tbuckley/cabot-search huggingface dataset:
The Ovarian Cancer Chemokine Landscape Is Conducive to Homing of Vaccine-Primed and CD3/CD28–Costimulated T Cells Prepared for Adoptive Therapy
Authors: Emese Zsiros, Priyanka Duttagupta, Denarda Dangaj, Hongzhe Li, Renee Frank, Thomas Garrabrant, Ian S. Hagemann, Bruce L. Levine, Carl H. June, Lin Zhang, Ena Wang, Francesco M. Marincola, Davide Bedognetti, Daniel J. Powell, Janos Tanyi, Michael D. Feldman, Lana E. Kandalaft, George Coukos
Journal: Clinical Cancer Research (2015)

Abstract Purpose: Chemokines are implicated in T-cell trafficking. We mapped the chemokine landscape in advanced stage ovarian cancer and characterized the expression of cognate receptors in autologous dendritic cell (DC)–vaccine primed T cells in the context of cell-based immunotherapy. Experimental Design: The expression of all known human chemokines in patients with primary ovarian cancer was analyzed on two independent microarray datasets and validated on tissue microarray. Peripheral blood T cells from five HLA-A2 patients with recurrent ovarian cancer, who previously received autologous tumor DC vaccine, underwent CD3/CD28 costimulation and expansion ex vivo. Tumor-specific T cells were identified by HER2/neu pentamer staining and were evaluated for the expression and functionality of chemokine receptors important for homing to ovarian cancer. Results: The chemokine landscape of ovarian cancer is heterogeneous with high expression of known lymphocyte-recruiting chemokines (CCL2, CCL4, and CCL5) in tumors with intraepithelial T cells, whereas CXCL10, CXCL12, and CXCL16 are expressed quasi-universally, including in tumors lacking tumor-infiltrating T cells. DC-vaccine primed T cells were found to express the cognate receptors for the above chemokines. Ex vivo CD3/CD28 costimulation and expansion of vaccine-primed Tcells upregulated CXCR3 and CXCR4, and enhanced their migration toward universally expressed chemokines in ovarian cancer. Conclusions: DC-primed tumor-specific T cells are armed with the appropriate receptors to migrate toward universal ovarian cancer chemokines, and these receptors are further upregulated by ex vivo CD3/CD28 costimulation, which render T cells more fit for migrating toward these chemokines. Clin Cancer Res; 21(12); 2840–50. ©2015 AACR.
P2X7 receptor signaling contributes to tissue factor–dependent thrombosis in mice
Authors: Christian Furlan-Freguia, Patrizia Marchese, András Gruber, Zaverio M. Ruggeri, Wolfram Ruf
Journal: Journal of Clinical Investigation (2011)

Thrombosis is initiated by tissue factor (TF), a coagulation cofactor/receptor expressed in the vessel wall, on myeloid cells, and on microparticles (MPs) with variable procoagulant activity. However, the molecular pathways that generate prothrombotic TF in vivo are poorly defined. The oxidoreductase protein disulfide isomerase (PDI) is thought to be involved in the activation of TF. Here, we found that in mouse myeloid cells, ATP-triggered signaling through purinergic receptor P2X, ligand-gated ion channel, 7 (P2X7 receptor; encoded by P2rx7) induced activation (decryption) of TF procoagulant activity and promoted release of TF+ MPs from macrophages and SMCs. The generation of prothrombotic MPs required P2X7 receptor–dependent production of ROS leading to increased availability of solvent-accessible extracellular thiols. An antibody to PDI with antithrombotic activity in vivo attenuated the release of procoagulant MPs. In addition, P2rx7–/– mice were protected from TF-dependent FeCl3-induced carotid artery thrombosis. BM chimeras revealed that P2X7 receptor prothrombotic function was present in both hematopoietic and vessel wall compartments. In contrast, an alternative anti-PDI antibody showed activities consistent with cellular activation typically induced by P2X7 receptor signaling. This anti-PDI antibody restored TF-dependent thrombosis in P2rx7–/– mice. These data suggest that PDI regulates a critical P2X7 receptor–dependent signaling pathway that generates prothrombotic TF, defining a link between inflammation and thrombosis with potential implications for antithrombotic therapy.
Helicobacter pylori increases proliferation of gastric epithelial cells.
Authors: X G Fan, D Kelleher, X J Fan, H X Xia, P W Keeling
Journal: Gut (1996)

The direct and indirect effects of helicobacter pylori on cell kinetics of gastric epithelial cell line AGS were investigated by flow cytometric analysis of Ki-67 positive cells and by MTT assay. Flow cytometric analysis of Ki-67 positivity permits detection of cells that are in S-phase, whereas the MTT assay is a colometric measure of the number of viable cells. In the absence of added stimulants, 23.06 (4.88)% mean (SD) of AGS cells were Ki-67 positive. When cells were preincubated in the presence of H pylori, there was a significant increase in Ki-67 positivity (66.20 (7.89)%, p &lt; 0.001). This increase was not seen in cells cultured in the presence of Campylobacter jejuni (24.63 (8.11)% or Escherichia coli (21.66 (9.78)%). Pre-incubation of AGS cells with supernatants from both H pylori and mitogen activated peripheral blood lymphocytes also increased the per cent of cells that were Ki-67 positive (72.93 (8.68) and 69.96 (12.35)%; p, 0.001) respectively. Similar results were also found in MTT assay. These data show that both H pylori directly and the immune/inflammatory response to H pylori indirectly can influence the rate of epithelial cell proliferation, suggesting this bacterium may be an initiating step in gastric carcinogenesis and an important co-carcinogenic factor in H pylori positive subjects.
Triggering CD40 on endothelial cells contributes to tumor growth
Authors: Claudia Chiodoni, Manuela Iezzi, Cristiana Guiducci, Sabina Sangaletti, Isabella Alessandrini, Chiara Ratti, Francesca Tiboni, Piero Musiani, D. Neil Granger, Mario P. Colombo
Journal: The Journal of Experimental Medicine (2006)

Inflammatory cells can either promote or inhibit tumor growth. Here we studied whether CD40, a key molecule for adaptive immune response, has any role in mammary carcinogenesis of BALB/NeuT transgenic tumor-prone mice. We transferred the HER2/neu oncogene into CD40-null background to obtain the CD40-KO/NeuT strain. CD40-KO/NeuT mice showed delayed tumor onset and reduced tumor multiplicity. BM (BM) transplantation experiments excluded a role of BM-derived cells in the reduced tumorigenicity associated with CD40 deficiency. Rather, CD40 expressed by endothelial cells (ECs) takes part to the angiogenic process. Accordingly, large vessels, well organized around the tumor lobular structures, characterize BALB/NeuT tumors, whereas tiny numerous vessels with scarce extracellular matrix are dispersed in the parenchyma of poorly organized CD40-KO/NeuT tumors. Activated platelets, which may interact with and activate ECs, are a possible source of CD40L. Their localization within tumor vessels prompted the idea of treating BALB/NeuT and CD40-KO/NeuT mice chronically with the anti-platelet drug clopidogrel, known to inhibit platelet CD40L expression. Treatment of BALB/NeuT mice reduced tumor growth to a level similar to CD40-deficient mice, whereas CD40-KO/NeuT mice treated or not showed the same attenuated tumor outgrowth, indicating that activated platelets are the likely source of CD40L in this model. Collectively, these data point to a participation of CD40/CD40L in the angiogenic processes associated with mammary carcinogenesis of BALB/NeuT mice.
Characterization of <i>TMPRSS2</i>-ETS Gene Aberrations in Androgen-Independent Metastatic Prostate Cancer
Authors: Rohit Mehra, Scott A. Tomlins, Jianjun Yu, Xuhong Cao, Lei Wang, Anjana Menon, Mark A. Rubin, Kenneth J. Pienta, Rajal B. Shah, Arul M. Chinnaiyan
Journal: Cancer Research (2008)

Abstract Recurrent gene fusions between the androgen-regulated gene TMPRSS2 and the ETS transcription factor family members ERG, ETV1, and ETV4 have been identified as a critical event in prostate cancer development. In this study, we characterized the prevalence and diversity of these rearrangements in hormone-refractory metastatic prostate cancer. We used a fluorescence in situ hybridization (FISH) split probe strategy to comprehensively evaluate TMPRSS2-ETS aberrations across 97 nonosseous metastatic sites of prostate cancer from 30 rapid autopsies of men who died of androgen-independent disease. Tissue microarrays were constructed representing multiple metastatic sites from each patient, and split signal FISH probes for TMPRSS2, ERG, ETV1, and ETV4 were used to assess for TMPRSS2-ETS rearrangements. In patients exhibiting these aberrations, multiple sites from an individual case harbored the same gene fusion molecular subtype suggesting clonal expansion of disease. The most common prostate cancer gene fusion, TMPRSS2-ERG, can be generated by the mechanism of interstitial deletion (Edel) about 39% to 60% of the time in clinically localized disease. Interestingly, we observed that all of the androgen-independent metastatic prostate cancer sites harboring TMPRSS2-ERG were associated with Edel. These findings suggest that TMPRSS2-ERG with Edel is an aggressive and, in this study, uniformly lethal molecular subtype of prostate cancer associated with androgen-independent disease. [Cancer Res 2008;68(10):3584–90]
Diagnostic Utility of 18F-FDG PET/CT in Inflammation of Unknown Origin
Authors: Hans Balink, Roel J Bennink, Nic J G M Veeger, Berthe L F van Eck-Smit, Hein J Verberne
Journal: Clinical Nuclear Medicine (2014)

The goal of this multicenter retrospective study was to evaluate the contribution of F-FDG PET/CT in the diagnosis of patients with inflammation of unknown origin (IUO). In addition, C-reactive protein (CRP) level and erythrocyte sedimentation rate were assessed as possible predictors for the outcome of F-FDG PET/CT.Inflammation of unknown origin was defined as prolonged and perplexing inflammation, with repeated CRP levels more than 20 mg/L or erythrocyte sedimentation rate more than 20 mm/h, body temperature of less than 38.3°C, and without a diagnosis after a variety of conventional diagnostic procedures.A total of 140 patients with IUO (67 men, 73 women; mean age, 64.2 years; age range, 18-87 years) underwent F-FDG PET/CT. F-FDG PET/CT was considered helpful when the imaging findings led to a diagnosis, either confirmed by histopathology, microbiological assays, clinical and imaging follow-up, or response to treatment.In 104 patients (73%), a final diagnosis could be established as follows: infection in 35 patients, malignancy in 18 patients, noninfectious inflammatory disease in 44 patients, and a variety of uncommon conditions in 7 patients. F-FDG PET/CT was true positive in 95 patients, true negative in 30 patients (ie, self-limiting conditions), false positive in 6 patients, and false negative in 9 patients (predominantly systemic diseases). In this population, the positive predictive value, negative predictive value, and diagnostic accuracy of F-FDG PET/CT were 94%, 77%, and 89%, respectively. In a multivariate analysis, CRP was the only independent predictor for the outcome of F-FDG PET/CT.F-FDG PET/CT correctly identified or excluded a causal explanation in approximately 90% of patients with IUO. However, a negative F-FDG PET/CT is indicative for a self-limiting condition only after systemic diseases are excluded by other diagnostic tests.
Metabolic alteration – Overcoming therapy resistance in gastric cancer via PGK-1 inhibition in a combined therapy with standard chemotherapeutics
Authors: Carl Christoph Schneider, Rami Archid, Nathania Fischer, Sarah Bühler, Sascha Venturelli, Alexander Berger, Markus Burkard, Andreas Kirschniak, Robert Bachmann, Alfred Königsrainer, Jörg Glatzle, Derek Zieker
Journal: International Journal of Surgery (2015)
Mechanisms of the Anti-Cancer and Anti-Inflammatory Actions of Vitamin D
Authors: Aruna V. Krishnan, David Feldman
Journal: The Annual Review of Pharmacology and Toxicology (2011)

Calcitriol, the hormonally active form of vitamin D, is being evaluated in clinical trials as an anti-cancer agent. Calcitriol exerts multiple anti-proliferative, pro-apoptotic, and pro-differentiating actions on various malignant cells and retards tumor growth in animal models of cancer. Calcitriol also exhibits several anti-inflammatory effects including suppression of prostaglandin (PG) action, inhibition of p38 stress kinase signaling, and the subsequent production of pro-inflammatory cytokines and inhibition of NF-κB signaling. Calcitriol also decreases the expression of aromatase, the enzyme that catalyzes estrogen synthesis in breast cancer, both by a direct transcriptional repression and indirectly by reducing PGs, which are major stimulators of aromatase transcription. Other important effects include the suppression of tumor angiogenesis, invasion, and metastasis. These calcitriol actions provide a basis for its potential use in cancer therapy and chemoprevention. We summarize the status of trials involving calcitriol and its analogs, used alone or in combination with known anti-cancer agents.
What's hot that the other lot got
Authors: Simon Rolin
Journal: Thorax (2015)

A substantial proportion of patients with chronic cough (lasting longer than 8 weeks) have no obvious cause after extensive investigation and their symptoms persist despite commonly prescribed antitussive medication. P2X3 receptors are expressed by airway vagal afferent nerves and contribute to the hypersensitisation of sensory neurons. This randomised, double-blind, placebo-controlled UK based phase II study ( Lancet , doi:10.1016/S0140-6736(14)61255-1) aimed to investigate the efficacy of a first-in-class oral P2X3 antagonist, AF-219, to reduce cough frequency in patients with refractory chronic cough. After 2 weeks of treatment, cough frequency was reduced by 75% when patients were allocated to AF-219 compared with placebo (p=0.0003). Taste disturbance was reported by all patients taking AF-219, leading to six patients withdrawing from the study. Inhibition of P2X3 receptors, by antagonists such as AF-219, seems to have significant effect on cough neuronal hypersensitivity and is a promising new …
Distribution of the Sodium/Phosphate Transporter during Postnatal Ontogeny of the Rat Kidney
Authors: MARTIN TRAEBERT, MARIUS LÖTSCHER, RALPH ASCHWANDEN, THERESIA RITTHALER, JÜRG BIBER, HEINI MURER, BRIGITTE KAISSLING
Journal: Journal of the American Society of Nephrology (1999)

Abstract. Renal phosphate reabsorption via the type II sodium/phosphate cotransporter (NaPi-2) in the brush border membrane (BBM) of proximal tubules underlies alterations during aging. The ontogeny of NaPi-2 in kidneys from newborn to 6-wk-old rats was investigated. NaPi-2 protein distribution in the kidneys of neonatal, 13-d-old, 22-d-old, and 6-wk-old rats was immunohistochemically analyzed, and NaPi-2 mRNA distribution in neonatal and 6-wk-old rats was analyzed by in situ hybridization. In kidneys of newborn rats, the appearance of NaPi-2 protein and mRNA coincided with the development of the brush border (assessed by actin staining) on proximal tubular cells. NaPi-2 was not detectable in the nephrogenic zone or in the outgrowing straight sections of proximal tubules, which lack a brush border. In 13-d-old suckling rats, strong NaPi-2 staining was seen in the BBM of convoluted proximal tubules of all nephron generations. In contrast, in 22-d-old weaned rats, NaPi-2 staining in the BBM of superficial nephrons was weaker than that in the BBM of juxtamedullary nephrons. Western blotting demonstrated that the overall abundance of NaPi-2 protein in the BBM of 22-d-old rats was decreased to approximately 70% of that in 13-d-old rats. In kidneys of 6-wk-old rats, the internephron gradient for NaPi-2 abundance in the BBM corresponded to that in adult rats. The data suggest that the NaPi-2 system in the kidney is fully functional and possesses the capacity for regulation as soon as nephrogenesis is completed. The manifestation of NaPi-2 internephron heterogeneity immediately after weaning might be related to the change in dietary inorganic phosphate content.
Employment after Coronary Angioplasty or Coronary Bypass Surgery in Patients Employed at the Time of Revascularization
Authors: Mark A. Hlatky
Journal: Annals of Internal Medicine (1998)

Background: Patients who undergo coronary angioplasty have a shorter convalescence than those who undergo coronary bypass surgery. This may improve subsequent employment. Objective: To compare employment patterns after coronary angioplasty or surgery. Design: Multicenter, randomized clinical trial. Setting: Seven tertiary care hospitals. Patients: 409 employed patients with multivessel coronary artery disease. Intervention: Coronary bypass surgery or balloon angioplasty. Measurements: Time to return to work and time spent working during 4 years of follow-up. Results: Patients who underwent angioplasty returned to work 6 weeks sooner than patients who underwent coronary bypass surgery (P < 0.001), but long-term employment did not differ significantly (P > 0.2). Long-term employment was significantly lower among patients who were 60 to 64 years of age (P < 0.001), those who worked less than full-time at study entry (P < 0.001), and those who had less formal education (P = 0.005). Patients with only one source of health insurance were more likely to continue working (P = 0.005). Conclusions: Faster recovery after angioplasty speeds return to work but does not improve long-term employment, which is primarily associated with nonmedical factors.
Recurrent viral infections associated with a homozygous CORO1A mutation that disrupts oligomerization and cytoskeletal association
Authors: Christina S. Yee, Michel J. Massaad, Wayne Bainter, Toshiro K. Ohsumi, Niko Föger, Andrew C. Chan, Nurten A. Akarsu, Caner Aytekin, Deniz Çagdas Ayvaz, Ilhan Tezcan, Özden Sanal, Raif S. Geha, Janet Chou
Journal: Journal of Allergy and Clinical Immunology (2015)
Dependence of Cardiac Transverse Tubules on the BAR Domain Protein Amphiphysin II (BIN-1)
Authors: Jessica L. Caldwell, Charlotte E.R. Smith, Rebecca F. Taylor, Ashraf Kitmitto, David A. Eisner, Katharine M. Dibb, Andrew W. Trafford
Journal: Circulation Research (2014)

Transverse tubules (t-tubules) regulate cardiac excitation-contraction coupling and exhibit interchamber and interspecies differences in expression. In cardiac disease, t-tubule loss occurs and affects the systolic calcium transient. However, the mechanisms controlling t-tubule maintenance and whether these factors differ between species, cardiac chambers, and in a disease setting remain unclear.To determine the role of the Bin/Amphiphysin/Rvs domain protein amphiphysin II (AmpII) in regulating t-tubule maintenance and the systolic calcium transient.T-tubule density was assessed by di-4-ANEPPS, FM4-64 or WGA staining using confocal microscopy. In rat, ferret, and sheep hearts t-tubule density and AmpII protein levels were lower in the atrium than in the ventricle. Heart failure (HF) was induced in sheep using right ventricular tachypacing and ferrets by ascending aortic coarctation. In both HF models, AmpII protein and t-tubule density were decreased in the ventricles. In the sheep, atrial t-tubules were also lost in HF and AmpII levels decreased. Conversely, junctophilin 2 levels did not show interchamber differences in the rat and ferret nor did they change in HF in the sheep or ferret. In addition, in rat atrial and sheep HF atrial cells where t-tubules were absent, junctophilin 2 had sarcomeric intracellular distribution. Small interfering RNA-induced knockdown of AmpII protein reduced t-tubule density, calcium transient amplitude, and the synchrony of the systolic calcium transient.AmpII is intricately involved in t-tubule maintenance. Reducing AmpII protein decreases t-tubule density, reduces the amplitude, and increases the heterogeneity of the systolic calcium transient.
Comparison of vasopeptidase inhibitor, omapatrilat, and lisinopril on exercise tolerance and morbidity in patients with heart failure: IMPRESS randomised trial
Authors: Jean L Rouleau, Marc A Pfeffer, Duncan J Stewart, Debra Isaac, Francois Sestier, Edmund K Kerut, Charles B Porter, Guy Proulx, Chunlin Qian, Alan J Block
Journal: The Lancet (2000)
Predicting recurrent shoulder instability
Authors: Mark R Hutchinson, Bob McCormack
Journal: British Journal of Sports Medicine (2015)

BackgroundRecurrent instability following a first time anterior traumatic shoulder dislocation may exceed 26%.We systematically reviewed risk factors which predispose this population to events of recurrence. MethodsA systematic review of studies published before July 1, 2014.Risk factors which predispose recurrence following a first time traumatic anterior shoulder dislocation were documented and rates of recurrence were compared.Pooled odds ratios were analysed using random effects meta-analysis. ResultsTen studies comprising 1,324 subjects met the criteria for inclusion.Recurrent instability following a first time traumatic anterior shoulder dislocation was 39%.Increased risk of recurrent instability was reported in people aged 40 years and under (OR=13.46), in men (OR=3.18)and in people with hyperlaxity (OR=2.68).Decreased risk of recurrent instability was reported in people with a greater tuberosity fracture (OR=0.13).The rate of recurrent instability decreased as time from the initial dislocation increased.Other factors such as a bony Bankart lesion, nerve palsy, and occupation influenced rates of recurrent instability. ConclusionSex, age at initial dislocation, time from initial dislocation, hyperlaxity and greater tuberosity fractures were key risk factors in at least two good quality cohort studies resulting in strong evidence as concluded in the GRADE criteria.Although bony Bankart lesions, Hill Sachs lesions, occupation, physiotherapy treatment and nerve palsy were risk factors for recurrent instability, the evidence was weak using the GRADE criteria -these findings relied on poorer quality studies or were inconsistent among studies.
Interpreting a post‐partum Kleihauer test
Authors: Barbara J Bain, Linda Chapple
Journal: American Journal of Hematology (2014)

A 23-year-old blood group O RhD-negative woman presented already in labour and gave birth to an O RhD-positive baby.The baby's direct antiglobulin test was negative.Following delivery, the mother received a standard dose of anti-D and a post-delivery maternal blood sample was sent to quantitate any fetomaternal hemorrhage and thus determine the adequacy of the dose given.The test was positive but it was noted that the distribution of hemoglobin F was heterogeneous (top) rather than showing the two clear populations of cells expected if a fetomaternal hemorrhage had occurred.The expected pattern is shown in the positive control (bottom).The absence of fetal cells in the maternal circulation was confirmed by flow cytometry, which showed no D-positive cells.High performance liquid chromatography showed the mother to have 4.9% hemoglobin F..