Intravoxel Incoherent Motion Diffusion Weighted MR Imaging at 3.0 T: Assessment of Steatohepatitis and Fibrosis Compared with Liver Biopsy in Type 2 Diabetic Patients

ObjectiveTo evaluate the capability of intravoxel incoherent motion (IVIM) diffusion-weighted imaging (DWI) to assess steatohepatitis and fibrosis determined by histopathology in type 2 diabetic patients.MethodsFifty-nine type 2 diabetic patients (49 women, 10 men; mean age, 54 ± 9 years) were submitted to liver biopsy for the evaluation of non-alcoholic fatty liver disease (NAFLD) and underwent DWI on a 3.0T MR system using 10 b values. Institutional approval and patient consent were obtained. Pure molecular-based (D), perfusion-related (D*), and vascular fraction (f) were calculated using a double exponential model and least squares curve fitting. D, D*, and f were compared between patients with and without steatohepatitis and between patients with and without fibrosis. The variables were compared by using the Ranksum test and Student t-test.ResultsSteatohepatitis was observed in 22 patients and fibrosis in 16 patients. A lower D median (0.70 s/mm² vs. 0.83 s/mm², p<0.05) and a lower D* median (34.39 s/mm² vs. 45.23 s/mm², p<0.05) were observed among those with steatohepatitis. A lower D median (0.70 s/mm² vs. 0.82 s/mm², p<0.05) and a lower D* median (35.01 s/mm² vs. 44.76 s/mm², p=0.05) were also observed among those with fibrosis.ConclusionIVIM-DWI has the potential to aid in the characterization of steatohepatitis and fibrosis.     

Bioactive Molecules Derived from Snake Venoms with Therapeutic Potential for the Treatment of Thrombo-Cardiovascular Disorders Associated with COVID-19

The Protein Journal - As expected, several new variants of Severe Acute Respiratory Syndrome-CoronaVirus-2 (SARS-CoV-2) emerged and have been detected around the world throughout this Coronavirus...     

Parthenolide sensitizes cells to X-ray-induced cell killing through inhibition of NF-kappaB and split-dose repair

Human cancers have multiple alterations in cell signaling pathways that promote resistance to cytotoxic therapy such as X rays. Parthenolide is a sesquiterpene lactone that has been shown to inhibit several pro-survival cell signaling pathways, induce apoptosis, and enhance chemotherapy-induced cell killing. We investigated whether parthenolide would enhance X-ray-induced cell killing in radiation resistant, NF-kappaB-activated CGL1 cells. Treatment with 5 microM parthenolide for 48 to 72 h inhibited constitutive NF-kappaB binding and cell growth, reduced plating efficiency, and induced apoptosis through stabilization of p53 (TP53), induction of the pro-apoptosis protein BAX, and phosphorylation of BID. Parthenolide also enhanced radiation-induced cell killing, increasing the X-ray sensitivity of CGL1 cells by a dose modification factor of 1.6. Flow cytometry revealed that parthenolide reduced the percentage of X-ray-resistant S-phase cells due to induction of p21 waf1/cip1 (CDKN1A) and the onset of G1/S and G2/M blocks, but depletion of radioresistant S-phase cells does not explain the observed X-ray sensitization. Further studies demonstrated that the enhancement of X-ray-induced cell killing by parthenolide is due to inhibition of split-dose repair.     

Exploring structural features of EGFR–HER2 dual inhibitors as anti-cancer agents using G-QSAR approach

Abstract

Simultaneous inhibition of EGFR and HER2 by dual-targeting inhibitors is an established anti-cancer strategy. Therefore, a recent trend in drug discovery involves understanding the features of such dual inhibitors. In this study, three different G-QSAR models were developed corresponding to individual EGFR, HER2 and the dual-model for both receptors. The dual-model provided site-specific information wherein (i) increasing electronegative character and higher index of saturated carbon at R4 position; (ii) presence of chlorine atom at R2 position; (iii) decreasing alpha modified shape index at R1 and R3 positions; and (iv) less electronegativity at R2 position; were found important for enhancing the dual activity. Also, comparison of dual-model with the EGFR/HER2 individual models revealed that it incorporates the properties of both models and, thus, represents a combination of EGFR/HER2. Further, fragment analysis revealed that R2 and R4 are important for imparting high potency while specificity is decided by R1/R3 fragment. We also checked the predictive ability of the dual-model by determining applicability domain using William’s plot. Also, analysis of active molecules showed they show favorable substitutions that agree with the constructed dual-model. Thus, we have been successful in developing a single dual-response QSAR model to get an insight into various structural features influencing EGFR/HER2 activity.     

Population density of Sotalia guianensis (Cetacea: Delphinidae) in the Cananéia region, Southeastern Brazil

Population density in cetaceans can be estimated through photo-identification, mark-recapture, land-based observations and visual estimative. We the aim to contribute with conservation strategies, we used line transects (distance method) to estimate the population density of the river dolphin, S. guianensis, in the estuarine region of Cananéia, Southeastern Brazil. The study, developed from May 2003 until April 2004, during dry and rainy seasons and different times of the day, included a sampling area divided into three sectors according to their proximity to the open sea: Sector I (the closest to the open sea); Sector II (with a large flow of fresh water and a salient declivity); and Sector III (with a large flow of fresh water and non salient declivity). Onboard random sampling was carried out in all three sectors, and dolphins seen from the bow to 90 degrees on both port and starboard sides, were registered along with their position and distance from the boat. The total density found was 12.41 ind/km2 (CV = 25.53%) with an average of 2.2 individuals per group for both periods of the day, morning and afternoon. Densities also varied between dry and rainy seasons, being lower in the first with 5.77 ind/km2 (CV = 27.87%) than in the second 20.28 ind/km2 (CV = 31.95%), respectively. Regarding the three sectors, a non-causal heterogeneous distribution was found: Sector I was the most populated (D = 33.10 ind/km2, CV = 13.34%), followed by Sector II (D = 7.8 ind/km2, CV = 21.07%) and Sector III (D = 3.04 ind/km2, CV = 34.04%). The aforementioned area, due to its proximity to the open sea, has the highest salinity level and therefore has the greatest chance of holding most of the marine fish schools which can be cornered by dolphins on high declivity areas during fishing activities. This suggests that food availability may be the most important factor on the river dolphin's distribution in the estuary. Similar studies will contribute to a better understanding of these populations and are essential for future conservation strategies.     

HIV-2 Integrase Variation in Integrase Inhibitor-Na?ve Adults in Senegal,West Africa

Background

Antiretroviral therapy for HIV-2 infection is hampered by intrinsic resistance to many of the drugs used to treat HIV-1. Limited studies suggest that the integrase inhibitors (INIs) raltegravir and elvitegravir have potent activity against HIV-2 in culture and in infected patients. There is a paucity of data on genotypic variation in HIV-2 integrase that might confer intrinsic or transmitted INI resistance.

Methods

We PCR amplified and analyzed 122 HIV-2 integrase consensus sequences from 39 HIV-2–infected, INI-naive adults in Senegal, West Africa. We assessed genetic variation and canonical mutations known to confer INI-resistance in HIV-1.

Results

No amino acid-altering mutations were detected at sites known to be pivotal for INI resistance in HIV-1 (integrase positions 143, 148 and 155). Polymorphisms at several other HIV-1 INI resistance-associated sites were detected at positions 72, 95, 125, 154, 165, 201, 203, and 263 of the HIV-2 integrase protein.

Conclusion

Emerging genotypic and phenotypic data suggest that HIV-2 is susceptible to the new class of HIV integrase inhibitors. We hypothesize that intrinsic HIV-2 integrase variation at “secondary” HIV-1 INI-resistance sites may affect the genetic barrier to HIV-2 INI resistance. Further studies will be needed to assess INI efficacy as part of combination antiretroviral therapy in HIV-2–infected patients.     

A Hippo and Fibroblast Growth Factor Receptor Autocrine Pathway in Cholangiocarcinoma

Herein, we have identified cross-talk between the Hippo and fibroblast growth factor receptor (FGFR) oncogenic signaling pathways in cholangiocarcinoma (CCA). Yes-associated protein (YAP) nuclear localization and up-regulation of canonical target genes was observed in CCA cell lines and a patient-derived xenograft (PDX). Expression of FGFR1, -2, and -4 was identified in human CCA cell lines, driven, in part, by YAP coactivation of TBX5. In turn, FGFR signaling in a cell line with minimal basal YAP expression induced its cellular protein expression and nuclear localization. Treatment of YAP-positive CCA cell lines with BGJ398, a pan-FGFR inhibitor, resulted in a decrease in YAP activation. FGFR activation of YAP appears to be driven largely by FGF5 activation of FGFR2, as siRNA silencing of this ligand or receptor, respectively, inhibited YAP nuclear localization. BGJ398 treatment of YAP-expressing cells induced cell death due to Mcl-1 depletion. In a YAP-associated mouse model of CCA, expression of FGFR 1, 2, and 4 was also significantly increased. Accordingly, BGJ398 treatment was tumor-suppressive in this model and in a YAP-positive PDX model. These preclinical data suggest not only that the YAP and Hippo signaling pathways culminate in an Mcl-1-regulated tumor survival pathway but also that nuclear YAP expression may be a biomarker to employ in FGFR-directed therapy.