tbuckley/cabot-search huggingface dataset:
Anthropometry, Physical Activity, and Endometrial Cancer Risk: Results From The Netherlands Cohort Study
Authors: L. J. Schouten, R. A. Goldbohm, P. A. van den Brandt
Journal: JNCI Journal of the National Cancer Institute (2004)

Although obesity is an established risk factor for endometrial cancer, evidence linking risk to height, weight change since age 20, and physical activity is limited. In this case-cohort study, 62 573 women from The Netherlands Cohort Study on Diet and Cancer were followed up from 1986 to 1995, and 226 endometrial cancer case patients were identified. In Cox proportional hazards analyses, women 175 cm or taller had an increased risk of endometrial cancer compared with those less than 160 cm (rate ratio [RR] = 2.57, 95% confidence interval [CI] = 1.32 to 4.99). Compared with women with a body mass index (BMI; kg/m2) between 20 and 22.9, women with a BMI of 30 or greater had a higher risk (RR = 4.50, 95% CI = 2.62 to 7.72; P(trend)<.001). Moreover, BMI at age 20 and BMI gain since age 20 were positively associated with endometrial cancer risk (P(trend) = .02 and <.001, respectively). Women who spent 90 minutes per day or more doing nonoccupational physical activities had a lower risk (RR = 0.54, 95% CI = 0.34 to 0.85; P(trend) = .002) compared with those who spent less than 30 minutes per day. High BMI and low physical activity were strong and independent risk factors for endometrial cancer.
Enhanced hepatocarcinogenesis in mouse models and human hepatocellular carcinoma by coordinate KLF6 depletion and increased messenger RNA splicing
Authors: Diana Vetter, Michal Cohen-Naftaly, Augusto Villanueva, Youngmin A. Lee, Peri Kocabayoglu, Rebekka Hannivoort, Goutham Narla, Josep M. Llovet, Swan N. Thung, Scott L. Friedman
Journal: Hepatology (2012)

KLF6-SV1 (SV1 ), the major splice variant of KLF6 , antagonizes the KLF6 tumor suppressor by an unknown mechanism. Decreased KLF6 expression in human hepatocellular carcinoma (HCC) correlates with increased mortality, but the contribution of increased SV1 is unknown. We sought to define the impact of SV1 on human outcomes and experimental murine hepatocarcinogenesis and to elucidate its mechanism of action. In hepatitis C virus (HCV)-related HCC, an increased ratio of SV1/KLF6 within the tumor was associated with features of more advanced disease. Six months after a single injection of diethylnitrosamine (DEN), SV1 hepatocyte transgenic mice developed more histologically advanced tumors, whereas Klf6 -depleted mice developed bigger tumors compared to the Klf6 fl(+/+) control mice. Nine months after DEN, SV1 transgenic mice with Klf6 depletion had the greatest tumor burden. Primary mouse hepatocytes from both the SV1 transgenic animals and those with hepatocyte-specific Klf6 depletion displayed increased DNA synthesis, with an additive effect in hepatocytes harboring both SV1 overexpression and Klf6 depletion. Parallel results were obtained by viral SV1 transduction and depletion of Klf6 through adenovirus-Cre infection of primary Klf6 fl(+/+) hepatocytes. Increased DNA synthesis was due to both enhanced cell proliferation and increased ploidy. Coimmunoprecipitation studies in 293T cells uncovered a direct interaction of transfected SV1 with KLF6 . Accelerated KLF6 degradation in the presence of SV1 was abrogated by the proteasome inhibitor MG132. Conclusion: An increased SV1/KLF6 ratio correlates with more aggressive HCC. In mice, an increased SV1/KLF6 ratio, generated either by increasing SV1, decreasing KLF6, or both, accelerates hepatic carcinogenesis. Moreover, SV1 binds directly to KLF6 and accelerates its degradation. These findings represent a novel mechanism underlying the antagonism of tumor suppressor gene function by a splice variant of the same gene. (Hepatology 2012)
THE EFFECT OF HYDROCORTISONE ON THE RESPONSE OF FETAL RAT SKIN IN CULTURE TO ULTRAVIOLET IRRADIATION
Authors: Gerald Weissmann, Honor B. Fell
Journal: The Journal of Experimental Medicine (1962)

1. The effect of hydrocortisone on the development of fetal rat skin in organ culture, and on its repair after exposure to a mixed beam from a mercury lamp, are described. 2. The addition of hydrocortisone (7.5 microg/ml) to the culture medium (HC medium) caused accelerated differentiation and keratinisation of the epidermis followed by atrophic changes as in vivo. 3. Explants were grown for 2 days in either normal or HC medium and then irradiated with light from an Hanovia lamp. 4. Irradiation of the control explants produced severe necrosis in both epidermis and dermis and much disorganisation of the dermal intercellular material; 2 days after exposure the s. corneum with adherent cellular debris had become either completely detached from the denuded dermis, or raised to form a fluid-filled blister. Epidermal regeneration had begun by the 4th day after irradiation and was usually complete by the 6th day. 5. Hydrocortisone modified the response to irradiation as follows: (1) reduced and retarded cellular breakdown, (2) prevented vesication, (3) preserved the organisation of the dermal intercellular material, (4) hastened epithelialisation, (5) accelerated the differentiation of the new epidermis. Effects (2), (3), and (4) were probably secondary to (1). 6. Experiments with various light filters showed that the effective wavelengths for producing lesions in the skin explants were those below 3000 A. 7. It is suggested that the beneficial effect of hydrocortisone on the repair of irradiated skin explants might be due, at least in part, to a reduced proteolytic activity in the damaged tissue through a stabilising action of the hormone on the lysosomes. 8. The relationship of these findings to clinical observations is discussed.
rAAV2/7 vector-mediated overexpression of alpha-synuclein in mouse substantia nigra induces protein aggregation and progressive dose-dependent neurodegeneration
Authors: Marusela Oliveras-Salvá, Anke Van der Perren, Nicolas Casadei, Stijn Stroobants, Silke Nuber, Rudi D’Hooge, Chris Van den Haute, Veerle Baekelandt
Journal: Molecular Neurodegeneration (2013)

Abstract Background Alpha-synuclein is a key protein implicated in the pathogenesis of Parkinson's disease (PD). It is the main component of the Lewy bodies, a cardinal neuropathological feature in the disease. In addition, whole locus multiplications and point mutations in the gene coding for alpha-synuclein lead to autosomal dominant monogenic PD. Over the past decade, research on PD has impelled the development of new animal models based on alpha-synuclein. In this context, transgenic mouse lines have failed to reproduce several hallmarks of PD, especially the strong and progressive dopaminergic neurodegeneration over time that occurs in the patients. In contrast, viral vector-based models in rats and non-human primates display prominent, although highly variable, nigral dopaminergic neuron loss. However, the few studies available on viral vector-mediated overexpression of alpha-synuclein in mice report a weak neurodegenerative process and no clear Lewy body-like pathology. To address this issue, we performed a comprehensive comparative study of alpha-synuclein overexpression by means of recombinant adeno-associated viral vectors serotype 2/7 (rAAV2/7) at different doses in adult mouse substantia nigra. Results We noted a significant and dose-dependent alpha-synucleinopathy over time upon nigral viral vector-mediated alpha-synuclein overexpression. We obtained a strong, progressive and dose-dependent loss of dopaminergic neurons in the substantia nigra, reaching a maximum of 82% after 8 weeks. This effect correlated with a reduction in tyrosine hydroxylase immunoreactivity in the striatum. Moreover, behavioural analysis revealed significant motor impairments from 12 weeks after injection on. In addition, we detected the presence of alpha-synuclein-positive aggregates in the remaining surviving neurons. When comparing wild-type to mutant A53T alpha-synuclein at the same vector dose, both induced a similar degree of cell death. These data were supported by a biochemical analysis that showed a net increase in soluble and insoluble alpha-synuclein expression over time to the same extent for both alpha-synuclein variants. Conclusions In conclusion, our in vivo data provide evidence that strong and significant alpha-synuclein-induced neuropathology and progressive dopaminergic neurodegeneration can be achieved in mouse brain by means of rAAV2/7.
RISK FACTORS FOR ISCHqMIC HEART-DISEASE IN NORMAL MEN AGED 40 Edinburgh?Stockholm Study
Authors: R.L Logan, M Thomson, R.A Riemersma, M.F Oliver, A.G Olsson, S Rössner, E Callmer, G Walldius, L Kaijser, L.A Carlson, L Lockerbie, W Lutz
Journal: The Lancet (1978)
Adalimumab elicits a restricted anti-idiotypic antibody response in autoimmune patients resulting in functional neutralisation
Authors: Pauline A van Schouwenburg, Lotte A van de Stadt, Rob N de Jong, Esther E L van Buren, Simone Kruithof, Els de Groot, Margreet Hart, S Marieke van Ham, Theo Rispens, Lucien Aarden, Gerrit Jan Wolbink, Diana Wouters
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Objectives</h3> Millions of patients worldwide are treated with therapeutic monoclonal antibodies. These biological therapeutics can be immunogenic, resulting in anti-drug antibody formation which leads to loss of response. Fully human biological agents, such as the anti-tumour necrosis factor α (anti-TNFα) antibody adalimumab, are considered to be weakly immunogenic, but anti-adalimumab antibodies (AAA) were recently detected in more than half of treated patients with rheumatoid arthritis (RA) within 28 weeks of treatment. A study was undertaken to determine the mechanism by which AAA lead to loss of response. <h3>Methods</h3> The specificity of the repertoire of AAA was investigated in a cohort of 50 AAA-positive RA patients. Inhibition experiments using TNFα and patient-derived anti-adalimumab monoclonal antibodies were performed. <h3>Results</h3> The antibody response against adalimumab is highly restricted: Fab fragments of a single monoclonal antibody specific for the idiotype of adalimumab inhibited 98.65% (25th–75th percentiles: 98.25–99.90) of the total anti-adalimumab reactivity in serum from 50 AAA-positive patients. The anti-adalimumab response was confined to the TNFα binding region of adalimumab, thereby neutralising its therapeutic efficacy. In line with this restricted specificity, small immune complexes were found in the circulation of AAA-forming patients. <h3>Conclusions</h3> The humoral immune response against adalimumab is highly restricted and limited to the idiotype of the therapeutic antibody. All antibodies result in functional neutralisation of the drug, thereby providing a mechanism by which AAA formation leads to clinical non-response.
An evidence-based alcohol policy
Authors: N. Sheron, N. Olsen, I. Gilmore
Journal: Gut (2008)

In October 2007 the BBC performed a survey of British Society of Gastroenterology (BSG) members in which a number of questions were asked about the changing patterns of alcohol-related disease the BSG was seeing in the UK. Of the 115 responses, only nine members had seen no change in alcohol-related liver disease over the last 10 years; 92% reported a rise, usually large. Recurrent themes were the increase in women presenting with alcoholic liver disease and the younger age of presentation. Nearly three-quarters of responders had seen patients of 25 years or under with alcoholic hepatitis or cirrhosis, and nearly a quarter had patients in their late teens. These depressing findings are in line with the report by the Chief Medical Officer in 2001:

> In the last 30 years of the 20th century deaths from liver cirrhosis steadily increased, in people aged 35 to 44 years the death rate went up 8-fold in men and almost 7-fold in women, in 25–34 year-olds a 4-fold increase was seen over the 30 year period.

The UK situation is in stark contrast to the decrease in liver mortality in Mediterranean countries over the same period of time (fig 1).



Figure 1 Over the last 30 years standardised cirrhosis mortality rates (cirrhosis deaths/100 000 under the age of 64 years) have increased in the UK, Finland, Denmark and Ireland, countries where traditionally tight controls on alcohol have been relaxed, and decreased in the wine drinking countries of France, Italy and Spain where the traditionally high consumption of cheap wine with meals has reduced. The biggest drop is in France where strict controls ( la loi Evin ) on the promotion of alcohol were also introduced. (Data obtained from the WHO HFA database.31)

So why is the UK facing this increase in liver deaths when mortality elsewhere is falling? According to death certification data more than 80% of UK liver deaths are due to alcohol-related cirrhosis.1 Other causes of liver disease are also increasing; for example, steatosis and viral hepatitis, but only 205 out of 6889 reported liver deaths in 2005 were due to viral hepatitis.2 While viruses and, more importantly, steatosis secondary to obesity3 may be co-factors in some cases, the evidence suggests that it is our drinking habits that are the problem.

Since 1970 the standardised death rate (SDR) for cirrhosis …
Changes in BMI, Duration of Overweight and Obesity, and Glucose Metabolism: 45 Years of Follow-up of a Birth Cohort
Authors: Chris Power, Claudia Thomas
Journal: Diabetes Care (2011)

OBJECTIVE Long-term implications of childhood obesity and BMI change over the life course for risk of type 2 diabetes remain uncertain. The objective was to establish whether there are effects on adult glucose metabolism of 1) sensitive periods of BMI gain or 2) long duration of overweight and obesity. RESEARCH DESIGN AND METHODS Participants in the 1958 British birth cohort with child to adult BMI and glycosylated hemoglobin (HbA1c) at 45 years (n = 7,855). RESULTS Prevalence of type 2 diabetes or HbA1c ≥7 was 2%. BMI gains in child- and adulthood were associated with higher HbA1c: for every SD of 5-year BMI increase from 0 to 7 years, there was a 75% (95% CI 1.42–2.16) increased risk of HbA1c ≥7, increasing to a 4.7-fold (3.12–7.00) risk for the interval 23–33 years. Associations for BMI gain in adulthood were related to attained BMI but were independent for the longer period birth (or 7 years) to 45 years. Duration of obesity was also associated with HbA1c; compared with the never obese, those with childhood onset had a 23.9-fold risk (13.5–42.1) of HbA1c ≥7%; odds ratios were 16.0 (10.6–24.2) and 2.99 (1.77–5.03), respectively, for young and midadulthood onset. Similar trends by onset age were found in mean HbA1c levels and for onset of overweight. Those with the earliest age of onset had higher BMI and waist circumference at 45 years, which markedly explained the associations for onset age and HbA1c. CONCLUSIONS Excessive BMI gain across the life span and earlier onset of overweight/obesity are associated with impaired glucose metabolism, in part through attained adult BMI.
Amelioration of hyperoxia-induced lung injury using a sphingolipid-based intervention
Authors: Jeroen Tibboel, Stephen Joza, Irwin Reiss, Johan C. de Jongste, Martin Post
Journal: European Respiratory Journal (2012)

The aim of this study was to characterise lung function and bronchoalveolar lavage sphingolipid profile in newborn mice during hyperoxia exposure and recovery in room air, and to examine the effect of d -sphingosine supplementation during recovery. Newborn mice were exposed to 80% oxygen for 4 weeks and allowed to recover in room air for another 4 weeks. Lung function measurements and morphometrical analysis of lung tissue were performed and bronchoalveolar lavage fluid was collected during hyperoxia and recovery with and without d -sphingosine supplementation. Hyperoxia exposure altered lung function, which partially recovered in room air. Lungs had fewer and enlarged alveoli which persisted during recovery. Multiple sphingolipids were significantly increased after hyperoxia. Ceramides were increased after 2 weeks of recovery, but normalised to control values after 4 weeks. The addition of d -sphingosine during the first 5 days of recovery accelerated the normalisation of ceramide levels at 2 weeks and partially reversed the hyperoxia-induced increase in alveolar size and arrest in alveolarisation at 4 weeks. Exposure of newborn mice to hyperoxia caused restrictive and obstructive lung function changes that partially recovered in room air, while alveolar morphology remained abnormal. Hyperoxia increased ceramide levels, with normalisation after recovery. d -sphingosine addition during recovery reduced ceramide levels and ameliorated hyperoxia-induced alveolar arrest.
Skin cancers, blindness, and anterior tongue mass in African brothers
Authors: Priya Mahindra, John J. DiGiovanna, Deborah Tamura, Jaime S. Brahim, Thomas J. Hornyak, Jere B. Stern, Chyi-Chia Richard Lee, Sikandar G. Khan, Brian P. Brooks, Janine A. Smith, Brian P. Driscoll, Andrew D. Montemarano, Kate Sugarman, Kenneth H. Kraemer
Journal: Journal of the American Academy of Dermatology (2008)
Hepatopulmonary syndrome in patients listed for liver transplantation
Authors: Fernanda Martins, Eduardo Garcia
Journal: European Respiratory Journal (2013)

Introduction:  The hepatopulmonary syndrome (HPS) is defined by the clinical triad consists of liver disease, pulmonary vascular dilatation and changes in arterial blood gases.  Objectives:  To describe the prevalence of the disease and the profile of patients with SHP liver transplant candidates; evaluate the presence of risk factors and analyzis the variations of gas exchange and pulmonary function in patients with the syndrome.  Methods:  Patients listed for liver transplantation, the period from January 2004 to January 2010, who had echocardiography and arterial blood gas analysis.  Results:  The prevalence of HPS was 36.84% using a cutoff of alveolar-arterial gradient (PA-aO2) ≥ 15mmHg (≥ 20 mm Hg if age> 64 years), as determined by Guideline Hepatopulmonares Vascular Diseases (PHD) published in 2004. Of the patients with MELD scores greater than 15, the HPS was present in 44.9%. Within the study sample, 100 patients had spirometry with measurement of diffusion of carbon monoxide (DLCO), 22.37% of patients had DLCO less than 60% predicted, these only 41.18% had a diagnosis of HPS. The PaO2 proved statistically different.  Conclusions:  The prevalence in our sample was considerably higher than most publications, where the occurrence of the disease was around 13 to 18%, possibly due to the cutoff adequacy of alveolar-arterial gradient, as determined by Guideline Hepatopulmonares Vascular Diseases (PHD). The presence of older than 50 years and cirrhosis caused by hepatitis C virus were defined as statistically significant risk factors, respectively p
<i>RRM1</i> and <i>PTEN</i> As Prognostic Parameters for Overall and Disease-Free Survival in Patients With Non–Small-Cell Lung Cancer
Authors: Gerold Bepler, Swati Sharma, Alan Cantor, Ashish Gautam, Eric Haura, George Simon, Anupama Sharma, Eric Sommers, Lary Robinson
Journal: Journal of Clinical Oncology (2004)

Purpose RRM1 has important functions in the determination of the malignant phenotype. It controls cell proliferation through deoxynucleotide production and metastatic propensity through PTEN induction. It is located in a region of loss of heterozygosity in non–small-cell lung cancer (NSCLC), which is a predictor of poor survival. We hypothesized that RRM1 expression would be a significant predictor of outcome in NSCLC. Patients and Methods A retrospective data set of 49 patients and a prospective data set of 77 patients with resectable NSCLC were studied. RNA was extracted from tumor and normal lung tissue, and expression of the genes RRM1, PTEN, and RRM2 was determined by real-time quantitative polymerase chain reaction. Results RRM1 expression was significantly correlated with PTEN and RRM2 expression in tumor tissue. RRM1 and PTEN expression in tumor tissue was highly predictive of overall (P = .011 and .018, respectively) and disease-free survival (P = .002 and .026, respectively). Patients with high levels of expression lived longer and had disease recurrence later than patients with low levels of RRM1 and PTEN. In a multivariate analysis, high RRM1 expression was predictive of long survival independent of tumor stage, performance status, and weight loss. Conclusion RRM1 is a biologically and clinically important determinant of malignant behavior in NSCLC. Knowing the level of expression of this gene adds significant information to management decisions independent of the currently used outcome predictors of tumor stage, performance status, and weight loss. Future clinical trials should stratify patients based on expression of this gene to avoid unwanted biases.
Neuroprotective intervention by interferon-γ blockade prevents CD8+ T cell–mediated dendrite and synapse loss
Authors: Mario Kreutzfeldt, Andreas Bergthaler, Marylise Fernandez, Wolfgang Brück, Karin Steinbach, Mariann Vorm, Roland Coras, Ingmar Blümcke, Weldy V. Bonilla, Anne Fleige, Ruth Forman, Werner Müller, Burkhard Becher, Thomas Misgeld, Martin Kerschensteiner, Daniel D. Pinschewer, Doron Merkler
Journal: The Journal of Experimental Medicine (2013)

Neurons are postmitotic and thus irreplaceable cells of the central nervous system (CNS). Accordingly, CNS inflammation with resulting neuronal damage can have devastating consequences. We investigated molecular mediators and structural consequences of CD8(+) T lymphocyte (CTL) attack on neurons in vivo. In a viral encephalitis model in mice, disease depended on CTL-derived interferon-γ (IFN-γ) and neuronal IFN-γ signaling. Downstream STAT1 phosphorylation and nuclear translocation in neurons were associated with dendrite and synapse loss (deafferentation). Analogous molecular and structural alterations were also found in human Rasmussen encephalitis, a CTL-mediated human autoimmune disorder of the CNS. Importantly, therapeutic intervention by IFN-γ blocking antibody prevented neuronal deafferentation and clinical disease without reducing CTL responses or CNS infiltration. These findings identify neuronal IFN-γ signaling as a novel target for neuroprotective interventions in CTL-mediated CNS disease.
Function of JunB in Transient Amplifying Cell Senescence and Progression of Human Prostate Cancer
Authors: Noboru Konishi, Keiji Shimada, Mitsutoshi Nakamura, Eiwa Ishida, Ichiro Ota, Nobumichi Tanaka, Kiyohide Fujimoto
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Replicative senescence in cells acts as a barrier against excessive proliferation and carcinogenesis. Transient amplifying cells (TAC) are a subset of basal cell populations within the prostate from which cancers are thought to originate; therefore, we focused on prostate TAC to investigate the molecular mechanisms by which the TAC may be able to evade senescence. Experimental Design: TAC clones were isolated from each zone within the whole prostate and analyzed in flow cytometry. Prostate cancer cells were transfected with junB small interfering RNA (siRNA) and examined by chorioallantoic membrane assay for cancer invasion. Immunohistochemical analysis was done in primary and metastatic prostate cancer specimens. Results: TAC populations showed increased expression of p53, p21, p16, and pRb, resulting in senescence. TAC clones with reduced p16 expression successfully bypassed this phase. We further found close correlation between the levels of junB and p16 expression. Repeated transfection of junB siRNA in prostatic TAC allowed the cells to escape senescence presumably through inactivation of p16/pRb. The chorioallantoic membrane invasion assay showed much lower in invasive cancer cells with high expression of junB; conversely, silencing of junB by transfection with junB siRNA promoted invasion. We also found that metastatic prostate cancers, as well as cancers with high Gleason scores, showed significantly low junB immunopositivity. Conclusions: JunB is an essential upstream regulator of p16 and contributes to maintain cell senescence that blocks malignant transformation of TAC. JunB thus apparently plays an important role in controlling prostate carcinogenesis and may be a new target for cancer prevention and therapy.