tbuckley/cabot-search huggingface dataset:
Safety and Efficacy of Simeprevir/Sofosbuvir in Hepatitis C–Infected Patients With Compensated and Decompensated Cirrhosis
Authors: Varun Saxena, Lisa Nyberg, Marypat Pauly, Aditi Dasgupta, Anders Nyberg, Barbara Piasecki, Bradley Winston, Jacquelyn Redd, Joanna Ready, Norah A. Terrault
Journal: Hepatology (2015)

Risks and benefits of simeprevir plus sofosbuvir (SIM+SOF) in patients with advanced cirrhosis are unknown. We assessed the safety and sustained virological responses (SVR) of SIM+SOF with and without ribavirin (RBV) in patients with Child‐Pugh (CP)‐B/C versus CP‐A cirrhosis and compared to matched untreated controls. This study was of a multicenter cohort of adults with hepatitis C virus genotype 1 and cirrhosis treated with SIM+SOF with/without RBV for 12 weeks. Controls were matched on treatment center, age, CP class, and Model for End‐Stage Liver Disease (MELD) score. Of 160 patients treated with SIM+SOF with/without RBV, 35% had CP‐B/C and 64% had CP‐A, with median baseline MELD 9 (interquartile range, 8‐11). Sustained virological response at week 12 (SVR12) was achieved by 73% of CP‐B/C versus 91% of CP‐A ( P &lt; 0.01). CP‐B/C versus CP‐A had more early treatment discontinuations (11% vs. 1%), adverse events (AEs) requiring hospitalization (22% vs. 2%), infections requiring antibiotics (20% vs. 1%), and hepatic decompensating events (20% vs. 3%; all P &lt; 0.01). There were 2 deaths: 1 CP‐B/C (liver related) and 1 CP‐A (not liver related). In multivariate analysis, CP‐B/C independently predicted lack of SVR12 (odds ratio, 0.27; 95% confidence interval: 0.08‐0.92). In comparing SIM+SOF‐treated patients versus matched untreated controls, AEs requiring hospitalization (9% vs. 13%; P = 0.55), infections (8% vs. 6%; P = 0.47), and events of decompensation (9% vs. 10%; P = 0.78) occurred at similar frequency. Conclusions : SIM+SOF with/without RBV has lower efficacy and higher rates of AEs in patients with CP‐B/C cirrhosis, compared to CP‐A. Frequency of adverse safety outcomes were similar to matched untreated controls, suggesting that safety events reflect the natural history of cirrhosis and are not related to treatment. (H epatology 2015;62:715–725)
What's been added to 1989 certificate? Well..
Authors: S. Silverman
Journal: JAMA (1989)

THE COMMITTEE that revised the national death certificate model for 1989 has provided more detailed instructions for the cause-of-death section and added two examples of how to fill it out. One illustrates a possible natural cause (a heart attack), and the other, a traumatic cause (an automobile accident).  Further instructions and more examples appear in an accompanying handbook, thePhysicians' Handbook on Medical Certification of Death(Dept of Health and Human Services publication [PHS]87-1108).  Committee members (a subgroup of the Panel to Evaluate the US Standard Certificates and Reports) also added more space in the cause-of-death section itself. We're seeing that physicians enter more and more detailed information, says Harry M. Rosenberg, MD, National Center for Health Statistics, Hyattsville, Md. It [the section] has been too cramped.  How Much Is Enough?  Daniel Fife, PhD, director of research at the New Jersey Department of Health, Trenton, suggests that just adding space
Growth-supporting activity of fragment Ba of the human alternative complement pathway for activated murine B lymphocytes.
Authors: F Praz, E Ruuth
Journal: The Journal of Experimental Medicine (1986)

We have investigated the effects of cleavage of factor B by its activating enzyme, factor D, as well as its activation fragments Bb and Ba, on the growth of mouse spleen B lymphocytes preactivated by LPS. Neither factor B nor factor D show any growth-supporting activity when tested alone. The coaddition of factor B and factor D to serum-free cultures of LPS-preactivated B cell blasts increased the proliferation of the responding cells up to the level obtained by restimulation with LPS. Such growth-supporting activity was shown to be mediated by Ba, whereas Bb did not show any significant effect. Furthermore, this effect was not restricted to the LPS-preactivated B cell blasts; in fact, Ba also supported the growth of in vivo, activated B cell blasts of unprimed mice of the LPS-nonresponder C3H/HeJ strain. In contrast, Ba did not maintain growth of Con A-activated T cells or TCGF-dependent CTL cells. Taken together, these results describe the first biological activity of human Ba as a B cell stimulatory factor.
Inter-relationships between inflammatory markers in patients with stable COPD with bronchitis: intra-patient and inter-patient variability
Authors: E Sapey, D Bayley, A Ahmad, P Newbold, N Snell, R A Stockley
Journal: Thorax (2007)

Background: Measurements of pulmonary biomarkers can be used to monitor airway inflammation in chronic obstructive pulmonary disease (COPD), but the variability of sampled biomarkers and their inter-relationships are poorly understood. A study was undertaken to examine the intra- and inter-patient variability in spontaneous sputum samples from patients in the stable state and to describe the relationship between biomarkers, cell counts and markers of disease. Methods: Sputum interleukin-1β, tumour necrosis factor α, interleukin 8, myeloperoxidase, leucotriene B4, growth-related oncogene α and differential cell counts were measured in patients with moderate to severe stable COPD (n = 14) on 11 occasions over a 1-month period. Results: There was significant variability in all inflammatory indices (median intra-patient coefficient of variation (CV) 35% (IQR 22–69), median inter-patient CV 102% (IQR 61–145)). Variability could be reduced by using a rolling mean of individual patient data points. Sample size calculations were undertaken to determine the number of patients required to detect a 50% reduction in neutrophil count. Using a crossover design of a putative effective treatment, the number needed using one data point per patient was 72, reducing to 23 when a mean of three data points was used. Significant correlations were demonstrated both between the inflammatory biomarkers themselves and between inflammatory biomarkers and markers of disease. Some relationships were not apparent when results from a single sample were used. The reliability of inter-relationships improved as more data points were used for each patient. Conclusions: Clear relationships exist between inflammatory biomarkers in patients with stable COPD. Sequential sampling reduced the variability of individual mediators and the potential number of patients needed to power proof of concept interventional studies.
PTEN Gene and Integrin Signaling in Cancer
Authors: M. Tamura, J. Gu, H. Tran, K. M. Yamada
Journal: JNCI Journal of the National Cancer Institute (1999)

Integrins are major adhesion- and signaling-receptor proteins that mediate cell migration and invasion. They also trigger a variety of signal transduction pathways and regulate cytoskeletal organization, specific gene expression, growth control, and apoptosis (programmed cell death). Consequently, integrins are thought to play important roles in embryonic development and in the biology of cancers. The functions of integrins can be negatively regulated by the recently discovered tumor suppressor PTEN, a protein with homology to protein tyrosine phosphatases and tensin. The PTEN gene is mutated in a wide range of human cancers. PTEN inhibits cell migration and invasion by directly dephosphorylating two key tyrosine-phosphorylated proteins, thereby antagonizing interactions of integrins with the extracellular matrix and integrin-triggered signaling pathways. Other studies demonstrate important roles for PTEN in dephosphorylating a key signal transduction lipid. In the absence of PTEN, this lipid signal transduction pathway can protect tumor cells from apoptosis. Thus, PTEN appears to be a unique tumor suppressor-with both lipid phosphatase and protein tyrosine phosphatase activities-that negatively regulates cell interactions with the extracellular matrix and that maintains cell sensitivity to apoptosis, e.g., after loss of cell contact with the extracellular matrix. The complex signal transduction pathways regulated by PTEN are described in this review. PTEN and the signaling pathways it regulates may provide novel targets for potential therapy.
Pulmonary function and exercise capacity after lung resection
Authors: CT Bolliger, P Jordan, M Soler, P Stulz, M Tamm, C Wyser, M Gonon, AP Perruchoud
Journal: European Respiratory Journal (1996)

The influence of pulmonary resection on functional capacity can be assessed in different ways. The aim of this study was to compare the effect of lobectomy and pneumonectomy on pulmonary function tests (PFT), exercise capacity and perception of symptoms. Sixty eight patients underwent functional assessment with PFT and exercise testing before (Preop), and 3 and 6 months after lung resection. In 50 (36 males and 14 females; mean age 61 yrs) a lobectomy was performed and in 18 (13 males and 5 females; mean age 59 yrs) a pneumonectomy was performed. Three months after lobectomy, forced vital capacity (FVC), forced expiratory volume in one second (FEV1), total lung capacity (TLC), transfer factor of the lungs for carbon monoxide (TL,CO) and maximal oxygen uptake (V'O2,max) were significantly lower than Preop values, increasing significantly from 3 to 6 months after resection. Three months after pneumonectomy, all parameters were significantly lower than Preop values and significantly lower than postlobectomy values and did not recover from 3 to 6 months after resection. At 6 months after resection significant deficits persisted in comparison with Preop: for FVC 7% and 36%, FEV1 9% and 34%, TLC 10% and 33% for lobectomy and pneumonectomy, respectively; and V'O2,max 20% after pneumonectomy only. Exercise was limited by leg muscle fatigue in 53% of all patients at Preop. This was not altered by lobectomy, but there was a switch to dyspnoea as the limiting factor after pneumonectomy (61% of patients at 3 months and 50% at 6 months after resection). Furthermore, pneumonectomy compared to lobectomy led to a significantly smaller breathing reserve (mean +/- SD) (28 +/- 13 vs 37 +/- 16% at 3 months; and 24 +/- 11% vs 33 +/- 12% at 6 months post resection) and lower arterial oxygen tension at peak exercise 10.1 +/- 1.5 vs 11.5 +/- 1.6 kPa (76 +/- 11 vs 86 +/- 12 mmHg) at 3 months; 10.1 +/- 1.3 vs 11.3 +/- 1.6 kPa (76 +/- 10 vs 85 +/- 12 mmHg) at 6 months postresection. We conclude that measurements of conventional pulmonary function tests alone overestimate the decrease in functional capacity after lung resection. Exercise capacity after lobectomy is unchanged, whereas pneumonectomy leads to a 20% decrease, probably due to the reduced area of gas exchange.
Cytokine-induced protein tyrosine phosphorylation is essential for cytokine priming of human eosinophils
Authors: Tjomme van der Bruggen, Deon Kanters, Anton T.J. Tool, Jan A.M. Raaijmakers, Jan-Willem J. Lammers, Arthur J. Verhoeven, Leo Koenderman
Journal: Journal of Allergy and Clinical Immunology (1998)
Epidermal Growth Factor Receptor–Related Protein Inhibits Cell Growth and Induces Apoptosis of BxPC3 Pancreatic Cancer Cells
Authors: Yuxiang Zhang, Sanjeev Banerjee, Zhi-wei Wang, Dorota J. Marciniak, Adhip P.N. Majumdar, Fazlul H. Sarkar
Journal: Cancer Research (2005)

Abstract Dysregulation of the epidermal growth factor receptor (EGFR) signaling network has been frequently reported in pancreatic cancer. Inhibition of EGFR was associated with antitumor effects in both in vitro and in vivo studies of pancreatic cancer. We have previously reported the isolation and characterization of an EGFR-related protein (ERRP), which seems to be a negative regulator of EGFR. In the present investigation, we tested our hypothesis whether recombinant ERRP could be an effective inhibitor of growth of BxPC3 pancreatic cancer cells. Cell growth and apoptosis were measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and apoptosis ELISA assay, respectively, in the presence and absence of recombinant ERRP in BxPC3 cells. To evaluate activation of EGFR and its downstream signaling events, levels of phospho-EGFR, phospho-AKT, and phospho-extracellular signal-regulated kinase (phospho-ERK) were determined by Western blot analysis. NF-κB activity was measured by electrophoretic mobility shift assay. Our data show, for the first time, that ERRP inhibits the growth of BxPC3 cells in a dose- and time-dependent manner. The EGF or transforming growth factor (TGF)-α–induced stimulation of cell growth and activation of EGFR was also inhibited by ERRP. These changes were accompanied by a concomitant attenuation of activation of mitogen-activated protein (MAP) kinases, AKT, and NF-κB. ERRP also induced apoptosis as evidenced by increased poly(ADP-ribose) polymerase cleavage and reduction in procaspase3. From these results, we conclude that ERRP is a potent inhibitor of growth of BxPC-3 pancreatic cancer cells, which could be due to attenuation of EGFR cellular signaling processes. We also suggest that ERRP could be a potential therapeutic agent for pancreatic cancer.
Cytokine-Induced Killer Cells Eradicate Bone and Soft-Tissue Sarcomas
Authors: Dario Sangiolo, Giulia Mesiano, Loretta Gammaitoni, Valeria Leuci, Maja Todorovic, Lidia Giraudo, Cristina Cammarata, Carmine Dell'Aglio, Lorenzo D'Ambrosio, Alberto Pisacane, Ivana Sarotto, Sara Miano, Ivana Ferrero, Fabrizio Carnevale-Schianca, Ymera Pignochino, Francesco Sassi, Andrea Bertotti, Wanda Piacibello, Franca Fagioli, Massimo Aglietta, Giovanni Grignani
Journal: Cancer Research (2013)

Unresectable metastatic bone sarcoma and soft-tissue sarcomas (STS) are incurable due to the inability to eradicate chemoresistant cancer stem-like cells (sCSC) that are likely responsible for relapses and drug resistance. In this study, we investigated the preclinical activity of patient-derived cytokine-induced killer (CIK) cells against autologous bone sarcoma and STS, including against putative sCSCs. Tumor killing was evaluated both in vitro and within an immunodeficient mouse model of autologous sarcoma. To identify putative sCSCs, autologous bone sarcoma and STS cells were engineered with a CSC detector vector encoding eGFP under the control of the human promoter for OCT4, a stem cell gene activated in putative sCSCs. Using CIK cells expanded from 21 patients, we found that CIK cells efficiently killed allogeneic and autologous sarcoma cells in vitro. Intravenous infusion of CIK cells delayed autologous tumor growth in immunodeficient mice. Further in vivo analyses established that CIK cells could infiltrate tumors and that tumor growth inhibition occurred without an enrichment of sCSCs relative to control-treated animals. These results provide preclinical proof-of-concept for an effective strategy to attack autologous sarcomas, including putative sCSCs, supporting the clinical development of CIK cells as a novel class of immunotherapy for use in settings of untreatable metastatic disease.
Cimetidine for hypertrophic prostate?
Authors: M Cohen
Journal: BMJ (1979)

months.Three of them had had unsuccessful kidney transplants before CAPD and the fourth, a 3-year old, had Wilms's tumours.Although our experience is still too short to allow us more generalised conclusions, we are convinced that the availability of CAPD in- creases the therapeutic armamentarium in the management of children with end-stage renal disease.
Oncology Curriculum in Developing Countries and the Lessons to Be Learned
Authors: Irfan Jeeva, Rakesh Jayasawal, Naveen Kermani, Pankaj Pauri
Journal: Journal of Clinical Oncology (2007)

We read with great interest the article by Gaffan et al 1 on educating undergraduate medical students about oncology.We come from a developing country where oncology teaching was effectively nonexistent.We admire the efforts invested in creating an oncology curriculum for training.Oncology is an ever-expanding field, and with the current progress in research of new treatment modalities and the ever-aging population, this trend will no doubt continue.Trained properly, the doctors of tomorrow will be in a better position to understand and subsequently better manage this complex group of patients.From our personal perspectives, having moved to the United Kingdom where the management of oncologic conditions is much more aggressive and effective, we can appreciate the importance for the early foundations of knowledge.Good undergraduate training is dependent not only on the teaching methodology, but also on the curriculum content, which we acknowledge can be hard to balance for such a vast subject.Both aspects, however, seem to have been thoroughly addressed by the Oncology Education Committee of the Cancer Council of Australia, 2 with its work on the ideal oncology curriculum, and by Gaffan et al, regarding the teaching methods. 1 While we appreciate the epidemiologic differences and variability of disease between the developed and developing worlds, we would like to see this approach to training being mirrored in Pakistan for the future generations of doctors.Developing countries with limited research resources must make use of the ideal oncology curriculum.This would be an immense contribution to the medical community of the lessdeveloped countries.
Atrasentan, an Endothelin-Receptor Antagonist for Refractory Adenocarcinomas: Safety and Pharmacokinetics
Authors: Michael A. Carducci, Joel B. Nelson, M. Kathy Bowling, Theresa Rogers, Mario A. Eisenberger, Victoria Sinibaldi, Ross Donehower, Terri L. Leahy, Robert A. Carr, Jeffrey D. Isaacson, Todd J. Janus, Amy Andre, Balakrishna S. Hosmane, Robert J. Padley
Journal: Journal of Clinical Oncology (2002)

Endothelin receptors, particularly the ET(A) receptor, have been shown to participate in the pathophysiology of prostate and other cancers. Atrasentan, an endothelin antagonist, binds selectively to the ET(A) receptor. This study evaluated the safety, pharmacokinetics, and maximum-tolerated dose of atrasentan in cancer patients.Patients who were 18 years or older and had histologically confirmed adenocarcinoma refractory to therapy enrolled in this 28-day, open-label, phase I study. Enrollment was planned for cohorts of three patients at doses escalating from 10 to 140 mg/d. When any patient had dose-limiting toxicity, that cohort was expanded. The primary outcome variable was safety; secondary outcome variables were pharmacokinetics, tumor response, and pain relief.Thirty-one cancer patients (14 prostate) were treated at daily atrasentan doses of 10, 20, 30, 45, 60, and 75 mg (n = 3 to 8 per cohort). The most common adverse events, such as rhinitis, headache, asthenia, and peripheral edema, were reversible on drug discontinuation and responded to symptom-specific treatment. Reversible hemodilution was apparent in laboratory findings and weight gain. Clinically significant headache was the dose-limiting adverse event; the maximum-tolerated dose was 60 mg/d. Pharmacokinetics were dose-proportional across the 10- to 75-mg dose range. Atrasentan was rapidly absorbed; the time to maximum observed concentration was approximately 1.5 hours. The terminal elimination half-life was approximately 24 hours, and steady-state plasma concentrations were achieved within 7 days. Decreases in prostate-specific antigen and pain relief were noted in a patient subset.Adverse events were consistent with atrasentan's pharmacologic vasodilatory effect. Linear, dose-proportional pharmacokinetics suggest that atrasentan can be easily and consistently dosed.
GENETIC CHANGES IN RADIATION-ASSOCIATED MENINGIOMA
Authors: E. B. Claus, L. Calvocoressi, S. Greenhalgh, K. Walsh, J. Schildkraut, M. Bondy, J. Wiemels, M. Wrensch, O. Al-Mefty, J. Townsend
Journal: Neuro-Oncology (2014)

BACKGROUND: Meningiomas represent the most frequently diagnosed primary brain tumor in the United States accounting for approximately one third of such tumors in adults. To date the sole consistently identified risk factor remains exposure to ionizing radiation with risks from 6-10 fold reported. Persons diagnosed with meningioma after exposure to therapeutic ionizing radiation likely represent a genetically-sensitive subpopulation of patients. Currently, radiation-associated meningiomas (RAM) are the most common form of radiation-induced neoplasm yet no sequencing data exist for this class of tumor. METHODS: Our group has identified 22 persons with confirmed high-dose therapeutic radiation treatments to the head, face or neck and subsequent pathologic confirmation of intra-cranial meningioma. To identify genetic changes and the mean number of protein altering somatic mutations associated with the development of RAM we perform whole genome sequencing on matched paraffin-embedded tumor and constitutive DNA for this group of patients. We compare these results with those obtained from the recent genetic analyses of two series of non-RAM meningiomas to determine how mutation profiles differ between RAM and non-RAM meningiomas. RESULTS: Treatment is problematic as many RAMs are in anatomic locations that are difficult to surgically access, most patients are not candidates for additional radiation therapy given their previous exposure and no beneficial chemotherapeutic agent exists. (Sequencing in process) CONCLUSIONS: RAMs represent a difficult clinical issue in neurosurgery. Our study is a focused effort to define genetic variants associated with meningioma development using cases with a unique gene*environment exposure. In addition, these data may identify mutational profiles that predict drug response for this hard to treat lesion. SECONDARY CATEGORY: Tumor Biology.
Extent of underdiagnosis of familial hypercholesterolaemia in routine practice: prospective registry study
Authors: H A W Neil
Journal: BMJ (2000)

In heterozygous familial hypercholesterolaemia the cumulative risk of a fatal or non-fatal coronary event by the age of 60 without effective treatment is at least 50% in men and about 30% in women. 1 2 The prognosis has improved substantially with widespread use of statins for lipid lowering. 3 The estimated occurrence of the condition is about 1 in 500. 4 We aimed to determine the prevalence of diagnosed familial hypercholesterolaemia and to estimate the proportion of expected cases that are identified in routine clinical practice.