AXL receptor tyrosine kinase: a possible therapeutic target in acute promyelocytic leukemia.

BACKGROUND: Acute promyelocytic leukemia (APL) is a subset of acute myeloid leukemia (AML) which is characterized by the fusion of promyelocytic leukemia PML and retinoic acid receptor- alpha (RAR-alpha) genes. All-trans retinoic acid (ATRA) and/or arsenic trioxide (ATO) have resulted in durable cytogenetic and molecular remissions in most APL patients and have altered the natural history of the disease. Most APL patients treated with ATRA and/or ATO are now anticipated to have a nearly normal life expectancy. Unfortunately, relapse and resistance to the current treatment occur in APL patients and the outcome remains dismal in these refractory patients. AXL receptor tyrosine kinase (AXL-RTK) has been shown to increase tumour burden, provide resistance to therapy and is critical to maintain cancer stem cells (CSCs) in chronic myeloid leukemia (CML) by stabilizing ß-catenin in the Wnt/ß-catenin signalling pathway. However, the role of AXL-RTK has not been explored in PML/RARα-positive APL. This study aimed to explore the role of AXL-RTK receptor in PML/RARα-positive APL. METHODS AND RESULTS: By using biochemical and pharmacological approaches, here we report that targeting of AXL-RTK is related to the down-regulation of ß-catenin target genes including c-myc (p < 0.001), AXIN2 (p < 0.001), and HIF1α (p < 0.01) and induction of apoptosis in PML/RARα-positive APL cell line. Resistance to all-trans retinoic acid (ATRA) was also overcomed by targeting AXL-RTK with R428 in APL (p < 0.05). CONCLUSION: Our results provide clear evidence of the involvement of AXL-RTK in leukemogenic potential of PML/RARα-positive APL and suggest targeting of AXL-RTK in the treatment of therapy resistant APL patients.

Integrated analysis to study the interplay between post-translational modifications (PTM) in hepatitis C virus proteins and hepatocellular carcinoma (HCC) development.

Many PTMs dysregulation is known to be the major cause of many cancers including HCV induced HCC. PTMs of hepatitis C virus (HCV) regions NS3/4A, NS5A and NS5B are crucial for proper protein functions and replication that directly affect the generation of infectious virus particles and completion of its life cycle. In this study, we have performed comprehensive analysis of PTMs within HCV non-structural proteins (NS3/4A, NS5A and NS5B) through bioinformatics analysis to examine post-translational crosstalk between phosphorylation, palmitoylation, methylation, acetylation and ubiquitination sites in selected viral proteins. Our analysis has revealed many highly putative PTMs sites that are also conserved among major genotypes conferring the importance of these sites. We have also analysed viral 3D structures in their modified and unmodified forms to address extent and signatures of structural changes upon PTM. This study provides evidence that PTMs induce significant conformational changes and make viral proteins more stable. To find the potential role of PTMs in HCV induced HCC, docking analysis between selected viral proteins and p38-MAPK has been performed which also confirms their strong association with HCV induced HCC. The major findings proposed that PTMs at specific sites of HCV viral proteins could dysregulate specific pathways that cause the development of HCC.

Challenges and recent trends with the development of hydrogel fiber for biomedical applications.

Hydrogel is the most emblematic soft material which possesses significantly tunable and programmable characteristics. Polymer hydrogels possess significant advantages including, biocompatible, simple, reliable and low cost. Therefore, research on the development of hydrogel for biomedical applications has been grown intensely. However, hydrogel development is challenging and required significant effort before the application at an industrial scale. Therefore, the current work focused on evaluating recent trends and issues with hydrogel development for biomedical applications. In addition, the hydrogel's development methodology, physicochemical properties, and biomedical applications are evaluated and benchmarked against the reported literature. Later, biomedical applications of the nano-cellulose-based hydrogel are considered and critically discussed. Based on a detailed review, it has been found that the surface energy, intermolecular interactions, and interactions of hydrogel adhesion forces are major challenges that contribute to the development of hydrogel. In addition, compared to other hydrogels, nanocellulose hydrogels demonstrated higher potential for drug delivery, 3D cell culture, diagnostics, tissue engineering, tissue therapies and gene therapies. Overall, nanocellulose hydrogel has the potential for commercialization for different biomedical applications.

Cellulose acetate-polyvinyl alcohol blend hemodialysis membranes integrated with dialysis performance and high biocompatibility.

Hemodialysis considered as therapy of end-stage renal disease (ESRD) for the separation of protein and uremic toxins based on their molecular weights using semi-permeable membranes. Cellulose Acetate (CA) hemodialysis membrane has been widely used in the biomedical field particularly for hemodialysis applications. The main issue of CA membrane is less selectivity and hemocompatibility. In this study, to enhance the filtration capability and biocompatibility of CA hemodialysis membrane modified by using Polyvinyl Alcohol (PVA) and Polyethylene Glycol (PEG) as additives. CA-PVA flat sheet membranes were cast by phase inversion method, and separation was done by dead-end filtration cell. The synthesized membranes were described in terms of chemical structure using Fourier Transform Infrared Spectroscopy (FTIR) and morphology by Scanning Electron Microscopy (SEM), Atomic Force Microscopy (AFM), pure water flux, solute permeation, and protein retention. Biocompatibility of the membranes was tested by the platelet adherence, hemolysis ratio, thrombus formation, and plasma recalcification time. SEM images exposed that the CA-PVA membrane has a uniform porous structure. 42.484 L/m2 h is the maximum pure water flux obtained. The CA-PVA rejected up to 95% of bovine serum albumin (BSA). A similar membrane separated 93% of urea and 89% of creatinine. Platelet adhesion and hemolysis ratio of casted membranes were less than the pure CA membrane. Increased clotting time and less thrombus formation on the membrane's surface showed that the fabricated membrane is biocompatible. CA-PVA hemodialysis membranes are more efficient than conventional reported hemodialysis membranes. It revealed that CA-PVA is high performing biocompatible hemodialysis membrane.

Nano architectured cues as sustainable membranes for ultrafiltration in blood hemodialysis.

Membranes with zeolites are encouraging for performing blood dialysis because zeolites can eliminate uremic toxins through molecular sieving. Although the addition of various pore-gen and adsorbent in the membrane can certainly impact the membrane production along with creatinine adsorption, however, it is not directed which pore-gen along with zeolite leads to better performance. The research was aimed at reducing the adsorption of protein-bound and uremic toxins by using mordenite zeolite as an adsorbent while polyethylene glycol and cellulose acetate as a pore generating agent. Membranes were cast by a phase-inversion technique which is cheap and easy to handle as compared to the electro-spinning technique. Through this strategy, the ability to adsorb creatinine and solute rejection percentage were measured and compared against the pristine PSU, when only PEG was used as a pore-modifier and when PEG along with CA was used as a pore-modifier along with a different concentration of zeolite. The experiments revealed that PEG membranes can give a better solute rejection percentage (93%) but with a low creatinine adsorption capacity that is 7654 µg/g and low bio-compatibility (PRT 392 s, HR 0.46%). However, PEG/CA membranes give maximum creatinine adsorption that is 9643 µg/g and also better bio-compatibility (PRT 490 s, HR 0.37%) but with a low BSA rejection (72%) as compared to the pristine PSU and PEG membranes. The present study finds that the concentration of mordenite zeolite affects the membrane performance because its entrapment and large pore size of the membrane decreases solute rejection but increases creatinine uptake level along with the better bio-compatibility.

Biodegradable Polymer Coated Granular Urea Slows Down N Release Kinetics and Improves Spinach Productivity.

Low nitrogen (N) utilization efficiency due to environmental N losses from fertilizers results in high-cost on-farm production. Urea coating with biodegradable polymers can prevent these losses by controlling the N release of fertilizers. We calculated N release kinetics of coated granular with various biodegradable polymeric materials and its impact on spinach yield and N uptake. Different formulations were used, (i) G-1: 10% starch + 5% polyvinyl alcohol (PVA) + 5% molasses; (ii) G-2: 10% starch + 5% PVA + 5% paraffin wax (PW); (iii) G-3: 5% gelatin + 10% gum arabic + 5% PW; (iv) G-4: 5% molasses + 5% gelatin + 10% gum arabic, to coat urea using a fluidized bed coater. The morphological and X-ray diffraction (XRD) analyses indicated that a uniform coating layer with no new phase formation occurred. In the G-2 treatment, maximum crushing strength (72.9 N) was achieved with a slowed-down N release rate and increased efficiency of 31%. This resulted in increased spinach dry foliage yield (47%), N uptake (60%) and apparent N recovery (ANR: 130%) from G-2 compared to uncoated urea (G-0). Therefore, coating granular urea with biodegradable polymers is a good choice to slower down the N release rate and enhances the crop yield and N utilization efficiency from urea.

Assessment of the risk for human health of Enterovirus and Hepatitis A virus in clinical and water sources from three metropolitan cities of Pakistan.

INTRODUCTION: Molecular studies have confirmed the silent circulation of enterovirus (EntV) and hepatitis A virus in the environment, even in the absence of clinical manifestation. Viral pathogens are among the major causes of disease outbreaks, particularly in the bigger cities and both in the developed and underdeveloped nations. MATERIAL AND METHODS: Between June 2016 - June 2017, 97 samples of drinking water, river water polluted with sewage and blood were selected and obtained from high risk communities in Pakistan. Negatively charged membrane filters were used to concentrate the virus, followed by the use of specific PCR primers set for quick identification of the waterborne viruses. RESULTS: Enteroviruses were recovered from 40%, 28.57% and 33.33% of river water polluted with sewage samples in Lahore, Islamabad and Rawalpindi, respectively, while the presence of 13.13% and 11.76% of viral load was also confirmed in the drinking water of Lahore and Rawalpindi, respectively. A high prevalence of HAV (12.5% and 21.05%) was also verified in the clinical samples. Phylogenetic analysis indicated close resemblance of HAV isolates with the Indian strains. This study is the first ever comparative analysis of the EntV and HAV isolated from environmental samples and clinical specimen on a molecular level. CONCLUSIONS: The parallel surveillance of EntV and HAV in the river water polluted with sewage, and clinical samples is quite helpful for controlling and reducing the disease burden of the waterborne illnesses.