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Introduction: The year 2020 brings in a paradigm shift in medical education with the emergence of the COVID‑19 pandemic. Since the government of India initiated the first countrywide lockdown, educational institutions, including medical colleges, have adopted online mode for undergraduate teaching. Medical education is virtually incomplete without appropriate practical exposure. This study was conducted to understand the opinion of the medical students towards online classes as an impact of this pandemic on medical education. Materials and Methods: A descriptive online survey was conducted using a google form among medical undergraduate students from across India. Snowball sampling was used to recruit study participants. The responses were analyzed using numbers and percentages. Continuous variables were expressed as the mean and standard deviation of the mean. Results: The mean age of the 1426 respondents was 20.46 years. The majority of the responses were from Karnataka (412), followed by Odisha (167). While fairly a good number of respondents agreed that online classes provided a conducive environment and independence in learning, a large proportion disagreed or remained neutral in terms of its usefulness. This could be attributed to several reasons, which may be categorized into three important groups: the technical competence of the students, the provision of an enabling environment and the ability of the teachers. Conclusion: Students had varying opinions on online classes, but most emphasized the need for redoing the lessons taught online. [ABSTRACT FROM AUTHOR]

Tumor-resident lymphocytes can mount a response against neoantigens expressed in microsatellite-stable gastrointestinal (GI) cancers, and adoptive transfer of neoantigen-specific lymphocytes has demonstrated antitumor activity in selected patients. However, whether peripheral blood could be used as an alternative minimally invasive source to identify lymphocytes targeting neoantigens in patients with GI cancer with relatively low mutation burden is unclear. We used a personalized high-throughput screening strategy to investigate whether PD-1 expression in peripheral blood could be used to identify [CD8.sup.+] or [CD4.sup.+] lymphocytes recognizing neoantigens identified by whole-exome sequencing in 7 patients with GI cancer. We found that neoantigen-specific lymphocytes were preferentially enriched in the [CD8.sup.+]PD-[1.sup.+/hi] or [CD4.sup.+]PD-[1.sup.+/hi] subsets, but not in the corresponding bulk or PD-[1.sup.-] fractions. In 6 of 7 individuals analyzed we identified circulating [CD8.sup.+] and [CD4.sup.+] lymphocytes targeting 6 and 4 neoantigens, respectively. Moreover, neoantigen-reactive T cells and a T cell receptor (TCR) isolated from the [CD8.sup.+]PD-[1.sup.+] subsets recognized autologous tumor, albeit at reduced levels, in 2 patients with available cell lines. These data demonstrate the existence of circulating T cells targeting neoantigens in GI cancer patients and provide an approach to generate enriched populations of personalized neoantigen-specific lymphocytes and isolate TCRs that could be exploited therapeutically to treat cancer., Introduction Cancer neoantigens derived from mutated gene products can elicit T cell responses and render tumors susceptible to immune attack (1-3). Immune checkpoint inhibitors often display clinical activity in tumors [...]

Background: Paediatric palliative medicine (PPM) is a holistic approach to care for children and their families. Services are growing and developing worldwide but significant disparity in service provision remains. The Paediatric Supportive and Palliative Care Team (PSPCT) at the Royal Hospital for Children in Glasgow was established in 2019, but there is still no clear integrated role within the paediatric intensive care unit (PICU) at present. Through analysing the attitudes, meaning, knowledge and understanding of PPM in the PICU environment, we hoped to explore the experiences of those providing paediatric palliative care and to identify any barriers to or facilitators of integrated working to gain a better understanding of providing this care. Methods: This qualitative study used a survey composed of five open-ended and five closed questions. Sixteen out of a possible thirty-two responses (50%) were accrued from PICU healthcare professionals, including consultants (n = 19), advanced nurse practitioners (n = 4) and band-seven nurses (n = 9). The data were comprehensively studied and analysed by two coders using summative content analysis with assistance from data management software. Codes were further developed to form categories and subcategories. Results: Two categories were found: (1) the role of palliative care and (2) experiences of providing palliative care. A total of five subcategories were found, demonstrating that the PSPCT can enhance care in PICU through collaborative working. Barriers identified included staffing, funding and stigma around palliative care. Conclusions: This study shows that PICU professionals have a good understanding of the concepts of PPM and view it as an essential part of PICU work. Barriers related to resources and misperceptions of palliative care can be overcome through improved education, funding and staff retention, but this would require buy-in from policymakers. The perspective from our relatively small team increases generalizability to growing teams across the country. [ABSTRACT FROM AUTHOR]

In children, renal cell carcinoma (RCC) is rare. This study is the first report of pediatric patients with RCC registered by the International Society of Pediatric Oncology‐Renal Tumor Study Group (SIOP‐RTSG). Pediatric patients with histologically confirmed RCC, registered in SIOP 93‐01, 2001 and UK‐IMPORT databases, were included. Event‐free survival (EFS) and overall survival (OS) were analyzed using the Kaplan‐Meier method. Between 1993 and 2019, 122 pediatric patients with RCC were registered. Available detailed data (n = 111) revealed 56 localized, 30 regionally advanced, 25 metastatic and no bilateral cases. Histological classification according to World Health Organization 2004, including immunohistochemical and molecular testing for transcription factor E3 (TFE3) and/or EB (TFEB) translocation, was available for 65/122 patients. In this group, the most common histological subtypes were translocation type RCC (MiT‐RCC) (36/64, 56.3%), papillary type (19/64, 29.7%) and clear cell type (4/64, 6.3%). One histological subtype was not reported. In the remaining 57 patients, translocation testing could not be performed, or TFE‐cytogenetics and/or immunohistochemistry results were missing. In this group, the most common RCC histological subtypes were papillary type (21/47, 44.7%) and clear cell type (11/47, 23.4%). Ten histological subtypes were not reported. Estimated 5‐year (5y) EFS and 5y OS of the total group was 70.5% (95% CI = 61.7%‐80.6%) and 84.5% (95% CI = 77.5%‐92.2%), respectively. Estimated 5y OS for localized, regionally advanced, and metastatic disease was 96.8%, 92.3%, and 45.6%, respectively. In conclusion, the registered pediatric patients with RCC showed a reasonable outcome. Survival was substantially lower for patients with metastatic disease. This descriptive study stresses the importance of full, prospective registration including TFE‐testing. What's new? Pediatric renal cell carcinoma (RCC) is a rare malignancy, knowledge of which is based largely on adult RCC. Here, pediatric RCC was retrospectively studied using data from the International Society of Pediatric Oncology – Renal Tumor Study Group (SIOP‐RTSG). Pediatric RCC patients had a 5‐year overall survival rate of 84.5 percent, with notably lower survival for patients with metastatic disease. In pediatric RCC patients tested for transcription factor E3 and EB, 56.3 percent presented with translocation type. The findings highlight the importance of full registration of pediatric RCCs, with information on germline genetics and transcription factor testing. [ABSTRACT FROM AUTHOR]

Introduction: Gastroesophageal Reflux Disease (GERD) is one of the most common conditions worldwide with a significant impact on quality of life. Almagate and simethicone act as antacid and antiflatulent agents, respectively and aid in relief of GERD symptoms. Aim: To evaluate the safety and efficacy of almagate and simethicone combination in symptomatic management of GERD. Materials and Methods: A prospective, post-marketing observational, multicenter study was conducted between January 2019 and May 2019. Patients aged between 18 and 65 years, with uncomplicated symptomatic GERD, frequent episodes of heartburn, regurgitation or dyspepsia symptoms, and those who required add-on antacid therapy were included. Patients received a suspension of almagate plus simethicone during their initial visit (5-10 mL thrice-a-day for 15 days). The intensity of heartburn, regurgitation, and dyspepsia was recorded using visual analog scale of 0 (no symptoms) to 10 (severe symptoms) at baseline and after 15 days. Overall, patient satisfaction score (0-5) was assessed and adverse events were recorded. Descriptive statistics and Mann-whitney U test was used for statistical analysis. Results: Out of the 1812 patients enrolled in the study, 1767 patients continued and completed the 15-day treatment. The mean age of patients was 43.59 years {male: 793 (44.9%); female: 974 (55.1%)}. The mean symptoms score for heartburn, regurgitation, and dyspepsia was significantly reduced after treatment compared with baseline (p<0.01). Post-treatment, around half of the patients (46%) had an overall satisfaction score of 4 followed by a satisfaction score of 5 (43%) and 3 (11%). The mean overall satisfaction score was 4.31 and 38 patients (2.15%) reported adverse events. All the adverse events were mild and were resolved within a week. Conclusion: The combination of almagate and simethicone was efficacious in relieving severe symptoms of heartburn, regurgitation, and dyspepsia and was well tolerated in patients with symptomatic GERD. [ABSTRACT FROM AUTHOR]

Development of broadly reactive or universal influenza vaccines will be a paradigm shifting event for the influenza vaccine field. These next generation vaccines could replace the current standard of care with vaccines that elicit broadly cross-protective immune responses. However, a variety of in vitro and in vivo models are necessary to make the best assessments of these vaccine formulations to determine their mechanisms of action, and allow for downselection of candidates prior to human clinical trials. Our group has developed the computationally optimized broadly reactive antigen (COBRA) technology to develop HA head-based strategies to elicit antibodies against H1, H3, and H5 influenza strains. These vaccines elicit broadly reactive antibody responses that neutralize not only historical and contemporary vaccine strains, but also co-circulating variants in mice. In this study, we used H1 and H3 HA antigens in a split, inactivated vaccine (IIV) formulation in combination with the AF03 squalene-in-water emulsion adjuvant in ferrets immunologically naïve to influenza virus. The H3 COBRA IIV vaccine T11 elicited antibodies with HAI activity against more H3N2 influenza strains compared to IIV expressing wild-type H3 HA antigens, except for IIV vaccines expressing the HA from A/Texas/50/2012 (Tx/12) virus. H1 COBRA IIV vaccines, P1 and X6, elicited antibodies that recognized a similar number of H1N1 viruses as those antibodies elicited by IIV expressing the A/California/07/2009 (CA/09) HA. Ferrets vaccinated with the P1 or X6 COBRA IIV were protected against CA/09 challege and cleared virus from the lungs of the ferrets, similar to ferrets vaccinated with the CA/09 IIV. [ABSTRACT FROM AUTHOR]

Background: Patients with hereditary diffuse gastric cancer (HDGC), a cancer predisposition syndrome associated with germline mutations of the CDH1 (E-cadherin) gene, have few effective treatment options. Despite marked differences in natural history, histopathology, and genetic profile to patients afflicted by sporadic gastric cancer, patients with HDGC receive, in large, identical systemic regimens. The lack of a robust preclinical in vitro system suitable for effective drug screening has been one of the obstacles to date which has hampered therapeutic advances in this rare disease.Methods: In order to identify therapeutic leads selective for the HDGC subtype of gastric cancer, we compared gene expression profiles and drug phenotype derived from an oncology library of 1912 compounds between gastric cancer cells established from a patient with metastatic HDGC harboring a c.1380delA CDH1 germline variant and sporadic gastric cancer cells.Results: Unsupervised hierarchical cluster analysis shows select gene expression alterations in c.1380delA CDH1 SB.mhdgc-1 cells compared to a panel of sporadic gastric cancer cell lines with enrichment of ERK1-ERK2 (extracellular signal regulated kinase) and IP3 (inositol trisphosphate)/DAG (diacylglycerol) signaling as the top networks in c.1380delA SB.mhdgc-1 cells. Intracellular phosphatidylinositol intermediaries were increased upon direct measure in c.1380delA CDH1 SB.mhdgc-1 cells. Differential high-throughput drug screening of c.1380delA CDH1 SB.mhdgc-1 versus sporadic gastric cancer cells identified several compound classes with enriched activity in c.1380 CDH1 SB.mhdgc-1 cells including mTOR (Mammalian Target Of Rapamycin), MEK (Mitogen-Activated Protein Kinase), c-Src kinase, FAK (Focal Adhesion Kinase), PKC (Protein Kinase C), or TOPO2 (Topoisomerase II) inhibitors. Upon additional drug response testing, dual PI3K (Phosphatidylinositol 3-Kinase)/mTOR and topoisomerase 2A inhibitors displayed up to >100-fold increased activity in hereditary c.1380delA CDH1 gastric cancer cells inducing apoptosis most effectively in cells with deficient CDH1 function.Conclusion: Integrated pharmacological and transcriptomic profiling of hereditary diffuse gastric cancer cells with a loss-of-function c.1380delA CDH1 mutation implies various pharmacological vulnerabilities selective to CDH1-deficient familial gastric cancer cells and suggests novel treatment leads for future preclinical and clinical treatment studies of familial gastric cancer. [ABSTRACT FROM AUTHOR]

The genetic profile of human pancreatic cancers harbors considerable heterogeneity, which suggests a possible explanation for the pronounced inefficacy of single therapies in this disease. This observation has led to a belief that custom therapies based on individual tumor profiles are necessary to more effectively treat pancreatic cancer. It has recently been discovered that axon guidance genes are affected by somatic structural variants in up to 25% of human pancreatic cancers. Thus far, however, some of these mutations have only been correlated to survival probability and no function has been assigned to these observed axon guidance gene mutations in pancreatic cancer. In this study we established three novel pancreatic cancer cell lines and performed whole genome sequencing to discover novel mutations in axon guidance genes that may contribute to the cancer phenotype of these cells. We discovered, among other novel somatic variants in axon guidance pathway genes, a novel mutation in the PLXNA1 receptor (c.2587G>A) in newly established cell line SB.06 that mediates oncogenic cues of increased invasion and proliferation in SB.06 cells and increased invasion in 293T cells upon stimulation with the receptor’s natural ligand semaphorin 3A compared to wild type PLXNA1 cells. Mutant PLXNA1 signaling was associated with increased Rho-GTPase and p42/p44 MAPK signaling activity and cytoskeletal expansion, but not changes in E-cadherin, vimentin, or metalloproteinase 9 expression levels. Pharmacologic inhibition of the Rho-GTPase family member CDC42 selectively abrogated PLXNA1 c.2587G>A-mediated increased invasion. These findings provide in-vitro confirmation that somatic mutations in axon guidance genes can provide oncogenic gain-of-function signals and may contribute to pancreatic cancer progression. [ABSTRACT FROM AUTHOR]

Objective: The standard therapy for advanced hepatocellular carcinoma (HCC) is sorafenib, with most patients experiencing disease progression within 6 months. Label-retaining cancer cells (LRCC) represent a novel subpopulation of cancer stem cells (CSC). The objective was to test whether LRCC are resistant to sorafenib. Methods: We tested human HCC derived LRCC and non-LRCC before and after treatment with sorafenib. Results: LRCC derived from human HCC are relatively resistant to sorafenib. The proportion of LRCC in HCC cell lines is increased after sorafenib while the general population of cancer cells undergoes growth suppression. We show that LRCC demonstrate improved viability and toxicity profiles, and reduced apoptosis, over non-LRCC. We show that after treatment with sorafenib, LRCC upregulate the CSC marker aldehyde dehydrogenase 1 family, wingless-type MMTVintegration- site family, cell survival and proliferation genes, and downregulate apoptosis, cell cycle arrest, cell adhesion and stem cells differentiation genes. This phenomenon was accompanied by non-uniform activation of specific isoforms of the sorafenib target proteins extracellular-signal-regulated kinases and v-aktmurine- thymoma-viral-oncogene homologue (AKT) in LRCC but not in non-LRCC. A molecular pathway map for sorafenib treated LRCC is proposed. Conclusions: Our results suggest that HCC derived LRCC are relatively resistant to sorafenib. Since LRCC can generate tumours with as few as 10 cells, our data suggest a potential role for these cells in disease recurrence. Further investigation of this phenomenon might provide novel insights into cancer biology, cancer recurrence and drug resistance with important implications for the development of novel cancer therapies based on targeting LRCC. [ABSTRACT FROM AUTHOR]

Label-retaining cells (LRCs) have been proposed to represent adult tissue stem cells. LRCs are hypothesized to result from either slow cycling or asymmetric cell division (ACD). However, the stem cell nature and whether LRC undergo ACD remain controversial. Here, we demonstrate label-retaining cancer cells (LRCCs) in several gastrointestinal (GI) cancers including fresh surgical specimens. Using a novel method for isolation of live LRCC, we demonstrate that a subpopulation of LRCC is actively dividing and exhibits stem cells and pluripotency gene expression profiles. Using real-time confocal microscopic cinematography, we show live LRCC undergoing asymmetric nonrandom chromosomal cosegregation LRC division. Importantly, LRCCs have greater tumor-initiating capacity than non-LRCCs. Based on our data and that cancers develop in tissues that harbor normal-LRC, we propose that LRCC might represent a novel population of GI stem-like cancer cells. LRCC may provide novel mechanistic insights into the biology of cancer and regenerative medicine and present novel targets for cancer treatment. S TEM C ELLS 2012; 30:591-598 [ABSTRACT FROM AUTHOR]

SHG2210, a fusion protein containing the N-terminus of human nicotinic acetylcholine receptor α (AchR-α; aa1-210) and human transferrin (TF), was characterized as a potential therapeutic for myasthenia gravis (MG) caused predominately by α subunit autoantibodies. SHG2210 was shown to be able to bind to α subunit autoantibodies and the TF receptor (TFR). SHG2210 and SHG2210-anti-AchR antibody complex are internalized through TFR-mediated endocytosis. The SHG2210 and SHG2210-anti-AchR antibody complex is present in Lamp1-positive lysosomal compartments after internalization; however, neither SHG2210 nor SHG2210-antibody complex is present in Rab11-positive recycling endosomes. SHG2210 bound to α subunit of AChR autoantibodies may be cleared by the lysosome, resulting in short cellular half-life relative to SHG2210. SHG2210 is shown to have a protective effect on antigenic modulation of the AChR induced by serum from select patients with MG, suggesting that a fusion protein approach may be an effective therapeutic for treating MG. [ABSTRACT FROM AUTHOR]

B-cell activation factor belonging to the tumor necrosis factor family (BAFF) is a major contributor to survival of B lymphocytes during development and maturation. A relationship between circulating BAFF levels and disease activity has been reported in patients with the autoimmune disease Systemic Lupus Erythematosus (SLE). Clinical trials targeting BAFF or its receptors are currently in progress. In order to further characterize a rabbit (Oryctolagus cuniculus) model of SLE, we investigated the expression of BAFF and its receptors in non-inbred, pedigreed rabbits derived from breeding and selection based on autoantibody responses. We immunized rabbits related to previous groups that developed autoantibodies and inflammatory responses after immunizations with peptides synthesized on multiple antigen-branched polylysine backbones. Blood and sera collected before immunization and after boosts were used for health monitoring, analyses of serum autoantibody responses by ELISA and immunofluorescence. Peripheral blood mononuclear cells (PBMC) were studied by flow cytometry and were the source of mRNA for quantitative PCR analyses. We hypothesized that BAFF mRNA expression and serum BAFF levels measured indirectly through BAFF receptor binding might increase in autoantibody-producing rabbits. Immunized rabbits developed elevated levels of leucocyte populations, anti-nuclear, anti-dsDNA and other autoantibodies. BR3 mRNA levels in total PBMC decreased and BAFF levels remained low and unchanged in most immunized rabbits. By flow cytometry, percentages of BAFF positive cells decreased. Percentages of transmembrane activator and CAML interactor (TACI) decreased in most rabbits from all the immunized groups. The rabbit is an important model for human autoimmune and infectious diseases, and a high quality draft rabbit genome assembly was recently completed. Human disease models developed in non-inbred pedigreed animals are better able to reflect the complexities of diseases such as SLE with familial patterns of inheritance. Although no consistent pattern of elevated expression of BAFF mRNA or protein was found in the rabbits studied, the data collected and reported here build upon previous data to refine understanding of a rabbit model of SLE. [ABSTRACT FROM AUTHOR]

The article discusses a study on a broad-spectrum mercury (Hg)-resistant Bacillus pasteurii strain DR2 that could volatilize different Hg compounds and utilize different aromatic compounds as sole carbon sources. Bacterial strain was isolated from the effluents of Durgapur-Steel Plant, India. Bacterial cells were grown in media containing benzene for studies of utilization of organic compounds. It shows that the bacterial strain volatilized over 90% of the mercury compounds.

Pediatric renal cell carcinoma (RCC) is a rare type of kidney cancer, most commonly occurring in teenagers and young adolescents. Few relatively large series of pediatric RCC have been reported. Knowledge of clinical characteristics, outcome and treatment strategies are often based on the more frequently occurring adult types of RCC. However, published pediatric data suggest that clinical, molecular and histological characteristics of pediatric RCC differ from adult RCC. This paper summarizes reported series consisting of ≥10 RCC pediatric patients in order to create an up-to-date overview of the clinical and histopathological characteristics, treatment and outcome of pediatric RCC patients. [ABSTRACT FROM AUTHOR]