tbuckley/cabot-search huggingface dataset:
Venous Thrombosis during Spaceflight
Authors: Serena M Auñón-Chancellor, James M Pattarini, Stephan Moll, Ashot Sargsyan
Journal: New England Journal of Medicine (2020)

To the Editor: Approximately 2 months into an International Space Station mission, obstructive left internal jugular venous thrombosis was suspected in an astronaut during an ultrasound examination that was performed as part of a vascular research study.The astronaut reported no headache or worsening of the facial plethora that is common in conditions of weightlessness.The astronaut had no personal or family history of venous thromboembolism.The physical examination revealed a prominent ipsilateral external jugular vein.Follow-up ultrasound examination performed by the astronaut, guided in real-time and interpreted by two radiologists on Earth, confirmed the presence of venous thrombosis with subacute characteristics (Fig. S1A in the Supplementary Appendix, available with the full text of this letter at NEJM.org); the contralateral internal jugular vein and the bilateral subclavian, axillary, popliteal, and femoral veins were unremarkable.Multispecialty discussions ensued, weighing the unknown risks of thrombus embolism and retrograde extension into the sinus and cerebral veins against those of anticoagulation.Twenty vials containing 300 mg of enoxaparin each were available in the pharmacy of the space station, but no anticoagulation-reversal agent was available.Treatment with enoxaparin at a dose of 1.5 mg per kilogram of body weight once daily was started; the dose was reduced to 1 mg per kilogram once daily after 33 days to extend therapy until oral apixaban could be delivered to the space station with a supply spacecraft.Protamine and prothrombin complex concentrate were also sent to the space station.Transition to apixaban at a dose of 5 mg twice daily occurred 42 days after the diagnosis of venous thrombo-
Nigrostriatal Degeneration in the Cognitive Part of the Striatum in Parkinson Disease Is Associated With Frontomedial Hypometabolism
Authors: Ivayla Apostolova, Catharina Lange, Lars Frings, Susanne Klutmann, Philipp T. Meyer, Ralph Buchert
Journal: Clinical Nuclear Medicine (2019)

Purpose The present study investigated possible associations between cortical dysfunction/degeneration as measured by 18 F-FDG PET and nigrostriatal degeneration according to the specific 123 I-FP-CIT binding ratio (SBR) in striatal subregions defined by striato-cortical anatomical connectivity in Parkinson disease (PD) patients. Materials and Methods The study included 41 patients (61.4 ± 12.8 years) with PD-typical reduction of striatal FP-CIT SBR and no sign of atypical parkinsonian syndrome on FDG PET. FP-CIT SBR was determined separately in the cognitive (composite of executive and limbic) and sensorimotor part of the striatum according to the Oxford-GSK-Imanova Striatal Connectivity Atlas. Scaled FDG uptake was tested voxelwise for correlation with FP-CIT SBR (familywise error corrected P &lt; 0.05). Results A large cluster (17.6 mL) of significant correlation of scaled FDG uptake with FP-CIT SBR in the cognitive part of the striatum, corrected for SBR in the sensorimotor part, was detected in the bilateral medial frontal cortex and the anterior cingulate cortex (partial correlation coefficient R = 0.767); small clusters were detected in ipsilateral caudate and ipsilateral thalamus. There was a small contralateral occipital cluster (3.0 mL) of significant correlation between FDG uptake and sensorimotor SBR corrected for cognitive SBR ( R = 0.709). Conclusions The correlation between nigrostriatal degeneration in the cognitive striatum and reduced cerebral glucose metabolism in the medial parts of the frontal cortex including the anterior cingulate suggests that nigrostriatal degeneration is specifically involved in the pathogenesis of cognitive deficits associated with medial frontal dysfunction such as impaired inhibitory control.
Glucose Oxidase-Instructed Traceable Self-Oxygenation/Hyperthermia Dually Enhanced Cancer Starvation Therapy
Authors: Ting He, Han Xu, Yifan Zhang, Shijian Yi, Run Cui, Shaojun Xing, Chaoliang Wei, Jing Lin, Peng Huang
Journal: Theranostics (2020)

Cancer theranostics based on glucose oxidase (GOx)-induced starvation therapy has got more and more attention in cancer management.Herein, GOx armed manganese dioxide nanosheets (denoted as MNS-GOx) were developed as cancer nanotheranostic agent for magnetic resonance (MR)/photoacoustic (PA) dual-modal imaging guided self-oxygenation/hyperthermia dually enhanced starvation cancer therapy.The manganese dioxide nanomaterials with different morphologies (such as nanoflowers, nanosheets and nanowires) were synthesized by a biomimetic approach using melanin as a biotemplate.Afterwards, the manganese dioxide nanosheets (MNS) with two sides and large surface area were selected as the vehicle to carry and deliver GOx.The as-prepared MNS-GOx can perform the circular reaction of glucose oxidation and H 2 O 2 decomposition for enhanced starvation therapy.Moreover, the catalytic activity of GOx could be further improved by the hyperthermia of MNS-GOx upon near-infrared laser irradiation.Most intriguingly, MNS-GOx could achieve "turn-on" MR imaging and "turn-off" PA imaging simultaneously.The theranostic capability of MNS-GOx was evaluated on A375 tumor-bearing mice with all tumor elimination.Our findings integrated molecular imaging and starvation-based synergistic cancer therapy, which provided a new platform for cancer nanotheranostics.
Abstract 15059: Development and Validation of a Risk Prediction Model for Cardiovascular Disease in Women of Reproductive Age
Authors: Sonia M Grandi, Kristian B Filion, Jennifer A Hutcheon, Graeme N Smith, Robert W Platt
Journal: Circulation (2019)

Background: Currently available risk prediction scores for cardiovascular disease (CVD) were developed in older age populations, which limits their ability to provide accurate estimates of risk in ...
Recurrent chromosomal rearrangements of <i>ROS1</i>, <i>FRK</i> and <i>IL6</i> activating JAK/STAT pathway in inflammatory hepatocellular adenomas
Authors: Quentin Bayard, Stefano Caruso, Gabrielle Couchy, Sandra Rebouissou, Paulette Bioulac Sage, Charles Balabaud, Valerie Paradis, Nathalie Sturm, Anne de Muret, Catherine Guettier, Benjamin Bonsang, Christiane Copie, Eric Letouzé, Julien Calderaro, Sandrine Imbeaud, Jean-Charles Nault, Jessica Zucman-Rossi
Journal: Gut (2020)

Background Inflammatory hepatocellular adenomas (IHCAs) are benign liver tumours characterised by an activation of the janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway caused by oncogenic activating mutations. However, a subset of IHCA lacks of identified mutation explaining the inflammatory phenotype. Methods 657 hepatocellular adenomas developed in 504 patients were analysed for gene expression of 17 genes and for mutations in seven genes by sequencing. 22 non-mutated IHCAs were analysed by whole-exome and/or RNA sequencing. Results We identified 296 IHCA (45%), 81% of them were mutated in either IL6ST (61%), FRK (8%), STAT3 (5%), GNAS (3%) or JAK1 (2%). Among non-mutated IHCA, RNA sequencing identified recurrent chromosome rearrangement involving ROS1, FRK or IL6 genes. ROS1 fusions were identified in 8 IHCA, involving C-terminal part of genes highly expressed in the liver ( PLG , RBP4 , APOB ) fused with exon 33–35 to 43 of ROS1 including the tyrosine kinase domain. In two cases a truncated ROS1 transcript from exon 36 to 43 was identified. ROS1 rearrangements were validated by fluorescence in situ hybridisation (FISH) and led to ROS1 overexpression. Among the 5 IHCA with FRK rearrangements, 5 different partners were identified ( MIA3 , MIA2 , LMO7 , PLEKHA5, SEC16B ) fused to a common region in FRK that included exon 3–8. No overexpression of FRK transcript was detected but the predicted chimeric proteins lacked the auto-inhibitory SH2–SH3 domains. In two IHCA, we identified truncated 3’UTR of IL6 associated with overexpression of the transcript. Conclusion Recurrent chromosomal alterations involving ROS1 , FRK or IL6 genes lead to activation of the JAK/STAT pathway in IHCAs.
Hepatitis C virus–specific CD4+ T cell phenotype and function in different infection outcomes
Authors: Diana Y. Chen, David Wolski, Jasneet Aneja, Lyndon Matsubara, Brandon Robilotti, Garrett Hauck, Paulo Sergio Fonseca de Sousa, Sonu Subudhi, Carlos Augusto Fernandes, Ruben C. Hoogeveen, Arthur Y. Kim, Lia Lewis-Ximenez, Georg M. Lauer
Journal: Journal of Clinical Investigation (2020)

CD4+ T cell failure is a hallmark of chronic hepatitis C virus (HCV) infection. However, the mechanisms underlying the impairment and loss of virus-specific CD4+ T cells in persisting HCV infection remain unclear. Here we examined HCV-specific CD4+ T cells longitudinally during acute infection with different infection outcomes. We found that HCV-specific CD4+ T cells are characterized by expression of a narrower range of T cell inhibitory receptors compared with CD8+ T cells, with initially high expression levels of PD-1 and CTLA-4 that were associated with negative regulation of proliferation in all patients, irrespective of outcome. In addition, HCV-specific CD4+ T cells were phenotypically similar during early resolving and persistent infection and secreted similar levels of cytokines. However, upon viral control, CD4+ T cells quickly downregulated inhibitory receptors and differentiated into long-lived memory cells. In contrast, persisting viremia continued to drive T cell activation and PD-1 and CTLA-4 expression, and blocked T cell differentiation, until the cells quickly disappeared from the circulation. Our data support an important and physiological role for inhibitory receptor-mediated regulation of CD4+ T cells in early HCV infection, irrespective of outcome, with persistent HCV viremia leading to sustained upregulation of PD-1 and CTLA-4.
Characterization of silk-hyaluronic acid composite hydrogels towards vitreous humor substitutes
Authors: Nicole R. Raia, Di Jia, Chiara E. Ghezzi, Murugappan Muthukumar, David L. Kaplan
Journal: Biomaterials (2019)

Multiple ophthalmic pathologies, such as retinal detachment and diabetic retinopathy, require the removal and replacement of the vitreous humor. Clinical tamponades such as silicone oil and fluorinated gases are utilized but limited due to complications and toxicity. Therefore, there is a need for biocompatible, stable, vitreous humor substitutes. In this study, enzymatically crosslinked silk-hyaluronic acid (HA) hydrogels formed using horseradish peroxidase and H2O2 were characterized for use as vitreous humor substitutes. The composite network structure was characterized with dynamic light scattering. In addition, the rheological, optical, and swelling properties of hydrogels with varying silk to HA ratios and crosslinking densities controlled via H2O2 were determined over time. Hydrogels had refractive indexes of 1.336 and were clear with 75–91% light transmission. Hydrogel shear storage modulus ranged between ~6 and 240 Pa where increased H2O2 increased the modulus. After 1 month of aging, there were no changes in modulus for hydrogels with lower silk ratios, while those with higher silk ratios exhibited a significant increase in modulus. Decreasing H2O2 concentration in the reactions led to increased hydrogel volume during swelling, with higher silk ratios returning to their original size after 15 days. Dynamic light scattering results show three diffusive modes, revealing the possible structures of the hydrogel composite and are consistent with the mechanical properties and swelling results. The normalized intraocular pressure of ex vivo porcine eyes after injecting hydrogels were comparable with those treated with silicone oil showing the potential clinical utility of the hydrogels as vitreous substitutes. The versatility of the silk-HA hydrogel system, the tunable swelling properties, and the stability of hydrogels with lower silk ratios show the benefit of utilizing silk-HA hydrogels as vitreous substitutes.
Survival of elderly Medicare patients after standard chemotherapy for advanced lung and gastrointestinal cancers in the real world.
Authors: Elizabeth B. Lamont, Yulei He, Lan Lan, Steven Joffe
Journal: Journal of Clinical Oncology (2012)

1605 Background: Elderly cancer patients are under-represented on clinical trials that determine standards of treatment, thus survival of such patients following standard treatment in the real world is not known. We describe unadjusted survivals for site, stage, and treatment-specific cohorts of elderly Medicare cancer patients who were treated in usual care settings. Methods: From SEER-Medicare data, we identified elderly Medicare patients with advanced lung or GI cancers who received specific standard chemotherapy regimens within six months of diagnosis. Of the 108,386 patients with the cancer sites and stages of interest, 39% (42,570/108,386) received some form of chemotherapy within six months of diagnosis. Only 32% (13,689/42,570) received one of the specific standard regimens we studied. Results: Median survival times and interquartile ranges (IQRs) varied according to cancer site, stage, and treatment. For 598 stage IV CRC patients on FOLFOX, the median survival was 19.4 mos (IQR 9.3-43.0); this is comparable to PRIME Study patients (19.7 mos). For 130 stage IV CRC patients on FOLFIRI, the median survival was 16.1 mos (IQR 5.6-30.0), which is lower than BICC-C Study patients (23.1 mos). For 3,815 advanced pancreatic cancer patients on gemcitabine, the median survival was 4.3 mos (IQR 2.0-8.7), which is slightly lower than CALGB 80303 patients (5.8 mos). For 8,040 stage IV NSC lung cancer patients on carboplatin and paclitaxel, the median survival was 7.0 mos (IQR 3.2-14.2); this is comparable to ECOG 1594 patients (7.8 mos). For 1,104 extensive stage SCLC patients on cisplatin and VP16, the median survival was 8.5 mos (IQR 4.7-12.9), which is slightly lower than CALGB 9732 patients (10.0 mos). Conclusions: The observed survival of cancer site, stage, and treatment-specific cohorts of elderly Medicare patients with advanced lung or GI cancers who were treated in real world settings with standard chemotherapy was, in general, similar to that of patients treated with nominally identical regimens on trials. Further analyses should explore the shorter survival for elderly Medicare patients with stage IV CRC treated with FOLFIRI in the usual care setting compared to patients treated on trials.
Exercise Pulmonary Hypertension Predicts Clinical Outcomes in Patients With Dyspnea on Effort
Authors: Jennifer E Ho, Emily K Zern, Emily S Lau, Luke Wooster, Cole S Bailey, Thomas Cunningham, Aaron S Eisman, Kathryn M Hardin, Robyn Farrell, John A Sbarbaro, Mark W Schoenike, Nicholas E Houstis, Aaron L Baggish, Ravi V Shah, Matthew Nayor, Rajeev Malhotra, Gregory D Lewis
Journal: Journal of the American College of Cardiology (2020)
Window-of-opportunity clinical trial of pembrolizumab in patients with recurrent glioblastoma reveals predominance of immune-suppressive macrophages
Authors: John de Groot, Marta Penas-Prado, Kristin Alfaro-Munoz, Kathy Hunter, Be Lian Pei, Barbara O’Brien, Shiao-Pei Weathers, Monica Loghin, Carlos Kamiya Matsouka, W K Alfred Yung, Jacob Mandel, Jimin Wu, Ying Yuan, Shouhao Zhou, Gregory N Fuller, Jason Huse, Ganesh Rao, Jeffrey S Weinberg, Sujit S Prabhu, Ian E McCutcheon, Frederick F Lang, Sherise D Ferguson, Raymond Sawaya, Rivka Colen, Shalini S Yadav, Jorge Blando, Luis Vence, James Allison, Padmanee Sharma, Amy B Heimberger
Journal: Neuro-Oncology (2019)

We sought to ascertain the immune effector function of pembrolizumab within the glioblastoma (GBM) microenvironment during the therapeutic window.In an open-label, single-center, single-arm phase II "window-of-opportunity" trial in 15 patients with recurrent (operable) GBM receiving up to 2 pembrolizumab doses before surgery and every 3 weeks afterward until disease progression or unacceptable toxicities occurred, immune responses were evaluated within the tumor.No treatment-related deaths occurred. Overall median follow-up time was 50 months. Of 14 patients monitored, 10 had progressive disease, 3 had a partial response, and 1 had stable disease. Median progression-free survival (PFS) was 4.5 months (95% CI: 2.27, 6.83), and the 6-month PFS rate was 40%. Median overall survival (OS) was 20 months, with an estimated 1-year OS rate of 63%. GBM patients' recurrent tumors contained few T cells that demonstrated a paucity of immune activation markers, but the tumor microenvironment was markedly enriched for CD68+ macrophages.Immune analyses indicated that pembrolizumab anti-programmed cell death 1 (PD-1) monotherapy alone can't induce effector immunologic response in most GBM patients, probably owing to a scarcity of T cells within the tumor microenvironment and a CD68+ macrophage preponderance.
Phase Ib study of TSPP (thymidilate synthase poly-epitope peptide) vaccine in combination with GOLFIG chemoimmuno-burst in advanced colon cancer patients: Results from the TSPP/VAC-1/c trial.
Authors: Pierpaolo Correale, Pierpaolo Pastina, Cirino Botta, Maria Grazia Rossetti, Serena Apollinari, Elena Bestoso, Antonella Fioravanti, Giacomo Guidelli, Federico Chellini, Giovanni Mantovani, Gianni Gori Savellini, Salvatore Francesco Carbone, Veronica Ricci, Assunta Basile, Marco Pagliuchi, Pierosandro Tagliaferri, Luigi Pirtoli, Maria Grazia Cusi
Journal: Journal of Clinical Oncology (2012)

e13098 Background: TSPP is a poly-epitope peptide anticancer vaccine able to generate a thymidylate syntase (TS) specific T cell response with antitumor activity in preclinical models, expecially when used in sequential combination with 5-FU. TS is in fact involved in DNA replication and is the major pharmacological target of fluoropyrimidines whose activity leads in turn to TS upregulation. On these basis we designed a phase Ib trial where we investigated the safety and the immunobiological activity of TSPP + GOLFIG (Gemcitabine + FOLFOX-4 + GM-CSF + IL-2) regimen. Methods: TSPP/VAC-1 (Eudract 2009-016897-33) is a monocentric dose finding Phase Ib trial. 12 pretreated metastatic colon cancer patients were enrolled between April and November 2011. All of them received biochemotherapy according to the GOLFIG regimen biweekly and TSPP (on day 7) diluted in motanide ISA720 (1:1) at the dosage of 100 (3 patients), 200 (3 patients) and 300 ug (6 patients). Results: No life-threatening adverse events were observed. Grade 3 leucopenia (2 cases), thrombocitopenia (3 cases), anemia (3 cases), nausea/vomiting (2 cases), and dyarrhea (4 cases) along with 3 cases of oxaliplatin reaction were recorded. Fever and flu-like symptoms were common along cytokine administration. An IFN-gamma ELISPOT assay recorded an increase in TS specific CTL precursors in 3/6 evaluable patients; it was also observed an increase in lymphocytes, eosinophils, terminal effector memory and central memory T cells and in both c-ANCA and p-ANCA (P= 0.02) in the peripheral blood and a significant reduction in inflammatory markers (LDH, CRP and ESR). Quality of life analysis revealed a general improvement in patients’health state along the treatment. 1 partial response, 6 disease stabilizations and 2 progessions of disease were recorded. TSPP Maximal Tolerated Dose was not reached, while the Optimal Biological Dose was identified at 300 ug. Conclusions: Our results suggest that the GOLFIG + TSPP vaccine combination is safe and immunologically active and deserves to be evaluated in a further phase II trial.
Ovarian Metastasis as Initial Presentation of Pancreatic Carcinoma on FDG PET/CT
Authors: Guozhu Hou, Yuanyuan Jiang, Fang Li, Xin Cheng
Journal: Clinical Nuclear Medicine (2019)

Pancreatic carcinoma metastasizing to the ovary is rare. We report the case of a 69-year-old woman with ovarian metastasis as initial presentation. Ultrasonography revealed a multicystic mass in the right adnexa, which was considered a malignancy. FDG PET/CT performed to detect possible metastasis revealed a right adnexal mass with mild activity and an additional FDG focus in the tail of the pancreas, which later proved to be ovarian metastasis from pancreatic carcinoma.
Abstract B03: Targeting tumor-intrinsic metabolic node in pancreatic cancer causes tumor regression, remodels extracellular matrix, and sensitizes to anti-PD1 therapy
Authors: Nikita S. Sharma, Vineet K. Gupta, Vanessa Garrido, Roey Hadad, Brittany Durden, Kousik Kesh, Anthony Ferrantella, Bhuwan Giri, Vikas Dudeja, Ashok Saluja, Sulagna Banerjee
Journal: Cancer Research (2019)

Abstract Background: Pancreatic adenocarcinoma (PDAC) is an extremely immunosuppressive and heterogenous neoplasm for which immune checkpoint inhibitor therapy has not been very successful. Hexosamine biosynthesis pathway (HBP), a shunt pathway of glycolysis, is a metabolic node in cancer cells that can promote survival pathways on one hand and also influence the extracellular matrix in the tumor microenvironment. Our study aims to sensitize pancreatic cancer to anti PD-1 therapy by targeting the HBP pathway. Methods: 6-Diazo-5-oxo L-norleucine or DON was used as a GFAT inhibitor. Tetracycline-inducible GFAT knockout cell lines were made using S2-VP10 as the parent cell line. Results: High-dose monotherapy of DON (1mg/kg/3days a week) caused significant decrease in tumor volume in immunocompetent KPC mice along with significant reduction in metastasis and circulating tumor cells. Circulating tumor cells (CTCs) were also found to be significantly reduced in DON-treated mice as compared to control, leading to reduced metastasis. Combination of low-dose DON (0.5mg/kg/3 days a week) with low-dose anti PD-1 (100 μgX3 times) caused an impressive reduction in tumor volume along with an increase in survival in KPC tumor-bearing mice. Flow-based analysis of tumor cells show a significant influx of CD8+ T cells along with an increase in M1 polarization of macrophages. Survival study of CD8 knockout mice (CD8KO), orthotopically implanted with KPC and fibroblast cells, show that at low doses DON loses its anticancer effect in absence of CD8 as demonstrated by decrease in survival in CD8KO mice as compared to tumor-bearing wild-type mice. Conclusion: Novel therapeutic strategies that can make PDAC more amenable to immune therapy are urgently needed. In this context, our study is extremely timely as it targets specific metabolic pathways in cancer cells to overcome immune resistance and sensitize the tumor to anti-PD1 therapy. Citation Format: Nikita S. Sharma, Vineet K. Gupta, Vanessa Garrido, Roey Hadad, Brittany Durden, Kousik Kesh, Anthony Ferrantella, Bhuwan Giri, Vikas Dudeja, Ashok Saluja, Sulagna Banerjee. Targeting tumor-intrinsic metabolic node in pancreatic cancer causes tumor regression, remodels extracellular matrix, and sensitizes to anti-PD1 therapy [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B03.