tbuckley/cabot-search huggingface dataset:
IGF1R Inhibition in Mammary Epithelia Promotes Canonical Wnt Signaling and Wnt1-Driven Tumors
Authors: Lauren M. Rota, Lidia Albanito, Marcus E. Shin, Corey L. Goyeneche, Sain Shushanov, Emily J. Gallagher, Derek LeRoith, Deborah A. Lazzarino, Teresa L. Wood
Journal: Cancer Research (2014)

Abstract Triple-negative breast cancer (TNBC) is an aggressive disease subtype that, unlike other subtypes, lacks an effective targeted therapy. Inhibitors of the insulin-like growth factor receptor (IGF1R) have been considered for use in treating TNBC. Here, we provide genetic evidence that IGF1R inhibition promotes development of Wnt1-mediated murine mammary tumors that offer a model of TNBC. We found that in a double transgenic mouse model carrying activated Wnt1 and mutant Igf1r, a reduction in IGF1R signaling reduced tumor latency and promoted more aggressive phenotypes. These tumors displayed a squamous phenotype with increased expression of keratins 5/6 and β-catenin. Notably, cell lineage analyses revealed an increase in basal (CD29hi/CD24+) and luminal (CD24+/CD61+/CD29lo) progenitor cell populations, along with increased Nanog expression and decreased Elf5 expression. In these doubly transgenic mice, lung metastases developed with characteristics of the primary tumors, unlike MMTV-Wnt1 mice. Mechanistic investigations showed that pharmacologic inhibition of the IGF1R in vitro was sufficient to increase the tumorsphere-forming efficiency ofMMTV-Wnt1 tumor cells. Tumors from doubly transgenic mice also exhibited an increase in the expression ratio of the IGF-II-sensitive, A isoform of the insulin receptor versus the IR-B isoform, which when stimulated in vitro resulted in enhanced expression of β-catenin. Overall, our results revealed that in Wnt-driven tumors, an attenuation of IGF1R signaling accelerates tumorigenesis and promotes more aggressive phenotypes with potential implications for understanding TNBC pathobiology and treatment. Cancer Res; 74(19); 5668–79. ©2014 AACR.
Costimulatory T cell engagement via a novel bispecific anti-CD137 /anti-HER2 protein
Authors: Marlon J Hinner, Rachida-Siham Bel Aiba, Alexander Wiedenmann, Corinna Schlosser, Andrea Allersdorfer, Gabriele Matschiner, Christine Rothe, Ulrich Moebius, Holbrook E Kohrt, Shane A Olwill
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts CD137 is a potent costimulatory immunoreceptor and a member of the TNF-receptor (TNFR) superfamily. The receptor, also known as 4-1BB, is mainly expressed on activated CD4+ and CD8+ T cells, activated B cells, and natural killer (NK) cells. While multiple lines of evidence show
Utility of 10 Immunohistochemical Markers Including Novel Markers (Desmocollin-3, Glypican 3, S100A2, S100A7, and Sox-2) for Differential Diagnosis of Squamous Cell Carcinoma from Adenocarcinoma of the Lung
Authors: Koji Tsuta, Yuko Tanabe, Akihiko Yoshida, Fumiaki Takahashi, Akiko M. Maeshima, Hisao Asamura, Hitoshi Tsuda
Journal: Journal of Thoracic Oncology (2011)
Increased Plasma-Soluble Tumor Necrosis Factor-α Receptor 2 Level in Lean Nondiabetic Offspring of Type 2 Diabetic Subjects
Authors: Marek Straczkowski, Irina Kowalska, Agnieszka Stepien, Stella Dzienis-Straczkowska, Malgorzata Szelachowska, Ida Kinalska
Journal: Diabetes Care (2002)

OBJECTIVE—Tumor necrosis factor-α (TNF-α) is one of the proposed mediators of insulin resistance, upregulated in human obesity. Insulin resistance, however, might precede the development of obesity, especially in subjects with a family history of type 2 diabetes. Therefore, the aim of the present study was to assess plasma levels of TNF-α and soluble forms of its receptors (soluble TNF-α receptors 1 [sTNFR1] and 2 [sTNFR2]) and to evaluate the relationship of the TNF-α system with insulin resistance in lean, nondiabetic offspring of type 2 diabetic patients. RESEARCH DESIGN AND METHODS—We compared 20 lean offspring (BMI &amp;lt;25 kg/m2, 8 men and 12 women) of type 2 diabetic patients with 20 lean subjects with no family history of diabetes, matched for age, sex, and BMI (control group). Anthropometry and blood biochemical parameters were measured, and insulin sensitivity was evaluated with the euglycemic-hyperinsulinemic clamp technique. RESULTS—Both men and women in the offspring group were markedly more insulin-resistant and had higher plasma levels of sTNFR2 (all P &amp;lt; 0.05). TNF-α, sTNFR1, and other examined parameters did not differ between the studied groups. Both TNF-α receptors were related to waist-to-hip ratio (WHR), fat-free mass (FFM), plasma total cholesterol, HDL cholesterol, LDL cholesterol, and nonesterified fatty acids (NEFAs). sTNFR2, but not sTNFR1, was also associated with insulin sensitivity (r = −0.49, P = 0.001). This relationship remained significant after adjustment for WHR, FFM, plasma insulin, and NEFA. CONCLUSIONS—TNF-α system might be involved in modulating insulin action before the onset of obesity in subjects at high risk for type 2 diabetes.
Staphylococcus epidermidis pan-genome sequence analysis reveals diversity of skin commensal and hospital infection-associated isolates
Authors: Sean Conlan, Lilia A Mijares, Jesse Becker, Robert W Blakesley, Gerard G Bouffard, Shelise Brooks, Holly Coleman, Jyoti Gupta, Natalie Gurson, Morgan Park, Brian Schmidt, Pamela J Thomas, Michael Otto, Heidi H Kong, Patrick R Murray, Julia A Segre
Journal: Genome biology (2012)

While Staphylococcus epidermidis is commonly isolated from healthy human skin, it is also the most frequent cause of nosocomial infections on indwelling medical devices. Despite its importance, few genome sequences existed and the most frequent hospital-associated lineage, ST2, had not been fully sequenced.We cultivated 71 commensal S. epidermidis isolates from 15 skin sites and compared them with 28 nosocomial isolates from venous catheters and blood cultures. We produced 21 commensal and 9 nosocomial draft genomes, and annotated and compared their gene content, phylogenetic relatedness and biochemical functions. The commensal strains had an open pan-genome with 80% core genes and 20% variable genes. The variable genome was characterized by an overabundance of transposable elements, transcription factors and transporters. Biochemical diversity, as assayed by antibiotic resistance and in vitro biofilm formation, demonstrated the varied phenotypic consequences of this genomic diversity. The nosocomial isolates exhibited both large-scale rearrangements and single-nucleotide variation. We showed that S. epidermidis genomes separate into two phylogenetic groups, one consisting only of commensals. The formate dehydrogenase gene, present only in commensals, is a discriminatory marker between the two groups.Commensal skin S. epidermidis have an open pan-genome and show considerable diversity between isolates, even when derived from a single individual or body site. For ST2, the most common nosocomial lineage, we detect variation between three independent isolates sequenced. Finally, phylogenetic analyses revealed a previously unrecognized group of S. epidermidis strains characterized by reduced virulence and formate dehydrogenase, which we propose as a clinical molecular marker.
Changes in the concentration and distribution of tissue factor pathway inhibitor in Behcet's disease and systemic lupus erythematosus: effect on the prethrombotic state
Authors: I Ertenli
Journal: Annals of the Rheumatic Diseases (2001)

Tissue factor pathway inhibitor (TFPI) is an anticoagulant which modulates the tissue factor (TF) dependent pathway, acting on the factor VIIa/TF complex, factor Xa, and thrombin. Although most TFPI is found in association with plasma lipoproteins and platelets, the functional pool is bound to vascular endothelium and is released into the circulation on stimulation with heparin or low molecular weight heparin (LMWH).To assess the vascular endothelial TFPI pool in patients with Behçet's disease (BD) or systemic lupus erythematosus (SLE).Plasma TFPI concentrations were determined before, and 20 and 60 minutes after subcutaneous LMWH injection in 15 newly diagnosed patients with BD and 12 with SLE, and in 12 healthy controls.Baseline median TFPI was 149.5 ng/ml in healthy subjects, and the percentage change in TFPI at 20 minutes (((value at 20th min - baseline value)/baseline value) x 100) was 575.2. TFPI concentrations in patients with BD were initially normal at baseline (136.0 ng/ml), but the percentage change (44.7) was significantly lower than in the patients with SLE and the controls. Baseline TFPI concentrations in patients with SLE (83.0 ng/ml) were lower than in the control group, but the TFPI response to stimulation with LMWH reached a level (626.4%) comparable to that of the controls.Depletion of the functional endothelial pool in BD and low circulating concentrations of TFPI despite an intact pool in SLE may be important in the pathogenesis of thrombosis in these vasculitic syndromes.
Vaccines and biologics: Table 1
Authors: Isabel Ferreira, David Isenberg
Journal: Annals of the Rheumatic Diseases (2014)

Patients with autoimmune rheumatic diseases are more susceptible to infectious complications during the course of their disease. The introduction of biologics has been a major achievement in treating these diseases, but an increased risk of infection associated with these therapies has become evident. Some infections can be prevented by vaccination and it is clearly worthwhile considering which immunisations would be sensible and practicable for these patients. To date no formal specific recommendations for patients on biologics have been published. A search was made of Medline (via PubMed) from 1970 to January 2014 to provide results. This review aims to provide a systematic analysis of the data about vaccines and biologics and considers recommendations for vaccination in adult patients with autoimmune rheumatic diseases treated with biologics.
Efficacy of hepatitis B vaccine against antiviral drug-resistant hepatitis B virus mutants in the chimpanzee model #
Authors: Saleem Kamili, Vitini Sozzi, Geoff Thompson, Katie Campbell, Christopher M. Walker, Stephen Locarnini, Krzysztof Krawczynski
Journal: Hepatology (2008)

Abstract Hepatitis B virus (HBV) mutants resistant to treatment with nucleoside or nucleotide analogs and those with the ability to escape from HBV-neutralizing antibody have the potential to infect HBV-vaccinated individuals. To address this potential serious public health challenge, we tested the efficacy of immunity induced by a commercial hepatitis B vaccine against a tissue culture-derived, clonal HBV polymerase mutant in HBV seronegative chimpanzees. The polymerase gene mutant contained a combination of three mutations (rtV173L, rtL180M, rtM204V), two of which resulted in changes to the overlapping viral envelope of the hepatitis B surface antigen (sE164D, sI195M). Prior to the HBV mutant challenge of vaccinated chimpanzees, we established virologic, serologic, and pathologic characteristics of infections resulting from intravenous inoculation of the HBV polymerase gene mutant and the sG145R vaccine-escape surface gene mutant. Cloning and sequencing experiments determined that the three mutations in the polymerase gene mutant remained stable and that the single mutation in the surface gene mutant reverted to the wild-type sequence. Immunological evidence of HBV replication was observed in the vaccinated chimpanzees after challenge with the polymerase gene mutant as well as after rechallenge with serum-derived wild-type HBV (5,000 chimpanzee infectious doses administered intravenously), despite robust humoral and cellular anti-HBV immune responses after hepatitis B vaccination. Conclusion: Our data showing successful experimental infection by HBV mutants despite the presence of high anti-HBs levels considered protective in the vaccinated host are consistent with clinical reports on breakthrough infection in anti-HBs-positive patients infected with HBV mutants. In the absence of a protective humoral immunity, adaptive cellular immune responses elicited by infection may limit HBV replication and persistence. (Hepatology 2009.)
Therapeutic Implications of the Emerging Molecular Biology of Uveal Melanoma
Authors: Mrinali Patel, Elizabeth Smyth, Paul B. Chapman, Jedd D. Wolchok, Gary K. Schwartz, David H. Abramson, Richard D. Carvajal
Journal: Clinical Cancer Research (2011)

Uveal melanoma represents the most common primary intraocular malignancy in adults. Although uveal and cutaneous melanomas both arise from melanocytes, uveal melanoma is clinically and biologically distinct from its more common cutaneous counterpart. Metastasis occurs frequently in this disease, and once distant spread occurs, outcomes are poor. No effective systemic therapies are currently available; however, recent advances in our understanding of the biology of this rare and devastating disease, combined with the growing availability of targeted agents, which can be used to rationally exploit these findings, hold the promise for novel and effective therapies in the foreseeable future. Herein, we review our rapidly growing understanding of the molecular biology of uveal melanoma, including the pathogenic roles of GNAQ (guanine nucleotide binding protein q polypeptide)/11, PTEN (phosphatase and tensin homolog), IGF (insulin-like growth factor)/IGF-1 receptor, MET (hepatocyte growth factor), BAP1 [breast cancer 1, early onset (BRCA1)-associated protein-1], and other key molecules, potential therapeutic strategies derived from this emerging biology, and the next generation of recently initiated clinical trials for the treatment of advanced uveal melanoma.
Arrhythmia in Heart and Brain: KCNQ1 Mutations Link Epilepsy and Sudden Unexplained Death
Authors: A. M. Goldman, E. Glasscock, J. Yoo, T. T. Chen, T. L. Klassen, J. L. Noebels
Journal: Science Translational Medicine (2009)

Mice engineered to carry a human mutation that causes heart problems also have epilepsy, suggesting a cause of SUDEP, sudden unexplained death in epilepsy.
Ultrasound Molecular Imaging of Vascular Endothelial Growth Factor Receptor 2 Expression for Endometrial Receptivity Evaluation
Authors: Hongmei Liu, Yihan Chen, Fei Yan, Xiaohua Han, Junru Wu, Xin Liu, Hairong Zheng
Journal: Theranostics (2014)

Ultrasound (US) molecular imaging by examining the expression of vascular endothelial growth factor receptor 2 (VEGFR2) on uterus vascular endothelium was applied to evaluate the endometrial receptivity.VEGFR2-targeted ultrasound contrast agents (UCA) and the control UCA (without VEGFR2) were prepared and characterized. Adhesion experiment in vitro was performed with mouse microvascular endothelial cells (bEnd.3) and the ratio of the number of UCA to that of cells at the same field was compared. In vivo study, randomized boluses of targeted or control UCA were injected into the animals of non-pregnancy (D0), pregnancy on day 2 (D2) and day 4 (D4), respectively. Sonograms were acquired by an ultrasound equipment with a 40-MHz high-frequency transducer (Vevo 2100; VisualSonics, Toronto, Canada). The ultrasonic imaging signals were quantified as the video intensity amplitudes generated by the attachment of VEGFR2-targeted UCA. Immunoblotting and immunofluorescence assays were used for confirmation of VEGFR2 expression.Our results showed that VEGFR2-targeted UCA could bind to bEnd.3 cells with significantly higher affinity than the control UCA (9.8 ± 1.0 bubbles/cell versus 0.7 ± 0.3 bubbles/cell, P < 0.01) in vitro. The mean video intensity from the US backscattering of the retained VEGFR2-targeted UCA was significantly higher than that of the control UCA in D2 and D4 mice (D2, 10.5 ± 2.5 dB versus 1.5 ± 1.1 dB, P < 0.01; D4, 15.7 ± 4.0 dB versus 1.5 ± 1.2 dB, P < 0.01), but not significantly different in D0 mice (1.0 ± 0.8 dB versus 0.9 ± 0.6 dB, P > 0.05). Moreover, D4 mice showed the highest video intensity amplitude, indicating the highest VEGFR2 expression when compared with D2 and D0 mice (P < 0.01). This was further confirmed by our immunoblotting and immunofluorescence experiments.Ultrasound molecular imaging with VEGFR2-targeted UCA may be used for noninvasive evaluation of endometrial receptivity in murine models.
Standard tobacco packaging has economic and health benefits, says Public Health England
Authors: A. O'Dowd
Journal: BMJ (2014)

Introducing standardised packaging for tobacco products in England could save the public around £500m (€630m; $842m) a year and bring major health benefits, Public Health England has claimed.

The agency has published its official response1 to a government consultation2 on regulations governing the introduction of standardised packaging, which closed on 7 August. The agency noted growing evidence of a “substantial and irrefutable case” to argue for standardised packaging as a way of reducing the numbers of smokers or encouraging them to cut down.

In its response the agency said that it wanted to see long term reductions in youth smoking and for the country to build on the success it had already …
p53, p21, pRB, and p16 Expression Predict Clinical Outcome in Cystectomy With Bladder Cancer
Authors: Shahrokh F. Shariat, Hideo Tokunaga, JainHua Zhou, JaHong Kim, Gustavo E. Ayala, William F. Benedict, Seth P. Lerner
Journal: Journal of Clinical Oncology (2004)

To determine whether p53, p21, pRB, and/or p16 expression is associated with bladder cancer stage, progression, and prognosis.Immunohistochemical staining for p53, p21, pRB, and p16 was carried out on serial sections from archival specimens of 80 patients who underwent bilateral pelvic lymphadenectomy and radical cystectomy for bladder cancer (median follow-up, 101 months).p53, p21, and pRB or p16 expression was altered in 45 (56%), 39 (49%), and 43 (54%) tumors, respectively. Sixty-six patients (83%) had at least one marker altered, and 21 patients (26%) had all three altered. Abnormal expressions of p53, p21, and pRB/p16 expression were associated with muscle-invasive disease (P=.007, P=.003, and P=.003, respectively). The alteration of each marker was independently associated with disease progression (P< or =.038) and disease-specific survival (P< or =.039). In multivariable models that included standard pathologic features and p53 with p21 or p53 with pRB/p16, only p53 and lymph node metastases were associated with bladder cancer progression (P< or =.026) and death (P< or =.028). In models that included p21 and pRB/p16, only p21 and lymph node metastases were associated with bladder cancer progression (P< or =.022) and death (P< or =.028). In a model that included the combined variables p53/p21 and pRB/p16, only p53/p21 and lymph node status were associated with bladder cancer progression (P< or =.047) and death (P< or =.036). The incremental number of altered markers was independently associated with an increased risk of bladder cancer progression (P=.005) and mortality (P=.007).Although altered expression of each of the four cell cycle regulators is associated with bladder cancer outcome in patients undergoing radical cystectomy, p53 is the strongest predictor, followed by p21, suggesting a more pivotal role of the p53/p21 pathway in bladder cancer progression.
Detection of a potent humoral response associated with immune-induced remission of chronic myelogenous leukemia
Authors: Catherine J. Wu, Xiao-Feng Yang, Stephen McLaughlin, Donna Neuberg, Christine Canning, Brady Stein, Edwin P. Alyea, Robert J. Soiffer, Glenn Dranoff, Jerome Ritz
Journal: Journal of Clinical Investigation (2000)

The effectiveness of donor-lymphocyte infusion (DLI) for treatment of relapsed chronic myelogenous leukemia (CML) after allogeneic bone marrow transplantation is a clear demonstration of the graft-versus-leukemia (GVL) effect. T cells are critical mediators of GVL, but the antigenic targets of this response are unknown. To determine whether patients who respond to DLI also develop B-cell immunity to CML-associated antigens, we analyzed sera from three patients with relapsed CML who achieved a complete molecular remission after infusion of donor T cells. Sera from these individuals recognized 13 distinct gene products represented in a CML-derived cDNA library. Two proteins, Jκ-recombination signal-binding protein (RBP-Jκ) and related adhesion focal tyrosine kinase (RAFTK), were recognized by sera from three of 19 DLI responders. None of these antigens were recognized by sera from healthy donors or patients with chronic graft-versus-host disease. Four gene products were recognized by sera from CML patients treated with hydroxyurea and nine were detected by sera from CML patients who responded to IFN-α. Antibody titers specific for RAFTK, but not for RBP-Jκ, were found to be temporally associated with the response to DLI. These results demonstrate that patients who respond to DLI generate potent antibody responses to CML-associated antigens, suggesting the development of coordinated T- and B-cell immunity. The characterization of B cell–defined antigens may help identify clinically relevant targets of the GVL response in vivo.
Increased number of B-cells in bronchial biopsies in COPD
Authors: M. M. E. Gosman, B. W. M. Willemse, D. F. Jansen, T. S. Lapperre, A. van Schadewijk, P. S. Hiemstra, D. S. Postma, W. Timens, H. A. M. Kerstjens
Journal: European Respiratory Journal (2005)

Recently, it has been shown that the accumulated volume of B-cells in small airways is increased in chronic obstructive pulmonary disease (COPD) Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages 3 and 4. Little is known about the number of B-cells in central airways in COPD. The present authors hypothesised that the number of B-cells in bronchial biopsies of large airways is higher in patients with COPD than in controls without airflow limitation and higher in more severe COPD. Therefore, bronchial biopsies were collected from 114 COPD patients (postbronchodilator forced expiratory volume in one second (FEV1) 63+/-9 % predicted value, FEV1/inspiratory vital capacity (IVC) 48+/-9%) and 28 controls (postbronchodilator FEV1 108+/-12 % predicted value, FEV1/IVC 78+/-4%). Paraffin sections were stained for B-cells (CD20+) and their number was determined in the subepithelial area (excluding muscle, glands and vessels). B-cell numbers were higher in patients with COPD versus controls (8.5 versus 3.9 cells x mm(-2), respectively) and higher in patients with GOLD severity stage 3 (n = 11) than stage 2 (n = 103; 22.3 versus 7.8 cells x mm(-2)). No relationship was found between the number of B-cells and clinical characteristics within the chronic obstructive pulmonary disease group. The authors suggest that these increased B-cell numbers may have an important contribution to the pathogenesis of chronic obstructive pulmonary disease.
Can we ever be certain of the diagnosis of acute pancreatitis?
Authors: A G ACHESON
Journal: Gut (1999)

Can we ever be certain of the diagnosis of acute pancreatitis?EDITOR,-The recent guidelines for the management of acute pancreatitis written on behalf of the Working Party of the British Society of Gastroenterology (Gut 1998;42 (suppl 2):S1-13) outline the initial steps in diagnosis, investigation and treatment of acute pancreatitis.The supplement summarises the indications for computed tomography (CT) scanning in pancreatitis and one of these is diagnostic uncertainty.Recently, I was involved in the management of two elderly patients who had a clinical history in keeping with acute pancreatitis and amylase concentrations of 2876 IU/l and 4861 IU/l, respectively (normal range 0-220 IU/l).These two patients subsequently died and postmortem examination in each case revealed evidence of gangrenous bowel and no macroscopic or microscopic evidence of pancreatitis.An amylase concentration of greater than five times normal is often considered diagnostic of acute pancreatitis but previous investigators have shown that significant hyperamylasaemia can be found in conditions other than pancreatitis. 1 Perhaps all patients with hyperamylasaemia should fit into this category of "uncertain diagnosis" and therefore undergo early diagnostic CT scanning rather than depending purely on clinical or biochemical findings.