tbuckley/cabot-search huggingface dataset:
EPHA2 Is a Mediator of Vemurafenib Resistance and a Novel Therapeutic Target in Melanoma
Authors: Benchun Miao, Zhenyu Ji, Li Tan, Michael Taylor, Jianming Zhang, Hwan Geun Choi, Dennie T. Frederick, Raj Kumar, Jennifer A. Wargo, Keith T. Flaherty, Nathanael S. Gray, Hensin Tsao
Journal: Cancer Discovery (2014)

Abstract BRAFV600E is the most common oncogenic lesion in melanoma and results in constitutive activation of the MAPK pathway and uncontrolled cell growth. Selective BRAF inhibitors such as vemurafenib have been shown to neutralize oncogenic signaling, restrain cellular growth, and improve patient outcome. Although several mechanisms of vemurafenib resistance have been described, directed solutions to overcome these resistance lesions are still lacking. Herein, we found that vemurafenib resistance can be (i) mediated by EPHA2, a member of the largest receptor tyrosine kinases (RTK) subfamily erythropoietin-producing hepatocellular (EPH) receptors, and (ii) associated with a greater phenotypic dependence on EPHA2. Furthermore, we developed a series of first-in-class EPHA2 inhibitors and show that these new compounds potently induce apoptosis, suppress viability, and abrogate tumorigenic growth of melanoma cells, including those that are resistant to vemurafenib. These results provide proof of concept that RTK-guided growth, and therapeutic resistance, can be prospectively defined and selectively targeted. Significance: In this study, we show that resistance to selective BRAF inhibitors can be mediated by the RTK EPHA2. Furthermore, direct targeting of EPHA2 can successfully suppress melanoma growth and mitigate therapeutic resistance. Cancer Discov; 5(3); 274–87. ©2014 AACR. See related article by Paraiso et al., p. 264 This article is highlighted in the In This Issue feature, p. 213
Upper gastrointestinal bleeding and a unique computed tomography scan
Authors: G S Abi Saad, K M Musallam, J Karam, A Al-Kutoubi, A N Tawil, A I Sharara
Journal: Gut (2008)

A 74-year-old man presented with a 24 h history of haematemesis and melena. He had had subtotal gastrectomy 40 years earlier for peptic ulcer disease. Upper gastrointestinal endoscopy revealed a gastric mass partially covered by a large pulsating clot (fig 1 …
Biological, Clinical, and Psychosocial Correlates at the Interface of Cancer and Aging Research
Authors: William Dale, Supriya G. Mohile, Basil A. Eldadah, Edward L. Trimble, Richard L. Schilsky, Harvey J. Cohen, Hyman B. Muss, Kenneth E. Schmader, Betty Ferrell, Martine Extermann, Susan G. Nayfield, Arti Hurria
Journal: JNCI Journal of the National Cancer Institute (2012)

In September 2010, the Cancer and Aging Research Group, in collaboration with the National Cancer Institute and the National Institute on Aging, conducted the first of three planned conferences to discuss research methodology to generate the highest quality research in older adults with cancer and then disseminate these findings among those working in the fields of cancer and aging. Conference speakers discussed the current level of research evidence in geriatric oncology, outlined the current knowledge gaps, and put forth principles for research designs and strategies that would address these gaps within the next 10 years. It was agreed that future oncology research trials that enroll older adults should include: (1) improved standardized geriatric assessment of older oncology patients, (2) substantially enhanced biological assessment of older oncology patients, (3) specific trials for the most vulnerable and/or those older than 75 years, and (4) research infrastructure that specifically targets older adults and substantially strengthened geriatrics and oncology research collaborations. This initial conference laid the foundation for the next two meetings, which will address the research designs and collaborations needed to enhance therapeutic and intervention trials in older adults with cancer.
Nek8 Regulates the Expression and Localization of Polycystin-1 and Polycystin-2
Authors: Eisei Sohara, Ying Luo, Jingjing Zhang, Danielle K. Manning, David R. Beier, Jing Zhou
Journal: Journal of the American Society of Nephrology (2008)

Nek8 is a serine/threonine kinase that is mutated in the jck (juvenile cystic kidneys) mouse, a model of autosomal recessive juvenile polycystic kidney disease, but its function is poorly understood. We used the jck mouse to study the functional relationship between Nek8 and other proteins that have been implicated in polycystic kidney diseases. In the collecting tubules and collecting ducts of wild-type mice, we found that Nek8 was localized to the proximal portion of primary cilia and was weakly detected in the cytosol. In the jck mutant, however, Nek8 was found along the entire length of cilia. Coimmunoprecipitation experiments demonstrated that Nek8 interacted with polycystin-2, but not with polycystin-1, and that the jck mutation did not affect this interaction. Western blot analysis and real-time reverse transcriptase PCR revealed that the protein and mRNA expression of polycystin-1 (PC1) and polycystin-2 (PC2) were increased in jck mouse kidneys. The jck mutation also led to abnormal phosphorylatin of PC2, and this was associated with longer cilia and ciliary accumulation of PC1 and PC2. Our data suggests that Nek8 interacts with the signal transduction pathways of the polycystins and may control the targeting of these ciliary proteins. Dysfunction Nek8 may lead to cystogenesis by altering the structure and function of cilia in the distal nephron.
Kidins220/ARMS binds to the B cell antigen receptor and regulates B cell development and activation
Authors: Gina J. Fiala, Iga Janowska, Fabiola Prutek, Elias Hobeika, Annyesha Satapathy, Adrian Sprenger, Thomas Plum, Maximilian Seidl, Jörn Dengjel, Michael Reth, Fabrizia Cesca, Tilman Brummer, Susana Minguet, Wolfgang W.A. Schamel
Journal: The Journal of Experimental Medicine (2015)

B cell antigen receptor (BCR) signaling is critical for B cell development and activation. Using mass spectrometry, we identified a protein kinase D–interacting substrate of 220 kD (Kidins220)/ankyrin repeat–rich membrane-spanning protein (ARMS) as a novel interaction partner of resting and stimulated BCR. Upon BCR stimulation, the interaction increases in a Src kinase–independent manner. By knocking down Kidins220 in a B cell line and generating a conditional B cell–specific Kidins220 knockout (B-KO) mouse strain, we show that Kidins220 couples the BCR to PLCγ2, Ca2+, and extracellular signal-regulated kinase (Erk) signaling. Consequently, BCR-mediated B cell activation was reduced in vitro and in vivo upon Kidins220 deletion. Furthermore, B cell development was impaired at stages where pre-BCR or BCR signaling is required. Most strikingly, λ light chain–positive B cells were reduced sixfold in the B-KO mice, genetically placing Kidins220 in the PLCγ2 pathway. Thus, our data indicate that Kidins220 positively regulates pre-BCR and BCR functioning.
Application of dot immunoenzyme filtration assay for rapid detection of influenza A virus
Authors: Ya-xia Tan, Cui Chen, Xiang Jie, Ke Cao
Journal: European Respiratory Journal (2012)

Objective To explore an approach for rapid influenza A virus detection.

Methods Nasopharyngeal swab specimens were collected for influenza A virus detection from 40 patients with suspected influenza who visited the First Affiliated Hospital of Guangzhou Medical College from November 2009 to March 2010. According to Ministry of Health of China in September 2009, the diagnostic criteria for the infection of influenza A is a positive test for influenza A virus via qRT-PCR. Based on the positive result with qRT-PCR, we compared dot immunoenzyme filtration assay(DIEFA) with colloid gold immunochromatography(GICA), the two rapid antigen tests, and the one with higher sensitivity and specificity would be the choice of rapid influenza A virus detection. Results 21 cases were founded influenza A virus positive by the way of qRT-PCR and the positive rate was 52.5%. 22 cases were found influenza A virus positive via DIEFA with a positive rate of 55%, while 12 cases were found influenza A virus positive via GICA with a positive rate of 30%. Compared with qRT-PCR detection, the sensitivity, specificity and consistency of DIEFA were 85.7%, 78.9% and 82.5% respectively, while the GICA's sensitivity, specificity and consistency were 42.8%, 84.2% and 62.5% respectively. The data showed that DIEFA had apparent superiority of sensitivity over GICA in rapid influenza A virus detection. Conclusions DIEFA can be an optimal approach for rapid detection of influenza A virus with the advantage of higher sensitivity and specificity, adapting for screening influenza A virus rapidly in influenza A virus epidemic conditions.
Ancient Origins of Vertebrate-Specific Innate Antiviral Immunity
Authors: Krishanu Mukherjee, Bryan Korithoski, Bryan Kolaczkowski
Journal: Molecular Biology and Evolution (2013)

Animals deploy various molecular sensors to detect pathogen infections. RIG-like receptor (RLR) proteins identify viral RNAs and initiate innate immune responses. The three human RLRs recognize different types of RNA molecules and protect against different viral pathogens. The RLR protein family is widely thought to have originated shortly before the emergence of vertebrates and rapidly diversified through a complex process of domain grafting. Contrary to these findings, here we show that full-length RLRs and their downstream signaling molecules were present in the earliest animals, suggesting that the RLR-based immune system arose with the emergence of multicellularity. Functional differentiation of RLRs occurred early in animal evolution via simple gene duplication followed by modifications of the RNA-binding pocket, many of which may have been adaptively driven. Functional analysis of human and ancestral RLRs revealed that the ancestral RLR displayed RIG-1-like RNA-binding. MDA5-like binding arose through changes in the RNA-binding pocket following the duplication of the ancestral RLR, which may have occurred either early in Bilateria or later, after deuterostomes split from protostomes. The sensitivity and specificity with which RLRs bind different RNA structures has repeatedly adapted throughout mammalian evolution, suggesting a long-term evolutionary arms race with viral RNA or other molecules.
Optical coherence tomography (OCT) features of nevi and melanomas and their association with intraepidermal or dermal involvement: A pilot study
Authors: Tatiana Cristina Moraes Pinto Blumetti, Marcela Pecora Cohen, Elimar Elias Gomes, Mariana Petaccia de Macedo, Maria Dirlei Ferreira de Souza Begnami, José Humberto Tavares Guerreiro Fregnani, João Pedreira Duprat, Giovanni Pellacani, Gisele Gargantini Rezze
Journal: Journal of the American Academy of Dermatology (2015)
Hospital-based Clostridium difficile infection surveillance reveals high proportions of PCR ribotypes 027 and 176 in different areas of Poland, 2011 to 2013
Authors: Hanna Pituch, Piotr Obuch-Woszczatyński, Dominika Lachowicz, Dorota Wultańska, Pawel Karpiński, Grazyna Młynarczyk, Sofie M van Dorp, Ed J Kuijper
Journal: Eurosurveillance (2015)

As part of the European Clostridium difficile infections (CDI) surveillance Network (ECDIS-Net), which aims to build capacity for CDI surveillance in Europe, we constructed a new network of hospital-based laboratories in Poland. We performed a survey in 13 randomly selected hospital-laboratories in different sites of the country to determine their annual CDI incidence rates from 2011 to 2013. Information on C. difficile laboratory diagnostic testing and indications for testing was also collected. Moreover, for 2012 and 2013 respectively, participating hospital-laboratories sent all consecutive isolates from CDI patients between February and March to the Anaerobe Laboratory in Warsaw for further molecular characterisation, including the detection of toxin-encoding genes and polymerase chain reaction (PCR)-ribotyping. Within the network, the mean annual hospital CDI incidence rates were 6.1, 8.6 and 9.6 CDI per 10,000 patient-days in 2011, 2012, and 2013 respectively. Six of the 13 laboratories tested specimens only on the request of a physician, five tested samples of antibiotic-associated diarrhoea or samples from patients who developed diarrhoea more than two days after admission (nosocomial diarrhoea), while two tested all submitted diarrhoeal faecal samples. Most laboratories (9/13) used tests to detect glutamate dehydrogenase and toxin A/B either separately or in combination. In the two periods of molecular surveillance, a total of 166 strains were characterised. Of these, 159 were toxigenic and the majority belonged to two PCR-ribotypes: 027 (n = 99; 62%) and the closely related ribotype 176 (n = 22; 14%). The annual frequency of PCR-ribotype 027 was not significantly different during the surveillance periods (62.9% in 2012; 61.8% in 2013). Our results indicate that CDIs caused by PCR-ribotype 027 predominate in Polish hospitals participating in the surveillance, with the closely related 176 ribotype being the second most common agent of infection.
Anthranoid laxative use is not a risk factor for colorectal neoplasia: results of a prospective case control study
Authors: G Nusko
Journal: Gut (2000)

Anthranoid laxatives are the most commonly used purgatives in the therapy of acute and chronic constipation. Recent experimental data and a prospective cohort study provide evidence of a possible risk of anthranoid use for the development of colorectal neoplasms.We performed a prospective case control study at the University of Erlangen to investigate the risk of anthranoid laxative use for the development of colorectal adenomas or carcinomas. A total of 202 patients with newly diagnosed colorectal carcinomas, 114 patients with adenomatous polyps, and 238 patients (controls) with no colorectal neoplasms who had been referred for total colonoscopy were studied. The use of anthranoid preparations was assessed by standardised interview, and endoscopically visible or microscopic melanosis coli was studied by histopathological examination.There was no statistically significant risk of anthranoid use for the development of colorectal adenomas (unadjusted odds ratio 1.0; 95% CI 0.5-1.9) or carcinomas (unadjusted odds ratio 1.0; 95% CI 0.6-1.8). Even after adjustment for the risk factors age, sex, and blood in the stools by logistic regression analysis the odds ratio for adenomas was 0.84 (95% CI 0. 4-1.7) and for carcinomas 0.93 (95% CI 0.5-1.7). Also, there were no differences between the patient and control groups for duration of intake. Macroscopic and high grade microscopic melanosis coli were not significant risk factors for the development of adenomas or carcinomas.Neither anthranoid laxative use, even in the long term, nor macroscopic or marked microscopic melanosis coli were associated with any significant risk for the development of colorectal adenoma or carcinoma.
<i>FOXE1</i> is a target for aberrant methylation in cutaneous squamous cell carcinoma
Authors: I. Venza, M. Visalli, B. Tripodo, G. De Grazia, S. Loddo, D. Teti, M. Venza
Journal: British Journal of Dermatology (2009)

Several cancer-related genes are silenced by promoter hypermethylation in skin cancers. However, to date the somatic epigenetic events that occur in cutaneous squamous cell carcinoma (SCC) tumorigenesis have not been well defined.To examine epigenetic abnormalities of FOXE1, a gene located on chromosome 9q22, a region frequently lost in SCC.We investigated the methylation status of FOXE1 in 60 cases of cutaneous SCC by methylation-specific polymerase chain reaction, and comparatively examined mRNA and protein expression by real-time polymerase chain reaction and Western blot, respectively.We found a higher frequency of FOXE1 promoter hypermethylation in SCCs (55%), as compared with the adjacent uninvolved skin (12%) and blood control samples (9.5%). FOXE1 methylation was frequently seen in association with a complete absence of or downregulated gene expression. Treatment with the demethylating agent 5-Aza-2'-deoxycytidine resulted in profound reactivation of FOXE1 expression.These results indicate that FOXE1 is a crucial player in development of cutaneous SCC.
Early-onset Crohn’s disease and autoimmunity associated with a variant in CTLA-4
Authors: Sebastian Zeissig, Britt-Sabina Petersen, Michal Tomczak, Espen Melum, Emilie Huc-Claustre, Stephanie K Dougan, Jon K Laerdahl, Björn Stade, Michael Forster, Stefan Schreiber, Dascha Weir, Alan M Leichtner, Andre Franke, Richard S Blumberg
Journal: Gut (2014)

<h3>Objective</h3> IBD is a group of complex, systemic disorders associated with intestinal inflammation and extraintestinal manifestations. Recent studies revealed Mendelian forms of IBD, which contributed significantly to our understanding of disease pathogenesis and the heritability of IBD. <h3>Design</h3> We performed exome sequencing in a family with Crohn's disease (CD) and severe autoimmunity, analysed immune cell phenotype and function in affected and non-affected individuals, and performed <i>in silico</i> and in vitro analyses of cytotoxic T lymphocyte-associated protein 4 (CTLA-4) structure and function. <h3>Results</h3> A novel missense variant was identified in <i>CTLA4</i> encoding CTLA-4, a coinhibitory protein expressed by T cells and required for regulation of T cell activation. The residue affected by the mutation, CTLA-4 Tyr60, is evolutionarily highly conserved, and the identified Y60C variant is predicted to affect protein folding and structural stability and demonstrated to cause impaired CTLA-4 dimerisation and CD80 binding. Intestinal inflammation and autoimmunity in carriers of CTLA-4 Y60C exhibit incomplete penetrance with a spectrum of clinical presentations ranging from asymptomatic carrier status to fatal autoimmunity and intestinal inflammation. In a clinically affected CTLA-4 Y60C carrier, T cell proliferation was increased <i>in vitro</i> and associated with an increased ratio of memory to naive T cells <i>in vivo</i>, consistent with impaired regulation of T cell activation. <h3>Conclusions</h3> Our results support the concept that variants in <i>CTLA4</i> provide the basis for a novel Mendelian form of early-onset CD associated with systemic autoimmunity. Incomplete penetrance of autoimmunity further indicates the presence of other genetic and/or environmental modifiers.
Adipose Tissue Macrophages Promote Myelopoiesis and Monocytosis in Obesity
Authors: Prabhakara Reddy Nagareddy, Michael J Kraakman, Seth L Masters, Roslynn A Stirzaker, Darren J Gorman, Ryan W Grant, Dragana Dragoljevic, Eun Shil Hong, Ahmed Abdel-Latif, Susan S Smyth, Sung Hee Choi, Judith Korner, Karin E Bornfeldt, Edward Allen Fisher, Vishwa Deep Dixit, Alan R Tall, Ira Jay Goldberg, Andrew James Murphy
Journal: Cell Metabolism (2014)
Telbivudine Prevents Vertical Transmission of Hepatitis B Virus From Women With High Viral Loads: A Prospective Long-Term Study
Authors: Quanxin Wu, Hongfei Huang, Xiaowen Sun, Meimin Pan, Yun He, Shun Tan, Yi Zeng, Li Li, Guohong Deng, Zehui Yan, Dengming He, Junnan Li, Yuming Wang
Journal: Clinical Gastroenterology and Hepatology (2014)
Gout is on the increase in New Zealand
Authors: P. Klemp, S. A Stansfield, B. Castle, M C. Robertson
Journal: Annals of the Rheumatic Diseases (1997)

<h3>OBJECTIVE</h3> To determine the current prevalence of hyperuricaemia and gout in New Zealand Maori and Europeans for comparison with previous studies. <h3>METHODS</h3> 342 Maori and 315 European men and women aged 15 years and older were studied by personal interview and a musculoskeletal system examination. The 1977 ARA criteria for gout in a survey setting were used and serum uric acid was determined by a uricase method. The data were compared with those of previous New Zealand studies. <h3>RESULTS</h3> Gout was significantly more common in Maori (6.4%) than Europeans (2.9%) (Δ = 3.6%, 95% confidence interval 0.4 to 6.8) and in Maori men (13.9%) than in European men (5.8%) (Δ = 8.1%, 95% CI 1.0 to 15.2). Hyperuricaemia was significantly more common in Maori men (27.1%) than in European men (9.4%) (Δ = 17.7%, 95% CI 8.3 to 27.1) and in Maori women (26.6%) than in European women (10.5%) (Δ = 16.1%, 95% CI 8.5 to 23.7). At least 14% of hyperuricaemic individuals were receiving diuretics, of whom 78% were women. Comparison with previous studies shows that the prevalence of gout has increased in both Maori and Europeans, particularly in men. In Maori men the prevalence of gout has risen from 4.5–10.4% previously to 13.9%, and in European men from 0.7%–2.0% previously to 5.8%. Clinical differences included a stronger family history, earlier age at onset, and a higher frequency of tophi and polyarticular gout in Maori than Europeans. Of those with gout, 62% of Maori and 63% of Europeans were hyperuricaemic on the day surveyed and six (19.4%) were on diuretics. Treatment of gout was inadequate in most cases. <h3>CONCLUSIONS</h3> Hyperuricaemia and gout remain common among Maori. Of concern is that the prevalence of gout appears to be on the increase, not only in Maori but also in Europeans in New Zealand.
First-line chemotherapy with paclitaxel by three-hour infusion and carboplatin in advanced breast cancer (final report): A phase II study conducted by the Hellenic Cooperative Oncology Group
Authors: G. Fountzilas, A.-M. Dimopoulos, C. Papadimitriou, A. Kalogera-Fountzila, G. Aravantinos, D. Bafaloukos, A. Athanassiades, C. Nicolaides, A. Keramopoulos, N. Pavlidis, P. Kosmidis, D. Skarlos
Journal: Annals of Oncology (1998)
Outcome and molecular characteristics of adolescent and young adult patients with newly diagnosed primary glioblastoma: a study of the Society of Austrian Neurooncology (SANO)
Authors: Annette Leibetseder, Michael Ackerl, Birgit Flechl, Adelheid Wöhrer, Georg Widhalm, Karin Dieckmann, Sabine-Spiegl Kreinecker, Josef Pichler, Johannes Hainfellner, Matthias Preusser, Christine Marosi
Journal: Neuro-Oncology (2012)

Young age is a favorable prognostic factor for patients with glioblastoma multiforme (GBM). We reviewed the outcomes and molecular tumor characteristics of adolescent and young adult patients with GBM treated in 2 Austrian centers. Data on patients with histologically proven primary GBM diagnosed from 18 through 40 years of age were retrospectively analyzed. All patients were treated with standard first-line therapy. The primary end points were overall survival (OS) and time to progression (TTP). IDH1-R132H mutation status was analyzed using immunohistochemistry, and MGMT promoter methylation was assessed using methylation-specific polymerase chain reaction. We included 70 patients (36 men and 34 women) with a median age of 33 years. IDH1-R132H mutations were detected in 22 (39.3%) of 56 cases and MGMT promoter methylation in 33 (61.1%) of 54 cases with available tissue samples. In patients with wild-type IDH, median TTP was 8.2 months and median OS was 24 months, compared with 18 months and 44 months, respectively, observed in patients with mutated IDH. Neither IDH1 nor MGMT status showed a statistically significant association with TTP or OS. Of note, the social and economical situation of the young patients with GBM was alarming, because only 17% succeeded in staying employed after receiving the diagnosis. We found a high frequency of IDH1 mutations and MGMT promoter methylation among young adult patients with primary GBM that may contribute to the generally favorable outcome associated with young age. The social and economic coverage of patients with glioma remains an unsolved socio-ethical problem.
Prognostic impact of age and gender in 897 untreated patients with primary myelodysplastic syndromes
Authors: T. Nösslinger, H. Tüchler, U. Germing, W.R. Sperr, O. Krieger, D. Haase, M. Lübbert, R. Stauder, A. Giagounidis, P. Valent, M. Pfeilstöcker
Journal: Annals of Oncology (2009)