tbuckley/cabot-search huggingface dataset:
Immune responses and HIV: a little order from the chaos
Authors: David H. O'Connor, Dennis R. Burton
Journal: The Journal of Experimental Medicine (2006)

HIV is evolution gone mad and bad. The virus infects a person and rapidly diversifies to become a huge swarm of viruses, each equipped differently to resist the onslaught of diverse T cells and antibodies. We can't expect to predict details of the struggle between virus and immunity, right? Wrong—maybe we can make some predictions, say two new landmark studies with potentially huge consequences for AIDS vaccine design.
An Open-Label, Two-Arm, Phase I Trial of Recombinant Human Interleukin-21 in Patients with Metastatic Melanoma
Authors: Ian D. Davis, Birte K. Skrumsager, Jonathan Cebon, Theo Nicholaou, John W. Barlow, Niels Peter Hundahl Moller, Kresten Skak, Dorthe Lundsgaard, Klaus Stensgaard Frederiksen, Peter Thygesen, Grant A. McArthur
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Human interleukin-21 (IL-21) is a pleiotropic class I cytokine that activates CD8+ T cells and natural killer cells. We report a phase 1 study of recombinant human IL-21 in patients with surgically incurable metastatic melanoma. The primary objective was to investigate safety and tolerability by determining dose-limiting toxicity (DLT). The secondary objectives were to identify a dose response for various biomarkers in the peripheral blood, estimate the minimum biologically effective dose, determine the pharmacokinetics of IL-21, determine if anti-IL-21 antibodies were induced during therapy, and measure effects on tumor size according to Response Evaluation Criteria in Solid Tumors. Experimental Design: Open-label, two-arm, dose escalation trial of IL-21 administered by i.v. bolus injection at dose levels from 1 to 100 μg/kg using two parallel treatment regimens: thrice weekly for 6 weeks (3/wk) or three cycles of daily dosing for 5 days followed by 9 days of rest (5+9). Results: Twenty-nine patients entered the study. IL-21 was generally well tolerated and no DLTs were observed at the 1, 3, and 10 μg/kg dose levels. In the 3/wk regimen, DLTs were increased in alanine aminotransferase, neutropenia, and lightheadedness with fever and rigors. DLTs in the 5+9 regimen were increased in aspartate aminotransferase and alanine aminotransferase, neutropenia, fatigue, and thrombocytopenia. The maximum tolerated dose was declared to be 30 μg/kg for both regimens. Effects on biomarkers were observed at all dose levels, including increased levels of soluble CD25 and up-regulation of perforin and granzyme B mRNA in CD8+ cells. One partial tumor response observed after treatment with IL-21 for 2 × 6 weeks (3/wk) became complete 3 months later. Conclusions: IL-21 is biologically active at all dose levels administered and is generally well tolerated, and phase 2 studies have commenced using 30 μg/kg in the 5+9 regimen.
hERG1 Channels Regulate VEGF-A Secretion in Human Gastric Cancer: Clinicopathological Correlations and Therapeutical Implications
Authors: Olivia Crociani, Elena Lastraioli, Luca Boni, Serena Pillozzi, Maria Raffaella Romoli, Massimo D'Amico, Matteo Stefanini, Silvia Crescioli, Antonio Taddei, Lapo Bencini, Marco Bernini, Marco Farsi, Stefania Beghelli, Aldo Scarpa, Luca Messerini, Anna Tomezzoli, Carla Vindigni, Paolo Morgagni, Luca Saragoni, Elisa Giommoni, Silvia Gasperoni, Francesco Di Costanzo, Franco Roviello, Giovanni De Manzoni, Paolo Bechi, Annarosa Arcangeli
Journal: Clinical Cancer Research (2014)

Abstract Purpose: hERG1 channels are aberrantly expressed in several types of human cancers, where they affect different aspects of cancer cell behavior. A thorough analysis of the functional role and clinical significance of hERG1 channels in gastric cancer is still lacking. Experimental Design: hERG1 expression was tested in a wide (508 samples) Italian cohort of surgically resected patients with gastric cancer, by immunohistochemistry and real-time quantitative PCR. The functional link between hERG1 and the VEGF-A was studied in different gastric cancer cell lines. The effects of hERG1 and VEGF-A inhibition were evaluated in vivo in xenograft mouse models. Results: hERG1 was positive in 69% of the patients and positivity correlated with Lauren's intestinal type, fundus localization of the tumor, G1–G2 grading, I and II tumor—node—metastasis stage, and VEGF-A expression. hERG1 activity modulated VEGF-A secretion, through an AKT-dependent regulation of the transcriptional activity of the hypoxia inducible factor. Treatment of immunodeficient mice xenografted with human gastric cancer cells, with a combination of hERG1 blockers and anti-VEGF-A antibodies, impaired tumor growth more than single-drug treatments. Conclusion: Our results show that hERG1 (i) is aberrantly expressed in human gastric cancer since its early stages; (ii) drives an intracellular pathway leading to VEGF-A secretion; (iii) can be exploited to identify a gastric cancer patients' group where a combined treatment with antiangiogenic drugs and noncardiotoxic hERG1 inhibitors could be proposed. Clin Cancer Res; 20(6); 1502–12. ©2014 AACR.
Resistance to Transplants of Recent Spontaneous Parental Line Tumors by F&lt;sub&gt;1&lt;/sub&gt;Hybrid Hosts&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Barbara H. Sanford, Sophie F. Soo
Journal: JNCI Journal of the National Cancer Institute (1971)

Experiments reported involved transplantation of recent, strain-specific mouse tumors into syngeneic and F1 hybrid recipients. Evidence is presented indicating an immunological basis for the greater resistance of the hybrid hosts, probably due to a more efficient immunological response of heterozygous animals to tumor-specific antigens.
Alcohol consumption and pancreatic cancer: a pooled analysis in the International Pancreatic Cancer Case–Control Consortium (PanC4)
Authors: E. Lucenteforte, C. La Vecchia, D. Silverman, G.M. Petersen, P.M. Bracci, B.T. Ji, C. Bosetti, D. Li, S. Gallinger, A.B. Miller, H.B. Bueno-de-Mesquita, R. Talamini, J. Polesel, P. Ghadirian, P.A. Baghurst, W. Zatonski, E. Fontham, W.R. Bamlet, E.A. Holly, Y.T. Gao, E. Negri, M. Hassan, M. Cotterchio, J. Su, P. Maisonneuve, P. Boffetta, E.J. Duell
Journal: Annals of Oncology (2011)
Participation in the ARGA study: Long term impact on asthma management
Authors: Sandra Baldacci, Sara Maio, Anna Angino, Marzia Simoni, Sonia Cerrai, Giuseppe Sarno, Franca Martini, Patrizia Silvi, Marco Borbotti, AnnaPaola Pala, Giovanni Viegi
Journal: European Respiratory Journal (2012)

Background : preliminary results of Respiratory allergic diseases: monitoring study of GINA and ARIA guidelines (ARGA) study show a poor effect of a medical education course on Global Initiative for Asthma (GINA) guidelines in improving asthma management. Aim : to evaluate the long term impact of participating in a prospective study on Italian General Practitioners (GP) focused on monitoring the utilization of GINA and Allergic Rhinitis and Its Impact on Asthma (ARIA) guidelines for asthma and allergic rhinitis management. Methods: 107 GP enrolled 936 asthmatic patients (mean age 44yrs). For each patient, a self-administered questionnaire on respiratory allergic diseases/symptoms, daily activity limitations, quality of life (by RHINASTHMA questionnaire), disease control (by Asthma Control Test – ACT), health self perception and the relative form filled in by GP were available at baseline and follow up 12 months apart. Results: comparing baseline with follow up, asthma outcomes show an improvement: from 54.2 to 67.4% for asthma control, from 85.2 to 80.0% for asthma-like symptoms in the last 12 months, from 71.9 to 67.2% for daily activity limitations, from 61.2 to 66.6% for good health self perception and from 21.7 to 18.9 for quality of life score. Conclusions : Involvement in a prospective study on asthma management seems to produce a long term effect in GP attitudes ameliorating their asthmatic patients quality of life.

This work was supported by the “Italian Medicines Agency (AIFA)”, within the independent drug research program, contract no. “FARM5JYS5A”.
Activation-dependent cumulative depletions of extracellular free calcium in guinea pig atrium measured with antipyrylazo III and tetramethylmurexide.
Authors: D W Hilgemann, M J Delay, G A Langer
Journal: Circulation Research (1983)

We have used a spectrophotometric method to monitor mean free extracellular calcium concentrations in isolated left atria of guinea pigs via extracellular application of the calcium-sensitive absorption dyes, antipyrylazo III and tetramethylmurexide. Exchange of extracellular free calcium with the bathing medium takes several minutes and closely parallels contractile response in this preparation. Under conditions favoring a rapid positive force staircase response during repetitive stimulation after a long rest period (2-10 minutes), cumulative depletions of extracellular calcium can clearly be differentiated from motion artifact due to muscle movement by multiple-wavelength spectrophotometry. Responses of similar magnitude and characteristics are obtained with both dyes employed. In the presence of 10(-7) M isoproterenol, the mean extracellular calcium concentration falls by at least 5% (0.25-0.8 mM total calcium concentration) in four beats at 0.5 Hz; extracellular calcium replenishes during rest with an apparent t1/2 of 25-60 seconds. A 10-minute pretreatment with 10(-8) M ryanodine greatly reduces the contraction force and motion artifact of the first beat after a rest period, whereby the magnitude of depletion response to one post-rest stimulation is increased 2- to 3-fold. With further ryanodine treatment, the magnitude of depletion responses remains stable, and the rate of calcium replenishment during rest increases many-fold. After ryanodine treatment and 10(-7) M isoproterenol, at least 10% of total dye accessible calcium (0.25-1.0 mM) is lost during two to five rapid stimulations, and returns to the extracellular space within 20 seconds of rest. Cumulative extracellular calcium depletion responses are strongly suppressed by 10(-6) M nifedipine. Cumulative depletion responses are also inhibited by 10 mM caffeine, whereby contraction and corresponding motion artifacts are increased at post-rest stimulation.
Outcomes in females hospitalised with community-acquired pneumonia are worse than in males
Authors: Forest W. Arnold, Timothy L. Wiemken, Paula Peyrani, Mehdi Mirsaeidi, Julio A. Ramirez
Journal: European Respiratory Journal (2012)

There is little recent information on sex-specific outcomes of patients with community-acquired pneumonia (CAP). The objective of this study was to determine whether female sex is associated with better clinical outcomes in hospitalised patients with CAP. A secondary analysis was conducted by the Community Acquired Pneumonia Organization regarding male and female patients with CAP from 80 hospitals in 17 countries from June 1, 2001 to August 2, 2011. Outcomes were time to clinical stability, length of stay and in-hospital and 28-day mortality. Propensity-adjusted, multivariate regression models were used to predict the probability of occurrence of each of the study outcomes. There were 6718 patients in this study, of whom 40% were female. The adjusted hazard ratio (HR) for time to clinical stability was 0.91 (95% CI 0.85–0.97; p=0.005). The adjusted HR for length of stay was 0.94 (95% CI 0.88–1.01; p=0.089). The adjusted risk ratio for in-hospital mortality was 1.04 (95% CI 0.86–1.24; p=0.717), and for 28-day mortality was 1.15 (95% CI 1.02–1.30; p=0.018). This study demonstrates that the epidemiology of CAP may be changing, and that females have worse outcomes for CAP than males. They are more likely to take longer to reach clinical stability, have longer hospital stays and are 15% more likely to have died after 28 days. Current pneumonia scoring systems may need to be revised regarding female mortality risk.
Biliary Tract Cancers: Understudied and Poorly Understood
Authors: Emily Chan, Jordan Berlin
Journal: Journal of Clinical Oncology (2015)

Biliary tract cancers are a heterogeneous group of cancers that arise in either the intra- or extrahepatic bile ducts or the gallbladder. Local therapy with surgical resection and perhaps radiation therapy is used for localized disease. There is no known effective adjuvant therapy, although various combinations have been used clinically without definitive data showing a benefit. The most standard chemotherapy for metastatic disease is gemcitabine plus cisplatin based on a single positive randomized trial. Genetic mutations that may lead to better, targeted therapy choices are being identified, albeit with variable frequency. Early studies of targeted agents have been negative, but these were in unselected patients where it was unknown whether the target was activated in any individual patient. Careful selection of patients enrolling onto trials of targeted agents will make the subsets of biliary tract cancers even smaller but is likely necessary to improve outcomes from these deadly diseases.
First-Line Treatment for Primary Testicular Diffuse Large B-Cell Lymphoma With Rituximab-CHOP, CNS Prophylaxis, and Contralateral Testis Irradiation: Final Results of an International Phase II Trial
Authors: Umberto Vitolo, Annalisa Chiappella, Andrés J.M. Ferreri, Maurizio Martelli, Ileana Baldi, Monica Balzarotti, Chiara Bottelli, Annarita Conconi, Henry Gomez, Armando Lopez-Guillermo, Giovanni Martinelli, Francesco Merli, Domenico Novero, Lorella Orsucci, Vincenzo Pavone, Umberto Ricardi, Sergio Storti, Mary K. Gospodarowicz, Franco Cavalli, Andreas H. Sarris, Emanuele Zucca
Journal: Journal of Clinical Oncology (2011)

Purpose Primary testicular lymphoma (PTL) has poor prognosis with failures in contralateral testis, CNS, and extranodal sites. To prevent these events, we designed an international phase II trial (International Extranodal Lymphoma Study Group 10 [IELSG-10]) that addressed feasibility and activity of conventional chemoimmunotherapy associated with CNS prophylaxis and contralateral testis irradiation. The trial was conducted by the IELSG and the Italian Lymphoma Foundation. Patients and Methods Fifty-three patients (age 22 to 79 years) with untreated stage I or II PTL were treated with six to eight courses of rituximab added to cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) every 21 days (R-CHOP21); four doses of intrathecal methotrexate (IT-MTX) and radiotherapy (RT) to the contralateral testis (30 Gy) for all patients and to regional lymph nodes (30 to 36 Gy) for stage II disease. Results All patients received R-CHOP21, 50 received CNS prophylaxis, and 47 received testicular RT. With a median follow-up of 65 months, 5-year progression-free survival and overall survival rates were 74% (95% CI, 59% to 84%) and 85% (95% CI, 71% to 92%), respectively. Ten patients relapsed or progressed: two in lymph nodes, five in extranodal organs, and three in the CNS. The 5-year cumulative incidence of CNS relapse was 6% (95% CI, 0% to 12%). No contralateral testis relapses occurred. Ten patients died: lymphoma (n = 6), secondary leukemia (n = 2), heart failure (n = 1), and gastric cancer (n = 1). Grade 3 to 4 toxicities were neutropenia, 28%; infections, 4%; and neurologic, 13%. No deaths occurred as a result of toxicity. Conclusion This international prospective trial shows that combined treatment with R-CHOP21, IT-MTX, and testicular RT was associated with a good outcome in patients with PTL. RT avoided contralateral testis relapses, but CNS prophylaxis deserves further investigation.
Efficacy of BET Bromodomain Inhibition in Kras-Mutant Non–Small Cell Lung Cancer
Authors: Takeshi Shimamura, Zhao Chen, Margaret Soucheray, Julian Carretero, Eiki Kikuchi, Jeremy H. Tchaicha, Yandi Gao, Katherine A. Cheng, Travis J. Cohoon, Jun Qi, Esra Akbay, Alec C. Kimmelman, Andrew L. Kung, James E. Bradner, Kwok-Kin Wong
Journal: Clinical Cancer Research (2013)

Amplification of MYC is one of the most common genetic alterations in lung cancer, contributing to a myriad of phenotypes associated with growth, invasion, and drug resistance. Murine genetics has established both the centrality of somatic alterations of Kras in lung cancer, as well as the dependency of mutant Kras tumors on MYC function. Unfortunately, drug-like small-molecule inhibitors of KRAS and MYC have yet to be realized. The recent discovery, in hematologic malignancies, that bromodomain and extra-terminal (BET) bromodomain inhibition impairs MYC expression and MYC transcriptional function established the rationale of targeting KRAS-driven non-small cell lung cancer (NSCLC) with BET inhibition.We performed functional assays to evaluate the effects of JQ1 in genetically defined NSCLC cell lines harboring KRAS and/or LKB1 mutations. Furthermore, we evaluated JQ1 in transgenic mouse lung cancer models expressing mutant kras or concurrent mutant kras and lkb1. Effects of bromodomain inhibition on transcriptional pathways were explored and validated by expression analysis.Although JQ1 is broadly active in NSCLC cells, activity of JQ1 in mutant KRAS NSCLC is abrogated by concurrent alteration or genetic knockdown of LKB1. In sensitive NSCLC models, JQ1 treatment results in the coordinate downregulation of the MYC-dependent transcriptional program. We found that JQ1 treatment produces significant tumor regression in mutant kras mice. As predicted, tumors from mutant kras and lkb1 mice did not respond to JQ1.Bromodomain inhibition comprises a promising therapeutic strategy for KRAS-mutant NSCLC with wild-type LKB1, via inhibition of MYC function. Clinical studies of BET bromodomain inhibitors in aggressive NSCLC will be actively pursued. Clin Cancer Res; 19(22); 6183-92. ©2013 AACR.
Nuclear Receptor Coregulators in Cancer Biology
Authors: Bert W. O'Malley, Rakesh Kumar
Journal: Cancer Research (2009)

Abstract Coregulators (coactivators and corepressors) occupy the driving seat for actions of all nuclear receptors, and consequently, selective receptor modulator drugs. The potency and selectivity for subreactions of transcription reside in the coactivators, and thus, they are critically important for tissue-selective gene function. Each tissue has a “quantitative finger print” of coactivators based on its relative inherited concentrations of these molecules. When the cellular concentration of a coactivator is altered, genetic dysfunction usually leads to a pathologic outcome. For example, many cancers overexpress “growth coactivators.” In this way, the cancer cell can hijack these coactivator molecules to drive proliferation and metastasis. The present review contains summaries of selective coactivators and corepressors that have been demonstrated to play important roles in the malignant process and emphasizes their importance for future therapeutic interventions. [Cancer Res 2009;69(21):8217–22]
Lack of association of the pregnane X receptor (PXR/NR1I2) gene with inflammatory bowel disease: parallel allelic association study and gene wide haplotype analysis
Authors: G-T Ho, N Soranzo, S K Tate, H Drummond, E R Nimmo, A Tenesa, I D Arnott, J Satsangi
Journal: Gut (2006)

The pregnane X receptor gene (PXR/NR1I2) regulates an array of genes involved in the response to xenobiotics.1,2 Dysregulation of this gene may critically influence intestinal barrier defence and susceptibility to inflammatory bowel disease (IBD).3 Recent data from Ireland have suggested strong associations between polymorphisms within the PXR/NR1I2 gene and IBD. Dring et al performed a case control study involving 422 patients with IBD (185 ulcerative colitis (UC) and 237 (Crohn’s disease (CD)) and 350 healthy controls, using eight candidate polymorphisms in this gene.4 Highly significant associations were demonstrated with UC, CD, and IBD as a whole. This effect was most significant for the two individual single nucleotide polymorphisms (SNPs) in the promoter region of this gene; compared between the IBD cohort and controls, rs3814055/−23585 (p = 0.000008; odds ratio (OR) 1.62 (95% confidence interval (CI) 1.31–2.00)) and rs1523127/−24381 (p = 0.0002; OR 1.50 (95% CI 1.21–1.84)).

We have critically re-evaluated the contribution of these allelic …
The immunogenicity of a viral cytotoxic T cell epitope is controlled by its MHC-bound conformation
Authors: Fleur E. Tynan, Diah Elhassen, Anthony W. Purcell, Jacqueline M. Burrows, Natalie A. Borg, John J. Miles, Nicholas A. Williamson, Kate J. Green, Judy Tellam, Lars Kjer-Nielsen, James McCluskey, Jamie Rossjohn, Scott R. Burrows
Journal: The Journal of Experimental Medicine (2005)

Thousands of potentially antigenic peptides are encoded by an infecting pathogen; however, only a small proportion induce measurable CD8+ T cell responses. To investigate the factors that control peptide immunogenicity, we have examined the cytotoxic T lymphocyte (CTL) response to a previously undefined epitope (77APQPAPENAY86) from the BZLF1 protein of Epstein-Barr virus (EBV). This peptide binds well to two human histocompatibility leukocyte antigen (HLA) allotypes, HLA-B*3501 and HLA-B*3508, which differ by a single amino acid at position 156 (156Leucine vs. 156Arginine, respectively). Surprisingly, only individuals expressing HLA-B*3508 show evidence of a CTL response to the 77APQPAPENAY86 epitope even though EBV-infected cells expressing HLA-B*3501 process and present similar amounts of peptide for CTL recognition, suggesting that factors other than peptide presentation levels are influencing immunogenicity. Functional and structural analysis revealed marked conformational differences in the peptide, when bound to each HLA-B35 allotype, that are dictated by the polymorphic HLA residue 156 and that directly affected T cell receptor recognition. These data indicate that the immunogenicity of an antigenic peptide is influenced not only by how well the peptide binds to major histocompatibility complex (MHC) molecules but also by its bound conformation. It also illustrates a novel mechanism through which MHC polymorphism can further diversify the immune response to infecting pathogens.
CELLULAR AND MOLECULAR DETERMINANTS OF SYMPATHETIC NEURON DEVELOPMENT
Authors: Nicole J. Francis, Story C. Landis
Journal: Annual Review of Neuroscience (1999)

▪ Abstract The development of the sympathetic nervous system can be divided into three overlapping stages. First, the precursors of sympathetic neurons arise from undifferentiated neural crest cells that migrate ventrally, aggregate adjacent to the dorsal aorta, and ultimately differentiate into catecholaminergic neurons. Second, cell number is refined during a period of cell death when neurotrophic factors determine the number of neuronal precursors and neurons that survive. The final stage of sympathetic development is the establishment and maturation of synaptic connections, which for sympathetic neurons can include alterations in neurotransmitter phenotype. Considerable progress has been made recently in elucidating the cellular and molecular mechanisms that direct each of these developmental decisions. We review the current understanding of each of these, focusing primarily on events in the peripheral nervous system of rodents.
Dichotomy between the induction of suppressor cells and immunologic tolerance by adult thymectomy.
Authors: Y Borel, L Kilham, S E Kurtz, C L Reinisch
Journal: The Journal of Experimental Medicine (1980)

Adult thymectomy prevents the development of suppressor T cells without impairing the induction of immunologic tolerance to the same antigenic determinant. This finding demonstrates that the cellular mechanisms underlying immune suppression and immune tolerance are different.