Role of PINCH and Its Partner Tumor Suppressor Rsu-1 in Regulating Liver Size and Tumorigenesis

Particularly interesting new cysteine-histidine-rich protein (PINCH) protein is part of the ternary complex known as the IPP (integrin linked kinase (ILK)-PINCH-Parvin-α) complex. PINCH itself binds to ILK and to another protein known as Rsu-1 (Ras suppressor 1). We generated PINCH 1 and PINCH 2 Double knockout mice (referred as PINCH DKO mice). PINCH2 elimination was systemic whereas PINCH1 elimination was targeted to hepatocytes. The genetically modified mice were born normal. The mice were sacrificed at different ages after birth. Soon after birth, they developed abnormal hepatic histology characterized by disorderly hepatic plates, increased proliferation of hepatocytes and biliary cells and increased deposition of extracellular matrix. After a sustained and prolonged proliferation of all epithelial components, proliferation subsided and final liver weight by the end of 30 weeks in livers with PINCH DKO deficient hepatocytes was 40% larger than the control mice. The livers of the PINCH DKO mice were also very stiff due to increased ECM deposition throughout the liver, with no observed nodularity. Mice developed liver cancer by one year. These mice regenerated normally when subjected to 70% partial hepatectomy and did not show any termination defect. Ras suppressor 1 (Rsu-1) protein, the binding partner of PINCH is frequently deleted in human liver cancers. Rsu-1 expression is dramatically decreased in PINCH DKO mouse livers. Increased expression of Rsu-1 suppressed cell proliferation and migration in HCC cell lines. These changes were brought about not by affecting activation of Ras (as its name suggests) but by suppression of Ras downstream signaling via RhoGTPase proteins. In conclusion, our studies suggest that removal of PINCH results in enlargement of liver and tumorigenesis. Decreased levels of Rsu-1, a partner for PINCH and a protein often deleted in human liver cancer, may play an important role in the development of the observed phenotype. © 2013 Donthamsetty et al

A cross sectional study of knowledge, attitude and practices related to fixed dose combinations use among clinicians and resident doctors at a tertiary care teaching hospital in India

Background: In the year 2016, Government of India had banned 350 fixed dose combinations (FDCs) for the safety and efficacy purpose. The present study was conducted to assess the knowledge, attitude and practices of the clinicians and residents about the use of FDCs at a tertiary care hospital.Methods: A questionnaire based study was conducted at a tertiary care hospital after getting approval from institutional ethics committee. A pre-validated questionnaire comprising of 30 items was distributed to 100 participants. The questionnaire focused on the prescribing behaviour, knowledge on therapeutic efficacy, advantages and limitations of FDC use, clinician perception regarding FDC use and the strategies to improve the awareness about the regulatory updates of the marketed drugs.Results: Total 52/100 clinicians responded. Out of these, 88% prescribed FDCs in their practice, 62% prescribed FDCs only after ensuring therapeutic efficacy and 50% prescribed WHO approved FDCs. 64% were aware of the recent ban on some FDCs by DCGI. Internet was the most common source of latest updates on the regulatory status of the drug, as stated by 55% clinicians. All clinicians agreed that efforts are needed to ensure that prescribers remain up to date about the post-marketing regulatory status of the drugs.Conclusions: Even though many clinicians prescribe FDCs regularly, they appreciated the step of banning some FDCs; however, the clinicians need to be trained to update themselves regularly. The source and relevance of these updates should be taught to the undergraduate students during their training period which can be reemphasized during post graduate training period

A prospective study on causality, severity and preventability assessment of adverse drug reactions in a tertiary care hospital in India

Background: The present study was undertaken to evaluate the incidence and pattern of adverse drug reaction (ADRs), causality, severity and preventability of ADRs.Methods: Data was collected and analyzed with the information such as patients’ demographic details, associated co-morbid conditions and detailed drug related information gathered from ADR reporting forms. World Health Organization (WHO) scale was used for assessing causality, modified Hartwig scale was used for assessing severity and modified Schumock and Thorntons scale were used for assessing preventability of ADRs. Data was analyzed using descriptive statistics.Results: Total 154 ADRs were reported in a period of one year (August 2016- July 2017). Out of 154 ADRs analyzed, 120 (77.9%) were in adults, 33 (21.4%) pediatric and 01 (0.7%) in geriatric patients. The most common ADR recorded was cutaneous reactions (43.5%) and the most common causative class of drugs for the same was found to be antimicrobials (46.7%) followed by non-steroidal anti-inflammatory drugs (15.6%). Causality assessment scale indicated 68.8% ADRs possible and 24% ADRs as probable. Severity assessment revealed that 45.5 % were mild, 50.6% moderate and 3.9% ADRs severe. Preventability assessment showed 84.4% of the cases were probably non-preventable.Conclusions: In this study it was found that, most of the ADRs were of possible category with mild to moderate severity and majority being non-preventable. Antimicrobial drugs being the most common offending drug class causing ADRs. Strategies targeting appropriate and cautious use of this class of drugs may benefit in reducing the number of ADRs and therefore the cost involved in the treatment

Evaluation of prescription pattern of antimicrobials in the treatment of respiratory tract infections in pediatric patients attending a tertiary care hospital

Background: Irrational use of antimicrobials is a complex and multifactorial problem in developing countries. Prescriptions not adhering to the treatment guidelines, self-medication, inappropriate use of drugs by patients can inadvertently lead to development of antimicrobial resistance. An observational study was designed to evaluate antimicrobial use in pediatric population with respiratory tract infections and its adherence to national treatment guidelines. Methods: This was a cross sectional observational study initiated after taking institutional ethics committee permission. The prescriptions of children diagnosed with upper respiratory tract infections and lower respiratory tract infections (LRTI) were screened. Their demographic profile and details of drugs prescribed were recorded. Results: Out of 230 pediatric prescriptions,155 (67%) were from outpatient department and 75 (33%) from those admitted in ward. Total 145 children were diagnosed with URTI whereas 85 had LRTI. In this study, 60 children with URTI received combination of amoxicillin and clavulanic acid (Co-amoxiclav) whereas 66 children with LRTI received Co-amoxiclav,18 ceftriaxone (N=18), 6 vancomycin (N=6) and 18 were prescribed oseltamivir (N=18), either alone or in combination. Other drugs prescribed included, paracetamol for fever and cough syrups. Out of 195 drugs prescribed by brand names, 138 (70.8%) were antimicrobials. Fixed dose combination amoxicillin and clavulanic acid, paracetamol and cough syrups were available from hospital pharmacy. None of the prescriptions had polypharmacy. Conclusions: URTI was treated using single antimicrobial whereas LRTI was treated with more than one antimicrobials or combination of antimicrobial and antiviral agent. The prescriptions were in accordance with the national treatment guidelines

Evaluation of prescribing pattern of drugs use in patients of coronary artery disease at a tertiary care hospital

Background: Coronary artery disease (CAD) is a major cause responsible for mortality more in younger age group than in elderly. Studies have reported underuse of four evidence based medicines namely aspirin, β-blockers, angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin receptor blockers (ARB), and statins in patients with CAD, particularly in developing countries. Therefore, this study was planned to analyse the prescriptions of patients with CAD to determine the appropriateness of the prescriptions.Methods: After obtaining the Institutional ethics committee permission, a cross sectional observational study was conducted at a tertiary care hospital. Total 150 patients were enrolled from the outpatient department, wards and intensive care unit of medicine department. Total 150 patients’ prescriptions presenting with varied category of CAD were screened and analysed.Results: The most common categories of CAD encountered was ST segment elevated myocardial infarction (N=50, 33%) followed by chronic stable angina (N=29, 20%). Among the drugs prescribed, antiplatelet drugs were prescribed to 135 (90%), hypolipidemics to 134 (89%), nitrates to 114 (76%), beta blockers to 97 (65%), ACE inhibitors to 94 (64%), anticoagulants to 60 (40%) and miscellaneous drugs to 52 (35%), patients. Of 68 (45%) patients with type 2 diabetes mellitus, 15 (22%) were prescribed only metoprolol and others were given ACE-I or ARBs.Conclusions: Among four evidence based drugs, use of 3 drugs, antiplatelets, beta blockers and hypolipidemics was apparent in 90% of prescriptions. Use of ACE inhibitors and ARBs was observed in type 2 diabetic patients with CAD, reflecting rational prescribing behavior of clinicians

Automated advanced calibration and optimization of thermochemical models applied to biomass gasification and pyrolysis

This paper presents a methodology that combines physicochemical modeling with advanced statistical analysis algorithms as an efficient workflow, which is then applied to the optimization and design of biomass pyrolysis and gasification processes. The goal was to develop an automated flexible approach for the analyses and optimization of such processes. The approach presented here can also be directly applied to other biomass conversion processes and, in general, to all those processes for which a parametrized model is available. A flexible physicochemical model of the process is initially formulated. Within this model, a hierarchy of sensitive model parameters and input variables (process conditions) is identified, which are then automatically adjusted to calibrate the model and to optimize the process. Through the numerical solution of the underlying mathematical model of the process, we can understand how species concentrations and the thermodynamic conditions within the reactor evolve for the two processes studied. The flexibility offered by the ability to control any model parameter is critical in enabling optimization of both efficiency of the process as well as its emissions. It allows users to design and operate feedstock-flexible pyrolysis and gasification processes, accurately control product characteristics, and minimize the formation of unwanted byproducts (e.g., tar in biomass gasification processes) by exploiting various productivity-enhancing simulation techniques, such as parameter estimation, computational surrogate (reduced order model) generation, uncertainty propagation, and multi-response optimization

Oct4 Is Crucial for Transdifferentiation of Hepatocytes to Biliary Epithelial Cells in an in Vitro Organoid Culture Model

BACKGROUND: Hepatocyte to biliary transdifferentiation has been documented in various models of bile duct injury. In this process, mature hepatocytes transform into mature biliary epithelial cells by acquiring biliary phenotypic markers. Several signaling pathways including PI3 kinase, Notch, Hes1, Sox9, and Hippo are shown to be involved in the process. However, if Oct4 is involved in hepatocyte to biliary transdifferentiation is unknown. METHODS: We investigated the role of Oct4 in hepatocyte to biliary transdifferentiation utilizing an in vitro organoid culture system as a model of transdifferentiation. Oct4 was inhibited using adenovirus containing Oct4 shRNA. Hepatocyte specific HNF-4α and biliary specific HNF-1β & CK19 expression were assessed to gauge the extent of transdifferentiation. RESULTS: Oct4 was induced during hepatocyte to biliary transdifferentiation. Oct4 inhibition significantly downregulated the appearance of biliary cells from hepatocytes. This was accompanied by a significant downregulation of signaling pathways including Notch, Sox9, and Hippo. CONCLUSION: Our findings suggest that Oct4 is crucial for hepatocyte to biliary transdifferentiation and maturation and that it acts upstream of Notch, Sox9, and Hippo signaling in this model. This finding identifies new signaling through Oct4 in plasticity between hepatocytes and biliary epithelial cells, which can be potentially utilized to identify new strategies in chronic biliary diseases

Model Guided Application for Investigating Particle Number (PN) Emissions in GDI Spark Ignition Engines

&lt;div class="section abstract"&gt;&lt;div class="htmlview paragraph"&gt;Model guided application (MGA) combining physico-chemical internal combustion engine simulation with advanced analytics offers a robust framework to develop and test particle number (PN) emissions reduction strategies. The digital engineering workflow presented in this paper integrates the &lt;i&gt;k&lt;/i&gt;inetics &amp;amp; SRM Engine Suite with parameter estimation techniques applicable to the simulation of particle formation and dynamics in gasoline direct injection (GDI) spark ignition (SI) engines. The evolution of the particle population characteristics at engine-out and through the sampling system is investigated. The particle population balance model is extended beyond soot to include sulphates and soluble organic fractions (SOF). This particle model is coupled with the gas phase chemistry precursors and is solved using a sectional method. The combustion chamber is divided into a wall zone and a bulk zone and the fuel impingement on the cylinder wall is simulated. The wall zone is responsible for resolving the distribution of equivalence ratios near the wall, a factor that is essential to account for the formation of soot in GDI SI engines. In this work, a stochastic reactor model (SRM) is calibrated to a single-cylinder test engine operated at 12 steady state load-speed operating points. First, the flame propagation model is calibrated using the experimental in-cylinder pressure profiles. Then, the population balance model parameters are calibrated based on the experimental data for particle size distributions from the same operating conditions. Good agreement was obtained for the in-cylinder pressure profiles and gas phase emissions such as NO&lt;sub&gt;x&lt;/sub&gt;. The MGA also employs a reactor network approach to align with the particle sampling measurements procedure, and the influence of dilution ratios and temperature on the PN measurement is investigated. Lastly, the MGA and the measurements procedure are applied to size-resolved chemical characterisation of the emitted particles.&lt;/div&gt;&lt;/div&gt;</jats:p

Coexistence and Phase Separation in Sheared Complex Fluids

We demonstrate how to construct dynamic phase diagrams for complex fluids that undergo transitions under flow, in which the conserved composition variable and the broken-symmetry order parameter (nematic, smectic, crystalline, etc.) are coupled to shear rate. Our construction relies on a selection criterion, the existence of a steady interface connecting two stable homogeneous states. We use the (generalized) Doi model of lyotropic nematic liquid crystals as a model system, but the method can be easily applied to other systems, provided non-local effects are included.Comment: 4 pages REVTEX, 5 figures using epsf macros. To appear in Physical Review E (Rapid Communications