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Introduction: Accurate, patient-centered evaluation of physical function in patients with cancer can provide important information on the functional impacts experienced by patients both from the disease and its treatment. Increasingly, digital health technology is facilitating and providing new ways to measure symptoms and function. There is a need to characterize the longitudinal measurement characteristics of physical function assessments, including clinician-reported physical function (ClinRo), patient-reported physical function (PRO), performance outcome tests (PerfO) and wearable data, to inform regulatory and clinical decision-making in cancer clinical trials and oncology practice. Methods and analysis: In this prospective study, we are enrolling 200 English- and/or Spanish-speaking patients with breast cancer or lymphoma seen at Mayo Clinic or Yale University who will receive standard of care intravenous cytotoxic chemotherapy. Physical function assessments will be obtained longitudinally using multiple assessment modalities. Participants will be followed for 9 months using a patient-centered health data aggregating platform that consolidates study questionnaires, electronic health record data, and activity and sleep data from a wearable sensor. Data analysis will focus on understanding variability, sensitivity, and meaningful changes across the included physical function assessments and evaluating their relationship to key clinical outcomes. Additionally, the feasibility of multi-modal physical function data collection in real-world patients with cancer will be assessed, as will patient impressions of the usability and acceptability of the wearable sensor, data aggregation platform, and PROs. Ethics and dissemination: This study has received approval from IRBs at Mayo Clinic, Yale University, and the U.S. Food & Drug Administration. Results will be made available to participants, funders, the research community, and the public. Registration Details: The trial registration number for this study is NCT05214144. Strengths & Limitations: This study addresses an important unmet need by characterizing the performance characteristics of multiple patient-centered physical function measures in patients with cancerPhysical function is an important and undermeasured clinical outcome. Scientifically rigorous capture and measurement of physical function constitutes a key component of cancer treatment tolerability assessment both from a regulatory and clinical perspective.This study will include patients with lymphoma or breast cancer receiving a broad range of cytotoxic chemotherapy regimens. While recruitment will occur at two academic sites, patients who ultimately receive treatment at local community sites will be included.A patient-centered health data aggregating platform facilitates the delivery of patient-reported outcome measures and collection of wearable data to researchers, while reducing patient burden compared to traditional patient-generated data collection and aggregation methodsHeterogeneity in patient willingness or comfort engaging with mobile products including smartphones and wearables, enrollment primarily at large academic centers, and the modest sample size are potential limitations to the external validity of the study.
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The majority of GLUT4 is sequestered in unique intracellular vesicles in the absence of insulin. Upon insulin stimulation GLUT4 vesicles translocate to, and fuse with, the plasma membrane. To determine the effect of GLUT4 content on the distribution and subcellular trafficking of GLUT4 and other vesicle proteins, adipocytes of adipose-specific, GLUT4-deficient (aP2-GLUT4-/-) mice and adipose-specific, GLUT4-overexpressing (aP2-GLUT4-Tg) mice were studied. GLUT4 amount was reduced by 80-95% in aP2-GLUT4-/- adipocytes and increased approximately 10-fold in aP2-GLUT4-Tg adipocytes compared with controls. Insulin-responsive aminopeptidase (IRAP) protein amount was decreased 35% in aP2-GLUT4-/- adipocytes and increased 45% in aP2-GLUT4-Tg adipocytes. VAMP2 protein was also decreased by 60% in aP2-GLUT4-/- adipocytes and increased 2-fold in aP2-GLUT4-Tg adipocytes. IRAP and VAMP2 mRNA levels were unaffected in aP2-GLUT4-Tg, suggesting that overexpression of GLUT4 affects IRAP and VAMP2 protein stability. The amount and subcellular distribution of syntaxin4, SNAP23, Munc-18c, and GLUT1 were unchanged in either aP2-GLUT4-/- or aP2-GLUT4-Tg adipocytes, but transferrin receptor was partially redistributed to the plasma membrane in aP2-GLUT4-Tg adipocytes. Immunogold electron microscopy revealed that overexpression of GLUT4 in adipocytes increased the number of GLUT4 molecules per vesicle nearly 2-fold and the number of GLUT4 and IRAP-containing vesicles per cell 3-fold. In addition, the proportion of cellular GLUT4 and IRAP at the plasma membrane in unstimulated aP2-GLUT4-Tg adipocytes was increased 4- and 2-fold, respectively, suggesting that sequestration of GLUT4 and IRAP is saturable. Our results show that GLUT4 overexpression or deficiency affects the amount of other GLUT4-vesicle proteins including IRAP and VAMP2 and that GLUT4 sequestration is saturable.