Human epidermal growth factor receptor 2 (HER2)-positive is an aggressive subtype of breast cancer and has historically been associated with poor outcomes. The availability of various anti-HER2 therapies, including trastuzumab, lapatinib, pertuzumab, and trastuzumab emtansine (TDM-1), has remarkably improved the clinical outcomes in patients with HER2-positive metastatic breast cancer (mBC). However, there is a need to optimize treatment within this population, given the wide variability in clinical presentation. Additionally, geographical and socio-economic considerations too need to be taken into account. To clarify and collate evidence pertaining to HER2-positive metastatic breast cancer, a panel of medical and clinical oncologists from across India developed representative clinical scenarios commonly encountered in clinical practice in the country. This was followed by two meetings wherein each clinical scenario was discussed in detail and relevant evidence appraised. The result of this process is presented in this manuscript as evidence followed by therapeutic recommendations of this panel for management of HER2-positive mBC in the Indian population.
Background: Nitric oxide synthase (NOS) is an enzyme that catalyzes the synthesis of nitric oxide (NO) from L-arginine. It has three isoforms: (1) neuronal NOS (nNOS or NOS1), which participates in neural transmission; (2) inducible NOS (iNOS or NOS2), which produces NO in macrophages; and (3) endothelial NOS (eNOS or NOS3) that regulates blood pressure. The eNOS is mainly expressed in blood vessels and is a crucial regulator of endothelial homeostasis. Objective: The present study aimed to unravel the role of eNOS in different signaling pathways and its involvement as a therapeutic target in various neurodegenerative disorders. Methods: This study used various in silico methods for comprehensive genomic analysis of eNOS in 16 organisms from 7 different phyla. Prediction of conserved domains and evolutionary relationship for eNOS among 16 organisms was made. Various physical and chemical parameters, signal peptides, and transmembrane regions that helped understand its functional relevance were also studied. Results: Three transcription factor binding sites (TFBS), i.e., CP2, AR, and LDSPOLYA, were identified in human eNOS, while ATF1, T3R, and STAT1 were predicted in mouse eNOS. Transcription factors were identified for each regulatory region in human as well as mouse eNOS. eNOS protein was predicted to harbor 14 different post-translational modification (PTM) sites, most of which have phosphorylation (serine followed by threonine and tyrosine phosphorylation) followed by sumoylation and palmitoylation among all the organisms used in the current study. However, human eNOS has a relatively lower number of PTM sites for tyrosine phosphorylation. Conclusion: Structures of eNOS isoform, consistent with available biochemical and structural data, provide substantial insight into the NOS conformational changes, which give in-depth knowledge of the mechanism of eNOS, and will be helpful for better understanding the role of eNOS in pathophysiology.
Introduction: Nitric oxide (NO) is a diatomic free radical gaseous molecule that is formed from L-arginine through NOS (Nitric oxide synthase) catalyzed reaction. NO controls vascular tone (hence blood pressure), insulin secretion, airway tone, and peristalsis and is involved in angiogenesis (growth of new blood vessels) and in the development of the nervous system. In the CNS, NO is an important messenger molecule, which is involved in various major functions in the brain. NOS has been classified into three isoforms which include nNOS (neuronal NOS), eNOS (endothelial NOS), and iNOS (inducible NOS). NOS1 is localized on chromosome 12, consisting of 1434 amino acids and 161 KDa molecular weight. nNOS is involved in synaptic transmission, regulating the tone of smooth muscles, penile erection. We studied NOS1 gene and protein network analysis through in silico techniques as human nNOS sequence was fetched from GenBank, and its homologous sequences were retrieved through BLAST search. Moreover, the results of this study exploit the role of NOS1 in various pathways, which provide ways to regulate it in various neurodegenerative diseases. Background: Previous research has revealed the role of Nitric Oxide (NO) formed from L-arginine through NOS (Nitric Oxide Synthase) as a physiological inter/intracellular messenger in the central as well as the peripheral nervous system. The diverse functions of NOS include insulin secretion, airway tone, vascular tone regulation, and in the brain, it is involved in differentiation, development, synaptic plasticity, and neurosecretion. Objective: The objective of this study is to unravel the role of neuronal Nitric Oxide Synthase (nNOS) in different pathways and its involvement as a therapeutic target in various neurodegenerative disorders, which can surely provide ways to regulate its activity in different aspects. Materials and Methods: In this study, we employed various bioinformatics tools and databases, initiating the study by fetching the neuronal Nitric Oxide Synthase (nNOS) sequence(GenBank) to find its homologous sequences(BLAST) and then exploring its physical properties and post-translational modifications, enhancing the research by network analysis(STRING), leading to its functional enrichment(Panther). Results : The results positively support the hypothesis of its role in various pathways related to neurodegeneration., Its interacting partners are the probable therapeutic targets of various neurodegenerative diseases focusing on specifically multi-target analysis. Conclusion: This study considered the evolutionary trend of physical, chemical, and biological properties of NOS1 through different phyla. The neuronal Nitric Oxide Synthase (nNOS), being one of the three isoforms of NOS (Nitric Oxide Synthase), is found to be involved in more pathways than just forming Nitric Oxide. This research provides the base for further neurological research.
e18334 Background: Practicing precision oncology is challenging due to the complex molecular interpretation and its implications in deciding pertinent treatment options. This is addressed by institutional Molecular Tumor Board (MTB) which is presided by all oncology sub-specialists including molecular biologist and bioinformatician, doing a meticulous job in untwining the intricacies but fail to obtain experiences across institutes. Further, meeting of all MTB members is neither always feasible nor accessible for the community oncologists. We hereby offer a virtual formation of MTB that is easily accessible and remotely attended by various experts across institutes, giving their opinion objectively at their ease that can be documented and archived. Methods: Virtual MTB (vMTB), a mobile cloud-based application was developed for both android and iOS platforms. The vMTB process involves submission and review of cases, whereby assigned members can opine blindly and rate different treatment options. Followed by averaging of rating score and then a final recommendation generated by the vMTB case-convener within 7 days, based on clinical context. A pilot study (2 months duration) was carried out where clinical cases bearing molecular information were invited from various oncology centers across India. Results: 21 cases were submitted (19 relapsed refractory, 3 treatment naïve) that included Breast (6), Lung (5), Leukemia/Lymphoma (3), Gall bladder (2), Uterine (2), Urinary bladder (1), GBM (1) and Sarcoma (1) cancers. The molecular query was based on 18 somatic (8 FoundationOne & 10 Others) and 3 germline testing. Cases assigned to vMTB members (~7 members/case) had ~ 6 treatment options/case with a response turn-around time ~4 days. Therapeutic final recommendation(s) were given for all cases with 95% concordance among the members; 6 cases where multiple options were advised, discordance rate was 14%. Additional molecular diagnostic workup was advised in 3 cases. vMTB recommendations including 10 off label treatment options were accepted by majority of the submitting physicians (82%). Clinical benefit was observed in 5 (24%) cases within the stipulated analysis duration. Conclusions: vMTB is a user-friendly, feasible, acceptable mobile solution alternate to MTB for objectively generating clinically meaningful consensus document for complex molecular clinical case scenarios, where guidelines are limited. To best of our knowledge, this is a first smart mobile solution connecting various oncology experts and have an immediate utility for the practicing community oncologists globally.
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