CD8 T cell-mediated depletion of HBV surface-antigen-expressing, bilineal-differentiated liver carcinoma cells generates highly aggressive escape variants.

The expression of viral antigens in chronic hepatitis B virus (HBV) infection drives continuous liver inflammation, one of the main risk factors to develop liver cancer. HBV developed immune-suppressive functions to escape from the host immune system, but their link to liver tumor development is not well understood. Here, we analyzed if and how HBV surface antigen (HBs) expression in combined hepatocellular-cholangiocarcinoma (cHCC/iCCA) cells influences their antigenicity for CD8 T cells. We randomly isolated liver tumor tissues from AlfpCre+-Trp53fl/fl/Alb-HBs+ tg mice and established primary carcinoma cell lines (pCCL) that showed a bilineal (CK7+/HNF4α+) cHCC/iCCA phenotype. These pCCL uniformly expressed HBs (HBshi), and low levels of MHC-I (MHC-Ilo), and were transiently convertible to a high antigenicity (MHC-Ihi) phenotype by IFN-γ treatment. HBshi/pCCL induced HBs/(Kb/S190-197)-specific CD8 T cells and developed slow-growing tumors in subcutaneously transplanted C57Bl/6J (B6) mice. Interestingly, pCCL-ex cells, established from HBshi/pCCL-induced and re-explanted tumors in B6 but not those in immune-deficient Rag1-/- mice showed major alterations, like an MHC-Ihi phenotype, a prominent growth-biased gene expression signature, a significantly decreased HBs expression (HBslo) and a switch to fast-growing tumors in re-transplanted B6 or PD-1-/- hosts with an unlocked PD-1/PD-L1 control system. CD8 T cell-mediated elimination of HBshi/pCCL, together with the attenuation of the negative restraints of HBs in the tumor cells, like ER-stress, reveals a novel mechanism to unleash highly aggressive HBslo/pCCL-ex immune-escape variants. Under certain conditions, HBs-specific CD8 T-cell responses thus potentiate tumor growth, an aspect that should be considered for therapeutic vaccination strategies against chronic HBV infection and liver tumors.

Sulfonated inhibitors of the RNA editing ligases validate the essential role of the MRP1/2 proteins in kinetoplastid RNA editing.

The RNA editing core complex (RECC) catalyzes mitochondrial U-insertion/deletion mRNA editing in trypanosomatid flagellates. Some naphthalene-based sulfonated compounds, such as C35 and MrB, competitively inhibit the auto-adenylylation activity of an essential RECC enzyme, kinetoplastid RNA editing ligase 1 (KREL1), required for the final step in editing. Previous studies revealed the ability of these compounds to interfere with the interaction between the editosome and its RNA substrates, consequently affecting all catalytic activities that comprise RNA editing. This observation implicates a critical function for the affected RNA binding proteins in RNA editing. In this study, using the inhibitory compounds, we analyzed the composition and editing activities of functional editosomes and identified the mitochondrial RNA binding proteins 1 and 2 (MRP1/2) as their preferred targets. While the MRP1/2 heterotetramer complex is known to bind guide RNA and promote annealing to its cognate pre-edited mRNA, its role in RNA editing remained enigmatic. We show that the compounds affect the association between the RECC and MRP1/2 heterotetramer. Furthermore, RECC purified post-treatment with these compounds exhibit compromised in vitro RNA editing activity that, remarkably, recovers upon the addition of recombinant MRP1/2 proteins. This work provides experimental evidence that the MRP1/2 heterotetramer is required for in vitro RNA editing activity and substantiates the hypothesized role of these proteins in presenting the RNA duplex to the catalytic complex in the initial steps of RNA editing.

Evaluation of Workload and its Impact on Satisfaction Among Pharmacy Academicians in Southern India.

OBJECTIVE: The purpose of this study was to determine the level of workload among pharmacy academicians working in public and private sector universities in India. The study also aimed to assess the satisfaction of academicians towards their workload. MATERIALS AND METHODS: A cross-sectional study was conducted for a period of 2 months among pharmacy academicians in Karnataka state of Southern India. Convenience sampling was used to select a sample and was contacted via email and/or social networking sites. Questionnaire designed by thorough review literature was used as a tool to collect data on workload (teaching, research, extracurricular services) and satisfaction. RESULTS: Of 214 participants, 95 returned the filled questionnaire giving the response rate of 44.39%. Private sector academicians had more load of teaching (p=0.046) and they appeared to be less involved in research activities (p=0.046) as compared to public sector academicians. More than half of the respondents (57.9%) were satisfied with their workload with Assistant Professors were least satisfied as compared to Professors (p=0.01). CONCLUSION: Overall, private sector academicians are more burdened by teaching load and also are less satisfied of their workload. Revision of private universities policies may aid in addressing this issue.

Knowledge, awareness, and perception of contraception among senior pharmacy students in Malaysia: A pilot study.

OBJECTIVE: This study aimed to assess the knowledge, awareness, and perception of contraception among senior pharmacy students of a public sector university in Malaysia. METHODS: A cross-sectional, questionnaire-based study was conducted among senior pharmacy students. The pretested questionnaire was used to collect data from the participants over the period of 1-month. The questionnaire was divided into four sections, for gathering the information about students' demographic data, and their knowledge, attitudes, and perception toward contraception. Data were statistically analyzed using SPSS version 20. FINDINGS: The response rate was 68.6%. The results showed that the contraceptive knowledge was comparatively higher in year four students (P < 0.001), married respondents (P < 0.001) and those taking elective courses (P = 0.022) as compared to their respective counterparts. Majority of the students were well aware and had a positive perception about contraception. CONCLUSION: Overall findings reflect that the majority of the students had good knowledge, perception, and awareness about contraception. The study recommends future studies to be conducted covering different pharmacy schools across the country to further establish the results.

Prevalence of potential drug-drug interactions among internal medicine ward in University of Gondar Teaching Hospital, Ethiopia

Objective: To determine the prevalence, clinical significance and the associated risk factors of potential drug-drug interactions (DDIs) at internal medicine ward of University of Gondar (UOG) hospital.Method:medicine ward of UOG hospital from April 29, 2013 to June 2, 2013. Data was collected from medical records and by interviewing the patients face to face. Descriptive analysis was conducted for back ground characteristics and logistic regression was used to determine the associated risk factors.Result:A prospective cross-sectional study was conducted on patients treated in internal interacting combinations with 4.13 potential DDIs per patient. Among 413 potential DDIs most were of moderate interactions 61.2% (n=253) followed by 26% (n=107) of minor interactions and 12.8% (n=53) of major interactions. There was significant association of occurrence of potential DDIs only with taking three or more medications.Conclusion:We have recorded a high rate of prevalence of potential DDI in the internal In our study, we have identified a total number of 413 potential DDIs and 184 types of medicine ward of UOG hospital and a high number of clinically significant DDIs which the most prevalent DDI were of moderate severity. Careful selection of drugs and active pharmaceutical care is encouraged in order to avoid negative consequences of these interactions.