tbuckley/cabot-search huggingface dataset:
Dietary cholesterol deprivation improves survival and reduces incidence of metastatic colon cancer in dimethylhydrazine-pretreated rats.
Authors: J P Cruse, M R Lewin, C G Clark
Journal: Gut (1982)

Cholesterol feeding of rats with colon cancer induced by dimethylhydrazine results in reduced survival and an increased incidence of metastatic colon cancer. As cholesterol may be implicated in the induction or maintenance of the metastatic process, an experiment was designed to determine whether rats with colon cancer would benefit from the removal of cholesterol from the diet. Female Wistar rats were treated with a colon cancer-inducing regimen of dimethylhydrazine (40 mg/kg/week for 10 weeks) while being fed on a standard cholesterol-containing rat pellet diet. After two rats had died spontaneously of histologically proven adenocarcinoma of the colon at 24 weeks, the remaining rats were randomly allocated in groups of 15 to one of three dietary regimens. Group S continued to receive standard pellet diet, group V were fed on Vivonex alone and group VC were fed Vivonex plus cholesterol (10 mg/100 ml Vivonex). Each group was assessed for survival and incidence of histologically proven metastatic disease. There were no differences in either survival or incidence of metastases when groups S and VC were compared. In the cholesterol deprived group V, however, there was a significant increase in survival compared with groups S and VC (p less than 0.02) and this was due to a significant reduction in the incidence of metastases (p less than 0.05). Cholesterol deprivation therefore benefits rats with established colon cancer induced by dimethylhydrazine by improving survival and reducing the incidence of metastases.
REGULATION OF MHC CLASS II GENES: Lessons from a Disease
Authors: Bernard Mach, Viktor Steimle, Eduardo Martinez-Soria, Walter Reith
Journal: Annual Review of Immunology (1996)

▪ Abstract Precise regulation of major histocompatibility complex class II (MHC-II) gene expression plays a crucial role in the control of the immune response. A major breakthrough in the elucidation of the molecular mechanisms involved in MHC-II regulation has recently come from the study of patients that suffer from a primary immunodeficiency resulting from regulatory defects in MHC-II expression. A genetic complementation cloning approach has led to the isolation of CIITA and RFX5, two essential MHC-II gene transactivators. CIITA and RFX5 are mutated in these patients, and the wild-type genes are capable of correcting their defect in MHC-II expression. The identification of these regulatory factors has furthered our understanding of the molecular mechanisms that regulate MHC-II genes. CIITA was found to be a non-DNA binding transactivator that functions as a molecular switch controlling both constitutive and inducible MHC-II expression. The finding that RFX5 is a subunit of the nuclear RFX-complex has confirmed that a deficiency in the binding of this complex is indeed the molecular basis for MHC-II deficiency in the majority of patients. Furthermore, the study of RFX has demonstrated that MHC-II promoter activity is dependent on the binding of higher-order complexes that are formed by highly specific cooperative binding interactions between certain MHC-II promoter-binding proteins. Two of these proteins belong to families of which the other members, although capable of binding to the same DNA motifs, are probably not directly involved in the control of MHC-II expression. Finally, the facts that CIITA and RFX5 are both essential and highly specific for MHC-II genes make possible novel strategies designed to achieve immunomodulation via transcriptional intervention.
THE COMPLICATIONS OF BARIATRIC SURGERY IN NORTHERN IRELAND
Authors: R J Thompson, M J Mullan, W B Clements, J A Kennedy
Journal: Gut (2013)

<h3>Introduction</h3> Bariatric surgery has increased by 530% in the UK in the past 6 years. Benefits include weight reduction, improvement in weight related co-morbidities and cost-effectiveness compared to conventional weight reduction programmes. <h3>Aims/Background</h3> NICE clinical guidance 43 recommends that bariatric surgery be considered for patients with a BMI &gt;40 or &gt;35 with other co-morbidities. There are over 25,000 with a BMI &gt;40 in Northern Ireland (NI). Bariatric surgery is not commissioned on the NHS in NI. Despite this, clinicians in NI increasingly have to treat its complications. This study was undertaken in order to review the complications of bariatric surgery that have presented to our hospital in the past 6 years. <h3>Method</h3> The hospital PAS system was interrogated for codes relating to emergency admissions due to complications following bariatric surgery between 2007 and 2012. <h3>Results</h3> There were 38 admissions across 32 female patients. Thirty had a gastric band, 1 bypass and 1 gastric balloon. Only one of the procedures was performed in NI. The mean length of stay was 6 days (range 1–20). The mean time since the procedure was 32 months (range 0–120). Complications included abdominal pain, vomiting, infected ports, internal hernia, infected bands, band erosion and gastric/oesophageal perforation. Twenty-five bands and 2 ports were removed. <h3>Conclusion</h3> It is anticipated that healthcare professionals in NI will continue to see increasing numbers of patients admitted with complications from bariatric procedures. Regardless of the current lack of commissioning for bariatric services, significant expertise and resources will continue to be required in order to manage these patients.
miR-574-5p negatively regulates<i>Qki6/7</i>to impact<i>β-catenin</i>/Wnt signalling and the development of colorectal cancer
Authors: Shunlong Ji, Gengtai Ye, Jun Zhang, Linpei Wang, Tao Wang, Zhen Wang, Tiantian Zhang, Guanghui Wang, Zongsheng Guo, Yu Luo, Jianchun Cai, James Y Yang
Journal: Gut (2012)

Deficiency or reduced expression of signal transduction and activation of RNA family protein Quaking (Qki) is associated with developmental defects in neural and vascular tissues and the development of debilitating human diseases including colorectal cancer (CRC). However, the mechanisms underlying the aberrant downregulation or deficiency of Qki were uncertain.Expression of miR-574-5p, Qki5/6/7/7b splicing variants, β-catenin and p27(Kip1) was determined in mouse and human CRC cells and tissues to investigate the post-transcriptional regulation of Qki isoforms by miR-574-5p and its impact on β-catenin/p27(Kip1) signalling, cell cycle progression, proliferation, migration, invasion and tumour growth.In the CRC tissues of C57BL/6-Apc(min/+) mice, miR-574-5p was found to be significantly upregulated and negatively correlated with the expression of Qki but positively correlated with the expression of β-catenin. In mouse and human CRC cells, miR-574-5p was shown to regulate Qki isoforms (Qki6/7 in particular) post-transcriptionally and caused altered expression in β-catenin and p27(Kip1) , increased proliferation, migration and invasion and decreased differentiation and cell cycle exit. Furthermore, in clinical CRC tissues, miR-574-5p was shown to be greatly upregulated and inversely correlated with the expression of Qkis. Finally, inhibition of miR-574-5p was shown to suppress the growth of tumours in the nude mice.Together, these novel findings suggest that miR-574-5p is a potent ribo-regulator for Qkis and that aberrant miR-574-5p upregulation can be oncogenic.
Does location of vertebral deformity within the spine influence back pain and disability?
Authors: W Cockerill
Journal: Annals of the Rheumatic Diseases (2000)

<h3>OBJECTIVE</h3> Vertebral deformity is associated with back pain and disability. The aim of this analysis was to determine whether location within the spine influences the strength of association between vertebral deformity, back pain and disability. <h3>METHODS</h3> Men and women aged 50 years and over were recruited from population registers in 30 European centres. Subjects were invited for an interviewer administered questionnaire, and for lateral spinal radiographs. The questionnaire included questions about back pain, general health and functional ability. The spinal radiographs were evaluated morphometrically and vertebral deformity defined according to the McCloskey-Kanis method. <h3>RESULTS</h3> 756 (11.7%) men and 885 (11.8%) women had evidence of one or more vertebral deformities. Among women with a single deformity, after adjusting for age and centre, those with a lumbar deformity were more likely than those with a thoracic deformity to report back pain, both currently (OR=1.4; 95% CI 1.0, 2.0) and in the past year (OR=1.5; 95% CI 1.0, 2.3). No association was observed in men. Among women with two deformities, those with adjacent deformities were more likely than those with non-adjacent deformities to report poor general health (OR=2.2; 95%CI 0.9, 5.6), impaired functional ability (OR=1.9; 95%CI 0.8, 4.7) and current back pain (OR=2.1; 95%CI 0.9, 4.9), though none of these associations were statistically significant. By contrast, among men, non-adjacent deformities were associated with impaired functional ability compared with those with adjacent deformities. <h3>CONCLUSION</h3> Location within the spine influences the strength of association between self reported health factors and vertebral deformity.
Molecular Genetics and Pathogenesis of Autosomal Dominant Polycystic Kidney Disease
Authors: M. Amin Arnaout
Journal: Annual Review of Medicine (2001)

▪ Abstract Autosomal dominant polycystic kidney disease (ADPKD) is a common and systemic disease characterized by formation of focal cysts. Of the three potential causes of cysts, downstream obstruction, compositional changes in extracellular matrix, and proliferation of partially dedifferentiated cells, evidence strongly supports the latter as the primary abnormality. In the vast majority of cases, the disease is caused by mutations in PKD1 or PKD2, and appears to be recessive at the cellular level. Somatic second hits in the normal allele of cells containing the germ line mutation initiate or accelerate formation of cysts. The intrinsically high frequency of somatic second hits in epithelia appears to be sufficient to explain the frequent occurrence of somatic second hits in the disease-causing genes. PKD1 and PKD2 encode a putative adhesive/ion channel regulatory protein and an ion channel, respectively. The two proteins interact directly in vitro. Their cellular and subcellular localization suggest that they may also function independently in a common signaling pathway that may involve the membrane skeleton and that links cell-cell and cell-matrix adhesion to the development of cell polarity.
Physio-pharmacological evaluation of myocardial performance: an integrative approach
Authors: Ajay M. Shah, Steven J. Sollott, Edward G. Lakatta
Journal: Cardiovascular Research (1998)

Time for primary review 14 days. 

Despite major advances in the understanding of cardiovascular physiology and pathophysiology and the development of new therapies in the 20th century, cardiovascular disease is projected to become the leading overall cause of mortality worldwide within the next couple of decades [1]. In the western world, an increasing proportion of older people in the population accounts for the lack of reduction in the absolute number of cardiovascular deaths, whereas in developing countries, part of the reason is the adoption of “western” lifestyles and their accompanying coronary risk factors as socioeconomic status gradually improves and mortality from infectious and other diseases of early life decrease. There remain significant gaps in our understanding of many aspects of cardiovascular diseases and the contribution of risk factors such as smoking, hypercholesterolaemia, hypertension and diabetes. In addition, increasing numbers of patients who survive ischaemic cardiac disorders develop heart failure.

Traditionally, the focus of research into cardiovascular disease was the heart and myocardium, but in the last several decades, the importance of the vasculature and of other body systems has been better appreciated. The field of vascular biology has blossomed. Traditionally, investigators focused on mechanical function. However, in the last several decades, investigative approaches have broadened dramatically, ranging from molecular and cellular biology and physiology, to in vitro and in vivo studies in animal models of disease, to studies of individual human subjects, to population genetics and epidemiology. The methodologies available and their precision have altered out of all recognition compared to the approaches of 40–50 years ago.

Within this context, the questions that are considered in this article are: How should myocardial performance best be assessed? What are the advantages and disadvantages of currently used methodologies? How far can and should reductionism be pursued? What is the relevance of … 

* Corresponding author. Tel.: +44 1222 742338; Fax: +44 1222 743500; E-mail: shaham2@cf.ac.uk
Quantitative liver imaging using 131-I Rose Bengal as an index of liver function and prognosis.
Authors: T R Gamlen, D R Triger, D M Ackery, J S Fleming, R W Grant, R W Kenny, A G Maciver, R Wright
Journal: Gut (1975)

A technique for assessing quantitatively hepatic function by direct measurement of liver parenchymal cell uptake of 131I Rose Bengal using a scintillation camera with a digital store and retrieval system is described. Ninety-four studies were performed on 84 patients with a variety of hepatic disorders over a two-year period, the diagnosis in each case being established by liver biopsy or laparotomy. The results were compared with the clinical, biochemical and histological assessment of the patients. A good correlation was found between the half-time for hepatic uptake of 131I Rose Bengal and the histological changes, as well as with clinical prognosis measured in terms of clinical improvement or deterioration to death. The rate of liver uptake was found to be a better index than the clearance of radioisotope from the blood and was superior to conventional biochemical investigations in both icteric and anicteric patients. The test was not shown to be of clinical value in discriminating between intra- and extrahepatic causes of jaundice. It is suggested that this technique may provide a safe and sensitive method for assessing the severity of liver dysfunction and also for monitoring clinical progress, especially in situations where liver biopsy may be unreliable or hazardous.
Safety and efficacy of denileukin diftitox in patients with steroid-refractory acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation
Authors: Vincent T. Ho, David Zahrieh, Ephraim Hochberg, Eileen Micale, Jesse Levin, Carol Reynolds, Steve Steckel, Corey Cutler, David C. Fisher, Stephanie J. Lee, Edwin P. Alyea, Jerome Ritz, Robert J. Soiffer, Joseph H. Antin
Journal: Blood (2004)
Carotid ultrasound is useful for the cardiovascular risk stratification of patients with rheumatoid arthritis: results of a population-based study
Authors: Alfonso Corrales, Carlos González-Juanatey, María E Peiró, Ricardo Blanco, Javier Llorca, Miguel A González-Gay
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Objective</h3> To determine if the use of carotid ultrasonography (US) may improve the stratification of the cardiovascular (CV) risk in rheumatoid arthritis (RA). <h3>Methods</h3> A set of 370 consecutive patients without history of CV events were studied to assess carotid intima-media thickness (cIMT) and plaques. As previously proposed, CV risk was calculated according to the modified EULAR systematic coronary risk evaluation (mSCORE) for RA that was adapted by the application of a multiplier factor of 1.5 in those patients fulfilling ≥2 of 3 specific criteria. <h3>Results</h3> The mean disease duration was 9.8 years, 250 (68%) had rheumatoid factor/anticyclic citrullinated peptide positivity and 61 (17%) extra-articular manifestations. 43 were excluded because they had type 2 diabetes mellitus or severe chronic kidney disease. CV risk was categorised in the remaining 327 RA patients according to the mSCORE: mild (96 cases; 29.3%), moderate (201; 61.5%) and high/very high risk (30; 9.2%). Only five patients were reclassified as having high/very high CV risk when the mSCORE was applied. Severe carotid US abnormalities (cIMT &gt;0.90 mm and/or plaques) were uncommon in patients with low mSCORE (13%). Nevertheless, in patients with moderate mSCORE, severe carotid US abnormalities were observed in 63% of cases. A model that included a chart mSCORE risk ≥5% plus the presence of severe carotid US findings in patients with moderate mSCORE risk (≥1% and &lt;5%) yielded high sensitivity for high/very high CV risk (93 (95% CI 88 to 96)). <h3>Conclusions</h3> Our results support the use of carotid US in the assessment of CV risk in patients with RA.
Novel Epidermal Growth Factor Receptor Mutation-Specific Antibodies for Non-small Cell Lung Cancer: Immunohistochemistry as a Possible Screening Method for Epidermal Growth Factor Receptor Mutations
Authors: Yasufumi Kato, Nir Peled, Murry W. Wynes, Koichi Yoshida, Marta Pardo, Celine Mascaux, Tatsuo Ohira, Masahiro Tsuboi, Jun Matsubayashi, Toshitaka Nagao, Norihiko Ikeda, Fred R. Hirsch
Journal: Journal of Thoracic Oncology (2010)
Outcome in a Prospective Phase II Trial of Medically Inoperable Stage I Non–Small-Cell Lung Cancer Patients Treated With Stereotactic Body Radiotherapy
Authors: Pia Baumann, Jan Nyman, Morten Hoyer, Berit Wennberg, Giovanna Gagliardi, Ingmar Lax, Ninni Drugge, Lars Ekberg, Signe Friesland, Karl-Axel Johansson, Jo-Åsmund Lund, Elisabeth Morhed, Kristina Nilsson, Nina Levin, Merete Paludan, Christer Sederholm, Anders Traberg, Lena Wittgren, Rolf Lewensohn
Journal: Journal of Clinical Oncology (2009)

The impact of stereotactic body radiotherapy (SBRT) on 3-year progression-free survival of medically inoperable patients with stage I non-small-cell lung cancer (NSCLC) was analyzed in a prospective phase II study.Fifty-seven patients with T1NOMO (70%) and T2N0M0 (30%) were included between August 2003 and September 2005 at seven different centers in Sweden, Norway, and Denmark and observed up to 36 months. SBRT was delivered with 15 Gy times three at the 67% isodose of the planning target volume.Progression-free survival at 3 years was 52%. Overall- and cancer-specific survival at 1, 2, and 3 years was 86%, 65%, 60%, and 93%, 88%, 88%, respectively. There was no statistically significant difference in survival between patients with T1 or T2 tumors. At a median follow-up of 35 months (range, 4 to 47 months), 27 patients (47%) were deceased, seven as a result of lung cancer and 20 as a result of concurrent disease. Kaplan-Meier estimated local control at 3 years was 92%. Local relapse was observed in four patients (7%). Regional relapse was observed in three patients (5%). Nine patients (16%) developed distant metastases. The estimated risk of all failure (local, regional, or distant metastases) was increased in patients with T2 (41%) compared with those with T1 (18%) tumors (P = .027).With a 3-year local tumor control rate higher than 90% with limited toxicity, SBRT emerges as state-of-the-art treatment for medically inoperable stage I NSCLC and may even challenge surgery in operable instances.
Differentiation-stage specific self-peptides bound by major histocompatibility complex class I molecules.
Authors: P E Harris, F Lupu, B Hong, E F Reed, N Suciu-Foca
Journal: The Journal of Experimental Medicine (1993)

We have tested the hypothesis that phenotypic changes of development are accompanied by expression of differentiation-stage specific peptides bound to major histocompatibility complex (MHC) class I molecules. The U937 cell line, when cultured in the presence of phorbol myristate acetate (PMA), undergoes differentiation from monoblasts to macrophage-like cells. The high-performance liquid chromatography profile of peptides eluted from purified human histocompatibility leukocyte antigen class I molecules expressed by U937 treated with PMA differs from that obtained from control, untreated U937 cells. Chemical sequencing of eluted peptides identified a peptide derived from cytomegalovirus in both treated and untreated cells. PMA-treated, but not untreated cells, displayed an additional peptide derived from interleukin 1 beta. Hence, differentiation-induction of U937 is accompanied by the presentation of at least one differentiation-stage specific peptide. Our results indicate that, similar to viral infection, cellular development and transformation is accompanied by the de novo synthesis of proteins which are processed and presented on MHC class I molecules.
HCV genotype-3a T cell immunity: specificity, function and impact of therapy
Authors: Isla S Humphreys, Annette von Delft, Anthony Brown, Linda Hibbert, Jane D Collier, Graham R Foster, Monira Rahman, Annabel Christian, Paul Klenerman, Eleanor Barnes
Journal: Gut (2012)

Hepatitis C virus (HCV) genotype-3a infection is now the dominant strain in South Asia and the UK. Characteristic features include a favourable response to therapy; the reasons for this are unknown but may include distinct genotype-3a-specific T cell immunity. In contrast to genotype-1 infection, T cell immunity to this subtype is poorly defined.The aims of the study were to (1) define the frequency, specificity and cross-reactivity of T cell immunity across the whole viral genome in genotype-3a infection and (2) assess the impact of interferon (IFN)-α/ribavirin on T cell immunity.T cell responses in chronic and resolved HCV genotype-3a were analysed in comparison with genotype-1 infection (total n=85) using specific peptide panels in IFN-γ ELISpot assays. T cell responses were followed longitudinally in a subset of genotype-3a infected patients receiving therapy. Responses were further defined by CD4 and CD8 subset analysis, sequencing of autologous virus and cross-reactivity of genotype-3a with genotype-1a/-1b antigens.CD8 T cell responses commonly targeted the non-structural (NS) proteins in chronic genotype-3a infection whereas in genotype-1 infection CD4 responses targeting HCV core predominated (p=0.0183). Resolved infection was associated with CD4 T cells targeting NS proteins. Paradoxically, a sustained response to therapy was associated with a brisk decline in virus-specific and total lymphocyte counts that recovered after treatment.HCV genotype-3a exhibits a distinct T cell specificity with implications for vaccine design. However, our data do not support the theory that genotype-3a viral clearance with therapy is associated with an enhanced antiviral T cell response. Paradoxically, a reduction in these responses may serve as a biomarker of IFN responsiveness.