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Authors = Sravani Ramisetty

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13 pages, 1043 KiB  
Review
From Bench to Bedside: A Team’s Approach to Multidisciplinary Strategies to Combat Therapeutic Resistance in Head and Neck Squamous Cell Carcinoma
by Bridget E. Crossman, Regan L. Harmon, Kourtney L. Kostecki, Nellie K. McDaniel, Mari Iida, Luke W. Corday, Christine E. Glitchev, Madisen T. Crow, Madelyn A. Harris, Candie Y. Lin, Jillian M. Adams, Colin A. Longhurst, Kwangok P. Nickel, Irene M. Ong, Roxana A. Alexandridis, Menggang Yu, David T. Yang, Rong Hu, Zachary S. Morris, Gregory K. Hartig, Tiffany A. Glazer, Sravani Ramisetty, Prakash Kulkarni, Ravi Salgia, Randall J. Kimple, Justine Y. Bruce, Paul M. Harari and Deric L. Wheeleradd Show full author list remove Hide full author list
J. Clin. Med. 2024, 13(20), 6036; https://doi.org/10.3390/jcm13206036 - 10 Oct 2024
Cited by 4 | Viewed by 1639
Abstract
Head and neck squamous cell carcinoma (HNSCC) is diagnosed in more than 71,000 patients each year in the United States, with nearly 16,000 associated deaths. One significant hurdle in the treatment of HNSCC is acquired and intrinsic resistance to existing therapeutic agents. Over [...] Read more.
Head and neck squamous cell carcinoma (HNSCC) is diagnosed in more than 71,000 patients each year in the United States, with nearly 16,000 associated deaths. One significant hurdle in the treatment of HNSCC is acquired and intrinsic resistance to existing therapeutic agents. Over the past several decades, the University of Wisconsin has formed a multidisciplinary team to move basic scientific discovery along the translational spectrum to impact the lives of HNSCC patients. In this review, we outline key discoveries made throughout the years at the University of Wisconsin to deepen our understanding of therapeutic resistance in HNSCC and how a strong, interdisciplinary team can make significant advances toward improving the lives of these patients by combatting resistance to established therapeutic modalities. We are profoundly grateful to the many scientific teams worldwide whose groundbreaking discoveries, alongside evolving clinical paradigms in head and neck oncology, have been instrumental in making our work possible. Full article
(This article belongs to the Section Clinical Laboratory Medicine)
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12 pages, 944 KiB  
Review
Phenotypic Plasticity and Cancer: A System Biology Perspective
by Ayalur Raghu Subbalakshmi, Sravani Ramisetty, Atish Mohanty, Siddhika Pareek, Dana Do, Sagun Shrestha, Ajaz Khan, Neel Talwar, Tingting Tan, Priya Vishnubhotla, Sharad S. Singhal, Ravi Salgia and Prakash Kulkarni
J. Clin. Med. 2024, 13(15), 4302; https://doi.org/10.3390/jcm13154302 - 23 Jul 2024
Cited by 1 | Viewed by 1689
Abstract
Epithelial-to-mesenchymal transition (EMT) is a major axis of phenotypic plasticity not only in diseased conditions such as cancer metastasis and fibrosis but also during normal development and wound healing. Yet-another important axis of plasticity with metastatic implications includes the cancer stem cell (CSCs) [...] Read more.
Epithelial-to-mesenchymal transition (EMT) is a major axis of phenotypic plasticity not only in diseased conditions such as cancer metastasis and fibrosis but also during normal development and wound healing. Yet-another important axis of plasticity with metastatic implications includes the cancer stem cell (CSCs) and non-CSC transitions. However, in both processes, epithelial (E) and mesenchymal (M) phenotypes are not merely binary states. Cancer cells acquire a spectrum of phenotypes with traits, properties, and markers of both E and M phenotypes, giving rise to intermediary hybrid (E/M) phenotypes. E/M cells play an important role in tumor initiation, metastasis, and disease progression in multiple cancers. Furthermore, the hybrid phenotypes also play a major role in causing therapeutic resistance in cancer. Here, we discuss how a systems biology perspective on the problem, which is implicit in the ‘Team Medicine’ approach outlined in the theme of this Special Issue of The Journal of Clinical Medicine and includes an interdisciplinary team of experts, is more likely to shed new light on EMT in cancer and help us to identify novel therapeutics and strategies to target phenotypic plasticity in cancer. Full article
(This article belongs to the Section Clinical Laboratory Medicine)
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15 pages, 3544 KiB  
Perspective
Leveraging Cancer Phenotypic Plasticity for Novel Treatment Strategies
by Sravani Ramisetty, Ayalur Raghu Subbalakshmi, Siddhika Pareek, Tamara Mirzapoiazova, Dana Do, Dhivya Prabhakar, Evan Pisick, Sagun Shrestha, Srisairam Achuthan, Supriyo Bhattacharya, Jyoti Malhotra, Atish Mohanty, Sharad S. Singhal, Ravi Salgia and Prakash Kulkarni
J. Clin. Med. 2024, 13(11), 3337; https://doi.org/10.3390/jcm13113337 - 5 Jun 2024
Cited by 3 | Viewed by 2218
Abstract
Cancer cells, like all other organisms, are adept at switching their phenotype to adjust to the changes in their environment. Thus, phenotypic plasticity is a quantitative trait that confers a fitness advantage to the cancer cell by altering its phenotype to suit environmental [...] Read more.
Cancer cells, like all other organisms, are adept at switching their phenotype to adjust to the changes in their environment. Thus, phenotypic plasticity is a quantitative trait that confers a fitness advantage to the cancer cell by altering its phenotype to suit environmental circumstances. Until recently, new traits, especially in cancer, were thought to arise due to genetic factors; however, it is now amply evident that such traits could also emerge non-genetically due to phenotypic plasticity. Furthermore, phenotypic plasticity of cancer cells contributes to phenotypic heterogeneity in the population, which is a major impediment in treating the disease. Finally, plasticity also impacts the group behavior of cancer cells, since competition and cooperation among multiple clonal groups within the population and the interactions they have with the tumor microenvironment also contribute to the evolution of drug resistance. Thus, understanding the mechanisms that cancer cells exploit to tailor their phenotypes at a systems level can aid the development of novel cancer therapeutics and treatment strategies. Here, we present our perspective on a team medicine-based approach to gain a deeper understanding of the phenomenon to develop new therapeutic strategies. Full article
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11 pages, 1487 KiB  
Perspective
A Nexus between Genetic and Non-Genetic Mechanisms Guides KRAS Inhibitor Resistance in Lung Cancer
by Prakash Kulkarni, Atish Mohanty, Sravani Ramisetty, Herbert Duvivier, Ajaz Khan, Sagun Shrestha, Tingting Tan, Amartej Merla, Michelle El-Hajjaoui, Jyoti Malhotra, Sharad Singhal and Ravi Salgia
Biomolecules 2023, 13(11), 1587; https://doi.org/10.3390/biom13111587 - 28 Oct 2023
Cited by 1 | Viewed by 2796
Abstract
Several studies in the last few years have determined that, in contrast to the prevailing dogma that drug resistance is simply due to Darwinian evolution—the selection of mutant clones in response to drug treatment—non-genetic changes can also lead to drug resistance whereby tolerant, [...] Read more.
Several studies in the last few years have determined that, in contrast to the prevailing dogma that drug resistance is simply due to Darwinian evolution—the selection of mutant clones in response to drug treatment—non-genetic changes can also lead to drug resistance whereby tolerant, reversible phenotypes are eventually relinquished by resistant, irreversible phenotypes. Here, using KRAS as a paradigm, we illustrate how this nexus between genetic and non-genetic mechanisms enables cancer cells to evade the harmful effects of drug treatment. We discuss how the conformational dynamics of the KRAS molecule, that includes intrinsically disordered regions, is influenced by the binding of the targeted therapies contributing to conformational noise and how this noise impacts the interaction of KRAS with partner proteins to rewire the protein interaction network. Thus, in response to drug treatment, reversible drug-tolerant phenotypes emerge via non-genetic mechanisms that eventually enable the emergence of irreversible resistant clones via genetic mutations. Furthermore, we also discuss the recent data demonstrating how combination therapy can help alleviate KRAS drug resistance in lung cancer, and how new treatment strategies based on evolutionary principles may help minimize or even preclude the emergence of drug resistance. Full article
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29 pages, 3404 KiB  
Review
Recent Advancement in Breast Cancer Research: Insights from Model Organisms—Mouse Models to Zebrafish
by Sharad S. Singhal, Rachana Garg, Atish Mohanty, Pankaj Garg, Sravani Keerthi Ramisetty, Tamara Mirzapoiazova, Raffaella Soldi, Sunil Sharma, Prakash Kulkarni and Ravi Salgia
Cancers 2023, 15(11), 2961; https://doi.org/10.3390/cancers15112961 - 29 May 2023
Cited by 21 | Viewed by 8782
Abstract
Animal models have been utilized for decades to investigate the causes of human diseases and provide platforms for testing novel therapies. Indeed, breakthrough advances in genetically engineered mouse (GEM) models and xenograft transplantation technologies have dramatically benefited in elucidating the mechanisms underlying the [...] Read more.
Animal models have been utilized for decades to investigate the causes of human diseases and provide platforms for testing novel therapies. Indeed, breakthrough advances in genetically engineered mouse (GEM) models and xenograft transplantation technologies have dramatically benefited in elucidating the mechanisms underlying the pathogenesis of multiple diseases, including cancer. The currently available GEM models have been employed to assess specific genetic changes that underlay many features of carcinogenesis, including variations in tumor cell proliferation, apoptosis, invasion, metastasis, angiogenesis, and drug resistance. In addition, mice models render it easier to locate tumor biomarkers for the recognition, prognosis, and surveillance of cancer progression and recurrence. Furthermore, the patient-derived xenograft (PDX) model, which involves the direct surgical transfer of fresh human tumor samples to immunodeficient mice, has contributed significantly to advancing the field of drug discovery and therapeutics. Here, we provide a synopsis of mouse and zebrafish models used in cancer research as well as an interdisciplinary ‘Team Medicine’ approach that has not only accelerated our understanding of varied aspects of carcinogenesis but has also been instrumental in developing novel therapeutic strategies. Full article
(This article belongs to the Topic Animal Model in Biomedical Research, 2nd Volume)
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12 pages, 1732 KiB  
Perspective
A Systems Biology Approach for Addressing Cisplatin Resistance in Non-Small Cell Lung Cancer
by Sravani Ramisetty, Prakash Kulkarni, Supriyo Bhattacharya, Arin Nam, Sharad S. Singhal, Linlin Guo, Tamara Mirzapoiazova, Bolot Mambetsariev, Sandeep Mittan, Jyoti Malhotra, Evan Pisick, Shanmuga Subbiah, Swapnil Rajurkar, Erminia Massarelli, Ravi Salgia and Atish Mohanty
J. Clin. Med. 2023, 12(2), 599; https://doi.org/10.3390/jcm12020599 - 11 Jan 2023
Cited by 13 | Viewed by 3401
Abstract
Translational research in medicine, defined as the transfer of knowledge and discovery from the basic sciences to the clinic, is typically achieved through interactions between members across scientific disciplines to overcome the traditional silos within the community. Thus, translational medicine underscores ‘Team Medicine’, [...] Read more.
Translational research in medicine, defined as the transfer of knowledge and discovery from the basic sciences to the clinic, is typically achieved through interactions between members across scientific disciplines to overcome the traditional silos within the community. Thus, translational medicine underscores ‘Team Medicine’, the partnership between basic science researchers and clinicians focused on addressing a specific goal in medicine. Here, we highlight this concept from a City of Hope perspective. Using cisplatin resistance in non-small cell lung cancer (NSCLC) as a paradigm, we describe how basic research scientists, clinical research scientists, and medical oncologists, in true ‘Team Science’ spirit, addressed cisplatin resistance in NSCLC and identified a previously approved compound that is able to alleviate cisplatin resistance in NSCLC. Furthermore, we discuss how a ‘Team Medicine’ approach can help to elucidate the mechanisms of innate and acquired resistance in NSCLC and develop alternative strategies to overcome drug resistance. Full article
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19 pages, 1613 KiB  
Review
Illuminating Intrinsically Disordered Proteins with Integrative Structural Biology
by Rachel Evans, Sravani Ramisetty, Prakash Kulkarni and Keith Weninger
Biomolecules 2023, 13(1), 124; https://doi.org/10.3390/biom13010124 - 7 Jan 2023
Cited by 15 | Viewed by 5310
Abstract
Intense study of intrinsically disordered proteins (IDPs) did not begin in earnest until the late 1990s when a few groups, working independently, convinced the community that these ‘weird’ proteins could have important functions. Over the past two decades, it has become clear that [...] Read more.
Intense study of intrinsically disordered proteins (IDPs) did not begin in earnest until the late 1990s when a few groups, working independently, convinced the community that these ‘weird’ proteins could have important functions. Over the past two decades, it has become clear that IDPs play critical roles in a multitude of biological phenomena with prominent examples including coordination in signaling hubs, enabling gene regulation, and regulating ion channels, just to name a few. One contributing factor that delayed appreciation of IDP functional significance is the experimental difficulty in characterizing their dynamic conformations. The combined application of multiple methods, termed integrative structural biology, has emerged as an essential approach to understanding IDP phenomena. Here, we review some of the recent applications of the integrative structural biology philosophy to study IDPs. Full article
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13 pages, 1784 KiB  
Perspective
Addressing Drug Resistance in Cancer: A Team Medicine Approach
by Prakash Kulkarni, Atish Mohanty, Supriyo Bhattacharya, Sharad Singhal, Linlin Guo, Sravani Ramisetty, Tamara Mirzapoiazova, Bolot Mambetsariev, Sandeep Mittan, Jyoti Malhotra, Naveen Gupta, Pauline Kim, Razmig Babikian, Swapnil Rajurkar, Shanmuga Subbiah, Tingting Tan, Danny Nguyen, Amartej Merla, Sudarsan V. Kollimuttathuillam, Tanyanika Phillips, Peter Baik, Bradford Tan, Pankaj Vashi, Sagun Shrestha, Benjamin Leach, Ruchi Garg, Patricia L. Rich, F. Marc Stewart, Evan Pisick and Ravi Salgiaadd Show full author list remove Hide full author list
J. Clin. Med. 2022, 11(19), 5701; https://doi.org/10.3390/jcm11195701 - 27 Sep 2022
Cited by 7 | Viewed by 2744
Abstract
Drug resistance remains one of the major impediments to treating cancer. Although many patients respond well initially, resistance to therapy typically ensues. Several confounding factors appear to contribute to this challenge. Here, we first discuss some of the challenges associated with drug resistance. [...] Read more.
Drug resistance remains one of the major impediments to treating cancer. Although many patients respond well initially, resistance to therapy typically ensues. Several confounding factors appear to contribute to this challenge. Here, we first discuss some of the challenges associated with drug resistance. We then discuss how a ‘Team Medicine’ approach, involving an interdisciplinary team of basic scientists working together with clinicians, has uncovered new therapeutic strategies. These strategies, referred to as intermittent or ‘adaptive’ therapy, which are based on eco-evolutionary principles, have met with remarkable success in potentially precluding or delaying the emergence of drug resistance in several cancers. Incorporating such treatment strategies into clinical protocols could potentially enhance the precision of delivering personalized medicine to patients. Furthermore, reaching out to patients in the network of hospitals affiliated with leading academic centers could help them benefit from such innovative treatment options. Finally, lowering the dose of the drug and its frequency (because of intermittent rather than continuous therapy) can also have a significant impact on lowering the toxicity and undesirable side effects of the drugs while lowering the financial burden carried by the patient and insurance providers. Full article
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