tbuckley/cabot-search huggingface dataset:
Clinical Nature and Prognosis of Locally Recurrent Rectal Cancer After Total Mesorectal Excision With or Without Preoperative Radiotherapy
Authors: Mandy van den Brink, Anne M. Stiggelbout, Wilbert B. van den Hout, Job Kievit, Elma Klein Kranenbarg, Corrie A.M. Marijnen, Iris D. Nagtegaal, Harm J.T. Rutten, Theo Wiggers, Cornelis J.H. van de Velde
Journal: Journal of Clinical Oncology (2004)

To document the clinical nature and prognosis of locally recurrent rectal cancer after total mesorectal excision (TME) with or without 5 x 5 Gy preoperative radiotherapy (PRT) and to identify patient-, disease-, and treatment-related factors associated with differences in prognosis after local recurrence.For 96 Dutch patients with a local recurrence who participated in a multicenter randomized clinical trial, data on treatments and follow-up were gathered from surgeons and radiation and medical oncologists. Twenty-three patients (24%) had previously been treated with PRT plus TME, and 73 patients (76%) had been treated with TME alone. Eighty-one patients (84%) were followed until death; median follow-up time of the alive patients after local recurrence was 21 months (range, 5 to 48 months).Survival after local recurrence in the PRT + TME group was significantly shorter than in the TME group (median survival, 6.1 v 15.9 months; hazard ratio for death, 2.1; P =.008). Patients with a local recurrence in the PRT + TME group had distant metastases more often (74% v 40%; P =.004), underwent surgical resection of local recurrence less often (17% v 35%; P =.11), and received radiotherapy for local recurrence at a total dose >/= 45 Gy less often (4% v 42%; P =.001) than patients without PRT. In a multivariate analysis, the difference in survival after local recurrence between randomization groups was no longer statistically significant (hazard ratio for death of PRT, 1.53; P =.16).The clinical nature and prognosis of patients with locally recurrent rectal cancer has changed since the introduction of PRT. The majority of patients who present with a local recurrence after previous PRT have simultaneous distant metastases, and median survival has decreased to 6 months.
The Proinflammatory Myeloid Cell Receptor TREM-1 Controls Kupffer Cell Activation and Development of Hepatocellular Carcinoma
Authors: Juan Wu, Jiaqi Li, Rosalba Salcedo, Nahid F. Mivechi, Giorgio Trinchieri, Anatolij Horuzsko
Journal: Cancer Research (2012)

Chronic inflammation drives liver cancer pathogenesis, invasion, and metastasis. Liver Kupffer cells have crucial roles in mediating the inflammatory processes that promote liver cancer, but the mechanistic basis for their contributions are not fully understood. Here we show that expression of the proinflammatory myeloid cell surface receptor TREM-1 expressed by Kupffer cells is a crucial factor in the development and progression of liver cancer. Deletion of the murine homolog Trem1 in mice attenuated hepatocellular carcinogenesis triggered by diethylnitrosamine (DEN). Trem1 deficiency attenuated Kupffer cell activation by downregulating transcription and protein expression of interleukin (IL)-6, IL-1β, TNF, CCL2, and CXCL10. In addition, Trem1 ablation diminished activation of the p38, extracellular regulated kinase 1/2, JNK, mitogen-activated protein kinase, and NF-κB signaling pathways in Kupffer cells, resulting in diminished liver injury after DEN exposure. Adoptive transfer of wild-type Kupffer cells to Trem1-deficient mice complemented these defects and reversed unresponsiveness to DEN-induced liver injury and malignant development. Together, our findings offer causal evidence that TREM-1 is a pivotal determinant of Kupffer cell activation in liver carcinogenesis, deepening mechanistic insights into how chronic inflammation underpins the development and progression of liver cancer.
The Effect of KCl on Atrial Fibrillation Caused by Acetylcholine
Authors: J. H. BURN, A. J. GUNNING, J. M. WALKER
Journal: Circulation Research (1956)

Atrial fibrillation can be produced in the heart-lung preparation of the dog by the slow infusion of acetylcholine and the application of electric stimuli to the auricle. The fibrillation can then be maintained indefinitely, after stimulation ceases, by continuing the infusion of acetylcholine. The fibrillation can be restored to normal rhythm by the infusion of KCl. This throws light on the action of acetylcholine in maintaining atrial fibrillation.
Specificity of antinuclear antibodies in scleroderma-like chronic graft-versus-host disease: clinical correlation and histocompatibility locus antigen association
Authors: S.A. BELL, H. FAUST, J. MITTERMÜLLER, H.-J. KOLB, M. MEURER
Journal: British Journal of Dermatology (1996)

Chronic graft-versus-host disease after bone marrow transplantation presents, in a few cases, as mild to severe scleroderma-like changes. Patients with chronic graft-versus-host disease with and without sclerodermatous skin changes were analysed for antinuclear autoantibodies (ANA) and antinucleolar autoantibodies (ANoA) and the results correlated with disease symptoms and histocompatibility locus antigen (HLA) pattern. Nineteen patients with chronic graft-versus-host disease and scleroderma-like skin changes, 18 with chronic graft-versus-host disease without scleroderma, and 17 controls on immunosuppressive treatment were screened for ANA and ANoA using enzyme-linked immunosorbent assay, immunodiffusion and immunoblot techniques. Four patients with severe scleroderma had antibodies to topoisomerase I, two had antibodies against PM-Scl, both characteristic serological findings in idiopathic systemic scleroderma. One patient had La/SSB antibodies and, in three cases, antibodies to the nucleolar antigen C23 (nucleolin) could be identified. A possible correlation between antinucleolin antibodies and disease activity was observed. HLA-A1, -B1, and -B2 were found significantly more often in patients with scleroderma-like symptoms in comparison to patients without scleroderma-like symptoms. Chronic graft-versus-host disease with scleroderma-like manifestations can be associated with the occurrence of ANA specific for idiopathic scleroderma. The development of scleroderma after bone marrow transplantation might have a HLA-linked genetic background.
Pharmacogenetics in Biological Perspective
Authors: W. Kalow
Journal: Pharmacological Reviews (1997)

What have we learned? Pharmacogenetics, heritable variation in response to xenobiotics, is present in all forms of life. Initially, human data perhaps have created the most excitement, and they provide much biochemical detail. However, if we look at pharmacogenetic variation of insects and bacteria, we see it as a characteristic of populations; individuals with inborn resistance to various toxicants can cause the survival of a population by the process of Darwinian selection. Diversity of a population and Darwinian selection are different milestones serving population survival. Variation of drug response may represent variation of drug targets, drug metabolism, and probably drug transport. Metabolic variation appears to be the most prominent; at present, it is not clear whether this prominence has historical or biological causes. It is an interesting exercise to compare pharmacogenetic resistance with intoxication and resistance to infection by invasion of disease-carrying bacteria or other pathogens. The big difference is that pathogens tend to show variabilities that drugs do not have. The immune system is made to deal with the genetic variabilities linked to the short life span of most pathogens. However, there are, besides the immune system, several cases of genetic host resistance associated with the long life span of mammalian hosts. Such genetic host resistances are factors equivalent to pharmacogenetic variation. Current data pertain to resistance against malaria, tuberculosis, cholera, and AIDS. Most pharmacogenetic variants within a population are preadaptive, that is, they are established before xenobiotic exposure. Hence, one must postulate a multiplicity of variants in a population capable of resisting a multiplicity of drugs. The persistence of this multiplicity suggests that most variants are either present in heterozygous form and are thereby advantageous for their carriers, or they are selectively neutral mutants. It means that the biological cost of pharmacogenetic diversity, measured in terms of reduced fertility, should be low in a population. The frequencies of variant genes are usually not the same in different populations. Also the nucleotide substitutions in a variable gene often differ between populations. In other words, pharmacogenetic differences between populations are typical events. Pharmacogenetics is usually thought of as the study of a situation in which a single gene product exerts control over a given drug response so that a failure to respond, or an excessive response, may result. However, one should not forget that random variation is always present, probably reflecting the randomness of mutations plus variation of any environmental factors that might contribute. This underlying randomness of variation will always affect the picture of any all-or-none variation. Future pharmacogenetics must deal with both random and monogenic variation.
Mortality in patients with coeliac disease and their relatives: a cohort study
Authors: Giovanni Corrao, Gino Roberto Corazza, Vincenzo Bagnardi, Giovanna Brusco, Carolina Ciacci, Mario Cottone, Carla Sategna Guidetti, Paolo Usai, Pietro Cesari, Maria Antonietta Pelli, Silvano Loperfido, Umberto Volta, Antonino Calabró, Maria Certo
Journal: The Lancet (2001)
Estrogen Relaxes Coronary Arteries by Opening BK <sub>Ca</sub> Channels Through a cGMP-Dependent Mechanism
Authors: Richard E. White, David J. Darkow, Jessica L. Falvo Lang
Journal: Circulation Research (1995)

Abstract Women rarely suffer cardiovascular dysfunction before menopause, but by the age of 65 a woman becomes as vulnerable to cardiovascular mortality as a man. It has been proposed that estrogens protect against cardiovascular disease; however, the physiological basis of estrogen protection is unknown. In the present study the mechanism of estrogen-induced relaxation of coronary arteries was investigated at the tissue, cellular, and molecular levels. Tissue studies demonstrated that 17β-estradiol relaxes porcine coronary arteries by an endothelium-independent mechanism involving K + efflux, and subsequent studies employing the patch-clamp technique confirmed that estrogen stimulates K + channel gating in coronary smooth muscle. Perforated-patch recordings from metabolically intact coronary myocytes revealed that 17β-estradiol more than doubles steady state outward currents in these cells at positive voltages. Studies of on-cell patches demonstrated a potent stimulatory effect of 17β-estradiol on the gating of the large-conductance, Ca 2+ - and voltage-activated K + (BK Ca ) channels, while 17α-estradiol had no effect. Furthermore, blocking BK Ca channels in intact arteries inhibited estrogen-induced relaxation. The effect of 17β-estradiol on BK Ca channels was blocked by inhibiting cGMP-dependent protein kinase (PKG) activity and was mimicked by exogenous cGMP or by stimulating PKG activity. Therefore, we propose that 17β-estradiol relaxes coronary arteries by opening BK Ca channels via cGMP-dependent phosphorylation. This novel mechanism could account for the hypotensive effect of estrogens and help explain, at least in part, why postmenopausal estrogen therapy lowers the risk of cardiovascular disease.
Mixed glandular and squamous-cell carcinoma of the bronchus
Authors: D. J. B. Ashley, H. D. Davies
Journal: Thorax (1967)

A group of 26 examples of lung carcinoma showing mixed squamous and glandular differentiation is described. The clinical and biological features of the lesions are intermediate between those of squamous-cell carcinoma and adenocarcinoma of the bronchus. It is suggested that bronchial carcinoma is a single entity in which the type of cell, whether glandular or squamous, plays a much smaller part in determining the biological behaviour than the anatomical site of the tumour and the degree of differentiation of its component cells. It is suggested that mixed adenosquamous tumours arise from bronchial epithelial cells in the process of metaplastic change from the columnar to the squamous form.
Myeloid-derived Regulatory Cells in the Airways of Asthmatic and COPD Patients
Authors: J.S. Deshane, M. Zeng, J.W. Zmijewski, M. Spell, J.T. Anderson, D. Redden, E. Abraham, A. Gaggar, M. Dransfield, D.D. Chaplin
Journal: Journal of Allergy and Clinical Immunology (2011)
A <i>CDKN2A</i> Mutation in Familial Melanoma that Abrogates Binding of p16INK4a to CDK4 but not CDK6
Authors: Rebecca Jones, Margarida Ruas, Fiona Gregory, Stephanie Moulin, Domenico Delia, Siranoush Manoukian, Janice Rowe, Sharon Brookes, Gordon Peters
Journal: Cancer Research (2007)

Abstract The CDKN2A locus encodes two distinct proteins, p16INK4a and p14ARF, both of which are implicated in replicative senescence and tumor suppression in different contexts. Here, we describe the characterization of a novel strain of human diploid fibroblasts (designated Milan HDFs) from an individual who is homozygous for the R24P mutation in p16INK4a. As this mutation occurs in the first exon of INK4a (exon 1α), it has no effect on the primary sequence of p14ARF. Based on both in vitro and in vivo analyses, the R24P variant is specifically defective for binding to CDK4 but remains able to associate with CDK6. Nevertheless, Milan HDFs behave as if they are p16INK4a deficient, in terms of sensitivity to spontaneous and oncogene-induced senescence, and the R24P variant has little effect on proliferation when ectopically expressed in normal fibroblasts. It can, however, impair the proliferation of U20S cells, presumably because they express more CDK6 than primary fibroblasts. These observations suggest that CDK4 and CDK6 are not functionally redundant and underscore the importance of CDK4 in the development of melanoma. [Cancer Res 2007;67(19):9134–41]
Hepatitis B Virus X Protein (HBx) Is Responsible for Resistance to Targeted Therapies in Hepatocellular Carcinoma: <i>Ex Vivo</i> Culture Evidence
Authors: Pinbo Huang, Baoxiong Zhuang, Heyun Zhang, Haiyan Yan, Zhiyu Xiao, Wenbin Li, Jianlong Zhang, Qibin Tang, Kaishun Hu, H. Phillip Koeffler, Jie Wang, Dong Yin
Journal: Clinical Cancer Research (2015)

Molecular targeted therapy is an important approach for advanced hepatocellular carcinoma (HCC). Hepatitis B virus-related HCC (HBV-HCC) accounts for approximately 50% of all HCC cases. Bortezomib, a proteasome inhibitor (PI), is used extensively for the treatment of hematologic malignancies, but its application in HCC, particularly in HBV-HCC, has not been fully explored.The effects of bortezomib on HCC tissues were evaluated by TUNEL assays. The growth inhibitory activity was measured using cell viability assays, and apoptosis was measured using flow cytometry. The levels of HBx, P-Raf/Raf, and P-Erk/Erk expression were measured by Western blot analysis. The ability of the MEK inhibitor PD98059 to enhance the cell killing activity of bortezomib was evaluated using ex vivo and in vivo methods.The potency of bortezomib varied among HCC samples and cell lines, and HBV/HBx expression was associated with resistance to bortezomib. Bortezomib increased the levels of P-Raf and P-Erk in HBV/HBx-positive cells but not in HBV/HBx-negative HCC cells or in breast cancer or glioblastoma multiform cells. HBx was also upregulated after exposure to bortezomib, which was associated with the inhibition of proteasome activity. P-Erk upregulation mediated by bortezomib was effectively suppressed by the addition of the MEK inhibitor PD98059. Moreover, bortezomib and PD98059 synergistically inhibited HCC cell proliferation, as measured using both ex vivo and in vivo models.Our studies demonstrate for the first time that HBx causes resistance to bortezomib in HCC, and this resistance can be antagonized by a MEK signaling inhibitor, providing a novel therapeutic approach.
Phenotypic and functional changes in peripheral blood monocytes during progression of human immunodeficiency virus infection. Effects of soluble immune complexes, cytokines, subcellular particulates from apoptotic cells, and HIV-1-encoded proteins on monocytes phagocytic function, oxidative burst, transendothelial migration, and cell surface phenotype.
Authors: J Trial, H H Birdsall, J A Hallum, M L Crane, M C Rodriguez-Barradas, A L de Jong, B Krishnan, C E Lacke, C G Figdor, R D Rossen
Journal: Journal of Clinical Investigation (1995)

We postulated that changes in the cell surface display of molecules that facilitate cell-cell and cell-matrix adhesions may reflect the changing immunosurveillance capacity of blood monocytes during progression of human immunodeficiency virus (HIV) infections. In Centers for Disease Control (CDC) stage A patients, whose monocytes' ability to phagocytose bacteria and generate reactive oxygen intermediates is often increased, the frequency of monocytes expressing CD49d, HLA-DP, HLA-DQ, and an activation epitope of CD11a/CD18 was increased and monocyte transendothelial migration was unimpaired. In CDC stage B/C patients, whose monocytes' ability to phagocytose bacteria and migrate across confluent endothelial monolayers was diminished, surface expression of CD49e and CD62L and the percentage of monocytes expressing CD18, CD11a, CD29, CD49e, CD54, CD58, CD31, and HLA-I were significantly decreased. Incubating normal donor monocytes with immune complexes in vitro reproduced the phenotypic and functional abnormalities seen in stage B/C patients. By contrast, in vitro stimulation with subcellular particulates released by apoptotic lymphocytes reproduced changes seen in stage A patients' monocytes. Although circulating monocytes appear to be activated at all stages, these data suggest that the high levels of circulating immune complexes, found predominantly in the later stages of HIV infection, may be particularly instrumental in reducing the monocyte's capacity to maintain surveillance against infection.
Promoting children's home safety
Authors: R H. Jackson
Journal: BMJ (1983)

Disciplinary attitudes and cigarette smoking: a comparison of two schools SIR,-I agree with Dr Alan Porter's suggestion (1 1 December, p 1725) that measures that reduce the exposure of an uncommitted adolescent to peer group smoking may de- crease the chances of tobacco dependence in childhood.The recognition of the immediate rather than long term harmful effects of smoking is an important consideration in persuading patients not to smoke, and parental attitudes and smoking behaviour influence a child's propensity to smoke.'Most smokers begin smoking before the age of 20, and those who have not smoked before this age are un- likely to begin.2 3 Our unpublished data on the effects of smoking on cardiorespiratory dis- orders suggest that smoking does much more harm to younger patients than to middle aged patients and that-over the age of 60 there is no difference between smokers and non-smokers.This suggests that a preventive approach must be directed at those in the first two decades of life and "no smoking" should become a family affair in view of the fact that young people are much less likely to smoke when neither parent does.
Provision of Community Benefits by Tax-Exempt U.S. Hospitals
Authors: Gary J. Young, Chia-Hung Chou, Jeffrey Alexander, Shoou-Yih Daniel Lee, Eli Raver
Journal: New England Journal of Medicine (2013)

The Patient Protection and Affordable Care Act (ACA) requires tax-exempt hospitals to conduct assessments of community needs and address identified needs. Most tax-exempt hospitals will need to meet this requirement by the end of 2013.We conducted a national study of the level and pattern of community benefits that tax-exempt hospitals provide. The study comprised more than 1800 tax-exempt hospitals, approximately two thirds of all such institutions. We used reports that hospitals filed with the Internal Revenue Service for fiscal year 2009 that provide expenditures for seven types of community benefits. We combined these reports with other data to examine whether institutional, community, and market characteristics are associated with the provision of community benefits by hospitals.Tax-exempt hospitals spent 7.5% of their operating expenses on community benefits during fiscal year 2009. More than 85% of these expenditures were devoted to charity care and other patient care services. Of the remaining community-benefit expenditures, approximately 5% were devoted to community health improvements that hospitals undertook directly. The rest went to education in health professions, research, and contributions to community groups. The level of benefits provided varied widely among the hospitals (hospitals in the top decile devoted approximately 20% of operating expenses to community benefits; hospitals in the bottom decile devoted approximately 1%). This variation was not accounted for by indicators of community need.In 2009, tax-exempt hospitals varied markedly in the level of community benefits provided, with most of their benefit-related expenditures allocated to patient care services. Little was spent on community health improvement.
FeNO and web-based monitoring in paediatric asthma managemant; the BATMAN study
Authors: Sandra Voorend-van Bergen, Anja Vaessen-Verberne, Anneke Landstra, Hein Brackel, Norbert van den Berg, Johan de Jongste, Peter Merkus, Mariëlle Pijnenburg
Journal: European Respiratory Journal (2013)

Introduction : Asthma control in children is far from optimal. We studied 3 treatment strategies for their ability to improve asthma control: (1) usual care, (2) 4-monthly monitoring of the fraction of nitric oxide in exhaled air (FeNO) in addition to usual care and (3) web-based monthly monitoring of asthma control .    Methods:  In this randomized, controlled multi-centre trial, asthmatic children 4-18 years were randomized to 1 of the 3 groups. All children were seen every 4 months for 1 year. Asthma control was assessed using the Asthma Control Test (ACT or C-ACT). In the usual care and web group, treatment was adapted according to the ACT score respectively at 4 and 1 months intervals; in the FeNO group according to ACT and FeNO. Primary endpoint was the proportion of symptom-free days (SFD), for which a 4-week web-based diary was filled in at the start and after 1 year. Changes from baseline of SFD were compared between groups with ANCOVA.   Results:  280 children (mean age 10.4 yrs, 66% boys) were included, 268 completed the study. Overall median ACT score at baseline was 22, range 19-24. Mean changes from baseline in SFD did not significantly differ between the groups. A significant within-group change was only seen in the FeNO group (improvement SFD 0.53 to 0.61, p   Conclusion:  The change from baseline in SFD after 1 year of treatment did not differ between treatment strategies. Only the FeNO strategy showed within-group improvement of SFD, while in children with additional monthly web-based consultations the dose of ICS could be reduced while control was maintained.