tbuckley/cabot-search huggingface dataset:
Cardiac telocytes inhibit cardiac microvascular endothelial cell apoptosis through exosomal miRNA-21-5p-targeted <i>cdip1</i> silencing to improve angiogenesis following myocardial infarction
Authors: Zhaofu Liao, Yilin Chen, Chuncui Duan, Kuikui Zhu, Ruijin Huang, Hui Zhao, Maik Hintze, Qin Pu, Ziqiang Yuan, Luocheng Lv, Hongyi Chen, Binglin Lai, Shanshan Feng, Xufeng Qi, Dongqing Cai
Journal: Theranostics (2020)

Promotion of cardiac angiogenesis in ischemic myocardium is a critical strategy for repairing and regenerating the myocardium after myocardial infarction (MI). Currently, effective methods to aid in the survival of endothelial cells, to avoid apoptosis in ischemic myocardium and to achieve long-term cardiac angiogenesis are still being pursued. Here, we investigated whether cardiac telocyte (CT)-endothelial cell communication suppresses apoptosis and promotes the survival of endothelial cells to facilitate cardiac angiogenesis during MI. Methods: CT exosomes were isolated from CT conditioned medium, and their miRNA profile was characterized by small RNA sequencing. A rat model of left anterior descending coronary artery ligation (LAD)-mediated MI was assessed with histology for infarct size and fibrosis, immunostaining for angiogenesis and cell apoptosis and echocardiography to evaluate the therapeutic effects. Cardiac microvascular endothelial cells (CMECs) and the LAD-MI model treated with CT exosomes or CT exosomal miRNA-21-5p in vitro and in vivo were assessed with cellular and molecular techniques to demonstrate the underlying mechanism. Results: CTs exert therapeutic effects on MI via the potent paracrine effects of CT exosomes to facilitate the inhibition of apoptosis and survival of CMECs and promote cardiac angiogenesis. A novel mechanism of CTs is revealed, in which CT-endothelial cell communication suppresses apoptosis and promotes the survival of endothelial cells in the pathophysiological myocardium. CT exosomal miRNA-21-5p targeted and silenced the cell death inducing p53 target 1 (Cdip1) gene and thus down-regulated the activated caspase-3, which then inhibited the apoptosis of recipient endothelial cells under ischemic and hypoxic conditions, facilitating angiogenesis and regeneration following MI. Conclusions: The present study is the first to show that CTs inhibit cardiac microvascular endothelial cell apoptosis through exosomal miRNA-21-5p-targeted Cdip1 silencing to improve angiogenesis in myocardial infarction. It is believed that these novel findings and the discovery of cellular and molecular mechanisms will provide new opportunities to tailor novel cardiac cell therapies and cell-free therapies for the functional and structural regeneration of the injured myocardium.
Patterns of care in <i>ALK+</i> or <i>ROS1</i>+ non-small cell lung cancer (NSCLC) in community systems.
Authors: Benjamin Philip Levy, Breanne Y Farris, Rebecca R Crawford, Jeffrey D. Carter, Tamar Sapir
Journal: Journal of Clinical Oncology (2020)

232 Background: For patients who have ALK or ROS1+ NSCLC, targeted therapies have greatly improved treatment options, though challenges personalizing care have hindered effective integration. In a quality improvement (QI) program conducted in 2 community oncology systems, practices involving the use of targeted therapies for NSCLC were assessed. Methods: Between 01-04/2020, retrospective EMR audits of 100 patients with ALK or ROS1+ NSCLC were analyzed for demographics, molecular testing, disease characteristics, treatment history, and shared decision-making (SDM). Surveys were administered to evaluate healthcare professionals’ (HCP; N = 47) challenges and barriers. HCP teams participated in audit-feedback sessions and developed action plans for resolving identified gaps. Results: 64% of HCPs indicated high confidence in utilizing molecular tests to inform treatment and properly sequencing targeted therapies; however, the EMR audit demonstrated challenges efficiently integrating guideline-aligned testing into practice. The mean time from diagnosis to molecular testing results was 22 days and documentation of testing for genetic aberrations other than ALK/ROS1 during work-up were low (Table). Delays in receiving molecular testing results may have presented challenges aligning treatment practices to guidelines as some patients were not receiving frontline targeted therapies (31% ALK+, 24% ROS1+). Additionally, EMR audits suggested sub-optimal use of distress screening (37%), tobacco counseling (38%), quality of life screening (60%), and engagement/documentation of various aspects of SDM (Table) for patient-centered care. Importantly, given the role internalized stigma can play in lung cancer, only 59% of those surveyed indicated that they routinely use tools to identify patients affected by stigma. During audit-feedback sessions, teams identified increased documentation, improved molecular testing/collaboration with pathology team, and provision of patient-centered care, including reduction of smoking-associated stigma as action items. Conclusions: These findings reveal important performance gaps in providing targeted and patient-centered treatment for NSCLC in community settings. These findings may be relevant for future QI programs. [Table: see text]
99mTc-Mebrofenin SPECT/CT in Hepatic Infarction
Authors: Govind S. Mattay, Cathal O’Leary, Jacob G. Dubroff, Austin R. Pantel
Journal: Clinical Nuclear Medicine (2020)

Abstract A 68-year-old man with hereditary hypercoagulability was referred to nuclear medicine for elevated aminotransferases after a recent living-donor liver transplant. A hepatic infarction was suspected. A 99m Tc-mebrofenin SPECT/CT was performed and showed decreased radiotracer uptake in a wedge-shaped distribution in the anterior liver suggestive of a hepatic infarction. Subsequently, an enhanced MRI corroborated the diagnosis. Oral anticoagulation therapy was then initiated, and aminotransferases soon normalized.
Bio-inspired chiral self-assemblies promoted neuronal differentiation of retinal progenitor cells through activation of metabolic pathway
Authors: Na Sun, Xiaoqiu Dou, Zhimin Tang, Dandan Zhang, Ni Ni, Jiajing Wang, Huiqin Gao, Yahan Ju, Xiaochan Dai, Changli Zhao, Ping Gu, Jing Ji, Chuanliang Feng
Journal: Bioactive Materials (2020)

Retinal degeneration is a main class of ocular diseases. So far, retinal progenitor cell (RPC) transplantation has been the most potential therapy for it, in which promoting RPCs neuronal differentiation remains an unmet challenge. To address this issue, innovatively designed L/d-phenylalanine based chiral nanofibers (LPG and DPG) are employed and it finds that chirality of fibers can efficiently regulate RPCs differentiation. qPCR, western blot, and immunofluorescence analysis show that right-handed helical DPG nanofibers significantly promote RPCs neuronal differentiation, whereas left-handed LPG nanofibers decrease this effect. These effects are mainly ascribed to the stereoselective interaction between chiral helical nanofibers and retinol-binding protein 4 (RBP4, a key protein in the retinoic acid (RA) metabolic pathway). The findings of chirality-dependent neuronal differentiation provide new strategies for treatment of neurodegenerative diseases via optimizing differentiation of transplanted stem cells on chiral nanofibers.
Combinations with Allosteric SHP2 Inhibitor TNO155 to Block Receptor Tyrosine Kinase Signaling
Authors: Chen Liu, Hengyu Lu, Hongyun Wang, Alice Loo, Xiamei Zhang, Guizhi Yang, Colleen Kowal, Scott Delach, Ye Wang, Silvia Goldoni, William D. Hastings, Karrie Wong, Hui Gao, Matthew J. Meyer, Susan E. Moody, Matthew J. LaMarche, Jeffrey A. Engelman, Juliet A. Williams, Peter S. Hammerman, Tinya J. Abrams, Morvarid Mohseni, Giordano Caponigro, Huai-Xiang Hao
Journal: Clinical Cancer Research (2020)

Abstract Purpose: SHP2 inhibitors offer an appealing and novel approach to inhibit receptor tyrosine kinase (RTK) signaling, which is the oncogenic driver in many tumors or is frequently feedback activated in response to targeted therapies including RTK inhibitors and MAPK inhibitors. We seek to evaluate the efficacy and synergistic mechanisms of combinations with a novel SHP2 inhibitor, TNO155, to inform their clinical development. Experimental Design: The combinations of TNO155 with EGFR inhibitors (EGFRi), BRAFi, KRASG12Ci, CDK4/6i, and anti–programmed cell death-1 (PD-1) antibody were tested in appropriate cancer models in vitro and in vivo, and their effects on downstream signaling were examined. Results: In EGFR-mutant lung cancer models, combination benefit of TNO155 and the EGFRi nazartinib was observed, coincident with sustained ERK inhibition. In BRAFV600E colorectal cancer models, TNO155 synergized with BRAF plus MEK inhibitors by blocking ERK feedback activation by different RTKs. In KRASG12C cancer cells, TNO155 effectively blocked the feedback activation of wild-type KRAS or other RAS isoforms induced by KRASG12Ci and greatly enhanced efficacy. In addition, TNO155 and the CDK4/6 inhibitor ribociclib showed combination benefit in a large panel of lung and colorectal cancer patient–derived xenografts, including those with KRAS mutations. Finally, TNO155 effectively inhibited RAS activation by colony-stimulating factor 1 receptor, which is critical for the maturation of immunosuppressive tumor-associated macrophages, and showed combination activity with anti–PD-1 antibody. Conclusions: Our findings suggest TNO155 is an effective agent for blocking both tumor-promoting and immune-suppressive RTK signaling in RTK- and MAPK-driven cancers and their tumor microenvironment. Our data provide the rationale for evaluating these combinations clinically.
Costs to healthcare payers associated with clinical trial (CT) participation in metastatic non-small cell lung cancer (NSCLC).
Authors: Cristina Merkhofer, Shasank Chennupati, Qin Sun, Keith D. Eaton, Renato G. Martins, Scott David Ramsey, Bernardo H. L. Goulart
Journal: Journal of Clinical Oncology (2020)

3 Background: To assess the financial implications of therapeutic CT participation for healthcare payers, we compared first-line (1L) and second-line (2L) total direct medical costs between patients enrolled in 2L CT vs non-CT participants receiving 2L therapy for metastatic NSCLC. Methods: We linked electronic health records from a single academic center with tumor registry and claims data to identify patients with metastatic NSCLC diagnosed from 1/1/2007-12/31/2015. Eligibility criteria included 60 day minimum survival, receipt of ≥ 1 anti-cancer drug within 180 days of diagnosis, insurance enrollment for ≥ 12 months after diagnosis and receipt of ≥ 2 therapy lines. Patients on 1L trials were excluded. We calculated mean per-patient-per-month (PPPM) total direct medical costs from the payer perspective for 1L and 2L. We performed a difference-of-difference analysis to estimate the effect of trial enrollment on costs by calculating the mean PPPM difference between 2L and 1L in trial (Diff trial) and non-trial enrollees (Diff non-trial). Then we calculated the difference between Diff trial and Diff non-trial. We used paired and non-paired t-tests for statistical comparisons and report all costs in 2019 US dollars. Results: Of 63 patients, 22 (35%) enrolled in a 2L CT. CT enrollees were younger (mean age 63.5 vs 66.7 years), female (73% vs 41%), had commercial insurance (36% vs 32%), were never smokers (36% vs 32%), had EGFR mutations (27% vs 22%) and fewer had brain metastases (14% vs 29%). The mean PPPM total direct medical costs decreased between 2L and 1L for patients enrolled in 2L CTs but increased in non-trial participants (Diff trial = -$5,585, SD ± $6,541; Diff non-trial = $1,532, SD ± $14,739). The mean difference of difference (Diff trial - Diff non-trial) was -$7,117 (p = 0.01; Table). Conclusions: This small observational study suggests that CT enrollment results in substantial cost-savings to payers. If confirmed in larger studies, our findings suggest that insurers support trial participation for patients with NSCLC. [Table: see text]
Pharmacology of Chimeric Antigen Receptor–Modified T Cells
Authors: Edward Z. Song, Michael C. Milone
Journal: The Annual Review of Pharmacology and Toxicology (2020)

Cell-based immunotherapies using T cells that are engineered to express a chimeric antigen receptor (CAR-T cells) are an effective treatment option for several B cell malignancies. Compared with most drugs, CAR-T cell products are highly complex, as each cell product is composed of a heterogeneous mixture of millions of cells. The biodistribution and kinetics of CAR-T cells, following administration, are unique given the ability of T cells to actively migrate as well as replicate within the patient. CAR-T cell therapies also have multiple mechanisms of action that contribute to both their antitumor activity and their toxicity. This review provides an overview of the unique pharmacology of CAR-T cells, with a focus on CD19-targeting and B cell maturation antigen (BCMA)-targeting CAR-T cells.
18F-Fluciclovine–Avid Mediastinal Lymph Node Metastasis of Cutaneous Malignant Melanoma
Authors: Ahmad Shariftabrizi, Ravishankar Pillenahalli Maheshwarappa, Daniel Kahn, Janet Pollard
Journal: Clinical Nuclear Medicine (2020)

Abstract A 63-year-old man with recent diagnosis of high-risk prostate adenocarcinoma was referred to our Nuclear Medicine Department for 18 F-fluciclovine PET/CT to rule out metastasis in the setting of elevated serum prostate-specific antigen levels. The patient had previous history of nodular melanoma of the right cheek treated 6 years back with surgery and adjuvant radiation. Surveillance 18 F-FDG PET/CT for melanoma 1 month back had revealed enlarged FDG-avid mediastinal para-aortic lymph nodes, which on endoscopic biopsy had revealed melanoma metastasis. On current fluciclovine PET/CT, the same enlarged para-aortic lymph nodes showed fluciclovine uptake, suggesting false-positive uptake.
Molecular Landscape and Actionable Alterations in a Genomically Guided Cancer Clinical Trial: National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH)
Authors: Keith T. Flaherty, Robert J. Gray, Alice P. Chen, Shuli Li, Lisa M. McShane, David Patton, Stanley R. Hamilton, P. Mickey Williams, A. John Iafrate, Jeffrey Sklar, Edith P. Mitchell, Lyndsay N. Harris, Naoko Takebe, David J. Sims, Brent Coffey, Tony Fu, Mark Routbort, James A. Zwiebel, Larry V. Rubinstein, Richard F. Little, Carlos L. Arteaga, Robert Comis, Jeffrey S. Abrams, Peter J. O’Dwyer, Barbara A. Conley
Journal: Journal of Clinical Oncology (2020)

Therapeutically actionable molecular alterations are widely distributed across cancer types. The National Cancer Institute Molecular Analysis for Therapy Choice (NCI-MATCH) trial was designed to evaluate targeted therapy antitumor activity in underexplored cancer types. Tumor biopsy specimens were analyzed centrally with next-generation sequencing (NGS) in a master screening protocol. Patients with a tumor molecular alteration addressed by a targeted treatment lacking established efficacy in that tumor type were assigned to 1 of 30 treatments in parallel, single-arm, phase II subprotocols.Tumor biopsy specimens from 5,954 patients with refractory malignancies at 1,117 accrual sites were analyzed centrally with NGS and selected immunohistochemistry in a master screening protocol. The treatment-assignment rate to treatment arms was assessed. Molecular alterations in seven tumors profiled in both NCI-MATCH trial and The Cancer Genome Atlas (TCGA) of primary tumors were compared.Molecular profiling was successful in 93.0% of specimens. An actionable alteration was found in 37.6%. After applying clinical and molecular exclusion criteria, 17.8% were assigned (26.4% could have been assigned if all subprotocols were available simultaneously). Eleven subprotocols reached their accrual goal as of this report. Actionability rates differed among histologies (eg, > 35% for urothelial cancers and < 6% for pancreatic and small-cell lung cancer). Multiple actionable or resistance-conferring tumor mutations were seen in 11.9% and 71.3% of specimens, respectively. Known resistance mutations to targeted therapies were numerically more frequent in NCI-MATCH than TCGA tumors, but not markedly so.We demonstrated feasibility of screening large numbers of patients at numerous accruing sites in a complex trial to test investigational therapies for moderately frequent molecular targets. Co-occurring resistance mutations were common and endorse investigation of combination targeted-therapy regimens.
Exposure to Static Magnetic and Electric Fields Treats Type 2 Diabetes
Authors: Calvin S. Carter, Sunny C. Huang, Charles C. Searby, Benjamin Cassaidy, Michael J. Miller, Wojciech J. Grzesik, Ted B. Piorczynski, Thomas K. Pak, Susan A. Walsh, Michael Acevedo, Qihong Zhang, Kranti A. Mapuskar, Ginger L. Milne, Antentor O. Hinton, Deng-Fu Guo, Robert Weiss, Kyle Bradberry, Eric B. Taylor, Adam J. Rauckhorst, David W. Dick, Vamsidhar Akurathi, Kelly C. Falls-Hubert, Brett A. Wagner, Walter A. Carter, Kai Wang, Andrew W. Norris, Kamal Rahmouni, Garry R. Buettner, Jason M. Hansen, Douglas R. Spitz, E. Dale Abel, Val C. Sheffield
Journal: Cell Metabolism (2020)
A Pilot Study of a Comprehensive Financial Navigation Program in Patients With Cancer and Caregivers
Authors: Kate Watabayashi, Jordan Steelquist, Karen A. Overstreet, Anthony Leahy, Erin Bradshaw, Kathleen D. Gallagher, Alan J. Balch, Rebecca Lobb, Laura Lavell, Hannah Linden, Scott D. Ramsey, Veena Shankaran
Journal: Journal of the National Comprehensive Cancer Network (2020)

Few studies have engaged patients and caregivers in interventions to alleviate financial hardship. We collaborated with Consumer Education and Training Services (CENTS), Patient Advocate Foundation (PAF), and Family Reach (FR) to assess the feasibility of enrolling patient-caregiver dyads in a program that provides financial counseling, insurance navigation, and assistance with medical and cost of living expenses.Patients with solid tumors aged ≥18 years and their primary caregiver received a financial education video, monthly contact with a CENTS counselor and PAF case manager for 6 months, and referral to FR for help with unpaid cost of living bills (eg, transportation or housing). Patient financial hardship and caregiver burden were measured using the Comprehensive Score for Financial Toxicity-Patient-Reported Outcomes (COST-PRO) and Caregiver Strain Index (CSI) measures, respectively, at baseline and follow-up.Thirty patients (median age, 59.5 years; 40% commercially insured) and 18 caregivers (67% spouses) consented (78% dyad participation rate). Many participants faced cancer-related financial hardships prior to enrollment, such as work change or loss (45% of patients; 39% of caregivers) and debt (64% of patients); 39% of caregivers reported high levels of financial burden at enrollment. Subjects received $11,000 in assistance (mean, $772 per household); 66% of subjects with income ≤$50,000 received cost-of-living assistance. COST-PRO and CSI scores did not change significantly.Patient-caregiver dyads were willing to participate in a financial navigation program that addresses various financial issues, particularly cost of living expenses in lower income participants. Future work should address financial concerns at diagnosis and determine whether doing so improves patient and caregiver outcomes.
Patient and physician decision-making on the use of novel agents in chronic lymphocytic leukemia (CLL): What drives preferences?
Authors: Hannah Le, Kellie Ryan, Svea K Wahlstrom, Trudy Pendergraft, Martine C Maculaitis, Oliver Will, Emily Mulvihill, Thomas William LeBlanc
Journal: Journal of Clinical Oncology (2020)

148 Background: CLL treatment has changed dramatically with the approval of novel agents, but data to guide treatment decisions are still lacking. How patients (PTs) and oncologists (ONCs) prioritize treatment attributes is unknown. Methods: ONCs and PTs completed an online survey to quantify preferences for first-line (1L) CLL treatment with novel agents via a discrete choice experiment; ONCs and PTs chose between hypothetical treatment profiles with varying attribute levels taken from product labels, registrational trials, and real-world studies. Hierarchical Bayes models were used to estimate attribute level preference weights, which were used to compute relative importance (RI), a measure of how influential an attribute is in treatment choice out of a total of 100%. Results: For ONCs (N=151), 72% were in community practice. PTs (N=220) had a median age of 56 years; 32% were in active surveillance, 36% were in/had completed 1L treatment, and 32% were relapsed/refractory. Increasing 2-year progression-free survival (PFS) from 75% to 95% had the greatest impact on preferences, with a mean RI of 40% for PTs and 30% for ONCs (Table). When assessing trade-offs between 2-year PFS and other attributes, ONCs required the largest increase in PFS (11%) to compensate for an increased risk of atrial fibrillation (AF) from 5% to 20%. PTs required the largest increase in PFS (6%) to compensate for an increased risk of infection from 7% to 20%. ONCs (vs PTs) required 2–4-times higher increases in PFS to accept an increased risk of AF, discontinuation due to adverse events (AEs), bleeding, tumor lysis syndrome (TLS), and arthralgia/myalgia. Conclusions: ONCs and PTs valued PFS most when selecting a novel CLL agent. While both groups accepted potential risks in exchange for increased PFS, ONCs were less likely to accept a higher risk of AEs. ONCs and PTs may perceive the risks and benefits of novel agents differently. ONC–PT communication may be improved by a more focused discussion on the risks of AEs, relative to treatment outcomes, with patient goals in mind. [Table: see text]
Healthcare resource utilization and total cost of care in older patients with acute myeloid leukemia ineligible for intensive chemotherapy.
Authors: Thomas William LeBlanc, Arpamas Seetasith, Michelle E Choi, Andy Surinach, Tu My To, Melissa Montez, Esprit Ma
Journal: Journal of Clinical Oncology (2020)

72 Background: Limited data are available on the economic burden of care for older patients with AML ineligible for intensive chemotherapy. This study aimed to evaluate healthcare resource utilization (HRU) and total cost of care (TCC) in this population. Methods: A retrospective observational study of Surveillance, Epidemiology, and End Results data (Jan 1, 2010 – Dec 31, 2015) linked to Medicare claims (up to Dec 31, 2017). Patients were ≥ 60 years old; newly diagnosed with AML; had ≥ 12 months of continuous Part A and B coverage before diagnosis; and initiated treatment on a hypomethylating agent: azacytidine (AZA) or decitabine (DEC) ≤ 90 days after diagnosis, or best supportive care (BSC). HRU (hospitalization, monitoring, transfusions, office visits, emergency department [ED] visits) and TCC reported in per patient per month (PPPM) were evaluated. Results: Among 3,905 patients identified, 877 (22%) received AZA, 899 (23%) received DEC, 2,129 (55%) received BSC. At a mean follow-up of 4.1 month (mo), mean TCC in BSC was $22,479.48 PPPM (standard deviation [SD]: $20,183.72). Hospitalization was the main cost driver (83.7% of TCC) in BSC, followed by Part B services and transfusions. At a mean follow-up of 11.9 vs. 13.0 mo, and mean treatment duration both at 5.4 mo, the mean TCC was $15,805.76 PPPM (SD: $19,368.16) in AZA vs. $20,518.71 PPPM (SD: $23,400.68) in DEC. All HRU decreased after AZA or DEC treatment initiation, except an increase in hospitalizations after treatment discontinuation (Table). During treatment on AZA and DEC, the main cost driver was hospitalization (60.7% vs. 60.9%) followed by drug costs and transfusions. After treatment discontinuation, hospitalization remained the main cost driver (77.2% vs. 78.9%) followed by transfusions and Part B services. Conclusions: This study quantifies the sizeable TCC in older patients with AML ineligible for intensive chemotherapy with hospitalization as the primary cost driver. Novel treatments that reduce hospitalizations, transfusions, and Part B services could lower the burden to the overall healthcare system. [Table: see text]