Radiation Therapy in Metastatic Neuroblastoma

Neuroblastoma is the commonest extracranial solid tumor in children, and metastasis at presentation is seen in more than 50% of cases. The role of radiotherapy as a palliative modality in patients with advanced neuroblastoma provides better symptomatic relief. Palliative radiotherapy dose schedules can be given either in single hypofractionation from 4 to 8 Gy or fractionated radiotherapy that can range from 21 to 30.6 Gy. Dose-response relationship trend has been reported in the palliative setting of bone metastasis. Because of the proximity of tumor to critical organs, serious adverse effects can be avoided with conformal techniques. Although currently there is limited data available, new treatments with particle therapies are undergoing clinical evaluation and may offer new hope for good quality of life in these patients

Systems Network Analysis of Protein Interaction Network (PIN) for deducing molecular mechanistic action of BaP induced carcinogenesis

Background: Benzo[a]pyrene (BaP), a polycyclic aromatic hydrocarbon, has been placed in group 1 by IARC which indicates that it is a potential carcinogen to human beings. It has shown tumorigenic properties in approximately all animal model systems. In the current study, we have tried to identify the most probable biomolecular targets of BaP using systems biology approach. Method: All the proteins that interact with BaP were extracted from T3DB. STRING-db was used to generate the Protein- protein interaction network (PPIN). Various apps of cytoscape software were used for network analysis, modulation and GO enrichment analysis. By developing biokinetic models, we then tried to find the impact of BaP on the top three most probable biomolecular targets and how whole of the cell cycle is getting perturbed which may ultimately lead to carcinogenesis. Apart from this, in this study we have also tried to propose a hypothesis of removing BaP from the cell vicinity by exploiting the scavenging properties of carbon based nanoparticles using in silico approach. Result: 4000 genes were extracted from T3DB for which network was generated. On network analysis, 2058 nodes were obtained that were connected by 13850 edges. MCODE created 65 clusters which had 411 seed proteins and enrichment analysis showed that most of the proteins present in the network participate in cell cycle regulatory pathways. On molecular docking analysis QSOX1, PTGS2 and NOS2 emerged out to be top three most probable biomolecular targets of BaP out of which PTGS2 is directly involved in cell cycle regulatory pathways. Biomolecular kinetics showed that when PTGS2 gets hampered by BaP, cell cycle regulation gets disturbed and cell may become cancerous. On in silico analysis of the scavenging potential of carbon based nanoparticles, BaP showed higher binding efficiencies for SWCNT and MWCNT as compared with QSOX1. Conclusion: Based on the in silico docking results we can hypothesize that carbon based nanoparticles can be used to scavenge BaP molecules from the cell vicinity

Developing an assay for easy and rapid detection of ALS biomarker(s): A Hypothesis

Background: Death of motor neurons is the key pathology underlying neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS). Biomarkers are chemical changes in the biological fluids. Biomarkers serving as a diagnostic tool should be specific to the concerned disease. Biomarkers indicating disease progression should be very sensitive to demonstrate changes during the disease process as well as therapeutics development. Biomarkers proposed for ALS include poly (GP) repeats in C9orf72, neurofilaments, miRNAs, glutathione and 4HNE in CSF, SOD1/TDP43 protein, poly (GP) repeats in C9orf72, neurofilaments, T regulatory cells, CRP, chitotriosidase, creatinine, creatinine kinase, miRNAs, glutamate, albumin, uric acid, glutathione, ferritin, 3-nitrotyrosine and 4HNE in blood, p75ECD, F2-isoprostane, collagen type 4, lucosylgalactosyl hydroxylysine, neoptrin and 8hydroxy-2`-deoxyguanosine in urine. Our hypothesis is to develop a kit-based assay for detection of ALS. Lateral flow immunoassays are one of the rapid, point-of-care diagnostic tests enabling high sensitivity and multiplexing. Methods: Leftover biological samples of ALS/Non-ALS individuals can be obtained from the clinics, age group 40-90. The samples can be evaluated for the expression of biomarkers and the levels can be compared between ALS and Non-ALS individuals. Using this preliminary data, kit-based assay can be developed that might be based on lateral flow principle. Result: The assay developed should be chromogenic and the intensity of chromogen should indicate the disease severity when compared to the reference. Conclusion: Development of a successful kit-based assay will enable its rapid and easy detection and establish a new milestone in the field of ALS

INTERACTION PATTERN OF FULLERENE FAMILY WITH DIFFERENT FORMS OF DNA

Fullerenes have attracted considerable attention due to their unique chemical structure and potential applications. In this study fullerenes (C20 to C180) were interacted with different forms of DNA i.e. A, B and Z-forms. And no such change in the binding score was observed with the change in the sequence of DNA. In fact, binding score increases with the increase in the molecular weight of the fullerene while interacting with A & B-form of DNA but Z-form of DNA shows no regular pattern of binding. Number of interacting base pairs increases as the molecular size of fullerene increases. And the groove binding depends on the form of DNA, fullerene and fullerene family binds in major groove of A-DNA while binds in both major and minor grooves in B and Z-form of DNA. This study reveals that binding pattern of fullerene family with DNA, which can disrupt its structure and may leads to several biological errors

Anticancer Activity of Cissus quadrangularis: An in vitro 2D Model Based Study

Cissus quadrangularis (CQ) is a perennial rambling shrub of the grape family commonly known as “Hadjora” (in Hindi) probably native to India or Sri Lanka. It is one of the valuable medicines in the Indian Traditional Systems of Medicine because of the presence of several bioactive compounds. However, in the present study we have checked its anticancer activity along with its safety profile on normal skin cells. Apart from this we have generated the spheroid HeLa culture in vitro model for analyzing the CQ extract response on the growth of HeLa tumoroid. From the present findings we have observed that the CQ selectively induces cytotoxicity, ROS liberation and G1 phase cell cycle arrest only in HeLa cancer cells without affecting the normal skin cells at similar dose. CQ also significantly inhibits the growth of tumoroid and finally leads to cell death as revealed by phase contrast microscopy. Therefore, it can be concluded from the present findings that CQ extract shows targeted anticancer activity, though the mechanism of action in support of its exhibited activity needs to be further explored

ATRA reduces inflammation and improves alveolar epithelium regeneration in emphysematous rat lung

Introduction Pulmonary emphysema characterized by alveolar wall destruction is resultant of persistent chronic inflammation. All-trans retinoic acid (ATRA) has been reported to reverse elastase-induced emphysema in rats. However, the underlying molecular mechanisms are so far unknown. Objective To investigate the therapeutic potential effect of ATRA via the amelioration of the ERK/JAK-STAT pathways in the lungs of emphysematous rats. Methods In silico analysis was done to find the binding efficiency of ATRA with receptor and ligands of ERK & JAK-STAT pathway. Emphysema was induced by porcine pancreatic elastase in Sprague-Dawley rats and ATRA was supplemented as therapy. Lungs were harvested for histopathological, genomics and proteomics analysis. Results and Discussion In silico docking, analysis confirms that ATRA interferes with the normal binding of ligands (TNF-α, IL6ST) and receptors (TNFR1, IL6) of ERK/JAK-STAT pathways respectively. ATRA restored the histology, proteases/antiproteases balance, levels of inflammatory markers, antioxidants, expression of candidate genes of ERK and JAK-STAT pathways in the therapy group. Conclusion ATRA ameliorates ERK/JAK-STAT pathway in emphysema condition, resulting in alveolar epithelium regeneration. Hence, ATRA may prove to be a potential drug in the treatment of emphysema

Further Decoding the Molecular Relationship Between Pancreatic Ductal Adenocarcinoma and Diabetes Mellitus

Background: Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy, especially as there are no current reliable methods of screening. A significant relationship between PDAC and Diabetes Mellitus (DM), specifically a new onset of diabetes mellitus (NOD). The molecular network of PDAC and new onset DM is not completely understood. We sought to investigate the molecular network of these two diseases with the ultimate goal of identifying potential biomarkers to aid in the screening of PDAC. Methods: We conducted a review for relevant articles concerning the molecular relationship between PDAC and DM. We compiled a list of 74 genes which have been implicated in the relationship between PDAC and DM. These genes were used for the construction of gene interaction network (GIN) by using GeneMANIA on the bases of genetic interactions, co-expression, co-localization, pathway, physical interactions, predicted interaction and shared protein domains. The GIN input file was imported in the cytoscape for the pathways enrichment analyses by using KEGG plugin. The cytoscape was used for the construction of the final GIN of both normal and cancer genes separately. Results: GIN and pathways enrichment analyses of genes known to be altered during NOD/DM and PDAC indicate their association with different pathways. in this study we have mentioned around 20 enriched pathways in the associated tables and figures which promptly show the direct and indirect association with pancreatic cancer. The major signaling pathways that were observed to be upregulated include NABA Matrisome, protein phosphorylation, metabolic processes and proteins upregulated a s a result of hormone response. Out of all pathways, proteins that are more involved in metabolic processes were found most influenced. Conclusion: In conclusion, we have contributed to identifying the molecular network relating PDAC and DM. Our future aim is to investigate the genes associated in this pathway. We will use this data to design a panel for next generation sequencing in tissue samples of patients diagnosed with PDAC

Exploration of potential natural inhibitors against KRAS-G12D in PanCan: Protein centered pharmacophore HTVS approach.

Background: As per key statistics of American Cancer Society 2021, Pancreatic Cancer (PanCan) affects around 60,430 persons a year in the U.S. and is tricky to diagnose & treat. Studies revealed that African Americans have a 50–90% higher incidence of PanCan compared to other ethnic groups. Oncogenic KRAS mutation is the signature genetic incident in the progression and development of PDAC. KRAS is the most common protein which is 95% times mutated in PDAC condition. By considering this alarming situation our group is now focused on to develop therapeutic portfolio against KRAS-G12D mutation associated PanCan by using high through-put virtual screening (HTVS) approach. Methodology: In this study, prompt HTVS for vetting the best possible drug candidates from natural compound (NCs) databases has been implemented. Herein, time tested rigorous multi-layered drug screening process to narrow down 66,969 NCs for the identification of potential lead(s) is implemented. Druggability parameters, protein centered pharmacophore-based drug selections & different docking approaches (Rigid & Flexible) were employed in this study. Result: By using different NCs databases around 66,969 NCs were screened based on protein-centered pharmacophore fit score & binding energies. Less than 0.001% of potential NCs were selected against the known & reference KRAS-G12D inhibitor (BI2852). Conclusion: By using HTVS approach we have identified a pool of natural inhibitors against KRAS G12D

Molecular Modelling a Key Method for Potential Therapeutic Drug Discovery

The well-defined and characterized 3D crystal structure of a protein is important to explore the topological and physiological features of the protein. The distinguished topography of a protein helps medical chemists design drugs on the basis of the pharmacophoric features of the protein. Structure-based drug discovery, specifically for pathological proteins that cause a higher risk of disease, takes advantage of this fact. Current tools for studying drug-protein interactions include physical, chromatographic, and electrophoretic methods. These techniques can be separated into either non-spectroscopic (equilibrium dialysis, ultrafiltration, ultracentrifugation, etc.) or spectroscopic (Fluorescence spectroscopy, NMR, X-ray diffraction, etc.) methods. These methods, however, can be time-consuming and expensive. On the other hand, in silico methods of analyzing protein-drug interactions, such as docking, molecular simulations, and High-Throughput Virtual Screenings (HTVS), are heavily underutilized by core drug discovery laboratories. These kinds of approaches have a great potential for the mass screening of potential small drugs molecules. Studying protein-drug interactions is of particular importance for understanding how the structural conformation of protein elements affect overall ligand binding affinity. By taking a bioinformatics approach to analyzing drug-protein interactions, the speed with which we identify potential drugs for genetic targets can be greatly increased

Comparative Molecular Docking Studies with ABCC1 and Aquaporin 9 in the Arsenite Complex Efflux

Arsenic is the most toxic metalloid present in the natural environment in both organic and inorganic arsenic forms. Inorganic arsenic is often more hazardous than the organic form. Arsenite and arsenate compounds are the major inorganic forms which are toxic causing severe human health dysfunction including cancer. Excretion of arsenic from the system is found elusive. Therefore, it is of interest to screen channel proteins with the arsenic complex in the different combination of arsenic, GSH (glutathione) and arsenic, selenium using docking methods. The mode of arsenic removal. The complex structure revealed the mode of arsenic binding efficiency with the receptor aquaporine 9 and ABCC1 channel protein. This provides insights to understand the mechanism of arsenic efflux. These inferences find application in the design, identification and development of novel nutracetucal or any other formulation useful in the balance of arsenic efflux