CTNI-42. PHASE I STUDY OF RUXOLITINIB WITH RADIATION AND TEMOZOLOMIDE IN PATIENTS WITH NEWLY DIAGNOSED GRADE III GLIOMAS AND GLIOBLASTOMA

BACKGROUND Ruxolitinib is a novel, potent, selective inhibitor of JAK1 (Janus kinase 1) and JAK2 with modest to marked selectivity against TYK2 (tyrosine kinase 2) and JAK3. Ruxolitinib interferes with the signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune function. JAK signaling involves recruitment of signal transducers and activators of transcription to cytokine receptors, activation, and subsequent localization of STATs to the nucleus leading to modulation of gene expression. METHODS Newly diagnosed patients with MGMT not hypermethylated, Glioblastoma or grade III glioma were recruited to Arm 1. Every patient received ruxolitinib and 60 Gy radiation for 6 weeks (2Gy x 30). The dose of Ruxolitinib was administered given the 3 + 3 design. Level 1 or starting dose was 10 mg twice daily, level 2 was 15 mg twice daily, level 3 was 20 mg twice daily. Patients with MGMT hypermethylated glioblastoma or grade III glioma were eligible for Arm 2. Every patient received ruxolitinib + radiation x 60 Gy + daily temozolomide at 75 mg/m2 for 6 weeks. RESULTS 45 patients had survival data, 25 patients were in Arm I and 20 arm in II. The median OS and PFS were 18.2 (95% CI: 3.6-NA) months for Arm 1 and were not reached for Arm 2. OS and PFS Rate at 1 year was 61% (95% CI: 43-85%) and 51% (35-76%) for Arm 1, and 95% (85-100%) for Arm 2 (p=0.01 and p= 0.002), respectively. 9 patients had partial response, 16 patients were stable, and 28 patients had progression. CONCLUSION Patients that received ruxolitinib + radiation x 60 Gy + daily temozolomide at 75 mg/m2 for 6 weeks over 6 weeks (Arm 2) had significantly better PFS and OS than those that received ruxolitinib + radiation x 60 Gy alone..

Repurposing Ruxolitinib in Combating COVID-19: a mini review

Background: The pandemic caused by Coronavirus Disease 2019 (COVID-19), also known as Severe Acute Respiratory Syndrome-Related Coronavirus (SARS-CoV-2), is believed to be one of the greatest threats to global health in the 21st century. Recent collective evidence has warranted Ruxolitinib as a potential agent in recovery. Ruxolitinib is a potent and selective inhibitor of Jack kinase (JAK) 1 and 2 with modest to marked selectivity against tyrosine kinase two and JAK3. Objective: The review aims to outline the current evidence regarding the repurposed treatment for COVID- 19 and give insight into the clinical trials. There has been considerable interest in introducing existing therapeutic agents against COVID-19 to reduce the severity of illness and ease the burden on public healthcare systems. Method: A literature search was conducted using keywords like ‘Ruxolitinib trial’ and ‘COVID-19 Ruxolitinib’ on PubMed, Google Scholar, Science Direct, and Cochrane databases to select research papers and articles on the topic published from January to October 2020. Inclusion criteria were restricted to articles on Ruxolitinib and COVID. In contrast, the exclusion criteria stipulated that any study done on COVID-19 involving a mixed treatment regimen with Ruxolitinib and other drug/s or any studies not pertinent to the purpose of the study would be omitted. Conclusion: Based on the successful outcomes of various researches conducted and clinical trials performed, the use of Ruxolitinib has shown significant improvement and faster clinical recovery among COVID-19 patients of varying severity of infection, advanced age, and multiple comorbidities. This review provides an overview of various such studies with their promising outcomes.

A Novel Thiosemicarbazide-Based Fluorescent Chemosensor for Hypochlorite in Near-Perfect Aqueous Solution and Zebrafish

A novel thiosemicarbazide-based fluorescent sensor (AFC) was developed. It was successfully applied to detect hypochlorite (ClO−) with fluorescence quenching in bis-tris buffer. The limit of detection of AFC for ClO− was analyzed to be 58.7 μM. Importantly, AFC could be employed as an efficient and practical fluorescent sensor for ClO− in water sample and zebrafish. Moreover, AFC showed a marked selectivity to ClO− over varied competitive analytes with reactive oxygen species. The detection process of AFC to ClO− was illustrated by UV–visible and fluorescent spectroscopy and electrospray ionization–mass spectrometry (ESI–MS).

Thiazole Analogues of the Marine Alkaloid Nortopsentin as Inhibitors of Bacterial Biofilm Formation

Anti-virulence strategy is currently considered a promising approach to overcome the global threat of the antibiotic resistance. Among different bacterial virulence factors, the biofilm formation is recognized as one of the most relevant. Considering the high and growing percentage of multi-drug resistant infections that are biofilm-mediated, new therapeutic agents capable of counteracting the formation of biofilms are urgently required. In this scenario, a new series of 18 thiazole derivatives was efficiently synthesized and evaluated for its ability to inhibit biofilm formation against the Gram-positive bacterial reference strains Staphylococcus aureus ATCC 25923 and S. aureus ATCC 6538 and the Gram-negative strain Pseudomonas aeruginosa ATCC 15442. Most of the new compounds showed a marked selectivity against the Gram-positive strains. Remarkably, five compounds exhibited BIC50 values against S. aureus ATCC 25923 ranging from 1.0 to 9.1 µM. The new compounds, affecting the biofilm formation without any interference on microbial growth, can be considered promising lead compounds for the development of a new class of anti-virulence agents.

Taraxacum officinale extracts exhibit safe and selective anticancer activity

Background:: Medicinal plants have been and continue to be the primary source of treatment for many diseases. Taraxacum officinale (dandelion), has been used for hundreds of years as a traditional medical remedy for several diseases. However, the anti-cancer potential of this plant has not been fully screened. Genotoxicity screening which is an integral part of the evaluation of the safety of this plant is also lacking. Objective:: The aim of this study was to investigate the cytotoxic and genotoxic effects of different extracts of T. officinale. Method:: Plant sample was extracted in different solvents to prepare ethanol, methanol, chloroform and water extracts. These extracts were then tested for their ability to inhibit the proliferation of colorectal cancer (Caco-2), chronic myelogenous leukemia (K562), prostate cancer (PC-3), and breast cancer (MCF-7) cells. Cell viability was evaluated using MTT assay and the selectivity indices was determined with the aid of mortal human fibroblasts. Then the most active extract, chloroform extract, was used to detect the genotoxicity of the constituents on mice bone marrow cells. Results:: The results showed that the T. officinale chloroform extract was found to be most effective against leukemia (K562) and prostate cancer (PC-3) cell lines. The extracts showed marked selectivity towards these cancer cells. Genotoxic studies revealed that genotoxic changes occurred after chloroform extract treatment, however, these changes were observed at the very high concentrations only. Conclusion:: The results suggest that T. officinale exhibits selective anti-tumor activity and it is safe for use.

Highly Robust and Selective System for Water Pollutants Removal: How to Transform a Traditional Photocatalyst into a Highly Robust and Selective System for Water Pollutants Removal

Highly porous monolithic aerogels based on ZnO photocatalyst and syndiotactic polystyrene (s-PS) were obtained by supercritical CO2 treatment of ZnO/s-PS gels. The prepared aerogels were characterized and their photocatalytic activity was evaluated using phenol and toluene as water pollutant models. The s-PS nanoporous crystalline phase, able to absorb pollutant molecules, was proven to be necessary to ensure high photocatalytic efficiency as the aerogel acts not only as a support, but also as pollutant pre-concentrator. The reusability of ZnO/s-PS aerogels is also strong showing no decrease in photocatalytic activity after six consecutive degradation trials. Finally, the aerogel matrix prevents ZnO dissolution occurring under acidic conditions and promotes a selective removal of the pollutants. The synergy between the photocatalyst and the innovative polymeric support provides the composite system with robustness, chemical stability, easy recovery after treatment, high efficiency of pollutant removal with a marked selectivity which make these materials promising for large scale applications.

Design–functionality relationships for adhesion/growth-regulatory galectins

Glycan-lectin recognition is assumed to elicit its broad range of (patho)physiological functions via a combination of specific contact formation with generation of complexes of distinct signal-triggering topology on biomembranes. Faced with the challenge to understand why evolution has led to three particular modes of modular architecture for adhesion/growth-regulatory galectins in vertebrates, here we introduce protein engineering to enable design switches. The impact of changes is measured in assays on cell growth and on bridging fully synthetic nanovesicles (glycodendrimersomes) with a chemically programmable surface. Using the example of homodimeric galectin-1 and monomeric galectin-3, the mutual design conversion caused qualitative differences, i.e., from bridging effector to antagonist/from antagonist to growth inhibitor and vice versa. In addition to attaining proof-of-principle evidence for the hypothesis that chimera-type galectin-3 design makes functional antagonism possible, we underscore the value of versatile surface programming with a derivative of the pan-galectin ligand lactose. Aggregation assays with N,N′-diacetyllactosamine establishing a parasite-like surface signature revealed marked selectivity among the family of galectins and bridging potency of homodimers. These findings provide fundamental insights into design-functionality relationships of galectins. Moreover, our strategy generates the tools to identify biofunctional lattice formation on biomembranes and galectin-reagents with therapeutic potential.

Characterizing the uptake, accumulation and toxicity of silver sulfide nanoparticles in plants

Plants take up Ag2S-NPs without a marked selectivity in regard to particle size and without substantial transformation during upward translocation.

Study on Transformation Behavior of Retained Austenite in TRIP Steel

The microstructures of CR600TR steel were characterized using optical metallography, SEM, TEM and EBSD techniques, especially the transformation behavior of retained austenite and fracture mechanism of TRIP steel under stress-strain were studied in detail. It is discovered that there is marked selectivity for those retained austenite grains in their transition sequences: they are even dependent on the extension paths of stress-strain in steel and that curvatures of grain-boundaries which the retained austenite grains lie in.