School Of Basic And Applied Sciences
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Item Evolution of Frozen Section in Carcinoma Breast: Systematic Review(Hindawi Limited, 2022-05-23T00:00:00) Rana, Manjit Kaur; Rana, Amrit Pal Singh; Sharma, Uttam; Barwal, Tushar Singh; Jain, AklankBackground. The frozen section (FS) has been a good technique in surgical management of breast lesions since many years. But complete agreement and cooperation have not been achieved everywhere among surgeons and pathologists especially in the developing countries. FS undergoes continuous criticism due to various shortcomings but continued to be evaluated especially in developing countries. Objectives. This review was conducted to synthesize information on the use of frozen section in carcinoma breast. Data Sources. The MEDLINE database for frozen section since its origin and its implication in recent breast surgery techniques was studied. Study Eligibility Criteria. Sixty-five articles were reviewed with complete analysis on FS in both benign and malignant breast lesions. Study Appraisal and Synthesis Methods. The analysis of frozen section was done as a diagnostic tool in breast lesions, margin status in breast conservative surgery in carcinoma breast, and sentinel lymph node and use of immunohistochemistry for sentinel lymph node FS. Results. It was analysed that the FS gives accurate results in margin status analysis, decreasing rerecurrence. Conclusion. The accuracy of FSA, low recurrence rate, avoidance of reoperation, and good cosmesis are the key points of its use in breast conservative surgery. Its use in sentinel lymph node biopsy (SLNB) is equivocal. However, application of immunohistochemistry on frozen section of SLNB is an evolving trend in today's era. � 2022 Manjit Kaur Rana et al.Item MEK inhibitors in cancer treatment: structural insights, regulation, recent advances and future perspectives(Royal Society of Chemistry, 2023-08-10T00:00:00) Ram, Teja; Singh, Ankit Kumar; Kumar, Adarsh; Singh, Harshwardhan; Pathak, Prateek; Grishina, Maria; Khalilullah, Habibullah; Jaremko, Mariusz; Emwas, Abdul-Hamid; Verma, Amita; Kumar, PradeepMEK1/2 are critical components of the RAS-RAF-MEK-ERK or MAPK signalling pathway that regulates a variety of cellular functions including proliferation, survival, and differentiation. In 1997, a lung cancer cell line was first found to have a MEK mutation (encoding MEK2P298L). MEK is involved in various human cancers such as non-small cell lung cancer (NSCLC), spurious melanoma, and pancreatic, colorectal, basal, breast, and liver cancer. To date, 4 MEK inhibitors i.e., trametinib, cobimetinib, selumetinib, and binimetinib have been approved by the FDA and several are under clinical trials. In this review, we have highlighted structural insights into the MEK1/2 proteins, such as the ?C-helix, catalytic loop, P-loop, F-helix, hydrophobic pocket, and DFG motif. We have also discussed current issues with all FDA-approved MEK inhibitors or drugs under clinical trials and combination therapies to improve the efficacy of clinical drugs. Finally, this study addressed recent developments on synthetic MEK inhibitors (from their discovery in 1997 to 2022), their unique properties, and their relevance to MEK mutant inhibition. � The Royal Society of Chemistry 2023.Item PROTAC�ing oncoproteins: targeted protein degradation for cancer therapy(BioMed Central Ltd, 2023-03-30T00:00:00) Kelm, Jeremy M.; Pandey, Deepti S.; Malin, Evan; Kansou, Hussein; Arora, Sahil; Kumar, Raj; Gavande, Navnath S.Molecularly targeted cancer therapies substantially improve patient outcomes, although the durability of their effectiveness can be limited. Resistance to these therapies is often related to adaptive changes in the target oncoprotein which reduce binding affinity. The arsenal of targeted cancer therapies, moreover, lacks coverage of several notorious oncoproteins with challenging features for inhibitor development. Degraders are a relatively new therapeutic modality which deplete the target protein by hijacking the cellular protein destruction machinery. Degraders offer several advantages for cancer therapy including resiliency to acquired mutations in the target protein, enhanced selectivity, lower dosing requirements, and the potential to abrogate oncogenic transcription factors and scaffolding proteins. Herein, we review the development of proteolysis targeting chimeras (PROTACs) for selected cancer therapy targets and their reported biological activities. The medicinal chemistry of PROTAC design has been a challenging area of active research, but the recent advances in the field will usher in an era of rational degrader design. � 2023, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.Item Targeting the Epidermal Growth Factor Receptor with Molecular Degraders: State-of-the-Art and Future Opportunities(American Chemical Society, 2023-02-22T00:00:00) Maity, Pritam; Chatterjee, Joydeep; Patil, Kiran T.; Arora, Sahil; Katiyar, Madhurendra K.; Kumar, Manvendra; Samarbakhsh, Amirreza; Joshi, Gaurav; Bhutani, Priyadeep; Chugh, Manoj; Gavande, Navnath S.; Kumar, RajEpidermal growth factor receptor (EGFR) is an oncogenic drug target and plays a critical role in several cellular functions including cancer cell growth, survival, proliferation, differentiation, and motility. Several small-molecule tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs) have been approved for targeting intracellular and extracellular domains of EGFR, respectively. However, cancer heterogeneity, mutations in the catalytic domain of EGFR, and persistent drug resistance limited their use. Different novel modalities are gaining a position in the limelight of anti-EGFR therapeutics to overcome such limitations. The current perspective reflects upon newer modalities, importantly the molecular degraders such as PROTACs, LYTACs, AUTECs, and ATTECs, etc., beginning with a snapshot of traditional and existing anti-EGFR therapies including small molecule inhibitors, mAbs, and antibody drug conjugates (ADCs). Further, a special emphasis has been made on the design, synthesis, successful applications, state-of-the-art, and emerging future opportunities of each discussed modality. � 2023 American Chemical Society.Item A Perspective on Medicinal Chemistry Approaches for Targeting Pyruvate Kinase M2(American Chemical Society, 2021-11-02T00:00:00) Arora, Sahil; Joshi, Gaurav; Chaturvedi, Anuhar; Heuser, Michael; Patil, Santoshkumar; Kumar, RajThe allosteric regulation of pyruvate kinase M2 (PKM2) affects the switching of the PKM2 protein between the high-activity and low-activity states that allow ATP and lactate production, respectively. PKM2, in its low catalytic state (dimeric form), is chiefly active in metabolically energetic cells, including cancer cells. More recently, PKM2 has emerged as an attractive target due to its role in metabolic dysfunction and other interrelated conditions. PKM2 (dimer) activity can be inhibited by modulating PKM2 dimer�tetramer dynamics using either PKM2 inhibitors that bind at the ATP binding active site of PKM2 (dimer) or PKM2 activators that bind at the allosteric site of PKM2, thus activating PKM2 from the dimer formation to the tetrameric formation. The present perspective focuses on medicinal chemistry approaches to design and discover PKM2 inhibitors and activators and further provides a scope for the future design of compounds targeting PKM2 with better efficacy and selectivity. � 2021 American Chemical SocietyItem U.S. FDA Approved Drugs from 2015-June 2020: A Perspective(American Chemical Society, 2021-02-22T00:00:00) Bhutani, Priyadeep; Joshi, Gaurav; Raja, Nivethitha; Bachhav, Namrata; Rajanna, Prabhakar K.; Bhutani, Hemant; Paul, Atish T.; Kumar, RajIn the present work, we report compilation and analysis of 245 drugs, including small and macromolecules approved by the U.S. FDA from 2015 until June 2020. Nearly 29% of the drugs were approved for the treatment of various types of cancers. Other major therapeutic areas of focus were infectious diseases (14%); neurological conditions (12%); and genetic, metabolic, and cardiovascular disorders (7-8% each). Itemization of the approved drugs according to the year of approval, sponsor, target, chemical class, major drug-metabolizing enzyme(s), route of administration/elimination, and drug-drug interaction liability (perpetrator or/and victim) is presented and discussed. An effort has been made to analyze the pharmacophores to identify the structural (e.g., aromatic, heterocycle, and aliphatic), elemental (e.g., boron, sulfur, fluorine, phosphorus, and deuterium), and functional group (e.g., nitro drugs) diversity among the approved drugs. Further, descriptor-based chemical space analysis of FDA approved drugs and several strategies utilized for optimizing metabolism leading to their discoveries have been emphasized. Finally, an analysis of drug-likeness for the approved drugs is presented. � 2021 American Chemical Society.Item Colistin Resistance and Management of Drug Resistant Infections(Hindawi Limited, 2022-12-10T00:00:00) Sharma, Juhi; Sharma, Divakar; Singh, Amit; Sunita, KumariColistin resistance is a globalized sensible issue because it has been considered a drug of the last-line resort to treat drug-resistant bacterial infections. The product of the mobilized colistin resistance (mcr) gene and its variants are the significant causes of colistin resistance, which is emerging due to the frequent colistin use in veterinary, and these genes circulate among the bacterial community. Apart from mcr genes, some other intrinsic genes and proteins are also involved in colistin resistance. Researchers focus on the most advanced genomics (whole genome sequencing), proteomics, and bioinformatics approaches to explore the question of colistin resistance. To combat colistin resistance, researchers developed various strategies such as the development of newer drugs, the repurposing of existing drugs, combinatorial treatment by colistin with other drugs, a nano-based approach, photodynamic therapy, a CRISPRi-based strategy, and a phage-based strategy. In this timeline review, we have discussed the development of colistin resistance and its management in developing countries. � 2022 Juhi Sharma et al.Item Colistin Resistance and Management of Drug Resistant Infections(Hindawi Limited, 2022-12-10T00:00:00) Sharma, Juhi; Sharma, Divakar; Singh, Amit; Sunita, KumariColistin resistance is a globalized sensible issue because it has been considered a drug of the last-line resort to treat drug-resistant bacterial infections. The product of the mobilized colistin resistance (mcr) gene and its variants are the significant causes of colistin resistance, which is emerging due to the frequent colistin use in veterinary, and these genes circulate among the bacterial community. Apart from mcr genes, some other intrinsic genes and proteins are also involved in colistin resistance. Researchers focus on the most advanced genomics (whole genome sequencing), proteomics, and bioinformatics approaches to explore the question of colistin resistance. To combat colistin resistance, researchers developed various strategies such as the development of newer drugs, the repurposing of existing drugs, combinatorial treatment by colistin with other drugs, a nano-based approach, photodynamic therapy, a CRISPRi-based strategy, and a phage-based strategy. In this timeline review, we have discussed the development of colistin resistance and its management in developing countries. � 2022 Juhi Sharma et al.