tbuckley/cabot-search huggingface dataset:
SARC044: A phase II trial of bezuclastinib in combination with sunitinib in patients with GIST who progressed on sunitinib monotherapy.
Authors: Candace L. Haddox, Karla V. Ballman, Margaret von Mehren, Michael C. Heinrich, Steven Bialick, Heather Jacene, Hina Shah, Brian D. Crompton, Scott H. Okuno, Jonathan Fletcher, Andrew J. Wagner
Journal: Journal of Clinical Oncology (2025)

TPS11579 Background: Gastrointestinal stromal tumors (GIST) are commonly driven by mutations in the receptor tyrosine kinase KIT . Resistance to approved tyrosine kinase inhibitors (TKIs) arises from additional KIT mutations in the ATP-binding pocket (AP) and activation loop (AL). No single approved TKI broadly suppresses all resistant clones, and overlapping VEGFR inhibition and toxicity limits TKI combinations. The type I TKI bezuclastinib (“BEZ,” CGT9486) inhibits KIT AL resistance mutations, does not inhibit VEGFR, and has complimentary activity with sunitinib (“SUN,” inhibitor of KIT AP resistance mutations). The first-in-human study (PLX121-01) and ongoing Peak trial (NCT05208047) evaluated BEZ+SUN showing promising safety and efficacy in GIST. SARC044 investigates BEZ+SUN in patients (pts) with SUN-resistant, KIT-mutant GIST, and correlatives aim to determine mechanisms of response and resistance (NCT06208748). Methods: SARC044 is a multi-center, open label, single-arm phase II trial enrolling up to 40 adult pts with KIT exon 9 or 11-mutant GIST resistant to imatinib and SUN. After TKI washout (baseline, “b/l”), pts initiate BEZ 600 mg daily for 2 weeks, then add SUN 37.5 mg daily, taking both drugs continuously (28-day cycles) until mRECISTv1.1 progression or unmanageable toxicity. Response evaluations (RE) are performed every 8 weeks (wk) through 15 months (mo) on study, then every 12 wk. Circulating tumor DNA (ctDNA) is collected at b/l, cycle 1 day 15 (C1D15), C2D1, C3D1, and progression. Targeted exome sequencing (TES) of ctDNA will track primary/resistant KIT mutation dynamics across therapy. 18 FDG PET/CTs are performed in 20 pts at b/l, C1D15, and C2D1, which guide a biopsy of a resistant tumor. TES, allele-specific and long-read PCR (to detect AP+AL mutation phasing), and immunoblotting (evaluating KIT pathway activation) will be performed on tissue. EORTC QLQ-C30 surveys collect pt-reported outcomes (PRO) at b/l, on treatment, and at progression. The primary endpoint is median progression-free survival (mPFS) and secondary endpoints include overall survival at 1 and 2 years, clinical benefit rate at 16 wk, adverse event rate, PRO, and KIT mutation profile in ctDNA and tissue. 35 evaluable pts achieves 83% power (p&lt;0.05, one-sided) in a one-sample log-rank test to detect a mPFS of 6.5 mo vs 4 mo (historic control). Expected accrual is 12 mo across 4 sites in the United States with ~36 mo to study completion. Clinical trial information: NCT06208748 .
Early on-treatment ctDNA dynamics and response by imaging in patients with sarcoma.
Authors: Adrienne I. Victor
Journal: Journal of Clinical Oncology (2025)

11537 Background: ctDNA holds promise as a prognostic and predictive biomarker for risk stratification and treatment response monitoring across multiple tumor types. However, the optimal timepoints and cutoffs for interpretation of ctDNA results are not well defined. Here we explored the ctDNA dynamics in patients with sarcomas on cytotoxic chemotherapy, with a focus on early time points to predict response. Methods: All sarcoma patients at the Wilmot Cancer Institute who had ctDNA (SignateraTM, Natera, Inc.) requested clinically from 03/01/22 – 12/31/25 were screened. Patients who had a positive baseline and at least 2 cycles of cytotoxic chemotherapy with serial ctDNA monitoring and response evaluation were selected for further analysis. Response was determined by imaging reports (CT, MRI, or PET) after 2-4 cycles of therapy. Results: One hundred and twenty-four patients were identified on initial screening, and 112 were able to generate a bespoke assay. Twenty-two patients met criteria for early on-treatment response analysis and 4 had results available from a second line of chemotherapy, for a total of 26 evaluations. Seventeen patients had metastatic disease while 5 were on neoadjuvant chemotherapy for high risk localized sarcomas. The most common sarcoma subtype was LMS (5), followed by undifferentiated small round cell sarcoma (Ewing, other EWSR1 fusions, BCOR; 4 patients), and osteosarcoma (3). Most patients, including those who progressed, showed some early decrease in ctDNA levels, but no patients whose ctDNA result converted to negative within the first two cycles progressed on the first reassessment. In this series a log10 fold change of -1.25 or greater by the end of cycle 2 separated responders and progressors. Conclusions: ctDNA is promising as an early biomarker of response across a wide variety of sarcoma subtypes and chemotherapy regimens. ctDNA dynamics may provide particular clinical utility in interpreting scans showing stable disease, as well as when response is difficult to capture on imaging, such as bony primaries or metastasis, or infiltrative malignancies such as angiosarcoma. Larger data sets and multi-institutional collaboration are needed to verify optimal time points and cutoffs for guiding patient care and interventional trials. Log10 change in ctDNA from baseline at end of cycle 1 and cycle 2 chemotherapy by initial imaging response. Initial Response Cycle 1 median log change Cycle 1 log change range Cycle 2 median log change Cycle 2 log change range Progression -0.17 -1.01— +0.16 -0.36 -1.23— +0.21 Stable disease (SD) -0.18 ND (Not Detected) — +0.27 -0.88 ND — +1.00 Partial response (PR) -1.62 ND — -0.21 -2.42 ND — -1.26 Complete response (CR) -2.72 ND — -1.00 -3.12 ND — -2.35 PR + CR -2.35 ND — -2.01 -2.08 ND — +1.00 SD + PR + CR -1.80 ND — +0.27 -2.47 ND — -1.26
Predicting abnormal fetal growth using deep learning
Authors: Kamil Wojciech Mikołaj, Anders Nymark Christensen, Caroline Amalie Taksøe-Vester, Aasa Feragen, Olav Bjørn Petersen, Manxi Lin, Mads Nielsen, Morten Bo Søndergaard Svendsen, Martin Grønnebæk Tolsgaard
Journal: npj Digital Medicine (2025)
Abstract 1847: Modulation of Cardiac Remodeling with Acellular Matrix Emulsion is Associated with Myofibroblast Proliferation and Angiogenesis via Recruiting C-Kit Positive Cells after Myocardial Infarction
Authors: Zhi-Qing Zhao, John D Puskas, Di Xu, Ning-Ping Wang, Robert A Guyton, Jakob Vinten-Johansen, Robert Matheny
Journal: Circulation (2008)

Degradation of native extracellular matrix (ECM) has been associated with maladaptive cardiac remodeling after infarction. This study tested the hypothesis that preservation of ECM by injecting a xenogegeic acellular matrix emulsion in infarct myocardium promotes myofibroblast proliferation and angiogenesis by recruiting host c-kit positive cells. Sixty-four rats were subjected to 45 minutes regional ischemia followed by 3, 7, 21 and 42 days of reperfusion. Histological examination was performed by immunohistological staining and cardiac function was analyzed using echocardiography. ECM emulsion (30–50 μ l) was injected into the area at risk myocardium after reperfusion and localization of the emulsion was confirmed with Masson Trichome staining. At 7 days of reperfusion, the population of c-kit positive cells within the emulsion area increased significantly relative to the control (32±0.6* vs. 15±3/1000 nuclei), consistent with significantly enhanced expression of 31 kDa stem cell factor detected by Western blotting. Along with this change, myofibroblasts accumulated in the emulsion region to a significant extent compared to the control (59±8* vs. 30±3/HPF). Strong immunoreactivity of VEGF was observed in the emulsion area and angiogenesis was significantly enhanced relative to the control, evidenced by increased density of α -smooth muscle actin-positive vessels (70±10* vs. 20±4/HPF) and vWF-positive vessels (95±14* vs. 34±8/HPF), respectively. At 42 days of reperfusion, echocardiography showed improvements in end-systolic volume (0.3±0.1* vs. 0.6±0.3 ml)), fractional shortening (33±5* vs. 24±6%) and ejection fraction (67±6* vs. 53±10%) in the emulsion group. The wall thickness of the infarcted middle anterior septum in the emulsion group was also significantly greater than that in the Control (0.19±0.02* vs. 0.15±0.02cm). Intramyocardial injection of an acellular extracellular matrix emulsion into the ischemic/reperfused myocardium attenuates maladaptive cardiac remodeling and preserves cardiac function, potentially mediated by enhanced myofibroblast proliferation and angiogenesis via recruiting c-kit positive cells. * p&lt;0.05 emulsion vs. control.
Abstract 17034: The Novel Extracellular Matrix Protein Podocan Shows a Distinct Expression Pattern in Human Primary versus Restenotic Atherosclerotic Coronary Lesions and its Lack of Extra-Cellular Expression in Restenotic Tissue is Associated with Increased Wnt-Pathway Activation
Authors: Randolph Hutter, Li Huang, Valentin Fuster, Paul Klotman, Juan Jose Badimon
Journal: Circulation (2011)

Background: Vascular smooth muscle cell (VSMC) migration and proliferation are associated with restenosis post percutaneous intervention. Podocan is a novel member of the small leucin rich repeat protein family. We recently have described podocan as an inhbitor of VSMC migration and proliferation via the Wnt-pathway. Now we are reporting the expression of podocan and Wnt-pathway related molecules in human primary stable coronary atherosclerosis compared to restenosis. Methods and Results: The expression of podocan and non-phospho-beta catenin (NPBC) an indicator of Wnt-pathway activation was evaluated by immunohistochemistry in coronary atherectomy samples (n=32) (data presented as mean % cells positive for NPBC, ± SEM). The antibody against the human form of podocan was generated in our lab whereas antibodies for NPBC, Wnt 1 and LRP-6 were obtained commercially. In atherectomy samples from patients with primary stable atherosclerosis (n=20) podocan expression was abundant in extra-cellular as well as intra-cellular location. Podocan deposits were seen especially in plaque areas surrounding neovessels. Out of 20 coronary primary lesions 16 showed podocan expression. In contrast, restenotic lesions showed a paucity of podocan with only 5 out of 12 lesions staining positive for podocan. Of note, extra-cellular podocan deposition was completely absent in all restenosis samples and podocan present was restricted to an intra-cellular/cytoplasmic staining pattern. The expression of NPBC was strongly increased in restenotic compared to primary lesions (35 ± 6 % vs. 4 ± 2 %, P&lt;0.05). Importantly, nuclear staining of NPBC indicative of nuclear translocation of beta catenin was observed only in restenotic lesions. Immuno-fluorescence double labeling showed a strong co-localization of Wnt-1 and LRP-6 on VSMC in areas of hyperplasia in restenotic lesions. Conclusions: We are reporting for the first time the expression of podocan in human coronary atheroma. The paucity of podocan and the absence of extra-cellular podocan in restenotic tissue were associated with a strong increase in NPBC expression in VSMC indicating increased Wnt-pathway activation. This points to podocan and the Wnt-pathway as possible key regulators of VSMC in human atherosclerosis.
Abstract 19709: Increasing Ca2+ Influx After Myocardial Infarction Improves Myocyte Contractility but Depresses Cardiac Pump Function by Increasing Myocyte Death
Authors: Hongyu Zhang, Erhe Gao, Wei Wang, Hiroyuki Nakayama, Hui Gao, Fang Wang, Yingxin Li, Remus Berretta, Xiongwen Chen, Walter Koch, Jeffery Molkentin, Annarosa Leri, Jan Kajstura, Steven Houser
Journal: Circulation (2010)

Introduction: Myocardial infarction (MI) causes death of cardiac tissue and depresses cardiac pump performance. Increasing the contractility of the surviving myocytes is one therapy thought to improve the function of the failing heart. However inotropic therapy involving sympathetic agonists can induce cell death and induce arrhythmias. We tested if increasing myocyte contractility without activating sympathetic signaling, by increasing Ca influx (ICa-L), would improve post MI heart function. Methods: Double transgenic mouse lines with inducible (Tet-off system) and cardiac myocyte specific overexpression of the β2a subunit of the L-type Ca2+ channel were used to increase ICa-L. ICa-L, and myocyte fractional shortening (FS) and in vivo cardiac function were measured in wild type (WT) and β2a hearts before, and 3 weeks after MI. Apoptosis (TUNEL), fibrosis (Masson's Trichrome staining) and myocyte proliferation (Ki67 staining, a nuclear marker of cellular replication), were measured. Results: ICa-L and FS ...
Hangovers
Authors: I. Calder
Journal: BMJ (1997)

“Wine is only sweet to happy men,” wrote an unhappy John Keats to his sweetheart.1 His observation seems to have been vindicated. Harburg et al found that psychosocial factors such as guilt about drinking, a neurotic personality, becoming angry or depressed while drinking, and having suffered “negative life events” in the past 12 months are better predictors of symptoms of hangover than the amount of ethanol drunk.2

In fact, ethanol itself may play only a minor part in producing the thirst, headache, fatigue, nausea, sweating, tremor, remorse, and anxiety that hangover sufferers report. Hangover symptoms are worst at a time when almost all ethanol and its metabolite acetaldehyde have been cleared from the blood, and …
Abstract 3741: Anatomic Right Ventricular Measurements with Live 3D Echocardiography and Magnetic Resonance Imaging: A Comparison Study Using a New 4D Analysis Method
Authors: Petra S Niemann, Luiz Pinho, Thomas Balbach, Christian Galuschky, Michael Brankenhagen, William J Woodward, Randal L Imus, Michael Silberbach, Craig Broberg, Florence H Sheehan, Michael Jerosch-Herold, David J Sahn
Journal: Circulation (2006)

Background: Asymmetry and anatomical complexity of the right ventricle (RV) make accurate determination of RV shape and volume difficult. We tested a newly developed 4D semiautomated RV analysis so...
Abstract 16022: Is Proximal Aortic Repair Sufficient for Autoimmune Aortitis?
Authors: Amr Arafat, Eric Roselli, Alison Clifford, Jahanzaib Idrees, Carmela Tan, Lars Svensson, Gary Hoffman, Eugene Blackstone
Journal: Circulation (2013)

OBJECTIVES: Autoimmune aortitis is an under-recognized cause of ascending aorta disease requiring surgery. Little is known about surgical outcomes and natural history thereafter. Objectives of this...
Abstract 14042: Brag2, an Arf6 Activator, Mediates Endocytosis of Beta1-Integrins in Endothelial Cells and Angiogenesis
Authors: Yosif Manavski, Guillaume Carmona, Jens Kroll, Stefanie Dimmeler, Emmanouil Chavakis
Journal: Circulation (2011)

The molecular mechanisms mediating angiogenesis are not completely understood. ADP-ribosylation factor 6 (ARF6) is a small GTPase activated by distinct guanine nucleotide exchange factors (GEF) and is involved in traffic and cytoskeletal organization in the cell periphery thereby regulating cell motility. Interestingly, the function of Arf6 is dependent on the upstream GEF activating it. Angiogenic factors such as VEGF have been shown to promote Arf6 activity. However, the regulation of Arf6 activity in endothelial cells (EC) is unclear. Recent evidence suggests that Brag2, a GEF for Arf6 GTPase, mediates receptor tyrosine kinase-induced Arf6 activity. In the present work we studied the role of Brag2 in angiogenesis. Human umbilical vein endothelial cells (HUVEC) express Brag2 as assessed by western blot. Silencing of Brag2 with siRNA significantly blocked angiogenic sprouting of HUVEC under basal conditions and after VEGF stimulation (by 40 ± 7 %) in a 3-dimensional spheroidal EC culture system and tube formation in a matrigel assay in comparison to scrambled siRNA-transfected EC. Moreover, silencing of Brag2 with siRNA significantly reduced the VEGF-induced 3-dimensional migration of EC (49 % inhibition), while not affecting proliferation. EC migration is dependent on adhesion to matrix proteins. Interestingly, knock down of Brag2 with siRNA significantly increased EC adhesion on the alpha5beta1-integrin ligand, fibronectin. In line with these results, silencing of Brag2 reduced the endocytosis of beta1-integrins and as consequence increased surface expression of the alpha5beta1-integrin in EC as assessed by FACS. In order to address the role of Brag2 in in vivo angiogenesis, we studied vessel formation in developing zebrafish embryos by employing the morpholino technology. Strikingly, in vivo silencing of the Brag2 homologue in zebrafish with a morpholino disturbed the formation of the parachordal vessels and led to defects in the dorsal longitudinal anastomotic vessel and in the intersomitic vessels. These data reveal for the first time that the Arf6 GEF, Brag2 is essential for in vivo angiogenesis probably by mediating EC migration and angiogenic sprouting through regulation of adhesion by promoting integrin internalization.
Abstract 87: The Impact of Coxsackievirus Infection on Cardiac Stem Cells and Postnatal Heart Development
Authors: Jon Sin, Jenna Tabor Godwin, Chengqun Huang, Roberta A Gottlieb, Ralph Feuer
Journal: Circulation Research (2012)

Coxsackievirus B (CVB) is an enterovirus that causes a self-limited febrile illness in infants, but can also cause myocarditis. Long-term consequences of mild CVB infection are unknown, although an association between heart failure and seropositive status has been previously described. We have shown that early postnatal exposure to doxorubicin depleted c-Kit+ cardiac stem cells (CSCs). Cardiac dysfunction in adult mice only developed after exercise challenge, or experimentally-induced myocardial infarction. We now report that CSCs from neonatal mouse hearts were susceptible to cytopathic CVB infection. To learn if mild CVB infection might deplete the CSC population in the heart, we inoculated newborn BALB/c mice with a recombinant CVB expressing eGFP. We observed CVB-infected CSCs 2 days post-inoculation and documented a reduction in the number of c-Kit+ cells in the hearts of animals at 4 and 11 weeks of age despite the absence of detectable virus. Moreover, CVB infection induced differentiation in the surviving CSCs. These results indicate that CVB can infect CSCs in the neonatal heart and trigger their destruction. Premature differentiation of surviving cells may also explain the reduced CSC population in adult mice. Despite normal histologic features in adult hearts, prolonged exercise challenge elicited cardiac hypertrophy and fibrosis in mice infected with CVB as pups. We suggest that the loss of CSCs after mild neonatal CVB infection may predispose to late-onset heart failure.
Single-Cell Mass Cytometry Reveals Phenotypic and Functional Heterogeneity In Acute Myeloid Leukemia At Diagnosis and In Remission
Authors: Lina Han, Zhihong Zeng, Peng Qiu, Jeffrey L. Jorgensen, Duncan H Mak, Jared K Burks, Teresa McQueen, Farhad Ravandi, Gail J Roboz, Hagop M. Kantarjian, Steven M. Kornblau, Monica L. Guzman, Michael Andreeff, Marina Konopleva
Journal: Blood (2013)
Effects of ß3-adrenergic receptor agonist on gene expression of leptin in glioblastoma
Authors: Johnathan E Lawrence, Nicholas J Cook, Richard A Rovin, Robert J Belton, Robert J Winn
Journal: Neuro-Oncology (2012)

LAB-CELL BIOLOGY AND SIGNALING CB-01. THE EFFECT OF WT1 ON TUMORGENECITY, CELL PROLIFERATION, AND APOPTOSIS IN GLIOBLASTOMA Noriyuki Kijima, Naoki Hosen, Naoki Kagawa, Naoya Hashimoto, Yasuyoshi Chiba, Manabu Kinoshita, Haruo Sugiyama, and Toshiki Yoshimine; Osaka University Graduate School of Medicine, Suita, Japan Glioblastoma (GBM), one of the most frequently occurring malignancies in the central nervous system, still has a very poor prognosis. To improve the prognosis of GBM patients, various attempts have been made. Immunotherapy targeting Wilms’ tumor 1 (WT1) has proved to be effective in GBM (Izumoto et al. 2008). However, the functional roles of WT1 in GBM have not been intensively studied. In this study, we aim to examine the functional roles of WT1 in GBM. We established WT1 shRNA knocked down GBM cell lines (U87 and U251) and examined the functional roles in vitro and in vivo. In cell-proliferation assays, we plated 3 × 10 cells in 12-well plates. On day 4 the numbers of the proliferated cells were (39+ 7.8) ×10, (19+3 .5) ×10, (17+6.5) ×10, and (3.4+0.5) ×10 cells in the U87 control shRNA, U87 WT1 shRNA, U251 control shRNA, and U251 WT1 shRNA, respectively (P , 0.05). Furthermore, an Annexin V apoptosis assay showed the numbers of the apoptotic cells per 30 times magnified microscopic field were 2.5+0.6, 15.3+5.7, 3.0+1.7, and 9.0+1.0 cells in the U87 control shRNA, U87 WT1 shRNA, U251 control shRNA, and U251 WT1 shRNA, respectively (P , 0.05). In the in vivo experiment, U87 control shRNA and U87 WT1 shRNA cells were intracranially injected into newborn pups of immunodeficient mice. At day 30, all of the mice transplanted with U87MG control shRNA developed GBM, whereas none of the mice transplanted with U87MG WT1 shRNA developed GBM. These results suggest that WT1 is involved in GBM cell proliferation, apoptosis, and tumor formation. CB-02. RESULTS OF IMMUNOHISTOCHEMICAL STAINING OF CELL-CYCLE REGULATORS—THE PREDICTION OF RECURRENCE-FREE SURVIVAL OF ANTERIOR PITUITARY
International Germ Cell Consensus Classification: a prognostic factor-based staging system for metastatic germ cell cancers. International Germ Cell Cancer Collaborative Group.
Authors: Peter M Wilkinson, G Read
Journal: Journal of Clinical Oncology (1997)

PURPOSE Cisplatin-containing chemotherapy has dramatically improved the outlook for patients with metastatic germ cell tumors (GCT), and overall cure rates now exceed 80%. To make appropriate risk-based decisions about therapy and to facilitate collaborative trials, a simple prognostic factor-based staging classification is required. MATERIALS Collaborative groups from 10 countries provided clinical data on patients with metastatic GCT treated with cisplatin-containing chemotherapy. Multivariate analyses of prognostic factors for progression and survival were performed and models were validated on an independent data set. RESULTS Data were available on 5,202 patients with nonseminomatous GCT (NSGCT) and 660 patients with seminoma. Median follow-up time was 5 years. For NSGCT the following independent adverse factors were identified: mediastinal primary site; degree of elevation of alpha-fetoprotein (AFP), human chorionic gonadotropin (HCG), and lactic dehydrogenase (LDH); and presence of nonpulmonary visceral metastases (NPVM), such as liver, bone, and brain. For seminoma, the predominant adverse feature was the presence of NPVM. Integration of these factors produced the following groupings: good prognosis, comprising 60% of GCT with a 91% (89% to 93%) 5-year survival rate; intermediate prognosis, comprising 26% of GCT with a 79% (75% to 83%) 5-year survival rate; and poor prognosis, comprising 14% of GCT (all with NSGCT) with a 48% (42% to 54%) 5-year survival rate. CONCLUSION An easily applicable, clinically based, prognostic classification for GCT has been agreed on between all the major clinical trial groups who are presently active worldwide. This should be used in clinical practice and in the design and reporting of clinical trials to aid international collaboration and understanding.