tbuckley/cabot-search huggingface dataset:
Phase I trial of retinol in cancer patients.
Authors: G E Goodman, D S Alberts, D L Earnst, F L Meyskens
Journal: Journal of Clinical Oncology (1983)

Vitamin A (all-trans-retinol) and its analogues are undergoing evaluation as antineoplastic and chemoprevention agents. Because its toxicity and activity are poorly defined, we have completed a phase I trial of retinol. Retinol was administered to 13 cancer patients in daily doses ranging from 100,000 units/m2 to 350,000 units/m2. Neuropsychiatric changes were the earliest dose-limiting symptomatic toxicities, noted in 3 of 5 patients receiving more than 240,000 U/m2 for 3-4 months. Two patients receiving more than 270,000 U/m2 developed hepatomegaly after 3 and 4 months. Liver biopsies were consistent with vitamin A toxicity. Three patients receiving 200,000 U/m2 developed an increase in serum triglycerides concentration. Mild skin and mucous membrane dryness occurred in most patients receiving more than 150,000 U/m2. A mixed response was seen in one patient with melanoma. Because of neuropsychiatric and hepatic toxicity a retinol dose of 200,000 U/m2/day is recommended for future phase II trials.
Statins inhibit cyclooxygenase-2 and matrix metalloproteinase-9 in human endothelial cells: anti-angiogenic actions possibly contributing to plaque stability
Authors: Marika Massaro, Antonella Zampolli, Egeria Scoditti, Maria Annunziata Carluccio, Carlo Storelli, Alessandro Distante, Raffaele De Caterina
Journal: Cardiovascular Research (2009)

Cyclooxygenase (COX)-2 expression is increased in inflammation and angiogenesis and also in atherosclerotic plaques, where it co-localizes with metalloproteinases (MMPs) involved in the fibrous cap weakening. Insight into the regulation of COX-2 and MMP-9 expression suggests the involvement of a Rho-dependent pathway. Because statins interfere with Rho activation, we investigated the statin effect on COX-2 and MMP expressions in the human endothelium. Simvastatin and atorvastatin were incubated with endothelial cells for 12 h before stimulation with phorbol myristate acetate or tumour necrosis factor-α, for times suitable to assess the endothelial tube differentiation on Matrigel and COX-2 and MMPs activities, proteins, and mRNA expressions. At 0.1–10 µmol/L, both statins reduced COX-2 expression and activity, without affecting COX-1. The statin effect was reversed by mevalonate and geranylgeranyl-pyrophosphate and mimicked by the Rho inhibitor C3 transferase, indicating the involvement of Rho in the signal transduction pathway leading to COX-2 expression. In parallel, statins, as well as COX-2 inhibitors, reduced the MMP-9 stimulated release and the endothelial tubular differentiation. In the human vascular endothelium, statins reduce COX-2 and MMP-9 expression and activity. Through this mechanism, statins exert an anti-angiogenic effect possibly contributing to the cholesterol-lowering-unrelated protective effects of statins against plaque inflammatory angiogenesis and rupture.
Kidney Dendritic Cells Become Pathogenic during Crescentic Glomerulonephritis with Proteinuria
Authors: Katharina Hochheiser, Daniel R. Engel, Linda Hammerich, Felix Heymann, Percy A. Knolle, Ulf Panzer, Christian Kurts
Journal: Journal of the American Society of Nephrology (2010)

It is unclear why kidney dendritic cells attenuate some models of kidney disease but aggravate others. Kidney dendritic cells ameliorate the early phase of nonaccelerated nephrotoxic nephritis, a murine model of crescentic glomerulonephritis, but their effect on the later phase is unknown. Here, we report that kidney dendritic cells at later stages of nephrotoxic nephritis expressed higher levels of costimulatory molecules but lower levels of the cosuppressor molecule ICOS-L and started production of IL-12/23p40 and TNF-α. Furthermore, we noted that kidney dendritic cells captured more filterable antigen in proteinuric mice at late time points of nephrotoxic nephritis and started to capture molecules that were too large for filtration by a healthy kidney. They presented filtered antigen to Th cells, which responded by producing the proinflammatory cytokines IL-2, IFN-γ, TNF-α, IL-6, and IL-17. Notably, production of the suppressive cytokine IL-10 further increased in late nephrotoxic nephritis. Depletion of kidney dendritic cells at a late stage attenuated nephrotoxic nephritis, in contrast to the exacerbation observed with depletion at an early stage, indicating that their acquired proinflammatory phenotype adversely affected disease. These findings indicate that the intrarenal inflammatory microenvironment determines how kidney dendritic cells affect nephritis. In addition, proteinuria may harm the kidney by providing dendritic cells with more antigens to stimulate potentially pathogenic Th cells.
Musings on genome medicine: the value of family history
Authors: Angus Clarke
Journal: Genome Medicine (2009)

Will the routine availability of genome sequence information on individuals render family history information obsolete? I argue that it will not, both because the taking of a family history has other uses for the health professional, and because genome sequence data on their own omit the effects of numerous factors important for modifying risks of disease. These include information derived from factors downstream of genetic variants and from upstream epigenetic effects. Further difficulties arise with uncertainties relating to gene-gene and gene-environment interactions, which may take decades to resolve if their resolution is even possible.
Rociletinib in <i>EGFR</i>-Mutated Non–Small-Cell Lung Cancer
Authors: Lecia V. Sequist, Jean-Charles Soria, Jonathan W. Goldman, Heather A. Wakelee, Shirish M. Gadgeel, Andrea Varga, Vassiliki Papadimitrakopoulou, Benjamin J. Solomon, Geoffrey R. Oxnard, Rafal Dziadziuszko, Dara L. Aisner, Robert C. Doebele, Cathy Galasso, Edward B. Garon, Rebecca S. Heist, Jennifer Logan, Joel W. Neal, Melody A. Mendenhall, Suzanne Nichols, Zofia Piotrowska, Antoinette J. Wozniak, Mitch Raponi, Chris A. Karlovich, Sarah Jaw-Tsai, Jeffrey Isaacson, Darrin Despain, Shannon L. Matheny, Lindsey Rolfe, Andrew R. Allen, D. Ross Camidge
Journal: New England Journal of Medicine (2015)

Non-small-cell lung cancer (NSCLC) with a mutation in the gene encoding epidermal growth factor receptor (EGFR) is sensitive to approved EGFR inhibitors, but resistance develops, mediated by the T790M EGFR mutation in most cases. Rociletinib (CO-1686) is an EGFR inhibitor active in preclinical models of EGFR-mutated NSCLC with or without T790M.In this phase 1-2 study, we administered rociletinib to patients with EGFR-mutated NSCLC who had disease progression during previous treatment with an existing EGFR inhibitor. In the expansion (phase 2) part of the study, patients with T790M-positive disease received rociletinib at a dose of 500 mg twice daily, 625 mg twice daily, or 750 mg twice daily. Key objectives were assessment of safety, side-effect profile, pharmacokinetics, and preliminary antitumor activity of rociletinib. Tumor biopsies to identify T790M were performed during screening. Treatment was administered in continuous 21-day cycles.A total of 130 patients were enrolled. The first 57 patients to be enrolled received the free-base form of rociletinib (150 mg once daily to 900 mg twice daily). The remaining patients received the hydrogen bromide salt (HBr) form (500 mg twice daily to 1000 mg twice daily). A maximum tolerated dose (the highest dose associated with a rate of dose-limiting toxic effects of less than 33%) was not identified. The only common dose-limiting adverse event was hyperglycemia. In an efficacy analysis that included patients who received free-base rociletinib at a dose of 900 mg twice daily or the HBr form at any dose, the objective response rate among the 46 patients with T790M-positive disease who could be evaluated was 59% (95% confidence interval [CI], 45 to 73), and the rate among the 17 patients with T790M-negative disease who could be evaluated was 29% (95% CI, 8 to 51).Rociletinib was active in patients with EGFR-mutated NSCLC associated with the T790M resistance mutation. (Funded by Clovis Oncology; ClinicalTrials.gov number, NCT01526928.).
Long-term Outcomes in Survivors of Neuroblastoma: A Report From the Childhood Cancer Survivor Study
Authors: Caroline Laverdière, Qi Liu, Yutaka Yasui, Paul C. Nathan, James G. Gurney, Marilyn Stovall, Lisa R. Diller, Nai-Kong Cheung, Suzanne Wolden, Leslie L. Robison, Charles A. Sklar
Journal: JNCI Journal of the National Cancer Institute (2009)

The 5-year survival rate for individuals with neuroblastoma is approaching 70%. Few data exist, however, on the long-term outcomes of these patients, who are often treated at a very young age.Outcome data were obtained for 954 5-year neuroblastoma survivors who were diagnosed in 1970-1986 and enrolled in the Childhood Cancer Survivor Study (CCSS). Late mortality, second malignant neoplasms, and chronic health conditions were analyzed in relation to treatment factors using Poisson regression models and their modification with generalized estimating equations. Neuroblastoma survivors were compared with a cohort of 3899 siblings of CCSS participants for risk of chronic health conditions and selected sociodemographic outcomes. All statistical tests were two-sided.Six percent of patients died more than 5 years after their diagnosis (standardized mortality ratio = 5.6; 95% confidence interval [CI] = 4.4 to 6.9). The most common causes of death were disease recurrence (n = 43) and second malignant neoplasms (n = 13). The cumulative incidence of second malignant neoplasms was 3.5% at 25 years and 7.0% at 30 years after diagnosis. Compared with the sibling cohort, survivors had an increased risk of selected chronic health conditions (risk ratio [RR] = 8.3; 95% CI = 7.1 to 9.7) with a 20-year cumulative incidence of 41.1%. The most prevalent outcomes involved the neurological, sensory, endocrine, and musculoskeletal systems, with 20-year cumulative incidences of 29.8%, 8.6%, 8.3%, and 7.8%, respectively. Neuroblastoma survivors who were treated with multimodality therapy were more likely to develop a chronic health condition than survivors treated with surgery alone (RR = 2.2; 95% CI = 1.6 to 3.0). Neuroblastoma survivors were less likely than siblings to have ever been employed (P = .04) or to be married (P < .001) and had a lower personal income (P = .009).Neuroblastoma survivors have an increased rate of mortality and second malignant neoplasms, relative to the age- and sex-comparable US population, and of chronic health conditions, relative to their siblings, which underscores the need for long-term medical surveillance.
Prognostic Role of Brain Natriuretic Peptide in Acute Pulmonary Embolism
Authors: Nils Kucher, Gert Printzen, Samuel Z. Goldhaber
Journal: Circulation (2003)

Background— Rapid, noninvasive, and accurate prognostic assessment with an inexpensive cardiac biomarker is an appealing approach for patients with acute pulmonary embolism (PE). Methods and Results— We measured at the time of admission the plasma level of plasma brain natriuretic peptide (BNP) to determine its utility in prognosticating the clinical course of 73 consecutive patients with acute PE. We used a prespecified BNP cut-off level (&lt;90 pg/mL) for the prediction of the absence of a major adverse cardiovascular event, defined as any of the following: death, cardiopulmonary resuscitation, mechanical ventilation, or use of pressors, thrombolysis, catheter fragmentation, or surgical embolectomy. In the 20 (27%) patients with adverse events, median BNP (194.2, range 3.7 to 1201.1 pg/mL) was higher than in patients with a benign course (39.1, range 1.0 to 1560.0 pg/mL; P &lt;0.001). However, 3 patients with adverse outcomes had low BNP levels on admission: 1 death, BNP 52 pg/mL; 1 patient with prolonged cardiopulmonary resuscitation, BNP 3.7 pg/mL; and 1 patient undergoing rescue thrombolysis, BNP 75 pg/mL. Sensitivity, specificity, and negative and positive predictive value of BNP levels &lt;90 pg/mL for absence of adverse outcomes were 85% (64% to 95%), 75% (62% to 85%), 93% (95% CI 81% to 98%), and 57% (39% to 73%), respectively. The optimal BNP cut-off level, identified by receiver operating characteristic analysis, was &lt;50 pg/mL. Conclusions— Low BNP levels do not guarantee an uncomplicated hospital course in patients with acute PE, using a “congestive heart failure” cut-off level of 90 pg/mL. A lower cut-off level of &lt;50 pg/mL identifies 95% of patients with a benign clinical course.
LEFT ATRIAL FUNCTION ASSESSED BY VELOCITY VECTOR IMAGING IS A NOVEL AND USEFUL MARKER TO PREDICT THE RISK FOR THE DEVELOPMENT OF ATRIAL FIBRILLATION
Authors: Takeshi Hirose, Ryuhei Tanaka, Michio Arakawa, Koji Ono, Ritsuko Tanaka, Tomomi Endo, Humitaka Tokoro, Reiko Matsuoka, Shintaro Abe, Yoshiyuki Goto, Tomoko Hirose, Takashi kato, Tai Kojima, Makoto Iwama, Shunichiro Warita, Toshiyuki Noda, Sachiro Watanabe, Takatomo Watanabe, Masanori Kawasaki, Sinya Minatoguchi
Journal: Journal of the American College of Cardiology (2010)
Combination therapy targeting integrins reduces glioblastoma tumor growth through antiangiogenic and direct antitumor activity and leads to activation of the pro-proliferative prolactin pathway
Authors: Leticia Oliveira-Ferrer, Jasmin Wellbrock, Udo Bartsch, Eva Maria Murga Penas, Jessica Hauschild, Marianne Klokow, Carsten Bokemeyer, Walter Fiedler, Gunter Schuch
Journal: Molecular Cancer (2013)

Tumors may develop resistance to specific angiogenic inhibitors via activation of alternative pathways. Therefore, multiple angiogenic pathways should be targeted to achieve significant angiogenic blockade. In this study we investigated the effects of a combined application of the angiogenic inhibitors endostatin and tumstatin in a model of human glioblastoma multiforme. Inhibitors released by stably transfected porcine aortic endothelial cells (PAE) showed anti-angiogenic activity in proliferation and wound-healing assays with endothelial cells (EC). Interestingly, combination of endostatin and tumstatin (ES + Tum) also reduced proliferation of glioma cells and additionally induced morphological changes and apoptosis in vitro. Microencapsulated PAE-cells producing these inhibitors were applied for local therapy in a subcutaneous glioblastoma model. When endostatin or tumstatin were applied separately, in vivo tumor growth was inhibited by 58% and 50%, respectively. Combined application of ES + Tum, in comparison, resulted in a significantly more pronounced inhibition of tumor growth (83%). cDNA microarrays of tumors treated with ES + Tum revealed an up-regulation of prolactin receptor (PRLR). ES + Tum-induced up-regulation of PRLR in glioma cells was also found in in vitro. Moreover, exogenous PRLR overexpression in vitro led to up-regulation of its ligand prolactin and increased proliferation suggesting a functional autocrine growth loop in these cells. Our data indicate that integrin-targeting factors endostatin and tumstatin act additively by inhibiting glioblastoma growth via reduction of vessel density but also directly by affecting proliferation and viability of tumor cells. Treatment with the ES + Tum-combination activates the PRLR pro-proliferative pathway in glioblastoma. Future work will show whether the prolactin signaling pathway represents an additional target to improve therapeutic strategies in this entity.
Development, Evaluation, and Multinational Dissemination of the Triple P-Positive Parenting Program
Authors: Matthew R. Sanders
Journal: Annual Review of Clinical Psychology (2012)

The quality of parenting children receive has a major influence on their development, well-being, and life opportunities. Of all the potentially modifiable influences that can be targeted through preventive interventions, none are more important than the quality of parenting children experience. Prevention interventions targeting parenting should be widely used to promote positive developmental outcomes for children and adolescents. This review argues that the development of comprehensive evidence-based strategies to improve the quality of parenting is best viewed as a major public health challenge. Using the Triple P-Positive Parenting Program as an exemplar, the initial development, gradual transformation into a public health model, and then global dissemination of the approach is described. The assumptions underpinning the public health approach to parenting support are discussed, along with key criteria that need to be met for the approach to work. Factors that facilitate and impede the global implementation and dissemination of evidence-based parenting programs are considered along with implications for future research, policy, and practice.
Non-host cells in the pathogenesis of autoimmune disease: a new paradigm?
Authors: J L. NELSON
Journal: Annals of the Rheumatic Diseases (1999)

Autoimmune diseases are thought of as disorders in which a body’s cells inexplicably attack its own tissues. Usually there is little evidence that anything is abnormal in the body tissues before the immunological attack begins. Drawing together observations from unrelated fields of medicine and science, microchimerism has been proposed as a new consideration in the pathogenesis of some autoimmune disorders.1 The term chimerism is used to indicate a body that contains cell populations derived from different individuals and microchimerism refers to low levels of non-host cells. The observations draw from pregnancy immunology, transplantation biology, prenatal diagnostics, and autoimmunity. The key observation that led to the proposal came from investigators working to establish sensitive techniques for prenatal diagnosis. As a result of the application of molecular techniques to prenatal diagnosis it is now known that fetal cells enter the mother’s blood early in the course of most pregnancies. In 1996 a report by Dr Diana Bianchi and colleagues cast a potentially new stage for the well recognised female predominance of autoimmunity disease. The investigators found that fetal cells also persist in the maternal circulation for decades after pregnancy completion.2 Long term persistence of fetal cells, when considered together with epidemiological observations of autoimmune disease in women and with observations in transplantation biology led me to propose the hypothesis that non-host cells are involved in the pathogenesis of some autoimmune diseases. The hypothesis was proposed in the question “Is some autoimmune disease auto-alloimmune or allo-autoimmune?”1 The term “allo” refers to non-host cells from an individual of the same species.

In addition to a strong female predominance of autoimmune disease the age specific incidence, for example of scleroderma (SSc) and primary biliary cirrhosis (PBC) in women peaks in middle age—that is after childbearing years.3 4 Interestingly, both of these …
Malignant Transformation of a Serous Borderline Tumor and Early Metastasis of Associated Low-Grade Serous Carcinoma Detected on Screening Mammography
Authors: Donata Rohsbach, Fabian Trillsch, Marc Regier, Matthias Choschzick, Friedrich Kommoss, Markus Hermsteiner, Thilo Töllner, Ute Marie Mattner, Fritz Jaenicke, Sven Mahner
Journal: Journal of Clinical Oncology (2011)
Is endoscopic ultrasound clinically useful for follow-up of gastric lymphoma?
Authors: F. Di Raimondo, L. Caruso, G. Bonanno, P. Naso, A. Chiarenza, P. Fiumara, A. Bari, G.A. Palumbo, A. Russo, R. Giustolisi
Journal: Annals of Oncology (2006)
Human Apolipoprotein A-IV
Authors: Peter H. R. Green, Robert M. Glickman, John W. Riley, Elaine Quinet
Journal: Journal of Clinical Investigation (1980)

The role of the human intestine has been explored as a site of synthesis of apoA-IV, a major apoprotein of human intestinal triglyceride-rich lipoproteins. Intestinal biopsies were performed on normal volunteers while fasting and after lipid ingestion. Indirect immunofluorescence demonstrated a marked increase in immunofluorescence for apoA-IV during lipid absorption consistent with an increased intracellular content. ApoA-IV comprised 10-13% of chylomicron apoprotein and 24-30% of intestinal very low density lipoprotein (VLDL) as assessed by densitometry of sodium dodecyl sulfate gels of lipoproteins from chylous urine (mesenteric lymphatic-urinary fistula) and thoracic duct lymph (postoperative fistula). After one subject with chyluria ingested 40 g of corn oil, triglyceride excretion in urine was accompanied by an increased excretion of apoA-IV. 11.5 g of triglyceride and 81 mg of apoA-IV were recovered in the urine. In chylous urine 56% of apoA-IV was in the triglyceride-rich lipoproteins (chylomicrons and intestinal VLDL) and 44% in the d > 1.006-g/ml fraction.
Effect of the 2011 vs 2003 Duty Hour Regulation–Compliant Models on Sleep Duration, Trainee Education, and Continuity of Patient Care Among Internal Medicine House Staff
Authors: Sanjay V. Desai, Leonard Feldman, Lorrel Brown, Rebecca Dezube, Hsin-Chieh Yeh, Naresh Punjabi, Kia Afshar, Michael R. Grunwald, Colleen Harrington, Rakhi Naik, Joseph Cofrancesco
Journal: JAMA Internal Medicine (2013)

<h3>Importance</h3>On July 1, 2011, the Accreditation Council for Graduate Medical Education implemented further restrictions of its 2003 regulations on duty hours and supervision. It remains unclear if the 2003 regulations improved trainee well-being or patient safety.<h3>Objective</h3>To determine the effects of the 2011 Accreditation Council for Graduate Medical Education duty hour regulations compared with the 2003 regulations concerning sleep duration, trainee education, continuity of patient care, and perceived quality of care among internal medicine trainees.<h3>Design and Setting</h3>Crossover study design in an academic research setting.<h3>Participants</h3>Medical house staff.<h3>Intervention</h3>General medical teams were randomly assigned using a sealed-envelope draw to an experimental model or a control model.<h3>Main Outcome Measures</h3>We randomly assigned 4 medical house staff teams (43 interns) using a 3-month crossover design to a 2003-compliant model of every fourth night overnight call (control) with 30-hour duty limits or to one of two 2011-compliant models of every fifth night overnight call (Q5) or a night float schedule (NF), both with 16-hour duty limits. We measured sleep duration using actigraphy and used admission volumes, educational opportunities, the number of handoffs, and satisfaction surveys to assess trainee education, continuity of patient care, and perceived quality of care.<h3>Results</h3>The study included 560 control, 420 Q5, and 140 NF days that interns worked and 834 hospital admissions. Compared with controls, interns on NF slept longer during the on call period (mean, 5.1 vs 8.3 hours; P = .003), and interns on Q5 slept longer during the postcall period (mean, 7.5 vs 10.2 hours; P = .05). However, both the Q5 and NF models increased handoffs, decreased availability for teaching conferences, and reduced intern presence during daytime work hours. Residents and nurses in both experimental models perceived reduced quality of care, so much so with NF that it was terminated early.<h3>Conclusions and Relevance</h3>Compared with a 2003-compliant model, two 2011 duty hour regulation–compliant models were associated with increased sleep duration during the on-call period and with deteriorations in educational opportunities, continuity of patient care, and perceived quality of care.