Browsing by Subject "Drug therapy"
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Item The archaeal Dps nanocage targets kidney proximal tubules via glomerular filtration(American Society for Clinical Investigation, 2019-09-03) Uchida, Masaki; Maier, Bernhard; Waghwani, Hitesh Kumar; Selivanovitch, Ekaterina; Pay, S. Louise; Avera, John; Yun, EJun; Sandoval, Ruben M.; Molitoris, Bruce A.; Zollman, Amy; Douglas, Trevor; Hato, Takashi; Medicine, School of MedicineNature exploits cage-like proteins for a variety of biological purposes, from molecular packaging and cargo delivery to catalysis. These cage-like proteins are of immense importance in nanomedicine due to their propensity to self-assemble from simple identical building blocks to highly ordered architecture and the design flexibility afforded by protein engineering. However, delivery of protein nanocages to the renal tubules remains a major challenge because of the glomerular filtration barrier, which effectively excludes conventional size nanocages. Here, we show that DNA-binding protein from starved cells (Dps) — the extremely small archaeal antioxidant nanocage — is able to cross the glomerular filtration barrier and is endocytosed by the renal proximal tubules. Using a model of endotoxemia, we present an example of the way in which proximal tubule–selective Dps nanocages can limit the degree of endotoxin-induced kidney injury. This was accomplished by amplifying the endogenous antioxidant property of Dps with addition of a dinuclear manganese cluster. Dps is the first-in-class protein cage nanoparticle that can be targeted to renal proximal tubules through glomerular filtration. In addition to its therapeutic potential, chemical and genetic engineering of Dps will offer a nanoplatform to advance our understanding of the physiology and pathophysiology of glomerular filtration and tubular endocytosis.Item Clinical implications of retinal oximetry in retinal vein occlusion: a review(Wiley, 2022) Belamkar, Aditya V.; Jabbehdari, Sayena; Harris, Alon; Hajrasouliha, Amir R.; Ophthalmology, School of MedicinePurpose: To review retinal vein occlusion (RVO) and its relationship with retinal oxygen saturation via automated retinal oximetry in eyes with RVO. Methods: A literature review was performed in PubMed and Medline until October 2021 utilizing specific keywords and cross-matched reference lists. Results: This review found RVO to be associated with risk factors including age, hypertension, cardiovascular and metabolic conditions, male gender, and glaucoma. These may be attributed to a breakdown of regulatory processes in the retina. Retinal venous oxygen saturation (SvO2 ) and arteriovenous difference in eyes with central RVO have been found to be reduced and elevated, respectively. The literature indicates variable and contradictory findings in regard to branch RVO and retinal oxygenation. Additionally, ischaemic eyes have been found to have elevated retinal arterial oxygen saturation; however, the literature reports variable results regarding SvO2 levels. Medications have been suggested to increase SvO2 in RVO eyes, which may represent an important mechanism for disease management. Ranibizumab is currently the most studied drug for retinal oxygenation in RVO and has been suggested to increase SvO2 in RVO eyes. In comparison, dexamethasone was found to decrease SvO2 . Conclusion: The current literature on retinal oxygenation in ischaemic subtypes of RVO and in drug therapies is minimal, and further work is required to expand upon our understanding of how ischaemia and drugs influence retinal oxygenation and clinical outcomes.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 Effects of a Novel Nitroxyl Donor in Acute Heart Failure: The STAND-UP AHF Study(Elsevier, 2021) Felker, G. Michael; McMurray, John J. V.; Cleland, John G.; O’Connor, Christopher M.; Teerlink, John R.; Voors, Adriaan A.; Belohlavek, Jan; Böhm, Michael; Borentain, Maria; Bueno, Hector; Cole, Robert T.; DeSouza, Mary M.; Ezekowitz, Justin A.; Filippatos, Gerasimos; Lang, Ninian N.; Kessler, Paul D.; Martinez, Felipe A.; Mebazaa, Alex; Metra, Marco; Mosterd, Arend; Pang, Peter S.; Ponikowski, Piotr; Sato, Naoki; Seiffert, Dietmar; Ye, June; Emergency Medicine, School of MedicineObjectives: The primary objective was to identify well-tolerated doses of cimlanod in patients with acute heart failure (AHF). Secondary objectives were to identify signals of efficacy, including biomarkers, symptoms, and clinical events. Background: Nitroxyl (HNO) donors have vasodilator, inotropic and lusitropic effects. Bristol-Myers Squibb-986231 (cimlanod) is an HNO donor being developed for acute heart failure (AHF). Methods: This was a phase IIb, double-blind, randomized, placebo-controlled trial of 48-h treatment with cimlanod compared with placebo in patients with left ventricular ejection fraction ≤40% hospitalized for AHF. In part I, patients were randomized in a 1:1 ratio to escalating doses of cimlanod or matching placebo. In part II, patients were randomized in a 1:1:1 ratio to either of the 2 highest tolerated doses of cimlanod from part I or placebo. The primary endpoint was the rate of clinically relevant hypotension (systolic blood pressure <90 mm Hg or patients became symptomatic). Results: In part I (n = 100), clinically relevant hypotension was more common with cimlanod than placebo (20% vs. 8%; relative risk [RR]: 2.45; 95% confidence interval [CI]: 0.83 to 14.53). In part II (n = 222), the incidence of clinically relevant hypotension was 18% for placebo, 21% for cimlanod 6 μg/kg/min (RR: 1.15; 95% CI: 0.58 to 2.43), and 35% for cimlanod 12 μg/kg/min (RR: 1.9; 95% CI: 1.04 to 3.59). N-terminal pro-B-type natriuretic peptide and bilirubin decreased during infusion of cimlanod treatment compared with placebo, but these differences did not persist after treatment discontinuation. Conclusions: Cimlanod at a dose of 6 μg/kg/min was reasonably well-tolerated compared with placebo. Cimlanod reduced markers of congestion, but this did not persist beyond the treatment period.Item Genome-Wide Discovery of Drug-Dependent Human Liver Regulatory Elements(PLOS (Public Library of Science), 2014-10-02) Smith, Robin P.; Eckalbar, Walter L.; Morrissey, Kari M.; Luizon, Marcelo R.; Hoffmann, Thomas J.; Sun, Xuefeng; Jones, Stacy L.; Aldred, Shelley Force; Ramamoorthy, Anuradha; Desta, Zeruesenay; Liu, Yunlong; Skaar, Todd C.; Trinklein, Nathan D.; Giacomini, Kathleen M.; Ahituv, Nadav; Department of Medicine, School of MedicineInter-individual variation in gene regulatory elements is hypothesized to play a causative role in adverse drug reactions and reduced drug activity. However, relatively little is known about the location and function of drug-dependent elements. To uncover drug-associated elements in a genome-wide manner, we performed RNA-seq and ChIP-seq using antibodies against the pregnane X receptor (PXR) and three active regulatory marks (p300, H3K4me1, H3K27ac) on primary human hepatocytes treated with rifampin or vehicle control. Rifampin and PXR were chosen since they are part of the CYP3A4 pathway, which is known to account for the metabolism of more than 50% of all prescribed drugs. We selected 227 proximal promoters for genes with rifampin-dependent expression or nearby PXR/p300 occupancy sites and assayed their ability to induce luciferase in rifampin-treated HepG2 cells, finding only 10 (4.4%) that exhibited drug-dependent activity. As this result suggested a role for distal enhancer modules, we searched more broadly to identify 1,297 genomic regions bearing a conditional PXR occupancy as well as all three active regulatory marks. These regions are enriched near genes that function in the metabolism of xenobiotics, specifically members of the cytochrome P450 family. We performed enhancer assays in rifampin-treated HepG2 cells for 42 of these sequences as well as 7 sequences that overlap linkage-disequilibrium blocks defined by lead SNPs from pharmacogenomic GWAS studies, revealing 15/42 and 4/7 to be functional enhancers, respectively. A common African haplotype in one of these enhancers in the GSTA locus was found to exhibit potential rifampin hypersensitivity. Combined, our results further suggest that enhancers are the predominant targets of rifampin-induced PXR activation, provide a genome-wide catalog of PXR targets and serve as a model for the identification of drug-responsive regulatory elements.Item HB007 Administration Inhibits LN-229 and Patient-Derived Neurospheroid Glioblastoma Cell Growth With the Degradation of SUMO1 and Cell Cycle Regulator CDK4(2023-07-27) Dougherty, Carson; Wohlford, Reagan; Jung, Sunghan; Hao, ChunhaiBackground and Hypothesis: Glioblastoma is the most common and malignant brain cancer and there is no effective therapy currently available to patients with this malignancy. Small ubiquitin-related modifier 1 (SUMO1) is a key regulator of cancer cell proliferation through its role in its modification of cellular proteins in various human cancers, especially glioblastoma. Degradation of SUMO1 through small molecule degrader, HB007, has been shown to inhibit growth in cancer cell lines and xenografts. Here, we hypothesize that HB007 can inhibit the glioblastoma cell growth through degradation of SUMO1 protein in glioblastoma cells and the cancer stem cell enriched neurospheres. Experimental Design: LN-229 glioblastoma cell viability was measured in response to increasing concentrations of HB007. LN-229 and patient-derived neurospheroid glioblastoma cells were cultured and seeded in 4 different plates at 1000 cells/ml concentrations before being treated with HB007 at increasing concentrations encircling the previously described IC50. Cells were then subjected to a SUMO lysis buffer and analyzed via western blot with antibodies specific to SUMO1, CDK4, and actin. Results: HB007 treated LN-229 cells exhibited an IC50 of 1.470µM. Western blot analysis confirmed the dose dependent reduction in SUMO-1-ylated proteins in HB007 treated cells. A reduction in CDK4 confirmed that cell progression is halted in a dose dependent manner in LN-229 and patient-derived neurospheroid glioblastoma cells when treated with HB007. Specificity of HB007 is towards SUMO1 with no nonspecific degradation of SUMO2/3. Conclusion: The cell growth of LN-229 and patient-derived neurospheroid glioblastoma cells was confirmed, through western blot, to be inhibited in a dose dependent manner by HB007. These results further establish the therapeutic potential of SUMO1 degraders as a novel anticancer drug for glioblastoma therapy. In the future, it is hoped that the bioavailability, potency, and blood brain barrier permeability can be improved to make this drug a potential treatment for patients. Presentation recording available online: https://purl.dlib.indiana.edu/iudl/media/k71n501c5gItem Nephron-sparing management of upper tract urothelial carcinoma(Korean Urological Association, 2021-07) Farrow, Jason M.; Kern, Sean Q.; Gryzinski, Gustavo M.; Sundaram, Chandru P.; Urology, School of MedicineUrothelial carcinoma of the upper urinary tract is uncommon and presents unique challenges for diagnosis and management. Nephroureterectomy has been the preferred management option, but it is associated with significant morbidity. Nephron-sparing treatments are a valuable alternative and provide similar efficacy in select cases. A PubMed literature review was performed in English language publications using the following search terms: urothelial carcinoma, upper tract, nephron-sparing, intraluminal and systemic therapy. Contemporary papers published within the last 10 years were primarily included. Where encountered, systematic reviews and meta-analyses were given priority, as were randomized controlled trials for newer treatments. Core guidelines were referenced and citations reviewed for inclusion. A summary of epidemiological data, clinical diagnosis, staging, and treatments focusing on nephron-sparing approaches to upper tract urothelial carcinoma (UTUC) are outlined. Nephron-sparing management strategies are viable options to consider in patients with favorable features of UTUC. Adjunctive therapies are being investigated but the data remains mixed. Protocol variability and dosage differences limit statistical interpretation. New mechanisms to improve treatment dwell times in the upper tracts are being designed with promising preliminary results. Studies investigating systemic therapies are ongoing but implications for nephron-sparing management are uncertain. Nephron-sparing management is an acceptable treatment modality best suited for favorable disease. More work is needed to determine if intraluminal and/or systemic therapies can further optimize treatment outcomes beyond resection alone.Item The neurobiology of alcoholism in genetically selected rat models(The National Institute on Alcohol Abuse and Alcoholism, 1997) Stewart, Robert B.; Li, Ting-Kai; Psychology, School of ScienceRats selectively bred for their tendency to drink large or small quantities of alcohol are a useful model for investigators examining the possible neurobiological processes underlying alcoholism. Studies with the alcohol-preferring (P) and alcohol-nonpreferring (NP) and the high-alcohol-drinking (HAD) and low-alcohol-drinking (LAD) pairs of rat lines developed at Indiana University have illustrated differences in several behavioral and neurobiological characteristics associated with alcohol consumption. Specifically, compared with alcohol-avoiding rats, rats with an affinity for alcohol have a greater sensitivity to the stimulatory effects of low to moderate doses and a reduced sensitivity to the negative effects of high doses. Rats that voluntarily drink large quantities of alcohol also acquire tolerance to alcohol’s aversive effects. In addition, these rats differ from their alcohol-avoiding counterparts in the levels of several chemical mediators (i.e., neurotransmitters) found in the brain, including serotonin, dopamine, gamma-aminobutyric acid (GABA), and the endogenous opioids.Item Pharmacologic Treatment for Pediatric Gastroparesis: A Review of the Literature(Pediatric Pharmacy Advocacy Group, 2016-03) Tillman, Emma M.; Smetana, Keaton S.; Bantu, Likeselam; Buckley, Merrion G.; Department of Pediatrics, IU School of MedicineThere have been a number of agents that have been tried for treatment of gastroparesis over the past 3 decades, with varying levels of success. Guidelines exist for the management of gastroparesis in adults; however, even though the cause of gastroparesis in children is similar to that in adults, no guidelines exist for treating pediatric gastroparesis as studies on the topic are limited. With what little information we have on pediatric gastroparesis, medications used in children's studies do not seem to demonstrate the same results as in adult patients with gastroparesis; thus, future studies of whether certain medications are effective for treating pediatric gastroparesis and at what dose still need to be conducted. Pharmacological treatment options for pediatric gastroparesis do not show a clear correlation of resolving or even maintaining gastroparesis-associated symptoms or disease state. This article reviews the available studies of drugs that have shown some efficacy, with an emphasis on pediatric studies.Item Polo-like kinase 1 (Plk1) inhibition synergizes with taxanes in triple negative breast cancer(Public Library of Science, 2019-11-21) Giordano, Antonio; Liu, Yueying; Armeson, Kent; Park, Yeonhee; Ridinger, Maya; Erlander, Mark; Reuben, James; Britten, Carolyn; Kappler, Christiana; Yeh, Elizabeth; Ethier, Stephen; Pathology and Laboratory Medicine, School of MedicineWithin triple negative breast cancer, several molecular subtypes have been identified, underlying the heterogeneity of such an aggressive disease. The basal-like subtype is characterized by mutations in the TP53 gene, and is associated with a low pathologic complete response rate following neoadjuvant chemotherapy. In a genome-scale short hairpin RNA (shRNA) screen of breast cancer cells, polo-like kinase 1 (Plk1) was a frequent and strong hit in the basal breast cancer cell lines indicating its importance for growth and survival of these breast cancer cells. Plk1 regulates progression of cells through the G2-M phase of the cell cycle. We assessed the activity of two ATP-competitive Plk1 inhibitors, GSK461364 and onvansertib, alone and with a taxane in a set of triple negative breast cancer cell lines and in vivo. GSK461364 showed synergism with docetaxel in SUM149 (Combination Index 0.70) and SUM159 (CI, 0.62). GSK461364 in combination with docetaxel decreased the clonogenic potential (interaction test for SUM149 and SUM159, p<0.001 and p = 0.01, respectively) and the tumorsphere formation of SUM149 and SUM159 (interaction test, p = 0.01 and p< 0.001). In the SUM159 xenograft model, onvansertib plus paclitaxel significantly decreased tumor volume compared to single agent paclitaxel (p<0.0001). Inhibition of Plk1 in combination with taxanes shows promising results in a subset of triple negative breast cancer intrinsically resistant to chemotherapy. Onvansertib showed significant tumor volume shrinkage when combined with paclitaxel in vivo and should be considered in clinical trials for the treatment of triple negative cancers.