Browsing by Subject "Therapy"
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Item A novel, safe, fast and efficient treatment for Her2-positive and negative bladder cancer utilizing an EGF-anthrax toxin chimera(Wiley, 2020) Jack, Sherwin; Madhivanan, Kayalvizhi; Ramadesika, Swetha; Subramanian, Sneha; Edwards, Daniel F., II; Elzey, Bennett D.; Dhawan, Deepika; McCluskey, Andrew; Kischuk, Erin M.; Loftis, Alexander R.; Truex, Nicholas; Santos, Michael; Lu, Mike; Rabideau, Amy; Pentelute, Bradley; Collier, John; Kaimakliotis, Hristos; Koch, Michael; Ratliff, Timothy L.; Knapp, Deborah W.; Aguilar, Ruben C.; Urology, School of MedicineBladder cancer is the sixth most common cancer in the United States, and it exhibits an alarming 70% recurrence rate. Thus, the development of more efficient antibladder cancer approaches is a high priority. Accordingly, this work provides the basis for a transformative anticancer strategy that takes advantage of the unique characteristics of the bladder. Unlike mucin-shielded normal bladder cells, cancer cells are exposed to the bladder lumen and overexpress EGFR. Therefore, we used an EGF-conjugated anthrax toxin that after targeting EGFR was internalized and triggered apoptosis in exposed bladder cancer cells. This unique agent presented advantages over other EGF-based technologies and other toxin-derivatives. In contrast to known agents, this EGF-toxin conjugate promoted its own uptake via receptor microclustering even in the presence of Her2 and induced cell death with a LC50 < 1 nM. Furthermore, our data showed that exposures as short as ≈3 min were enough to commit human (T24), mouse (MB49) and canine (primary) bladder cancer cells to apoptosis. Exposure of tumor-free mice and dogs with the agent resulted in no toxicity. In addition, the EGF-toxin was able to eliminate cells from human patient tumor samples. Importantly, the administration of EGF-toxin to dogs with spontaneous bladder cancer, who had failed or were not eligible for other therapies, resulted in ~30% average tumor reduction after one treatment cycle. Because of its in vitro and in vivo high efficiency, fast action (reducing treatment time from hours to minutes) and safety, we propose that this EGF–anthrax toxin conjugate provides the basis for new, transformative approaches against bladder cancer.Item Assessment and management of hypertension in patients on dialysis(American Society of Nephrology, 2014-08) Agarwal, Rajiv; Flynn, Joseph; Pogue, Velvie; Rahman, Mahboob; Reisin, Efrain; Weir, Matthew R.; Department of Medicine, IU School of MedicineHypertension is common, difficult to diagnose, and poorly controlled among patients with ESRD. However, controversy surrounds the diagnosis and treatment of hypertension. Here, we describe the diagnosis, epidemiology, and management of hypertension in dialysis patients, and examine the data sparking debate over appropriate methods for diagnosing and treating hypertension. Furthermore, we consider the issues uniquely related to hypertension in pediatric dialysis patients. Future clinical trials designed to clarify the controversial results discussed here should lead to the implementation of diagnostic and therapeutic techniques that improve long-term cardiovascular outcomes in patients with ESRD.Item B-type natriuretic peptide is not a volume marker among patients on hemodialysis(Oxford University Press, 2013-12) Agarwal, Rajiv; Department of Medicine, IU School of MedicineBackground Although the cardiac biomarker B-type natriuretic peptide (BNP) is strongly related to mortality in end-stage renal disease (ESRD), whether it is a predictor of weight change or blood pressure (BP) response upon probing dry weight among hypertensive hemodialysis patients remains unknown. The purpose of this study was to examine among people with hypertension on hemodialysis whether BNP is a biomarker of excess volume. Methods Hypertensive hemodialysis patients (n = 150) were randomized to a control group (n = 50) or an ultrafiltration group (n = 100) and followed up for 30 dialysis treatments. After a baseline run-in of six treatments, those assigned to the ultrafiltration group had dry weight probed over 8 weeks. Forty-four-hour interdialytic ambulatory BP and predialysis BNP were measured at the end of run-in period, at 4 weeks and at 8 weeks. Results The median BNP concentration was 93 pg/mL (interquartile range 31–257 pg/mL). The magnitude of decline in the BNP depended on the baseline concentration of BNP, but did not require probing dry weight or weight loss. No relationship existed between decline in postdialysis weight upon probing dry weight and baseline BNP. Furthermore, reduction in the BNP was not required for decline in postdialysis weight. Predialysis log BNP modestly predicted ambulatory systolic and pulse pressure independently of other risk factors. No relationship was found between decline in BP upon probing dry weight and baseline BNP. Upon probing dry weight, reduction in BNP was not required for decline in systolic ambulatory BP. Conclusion Taken together, these data suggest that among hypertensive patients on hemodialysis BNP is not a volume marker.Item Cancer Associated Fibroblasts: Naughty Neighbors That Drive Ovarian Cancer Progression(MDPI, 2018-10-29) Dasari, Subramanyam; Fang, Yiming; Mitra, Anirban K.; Medical and Molecular Genetics, School of MedicineOvarian cancer is the most lethal gynecologic malignancy, and patient prognosis has not improved significantly over the last several decades. In order to improve therapeutic approaches and patient outcomes, there is a critical need for focused research towards better understanding of the disease. Recent findings have revealed that the tumor microenvironment plays an essential role in promoting cancer progression and metastasis. The tumor microenvironment consists of cancer cells and several different types of normal cells recruited and reprogrammed by the cancer cells to produce factors beneficial to tumor growth and spread. These normal cells present within the tumor, along with the various extracellular matrix proteins and secreted factors, constitute the tumor stroma and can compose 10⁻60% of the tumor volume. Cancer associated fibroblasts (CAFs) are a major constituent of the tumor microenvironment, and play a critical role in promoting many aspects of tumor function. This review will describe the various hypotheses about the origin of CAFs, their major functions in the tumor microenvironment in ovarian cancer, and will discuss the potential of targeting CAFs as a possible therapeutic approach.Item Cardiomyopathy in Duchenne Muscular Dystrophy and the Potential for Mitochondrial Therapeutics to Improve Treatment Response(MDPI, 2024-07-09) Gandhi, Shivam; Sweeney, H. Lee; Hart, Cora C.; Han, Renzhi; Perry, Christopher G. R.; Pediatrics, School of MedicineDuchenne muscular dystrophy (DMD) is a progressive neuromuscular disease caused by mutations to the dystrophin gene, resulting in deficiency of dystrophin protein, loss of myofiber integrity in skeletal and cardiac muscle, and eventual cell death and replacement with fibrotic tissue. Pathologic cardiac manifestations occur in nearly every DMD patient, with the development of cardiomyopathy—the leading cause of death—inevitable by adulthood. As early cardiac abnormalities are difficult to detect, timely diagnosis and appropriate treatment modalities remain a challenge. There is no cure for DMD; treatment is aimed at delaying disease progression and alleviating symptoms. A comprehensive understanding of the pathophysiological mechanisms is crucial to the development of targeted treatments. While established hypotheses of underlying mechanisms include sarcolemmal weakening, upregulation of pro-inflammatory cytokines, and perturbed ion homeostasis, mitochondrial dysfunction is thought to be a potential key contributor. Several experimental compounds targeting the skeletal muscle pathology of DMD are in development, but the effects of such agents on cardiac function remain unclear. The synergistic integration of small molecule- and gene-target-based drugs with metabolic-, immune-, or ion balance-enhancing compounds into a combinatorial therapy offers potential for treating dystrophin deficiency-induced cardiomyopathy, making it crucial to understand the underlying mechanisms driving the disorder.Item A Case Series of Severe Hospitalized COVID-19 Patients Treated with Tocilizumab and Glucocorticoids: A Report from Saudi Arabian Hospital(Atlantis Press, 2021-01-22) Al Bahrani, Salma Yassin; Al-Tawfiq, Jaffar A.; Alshaer, Abdulaziz R.; Shilash, Amal; Alswefy, Khalid; Al-Zayer, Razan Salamah; Abouelela, Amr Mohamed; Medicine, School of MedicineBackground: The clinical spectrum of COVID-19 is variable and ranges from asymptomatic, mildly symptomatic, moderately severe and severe disease. A small proportion might develop severe disease and may have cytokine storm. One of the therapeutic options to treat such cases is Tocilizumab (TCZ). In this study, we present cases of severe COVID-19 treated with TCZ and glucocorticoids and discuss the treatment responses. Methods: This is a retrospective observational study of severe COVID-19 cases treated with TCZ and glucocorticoids. The case series examined the characteristics and outcome of those patients. Results: This study included 40 Severe Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) confirmed patients who received TCZ and glucocorticoids. The mean age of the included patients was 57.55 (±Standard deviation 12.86) years. There were 34 (85%) males, 19 (47.5%) were obese (BMI >30), 13 (32.5%) over weight, and five (12.5%) normal weight. The mean days from positive SARS-CoV-2 polymerase chain reaction (PCR) test to admission was 1.641 (±3.2) days. Of the patients, 18 (45%) had diabetes mellitus, 14 (35%) had hypertension. The mean days from hospital admission to ICU was 1.8 (±2.6), 20 (50%) required mechanical ventilation, 39 (97.5%) had received prone position, seven (17.5%) had renal replacement therapy, 13 (32.5%) required inotropes, four (10%) had plasmapheresis, one (2.5%) had intravenous immunoglobulin, all patients received steroid therapy, and the majority 31 (77.5%) did not receive any anti-viral therapy. Of all the patients, six (15%) died, 28 (70%) were discharged and six (15%) were still in hospital. Conclusion: The overall mortality rate was lower than those cited in meta-analysis. As our understanding of the COVID-19 continues, the approach and therapeutics are also evolving.Item Characterization of tumor immune microenvironment and cancer therapy for head and neck squamous cell carcinoma through identification of a genomic instability-related lncRNA prognostic signature(Frontiers Media, 2022-08-29) Jing, Lijun; Du, Yabing; Fu, Denggang; Medicine, School of MedicineHead and neck squamous cell carcinoma (HNSCC) represents one of the most prevalent and malignant tumors of epithelial origins with unfavorable outcomes. Increasing evidence has shown that dysregulated long non-coding RNAs (lncRNAs) correlate with tumorigenesis and genomic instability (GI), while the roles of GI-related lncRNAs in the tumor immune microenvironment (TIME) and predicting cancer therapy are still yet to be clarified. In this study, transcriptome and somatic mutation profiles with clinical parameters were obtained from the TCGA database. Patients were classified into GI-like and genomic stable (GS)-like groups according to the top 25% and bottom 25% cumulative counts of somatic mutations. Differentially expressed lncRNAs (DElncRNAs) between GI- and GS-like groups were identified as GI-related lncRNAs. These lncRNA-related coding genes were enriched in cancer-related KEGG pathways. Patients totaling 499 with clinical information were randomly divided into the training and validation sets. A total of 18 DElncRNAs screened by univariate Cox regression analysis were associated with overall survival (OS) in the training set. A GI-related lncRNA signature that comprised 10 DElncRNAs was generated through least absolute shrinkage and selection operator (Lasso)-Cox regression analysis. Patients in the high-risk group have significantly decreased OS vs. patients in the low-risk group, which was verified in internal validation and entire HNSCC sets. Integrated HNSCC sets from GEO confirmed the notable survival stratification of the signature. The time-dependent receiver operating characteristic curve demonstrated that the signature was reliable. In addition, the signature retained a strong performance of OS prediction for patients with various clinicopathological features. Cell composition analysis showed high anti-tumor immunity in the low-risk group which was evidenced by increased infiltrating CD8+ T cells and natural killer cells and reduced cancer-associated fibroblasts, which was convinced by immune signatures analysis via ssGSEA algorithm. T helper/IFNγ signaling, co-stimulatory, and co-inhibitory signatures showed increased expression in the low-risk group. Low-risk patients were predicted to be beneficial to immunotherapy, which was confirmed by patients with progressive disease who had high risk scores vs. complete remission patients. Furthermore, the drugs that might be sensitive to HNSCC were identified. In summary, the novel prognostic GILncRNA signature provided a promising approach for characterizing the TIME and predicting therapeutic strategies for HNSCC patients.Item Chx10+V2a interneurons in spinal motor regulation and spinal cord injury(Wolters Kluwer, 2023) Li, Wen-Yuan; Deng, Ling-Xiao; Zhai, Feng-Guo; Wang, Xiao-Yu; Li, Zhi-Gang; Wang, Ying; Neurological Surgery, School of MedicineChx10-expressing V2a (Chx10+V2a) spinal interneurons play a large role in the excitatory drive of motoneurons. Chemogenetic ablation studies have demonstrated the essential nature of Chx10+V2a interneurons in the regulation of locomotor initiation, maintenance, alternation, speed, and rhythmicity. The role of Chx10+V2a interneurons in locomotion and autonomic nervous system regulation is thought to be robust, but their precise role in spinal motor regulation and spinal cord injury have not been fully explored. The present paper reviews the origin, characteristics, and functional roles of Chx10+V2a interneurons with an emphasis on their involvement in the pathogenesis of spinal cord injury. The diverse functional properties of these cells have only been substantiated by and are due in large part to their integration in a variety of diverse spinal circuits. Chx10+V2a interneurons play an integral role in conferring locomotion, which integrates various corticospinal, mechanosensory, and interneuron pathways. Moreover, accumulating evidence suggests that Chx10+V2a interneurons also play an important role in rhythmic patterning maintenance, left-right alternation of central pattern generation, and locomotor pattern generation in higher order mammals, likely conferring complex locomotion. Consequently, the latest research has focused on postinjury transplantation and noninvasive stimulation of Chx10+V2a interneurons as a therapeutic strategy, particularly in spinal cord injury. Finally, we review the latest preclinical study advances in laboratory derivation and stimulation/transplantation of these cells as a strategy for the treatment of spinal cord injury. The evidence supports that the Chx10+V2a interneurons act as a new therapeutic target for spinal cord injury. Future optimization strategies should focus on the viability, maturity, and functional integration of Chx10+V2a interneurons transplanted in spinal cord injury foci.Item Computer-generated reminders and quality of pediatric HIV care in a resource-limited setting(American Academy of Pediatrics (AAP), 2013-03) Were, Martin C.; Nyandiko, Winstone M.; Huang, Kristin T. L.; Slaven, James E.; Shen, Changyu; Tierney, William M.; Vreeman, Rachel C.; Department of Medicine, IU School of MedicineOBJECTIVES: To evaluate the impact of clinician-targeted computer-generated reminders on compliance with HIV care guidelines in a resource-limited setting. METHODS: We conducted this randomized, controlled trial in an HIV referral clinic in Kenya caring for HIV-infected and HIV-exposed children (<14 years of age). For children randomly assigned to the intervention group, printed patient summaries containing computer-generated patient-specific reminders for overdue care recommendations were provided to the clinician at the time of the child's clinic visit. For children in the control group, clinicians received the summaries, but no computer-generated reminders. We compared differences between the intervention and control groups in completion of overdue tasks, including HIV testing, laboratory monitoring, initiating antiretroviral therapy, and making referrals. RESULTS: During the 5-month study period, 1611 patients (49% female, 70% HIV-infected) were eligible to receive at least 1 computer-generated reminder (ie, had an overdue clinical task). We observed a fourfold increase in the completion of overdue clinical tasks when reminders were availed to providers over the course of the study (68% intervention vs 18% control, P < .001). Orders also occurred earlier for the intervention group (77 days, SD 2.4 days) compared with the control group (104 days, SD 1.2 days) (P < .001). Response rates to reminders varied significantly by type of reminder and between clinicians. CONCLUSIONS: Clinician-targeted, computer-generated clinical reminders are associated with a significant increase in completion of overdue clinical tasks for HIV-infected and exposed children in a resource-limited setting.Item Disease progression pathways of wet AMD: opportunities for new target discovery(Taylor & Francis, 2022) Wolf, Amber T.; Harris, Alon; Oddone, Francesco; Siesky, Brent; Verticchio Vercellin, Alice; Ciulla, Thomas A.; Ophthalmology, School of MedicineIntroduction: Age-related macular degeneration (AMD) is the leading cause of irreversible blindness among people age 60 years or older in developed countries. Current standard-of-care anti-vascular endothelial growth factor (VEGF) therapy, which inhibits angiogenesis and vascular permeability, has been shown to stabilize choroidal neovascularization and increase visual acuity in neovascular AMD. However, therapeutic limitations of anti-VEGF therapy include limited durability with consequent need for frequent intravitreal injections, and a ceiling of efficacy. Current strategies under investigation include targeting VEGF-C and VEGF-D, integrins, tyrosine kinase receptors, and the Tie2/angiopoietin-2 pathway. A literature search was conducted through November 30, 2021 on PubMed, Medline, Google Scholar, and associated digital platforms with the following keywords: wet macular degeneration, age-related macular degeneration, therapy, VEGF-A, VEGF-C, VEGF-D, integrins, Tie2/Ang2, and tyrosine kinase inhibitors. Areas covered: The authors provide a comprehensive review of AMD disease pathways and mechanisms involved in wet AMD as well as novel targets for future therapies. Expert opinion: With novel targets and advancements in drug delivery, there is potential to address treatment burden and to improve outcomes for patients afflicted with neovascular AMD.