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Item A Bisphosphonate With a Low Hydroxyapatite Binding Affinity Prevents Bone Loss in Mice After Ovariectomy and Reverses Rapidly With Treatment Cessation(Wiley, 2021-03-03) Coffman, Abigail A.; Basta-Pljakic, Jelena; Guerra, Rosa M.; Ebetino, Frank H.; Lundy, Mark W.; Majeska, Robert J.; Schaffler, Mitchell B.; Anatomy, Cell Biology and Physiology, School of MedicineBisphosphonates (BPs) are a mainstay of osteoporosis treatment; however, concerns about bone health based on oversuppression of remodeling remain. Long‐term bone remodeling suppression adversely affects bone material properties with microdamage accumulation and reduced fracture toughness in animals and increases in matrix mineralization and atypical femur fractures in patients. Although a “drug holiday” from BPs to restore remodeling and improve bone quality seems reasonable, clinical BPs have long functional half‐lives because of their high hydroxyapatite (HAP) binding affinities. This places a practical limit on the reversibility and effectiveness of a drug holiday. BPs with low HAP affinity and strong osteoclast inhibition potentially offer an alternative approach; their antiresorptive effect should reverse rapidly when dosing is discontinued. This study tested this concept using NE‐58025, a BP with low HAP affinity and moderate osteoclast inhibition potential. Young adult female C57Bl/6 mice were ovariectomized (OVX) and treated with NE‐58025, risedronate, or PBS vehicle for 3 months to test effectiveness in preventing long‐term bone loss. Bone microarchitecture, histomorphometry, and whole‐bone mechanical properties were assessed. To test reversibility, OVX mice were similarly treated for 3 months, treatment was stopped, and bone was assessed up to 3 months post‐treatment. NE‐58025 and RIS inhibited long‐term OVX‐induced bone loss, but NE‐58025 antiresorptive effects were more pronounced. Withdrawing NE‐58025 treatment led to the rapid onset of trabecular resorption with a 200% increase in osteoclast surface and bone loss within 1 month. Cessation of risedronate treatment did not lead to increases in resorption indices or bone loss. These results show that NE‐58025 prevents OVX‐induced bone loss, and its effects reverse quickly following cessation treatment in vivo. Low‐HAP affinity BPs may have use as reversible, antiresorptive agents with a rapid on/off profile, which may be useful for maintaining bone health with long‐term BP treatment.Item A framework for translating tauopathy therapeutics: Drug discovery to clinical trials(Wiley, 2024) Feldman, Howard H.; Cummings, Jeffrey L.; Boxer, Adam L.; Staffaroni, Adam M.; Knopman, David S.; Sukoff Rizzo, Stacey J.; Territo, Paul R.; Arnold, Steven E.; Ballard, Clive; Beher, Dirk; Boeve, Bradley F.; Dacks, Penny A.; Diaz, Kristophe; Ewen, Colin; Fiske, Brian; Gonzalez, M. Isabel; Harris, Glenn A.; Hoffman, Beth J.; Martinez, Terina N.; McDade, Eric; Nisenbaum, Laura K.; Palma, Jose-Alberto; Quintana, Melanie; Rabinovici, Gil D.; Rohrer, Jonathan D.; Rosen, Howard J.; Troyer, Matthew D.; Kim, Doo Yeon; Tanzi, Rudolph E.; Zetterberg, Henrik; Ziogas, Nick K.; May, Patrick C.; Rommel, Amy; Medicine, School of MedicineThe tauopathies are defined by pathological tau protein aggregates within a spectrum of clinically heterogeneous neurodegenerative diseases. The primary tauopathies meet the definition of rare diseases in the United States. There is no approved treatment for primary tauopathies. In this context, designing the most efficient development programs to translate promising targets and treatments from preclinical studies to early-phase clinical trials is vital. In September 2022, the Rainwater Charitable Foundation convened an international expert workshop focused on the translation of tauopathy therapeutics through early-phase trials. Our report on the workshop recommends a framework for principled drug development and a companion lexicon to facilitate communication focusing on reproducibility and achieving common elements. Topics include the selection of targets, drugs, biomarkers, participants, and study designs. The maturation of pharmacodynamic biomarkers to demonstrate target engagement and surrogate disease biomarkers is a crucial unmet need. HIGHLIGHTS: Experts provided a framework to translate therapeutics (discovery to clinical trials). Experts focused on the "5 Rights" (target, drug, biomarker, participants, trial). Current research on frontotemporal degeneration, progressive supranuclear palsy, and corticobasal syndrome therapeutics includes 32 trials (37% on biologics) Tau therapeutics are being tested in Alzheimer's disease; primary tauopathies have a large unmet need.Item Advancements in APOE and dementia research: Highlights from the 2023 AAIC Advancements: APOE conference(Wiley, 2024) Kloske, Courtney M.; Belloy, Michael E.; Blue, Elizabeth E.; Bowman, Gregory R.; Carrillo, Maria C.; Chen, Xiaoying; Chiba-Falek, Ornit; Davis, Albert A.; Di Paolo, Gilbert; Garretti, Francesca; Gate, David; Golden, Lesley R.; Heinecke, Jay W.; Herz, Joachim; Huang, Yadong; Iadecola, Costantino; Johnson, Lance A.; Kanekiyo, Takahisa; Karch, Celeste M.; Khvorova, Anastasia; Koppes-den Hertog, Sascha J.; Lamb, Bruce T.; Lawler, Paige E.; Le Guen, Yann; Litvinchuk, Alexandra; Liu, Chia-Chen; Mahinrad, Simin; Marcora, Edoardo; Marino, Claudia; Michaelson, Danny M.; Miller, Justin J.; Morganti, Josh M.; Narayan, Priyanka S.; Naslavsky, Michel S.; Oosthoek, Marlies; Ramachandran, Kapil V.; Ramakrishnan, Abhirami; Raulin, Ana-Caroline; Robert, Aiko; Saleh, Rasha N. M.; Sexton, Claire; Shah, Nilomi; Shue, Francis; Sible, Isabel J.; Soranno, Andrea; Strickland, Michael R.; Tcw, Julia; Thierry, Manon; Tsai, Li-Huei; Tuckey, Ryan A.; Ulrich, Jason D.; van der Kant, Rik; Wang, Na; Wellington, Cheryl L.; Weninger, Stacie C.; Yassine, Hussein N.; Zhao, Na; Bu, Guojun; Goate, Alison M.; Holtzman, David M.; Neurology, School of MedicineIntroduction: The apolipoprotein E gene (APOE) is an established central player in the pathogenesis of Alzheimer's disease (AD), with distinct apoE isoforms exerting diverse effects. apoE influences not only amyloid-beta and tau pathologies but also lipid and energy metabolism, neuroinflammation, cerebral vascular health, and sex-dependent disease manifestations. Furthermore, ancestral background may significantly impact the link between APOE and AD, underscoring the need for more inclusive research. Methods: In 2023, the Alzheimer's Association convened multidisciplinary researchers at the "AAIC Advancements: APOE" conference to discuss various topics, including apoE isoforms and their roles in AD pathogenesis, progress in apoE-targeted therapeutic strategies, updates on disease models and interventions that modulate apoE expression and function. Results: This manuscript presents highlights from the conference and provides an overview of opportunities for further research in the field. Discussion: Understanding apoE's multifaceted roles in AD pathogenesis will help develop targeted interventions for AD and advance the field of AD precision medicine. Highlights: APOE is a central player in the pathogenesis of Alzheimer's disease. APOE exerts a numerous effects throughout the brain on amyloid-beta, tau, and other pathways. The AAIC Advancements: APOE conference encouraged discussions and collaborations on understanding the role of APOE.Item Burosumab treatment in adults with X-linked hypophosphataemia: 96-week patient-reported outcomes and ambulatory function from a randomised phase 3 trial and open-label extension(BMJ, 2021) Briot, Karine; Portale, Anthony A.; Brandi, Maria Luisa; Carpenter, Thomas O.; Cheong, Hae Ii; Cohen-Solal, Martine; Crowley, Rachel K.; Eastell, Richard; Imanishi, Yasuo; Ing, Steven; Insogna, Karl; Ito, Nobuaki; de Beur, Suzanne Jan; Javaid, Muhammad K.; Kamenicky, Peter; Keen, Richard; Kubota, Takuo; Lachmann, Robin H.; Perwad, Farzana; Pitukcheewanont, Pisit; Ralston, Stuart H.; Takeuchi, Yasuhiro; Tanaka, Hiroyuki; Weber, Thomas J.; Yoo, Han-Wook; Nixon, Annabel; Nixon, Mark; Sun, Wei; Williams, Angela; Imel, Erik A.; Medicine, School of MedicineObjectives: To report the impact of burosumab on patient-reported outcomes (PROs) and ambulatory function in adults with X-linked hypophosphataemia (XLH) through 96 weeks. Methods: Adults diagnosed with XLH were randomised 1:1 in a double-blinded trial to receive subcutaneous burosumab 1 mg/kg or placebo every 4 weeks for 24 weeks (NCT02526160). Thereafter, all subjects received burosumab every 4 weeks until week 96. PROs were measured using the Western Ontario and the McMaster Universities Osteoarthritis Index (WOMAC), Brief Pain Inventory-Short Form (BPI-SF) and Brief Fatigue Inventory (BFI), and ambulatory function was measured with the 6 min walk test (6MWT). Results: Subjects (N=134) were randomised to burosumab (n=68) or placebo (n=66) for 24 weeks. At baseline, subjects experienced pain, stiffness, and impaired physical and ambulatory function. At week 24, subjects receiving burosumab achieved statistically significant improvement in some BPI-SF scores, BFI worst fatigue (average and greatest) and WOMAC stiffness. At week 48, all WOMAC and BPI-SF scores achieved statistically significant improvement, with some WOMAC and BFI scores achieving meaningful and significant change from baseline. At week 96, all WOMAC, BPI-SF and BFI achieved statistically significant improvement, with selected scores in all measures also achieving meaningful change. Improvement in 6MWT distance and percent predicted were statistically significant at all time points from 24 weeks. Conclusions: Adults with XLH have substantial burden of disease as assessed by PROs and 6MWT. Burosumab treatment improved phosphate homoeostasis and was associated with a steady and consistent improvement in PROs and ambulatory function.Item Cetuximab for Immunotherapy-Refractory/Ineligible Cutaneous Squamous Cell Carcinoma(MDPI, 2023-06-14) Marin-Acevedo, Julian A.; Withycombe, Bethany M.; Kim, Youngchul; Brohl, Andrew S.; Eroglu, Zeynep; Markowitz, Joseph; Tarhini, Ahmad A.; Tsai, Kenneth Y.; Khushalani, Nikhil I.; Medicine, School of MedicineAnti-PD1 therapy demonstrated impressive, prolonged responses in advanced cutaneous squamous cell carcinoma (CSCC). Therapy for ICI-refractory/ineligible disease remains unclear. We performed a retrospective analysis in locally-advanced/metastatic CSCC using cetuximab across three cohorts: immediately after ICI failure (A), not immediately following ICI failure (B), or without prior ICI (C). The primary endpoint was the overall response rate (ORR). Secondary endpoints included disease-control rate (DCR), progression-free survival (PFS), overall survival (OS), time-to-response (TTR) and toxicity. Twenty-three patients were included. In cohort A (n = 11), the ORR was 64% and DCR was 91%, with six ongoing responses at data cutoff. In cohort B (n = 2), all patients had progression as the best response. At a median follow-up of 21 months for A and B, TTR and PFS were 2.0 and 17.3 months, respectively. The median OS was not reached. In cohort C (n = 10), the ORR and DCR were 80%, including five ongoing responses at the data cutoff. At a median follow-up of 22.4 months, the TTR, PFS and OS were 2.5, 7.3 and 23.1 months, respectively. Cetuximab was well tolerated in all cohorts. In summary, cetuximab is effective in patients with failure/contraindications to ICI. Cetuximab immediately after ICI failure yielded particularly fast, durable responses. If confirmed, this could be the preferred therapy following ICI failure.Item Cognitive dysfunction in cancer: Neuroimaging and genetic approaches to identify biological mechanisms(2015-04-22) Nudelman, Kelly N. H.; Saykin, Andrew J.; Foroud, Tatiana M.; McDonald, Brenna Cathleen; Schneider, Bryan Paul; Shen, LiAlthough cancer and treatment-associated cognitive dysfunction has been well-documented in the literature, much work remains to elucidate the biological mechanisms driving this effect, hampering current therapeutic efforts. To address this gap, we first reviewed studies utilizing neuroimaging to characterize cognitive dysfunction in cancer, as studies of neurodegenerative diseases point to neuroimaging as a sensitive measure of cognitive dysfunction. This review highlighted the need for longitudinal imaging studies of cancer and treatment-related changes in cerebral structure and function. Subsequently, we utilized multimodal neuroimaging techniques in a female breast cancer cohort to investigate the longitudinal impact of cancer and chemotherapy treatment on cerebral perfusion and gray matter. Our findings indicate that chemotherapy is associated with elevated perfusion, primarily in posterior brain regions, as well as depressed frontal perfusion associated with decreased frontal gray matter density. This pattern of results suggests the involvement of multiple mechanisms of chemotherapy-induced cognitive dysfunction. We also investigated the relationship of cognitive dysfunction and chemotherapy-induced peripheral neuropathy (CIPN), another type of chemotherapy-related nervous system sequelae, again utilizing multimodal, longitudinal neuroimaging, and found that peripheral neuropathy symptoms following chemotherapy were associated with changes in cerebral perfusion and gray matter density. Together, these findings support the hypothesis that multiple biological mechanisms drive cancer and treatment-related cognitive dysfunction. Interestingly, although cancer is associated with cognitive dysfunction, epidemiological studies have shown that cancer and Alzheimer's disease (AD) are inversely correlated. To extend our imaging analysis beyond breast cancer, we leveraged the Alzheimer's Disease Neuroimaging Initiative (ADNI) cohort to investigate the inverse relationship of cancer and AD and investigate the impact of both of these diseases on gray matter density. We found that though the inverse relationship of these diseases was replicated in the ADNI cohort, cancer history was associated with lower gray matter density, similar to findings from breast cancer studies, independent of AD diagnostic group. Finally, we reviewed microRNA studies, as microRNAs are important regulators of many cell signaling pathways and have been actively investigated in relation to both diseases. This review suggests several pathways that may be driving the inverse association and may contribute to cognitive dysfunction.Item Comprehensive biomedical applications of low temperature plasmas(Elsevier, 2020-08-26) Duarte, Simone; Panariello, Beatriz H.D.; Cariology, Operative Dentistry and Dental Public Health, School of DentistryThe main component of plasma medicine is the use of low-temperature plasma (LTP) as a powerful tool for biomedical applications. LTP generates high reactivity at low temperatures and can be activated with noble gases with molecular mixtures or compressed air. LTP reactive species are quickly produced, and are a remarkably good source of reactive oxygen and nitrogen species including singlet oxygen (O2), ozone (O3), hydroxyl radicals (OH), nitrous oxide (NO), and nitrogen dioxide (NO2). Its low gas temperature and highly reactive non-equilibrium chemistry make it appropriate for the alteration of inorganic surfaces and delicate biological systems. Treatment of oral biofilm-related infections, treatment of wounds and skin diseases, assistance in cancer treatment, treatment of viruses’ infections (e.g. herpes simplex), and optimization of implants surfaces are included among the extensive plasma medicine applications. Each of these applications will be discussed in this review article.Item Creating Structured Hydrogel Microenvironments for Regulating Stem Cell Differentiation(MDPI, 2020-12) Mills, David K.; Luo, Yangyang; Elumalai, Anusha; Esteve, Savannah; Karnik, Sonali; Yao, Shaomian; Mechanical and Energy Engineering, School of Engineering and TechnologyThe development of distinct biomimetic microenvironments for regulating stem cell behavior and bioengineering human tissues and disease models requires a solid understanding of cell–substrate interactions, adhesion, and its role in directing cell behavior, and other physico-chemical cues that drive cell behavior. In the past decade, innovative developments in chemistry, materials science, microfabrication, and associated technologies have given us the ability to manipulate the stem cell microenvironment with greater precision and, further, to monitor effector impacts on stem cells, both spatially and temporally. The influence of biomaterials and the 3D microenvironment’s physical and biochemical properties on mesenchymal stem cell proliferation, differentiation, and matrix production are the focus of this review chapter. Mechanisms and materials, principally hydrogel and hydrogel composites for bone and cartilage repair that create “cell-supportive” and “instructive” biomaterials, are emphasized. We begin by providing an overview of stem cells, their unique properties, and their challenges in regenerative medicine. An overview of current fabrication strategies for creating instructive substrates is then reviewed with a focused discussion of selected fabrication methods with an emphasis on bioprinting as a critical tool in creating novel stem cell-based biomaterials. We conclude with a critical assessment of the current state of the field and offer our view on the promises and potential pitfalls of the approaches discussed.Item Culture media composition influences patient-derived organoid ability to predict therapeutic responses in gastrointestinal cancers(American Society for Clinical Investigation, 2022-11-22) Hogenson, Tara L.; Xie, Hao; Phillips, William J.; Toruner, Merih D.; Li, Jenny J.; Horn, Isaac P.; Kennedy, Devin J.; Almada, Luciana L.; Marks, David L.; Carr, Ryan M.; Toruner, Murat; Sigafoos, Ashley N.; Koenig-Kappes, Amanda N.; Olson, Rachel Lo; Tolosa, Ezequiel J.; Zhang, Cheng; Li, Hu; Doles, Jason D.; Bleeker, Jonathan; Barrett, Michael T.; Boyum, James H.; Kipp, Benjamin R.; Mahipal, Amit; Hubbard, Joleen M.; Scheffler Hanson, Temperance J.; Petersen, Gloria M.; Dasari, Surendra; Oberg, Ann L.; Truty, Mark J.; Graham, Rondell P.; Levy, Michael J.; Zhu, Mojun; Billadeau, Daniel D.; Adjei, Alex A.; Dusetti, Nelson; Iovanna, Juan L.; Bekaii-Saab, Tanios S.; Ma, Wen Wee; Fernandez-Zapico, Martin E.; Anatomy, Cell Biology and Physiology, School of MedicineBACKGROUND: A patient-derived organoid (PDO) platform may serve as a promising tool for translational cancer research. In this study, we evaluated PDO’s ability to predict clinical response to gastrointestinal (GI) cancers. METHODS: We generated PDOs from primary and metastatic lesions of patients with GI cancers, including pancreatic ductal adenocarcinoma, colorectal adenocarcinoma, and cholangiocarcinoma. We compared PDO response with the observed clinical response for donor patients to the same treatments. RESULTS: We report an approximately 80% concordance rate between PDO and donor tumor response. Importantly, we found a profound influence of culture media on PDO phenotype, where we showed a significant difference in response to standard-of-care chemotherapies, distinct morphologies, and transcriptomes between media within the same PDO cultures. CONCLUSION: While we demonstrate a high concordance rate between donor tumor and PDO, these studies also showed the important role of culture media when using PDOs to inform treatment selection and predict response across a spectrum of GI cancers.Item From proteomics to discovery of first-in-class ST2 inhibitors active in vivo(American Society for Clinical Investigation, 2018-07-26) Ramadan, Abdulraouf M.; Daguindau, Etienne; Rech, Jason C.; Chinnaswamy, Krishnapriya; Zhang, Jilu; Hura, Greg L.; Griesenauer, Brad; Bolten, Zachary; Robida, Aaron; Larsen, Martha; Stuckey, Jeanne A.; Yang, Chao-Yie; Paczesny, Sophie; Pediatrics, School of MedicineSoluble cytokine receptors function as decoy receptors to attenuate cytokine-mediated signaling and modulate downstream cellular responses. Dysregulated overproduction of soluble receptors can be pathological, such as soluble ST2 (sST2), a prognostic biomarker in cardiovascular diseases, ulcerative colitis, and graft-versus-host disease (GVHD). Although intervention using an ST2 antibody improves survival in murine GVHD models, sST2 is a challenging target for drug development because it binds to IL-33 via an extensive interaction interface. Here, we report the discovery of small-molecule ST2 inhibitors through a combination of high-throughput screening and computational analysis. After in vitro and in vivo toxicity assessment, 3 compounds were selected for evaluation in 2 experimental GVHD models. We show that the most effective compound, iST2-1, reduces plasma sST2 levels, alleviates disease symptoms, improves survival, and maintains graft-versus-leukemia activity. Our data suggest that iST2-1 warrants further optimization to develop treatment for inflammatory diseases mediated by sST2.
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