tbuckley/cabot-search huggingface dataset:
<i>RAS</i> Mutations Contribute to Evolution of Chronic Myelomonocytic Leukemia to the Proliferative Variant
Authors: Clara Ricci, Elisa Fermo, Stefania Corti, Mauro Molteni, Alessio Faricciotti, Agostino Cortelezzi, Giorgio Lambertenghi Deliliers, Miloslav Beran, Francesco Onida
Journal: Clinical Cancer Research (2010)

The biological and clinical heterogeneity of chronic myelomonocytic leukemia features renders its classification difficult. Moreover, because of the limited knowledge of the mechanisms involved in malignant evolution, chronic myelomonocytic leukemia remains a diagnostic and therapeutic challenge and a poor prognosis disease. We aimed to verify the biological and clinical significance of the discrimination, based on the leukocyte count, between myelodysplastic chronic myelomonocytic leukemia (MD-CMML) and myeloproliferative chronic myelomonocytic leukemia (MP-CMML).Peripheral blood samples from 22 patients classified as MD-CMML and 18 as MP-CMML were collected at different time points during disease course, and patients' clinical characteristics were examined. RAS mutational screening was done by sequencing and, for each substitution identified, a highly selective allele-specific PCR was set up to screen all specimens.MP-CMML patients showed a significantly poorer survival (P = 0.003) and a higher frequency of RAS mutations (P = 0.033) by sequencing compared with MD-CMML. Overall, five MD-CMML patients progressed to myeloproliferative disease: in two, allele-specific PCR unveiled low levels of the RAS mutations predominating in the myeloproliferative phase at the time of myelodysplastic disease, documenting for the first time the expansion of a RAS mutated clone in concomitance with chronic myelomonocytic leukemia evolution. Moreover, one of the progressed patients harbored the FLT3-ITD and two MP-CMML patients presented with the JAK2 V617F substitution. All these lesions were mutually exclusive.Our results strongly suggest RAS mutations to function as a secondary event that contributes to development of the chronic myelomonocytic leukemia variant with the poorer prognosis (MP-CMML) and therefore advise their detection to be implemented in chronic myelomonocytic leukemia diagnostics and monitoring.
Gastric intramucosal pH as a therapeutic index of tissue oxygenation in critically ill patients
Authors: G. Gutierrez, F. Palizas, G. Doglio, J. Pusajo, N. Wainsztein, F. Klein, A. Gallesio, E. San Roman, J. Pacin, B. Dorfman, A. Dubin, E. Schiavi, J. Shottender, M. Jorge, R. Giniger
Journal: The Lancet (1992)
Controlled Trial of a Multifaceted Intervention for Improving Quality of Care for Rural Patients With Type 2 Diabetes
Authors: Sumit R. Majumdar, Lisa M. Guirguis, Ellen L. Toth, Richard Z. Lewanczuk, T.K. Lee, Jeffrey A. Johnson
Journal: Diabetes Care (2003)

OBJECTIVE—Despite good evidence and clinical practice guidelines, studies document that treatment of type 2 diabetes is less than optimal. Lack of resources or limited access may put patients in rural communities at particular risk for suboptimal care. RESEARCH DESIGN AND METHODS—We conducted a prospective, before/after study with concurrent controls to assess the effectiveness of a multidisciplinary diabetes outreach service (intervention) for improving the quality of care for rural patients with type 2 diabetes. Our intervention consisted of six monthly visits by a traveling team of specialist physicians, nurses, dieticians, and a pharmacist. The core of this service was specialist-to-rural primary care physician academic group detailing. Two comparable regions in Northern Alberta were randomly allocated to control or intervention. Data were collected before and 6 months after intervention in a representative volunteer sample. The primary outcome was a 10% improvement in any one of the following: blood pressure, total cholesterol, or HbA1c. RESULTS—Our analysis included 200 intervention and 179 control subjects; 14 subjects were at all three primary outcome targets at baseline. The intervention was associated with a trend toward improvement in primary outcome at 6 months (44% intervention vs. 37% control; odds ratio 1.32, 95% CI 0.87–1.99). The intervention was associated with a significant improvement in blood pressure (42% intervention vs. 25% control, P = 0.004); however, there were only small, nonsignificant changes in cholesterol or HbA1c. The intervention was associated with a significant increase in satisfaction with diabetes care. Multivariate adjustment for baseline differences between intervention and control subjects did not affect any of the main results. CONCLUSIONS—A diabetes outreach service has the potential to improve the quality of diabetes care for rural patients. Future studies need to involve longer timelines and larger sample sizes.
European Guidelines for Quality Assurance in Cervical Cancer Screening. Second Edition—Summary Document
Authors: M. Arbyn, A. Anttila, J. Jordan, G. Ronco, U. Schenck, N. Segnan, H. Wiener, A. Herbert, L. von Karsa
Journal: Annals of Oncology (2010)

European Guidelines for Quality Assurance in Cervical Cancer Screening have been initiated in the Europe Against Cancer Programme. The first edition established the principles of organised population-based screening and stimulated numerous pilot projects. The second multidisciplinary edition was published in 2008 and comprises approximately 250 pages divided into seven chapters prepared by 48 authors and contributors. Considerable attention has been devoted to organised, population-based programme policies which minimise adverse effects and maximise benefits of screening. It is hoped that this expanded guidelines edition will have a greater impact on countries in which screening programmes are still lacking and in which opportunistic screening has been preferred in the past. Other methodological aspects such as future prospects of human papillomavirus testing and vaccination in cervical cancer control have also been examined in the second edition; recommendations for integration of the latter technologies into European guidelines are currently under development in a related project supported by the European Union Health Programme. An overview of the fundamental points and principles that should support any quality-assured screening programme and key performance indicators are presented here in a summary document of the second guidelines edition in order to make these principles and standards known to a wider scientific community.
Epidermal Growth Factor Receptor Controls Flat Dysplastic Aberrant Crypt Foci Development and Colon Cancer Progression in the Rat Azoxymethane Model
Authors: Urszula Dougherty, Amikar Sehdev, Sonia Cerda, Reba Mustafi, Nathaniel Little, Weihua Yuan, Sujatha Jagadeeswaran, Anusara Chumsangsri, Jorge Delgado, Maria Tretiakova, Loren Joseph, John Hart, Ezra E.W. Cohen, Lata Aluri, Alessandro Fichera, Marc Bissonnette
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Colonic carcinogenesis deranges growth-regulating epidermal growth factor receptors (EGFR). We previously showed that EGFR signals were up-regulated in human aberrant crypt foci (ACF), putative colon cancer precursors. The azoxymethane model of colon cancer recapitulates many aspects of human colonic tumors. Recent studies indicate that flat dysplastic ACF with increased β-catenin are tumor precursors in this model. We asked, therefore, if EGFR signals are required for flat dysplastic ACF development and cancer progression. Experimental Design: Rats received azoxymethane or saline, and standard chow or chow supplemented with gefitinib, an EGFR inhibitor, for 44 weeks. EGFR signals were quantified in normal colon, flat ACF, and tumors by computerized analysis of immunostains and Western blots. K-ras mutations were assessed by PCR and mRNA for egfr ligands by quantitative real-time PCR. Results: EGFR inhibition with gefitinib decreased the incidence of flat dysplastic ACF from 66% to 36% and tumors from 71% to 22% (P &amp;lt; 0.05). This inhibitor also reduced the overexpressions of cyclin D1 and Cox-2 in flat ACF. Furthermore, in flat ACF, EGFR blockade decreased the up-regulation of c-Jun, FosB, phosphorylated active signal transducers and activators of transcription 3, and CCAAT/enhancer binding protein-β, potential regulators of cyclin D1 and Cox-2. In colonic tumors, EGFR blockade significantly decreased angiogenesis, proliferation, and progression while also increasing apoptosis (P &amp;lt; 0.05). Gefitinib also inhibited the activations of extracellular signal–regulated kinase, Src, and AKT pathways in tumors. Conclusions: We have shown for the first time that EGFR promotes the development of flat dysplastic ACF and the progression of malignant colonic tumors. Furthermore, we have mechanistically identified several transcription factors and their targets as EGFR effectors in colonic carcinogenesis.
Editing HIV to death
Authors: Heather L. Van Epps
Journal: The Journal of Experimental Medicine (2005)

Nod1 is a member of family of intracellular proteins that mediate host recognition of bacterial peptidoglycan.To characterize immune responses mediated by Nod1, synthetic ligand compounds possessing enhanced ability to stimulate Nod1 were developed to study the function of Nod1.Stimulation of epithelial cells with Nod1 stimulatory molecules induced chemokines and other proinfl ammatory molecules that are important for innate immune responses and recruitment of acute infl ammatory cells.Administration of Nod1 ligands into mice induced chemokines and recruitment of acute infl ammatory cells, an activity that was abolished in Nod1-null mice.Microarray analysis revealed that Nod1 stimulation induces a restricted number of genes in intestinal epithelial cells compared with that induced by tumor necrosis factor (TNF) .Nod1 stimulation did not induce TNF, interleukin 12, and interferon , suggesting that the primary role of Nod1 is to induce the recruitment of immune cells.These results indicate that Nod1 functions as a pathogen recognition molecule to induce expression of molecules involved in the early stages of the innate immune response.
Intestinal Bacteria and the Regulation of Immune Cell Homeostasis
Authors: David A. Hill, David Artis
Journal: Annual Review of Immunology (2010)

The human intestine is colonized by an estimated 100 trillion bacteria. Some of these bacteria are essential for normal physiology, whereas others have been implicated in the pathogenesis of multiple inflammatory diseases including IBD and asthma. This review examines the influence of signals from intestinal bacteria on the homeostasis of the mammalian immune system in the context of health and disease. We review the bacterial composition of the mammalian intestine, known bacterial-derived immunoregulatory molecules, and the mammalian innate immune receptors that recognize them. We discuss the influence of bacterial-derived signals on immune cell function and the mechanisms by which these signals modulate the development and progression of inflammatory disease. We conclude with an examination of successes and future challenges in using bacterial communities or their products in the prevention or treatment of human disease.
Insulin resistance in obese Zucker rat (fa/fa) skeletal muscle is associated with a failure of glucose transporter translocation.
Authors: P A King, E D Horton, M F Hirshman, E S Horton
Journal: Journal of Clinical Investigation (1992)

The genetically obese Zucker rat (fa/fa) is characterized by a severe resistance to the action of insulin to stimulate skeletal muscle glucose transport. The goal of the present study was to identify whether the defect associated with this insulin resistance involves an alteration of transporter translocation and/or transporter activity. Various components of the muscle glucose transport system were investigated in plasma membranes isolated from basal or maximally insulin-treated skeletal muscle of lean and obese Zucker rats. Measurements of D- and L-glucose uptake by membrane vesicles under equilibrium exchange conditions indicated that insulin treatment resulted in a four-fold increase in the Vmax for carrier-mediated transport for lean animals [from 4.5 to 17.5 nmol/(mg.s)] but only a 2.5-fold increase for obese rats [from 3.6 to 9.1 nmol/(mg.s)]. In the lean animals, this increase in glucose transport function was associated with a 1.8-fold increase in the transporter number as indicated by cytochalasin B binding, a 1.4-fold increase in plasma membrane GLUT4 protein, and a doubling of the average carrier turnover number (intrinsic activity). In the obese animals, there was no change in plasma membrane transporter number measured by cytochalasin B binding, or in GLUT4 or GLUT1 protein. However, there was an increase in carrier turnover number similar to that seen in the lean litter mates. Measurements of GLUT4 mRNA in red gastrocnemius muscle showed no difference between lean and obese rats. We conclude that the insulin resistance of the obese rats involves the failure of translocation of transporters, while the action of insulin to increase the average carrier turnover number is normal.
Perspectives for the Treatment of Brucellosis in the 21st Century: The Ioannina Recommendations
Authors: Javier Ariza, Mile Bosilkovski, Antonio Cascio, Juan D Colmenero, Michael J Corbel, Matthew E Falagas, Ziad A Memish, Mohammad Reza Hasanjani Roushan, Ethan Rubinstein, Nikolaos V Sipsas, Javier Solera, Edward J Young, Georgios Pappas
Journal: PLoS Medicine (2007)

Brucellosis is probably the commonest anthropozoonotic infection worldwide [1–3], but remains in various aspects an enigma in the 21st century [4]. Brucella melitensis remains the major cause of human disease worldwide, followed by B. abortus and B. suis, while rare but persisting cases of B. canis human infection and disease by novel Brucella pathogens of marine mammals have also emerged. The disease is re-emerging as a significant cause of travel-related disease [5] and represents an index of poor socioeconomic status (Figure 1). Its treatment is largely based even today on the principles applied half a century ago by pioneer researchers [6] and few modifications have been made in the following years, despite the emergence of new antibiotic classes and different therapeutic approaches [7].
Hierarchical accumulation of RyR post-translational modifications drives disease progression in dystrophic cardiomyopathy
Authors: Sergii Kyrychenko, Eva Poláková, Chifei Kang, Krisztina Pocsai, Nina D. Ullrich, Ernst Niggli, Natalia Shirokova
Journal: Cardiovascular Research (2012)

Duchenne muscular dystrophy (DMD) is a muscle disease with serious cardiac complications. Changes in Ca2+ homeostasis and oxidative stress were recently associated with cardiac deterioration, but the cellular pathophysiological mechanisms remain elusive. We investigated whether the activity of ryanodine receptor (RyR) Ca2+ release channels is affected, whether changes in function are cause or consequence and which post-translational modifications drive disease progression. Electrophysiological, imaging, and biochemical techniques were used to study RyRs in cardiomyocytes from mdx mice, an animal model of DMD. Young mdx mice show no changes in cardiac performance, but do so after ∼8 months. Nevertheless, myocytes from mdx pups exhibited exaggerated Ca2+ responses to mechanical stress and 'hypersensitive' excitation–contraction coupling, hallmarks of increased RyR Ca2+ sensitivity. Both were normalized by antioxidants, inhibitors of NAD(P)H oxidase and CaMKII, but not by NO synthases and PKA antagonists. Sarcoplasmic reticulum Ca2+ load and leak were unchanged in young mdx mice. However, by the age of 4–5 months and in senescence, leak was increased and load was reduced, indicating disease progression. By this age, all pharmacological interventions listed above normalized Ca2+ signals and corrected changes in ECC, Ca2+ load, and leak. Our findings suggest that increased RyR Ca2+ sensitivity precedes and presumably drives the progression of dystrophic cardiomyopathy, with oxidative stress initiating its development. RyR oxidation followed by phosphorylation, first by CaMKII and later by PKA, synergistically contributes to cardiac deterioration.
Substance Use Disorders: Realizing the Promise of Pharmacogenomics and Personalized Medicine
Authors: Kent E. Hutchison
Journal: Annual Review of Clinical Psychology (2010)

Current pharmacological and psychosocial approaches to the treatment of alcohol dependence may best be described as modestly effective, and it is unlikely that a magic bullet for the treatment of any substance use disorder will ever be developed. Rather, it seems more likely that there will be a number of treatment options, each of which will target different mechanisms. Thus, future treatment gains are likely to depend on the ability to match individuals with the treatment most likely to benefit them, which in turn is contingent on our ability to understand the mechanisms that drive the maintenance of substance use disorders on an individual level. On a more global scale, this type of effort has been described as “personalized medicine” and has focused largely on the human genome as a source of information that can be used to match individuals to treatments. This review enumerates barriers to realizing the potential of personalized medicine for substance use disorders and identifies opportunities to overcome those barriers, which involve the development of translational approaches that focus on the development of brain-based phenotypes that serve as the target of both treatment development and of genetic research.
ANA screening: an old test with new recommendations
Authors: P. L. Meroni, P. H. Schur
Journal: Annals of the Rheumatic Diseases (2010)

The impact of autoimmune diseases is growing from both a clinical and a laboratory point of view. Diagnostic assays are now being transferred from dedicated specialised laboratories into high-throughput service laboratories. The increasing number of available methods has raised the variability among the laboratories, making their reproducibility a critical problem. On the other hand, reliable tests are needed for early diagnosis and prompt treatment, and the cost of repeated confirmatory tests should be reduced and unnecessary further investigations avoided. New methodologies, particularly for antinuclear antibodies (ANAs), have been applied to autoantibody detection in order to screen and process larger volumes of clinical specimens more quickly and at less cost than the traditional methods. However, because of the lack of their sensitivity to detect all ANAs and standardisation, inaccuracies (including false positives and negatives) in the results have been reported. A committee of the American College of Rheumatology was formed to address this issue. Specific recommendations have been suggested that represent a realistic first step in the standardisation of diagnostic tests for autoimmune diseases.
Efficacy of video assisted thoracoscopic lung biopsy: an historical comparison with open lung biopsy.
Authors: F M Carnochan, W S Walker, E W Cameron
Journal: Thorax (1994)

BACKGROUND--Video assisted thoracoscopic lung biopsies were compared with historical controls undergoing open lung biopsy to determine the diagnostic accuracy, effect on length of postoperative stay, and cost effectiveness of the new thoracoscopic technique. METHODS--The first 25 video assisted thoracoscopic lung biopsies performed in the Edinburgh Thoracic Unit were compared with 25 historical controls for complications, diagnostic accuracy, and length of postoperative stay. RESULTS--Statistical comparison showed equal diagnostic accuracy in both groups (96% v 92%), but mean (SD) inpatient stay was reduced in the video assisted thoracoscopic group (1.4 (0.7) days) compared with those undergoing open lung biopsy (3.1 (1.8) days). No postoperative complications were reported in the group which underwent video assisted thoracoscopic lung biopsies but three patients had postoperative complications in the open lung biopsy group. CONCLUSIONS--Video assisted thoracoscopic lung biopsy is as effective in providing histological diagnosis as is open lung biopsy. All postoperative complications were related to post thoracotomy pain and occurred only in patients undergoing open lung biopsy. Reduced postoperative disability in the video assisted thoracoscopic group decreased hospital stay, offsetting the increased cost in disposables. The overall cost of video assisted thoracoscopic and open lung biopsy was 712 pounds and 1114 pounds, respectively.
Nocturnal oximetry for the diagnosis of the sleep apnoea hypopnoea syndrome: a method to reduce the number of polysomnographies?
Authors: E. Chiner, J. Signes-Costa, J. M. Arriero, J. Marco, I. Fuentes, A. Sergado
Journal: Thorax (1999)

Polysomnography (PSG) is currently the "gold standard" for the diagnosis of the sleep apnoea hypopnoea syndrome (SAHS). Nocturnal oximetry (NO) has been used with contradictory results. A prospective study was performed to determine the accuracy of NO as a diagnostic tool and to evaluate the reduction in the number of PSGs if the diagnosis of SAHS had been established by this method.Two hundred and seventy five patients with a clinical suspicion of SAHS were admitted to undergo, in the same night, full PSG and NO. Desaturation was defined as a fall in the haemoglobin saturation level (SaO(2)) to lower than 4% from the baseline level and an oxygen desaturation index per hour (ODI) was obtained in each patient with three cut off points: >/= 5 (ODI-5), >/= 10 (ODI-10), and >/= 15 (ODI-15).SAHS was diagnosed in 216 patients (194 men). After withdrawing patients with abnormal lung function (forced expiratory volume in one second (FEV(1)) lower than 80% predicted), sensitivity (SE), specificity (SP), positive and negative predictive values (PPV and NPV) of NO were: ODI-5 (80%, 89%, 97%, 48%); ODI-10 (71%, 93%, 97%, 42%); ODI-15 (63%, 96%, 99%, 38%). The accuracy for each ODI was 0.81, 0.75, and 0.70, respectively. If NO had been considered as a diagnostic tool and PSG had been performed only in patients with a negative NO (false negative and true negative) and those with a positive NO and abnormal pulmonary function tests, 135/275 (ODI-5), 156/275 (ODI-10), and 170/275 (ODI-15) PSGs would have been performed, a reduction of 140, 119, and 105, respectively.Nocturnal oximetry in patients with suspected SAHS and normal spirometric values permits the institution of therapeutic measures in most patients.