tbuckley/cabot-search huggingface dataset:
Carboplatin plus paclitaxel versus carboplatin plus Stealth liposomal doxorubicin in patients with advanced ovarian cancer (AOC): Preliminary activity results of the MITO-2 randomized multicenter trial
Authors: S. Pignata, G. Scambia, A. Savarese, E. Breda, R. Sorio, A. Vernaglia Lombardi, V. Gebbia, P. Scollo, D. Lorusso, A. Morabito
Journal: Journal of Clinical Oncology (2007)

5532 Background: The MITO-2 (Multicentre Italian Trials in Ovarian cancer) study is a randomized phase III study comparing the effect on progression-free survival of carboplatin/paclitaxel versus carboplatin/stealth liposomal doxorubicin (CLD) in 1 st -line AOC patients. Due to the lack of published phase II data on the CLD schedule, safety and activity analyses were planned within the trial. The former, previously reported for the first 50 patients treated with CLD, showed mild haematological toxicity, while non-hematological events seldom were higher than grade 2. Methods: AOC patients with AOC (stage IC-IV), aged =75, ECOG PS =2, are randomized to CP (carboplatin AUC 5 / paclitaxel 175 mg/m 2 , d1q21) or to CLD (carboplatin AUC 5 + Stealth liposomal doxorubicin 30 mg/m 2 , d1q21), both treatments for 6 cycles. According to a phase 2 design with p0=30%, p1=50%, alfa=0.10, 50 patients with measurable target lesions as defined by RECIST criteria were required and ≥20 responses had to be observed in order to define that the experimental schedule was sufficiently active to warrant phase III continuation. Results: Out of the first 137 patients randomly assigned to CLD, 87 were not eligible for response assessment by RECIST (35 had only non target lesions; 28 had only Ca 125 increased; 23 had no lesion and normal Ca 125; 1 never started treatment). Out the 50 patients eligible for response assessment, overall 34 responses were recorded (14 complete, 20 partial) for a response rate of 68% (95% CI: 53.3–80.5). In addition, among 35 patients with all non-target lesions 9 (26%) complete responses and 18 (51%) nonCR- nonPD were observed. In the remaining 28 patients evaluable only for Ca 125, this normalized in 96% of the cases at the end of the 6 cycles. Conclusions: An a priori planned activity analysis showed that CLD every 3 weeks is feasible and active in AOC patients suboptimally debulked and with measurable lesions. The trial is ongoing; as of December 28th, 2006, 615 patients have been enrolled out of 810 planned. No significant financial relationships to disclose.
Abstract 442: Modeling Endothelial Dysfunction in LMNA-Related Dilated Cardiomyopathy
Authors: Nazish Sayed, Chun Liu, Farhan Himmati, Joe Zhang, Vittavat Termglinchan, Jan-Ranier Moonen, Jon Stack, Haodong Chen, Elena Matsa, Karim Sallam, Marlene Rabinovitch, Joseph C Wu
Journal: Circulation Research (2017)

Background: Mutations in the gene that encodes the nuclear envelope proteins lamin A and C (LMNA) accounts for 6% of all cases of DCM. However, the molecular mechanisms that underlie “cardiolaminopathy” remain elusive, and it is unknown why mutations in this ubiquitously expressed gene have such a disproportionate effect on the heart. Hypothesis: Despite the fact that LMNA is abundantly expressed in endothelial cells (ECs) and mutations in LMNA are known to induce EC dysfunction, little is known about the EC-specific phenotype of LMNA-related DCM. As EC dysfunction has been known to contribute to DCM, we hypothesize that EC dysfunction due to LMNA mutation has a significant impact on the pathogenesis and disease progression of DCM. Results: Intriguingly, our preliminary data showed that iPSC-ECs derived from patients (n=5) harboring the LMNA-mutation exhibit decrease functionality as seen by impaired angiogenesis and decreased NO production (control iPSC-ECs vs LMNA iPSC-ECs; p&lt;0.05). Similarly, genome editing of isogenic iPSC lines enabled us to recapitulate the EC disease phenotype further allowing us to dissect the effects of LMNA mutations on EC function. LMNA corrected iPSC-ECs (via use of CRISPR/Cas9 genome editing tool to correct the single mutated copy in heterozygous patient’s iPSCs) showed restoration of EC function. Whole genome RNA-sequencing identified Krüppel-like Factor 2 (KLF2) as a potential transcript responsible for EC dysfunction in LMNA-mutated patients. Importantly, treatment of LMNA-mutated ECs with KLF2 agonists showed rescue of EC dysfunction. Furthermore, iPSC-derived cardiomyocytes (iPSC-CMs) from LMNA-mutated patients that exhibited DCM phenotype, showed improvement in CM physiology when co-cultured with iPSC-ECs treated with KLF2 agonists. Conclusion: This study is a first step towards understanding the molecular mechanisms of cardiolaminopathy by modeling endothelial dysfunction using patient-specific iPSCs. Moreover, our results suggest that improving EC function in cardiolaminopathy patients could have a significant impact on the pathogenesis of DCM. Results from this work could potentially lead to new strategies that could improve the management of DCM patients.
Abstract 98a: A Novel Rodent Model of HFpEF: a Potential Platform for Understanding Disease Mechanisms and Evaluating New Therapies
Authors: Huawei Zhao, Barry R Campbell, Xiaolan Shen, Jeffrey B Madwed, Maarten Hoek
Journal: Circulation Research (2017)

Heart failure with preserved ejection fraction (HFpEF) occurs in over 50% of total HF population today and is growing with no approved therapies today. A major challenge to the field is that truly representative experimental models of HFpEF do not exist and therefore, the advancement of the science and treatment is minimal. We have set out to develop a reliable and reproducible HFpEF rodent model to provide a platform for preclinical investigation of potential therapies. Diagnostic criteria to validate the model included (a) LVEDP &gt; 15 mmHg, (b) left ventricular (LV) stiffness and impaired LV relaxation, (c) preserved ejection fraction (EF ≥ 55%), and (d) LV concentric hypertrophy. Adult SHR were given isoproterenol by subcutaneous mini pump infusion for 4-weeks. After first week of isoproterenol treatment initiated, L-NAME was added for 8-weeks to accelerate transition from concentric hypertrophy to HFpEF. Echocardiography and invasive hemodynamics were used to evaluate cardiac structure and function at baseline, immediately after stopping L-NAME and at 4 and 8 weeks. Treated SHR had significantly increased LVEDP, Tau and left ventricular hypertrophy with preserved EF. A follow-up study confirmed these initial data and demonstrated this HFpEF phenotype remained for at least 8-week after end of L-NAME/Iso treatment (see table). This rodent model mimics many characteristics of HFpEF patients, such as concentric cardiac hypertrophy, slow LV relaxation, and increased LV stiffness with a chronic hypertensive background and may provide a valuable platform for understanding the pathophysiology of HFpEF, as well as facilitating preclinical investigation of potential therapies.
Use of Narrative Concepts in Electronic Health Records to Validate Associations Between Genetic Factors and Response to Treatment of Inflammatory Bowel Diseases
Authors: Ashwin N. Ananthakrishnan, Andrew Cagan, Tianxi Cai, Vivian S. Gainer, Guergana Savova, Stanley Y. Shaw, Susanne Churchill, Kristin E. Burke, Elizabeth W. Karlson, Shawn N. Murphy, Isaac Kohane, Katherine P. Liao, Ramnik J. Xavier
Journal: Clinical Gastroenterology and Hepatology (2019)
Defective mismatch repair proteins and microsatellite instability in young Mexican patients with colorectal cancer.
Authors: Arturo Quintanilla Guzman, Arturo Luevano Gonzalez, Augusto Rojas Martinez, Juan Pablo Flores Gutierrez, Juan Francisco Gonzalez Guerrero, Clara Patricia Rios Ibarra, Yamil Alonso Lopez Chuken, Claudia Rodriguez Silva, Rocio Ortiz Lopez
Journal: Journal of Clinical Oncology (2013)

e14708 Background: Colorectal carcinoma (CRC) is prevalent malignancy and a third of the cases affect young patients. 15% of CRC have microsatellite instability (MSI) due to disruptions in mismatch repair (MMR) genes, like germline mutations (3%) and hypermethylation of the MLH1 gene promoter associated to the BRAF V600E mutation (12%). The aim of this work was to assess MMR abnormalities in tumors of Mexican CRC patients under 50 years old. Methods: CRC paraffin-embedded tissues of 47 patients with available demographic/clinical data were studied by immunohistochemistry (IHC) for MLH1/MSH2, qPCR with specific probes/sequencing for the BRAF V600E mutation, and conventional PCR (5 markers) for MSI analysis. Results: Female:Male ratio was 0.81:1. Most of the cases were classified as TNM Stage II, were located in the cecum, invaded the serous coat, and showed intestinal-type histology. 20 samples showed alterations in MMR protein expression. MLH1, MSH2, and combined deficiency of both proteins were detected in 17, 4, and 4 tumors, respectively. No BRAF mutations were detected. MSI analysis restricted to the 20 altered IHC samples showed MSI in 10 tumors (3 MSI-low and 7 MSI-high tumors). The four cases with MLH1/MSH2 deficiency, showed MSI-high pattern. Conclusions: We found 42.6% cases with defective MMR expression. No epigenetic abnormalities associated to BRAF V600E mutation were registered. The lack of MSI in ten tumors with deficient MMR may be due to alternate DNA repair mechanisms. Acknowledgments. Work supported by the CHIBCHA Project (European Commission7FP grant #223678).
Low molecular weight heparin (LMWH) for primary thrombophylaxis in patients with solid malignancies: Systematic review and meta-analysis.
Authors: Irit Ben-Aharon, Salomon M. Stemmer, Ofer Shpilberg, Aaron Sulkes, Anat Gafter-Gvili
Journal: Journal of Clinical Oncology (2013)

e20595 Background: Patients receiving chemotherapy for cancer are at increased risk for venous thromboembolism (VTE). The role of low molecular weight heparin (LMWH) as antithrombotic prophylaxis has been appraised in several studies, yielding conflicting results. We performed a meta-analysis of all randomized controlled trials (RCTs) which evaluated the addition of LMWH as primary prophylaxis in patients with solid malignancies while receiving chemotherapy. Methods: RCTs were identified by searching the Cochrane Library, MEDLINE databases and conference proceedings. Relative risks (RR) of thrombotic events, mortality as well as adverse events were estimated and pooled. Results: Nine trials met the inclusion criteria, and evaluated a total of 6691 patients. Primary prophylaxis with LMWH reduced both symptomatic VTEs: (RR 0.47, 95% CI(0.32 to 0.69)) and the rate of pulmonary embolism(PE): (RR 0.51, 95% CI(0.30 to 0.86)).Symptomatic DVT was reduced as well (RR 0.35, 95% CI(0.21 to 0.60). Meta-analysis of six trials which reported survival outcomes revealed no statistically significant benefit for LMWH in 1 year mortality rates (RR 0.93, 95% CI(0.83 to1.04)). There was no significant increase in major bleeding events. Conclusions: LMWH reduces the incidence of symptomatic VTE and PE in patients receiving chemotherapy for cancer, with no apparent increase in major bleeding. Nevertheless, LMWH had no significant effect on survival outcomes. Future studies should delineate whether specific populations may derive a survival benefit from LMWH primary prophylaxis.
Fever-range whole body hyperthermia increases the efficacy of radiation therapy by selectively increasing the percentage of perfused tumor blood vessels
Authors: Maegan Capitano, John Schueckler, Wainwright Jaggernauth, Arindam Sen, Elizabeth Repasky
Journal: Cancer Research (2008)

5767  Cancer researchers have long recognized that the sensitivity of cancer cells to ionizing radiation is dependent upon their oxygenation status; therefore, in hypoxic tumors the full therapeutic potential of radiation may be blunted even with very high doses of ionizing radiation. Using localized heat to bring tumors to a relatively high temperature (41-43oC) is re-gaining support as a radiation sensitizer because of the improved survival seen in patients who receive combination hyperthermia and radiation over that seen in patients given radiation alone. This enhanced efficacy is thought to be due to the increase blood flow in the heated tumor which may bring more oxygen into the tumor microenvironment. We predict that this approach may not take full advantage of the radiosensitizing properties of hyperthermia. Instead, we hypothesize that that mild (between 38-39oC) hyperthermia treatment to the normal organs and tissues surrounding the tumor, or indeed, throughout wide regions of the body may provide superior radiosensitization to the tumor. Because tumor vessels are defective and unable to respond normally to homeostatic control mechanisms (including thermoregulation), they may be highly sensitive to increased blood flow coming from other regions of the body which do react strongly to modest increases in temperature. Further, tumor vessels may remain in a state of heightened perfusion for a longer period of time following mild thermal stress because they lack normal smooth muscle and neuronal connections that would help them respond to autonomic signals. To test these ideas, tumor-bearing mice were subjected to fever-range whole body hyperthermia (FR-WBH) for 6 hours at 39.5°C. Then, they were either injected intravenously with a fluorescent dye (DiOC7) to monitor vessel perfusion or they underwent local X-ray irradiation (20Gy fractioned over 5 days at 4Gy/day). Tumors from mice treated with fever-range whole body hyperthermia had significantly more functional vessels (i.e. vessels perfused with DiOC7+) than mice kept at room temperature. This change in number of functional vessels was not associated with an increase in the total number of CD31+ vessels and it lasted for more than 48 hours. Further, there was no increase in normal organ vascular perfusion seen at any time after heating. Mice that received localized radiation therapy after FR-WBH exhibited significant improvement in tumor growth control over that seen in mice receiving radiation alone, even though radiation was given 24 hours after the completion of the FR-WBH treatment. These finding suggest that mild whole body hyperthermia significantly and selectively increases tumor vessel perfusion and results in superior radiosensitization to the tumor. These data may lead to more feasible hyperthermia protocols for maximal radiosensitization of tumors.
Phosphoproteome of activated FLT3 in leukemia
Authors: Ting-Lei Gu, Julie Nardone, Marc Loriaux, Kim Lee, Judit Villen, Steven Gygi, John Rush, Michael Comb, Brian Druker, Michael Heinrich, Roberto Polakiewicz
Journal: Cancer Research (2007)

3134  Activating mutations of FMS-like tyrosine kinase-3 (FLT3) are found in approximately one third of patients with acute myeloid leukemia (AML) and are an attractive drug target. Recently, FLT3 has been implicated in the pathogenesis of infant and childhood ALL. There is substantial experimental evidence, both in vitro and in vivo, to support the notion that these mutations play an important role in the initiation and/or maintenance of AML in a subset of patients. However, the molecular mechanisms by which FLT3 mutations lead to transformation of hematopoietic stem cells remain unclear. To develop a better understanding of FLT3 signaling as well as its downstream mediators, we performed detailed phoshoproteomic analysis of FLT3 signaling in leukemia cells. Using immunoaffinity purification of phospho-tyrosine peptides (PhosphoScan®) followed by tandem mass spectrometry, we identified over 1000 tyrosine phosphorylation sites from approximately 20 AML (FLT3-ITD and wild type) and B-ALL (normal and amplification of FLT3) cell lines. Not only did we identify novel tyrosine phosphorylation sites in FLT3, but also we identified many phosphosites unique to FLT3-ITD AML cell lines. In addition, we investigated which of these phosphosites were responsive to FLT3 inhibitors. To further investigate the FLT3 signaling pathway, we employed stable isotopic amino acids in cell culture (SILAC) to differentially label proteins in FLT3 inhibited versus uninhibited leukemia cell lines. Quantitative SILAC experiment identified over 200 phosphorylation sites, whose tyrosine phosphorylation status is regulated by FLT3. Finally, for the first time, we performed phosphoproteomic analysis from AML patient samples. This study provided the most comprehensive tyrosine phosphorylation signaling profile reported for activated FLT3 to date These studies have important implications for the design of novel therapeutic approaches and for the identification of biomarkers for leukemia with activated FLT3.
Identifying and targeting pathogenic PI3K/AKT/mTOR signaling in IL-6 blockade–refractory idiopathic multicentric Castleman disease
Authors: David C. Fajgenbaum, Ruth-Anne Langan, Alberto Sada Japp, Helen L. Partridge, Sheila K. Pierson, Amrit Singh, Daniel J. Arenas, Jason R. Ruth, Christopher S. Nabel, Katie Stone, Mariko Okumura, Anthony Schwarer, Fábio Freire Jose, Nelson Hamerschlak, Gerald B. Wertheim, Michael B. Jordan, Adam D. Cohen, Vera Krymskaya, Arthur Rubenstein, Michael R. Betts, Taku Kambayashi, Frits van Rhee, Thomas S. Uldrick
Journal: Journal of Clinical Investigation (2019)

BACKGROUND. Idiopathic multicentric Castleman disease (iMCD) is a hematologic illness involving cytokine-induced lymphoproliferation, systemic inflammation, cytopenias, and life-threatening multi-organ dysfunction. The molecular underpinnings of interleukin-6 (IL-6) blockade–refractory patients remain unknown; no targeted therapies exist. In this study, we searched for therapeutic targets in IL-6 blockade–refractory iMCD patients with the thrombocytopenia, anasarca, fever/elevated C-reactive protein, reticulin myelofibrosis, renal dysfunction, organomegaly (TAFRO) clinical subtype.
Prostaglandin E2 provides a pro-neoangiogenic environment to colorectal neoplasia: Roles of intestinal subepithelial myofibroblasts
Authors: Yasuyuki Amoh, Lingna Li, Kazuhiko Tsuji, Abdool R. Moossa, Kensei Katsuoka, Robert M. Hoffman, Michael Bouvet
Journal: Cancer Research (2006)

1874  Cyclooxygenase-2 (COX-2) and its derived prostaglandins (PGs) play key roles in colorectal neoplasia. In studies of human colorectal cancer, COX-2 levels are increased in about 90% of cancers and ∼50% of pre-malignant colorectal adenomas, but the enzyme is not usually detected in adult intestinal tissues. Numerous studies indicate that COX-2 expression increases in both the epithelial and the stromal compartments. However, the precise mechanisms by which COX-2/PGs exert proneoplastic actions are largely unknown. Intestinal subepithelial myofibroblasts (ISEMF) are the major stromal cell type in both hyperplastic and neoplastic colonic polyps which express COX-2 and generate PGE2. In the present study, we show that PGE2 activated intestinal subepithelial myofibroblasts through Gs protein-coupled EP receptors and the cAMP/PKA pathway. Both primary colonic myofibroblast isolates and established myofibroblasts cell line (18Co) expressed a number of growth factors including pro-angiogenic factors of FGF, TGF-β, and VEGF families. Exposure to PGE2 rapidly induced the expression of VEGFA. Levels of VEGFA protein increased 4-fold in PGE2-activated 18Co conditioned media. VEGFA may stimulate neoangiogenesis by inducing endothelial cell proliferation, migration, and tubular organization. Effects of 18Co cells on the migration of endothelial cells were evaluated in a co-culture system, whereby human umbilical vascular endothelial cells (HUVEC) were seeded in the Transwell (8 μm) and 18Co cells were placed in the bottom chamber. The presence of 18Co cells in the bottom chamber significantly increased the motility of HUVEC. When co-cultured with PGE2-activated 18Co cells, HUVEC acquired a widely stretched morphology and the number of migrating cells was robustly increased, which, however, was significantly attenuated by the addition of anti-VEGFA neutralizing antibody. To determine the effects of 18Co cell-released growth factors on tubular organization, HUVEC cells were placed on growth factor-reduced Matrigel. HUVEC spontaneously formed tubular structures on extracellular matrix. Addition of PGE2 stimulated HUVEC tube formation by 8 h, as quantitated by the numbers and the length of tubes. The presence of conditioned media that were collected from PGE2-stimulated 18Co cells robustly increased the number and length of tubes of HUVEC. Moreover, HUVEC formed tubes were dissociated by 24 h. Addition of PGE2-treated 18Co conditioned media prevented HUVEC tube dissociation. Thus, our results suggest that myofibroblasts-generated growth factors are critical mediators for PGE2-induced pro-neoangiogenic environment, which plays critical roles in intestinal neoplasia.
Selenoprotein P Deficiency and Risk of Mortality and Rehospitalization in Acute Heart Failure
Authors: Amra Jujić, Olle Melander, Andreas Bergmann, Oliver Hartmann, Peter M. Nilsson, Erasmus Bachus, Joachim Struck, Martin Magnusson
Journal: Journal of the American College of Cardiology (2019)

Selenium is a nutrient with antioxidant effects and thus is protective against cardiovascular disease [(1)][1], as demonstrated by a meta-analysis revealing a significant inverse correlation between selenium levels and the incidence of atherosclerotic coronary heart disease (CHD) [(2)][2]. However,
Abstract 37: Effect of Fish Oil on Coagulation and Fibrinolysis: A Double-blind Randomized Trial in Obese Adolescents
Authors: Babu Balagopal, Rehana Lovely, Mustafa Khan, MD Jobayer Hossain, Samuel Gidding
Journal: Circulation (2016)

Background: A hypercoagulable state is reported in obese children and adolescents. Fish oil may reduce the propensity for thrombosis by favorably impacting coagulation and fibrinolysis. We hypothesized that pharmacologic fish oil supplementation would reduce the concentration of coagulation factors such as total-fibrinogen (T-Fib) and gamma prime fibrinogen (γ’-Fib) and fibrinolysis factors such as plasminogen activator inhibitor-1 (PAI-1) in obese dyslipidemic adolescents. Methods: Participants (n=42, age 14±2 years) with hypertriglyceridemia and low-density lipoprotein (LDL) cholesterol &lt;160 mg/dL were enrolled in a randomized, doubleblind, crossover trial comparing 4 g of fish oil daily with placebo. Treatment interval was 8 weeks with a 4-week washout. Glucose, insulin, high-sensitivity C-reactive protein (CRP), interleukin-6 (IL-6), T-Fib, γ’-Fib and PAI-1 were measured pre- and post-intervention or placebo. Results: PAI-1 significantly decreased (p = 0.03) with a trend towards a decrease in T-Fib in the fish oil group. Fish oil treatment group also showed significant decrease in γ’-Fib, but not in the placebo group; mean change (95% CI): -0.11 (-0.16, -0.06) vs -0.03 (-0.08, 0.02). The difference in the mean change in γ’-Fib concentration from baseline or washout measures between fish oil treatment and placebo was significant; reg coeff (SE):0.08 (0.03); p=0.02. The change in γ’-Fib was related to the change in log transformed PAI-1 (reg coeff (SE): -0.09 (.041); p=0.03). Further, log-transformed CRP and IL-6 (reg coeff (SE): 0.064 (.030), p=0.04) and 0.10 (.04); p=0.03 respectively) showed significant correlations with baseline or washout baseline γ’ fibrinogen, but there were no such relationships for mean changes. Conclusions: Fish oil-induced synchronized reduction of γ’-Fib, T-Fib and PAI-1 suggests attenuation of the obesity-related alterations in coagulation and fibrinolysis in adolescents. Intriguingly, these changes are independent of changes in other inflammatory factors. The reduction in elevated concentration of γ’-Fib is remarkable as it forms clots that are more fibrinolysis resistant. Further evaluation is warranted on the specific beneficial effect of fish oil on the obesity-related hypercoagulant-/hypofibrinolytic-state and the potential for thrombosis later in life.