Browsing by Subject "translational research"
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Item Open Access An innovative educational program for addressing health disparities in translational cancer research.(Journal of clinical and translational science, 2020-11) Oldham, Carla E; Gathings, MJ; Devi, Gayathri R; Patierno, Steven R; Williams, Kevin P; Hough, Holly J; Barrett, Nadine JNorth Carolina Central University (NCCU) and Duke Cancer Institute implemented an NCI-funded Translational Cancer Disparities Research Partnership to enhance translational cancer research, increase the pool of underrepresented racial and ethnic group (UREG) researchers in the translational and clinical research workforce, and equip UREG trainees with skills to increase diversity in clinical trials. The Cancer Research Education Program (C-REP) provided training for UREG graduate students and postdoctoral fellows at Duke and NCCU. An innovative component of C-REP is the Translational Immersion Experience (TIE), which enabled Scholars to gain knowledge across eight domains of clinical and translational research (clinical trials operations, data monitoring, regulatory affairs, UREG accrual, biobanking, community engagement, community outreach, and high-throughput drug screening). Program-specific evaluative metrics were created for three broad domains (clinical operations, basic science/lab research, and population-based science) and eight TIE domains. Two cohorts (n = 13) completed pre- and post-surveys to determine program impact and identify recommendations for program improvement. Scholars reported statistically significant gains in knowledge across three broad domains of biomedical research and seven distinct areas within TIE. Training in translational research incorporating immersions in clinical trials operation, biobanking, drug development, and community engagement adds value to career development of UREG researchers.Item Open Access Lost in Translation: The Gap in Scientific Advancements and Clinical Application.(Frontiers in bioengineering and biotechnology, 2016-01) Fernandez-Moure, Joseph SThe evolution of medicine and medical technology hinges on the successful translation of basic science research from the bench to clinical implementation at the bedside. Out of the increasing need to facilitate the transfer of scientific knowledge to patients, translational research has emerged. Significant leaps in improving global health, such as antibiotics, vaccinations, and cancer therapies, have all seen successes under this paradigm, yet today, it has become increasingly difficult to realize this ideal scenario. As hospital revenue demand increases, and financial support declines, clinician-protected research time has been limited. Researchers, likewise, have been forced to abandon time- and resource-consuming translational research to focus on publication-generating work to maintain funding and professional advancement. Compared to the surge in scientific innovation and new fields of science, realization of transformational scientific findings in device development and materials sciences has significantly lagged behind. Herein, we describe: how the current scientific paradigm struggles in the new health-care landscape; the obstacles met by translational researchers; and solutions, both public and private, to overcoming those obstacles. We must rethink the old dogma of academia and reinvent the traditional pathways of research in order to truly impact the health-care arena and ultimately those that matter most: the patient.Item Open Access New Insights into Gastrointestinal Involvement in Late-Onset Pompe Disease: Lessons Learned from Bench and Bedside.(Journal of clinical medicine, 2021-07-30) Korlimarla, Aditi; Lim, Jeong-A; McIntosh, Paul; Zimmerman, Kanecia; Sun, Baodong D; Kishnani, Priya SBackground
There are new emerging phenotypes in Pompe disease, and studies on smooth muscle pathology are limited. Gastrointestinal (GI) manifestations are poorly understood and underreported in Pompe disease.Methods
To understand the extent and the effects of enzyme replacement therapy (ERT; alglucosidase alfa) in Pompe disease, we studied the histopathology (entire GI tract) in Pompe mice (GAAKO 6neo/6neo). To determine the disease burden in patients with late-onset Pompe disease (LOPD), we used Patient-Reported Outcomes Measurements Information System (PROMIS)-GI symptom scales and a GI-focused medical history.Results
Pompe mice showed early, extensive, and progressive glycogen accumulation throughout the GI tract. Long-term ERT (6 months) was more effective to clear the glycogen accumulation than short-term ERT (5 weeks). GI manifestations were highly prevalent and severe, presented early in life, and were not fully amenable to ERT in patients with LOPD (n = 58; age range: 18-79 years, median age: 51.55 years; 35 females; 53 on ERT).Conclusion
GI manifestations cause a significant disease burden on adults with LOPD, and should be evaluated during routine clinical visits, using quantitative tools (PROMIS-GI measures). The study also highlights the need for next generation therapies for Pompe disease that target the smooth muscles.Item Open Access Pharmacokinetics and tolerability of the dual TORC1/2 inhibitor sapanisertib in combination with the MEK inhibitor trametinib in dogs.(Frontiers in veterinary science, 2022-01) Wei, Bih-Rong; Peer, Cody J; Richardson, William J; Hewitt, Stephen M; Figg, William D; Simpson, R MarkActivation of one or both the Ras/MAPK and PI3K/Akt/mTOR signal transduction pathways are known to mediate oncogenicity of several canine and human cancers, including mucosal melanomas. Reciprocal cross activation between the two pathways can be a source of drug resistance. Consequently, oral dosing for plasma pharmacokinetic (PK) analysis and tolerability to a combination of sapanisertib, a dual TORC1/2 inhibitor, and trametinib, a MEK inhibitor, was evaluated in nontumor-bearing laboratory dogs for its potential application in parallel pathway targeting. Twelve dogs, divided into three equal cohorts, received either the combination or single agents. Animals were monitored for PK following single dose and 17-day repeat dosing, and by clinical observations, hematology, serum biochemistry, coagulation studies and urinalyses. A single trametinib dose (0.025 mg/kg), sulfated as dimethyl sulfoxide which enhanced its absorption, reached mean maximum concentration (Cmax) 0.64 ng/mL [18% coefficient of variation (CV)] at a median time to maximum concentration (Tmax) of 1.5 h (hr), and mean area under the concentration-time curve (AUC) 16.8 hr*ng/mL (14%CV), which were similar when given alone or in combination with sapanisertib. A prolonged half-life afforded 3-4-fold plasma accumulation of trametinib with daily dosing, analogous to humans. Trametinib PK mirrored previous regulatory data in dogs, while exposure approximated some published human values but generally not all patients. Sapanisertib-alone in canine plasma following single 0.1 mg/kg dose [mean Cmax 26.3 ng/mL (21%CV), median Tmax 2.0 hr, and mean AUC 248 hr*ng/mL (41%CV)] resembled levels in human therapeutic trials; whereas canine sapanisertib exposure was reduced when combined with trametinib, a known cytochrome P450 CYP3A4 inducer. Sex differences were not observed for either drug. Side effects upon repeat dosing with either or both drugs may include body weight loss, maldigestion, and cutaneous discoloration. The combination was tolerated without dose limiting toxicity, although clinical laboratory analyses revealed drug-induced acute-phase inflammation, proteinuria, and decreased blood reticulocytes, mild changes not necessitating intervention. Short-term results in dogs with this combination would appear to hold translational promise for clinical trial evaluation to target canine and possibly human melanoma, as well as other cancers having one or both signal transduction pathway activations.