyse students’ and faculty feedback regarding the innovative student centric approach of integrated teaching (SCIT) and the effective ness of the SCIT to the traditional integrated teaching (IT). Methods: Mixed method approach. Need analysis ( qualitative approach)by freelisting and pile sorting. Free listing was to identify the perceptions of the students about the existing flaws/ lacunae and the suggestions that has to be incorporated to overcome the existing flaws/lacunae in existing integrated teaching method. Whole 100 students were divided in to 10 groups, each having 10 students. The objectives of the session were divided among the 10 groups one weeks prior to the SCIT session. From each department (Anatomy, Biochemistry and Physiology) two faculty were assigned to guide the students.SCIT ( student centric integrated teaching method)was conducted in two sessions. All the students & the faculty were subjected to a previously validated feedback questionnaire to assess the perceptions regarding the newer teaching –learning method (Student centric integrated teaching method -SCIT) A post test was conducted to all the students and their scores were analysed. These scores were compared with the scores of their senior batch students who were exposed to current Integrated teaching method. Results: The cognitive map (figure 1) revealed the distribution of the lacunae in the existing integrated teaching method (Session planning related and Student’s interaction related). The cognitive map (figure 2) depicted the solutions to fulfil the lacunae / expectations from the teaching learning methods (Division of session time, Assessment at end of session and Interactive sessions). post test scores between the two groups SCIT and IT Mean ±SD 11.03 ± 2.5 & 8.51 ± 2.14 respectively. Conclusion: A modified methods SCIT has been developed which is students centric and this method has addressed majority of the issues of the students towards integrated teaching. Post test scores revealed that students exposed to SCIT had better performance than those who were exposed to regular integrated teaching session. Students and faculty were satisfied with the new method SCIT

Qualitative approach to identify the challenges faced and the strategies to overcome during online teaching for medical undergraduates during Covid 19 Pandemic

Introduction& Aim: To identify challenges faced by the students and faculty and the solutions to overcome them on online teaching learning method during lockdown. Methods: A descriptive qualitative study of 6 months duration was conducted among the medical faculty and students. Non-probability purposive sampling was employed in the study. Free listing was done initially to elicit the views of faculty and students to meet the intended objectives. Visual Anthropac software was used to identify the salient variables using Smith’s Salience Score (free listing), and then pile sorting was done to identify the association between the salient variables. Results: Ten members participated in the free listing and pile sorting. A total of 42 responses were obtained pertaining to the challenges during online teaching, of which 25 were identified as the salient variables depending on the cut-off value of 0.125 (Smith’s Salience Score) and subjected to pile sorting. Similarly, 25 challenges were identified for the solutions to over come the challenges in implementation of the online teaching programme during the free listing, and all were included in the second stage of pile sorting. Cognitive maps were drawn to understand the relationship between the involved challenges and the solutions to overcome them separately. Conclusion: Online education changes all components of teaching and learning in higher education. Three major categories of findings were identified: issues related to online learners, instructors, and content development. Learners’ issues included learners’ expectations, readiness, identity, and participation in online courses. Instructors’ issues included changing faculty roles, transitioning from face-to-face to online, time management, and teaching styles. Content issues included the role of instructors in content development, integration of multimedia in content, role of instructional strategies in content development, and considerations for content development. To address these challenges in online education, higher education institutions need to provide professional development for instructors, trainings for learners, and technical support for content development. Keywords distance education and telelearning, teaching or learning strategies, postsecondary education, pedagogical issues, human–computer interface

Angiopoietin-2: a potential novel diagnostic marker in multiple myeloma

Background: Multiple myeloma (MM) was the first hematological malignancy in which a prognostic relevance of bone marrow (BM) angiogenesis was reported. Microenvironment formed by reactive oxygen species, growth factors and chemokines initiates the process of BM angiogenesis. Among the angiopoietins, angiopoietin-1 is involved in vessel stability, whereas angiopoietin-2 is involved in vessel sprouting. Design and methods: Circulatory levels of angiopoietin-1, angiopoietin-2 and VEGF in 62 MM patients and 50 healthy controls were determined using ELISA. Results: Significant increase in VEGF and angiopoietin-2 level was observed in patients which correlated positively with the severity of the disease, whereas no alteration was observed in angiopoietin-1 levels. Conclusion: Significant elevation in angiopoietin-2 and VEGF levels and their correlation with severity of the disease indicate their utility as potential tumor markers along with β 2- microglobulin and might also suggest new therapeutic target for anticancer treatment

Influence of filament distribution on transverse tow permeability: Model predictions and experimental validation

In the past, various analytical and semi-analytical permeability models have been implemented for process modeling of flow through single scale fabric with reasonable success. However, characterization of permeability for a dual scale fabric is relatively more complex requiring specification of permeability at tow and fabric length scales. In the current work, a semi-analytical model for transverse tow permeability is developed taking into consideration the details of microstructural filament arrangements within a single tow by conducting detailed scanning electron microscopy (SEM) of a cured tow cross-section. The current analysis indicates that by explicitly accounting for said local fiber volume fraction and its distribution, the transverse tow permeability predictions improve when compared to existing analytical results. In addition, a new experimental methodology for transverse tow permeability characterization has been developed and presented. The predictions considering locally varying fiber volume fractions were found to match well with the experimentally evaluated tow permeability

Unbiased in vivo preclinical evaluation of anticancer drugs identifies effective therapy for the treatment of pancreatic adenocarcinoma

Peer reviewe