tbuckley/cabot-search huggingface dataset:
Targeting GIPC/Synectin in Pancreatic Cancer Inhibits Tumor Growth
Authors: Michael H. Muders, Pawan K. Vohra, Shamit K. Dutta, Enfeng Wang, Yasuhiro Ikeda, Ling Wang, D. Gomika Udugamasooriya, Adnan Memic, Chamila N. Rupashinghe, Gustavo B. Baretton, Daniela E. Aust, Silke Langer, Kaustubh Datta, Michael Simons, Mark R. Spaller, Debabrata Mukhopadhyay
Journal: Clinical Cancer Research (2009)

Abstract Purpose: Various studies have shown the importance of the GAIP interacting protein, COOH-terminus (GIPC, also known as Synectin) as a central adaptor molecule in different signaling pathways and as an important mediator of receptor stability. GIPC/Synectin is associated with different growth-promoting receptors such as insulin-like growth factor receptor I (IGF-IR) and integrins. These interactions were mediated through its PDZ domain. GIPC/Synectin has been shown to be overexpressed in pancreatic and breast cancer. The goal of this study was to show the importance of GIPC/Synectin in pancreatic cancer growth and to evaluate a possible therapeutic strategy by using a GIPC-PDZ domain inhibitor. Furthermore, the effect of targeting GIPC on the IGF-I receptor as one of its associated receptors was tested. Experimental Design: The in vivo effects of GIPC/Synectin knockdown were studied after lentiviral transduction of luciferase-expressing pancreatic cancer cells with short hairpin RNA against GIPC/Synectin. Additionally, a GIPC-PDZ–targeting peptide was designed. This peptide was tested for its influence on pancreatic cancer growth in vitro and in vivo. Results: Knockdown of GIPC/Synectin led to a significant inhibition of pancreatic adenocarcinoma growth in an orthotopic mouse model. Additionally, a cell-permeable GIPC-PDZ inhibitor was able to block tumor growth significantly without showing toxicity in a mouse model. Targeting GIPC was accompanied by a significant reduction in IGF-IR expression in pancreatic cancer cells. Conclusions: Our findings show that targeting GIPC/Synectin and its PDZ domain inhibits pancreatic carcinoma growth and is a potential strategy for therapeutic intervention of pancreatic cancer.
Costimulation Modulation With Abatacept in Patients With Recent-Onset Type 1 Diabetes: Follow-up 1 Year After Cessation of Treatment
Authors: Tihamer Orban, Brian Bundy, Dorothy J. Becker, Linda A. DiMeglio, Stephen E. Gitelman, Robin Goland, Peter A. Gottlieb, Carla J. Greenbaum, Jennifer B. Marks, Roshanak Monzavi, Antoinette Moran, Mark Peakman, Philip Raskin, William E. Russell, Desmond Schatz, Diane K. Wherrett, Darrell M. Wilson, Jeffrey P. Krischer, Jay S. Skyler
Journal: Diabetes Care (2013)

OBJECTIVE We previously reported that 2 years of costimulation modulation with abatacept slowed decline of β-cell function in recent-onset type 1 diabetes (T1D). Subsequently, abatacept was discontinued and subjects were followed to determine whether there was persistence of effect. RESEARCH DESIGN AND METHODS Of 112 subjects (ages 6-36 years) with T1D, 77 received abatacept and 35 received placebo infusions intravenously for 27 infusions over 2 years. The primary outcome-baseline-adjusted geometric mean 2-h area under the curve (AUC) serum C-peptide during a mixed-meal tolerance test (MMTT) at 2 years-showed higher C-peptide with abatacept versus placebo. Subjects were followed an additional year, off treatment, with MMTTs performed at 30 and 36 months. RESULTS C-peptide AUC means, adjusted for age and baseline C-peptide, at 36 months were 0.217 nmol/L (95% CI 0.168-0.268) and 0.141 nmol/L (95% CI 0.071-0.215) for abatacept and placebo groups, respectively (P = 0.046). The C-peptide decline from baseline remained parallel with an estimated 9.5 months' delay with abatacept. Moreover, HbA1c levels remained lower in the abatacept group than in the placebo group. The slightly lower (nonsignificant) mean total insulin dose among the abatacept group reported at 2 years was the same as the placebo group by 3 years. CONCLUSIONS Costimulation modulation with abatacept slowed decline of β-cell function and improved HbA1c in recent-onset T1D. The beneficial effect was sustained for at least 1 year after cessation of abatacept infusions or 3 years from T1D diagnosis.
A Recurrent Chromosome Breakpoint in Breast Cancer at the <b> <i>NRG1</i> </b>/<b> <i>Neuregulin 1</i> </b>/<b> <i>Heregulin</i> </b> Gene
Authors: Huai-En Huang, Suet-Feung Chin, Christophe Ginestier, Valérie-Jeanne Bardou, José Adélaïde, N. Gopalakrishna Iyer, Maria J. Garcia, Jessica C. Pole, Grace M. Callagy, Stephen M. Hewitt, William J. Gullick, Jocelyne Jacquemier, Carlos Caldas, Max Chaffanet, Daniel Birnbaum, Paul A. W. Edwards
Journal: Cancer Research (2004)

Abstract Most studies of genomic rearrangements in common cancers have focused on regional gains and losses, but some rearrangements may break within specific genes. We previously reported that five breast cancer cell lines have chromosome translocations that break in the NRG1 gene and that could cause abnormal NRG1 expression. NRG1 encodes the Neuregulins 1 (formerly the Heregulins), ligands for members of the ErbB/epidermal growth factor-receptor family, which includes ErbB2/HER2. We have now screened for breaks at NRG1 in paraffin sections of breast tumors. Tissue microarrays were screened by fluorescence in situ hybridization, with hybridization probes proximal and distal to the expected breakpoints. This screen detects breaks but does not distinguish between translocation or deletion breakpoints. The screen was validated with array-comparative genomic hybridization on a custom 8p12 high-density genomic array to detect a lower copy number of the sequences that were lost distal to the breaks. We also precisely mapped the breaks in five tumors with different hybridization probes. Breaks in NRG1 were detected in 6% (19 of 323) of breast cancers and in some lung and ovarian cancers. In an unselected series of 213 cases with follow-up, breast cancers where the break was detected tended to be high-grade (65% grade III compared with 28% of negative cases). They were, like breast tumors in general, mainly ErbB2 low (11 of 13 were low) and estrogen receptor positive (11 of 13 positive).
Oral Contraceptives and the Risk of Breast Cancer in BRCA1 and BRCA2 Mutation Carriers
Authors: S. A. Narod
Journal: JNCI Journal of the National Cancer Institute (2002)

Background: Oral contraceptive use has been associated with an increase in the risk of breast cancer in young women. We examined whether this association is seen in women at high risk of breast cancer because they carry a mutation in one of two breast cancer susceptibility genes, BRCA1 and BRCA2. Methods: We performed a matched case–control study on 1311 pairs of women with known deleterious BRCA1 and/or BRCA2 mutations recruited from 52 centers in 11 countries. Women who had been diagnosed with breast cancer were matched to control subjects by year of birth, country of residence, mutation (BRCA1 or BRCA2), and history of ovarian cancer. All study subjects completed a questionnaire about oral contraceptive use. Odds ratios (ORs) and 95% confidence intervals (CIs) were derived by conditional logistic regression. All statistical tests were two-sided. Results: Among BRCA2 mutation carriers, ever use of oral contraceptives was not associated with an increased risk of breast cancer (OR = 0.94, 95% CI = 0.72 to 1.24). For BRCA1 mutation carriers, ever use of oral contraceptives was associated with a modestly increased risk of breast cancer (OR = 1.20, 95% CI = 1.02 to 1.40). However, compared with BRCA1 mutation carriers who never used oral contraceptives, those who used oral contraceptives for at least 5 years had an increased risk of breast cancer (OR = 1.33, 95% CI = 1.11 to 1.60), as did those who used oral contraceptives before age 30 (OR = 1.29, 95% CI = 1.09 to 1.52), those who were diagnosed with breast cancer before age 40 (OR = 1.38, 95% CI = 1.11 to 1.72), and those who first used oral contraceptives before 1975 (OR = 1.42, 95% CI = 1.17 to 1.75). Conclusions: Among BRCA1 mutation carriers, women who first used oral contraceptives before 1975, who used them before age 30, or who used them for 5 or more years may have an increased risk of early-onset breast cancer. Oral contraceptives do not appear to be associated with risk of breast cancer in BRCA2 carriers, but data for BRCA2 carriers are limited.
Neurologic Function and Health-Related Quality of Life in Patients Following Targeted Temperature Management at 33°C vs 36°C After Out-of-Hospital Cardiac Arrest
Authors: Tobias Cronberg, Gisela Lilja, Janneke Horn, Jesper Kjaergaard, Matt P. Wise, Tommaso Pellis, Jan Hovdenes, Yvan Gasche, Anders Åneman, Pascal Stammet, David Erlinge, Hans Friberg, Christian Hassager, Michael Kuiper, Michael Wanscher, Frank Bosch, Julius Cranshaw, Gian-Reto Kleger, Stefan Persson, Johan Undén, Andrew Walden, Per Winkel, Jørn Wetterslev, Niklas Nielsen
Journal: JAMA Neurology (2015)

Brain injury affects neurologic function and quality of life in survivors after cardiac arrest.To compare the effects of 2 target temperature regimens on long-term cognitive function and quality of life after cardiac arrest.In this multicenter, international, parallel group, assessor-masked randomized clinical trial performed from November 11, 2010, through January 10, 2013, we enrolled 950 unconscious adults with cardiac arrest of presumed cardiac cause from 36 intensive care units in Europe and Australia. Eleven patients were excluded from analysis for a total sample size of 939.Targeted temperature management at 33°C vs 36°C.Cognitive function was measured by the Mini-Mental State Examination (MMSE) and assessed by observers through the Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Patients reported their activities in daily life and mental recovery through Two Simple Questions and their quality of life through the Medical Outcomes Study 36-Item Short Form Health Survey, version 2.In the modified intent-to-treat population, including nonsurvivors, the median MMSE score was 14 in the 33°C group (interquartile range [IQR], 0-28) vs 17 in the 36°C group (IQR, 0-29) (P = .77), and the IQCODE score was 115 (IQR, 79-130) vs 115 (IQR, 80-130) (P = .57) in the 33°C and 36°C groups, respectively. The median MMSE score for survivors was within the reference range and similar (33°C group median, 28; IQR, 26-30; vs 36°C group median, 28; IQR, 25-30; P = .61). The median IQCODE score was within the minor deficit range (33°C group median, 79.5; IQR, 78.0-85.9; vs 36°C group median, 80.7; IQR, 78.0-86.9; P = .04). A total of 18.8% vs 17.5% of survivors reported needing help with everyday activities (P = .71), and 66.5% in the 33°C group vs 61.8% in the 36°C group reported that they thought they had made a complete mental recovery (P = .32). The mean (SD) mental component summary score was 49.1 (12.5) vs 49.0 (12.2) (P = .79), and the mean (SD) physical component summary score was 46.8 (13.8) and 47.5 (13.8) (P = .45), comparable to the population norm.Quality of life was good and similar in patients with cardiac arrest receiving targeted temperature management at 33°C or 36°C. Cognitive function was similar in both intervention groups, but many patients and observers reported impairment not detected previously by standard outcome scales.ClinicalTrials.gov NCT01020916.
Health department won't be able to show preference between NHS and private providers of health services
Authors: A. O'Dowd
Journal: BMJ (2011)

The Department of Health will not be able to show a preference for NHS, private, or voluntary sector providers of health services or promote one over any other, under new amendments to the planned reforms of the health service in England.

A briefing on the amendments, published on 27 June, state that the health secretary, the regulator Monitor, and the NHS Commissioning Board (which will oversee the new commissioning groups) will be prevented from using their abilities “for the purpose of increasing or decreasing the market share of any particular type of provider—whether public or private sector—in the provision of NHS services.”

This will prevent policy decisions made in the past from happening again, such …
Killing of Laminin Receptor-Positive Human Lung Cancers by Tumor-Infiltrating Lymphocytes Bearing γδ + T-Cell Receptors
Authors: Marina Ferrarini, Silvia Heltai, Serenella M. Pupa, Sylvie Menard, M. Raffaella Zocchi
Journal: JNCI Journal of the National Cancer Institute (1996)

The monomeric laminin receptor, a 67-kd high-affinity laminin-binding protein, is expressed by a variety of normal cell types. Overexpression and abnormal surface distribution of this receptor have been demonstrated in tumor cells where it appears to promote tumor invasion and metastasis. Previously, we reported the existence of an association between laminin receptor overexpression by lung cancer cells and the presence of tumor-infiltrating lymphocytes (TILs) bearing gammadelta T-cell receptors. Gammadelta(+) lymphocytes represents a sizable fraction of the TILs in approximately one fourth of lung cancers analyzed thus far.The aim of this study was to determine whether gammadelta(+) TILs might participate in the immune response against lung cancer through recognition of monomeric laminin receptors expressed by tumor cells.Tumor cells from 11 lung cancer specimens exhibiting sizable gammadelta(+) T-cell infiltrates and from 11 other specimens infiltrated predominantly by lymphocytes bearing alphabeta(+) T-cell receptors were analyzed for expression of the monomeric laminin receptor by use of the monoclonal antibody (MAb) MLuC5. Gammadalta TILs and chibeta+ TILs derived from four tumors were each examined for cytotoxic activity toward lung cancer target cells by use of a standard 51Cr-release assay and lung tumor cell lines expressing different levels of surface monomeric laminin receptor. The ability of MAbs directed against the laminin receptor (i.e., MLuC5) or against gammadelta T-cell receptors (i.e., TigammaA and A13) as well as laminin peptides known to bind to the laminin receptor to inhibit TIL-mediated target cells lysis was also determined.We confirmed that the association between overexpression of the monomeric laminin receptor by lung tumor cells and the presence of gammadeltadelta+ TILs is statistically significant (two sided P = .003; Fisher's exact test). We also observed a relationship between the levels of laminin receptor expression on cultured lung cancer cells and their susceptibility to specific lysis by gammadelta(+), but not alphabeta+, TILs. This specific cell killing was not T-cell receptor mediated, but it was inhibited by addition of the anti-monomeric laminin receptor MAb MLuC5 and by a synthetic peptide corresponding to amino acids 2091-2108 of the laminin A chain.Our results indicate gammadelta(+) TILs localized at human lung cancer sites can kill tumor cells in a process that involves interaction with the monomeric laminin receptor. The infiltration of gammadelta(+) TILs at lung tumor sites may represent a first line of defense against cells undergoing malignant transformation.
Chemical and biological properties of supramolecular polymer systems based on oligocaprolactones
Authors: Patricia Y.W. Dankers, Ellen N.M. van Leeuwen, Gaby M.L. van Gemert, A.J.H. Spiering, Martin C. Harmsen, Linda A. Brouwer, Henk M. Janssen, Anton W. Bosman, Marja J.A. van Luyn, E.W. Meijer
Journal: Biomaterials (2006)
P13 Mismatch Between Clinical and Radiological Diagnosis of Pneumonia: Abstract P13 Table 1
Authors: SV Ruickbie, E Kursumovic, B Narayan, K Opong, P Luce, T Toma, LV Baker, KK Lee
Journal: Thorax (2012)

<h3>Introduction</h3> National guidelines on management of pneumonia stipulate the need for radiological evidence of consolidation to confirm the diagnosis. An incorrect diagnosis may lead to sub-optimal management, inappropriate antibiotic use and prolonged hospital stay. We sought to determine the relationship between clinical diagnosis of pneumonia and radiological evidence on chest x-ray. <h3>Methods</h3> We performed a retrospective case-note study of admissions with a diagnosis of pneumonia in a large district general hospital during a three month period. Cases with pneumonia were identified using the ICD-10 coding system; those with co-existing diagnoses of malignancy or bronchiectasis were excluded. Clinician diagnoses of pneumonia were established by examination of clinical discharge summaries. All chest radiographs performed throughout the admission episode had been evaluated by a radiologist. Serum white cell count (WCC) and C-reactive protein (CRP) at admission were also examined. <h3>Results</h3> 132 coded records of pneumonia were identified, of which a clinician diagnosis of pneumonia was recorded on 91. Median (interquartile range) age was 75 (61–89) years, 57% female, and median length of stay was 9 (3–23) days. CAP accounted for 65%, hospital acquired pneumonia 15%, aspiration pneumonia 1% and in 19% the origin was unclear. In 37% of all cases, there was no evidence of consolidation on any of the chest radiographs performed during inpatient stay. Subjects without radiological consolidation had similar length of stay to those with consolidation. There was no significant difference in age (p=0.34) or gender (p=0.28) between groups. WCC and CRP were significantly lower in those without consolidation. Analysis of cases where pneumonia was highlighted as the primary reason for admission (n=47) was similar to the overall cohort: 26% had no radiological evidence of consolidation. <h3>Conclusion</h3> A significant proportion of clinical diagnoses of pneumonia are made despite no radiological evidence of consolidation. Studies are required to investigate if this could be due to a lack of awareness of diagnostic criteria, mismatch in chest x-ray interpretation or other factors in the clinical presentation.
Cirrhosis of the Liver and Icterus of Four Years' Duration: With Remarks on Biliary Cirrhosis
Authors: F. P. Weber
Journal: BMJ (1896)

turbance.This swelling of the epiphyses, with or without pain, as the lesion giving rise to it was a congenital one, might appear in infants of anly age.WVhen the enlargement of the epiphyses was of any considerable size, however, it usually occurred in infants of from three to six months old, but was rare after the latter age.Suppuration of epiphysial disease of the long bones was rare in infants under a year old."In older children," he continued, " suppuration over the ends of the long bones is, perlhaps, commoner than in young infants, owing possibly to walking and otlher uses of the limbs proving prejudicial to a previous epipliysitis not entirely cleared up.A symmetrical suppurative epiphysitis in ehildren between i and 3 years old is to me suffieient to warrant a strong suspicion of syphilis for its causation.In contradistinction to the case of the long bones, suppuration arising from epiphysitis of the phalanges, ' syphilitic dactyl- itiS,' is not very rare."ACQUIRED SYPHILIS.After quoting the differences between inlherited and acquired syphilis in the chlild, as enumerated by Kassowitz, Dr. Coutts said: " As far as my experienee goes the eommonest eruption in acquired syphilis in infants, as in adults, is the well-known roseola and its usual distribution, the same at all ages, namely, the front of the chest, the abdomen, and to a less degree the flexor aspects of the limbs.This syphilitic roseola, admittedly rare in inherited cases, was the form of eruption in seven out of my eight cases.In
End-of-life caregivers' perception of medical and psychological support during the final weeks of glioma patients: a questionnaire-based survey
Authors: Oliver Heese, Eva Vogeler, Tobias Martens, Oliver Schnell, Jörg-Christian Tonn, Matthias Simon, Johannes Schramm, Dietmar Krex, Gabriele Schackert, Thomas Reithmeier, Guido Nikkhah, Michael Sabel, Hans-Jakob Steiger, Uwe Schlegel, Markus Löffler, Michael Weller, Manfred Westphal
Journal: Neuro-Oncology (2013)

The prognosis for glioma remains dismal, and little is known about the final disease phase. To obtain information about this period, we surveyed caregivers of patients who were registered in the German Glioma Network and who died from the disease. A questionnaire with 15 items, focusing on medical, logistic, and mental health support and symptom control during the final 4 weeks, was sent to caregivers. For some of the questions, a scale from 1 (inadequate) to 10 (excellent) was used. Of 1655 questionnaires, 605 were returned (36.6%) and evaluated. We found that 67.9% of the patients were taken care of at home for the last 4 weeks; 47.7% died at home, 22.6% died in hospitals, and 19.3% died in hospice facilities. Medical support was provided by general practitioners in 72.3% of cases, by physicians affiliated with a nursing home or hospice in 29.9%, and by general oncologists in 17%. Specialized neuro-oncologists were involved in 6%. The caregivers ranked the medical support with a mean of 7.2 (using a 10-point scale), nursing service with 8.1, and mental health support with 5.5. In 22.9% of cases, no support for the caregivers themselves was offered by medical institutions. Although these data reflect the caregivers' subjective views, they are useful in understanding and improving current patterns of care. While patients and their caregivers are supported mainly by neuro-oncologists for most of the disease phase, the end-of-life phase is managed predominantly by general practitioners and specialists in palliative care. Close cooperation between these specialties is necessary to meet the specific needs of glioma patients.
The Behavioral Activation System and Mania
Authors: Sheri L. Johnson, Michael D. Edge, M. Kathleen Holmes, Charles S. Carver
Journal: Annual Review of Clinical Psychology (2012)

For over two decades, theorists have suggested that mania relates to heightened sensitivity of the behavioral activation system (BAS). In this article, we review a burgeoning empirical literature on this model, drawing on both cross-sectional and prospective studies. As evidence has emerged for this model, we argue that it is time to consider more specific aspects of BAS sensitivity in this disorder. We review evidence that bipolar disorder relates to an increased willingness to expend effort toward reward and to increases in energy and goal pursuit after an initial reward. We conclude by considering the strengths and weaknesses of this literature, with an eye toward future directions and implications for treatment.
Primary lymphoepithelioma-like carcinoma within an intralobular pulmonary sequestration
Authors: N Hekelaar, R van Uffelen, AC van Vliet, OC Varin, PJ Westenend
Journal: European Respiratory Journal (2000)

A 31-yr-old Chinese female, a nonsmoker, presented with digital clubbing and coughing. Diagnostic evaluation revealed a pulmonary sequestration in the left lower lobe. During surgery a tumour was discovered, which turned out to be a lymphoepithelioma-like carcinoma. These tumours are mainly found in Asians, and are associated with the Epstein Barr virus and not with smoking. They are thought to have a better prognosis and to be more chemosensitive. The need for surgical treatment of pulmonary sequestration and the recognition of lymphoepithelioma-like carcinoma as a distinct clinicopathological entity is emphasized.