tbuckley/cabot-search huggingface dataset:
FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic Cancer
Authors: Thierry Conroy, Françoise Desseigne, Marc Ychou, Olivier Bouché, Rosine Guimbaud, Yves Bécouarn, Antoine Adenis, Jean-Luc Raoul, Sophie Gourgou-Bourgade, Christelle de la Fouchardière, Jaafar Bennouna, Jean-Baptiste Bachet, Faiza Khemissa-Akouz, Denis Péré-Vergé, Catherine Delbaldo, Eric Assenat, Bruno Chauffert, Pierre Michel, Christine Montoto-Grillot, Michel Ducreux
Journal: New England Journal of Medicine (2011)

Data are lacking on the efficacy and safety of a combination chemotherapy regimen consisting of oxaliplatin, irinotecan, fluorouracil, and leucovorin (FOLFIRINOX) as compared with gemcitabine as first-line therapy in patients with metastatic pancreatic cancer.We randomly assigned 342 patients with an Eastern Cooperative Oncology Group performance status score of 0 or 1 (on a scale of 0 to 5, with higher scores indicating a greater severity of illness) to receive FOLFIRINOX (oxaliplatin, 85 mg per square meter of body-surface area; irinotecan, 180 mg per square meter; leucovorin, 400 mg per square meter; and fluorouracil, 400 mg per square meter given as a bolus followed by 2400 mg per square meter given as a 46-hour continuous infusion, every 2 weeks) or gemcitabine at a dose of 1000 mg per square meter weekly for 7 of 8 weeks and then weekly for 3 of 4 weeks. Six months of chemotherapy were recommended in both groups in patients who had a response. The primary end point was overall survival.The median overall survival was 11.1 months in the FOLFIRINOX group as compared with 6.8 months in the gemcitabine group (hazard ratio for death, 0.57; 95% confidence interval [CI], 0.45 to 0.73; P<0.001). Median progression-free survival was 6.4 months in the FOLFIRINOX group and 3.3 months in the gemcitabine group (hazard ratio for disease progression, 0.47; 95% CI, 0.37 to 0.59; P<0.001). The objective response rate was 31.6% in the FOLFIRINOX group versus 9.4% in the gemcitabine group (P<0.001). More adverse events were noted in the FOLFIRINOX group; 5.4% of patients in this group had febrile neutropenia. At 6 months, 31% of the patients in the FOLFIRINOX group had a definitive degradation of the quality of life versus 66% in the gemcitabine group (hazard ratio, 0.47; 95% CI, 0.30 to 0.70; P<0.001).As compared with gemcitabine, FOLFIRINOX was associated with a survival advantage and had increased toxicity. FOLFIRINOX is an option for the treatment of patients with metastatic pancreatic cancer and good performance status. (Funded by the French government and others; ClinicalTrials.gov number, NCT00112658.).
Quality Indicators for Colonoscopy and the Risk of Interval Cancer
Authors: Michal F. Kaminski, Jaroslaw Regula, Ewa Kraszewska, Marcin Polkowski, Urszula Wojciechowska, Joanna Didkowska, Maria Zwierko, Maciej Rupinski, Marek P. Nowacki, Eugeniusz Butruk
Journal: New England Journal of Medicine (2010)

Although rates of detection of adenomatous lesions (tumors or polyps) and cecal intubation are recommended for use as quality indicators for screening colonoscopy, these measurements have not been validated, and their importance remains uncertain.We used a multivariate Cox proportional-hazards regression model to evaluate the influence of quality indicators for colonoscopy on the risk of interval cancer. Data were collected from 186 endoscopists who were involved in a colonoscopy-based colorectal-cancer screening program involving 45,026 subjects. Interval cancer was defined as colorectal adenocarcinoma that was diagnosed between the time of screening colonoscopy and the scheduled time of surveillance colonoscopy. We derived data on quality indicators for colonoscopy from the screening program's database and data on interval cancers from cancer registries. The primary aim of the study was to assess the association between quality indicators for colonoscopy and the risk of interval cancer.A total of 42 interval colorectal cancers were identified during a period of 188,788 person-years. The endoscopist's rate of detection of adenomas was significantly associated with the risk of interval colorectal cancer (P=0.008), whereas the rate of cecal intubation was not significantly associated with this risk (P=0.50). The hazard ratios for adenoma detection rates of less than 11.0%, 11.0 to 14.9%, and 15.0 to 19.9%, as compared with a rate of 20.0% or higher, were 10.94 (95% confidence interval [CI], 1.37 to 87.01), 10.75 (95% CI, 1.36 to 85.06), and 12.50 (95% CI, 1.51 to 103.43), respectively (P=0.02 for all comparisons).The adenoma detection rate is an independent predictor of the risk of interval colorectal cancer after screening colonoscopy.
Durable Protection from Herpes Simplex Virus-2 Transmission Following Intravaginal Application of siRNAs Targeting Both a Viral and Host Gene
Authors: Yichao Wu, Francisco Navarro, Ashish Lal, Emre Basar, Rajendra K. Pandey, Muthiah Manoharan, Yang Feng, Sandra J. Lee, Judy Lieberman, Deborah Palliser
Journal: Cell Host & Microbe (2009)
Bronchial thermoplasty: Long-term safety and effectiveness in patients with severe persistent asthma
Authors: Michael E. Wechsler, Michel Laviolette, Adalberto S. Rubin, Jussara Fiterman, Jose R. Lapa e Silva, Pallav L. Shah, Elie Fiss, Ronald Olivenstein, Neil C. Thomson, Robert M. Niven, Ian D. Pavord, Michael Simoff, Jeff B. Hales, Charlene McEvoy, Dirk-Jan Slebos, Mark Holmes, Martin J. Phillips, Serpil C. Erzurum, Nicola A. Hanania, Kaharu Sumino, Monica Kraft, Gerard Cox, Daniel H. Sterman, Kyle Hogarth, Joel N. Kline, Adel H. Mansur, Brian E. Louie, William M. Leeds, Richard G. Barbers, John H.M. Austin, Narinder S. Shargill, John Quiring, Brian Armstrong, Mario Castro
Journal: Journal of Allergy and Clinical Immunology (2013)
Peripheral Artery Disease as a Manifestation of Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy (CADASIL) and Practical Implications
Authors: David F. Briceno, Meenakshi B. Bhattacharjee, Emilio Supsupin, Patricia Navarro, Modushudan Bhattacharjee
Journal: Circulation (2013)
Infection of Knee Joint by Mycobacterium kansasii
Authors: Melvin C. Godwin
Journal: JAMA (1965)

EXTRAPULMONARY infections caused by unclassified acid-fast mycobacteria of Runyon group I photochromogenic type without accompanying pulmonary disease have been rarely reported. It is generally accepted that two of the Runyon groups' of atypical mycobacteria are capable of producing progressive disease. One is group I, photochromogenic<i>Mycobacterium kansasii</i>. This group is characterized by colonial pigmentation following purposeful exposure of the culture to light. These microorganisms often possess a natural resistance to the major antituberculous drugs in low concentration. Experience with in vitro drugsensitivity testing has taught the need for initially higher doses of drugs, particularly isoniazid (INH). It is with this well-defined group of mycobacteria that the present case is identified. Group III, nonchromogenic Battey strain of atypical mycobacteria, produces indolent disease that is difficult, if at all possible, to reproduce in laboratory animals. It possesses natural resistance to low concentrations of antituberculous drugs. It is easily differentiated from<i>M tuberculosis</i>
Phase I Study of the Safety, Tolerability, and Pharmacokinetics of Oral CP-868,596, a Highly Specific Platelet-Derived Growth Factor Receptor Tyrosine Kinase Inhibitor in Patients With Advanced Cancers
Authors: Nancy L. Lewis, Lionel D. Lewis, Joseph P. Eder, Nandi J. Reddy, Feng Guo, Kristen J. Pierce, Anthony J. Olszanski, Roger B. Cohen
Journal: Journal of Clinical Oncology (2009)

This phase I, first-in-human study evaluated the safety, tolerability, pharmacokinetics, and maximum-tolerated dose (MTD) of an oral platelet-derived growth factor receptor inhibitor, CP-868,596.Patients with advanced solid tumors were eligible. Dose escalations were performed in three groups with two formulations: uncoated on an empty stomach (UES), uncoated with food (UFED), and film-coated (FC) without food. Initial dose escalation in the UES group was followed by parallel escalations in the UFED and FC groups.Fifty-nine patients enrolled. CP-868,596 was escalated from 100 mg to 340 mg daily in the UES group, from 60 mg to 100 mg twice daily in the UFED group, and from 100 mg once daily to 140 mg twice daily in the FC group. MTDs were 200 mg daily in the UES group and 100 mg twice daily in the FC group; MTD was not reached at 100 mg twice daily in the UFED group. Dose-limiting toxicities included hematuria, increased gamma-glutamyltransferase or ALT, insomnia, and nausea/vomiting. Most treatment-related AEs were of grades 1 to 2 severity; nausea, vomiting, and diarrhea were reported most frequently. Administration with food generally improved tolerability. CP-868,596 was absorbed slowly; systemic exposure parameters appeared to increase greater than proportionally with dose. Mean serum concentrations exceeded the preclinically predicted minimal efficacious concentration (ie, 16 ng/mL) at all dosages. Food and film coating apparently increased interpatient variability of the maximum observed plasma concentration and the area under the concentration-time curve. No objective responses were reported, and eight patients achieved stable disease (mean duration, 5.7 months).CP-868,596 potentially demonstrated greater than dose-proportional pharmacokinetics. The recommended dosage of 100 mg twice daily with food was well tolerated. Additional development as a single agent in selected populations or in combination with chemotherapy in broader populations is warranted.
PTEN and the PI3-Kinase Pathway in Cancer
Authors: Nader Chalhoub, Suzanne J. Baker
Journal: Annual Review of Pathology Mechanisms of Disease (2008)

PI3-kinase and PTEN are major positive and negative regulators, respectively, of the PI3-kinase pathway, which regulates growth, survival, and proliferation. These key signaling components are two of the most frequently mutated proteins in human cancers, resulting in unregulated activation of PI3K signaling and providing irrefutable genetic evidence of the central role of this pathway in tumorigenesis. PTEN regulates PI3K signaling by dephosphorylating the lipid signaling intermediate PIP 3 , but PTEN may have additional phosphatase-independent activities, as well as other functions in the nucleus. In this review, we highlight current work showing cancer-relevant complexities in the regulation of PTEN and PI3K activity, potential novel functions for PTEN, and feedback regulation within the pathway. The significance and complexity of PI3K signaling make it an important but challenging therapeutic target for cancer.
Clinical implications of postsurgical adhesions
Authors: M. P. Diamond
Journal: Human Reproduction Update (2001)

Adhesion development can have a major impact on a patient’s subsequent health. Adhesions are a significant source of impaired organ functioning, decreased fertility, bowel obstruction, difficult re-operation, and possibly pain. Consequently, their financial sequelae are also extraordinary, with more than one billion dollars spent in the USA in 1994 on the bowel obstruction component alone. Performing adhesiolysis for pain relief appears efficacious in certain subsets of women. Unfortunately even when lysed, adhesions have a great propensity to reform. Adhesions are prevalent in all surgical fields, and nearly any compartment of the body. For treatment of infertility and recurrent pregnancy loss, lysis of intrauterine adhesions results in improved fecundability and decreased pregnancy loss.
<i>In vitro</i>and<i>in vivo</i>contractile properties of the vastus lateralis muscle in males with COPD
Authors: R. Debigaré, C.H. Côté, F-S. Hould, P. LeBlanc, F. Maltais
Journal: European Respiratory Journal (2003)

Peripheral muscle weakness is common in chronic obstructive pulmonary disease (COPD) but it is still under debate whether weakness is due to atrophy or contractile dysfunction. <i>In vitro</i> and <i>in vivo</i> contractile properties of the vastus lateralis muscle were studied in 16 patients with stable COPD (forced expiratory volume in one second 39±16% of predicted, age 67±4 yrs (mean±sd)) and nine sedentary control subjects. Isometric knee extensor strength was measured while mid-thigh muscle cross-sectional area (MTMCSA) was obtained using computed tomography. Muscle strips from the vastus lateralis obtained through open biopsy were rapidly suspended in an oxygenated Krebs-Ringer solution that was maintained at 35°C with a pH of 7.40 to study their contractile properties. The isometric knee extensors strength/MTMCSA ratio was 0.50±0.08 <i>versus</i> 0.58±0.06 kg·cm<sup>−2</sup> for COPD and control subjects, respectively. The muscle bundle cross-sectional area (CSA) was 4.6±2.1 and 4.4±3.1 mm<sup>−2</sup>, the length at which active tension was maximum was 15±4 and 15±3 mm, and maximal isometric peak forces normalised for CSA were 4.3±2.7 and 4.8±2.6 N·cm<sup>−2</sup> for COPD and control subjects, respectively. The force/frequency relationship tended to be shifted to the right in patients with COPD, meaning that a higher stimulation frequency was necessary to produce the same relative force. Patients with COPD had a lower proportion of type I fibre than controls (26±12% <i>versus</i> 39±11%) with reciprocal significant increase in type IIb fibre proportion (20±16% <i>versus</i> 8±4%). The proportion of type IIa fibres was similar between the two groups. These results suggest that the contractile properties of the vastus lateralis are preserved in patients with chronic obstructive pulmonary disease. Therefore, the reduction in the quadriceps strength in patients with chronic obstructive pulmonary disease cannot be explained on the basis of an alteration of the contractile apparatus.
Liver enzymes in OSA patients at diagnosis: The Mallorca cohort
Authors: Claudia Gruttad'Auria, Emilia Mazzuca, Anna M. Marotta, Alessandra Castrogiovanni, Pierpaolo Baiamonte, Geraldine Lo Grasso, Cristina Esquinas, Antonia Barcelo, Ferran Barbé, Maria R. Bonsignore
Journal: European Respiratory Journal (2014)

Obstructive sleep apnea (OSA) could be associated with liver injury. The prevalence of increased liver enzymes (ALT/AST>40 IU/L) in OSA patients is undefined. We measured serum ALT and AST in a large series of consecutive patients (n=525) studied by polysomnography in the Sleep Laboratory of the University Hospital, Palma de Mallorca, Spain. Anthropometrics, OSA severity, insulin resistance (HOMA Index, n=320), and Metabolic Index (MetIndex, NCEP-ATP III criteria) were analyzed and correlated with ALT by univariate and stepwise forward multiple regression. Significance was at p<0.05. Increased ALT was found in 96 patients (18.3% of the sample). Increased AST was found in only 23 patients (4.4%). Patients with increased ALT were younger (47.2±10.1 [SD] vs 52.1±13.1 yr, p<0.001), more obese (BMI, 32.9±5.9 vs 30.5±6.3 kg/sqm, p=0.001), sleepier (Epworth 11.2±4.9 vs 9.4±5.1, p=0.002), more insulin resistant (HOMA Index 4.88±3.00 vs 3.53±2.93, p=0.002), and had more severe OSA (AHI 52.0±30.2 vs 41.2±26.3, p=0.0002; lowest SaO2 78.5±9.7 vs 81.3±9.0, p=0.008) than patients with normal ALT values. The MetIndex was higher in patients with increased ALT (2.82±1.25 vs 2.15±1.35, p<0.0001). Weak univariate relationships were found between ALT values and age, neck circumference, waist, waist-to-hip ratio, BMI, AHI, lowest SaO2,HOMA ln, and MetIndex, explaining each 2.5 to 9% of ALT variability. Multiple regression identified age, neck circumference and MetIndex as the only independent variables associated with ALT (R=0.39, p<0.0001, explaining 16% of variability). The data suggest that increased ALT levels in non-morbidly obese OSA patients are associated with markers of visceral obesity rather than OSA severity.
A Mitochondria-K+ Channel Axis Is Suppressed in Cancer and Its Normalization Promotes Apoptosis and Inhibits Cancer Growth
Authors: Sébastien Bonnet, Stephen L. Archer, Joan Allalunis-Turner, Alois Haromy, Christian Beaulieu, Richard Thompson, Christopher T. Lee, Gary D. Lopaschuk, Lakshmi Puttagunta, Sandra Bonnet, Gwyneth Harry, Kyoko Hashimoto, Christopher J. Porter, Miguel A. Andrade, Bernard Thebaud, Evangelos D. Michelakis
Journal: Cancer Cell (2007)
Multicenter, Phase II Study of Axitinib, a Selective Second-Generation Inhibitor of Vascular Endothelial Growth Factor Receptors 1, 2, and 3, in Patients with Metastatic Melanoma
Authors: John Fruehauf, Jose Lutzky, David McDermott, Charles K. Brown, Jean-Baptiste Meric, Brad Rosbrook, David R. Shalinsky, Katherine F. Liau, Andreas G. Niethammer, Sinil Kim, Olivier Rixe
Journal: Clinical Cancer Research (2011)

This multicenter, open-label, phase II study evaluated the safety and clinical activity of axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, 2, and 3, in patients with metastatic melanoma.Thirty-two patients with a maximum of one prior systemic therapy received axitinib at a starting dose of 5 mg twice daily. The primary endpoint was objective response rate.Objective response rate was 18.8% [95% confidence interval (CI), 7.2-36.4], comprising one complete and five partial responses with a median response duration of 5.9 months (95% CI, 5.0-17.0). Stable disease at 16 weeks was noted in six patients (18.8%), with an overall clinical benefit rate of 37.5%. Six-month progression-free survival rate was 33.9%, 1-year overall survival rate was 28.1%, and median overall survival was 6.6 months (95% CI, 5.2-9.0). The most frequently (>15%) reported nonhematologic, treatment-related adverse events were fatigue, hypertension, hoarseness, and diarrhea. Treatment-related fatal bowel perforation, a known class effect, occurred in one patient. Axitinib selectively decreased plasma concentrations of soluble VEGFR (sVEGFR)-2 and sVEGFR-3 compared with soluble stem cell factor receptor (sKIT). No significant association was noted between plasma levels of axitinib and response. However, post hoc analyses indicated potential relationships between efficacy endpoints and diastolic blood pressure of 90 mm Hg or higher as well as baseline serum lactate dehydrogenase levels.Axitinib was well tolerated, showed a selective VEGFR-inhibitory profile, and showed single-agent activity in metastatic melanoma. Further evaluations of axitinib, alone and combined with chemotherapy, are ongoing.
Overexpression of far upstream element (FUSE) binding protein (FBP)-interacting repressor (FIR) supports growth of hepatocellular carcinoma
Authors: Mona Malz, Michael Bovet, Jana Samarin, Uta Rabenhorst, Carsten Sticht, Michaela Bissinger, Stephanie Roessler, Justo Lorenzo Bermejo, Marcus Renner, Diego Francesco Calvisi, Stephan Singer, Matthias Ganzinger, Achim Weber, Norbert Gretz, Martin Zörnig, Peter Schirmacher, Kai Breuhahn
Journal: Hepatology (2014)

The far upstream element binding protein (FBP) and the FBP-interacting repressor (FIR) represent molecular tools for transcriptional fine tuning of target genes. Strong overexpression of FBP in human hepatocellular carcinoma (HCC) supports tumor growth and correlates with poor patient prognosis. However, the role of the transcriptional repressor FIR in hepatocarcinogenesis remains poorly delineated. We show that overexpression of FIR correlates with tumor dedifferentiation and tumor cell proliferation in about 60% of primary HCCs. Elevated FIR levels are associated with genomic gains of the FIR gene locus at chromosome 8q24.3 in human HCC specimens. In vitro , nuclear enrichment of FIR supports HCC cell proliferation and migration. Expression profiling of HCC cells after small interfering RNA (siRNA)-mediated silencing of FIR identified the transcription factor DP-1 (TFDP1) as a transcriptional target of FIR. Surprisingly, FIR stimulates the expression of FBP in a TFDP1/E2F1-dependent manner. FIR splice variants lacking or containing exon 2 and/or exon 5 are expressed in the majority of HCCs but not in normal hepatocytes. Specific inhibition of FIR isoforms with and without exon 2 revealed that both groups of FIR splice variants facilitate tumor-supporting effects. This finding was confirmed in xenograft transplantation experiments with lentiviral-infected short hairpin RNA (shRNA) targeting all FIR variants as well as FIR with and without exon 2. Conclusion : High-level nuclear FIR does not facilitate repressor properties but supports tumor growth in HCC cells. Thus, the pharmacological inhibition of FIR might represent a promising therapeutic strategy for HCC patients with elevated FIR expression. (Hepatology 2014;60:1241–1250)
Measurement of the Cardiac Output in Dogs by a Conductivity Method after Single Intravenous Injections of Autogenous Plasma
Authors: RICHARD S. GOODWIN, LEO A. SAPIRSTEIN
Journal: Circulation Research (1957)

Equations are developed for the estimation of cardiac output from hematocrit dilution, using the continuously recorded conductivity of whole blood drawn from an artery through a conductivity cell, after a single intravenous injection of autogenous plasma. The equipment used is described, the results are compared with those of simultaneously performed measurements of dye dilution and the advantages of the method are discussed.
Neoadjuvant and adjuvant trastuzumab in patients with HER2-positive locally advanced breast cancer (NOAH): follow-up of a randomised controlled superiority trial with a parallel HER2-negative cohort
Authors: Luca Gianni, Wolfgang Eiermann, Vladimir Semiglazov, Ana Lluch, Sergei Tjulandin, Milvia Zambetti, Angela Moliterni, Federico Vazquez, Mikhail J Byakhov, Mikhail Lichinitser, Miguel Angel Climent, Eva Ciruelos, Belen Ojeda, Mauro Mansutti, Alla Bozhok, Domenico Magazzù, Dominik Heinzmann, Jutta Steinseifer, Pinuccia Valagussa, Jose Baselga
Journal: The Lancet Oncology (2014)
Low-Dose Methotrexate Enhances Aminolevulinate-Based Photodynamic Therapy in Skin Carcinoma Cells <i>In vitro</i> and <i>In vivo</i>
Authors: Sanjay Anand, Golara Honari, Tayyaba Hasan, Paul Elson, Edward V. Maytin
Journal: Clinical Cancer Research (2009)

Abstract Purpose: To improve treatment efficacy and tumor cell selectivity of δ-aminolevulinic acid (ALA)-based photodynamic therapy (PDT) via pretreatment of cells and tumors with methotrexate to enhance intracellular photosensitizer levels. Experimental Design: Skin carcinoma cells, in vitro and in vivo, served as the model system. Cultured human SCC13 and HEK1 cells, normal keratinocytes, and in vivo skin tumor models were preconditioned with methotrexate for 72 h and then incubated with ALA for 4 h. Changes in protoporphyrin IX (PpIX) levels and cell survival after light exposure were assessed. Results: Methotrexate preconditioning of monolayer cultures preferentially increased intracellular PpIX levels 2- to 4-fold in carcinoma cells versus normal keratinocytes. Photodynamic killing was synergistically enhanced by the combined therapy compared with PDT alone. Methotrexate enhancement of PpIX levels was achieved over a broad methotrexate concentration range (0.0003-1.0 mg/L; 0.6 nmol/L-2 mmol/L). PpIX enhancement correlated with changes in protein expression of key porphyrin pathway enzymes, ∼4-fold increase in coproporphyrinogen oxidase and stable or slightly decreased expression of ferrochelatase. Differentiation markers (E-cadherin, involucrin, and filaggrin) were also selectively induced by methotrexate in carcinoma cells. In vivo relevance was established by showing that methotrexate preconditioning enhances PpIX accumulation in three models: (a) organotypic cultures of immortalized keratinocytes, (b) chemically induced skin tumors in mice; and (c) human A431 squamous cell tumors implanted subcutaneously in mice. Conclusion: Combination therapy using short-term exposure to low-dose methotrexate followed by ALA-PDT should be further investigated as a new combination modality to enhance efficacy and selectivity of PDT for epithelial carcinomas.