tbuckley/cabot-search huggingface dataset:
Entangling Ancient Allotetraploidization in Asian Mitella: An Integrated Approach for Multilocus Combinations
Authors: Y. Okuyama, A. S. Tanabe, M. Kato
Journal: Molecular Biology and Evolution (2011)

The reconstruction of an ancient polyploidization history is often challenging, although it is a crucial step in clarifying the mechanisms underlying the contemporary success and diversity of polyploids. Phylogenetic relationships of duplicated gene pairs of polyploids, with respect to their orthologs in related diploids, have been used to address this problem, but they often result in conflicting topologies among different genes. Asimitellaria is an East Asian endemic tetraploid lineage of perennials (genus Mitella; Saxifragaceae) that has diversified in riparian habitats. Phylogenetic analyses of four nuclear-encoded, single-copy (per haploid) genes GBSSI-A, GBSSI-B, GS-II, and PepCK all supported a single allopolyploid origin of Asimitellaria, but they did not lead to a consensus about which diploid lineage gave rise to each of the Asimitellaria subgenomes. To address this issue, we used an integrated approach, whereby the four gene data sets and an additional nuclear ribosomal external transcribed spacer and internal transcribed spacer (including a 5.8S ribosomal DNA) data set were concatenated in all possible combinations, and the most probable data combination was determined together with the phylogenetic inference. This resulted in relatively robust support for the two closely related North American diploid species as the ancestral lineages of the Asimitellaria subgenomes, suggesting ancient intercontinental migration of the diploid or tetraploid lineages and subsequent tetraploid diversification in the Japanese Archipelago. The present approach enabled sorting out the duplicated genes into their original combinations in their preduplication ancestors under a maximum-likelihood framework, and its extension toward genome sequencing data may help in the reconstruction of ancestral, preduplicated, whole-genome structures.
Human WISP1v, a member of the CCN family, is associated with invasive cholangiocarcinoma
Authors: Shinji Tanaka, Keishi Sugimachi, Toshifumi Kameyama, Shin-ichiro Maehara, Ken Shirabe, Mitsuo Shimada, Jack R. Wands, Yoshihiko Maehara
Journal: Hepatology (2003)

Family members of the connective tissue growth factor, cysteine–rich 61, nephroblastoma over–expressed gene (CCN) encode cysteine–rich secreted proteins with roles in human fibrotic disorders and tumor progression. In this study, we identified a CCN family member, WISP1v, as over–expressed in human cholangiocarcinomas. Genetic analysis of WISP1v was performed on surgically resected specimens of cholangiocarcinoma. The WISP1v biological effects were analyzed using the HuCCT1 human cholangiocarcinoma cell line. The WISP1v gene was expressed in 19 of 39 cholangiocarcinoma tissues (49%) but not in normal livers. Expression of WISP1v was significantly associated with lymphatic and perineural invasion of tumor cells ( P &lt; .05), as well as a poor clinical prognosis ( P &lt; .01). In the intraductal papillary cholangiocarcinomas, WISP1v was detected only in the cases with duct wall invasion but not in the cases without duct wall invasion ( P &lt; .05). No mutation of WISP1v gene was detected in the examined samples. In vitro analysis revealed that WISP1v stimulated the invasive phenotype of cholangiocarcinoma cells with activation of both p38 and p42/p44 mitogen–activated protein kinases (MAPKs). Furthermore, WISP1v–induced cholangiocarcinoma invasion was significantly suppressed by the p38 MAPK inhibitor SB203580 but not by the p42/p44 MAPK kinase (MEK) inhibitor PD98059. Our findings suggest that WISP1v–mediated signaling is involved in the generation of invasive cellular properties and leads to progression of cholangiocarcinoma.
High Gene Family Turnover Rates and Gene Space Adaptation in the Compact Genome of the Carnivorous Plant Utricularia gibba
Authors: Lorenzo Carretero-Paulet, Pablo Librado, Tien-Hao Chang, Enrique Ibarra-Laclette, Luis Herrera-Estrella, Julio Rozas, Victor A. Albert
Journal: Molecular Biology and Evolution (2015)

Utricularia gibba is an aquatic carnivorous plant with highly specialized morphology, featuring fibrous floating networks of branches and leaf-like organs, no recognizable roots, and bladder traps that capture and digest prey. We recently described the compressed genome of U. gibba as sufficient to control the development and reproduction of a complex organism. We hypothesized intense deletion pressure as a mechanism whereby most noncoding DNA was deleted, despite evidence for three independent whole-genome duplications (WGDs). Here, we explore the impact of intense genome fractionation in the evolutionary dynamics of U. gibba's functional gene space. We analyze U. gibba gene family turnover by modeling gene gain/death rates under a maximum-likelihood statistical framework. In accord with our deletion pressure hypothesis, we show that the U. gibba gene death rate is significantly higher than those of four other eudicot species. Interestingly, the gene gain rate is also significantly higher, likely reflecting the occurrence of multiple WGDs and possibly also small-scale genome duplications. Gene ontology enrichment analyses of U. gibba-specific two-gene orthogroups, multigene orthogroups, and singletons highlight functions that may represent adaptations in an aquatic carnivorous plant. We further discuss two homeodomain transcription factor gene families (WOX and HDG/HDZIP-IV) showing conspicuous differential expansions and contractions in U. gibba. Our results 1) reconcile the compactness of the U. gibba genome with its accommodation of a typical number of genes for a plant genome, and 2) highlight the role of high gene family turnover in the evolutionary diversification of U. gibba's functional gene space and adaptations to its unique lifestyle and highly specialized body plan.
Tumor β-1,4-Galactosyltransferase IV Overexpression Is Closely Associated with Colorectal Cancer Metastasis and Poor Prognosis
Authors: Wei-Shone Chen, Hong-Yi Chang, Chung-Pin Li, Jacqueline Ming Liu, Tze-Sing Huang
Journal: Clinical Cancer Research (2005)

Abstract Purpose: To elucidate the significance of β-1,4-galactosyltransferase IV (β-1,4-GT-IV) in the clinical presentation and prognostication of colorectal cancer. Experimental Design: Tissue lysates from paired tumor and nontumor tissues of a colon cancer patient were labeled separately with fluorescent dyes Cy5 and Cy3 for two-dimensional difference in-gel electrophoresis. Subsequent matrix-assisted laser desorption/ionization time-of-flight mass spectrometry and immunoblot analyses identified a down-regulated level of β-1,4-GT-IV in the tumor tissue. In the follow-up study, paired tissue lysates were obtained from 100 colorectal cancer patients with immunoblot analyses done to compare the levels of β-1,4-GT-IV expression in these patients. Results: Of 100 colorectal patients studied, 48% had down-regulated expression of β-1,4-GT-IV in the tumor tissue but 28% of patients exhibited elevated β-1,4-GT-IV levels. Increased β-1,4-GT-IV in the tumor tissue was significantly coexistent with raised serum level of CA-199 and the presence of tumor metastasis (P = 0.006 and P &amp;lt; 0.001, respectively) but was independent of age and gender of patient, tumor site, tumor size, serum level of carcinoembryonic antigen, grade of tumor cell differentiation, and depth of tumor invasion. The results of logistic regression analyses suggested that tumor β-1,4-GT-IV overexpression and tumor invasion, but not other patient variables such as tumor size and serum levels of carcinoembryonic antigen and CA19-9, were significantly correlated with the occurrence of metastases (P &amp;lt; 0.05). In a multivariate regression analysis, the patient group with tumor β-1,4-GT-IV overexpression strongly predicted for tumor metastasis (odds ratio, 10.009; 95% confidence interval, 2.992-33.484; P &amp;lt; 0.001). Likewise, tumor β-1,4-GT-IV overexpression was significantly associated with poor overall survival (P &amp;lt; 0.01). By Cox regression analysis, this association remained significant even after adjustment for tumor metastasis (P = 0.048). Conclusion: Increased β-1,4-GT-IV expression in tumor tissue was strongly associated with tumor metastases and poor prognosis in colorectal cancer.
Association Between Pak1 Expression and Subcellular Localization and Tamoxifen Resistance in Breast Cancer Patients
Authors: Caroline Holm, Suresh Rayala, Karin Jirström, Olle Stål, Rakesh Kumar, Göran Landberg
Journal: JNCI Journal of the National Cancer Institute (2006)

p21-activated kinase 1 (Pak1) phosphorylates many proteins in both normal and transformed cells. Its ability to phosphorylate and thereby activate the estrogen receptor alpha (ERalpha) potentially limits the effectiveness of antiestrogen treatment in breast cancer. Here we studied associations between Pak1 expression and subcellular localization in tumor cells and tamoxifen resistance.Pak1 protein expression was evaluated in 403 primary breast tumors from premenopausal patients who had been randomly assigned to 2 years of adjuvant tamoxifen or no treatment. Tamoxifen response was evaluated by comparing recurrence-free survival in relation to Pak1 and ERalpha expression in untreated versus tamoxifen-treated patients. Tamoxifen responsiveness of human MCF-7 breast cancer cells that inducibly expressed constitutively active Pak1 or that transiently overexpressed wild-type Pak1 (Wt-Pak1) or Pak1 that lacked functional nuclear localization signals (Pak1DeltaNLS) was evaluated by analyzing cyclin D1 promoter activation and protein levels as markers for ERalpha activation. The response to tamoxifen in relation to Pak1 expression was analyzed in naturally tamoxifen-resistant Ishikawa human endometrial cancer cells. All statistical tests were two-sided.Among patients who had ERalpha-positive tumors with low Pak1 expression, those treated with tamoxifen had better recurrence-free survival than those who received no treatment (hazard ratio [HR] = 0.502, 95% confidence interval [CI] = 0.331 to 0.762; P = .001) whereas there was no difference in recurrence-free survival between treatment groups for patients whose tumors had high cytoplasmic (HR = 0.893, 95% CI = 0.420 to 1.901; P = .769) or any nuclear Pak1 expression (HR = 0.955, 95% CI = 0.405 to 2.250; P = .916). In MCF-7 cells, overexpression of Wt-Pak1, but not of Pak1DeltaNLS, compromised tamoxifen response by stimulating cyclin D1 expression. Treatment of Ishikawa cells with tamoxifen led to an increase in the amount of nuclear Pak1 and Pak1 kinase activity, suggesting that tamoxifen, to some extent, regulates Pak1 expression.Our data support a role for Pak1, particular Pak1 localized to the nucleus, in ERalpha signaling and in tamoxifen resistance.
Glucokinase links Krüppel-like factor 6 to the regulation of hepatic insulin sensitivity in nonalcoholic fatty liver disease
Authors: Lars P. Bechmann, Amalia Gastaldelli, Diana Vetter, Gillian L. Patman, Laura Pascoe, Rebekka A. Hannivoort, Ursula E. Lee, Isabel Fiel, Ursula Muñoz, Demetrio Ciociaro, Young-Min Lee, Emma Buzzigoli, Luca Miele, Kei Y. Hui, Elisabetta Bugianesi, Alastair D. Burt, Christopher P. Day, Andrea Mari, Loranne Agius, Mark Walker, Scott L. Friedman, Helen L. Reeves
Journal: Hepatology (2011)

The polymorphism, KLF6-IVS1-27A, in the Krüppel-like factor 6 (KLF6) transcription factor gene enhances its splicing into antagonistic isoforms and is associated with delayed histological progression of nonalcoholic fatty liver disease (NAFLD). To explore a potential role for KLF6 in the development of insulin resistance, central to NAFLD pathogenesis, we genotyped KLF6-IVS1-27 in healthy subjects and assayed fasting plasma glucose (FPG) and insulin sensitivities. Furthermore, we quantified messenger RNA (mRNA) expression of KLF6 and glucokinase (GCK), as an important mediator of insulin sensitivity, in human livers and in liver tissues derived from a murine Klf6 knockdown model (DeltaKlf6). Klf6 overexpression studies in a mouse hepatocyte line were utilized to mechanistically link KLF6 with Gck promoter activity. KLF6-IVS1-27Gwt (i.e., less KLF6 splicing) was associated with stepwise increases in FPG and insulin and reduced hepatic insulin sensitivity. KLF6 binds to the liver-specific Gck promoter and activates a GCK promoter-reporter, identifying GCK as a KLF6 direct transcriptional target. Accordingly, in DeltaKlf6 hepatocytes Gck expression was reduced and stable transfection of Klf6 led to up-regulation of Gck. GCK and KLF6 mRNAs correlate directly in human NAFLD tissues and immunohistochemistry studies confirm falling levels of both KLF6 and GCK in fat-laden hepatocytes. In contrast to full-length KLF6, splice variant KLF6-SV1 increases in NAFLD hepatocytes and inversely correlates with glucokinase regulatory protein, which negatively regulates GCK activity.KLF6 regulation of GCK contributes to the development of hepatic insulin resistance. The KLF6-IVS1-27A polymorphism, which generates more KLF6-SV1, combats this, lowering hepatic insulin resistance and blood glucose.
History of dyspepsia in patients with gastric cancer Reply
Authors: R J F LAHEIJ, J B M J JANSEN, E H VAN DE LISDONK, A L M VERBEEK, Z SUVAKOVIC, M G BRAMBLE
Journal: Gut (1998)

Editor,—We read with interest the study by Suvakovic et al ( Gut 1997; 41 :308–13) reporting that 63% of the patients with early gastric cancer had a previous history of upper gastrointestinal symptoms. These authors concluded that guidelines for the appropriateness of gastroscopy in patients with dyspepsia need to reflect the importance of not starting treatment prior to gastroscopy. General practitioners need to be made more aware of the potential for antisecretory drugs to mask early gastric cancer, which will then have a major detrimental impact on patient management. We have also studied whether patients with gastric cancer had serious and persistent dyspeptic symptoms necessitating consultation with their general practitioner (Laheij et al , unpublished observations). The results of our study, however, differ from Suvakovic et al ’s.

We identified 46 patients with diagnostically verified early and late stage gastric cancer, using the Continuous Morbidity Register. This database is …
Epidemiology of life‐threatening and lethal anaphylaxis: a review
Authors: D. A. Moneret‐Vautrin, M. Morisset, J. Flabbee, E. Beaudouin, G. Kanny
Journal: Allergy (2005)

Severe anaphylaxis is a systemic reaction affecting two or more organs or systems and is due to the release of active mediators from mast cells and basophils. A four‐grade classification routinely places ‘severe’ anaphylaxis in grades 3 and 4 (death could be graded as grade 5). Studies are underway to determine the prevalence of severe and lethal anaphylaxis in different populations and the relative frequencies of food, drug, latex and Hymenoptera anaphylaxis. These studies will also analyse the risk arising from the lack of preventive measures applied in schools (personalized management protocols) and from the insufficient use of self‐injected adrenalin. Allergy‐related conditions may account for 0.2–1% of emergency consultations. Severe anaphylaxis affects 1–3 per 10 000 people, but for the United States and Australia figures are even higher. It is estimated to cause death in 0.65–2% of patients, i.e. 1–3 per million people. An increased prevalence has been revealed by monitoring hospitalized populations by reference to the international classification of disease (ICD) codes. The relative frequency of aetiological factors of allergy (food, drugs, insects and latex) varies in different studies. Food, drug and Hymenoptera allergies are potentially lethal. The risk of food‐mediated anaphylaxis can be assessed from the number of personalized management protocols in French schools: 0.065%. Another means of assessment may be the rate of adrenalin prescriptions. However, an overestimation of the anaphylaxis risk may result from this method (0.95% of Canadian children). Data from the literature leads to several possibilities. First, a definition of severe anaphylaxis should be agreed. Secondly, prospective, multicentre enquiries, using ICD codes, should be implemented. Moreover, the high number of anaphylaxis cases for which the aetiology is not identified, and the variation in aetiology in the published series, indicate that a closer cooperation between emergency specialists and allergists is essential.
Tamoxifen inhibits malignant peripheral nerve sheath tumor growth in an estrogen receptor-independent manner
Authors: S. J. Byer, J. M. Eckert, N. M. Brossier, B. J. Clodfelder-Miller, A. N. Turk, A. J. Carroll, J. C. Kappes, K. R. Zinn, J. K. Prasain, S. L. Carroll
Journal: Neuro-Oncology (2010)

Few therapeutic options are available for malignant peripheral nerve sheath tumors (MPNSTs), the most common malignancy associated with neurofibromatosis type 1 (NF1). Guided by clinical observations suggesting that some NF1-associated nerve sheath tumors are hormonally responsive, we hypothesized that the selective estrogen receptor (ER) modulator tamoxifen would inhibit MPNST tumorigenesis in vitro and in vivo. To test this hypothesis, we examined tamoxifen effects on MPNST cell proliferation and survival, MPNST xenograft growth, and the mechanism by which tamoxifen impeded these processes. We found that 1-5 μM 4-hydroxy-tamoxifen induced MPNST cell death, whereas 0.01-0.1 μM 4-hydroxy-tamoxifen inhibited mitogenesis. Dermal and plexiform neurofibromas, MPNSTs, and MPNST cell lines expressed ERβ and G-protein-coupled ER-1 (GPER); MPNSTs also expressed estrogen biosynthetic enzymes. However, MPNST cells did not secrete 17β-estradiol, exogenous 17β-estradiol did not stimulate mitogenesis or rescue 4-hydroxy-tamoxifen effects on MPNST cells, and the steroidal antiestrogen ICI-182,780 did not mimic tamoxifen effects on MPNST cells. Further, ablation of ERβ and GPER had no effect on MPNST proliferation, survival, or tamoxifen sensitivity, indicating that tamoxifen acts via an ER-independent mechanism. Consistent with this hypothesis, inhibitors of calmodulin (trifluoperazine, W-7), another known tamoxifen target, recapitulated 4-hydroxy-tamoxifen effects on MPNST cells. Tamoxifen was also effective in vivo, demonstrating potent antitumor activity in mice orthotopically xenografted with human MPNST cells. We conclude that 4-hydroxy-tamoxifen inhibits MPNST cell proliferation and survival via an ER-independent mechanism. The in vivo effectiveness of tamoxifen provides a rationale for clinical trials in cases of MPNSTs.
Role of NICE should be expanded, MPs told
Authors: Adrian O'Dowd
Journal: BMJ (2007)

The body that decides which drugs can be prescribed on the NHS in England and Wales should have a much expanded role looking at a greater breadth of health care and its effect, a parliamentary committee has been told.

Also, giving patients a stronger voice would help repair the reputation of the National Institute for Health and Clinical Excellence (NICE), witnesses told MPs on the parliamentary health select committee as part of their inquiry into NICE.

Tim Crayford, president of the Association of Directors of Public Health, giving evidence, said that NICE had not evaluated a large amount of what the NHS currently provided …
Antibiotics and Risk of Subsequent First-time Acute Myocardial Infarction
Authors: Christoph R. Meier
Journal: JAMA (1999)

We conducted the study using data from more than 350 general practices in the United Kingdom.Computerized patient records from the United Kingdom include patient demographics, symptoms, diagnoses, referrals, hospitalizations, drug prescriptions (including route of administration, number of tablets, and dosage), and additional information (eg, height, weight, and smoking status).All information is recorded by general practitioners on an ongoing daily basis (replacing the former paper-based patient charts), regardless of any future research hypotheses.Anonymous copies of hospital discharge and referrallettersareavailableforreviewandvalidation purposes on request.This large database, known as the General Practice Research Database (GPRD), encompasses approximately 3 million actively enrolled persons in the United Kingdom.This system, which has been extensively validated 14,15 and described in detail else-
Noninvasive Evaluation of Kidney Hypoxia and Fibrosis Using Magnetic Resonance Imaging
Authors: Tsutomu Inoue, Eito Kozawa, Hirokazu Okada, Kouichi Inukai, Shinichi Watanabe, Tomohiro Kikuta, Yusuke Watanabe, Tsuneo Takenaka, Shigehiro Katayama, Junji Tanaka, Hiromichi Suzuki
Journal: Journal of the American Society of Nephrology (2011)

Interstitial fibrosis and hypoxia accelerate the progression of CKD, but clinical tools to quantitate these factors in patients are lacking. Here, we evaluated the use of two magnetic resonance imaging (MRI) techniques, diffusion-weighted (DW)-MRI and blood oxygen level-dependent (BOLD)-MRI, to assess kidney fibrosis and hypoxia of the cortex in 142 patients with either diabetic nephropathy (n = 43), CKD without diabetes (n = 76), or acute kidney injury (AKI) (n = 23). Apparent diffusion coefficient (ADC) values of DW-MRI correlated with estimated glomerular filtration rates (eGFR) in the diabetic nephropathy and CKD groups (r(2) = 0.56 and r(2) = 0.46, respectively). Although the T2* values of BOLD-MRI and eGFR displayed good correlation in the CKD group (r(2) = 0.38), we did not observe a significant correlation between these values in the diabetic nephropathy group, suggesting that factors other than tubulointerstitial alteration determine the degree of hypoxia in the renal cortex. In the AKI group, neither the T2* nor ADC values correlated with eGFR. Renal biopsies from patients with CKD demonstrated that the T2* and ADC MRI values correlated with renal pathology. Taken together, ADC and T2* values appear to serve as accurate indices for evaluating renal tubulointerstitial alterations and parenchymal hypoxia, respectively, in the cortex. Functional MRI can thus contribute to multilateral, noninvasive, in vivo assessment of kidney function.
Functional Recovery from Syphilitic Cirrhosis of Liver following Penicillin and Bismuth Therapy
Authors: J. O. Doyle
Journal: BMJ (1956)

MEDICAL JOURtNAL contained 0.2%/ of sugar, with no acetone.Macroscopical examination of the organs revealed no abnormality, apart from a few petechial haemorrhages in the lungs, some fatty change in the liyer, and dilatation of the left renal calices.The right kidney was normal.Microscopical sections re- vealed glycogen in normal amounts in the liver.Sections of the brain, pituitary, pancreas, thyroid, suprarenals, heart, thyrmus.and spleen showed normal histology.COMMENT Schwartzman et al. (1947) collected from the world literature 57 cases of diabetes in infants under 1 year of age, 10 being under I month.The highest blood-sugar level reported was 952 mg. per 100 ml.Brodribb et al. (1952) reported a case of an.infant aged 11 months whose blood- sugar level was 1,160 mg. per 100 ml., and stated that this was " the highest recorded under the age of 1 year."The figures obtained before death in the present case were all higher than this.It is interesting to note the varying necropsy appearances of the islets of Langerhans in neonatal diabetes.Necropsies were carried out in six of the cases collected by Schwartzman et al.The islets were reported enlarged twice, reduced in number twice, scarred once, and normal once.The islets were normal in the present case.