tbuckley/cabot-search huggingface dataset:
Pheochromocytoma: The Expanding Genetic Differential Diagnosis
Authors: J. Bryant, J. Farmer, L. J. Kessler, R. R. Townsend, K. L. Nathanson
Journal: JNCI Journal of the National Cancer Institute (2003)

Pheochromocytomas and paragangliomas are tumors of the autonomic nervous system; pheochromocytomas are tumors of the adrenal medulla, and paragangliomas are extra-adrenal tumors arising from either the sympathetic nervous system or parasympathetic ganglia. It has previously been estimated that approximately 10%-15% of pheochromocytomas are due to hereditary causes. However, our increased understanding of the three hereditary syndromes (neurofibromatosis 1, multiple endocrine neoplasia type 2, and von Hippel-Lindau syndrome) in which pheochromocytoma is found and the recent discovery that mutations in genes in the succinate dehydrogenase family (SDHB and SDHD) predispose to pheochromocytoma have necessitated a re-evaluation of the genetic basis of pheochromocytoma. These studies indicate that the frequency of germline mutations associated with isolated pheochromocytoma is higher than previously estimated, with both hospital-based series and a large population-based series indicating that the frequency of germline mutations in RET, VHL, SDHB, and SDHD taken together approximates 20%. In all patients with pheochromocytoma, including those with known hereditary syndrome or a positive family history, the frequency of germline mutations in these four genes together approaches 30%. Given the frequency of germline mutations, consideration should be given to genetic counseling for all patients with pheochromocytoma and is particularly important for individuals with a positive family history, multifocal disease, or a diagnosis before age 50. Identification of patients with hereditary pheochromocytoma is important because it can guide medical management in mutation-positive patients and their families. This review provides an overview of the known genetic syndromes that are commonly associated with pheochromocytoma, examines recent data on the association of germline mutations in the succinate dehydrogenase gene family with pheochromocytoma, and suggests guidelines for the genetic evaluation of pheochromocytoma patients.
The Role of Gefitinib in Lung Cancer Treatment
Authors: Giuseppe Giaccone
Journal: Clinical Cancer Research (2004)

Abstract Gefitinib (Iressa) is a novel targeted therapy that inhibits the tyrosine kinase activity of the epidermal growth factor receptor by competitively blocking the ATP binding site. In preclinical studies gefitinib has shown potent activity in a number of tumor models, including several lung cancer cell lines and xenografts. Two large randomized Phase II studies (IDEAL 1 and IDEAL 2) in pretreated non-small cell lung cancer reported a response rate approaching 20% in second-line patients and ∼10% in those pretreated with two or more chemotherapy regimens. The median survival in these two studies approached 6–8 months. As a first-line therapy, gefitinib has been assessed in combination with two different chemotherapy regimens in two large randomized studies (INTACT 1 and INTACT 2). Both studies failed to show an improvement in survival on a total patient accrual of &amp;gt;1000 patients in each study. Other end points (e.g., time to progression and response rate) were also not improved by the addition of gefitinib. Additional studies are indicated to assess the possible role of gefitinib in the maintenance of patients who received chemotherapy or chemoradiotherapy. Studies investigating gefitinib as first-line monotherapy are also required.
Epidemiologic data and pathogen genome sequences: a powerful synergy for public health
Authors: Yonatan H Grad, Marc Lipsitch
Journal: Genome biology (2014)

Abstract Epidemiologists aim to inform the design of public health interventions with evidence on the evolution, emergence and spread of infectious diseases. Sequencing of pathogen genomes, together with date, location, clinical manifestation and other relevant data about sample origins, can contribute to describing nearly every aspect of transmission dynamics, including local transmission and global spread. The analyses of these data have implications for all levels of clinical and public health practice, from institutional infection control to policies for surveillance, prevention and treatment. This review highlights the range of epidemiological questions that can be addressed from the combination of genome sequence and traditional `line lists’ (tables of epidemiological data where each line includes demographic and clinical features of infected individuals). We identify opportunities for these data to inform interventions that reduce disease incidence and prevalence. By considering current limitations of, and challenges to, interpreting these data, we aim to outline a research agenda to accelerate the genomics-driven transformation in public health microbiology.
Gastro-oesophageal reflux monitoring: review and consensus report on detection and definitions of acid, non-acid, and gas reflux
Authors: D Sifrim, D Castell, J Dent, P J Kahrilas
Journal: Gut (2004)

To date, most concepts on the frequency of gastro-oesophageal reflux episodes and the efficiency of the antireflux barrier have been based on inferences derived from measurement of oesophageal pH. The development of intraluminal impedance monitoring has highlighted the fact that pH monitoring does not detect all gastro-oesophageal reflux events when little or no acid is present in the refluxate, even if special pH tracing analysis criteria are used. In November 2002, a workshop took place at which 11 specialists in the field of gastro-oesophageal reflux disease discussed and criticised all currently available techniques for measurement of reflux. Here, a summary of their conclusions and recommendations of how to achieve the best results from the various techniques now available for reflux measurement is presented.
Viral persistence redirects CD4 T cell differentiation toward T follicular helper cells
Authors: Laura M. Fahey, Elizabeth B. Wilson, Heidi Elsaesser, Chris D. Fistonich, Dorian B. McGavern, David G. Brooks
Journal: The Journal of Experimental Medicine (2011)

CD4 T cell responses are crucial to prevent and control viral infection; however, virus-specific CD4 T cell activity is considered to be rapidly lost during many persistent viral infections. This is largely caused by the fact that during viral persistence CD4 T cells do not produce the classical Th1 cytokines associated with control of acute viral infections. Considering that CD4 T cell help is critical for both CD8 T cell and B cell functions, it is unclear how CD4 T cells can lose responsiveness but continue to sustain long-term control of persistent viral replication. We now demonstrate that CD4 T cell function is not extinguished as a result of viral persistence. Instead, viral persistence and prolonged T cell receptor stimulation progressively redirects CD4 T cell development away from the Th1 response induced during an acute infection toward T follicular helper cells. Importantly, this sustained CD4 T cell functionality is critical to maintain immunity and ultimately aid in the control of persistent viral infection.
CSF Concentration of the Anaplastic Lymphoma Kinase Inhibitor Crizotinib
Authors: Daniel B. Costa, Susumu Kobayashi, Shuchi S. Pandya, Wee-Lee Yeo, Zhongzhou Shen, Weiwei Tan, Keith D. Wilner
Journal: Journal of Clinical Oncology (2011)

CSF Concentration of the Anaplastic Lymphoma Kinase Inhibitor Crizotinib Case ReportWe describe the case of a 29-year-old white man with a neversmoking history and EML4-ALK-E20A20 stage IV non-small-cell lung cancer (NSCLC) whose disease had progressed after first-line cisplatin plus pemetrexed and second-line erlotinib.He started crizotinib at 200 mg twice daily and attained significant symptomatic improvement and minor tumor regression of his intrathoracic disease best classified as stable disease. 1 Before start of therapy, brain imaging studies showed no abnormalities.His systemic disease retained radiographic control with crizotinib when he presented with new-onset headaches 7.5 months into his treatment course.Magnetic resonance imaging of the brain disclosed small enhancing masses throughout the supratentorial and infratentorial brain, as well as the leptomeninges.The sagittal view of the T1-weighted sequence shows these masses, with black arrows highlighting some of the lesions (Fig 1).CSF cytology was positive for malignant cells.The patient received 30 Gy of whole-brain radiotherapy.Crizotinib was restarted at 250 mg twice daily during month 8 after the initiation of drug.Two weeks later, CSF and plasma were sampled 5 hours after a dose of crizotinib 250 mg.Concentrations of crizotinib were measured using a validated high-D I A G N O S I S I N O N C O L O G
111Indium antimyosin antibody imaging of primary myocardial invovement in systemic diseases
Authors: L Sarda, P Assayag, E Palazzo, D Vilain, L Guillevin, M Faraggi, O Meyer, D Le Guludec
Journal: Annals of the Rheumatic Diseases (1999)

The diagnosis of primary myocardial involvement in systemic diseases is clinically relevant but difficult in the absence of specific criteria. Whatever the underlying disease, myocytes degeneration is observed during the active phase of myocardial damage. The aim of this study was to assess the diagnostic value of scintigraphic imaging with 111Indium antimyosin antibody (AM), a specific marker of the damaged myocyte, for ongoing myocardial damage related to systemic diseases.40 patients with histologically confirmed systemic diseases were studied. They were classified into two groups according to the presence (group 1, n = 30), or the absence (group 2, n = 10) of clinical, electrocardiographic (ECG) or echocardiographic signs suggestive of myocardial involvement. Planar and tomographic acquisitions were obtained 48 hours after injection of AM (90 MBq). Rest 201thallium (T1) scintigraphy was also performed to assess myocardial perfusion and scarring. Clinical, ECG, and echocardiographic +/- scintigraphic evaluations were repeated during follow up (17 +/- 19 months) in 36 of 40 patients.In group 1, 13 of 30 patients (43%) showed diffuse significant AM uptake throughout the left ventricle (LV), and no or mild T1 abnormality. Two of these were asymptomatic, four had normal ECG, and two had no clinical or echographic LV dysfunction. All patients in group 2 had negative AMA scintigraphy and normal T1 scintigraphy. During follow up of 12 AM positive patients, cardiac status improved after immunosuppressive treatment was intensified in nine cases, worsened in two cases, and remained stable in one. During follow up of 24 AM negative patients, cardiac status remained stable in 23 cases despite treatment not being increased in 20, including two patients with sequellary myocardial involvement. The last patient developed mild LV dysfunction after 36 months.AM scintigraphy allows detection of active myocardial damage related to systemic diseases, with increased specificity compared with conventional methods, and increased sensitivity in some cases. Further studies are needed to assess the potential value of AM scintigraphy as a therapeutic guide.
Effect of <i>SLCO1B3</i> Haplotype on Testosterone Transport and Clinical Outcome in Caucasian Patients with Androgen-Independent Prostatic Cancer
Authors: Akinobu Hamada, Tristan Sissung, Douglas K. Price, Romano Danesi, Cindy H. Chau, Nima Sharifi, David Venzon, Kenji Maeda, Keisuke Nagao, Alex Sparreboom, Hiroaki Mitsuya, William L. Dahut, William D. Figg
Journal: Clinical Cancer Research (2008)

The organic anion transporter OATP1B3, encoded by SLCO1B3, is involved in the transport of steroid hormones. However, its role in testosterone uptake and clinical outcome of prostatic cancer is unknown. This study examined (a) the SLCO1B3 genotype in cancer cells as well as the uptake of testosterone by cells transfected with genetic variants of SLCO1B3; (b) the expression of OATP1B3 in normal prostate, benign prostatic hyperplasia, and prostatic cancer; and (c) the role of SLCO1B3 haplotype on clinical outcome of Caucasian patients with androgen-independent prostatic cancer.SLCO1B3 genotype was assessed in the NCI-60 panel of tumor cells by sequencing, whereas testosterone transport was analyzed in Cos-7 cells transfected with WT, 334G, and 699A SLCO1B3 variants. OATP1B3 expression in prostatic tissues was examined by fluorescence microscopy, and the relationship between SLCO1B3 haplotypes and survival was examined in patients.Cells transfected with wild-type (334T/699G) SLCO1B3, or with a vector containing either the 334G or 699A variants, actively transported testosterone, whereas its uptake was impaired in cells transfected with a gene carrying both 334G and 699A single nucleotide polymorphisms. Prostatic cancer overexpresses OATP1B3 compared with normal or benign hyperplastic tissue; patients with SLCO1B3 334GG/699AA haplotype showed longer median survival (8.5 versus 6.4 years; P = 0.020) and improved survival probability at 10 years (42% versus 23%; P < 0.023) than patients carrying TT/AA and TG/GA haplotypes.The common SLCO1B3 GG/AA haplotype is associated with impaired testosterone transport and improved survival in patients with prostatic cancer.
Contribution of patient related differences to multidrug resistance in rheumatoid arthritis
Authors: C Morgan
Journal: Annals of the Rheumatic Diseases (2002)

There is a wide variation in responses to standard disease modifying antirheumatic drug (DMARD) treatment in rheumatoid arthritis (RA). Whether multidrug resistance, failure to respond to several DMARDs, is a specific entity over and above that expected by chance alone is unclear.To identify patients with RA who demonstrate a multidrug resistant phenotype and to determine what proportion of the variance in drug responses is due to patient related factors.Patients with RA (1987 American College of Rheumatology criteria) were identified from clinics at Manchester Royal Infirmary and through the Arthritis Research Campaign National RA Repository. The clinic records were reviewed and multidrug resistance was defined as stopping three or more DMARDs owing to lack of efficacy after an adequate trial of the drug. Logistic regression measured by a random effects model was used to determine the relative contribution of the drug and subject related differences to the multidrug resistance.265 patients (210 (79.3%) female) were studied. The mean (SD) age and disease duration were 52.2 (12.9) and 10.7 (8.8) years, respectively. Patients had a median (range) of 2 (1-8) DMARD courses. Failure of at least one DMARD due to inefficacy occurred in 105 (40%) and 13 (5%) were multidrug resistant. Overall, 35% of the variance in drug responses was due to between-subject differences (p=0.02). Rheumatoid factor (RF) status contributed significantly to this (OR=2.15, 95% confidence interval (95% CI) 1.00 to 4.62) but explained only 3% of the total variance in drug inefficacy.Multidrug resistance occurs in an uncommon (5%) but important subgroup of patients with RA. The between-subject variance is not fully explained by demographics and RF status. Understanding the biological mechanisms that contribute to multidrug resistance may suggest new therapeutic approaches and targets in RA.
Overexpression of ABCG5 and ABCG8 promotes biliary cholesterol secretion and reduces fractional absorption of dietary cholesterol
Authors: Liqing Yu, Jia Li-Hawkins, Robert E. Hammer, Knut E. Berge, Jay D. Horton, Jonathan C. Cohen, Helen H. Hobbs
Journal: Journal of Clinical Investigation (2002)

Two ATP-binding cassette (ABC) transporters, ABCG5 and ABCG8, have been proposed to limit sterol absorption and to promote biliary sterol excretion in humans. To test this hypothesis, a P1 clone containing the human ABCG5 and ABCG8 genes was used to generate transgenic mice. The transgenes were expressed primarily in the liver and small intestine, mirroring the expression pattern of the endogenous genes. Transgene expression only modestly affected plasma and liver cholesterol levels but profoundly altered cholesterol transport. The fractional absorption of dietary cholesterol was reduced by about 50%, and biliary cholesterol levels were increased more than fivefold. Fecal neutral sterol excretion was increased three- to sixfold and hepatic cholesterol synthesis increased two- to fourfold in the transgenic mice. No significant changes in the pool size, composition, and fecal excretion of bile acids were observed in the transgenic mice. Transgene expression attenuated the increase in hepatic cholesterol content induced by consumption of a high cholesterol diet. These results demonstrate that increased expression of ABCG5 and ABCG8 selectively drives biliary neutral sterol secretion and reduces intestinal cholesterol absorption, leading to a selective increase in neutral sterol excretion and a compensatory increase in cholesterol synthesis.
Prolonged Eosinophil Accumulation in Allergic Lung Interstitium of ICAM-2-Deficient Mice Results in Extended Hyperresponsiveness
Authors: Nicole Gerwin, Jose-Angel Gonzalo, Clare Lloyd, Anthony J Coyle, Yvonne Reiss, Naheed Banu, Baoping Wang, Hong Xu, Hava Avraham, Britta Engelhardt, Timothy A Springer, Jose C Gutierrez-Ramos
Journal: Immunity (1999)
Unlike Esophageal Squamous Cells, Barrett's Epithelial Cells Resist Apoptosis by Activating the Nuclear Factor-κB Pathway
Authors: Kathy Hormi-Carver, Xi Zhang, Hui Ying Zhang, Robert H. Whitehead, Lance S. Terada, Stuart J. Spechler, Rhonda F. Souza
Journal: Cancer Research (2009)

Abstract Apoptosis is an important mechanism for maintaining tissue homeostasis and for preventing the proliferation of cells with mutations that could result in malignancy. Barrett's epithelium has been reported to be more resistant to apoptosis than normal esophageal squamous epithelium. We have explored the contribution of the nuclear factor-κB (NF-κB) pathway to apoptotic resistance in non-neoplastic, telomerase-immortalized esophageal squamous (NES) and Barrett's (BAR-T) epithelial cell lines. We exposed these cells to UV-B irradiation in doses known to cause DNA damage and to induce apoptosis in normal cells, and studied apoptosis as well as the expression of phospho-H2AX, NF-κB, Bcl-2, XIAP, cIAP-1, and survivin proteins. We also used Bay 11-7085 and siRNAs to NF-κB and Bcl-2 to assess the effects of NF-κB and Bcl2 inhibition on apoptosis. UV-B irradiation at low doses (50 and 100 J/m2) caused DNA damage in both NES and BAR-T cells but significantly increased apoptosis only in NES cells. UV-B irradiation caused a decrease in the levels of NF-κB, Bcl-2, cIAP-1, XIAP, and survivin in NES cells but increased the levels of those proteins in BAR-T cells. The resistance of BAR-T cells to apoptosis induced by low-dose UV-B irradiation was abolished by Bay 11-7085 and by siRNA for NF-κB and was decreased significantly by siRNA for Bcl-2. We conclude that the ability of Barrett's epithelial cells to activate the NF-κB pathway when they have sustained DNA damage allows them to resist apoptosis. This capacity to avoid apoptosis despite genotoxic damage may underlie the persistence and malignant predisposition of Barrett's metaplasia. [Cancer Res 2009;69(2):672–7]
The Rate of Uptake of Nitrous Oxide in Man1
Authors: J. W. Severinghaus
Journal: Journal of Clinical Investigation (1954)

During inhalational anesthesia, an inert gas or vapor diffuses across the pulmonary membrane, dissolves in the blood and is carried by the circulation to all of the tissues of the body. The rate at which an anesthetic dissolves from the gaseous phase in the alveoli into the pulmonary capillary blood is termed the rate of uptake of that gas. The uptake of any inert gas continues for many hours at a slowly decreasing rate until the entire body is saturated with the gas at the inspired tension. For example, Behnke, studying nitrogen gas exchange, found that about 5 hours are required to reach 90 per cent of complete saturation
Time for Reappraisal of Progesterone-Receptor Testing in Breast Cancer Management
Authors: Gaëtan MacGrogan, Isabelle de Mascarel, Ghyslaine Sierankowski, Louis Mauriac, Marc Debled, Michel Durand, Christine Tunon De Lara, Antoine Avril, Véronique Picot, Simone Mathoulin-Pélissier
Journal: Journal of Clinical Oncology (2005)
Effects of Lovastatin and Warfarin on Early Carotid Atherosclerosis
Authors: Robert P. Byington, Gregory W. Evans, Mark A. Espeland, William B. Applegate, Donald B. Hunninghake, Jeffrey Probstfield, Curt D. Furberg
Journal: Circulation (1999)

Background —Few clinical trials have documented the efficacy of preventive treatment in asymptomatic women. Methods and Results —Lovastatin and minidose warfarin were evaluated in a factorially designed, placebo-controlled, randomized trial. The primary outcome was 3-year change in the mean maximum intimal-medial thickness of the carotid arteries as measured by B-mode ultrasonography. Participants (n=919) were randomized to 1 of 4 treatment groups: lovastatin alone, warfarin alone, lovastatin+warfarin combination, or a double-placebo group. Eligible participants were asymptomatic for cardiovascular disease, with evidence of early carotid atherosclerosis and moderately elevated LDL cholesterol level. Almost half (n=445) of the participants were women. To avoid confounding, 117 women taking estrogen were excluded from analysis. Both sexes experienced reductions in disease progression with lovastatin; there was no evidence of an overall sex×treatment interaction ( P =0.72). When estimates of the sex-specific results were examined post hoc, women experienced disease regression to the greatest extent with the lovastatin+warfarin combination ( P =0.02), although the women on lovastatin alone also had a reduction in progression ( P =0.09). Men experienced the greatest reduction with lovastatin alone ( P =0.02), although there is a suggestion that warfarin may also reduce progression to some extent. Conclusions —Lovastatin is beneficial in reducing disease progression in women and men. Warfarin has no effect in women, although it may reduce progression in men. In men, warfarin does not add to the benefit of lovastatin and has no advantage over lovastatin alone.
1166 THE HEPATITIS C VIRUS (HCV) F PUTATIVE-PROTEIN: A NOVEL MODULATING FACTOR OF THE PREDICTIVE VALUE TO ANTIVIRAL TREATMENT RESPONSE OF THE IL28B REGION
Authors: A. Madejon, M. Romero, A. Gracía-Sánchez, I. Martín, M. Sánchez- Carrillo, J. Carbó, J. García-Samaniego
Journal: Journal of Hepatology (2013)
Cervical Amyloidoma Successfully Treated With Bortezomib and Dexamethasone
Authors: Katrina Farrell, David B. Stobo, Richard Soutar
Journal: Journal of Clinical Oncology (2011)

neurologic sequelae.Treatment is typically neurosurgical.Chemotherapy is typically employed when suppression of systemic amyloidosis is required. 4,5ortezomib is a first-generation proteosome inhibitor, which has demonstrated clinical utility in multiple myeloma. 6Kastritis et al 1 demonstrated a 47% complete response rate when this agent was used-with or without dexamethasone-to treat systemic light chain amyloidosis.Other groups have also demonstrated clinical utility of this agent in systemic amyloidosis.Wechalekar et al 7 described 15% complete hematologic response and 65% partial response rates.A 20% complete hematologic response rate was demonstrated in a phase I dose-finding study using single-agent bortezomib. 8his report, to our knowledge, describes the first use of this agent to treat isolated amyloidoma.The treatment was well tolerated in our patient, with significant clinical benefit.The rarity of this condition makes standard randomized, controlled trials difficult to perform.We suggest that bortezomib and dexamethasone may be clinically useful, especially in cases in which standard surgical approaches are not appropriate.