tbuckley/cabot-search huggingface dataset:
Haploinsufficiency of Krüppel-Like Factor 4 Promotes Adenomatous Polyposis Coli–Dependent Intestinal Tumorigenesis
Authors: Amr M. Ghaleb, Beth B. McConnell, Mandayam O. Nandan, Jonathan P. Katz, Klaus H. Kaestner, Vincent W. Yang
Journal: Cancer Research (2007)

Abstract The zinc finger transcription factor Krüppel-like factor 4 (KLF4) is frequently down-regulated in colorectal cancer. Previous studies showed that the expression of KLF4 was activated by the colorectal cancer tumor suppressor adenomatous polyposis coli (APC) and that KLF4 repressed the Wnt/β-catenin pathway. Here, we examined whether KLF4 plays a role in modulating intestinal tumorigenesis by comparing the tumor burdens in mice heterozygous for the ApcMin allele (ApcMin/+) and those heterozygous for both the ApcMin and Klf4 alleles (Klf4+/−/ApcMin/+). Between 10 and 20 weeks of age, Klf4+/−/ApcMin/+ mice developed, on average, 59% more intestinal adenomas than ApcMin/+ mice (P &amp;lt; 0.0001). Immunohistochemical staining showed that Klf4 protein levels were lower in the normal-appearing intestinal tissues of Klf4+/−/ApcMin/+ mice compared with wild-type, Klf4+/−, or ApcMin/+ mice. In contrast, the levels of β-catenin and cyclin D1 were higher in the normal-appearing intestinal tissues of Klf4+/−/ApcMin/+ mice compared with the other three genotypes. Klf4 levels were further decreased in adenomas from both ApcMin/+ and Klf4+/−/ApcMin/+ mice compared with their corresponding normal-appearing tissues. Reverse transcription-PCR showed an inverse correlation between adenoma size and Klf4 mRNA levels in both Klf4+/−/ApcMin/+ and ApcMin/+ mice. There was also a progressive loss of heterozygosity of the wild-type Apc allele in adenomas with increasing size from Klf4+/−/ApcMin/+ and ApcMin/+ mice. Results from this study show that KLF4 plays an important role in promoting the development of intestinal adenomas in the presence of ApcMin mutation. [Cancer Res 2007;67(15):7147–54]
Tracing the Austronesian Footprint in Mainland Southeast Asia: A Perspective from Mitochondrial DNA
Authors: M.-S. Peng, H. H. Quang, K. P. Dang, A. V. Trieu, H.-W. Wang, Y.-G. Yao, Q.-P. Kong, Y.-P. Zhang
Journal: Molecular Biology and Evolution (2010)

As the relic of the ancient Champa Kingdom, the Cham people represent the major Austronesian speakers in Mainland Southeast Asia (MSEA) and their origin is evidently associated with the Austronesian diffusion in MSEA. Hitherto, hypotheses stemming mainly from linguistic and cultural viewpoints on the origin of the Cham people remain a welter of controversies. Among the points of dissension is the muddled issue of whether the Cham people arose from demic or cultural diffusion from the Austronesians. Addressing this issue also helps elucidate the dispersal mode of the Austronesian language. In the present study, we have analyzed mitochondrial DNA (mtDNA) control-region and coding-region sequence variations in 168 Cham and 139 Kinh individuals from Vietnam. Around 77% and 95% matrilineal components in the Chams and the Kinhs, respectively, could be assigned into the defined mtDNA haplogroups. Additionally, three common East Eurasian haplogroups B, R9, and M7 account for the majority (>60%) of maternal components in both populations. Entire sequencing of 20 representative mtDNAs selected from the thus far unclassified lineages, together with four new mtDNA genome sequences from Thailand, led to the identification of one new haplogroup M77 and helped to re-evaluate several haplogroups determined previously. Comparing the Chams with other Southeast Asian populations reveals that the Chams had a closer affinity with the Mon–Khmer populations in MSEA than with the Austronesian populations from Island Southeast Asia (ISEA). Further analyses failed to detect the potential homelands of the Chams in ISEA. Therefore, our results suggested that the origin of the Cham was likely a process of assimilation of massive local Mon–Khmer populations accompanied with language shift, thus indicating that the Austronesian diffusion in MSEA was mainly mediated by cultural diffusion, at least from the matrilineal genetic perspective, an observation in agreement with the hypothesis of the Nusantao Maritime Trading and Communication Networks.
The type II "receptor" as a decoy target for interleukin 1 in polymorphonuclear leukocytes: characterization of induction by dexamethasone and ligand binding properties of the released decoy receptor.
Authors: F Re, M Muzio, M De Rossi, N Polentarutti, J G Giri, A Mantovani, F Colotta
Journal: The Journal of Experimental Medicine (1994)

Whereas the signaling function of the interleukin 1 (IL-1) receptor type I (IL-1R I) has been well documented, the type II "receptor" has been suggested to act as a decoy target for this cytokine. Since IL-1 may represent a key target of the immunomodulatory and antiinflammatory properties of glucocorticoids (GC), the aim of this study was to investigate the effects of dexamethasone (Dex) on IL-1R expression in human polymorphonuclear leukocytes (PMN), which express predominantly the type II molecule (IL-1R II). We found that Dex augments the levels of steady state transcripts encoding the IL-1R I and, most prominently, those of IL-1R II. Dex induced both transcripts via transcription-dependent mechanisms and by prolongation of the mRNAs half-lives. Inhibition of protein synthesis superinduced basal and Dex-augmented IL-1R II mRNA, whereas it completely inhibited the induction by Dex of IL-1R I transcripts. Induction of IL-1R II mRNA by Dex was associated with augmented membrane expression and release of the type II IL-1 binding molecule. This effect was mediated by the GC receptor. Other steroids (17 beta-estradiol, progesterone, and testosterone) were ineffective. The concentrations of IL-1 alpha and IL-1 receptor antagonist required to displace the binding of IL-1 beta to the soluble form of the decoy molecule induced by Dex from PMN were, respectively, 100 and 2 times higher compared with IL-1 beta. The induction by Dex of the type II receptor, a decoy molecule for IL-1, may contribute to the immunosuppressive and antiinflammatory activities of Dex.
Combined assessment according to the new GOLD guidelines and its relation to outcome in COPD
Authors: Daiana Stolz, Kostantinos Kostikas, Francesco Blasi, Branislava Milenkovic, Wim Boersma, Joachim Aerts, Renaud Louis, Tobias Welte, Alicia Lacoma, Cristina Prat, Andreas Scherr, Janko Rakic, Marilena Pappalettera, Gernot Rohde, Antoni Torres, Sabine Hertel, Sven Giersdorf, Michael Tamm
Journal: European Respiratory Journal (2012)

BACKGROUND:    The new GOLD guidelines recommend pharmacological and non-pharmacological management of COPD to be individualized based on the assessment of symptoms and exacerbation risk (A=low risk, less symptoms, B=low risk, more symptoms, C=high risk, less symptoms, D=high risk, more symptoms). We hypothesize that functional parameters and the risk of future events differ among patients categorized by the combined assessment according to the guidelines.   METHODS:   We prospectively evaluated 638 patients with stable COPD for ≥ 6 weeks, > 10 PY and GOLD II-IV seeking care in pulmonary tertiary hospitals in 8 European countries and included in the PROMISE cohort. The outcome variables were exacerbation and death from any cause. Median observation time was 24 months.   RESULTS:   There were 1152 exacerbations, 225 severe exacerbations and 63 deaths among 586 patients classified as A=50 (7.8%), B =184 (28.8%), C =27 (4.2%), and D=325 (50.9%). Health-related QoL as assessed by all domains of the SGRQ (p   CONCLUSION:   The combined assessment according to the new GOLD guidelines is only partially associated with quality of life and the risk of future events in COPD.
Prognostic Value of Positron Emission Tomography (PET) With Fluorine-18 Fluorodeoxyglucose ([<sup>18</sup>F]FDG) After First-Line Chemotherapy in Non-Hodgkin’s Lymphoma: Is [<sup>18</sup>F]FDG-PET a Valid Alternative to Conventional Diagnostic Methods?
Authors: Karoline Spaepen, Sigrid Stroobants, Patrick Dupont, Steven Van Steenweghen, José Thomas, Peter Vandenberghe, Lucien Vanuytsel, Guy Bormans, Jan Balzarini, Christine De Wolf-Peeters, Luc Mortelmans, Gregor Verhoef
Journal: Journal of Clinical Oncology (2001)

A complete remission (CR) after first-line therapy is associated with longer progression-free survival (PFS). However, defining CR is not always easy because of the presence of residual masses. Metabolic imaging with fluorine-18 fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET) offers the ability to differentiate between viable and fibrotic inactive tissue. In this study, we evaluated the value of PET in detecting residual disease and, hence, predicting relapse after first-line treatment in patients with non-Hodgkin's lymphoma (NHL).Ninety-three patients with histologically proven NHL, who underwent a whole-body [18F]FDG-PET study after completion of first-line chemotherapy and who had follow-up of at least 1 year, were included. Persistence or absence of residual disease on PET was related to PFS using Kaplan-Meier survival analysis.Sixty-seven patients showed a normal PET scan after first-line chemotherapy; 56 of 67 remained in CR, with a median follow-up of 653 days. Nine of these patients with a residual mass considered as unconfirmed CR received additional radiotherapy. Only 11 of 67 patients relapsed (median PFS, 404 days). Persistent abnormal [18F]FDG uptake was seen in 26 patients, and all of them relapsed (median PFS, 73 days). Because standard restaging also suggested residual disease, 12 patients received immediate secondary treatment. In 14 of 26 patients, only PET predicted persistent disease. From these patients, relapse was proven either by biopsy (n = 8) or by progressive disease on computed tomography or magnetic resonance imaging (n = 6).Persistent abnormal [18F]FDG uptake after first-line chemotherapy in NHL is highly predictive for residual or recurrent disease. In relapsing patients, PFS was significantly shorter after a positive scan than after a negative scan.
Scottish health service is ordered to release data on surgeons' performance
Authors: Bryan Christie
Journal: BMJ (2005)

The Scottish health service has been ordered to release information to the media on the death rate data for named surgeons, under freedom of information legislation.

The order comes after a successful appeal by two newspapers, the Scotsman and Sunday Times , against a decision by NHS National Services Scotland (NSS) to refuse to make the information public. Scotland's information commissioner, Kevin Dunion, has ruled that there is a legitimate public interest in releasing the data. The NSS was meeting this week to decide whether to …
P5 Pulmonary hypertension in a mouse model with reduced macrophage number (MacLow)
Authors: A. Zawia, N. Arnold, J. Pickworth, A. Hameed, K. Hopkinson, G. Miller, A. Lawrie
Journal: Thorax (2011)

<h3>Introduction and Objectives</h3> Pulmonary arterial hypertension (PAH) is a devastating condition with high morbidity and poor life expectancy. Pathologically PAH is characterised by the medial thickening of the small distal pulmonary arteries. Early endothelial cell (EC) dysfunction and apoptosis, and the subsequent abnormal proliferation and migration of pulmonary artery smooth muscle cells are thought to be a major contributing factor. Macrophages are proposed to play an important role in regulating these processes and are recruited to remodelled pulmonary arteries but the exact role of macrophages, and whether they are required for this remodelling remains unclear. We have recently developed a mouse model (<i>MacLow</i>) where approximately 50% of macrophages are depleted and now aim to investigate whether <i>MacLow</i> mice would demonstrate a reduced pulmonary hypertension phenotype in response to hypoxia, when compared to non-macrophage ablated littermates. <h3>Methods</h3> Macrophage ablation was induced in CD68-rtTA-eGFP/tetDTA double transgenic mice (<i>MacLow</i>) where macrophage-specific (CD68) induction of the cytotoxic diphtheria toxin A chain (DTA) is achieved by administration of doxycycline containing chow diet (doxy-chow). Mice were divided by sex and then fed either regular or doxy-chow for 2 weeks prior to either 2 weeks exposure to hypoxia (10% oxygen), or room air. All mice were phenotyped for PH by echocardiography followed by closed chest cardiac catheterisation. Heart and lung tissue were harvested for morphological, immunohistochemical and biochemical analyses. <h3>Results</h3> Doxy-chow fed mice displayed the expected 50% reduction in macrophages (liver) compared to controls. <i>MacLow</i> mice with the induced ablation of macrophages were not protected from hypoxia induced pulmonary hypertension although females displayed a trend for higher RVSP after hypoxia (34 mm Hg vs 29 mm Hg). Interestingly male <i>MacLow</i> mice with induced macrophage ablation displayed a spontaneous PAH phenotype (33 mm Hg), in normoxia, that was not further increased by hypoxia. The changes in RVSP were accompanied by appropriate changes in RVH. <h3>Conclusion</h3> These data suggest that macrophages play a modulating role in pulmonary vascular remodelling but further work is required to explore the mechanisms involved in this phenotype, and to fully assess the change in macrophage number within the lungs of these mice.
Medicare Beneficiaries' Knowledge of Part D Prescription Drug Program Benefits and Responses to Drug Costs
Authors: John Hsu
Journal: JAMA (2008)

Medicare Part D drug benefits include substantial cost sharing.To determine beneficiaries' knowledge of benefits and cost responses.Telephone interviews were conducted in 2007 in a stratified random sample of community-dwelling Kaiser Permanente-Northern California Medicare Advantage beneficiaries aged 65 years or older, with a gap in coverage if they exceeded $2250 in drug costs (N = 1040; 74.9% response rate). Half were selected to have reached the gap in 2006. In the source population of Medicare Advantage Prescription Drug plan beneficiaries, 8% entered the coverage gap in 2006. Models were adjusted for individual characteristics and weighted for sampling proportions.Knowledge of cost sharing including awareness of the coverage gap, gap start and end amounts, and drug cost sharing before, during, and after the gap. Cost-related responses including cost-coping behaviors (eg, switching to lower-cost medications), reduced adherence (eg, not refilling prescriptions), and financial burden (eg, going without necessities).An estimated 40% (95% confidence interval [CI], 35%-45%) of beneficiaries were aware that their drug plan in 2006 included a coverage gap; knowledge of the gap was greater among individuals who reached the gap during the year. Approximately 36% (95% CI, 32%-41%) of beneficiaries reported at least 1 of the following responses to drug costs: cost-coping behavior (26%), reduced adherence (15%), or experiencing financial burden (7%). In multivariate analyses, beneficiaries with lower household income more frequently reported cost responses (difference of 14.5 percentage points for < $40,000/y vs > or = $40,000/y [95% CI, 3.6-25.4 percentage points]). Compared with beneficiaries who were unaware of having a coverage gap, those who were aware more frequently reported any cost response (difference of 11.3 percentage points [95% CI, 0.8-21.9 percentage points]), but had fewer reports of borrowing money or going without necessities (difference of 5.5 percentage points [95% CI, 1.1-10.0 percentage points]).Beneficiaries in this Medicare Advantage plan have limited knowledge of Part D cost sharing and often report behavioral responses to drug costs. Limited knowledge is associated with fewer reports of cost responses overall, but more reports of financial burden.
Development of a Prognostic Genetic Signature to Predict the Metastatic Risk Associated with Cutaneous Melanoma
Authors: Pedram Gerami, Robert W. Cook, Jeff Wilkinson, Maria C. Russell, Navneet Dhillon, Rodabe N. Amaria, Rene Gonzalez, Stephen Lyle, Clare E. Johnson, Kristen M. Oelschlager, Gilchrist L. Jackson, Anthony J. Greisinger, Derek Maetzold, Keith A. Delman, David H. Lawson, John F. Stone
Journal: Clinical Cancer Research (2015)

Abstract Purpose: The development of a genetic signature for the identification of high-risk cutaneous melanoma tumors would provide a valuable prognostic tool with value for stage I and II patients who represent a remarkably heterogeneous group with a 3% to 55% chance of disease progression and death 5 years from diagnosis. Experimental Design: A prognostic 28-gene signature was identified by analysis of microarray expression data. Primary cutaneous melanoma tumor tissue was evaluated by RT-PCR for expression of the signature, and radial basis machine (RBM) modeling was performed to predict risk of metastasis. Results: RBM analysis of cutaneous melanoma tumor gene expression reports low risk (class 1) or high risk (class 2) of metastasis. Metastatic risk was predicted with high accuracy in development (ROC = 0.93) and validation (ROC = 0.91) cohorts of primary cutaneous melanoma tumor tissue. Kaplan–Meier analysis indicated that the 5-year disease-free survival (DFS) rates in the development set were 100% and 38% for predicted classes 1 and 2 cases, respectively (P &amp;lt; 0.0001). DFS rates for the validation set were 97% and 31% for predicted classes 1 and 2 cases, respectively (P &amp;lt; 0.0001). Gene expression profile (GEP), American Joint Committee on Cancer stage, Breslow thickness, ulceration, and age were independent predictors of metastatic risk according to Cox regression analysis. Conclusions: The GEP signature accurately predicts metastasis risk in a multicenter cohort of primary cutaneous melanoma tumors. Preliminary Cox regression analysis indicates that the signature is an independent predictor of metastasis risk in the cohort presented. Clin Cancer Res; 21(1); 175–83. ©2015 AACR.
Divergence of Conserved Non-Coding Sequences: Rate Estimates and Relative Rate Tests
Authors: G. P. Wagner
Journal: Molecular Biology and Evolution (2004)

In many eukaryotic genomes only a small fraction of the DNA codes for proteins, but the non-protein coding DNA harbors important genetic elements directing the development and the physiology of the organisms, like promoters, enhancers, insulators, and micro-RNA genes. The molecular evolution of these genetic elements is difficult to study because their functional significance is hard to deduce from sequence information alone. Here we propose an approach to the study of the rate of evolution of functional non-coding sequences at a macro-evolutionary scale. We identify functionally important non-coding sequences as Conserved Non-Coding Nucleotide (CNCN) sequences from the comparison of two outgroup species. The CNCN sequences so identified are then compared to their homologous sequences in a pair of ingroup species, and we monitor the degree of modification these sequences suffered in the two ingroup lineages. We propose a method to test for rate differences in the modification of CNCN sequences among the two ingroup lineages, as well as a method to estimate their rate of modification. We apply this method to the full sequences of the HoxA clusters from six gnathostome species: a shark, Heterodontus francisci; a basal ray finned fish, Polypterus senegalus; the amphibian, Xenopus tropicalis; as well as three mammalian species, human, rat and mouse. The results show that the evolutionary rate of CNCN sequences is not distinguishable among the three mammalian lineages, while the Xenopus lineage has a significantly increased rate of evolution. Furthermore the estimates of the rate parameters suggest that in the stem lineage of mammals the rate of CNCN sequence evolution was more than twice the rate observed within the placental amniotes clade, suggesting a high rate of evolution of cis-regulatory elements during the origin of amniotes and mammals. We conclude that the proposed methods can be used for testing hypotheses about the rate and pattern of evolution of putative cis-regulatory elements.
The Acquired Immunodeficiency Syndrome in Haiti
Authors: JEAN W. PAPE
Journal: Annals of Internal Medicine (1985)

Two hundred twenty-nine patients in Haiti with the acquired immunodeficiency syndrome were studied between 1979 and 1984. The clinical spectrum of the syndrome in Haitians was similar in most aspects to that in patients with the disease in the United States. However, in contrast to findings in the United States, accepted risk factors (bisexuality, blood transfusions, intravenous drug abuse) were identified in only 43% of Haitian patients. Patients in Haiti with and without these risk factors were similar to each other but differed from age- and sex-matched siblings and friends in the number of heterosexual contacts and receipt of intramuscular injections. These latter activities were commoner in patients than in their siblings and friends, and represent potential modes of transmission of infection with the human T-lymphotropic virus type III.
Responsiveness and minimally important difference for the Patient-Reported Outcomes Measurement Information System (PROMIS) 20-item physical functioning short form in a prospective observational study of rheumatoid arthritis
Authors: Ron D Hays, Karen L Spritzer, James F Fries, Eswar Krishnan
Journal: Annals of the Rheumatic Diseases (2013)

Objective To estimate responsiveness (sensitivity to change) and minimally important difference (MID) for the Patient-Reported Outcomes Measurement Information System (PROMIS) 20-item physical functioning scale (PROMIS PF-20). Methods The PROMIS PF-20, short form 36 (SF-36) physical functioning scale, and Health Assessment Questionnaire (HAQ) were administered at baseline, and 6 and 12 months later to a sample of 451 persons with rheumatoid arthritis. A retrospective change (anchor) item was administered at the 12-month follow-up. We estimated responsiveness between 12 months and baseline, and between 12 months and 6 months using one-way analysis of variance F-statistics. We estimated the MID for the PROMIS PF-20 using prospective change for people reporting getting ‘a little better’ or ‘a little worse’ on the anchor item. Results F-statistics for prospective change on the PROMIS PF-20, SF-36 and HAQ by the anchor item over 12 and 6 months (in parentheses) were 16.64 (14.98), 12.20 (7.92) and 10.36 (12.90), respectively. The MID for the PROMIS PF-20 was 2 points (about 0.20 of an SD). Conclusions The PROMIS PF-20 is more responsive than two widely used (‘legacy’) measures. The MID is a small effect size. The measure can be useful for assessing physical functioning in clinical trials and observational studies.