tbuckley/cabot-search huggingface dataset:
HLA-DMA*0103 and HLA-DMB*0104 alleles as novel prognostic factors in rheumatoid arthritis
Authors: J Morel
Journal: Annals of the Rheumatic Diseases (2004)

To evaluate HLA-DM alleles as markers for disease severity in rheumatoid arthritis (RA).Two distinct cohorts of patients with RA were oligotyped for HLA-DB1 and HLA-DM genes using PCR amplified genomic DNA with sequence specific oligonucleotide probes. Cohort 1 comprised 199 unselected patients with RA (mean (SD) age 45.5 (13.5) years; disease duration 11.9(8.8) years), whose disease severity was assessed using Larsen score on hand and foot radiographs. Cohort 2 comprised 95 patients with severe RA and 70 patients with benign RA according to the Larsen method.In cohort 1, after stratification according to DRB1 genotypes, patients positive for HLA-DMA*0103 and negative for HLA-DRB1*04 tended to have greater articular damage on hands and wrists (p = 0.07 by Mann-Whitney U test) and reached statistical significance for the Larsen score per year (p = 0.05). This association between HLA-DMA*0103 and articular damage was especially observed in patients with HLA-DRB1*01. Similarly, HLA-DMB*0104 positive patients had higher Larsen score on hands and wrists (p = 0.02). This association was even stronger in DRB1*04 positive patients (p = 0.005). In cohort 2, HLA-DMA*0103 was associated with severe RA in patients negative for HLA-DRB1*04 (OD = 5.4; p = 0.014). HLA-DMB*0104 allele frequency tended to be higher in patients with severe RA but without reaching significance.This is the first study evaluating the role of HLA-DM genes in the severity of RA. Our results suggest that HLA-DMA*0103 and HLA-DMB*0104 alleles may represent new genetic markers of RA severity. The HLA-DMA*0103 allele tends to be associated with patients with RA negative for DRB1*04 and could predict a more severe form of disease especially in HLA-DRB1*01 positive patients. The HLA-DMB*0104 allele could have an additive effect in HLA-DRB1*04 patients. Combined determination of HLA-DM and HLA-DRB1 alleles could facilitate identification of patients likely to have a poor disease course.
Rhinovirus upregulates transient receptor potential channels in a human neuronal cell line: implications for respiratory virus-induced cough reflex sensitivity
Authors: H Abdullah, L G Heaney, S L Cosby, L P A McGarvey
Journal: Thorax (2013)

<h3>Background</h3> The mechanism underlying respiratory virus-induced cough hypersensitivity is unknown. Upregulation of airway neuronal receptors responsible for sensing physical and chemical stimuli is one possibility, and the transient receptor potential (TRP) channel family are potential candidates. We have used an in vitro model of sensory neurons and human rhinovirus (HRV-16) to study the effect of virus infection on TRP expression. <h3>Methods</h3> IMR-32 neuroblastoma cells were differentiated in culture to express three TRP channels: TRPV1, TRPA1 and TRPM8. Flow cytometry and qRT-PCR were used to measure TRP channel protein and mRNA levels following inoculation with live virus, inactivated virus, virus-induced soluble factors or pelleted virus particles. Multiplex bioassay was used to determine nerve growth factor (NGF), interleukin (IL)-1β, IL-6 and IL-8 levels in response to infection. <h3>Results</h3> Early upregulation of TRPA1 and TRPV1 expression occurred 2–4 h post infection. This was independent of replicating virus as virus-induced soluble factors alone were sufficient to increase channel expression 50-fold and 15-fold, respectively. NGF, IL-6 and IL-8 levels, increased in infected cell supernatants, represent possible candidates. In contrast, TRPM8 expression was maximal at 48 h (9.6-fold) and required virus replication rather than soluble factors. <h3>Conclusions</h3> We show for the first time that rhinovirus can infect neuronal cells. Furthermore, infection causes upregulation of TRP channels by channel-specific mechanisms. The increase in TRPA1 and TRPV1 levels can be mediated by soluble factors induced by infection whereas TRPM8 requires replicating virus. TRP channels may be novel therapeutic targets for controlling virus-induced cough.
Long-Term Outcome in Children With Relapsed ALL by Risk-Stratified Salvage Therapy: Results of Trial Acute Lymphoblastic Leukemia-Relapse Study of the Berlin-Frankfurt-Münster Group 87
Authors: Hagen Graf Einsiedel, Arend von Stackelberg, Reinhard Hartmann, Rüdiger Fengler, Martin Schrappe, Gritta Janka-Schaub, Georg Mann, Karel Hählen, Ulrich Göbel, Thomas Klingebiel, Wolf-Dieter Ludwig, Günter Henze
Journal: Journal of Clinical Oncology (2005)

Approximately 20% of children with acute lymphoblastic leukemia (ALL) suffer a relapse, and their prognosis is unfavorable. Between 1987 and 1990, the multicenter trial Acute Lymphoblastic Leukemia-Relapse Study of the Berlin-Frankfurt-Münster Group (ALL-REZ BFM) 87 was conducted to establish a uniform treatment for these children in Germany and Austria.Of 207 registered patients, 183 patients were stratified into three groups according to the protocol: A, early bone marrow (BM) relapse (n = 56); B, late BM relapse (n = 101); C, isolated extramedullary relapse (n = 26). Treatment consisted of risk-adapted alternating short-course multiagent systemic and intrathecal chemotherapy, cranial irradiation, if indicated, and conventional maintenance therapy. Additionally, 24 patients with an exceptionally poor prognosis (early BM or any relapse of T-cell ALL) were treated with individual regimens. In 35 patients, stem-cell transplantation was performed.The probability of event-free survival (EFS) and overall survival of all registered patients at 15 years was 0.30 +/- 0.03 and 0.37 +/- 0.03, respectively, with significant differences between the strategic groups (A, 0.18 +/- 0.05 and 0.20 +/- 0.05; B, 0.44 +/- 0.05 and 0.52 +/- 0.05; C, 0.35 +/- 0.09 and 0.42 +/- 0.10). Despite risk-adapted treatment, an early time point of relapse and T-lineage immunophenotype were significant predictors of inferior EFS in uni- and multivariate analyses.With the ALL-REZ BFM 87 protocol, more than one-third of patients may be regarded as cured from recurrent ALL with second complete remissions lasting more than 10 years. Immunophenotype and time point of relapse are important prognostic factors that allow us to adapt more precisely treatment intensity to individual prognosis in future trials.
Randomized Double-Blind Placebo-Controlled Trial of Thalidomide in Combination With Gemcitabine and Carboplatin in Advanced Non–Small-Cell Lung Cancer
Authors: Siow Ming Lee, Robin Rudd, Penella J. Woll, Christian Ottensmeier, David Gilligan, Allan Price, Stephen Spiro, Nicole Gower, Mark Jitlal, Allan Hackshaw
Journal: Journal of Clinical Oncology (2009)

Cancers rely on angiogenesis for their growth and dissemination. We hypothesized that thalidomide, an oral antiangiogenic agent, when combined with chemotherapy, and as maintenance treatment, would improve survival in patients with advanced non-small-cell lung cancer (NSCLC).Seven hundred twenty-two patients were randomly assigned to receive placebo or thalidomide capsules 100 to 200 mg daily for up to 2 years. All patients received gemcitabine and carboplatin every 3 weeks for up to four cycles. End points were overall survival (OS), progression-free survival (PFS), response rate, grade 3/4 toxicity, and quality of life (QoL).The median OS rates were 8.9 months (placebo) and 8.5 months (thalidomide). The hazard ratio (HR) was 1.13 (95% CI, 0.97 to 1.32; P = .12). The 2-year survival rate was 16% and 12% in the placebo and thalidomide arms, respectively. The PFS results were consistent with those for OS. The risk of having a thrombotic event was increased by 74% in the thalidomide group: HR of 1.74 (95% CI, 1.20 to 2.52; P = .003). There were no differences in hematologic toxicities, but a slight excess of rash and neuropathy in the thalidomide group. QoL scores were similar but thalidomide was associated with less insomnia, and more constipation and peripheral neuropathy. In a retrospective analysis, patients with nonsquamous histology in the thalidomide group had a poorer survival: 2-year risk difference of 10% (95% CI, 4% to 16%; P < .001).In this large trial of patients with NSCLC, thalidomide in combination with chemotherapy did not improve survival overall, but increased the risk of thrombotic events. Unexpectedly, survival was significantly worse in patients with nonsquamous histology.
Preferential Dependence of Breast Cancer Cells versus Normal Cells on Integrin-Linked Kinase for Protein Kinase B/Akt Activation and Cell Survival
Authors: Armelle A. Troussard, Paul C. McDonald, Elizabeth D. Wederell, Nasrin M. Mawji, Nolan R. Filipenko, Karen A. Gelmon, Jill E. Kucab, Sandra E. Dunn, Joanne T. Emerman, Marcel B. Bally, Shoukat Dedhar
Journal: Cancer Research (2006)

The emerging paradigm of "oncogene addiction" has been called an Achilles' heel of cancer that can be exploited therapeutically. Here, we show that integrin-linked kinase (ILK), which is either activated or overexpressed in many types of cancers, is a critical regulator of breast cancer cell survival through the protein kinase B (PKB)/Akt pathway but is largely dispensable for the survival of normal breast epithelial cells and mesenchymal cells. We show that inhibition of ILK activity with a pharmacologic ILK inhibitor, QLT-0267, results in the inhibition of PKB/Akt Ser473 phosphorylation, stimulation of apoptosis, and a decrease in mammalian target of rapamycin (mTOR) expression in human breast cancer cells. In contrast, QLT-0267 treatment has no effect on PKB/Akt Ser473 phosphorylation or apoptosis in normal human breast epithelial, mouse fibroblast, or vascular smooth muscle cells. The inhibition of PKB/Akt Ser473 phosphorylation by QLT-0267 in breast cancer cells was rescued by a kinase-active ILK mutant but not by a kinase-dead ILK mutant. Furthermore, a dominant-negative ILK mutant increased apoptosis in the MDA-MB-231 breast cancer cell line but not in normal human breast epithelial cells. The inhibitor was active against ILK isolated from all cell types but did not have any effect on cell attachment and spreading. Our data point to an "ILK addiction" of breast cancer cells whereby they become dependent on ILK for cell survival through the mTOR-PKB/Akt signaling pathway and show that ILK is a promising target for the treatment of breast cancer.
The hepatopulmonary syndrome: NO way out?: Fig. 1.—
Authors: A.T. Dinh-Xuan, R. Naeije
Journal: European Respiratory Journal (2004)

“How diseases of the liver affect lung function?” is one of those puzzling questions that can turn obsessive for those who want to understand how two seemingly distinctive organs can interact and eventually lead to severe disorders 1, 2. The most common respiratory consequence of liver disease is hypoxaemia, which is often mild to moderate 3. Seldom severe hypoxaemia occurs when the arterial pressure of oxygen ( P a,O2) falls below 8 kPa (60 mmHg), heralding the occurrence of a condition known as the “hepatopulmonary syndrome” (HPS). HPS is characterised by a triad of conditions, namely: 1) advanced liver disease (with or without liver cirrhosis); 2) widespread intrapulmonary vasodilatation; and 3) alveolar-arterial oxygen gradient ( P A‐a,O2) >2.6 kPa (20 mmHg) whilst breathing room air 2, 3. Clinical symptoms typically include shortness of breath, which may either worsen on standing (platypnoea) and/or be accompanied by a 10% fall in P a,O2 (orthodeoxia). As with other lung disorders, hypoxaemia results from impaired gas exchange, which, in HPS, is particularly perturbed by excessive and widespread dilatation of intrapulmonary vessels. After decades of careful investigations, the underlying mechanisms linking altered gas exchange and pulmonary vasodilatation are now well delineated 2–4. Reduced tone causing vascular relaxation occurs at both ends of the capillary bed, i.e. affecting pre-capillary and post-capillary vessels. This …
Determinants recognized by human cytotoxic T cells on a natural hybrid class I HLA molecule.
Authors: C Clayberger, N Holmes, P L Wang, T D Koller, P Parham, A M Krensky
Journal: The Journal of Experimental Medicine (1985)

The major histocompatibility complex class I HLA molecules are the primary determinants recognized by allogeneic cytotoxic T lymphocytes (CTL), and serve as restricting elements for CTL recognition of viral, chemical, or minor histocompatibility antigens. HLA-Aw69 is a naturally occurring hybrid class I molecule that we have used to investigate the regions of class I antigens involved in human CTL recognition. HLA-Aw69 appears to have resulted from an exon shuffle between two closely related class I genes: the alpha 1 domain of HLA-Aw69 is identical to that of HLA-Aw68, while the alpha 2 and alpha 3 domains are identical to HLA-A2. The determinants recognized by human allogeneic CTL clones specific for HLA-A2, -Aw68, and/or -Aw69 fall into three patterns: (a) CTL determinants are located on both the alpha 1 and alpha 2 domains; (b) interaction of the alpha 1 and alpha 2 domains results in new combinatorial determinants; (c) interaction of the alpha 1 and alpha 2 domains in the hybrid molecule results in the loss of CTL determinants that are present on both parental molecules. Thus, using human CTL clones, target cells, and HLA molecules, we show that the interaction of the alpha 1 and alpha 2 domains alters CTL determinants in ways not directly predictable from primary structure.
Oxford Radcliffe Hospitals told to improve team work
Authors: Adrian O'Dowd
Journal: BMJ (2007)

The hospital with some of the highest death rates among patients with heart problems in the United Kingdom has been ordered to improve poor team working and lack of quality checks.

The NHS standards watchdog, the Healthcare Commission, published the findings of its investigation into the Oxford Radcliffe Hospitals NHS Trust and said that mortality for heart surgery was within acceptable limits.

But the commission said that the trust's cardiothoracic surgical unit lacked key components of a high quality service and needed to improve.

The investigation was prompted by concern over higher than expected mortality and a history of problems …
Addition of interleukin-6 inhibition with tocilizumab to standard graft-versus-host disease prophylaxis after allogeneic stem-cell transplantation: a phase 1/2 trial
Authors: Glen A Kennedy, Antiopi Varelias, Slavica Vuckovic, Laetitia Le Texier, Kate H Gartlan, Ping Zhang, Gethin Thomas, Lisa Anderson, Glen Boyle, Nicole Cloonan, Justine Leach, Elise Sturgeon, Judy Avery, Stuart D Olver, Mary Lor, Ashish K Misra, Cheryl Hutchins, A James Morton, Simon TS Durrant, Elango Subramoniapillai, Jason P Butler, Cameron I Curley, Kelli P A MacDonald, Siok-Keen Tey, Geoffrey R Hill
Journal: The Lancet Oncology (2014)
Radiofrequency Ablation vs Antiarrhythmic Drugs as First-line Treatment of Symptomatic Atrial Fibrillation
Authors: Oussama M. Wazni, Nassir F. Marrouche, David O. Martin, Atul Verma, Mandeep Bhargava, Walid Saliba, Dianna Bash, Robert Schweikert, Johannes Brachmann, Jens Gunther, Klaus Gutleben, Ennio Pisano, Dominico Potenza, Raffaele Fanelli, Antonio Raviele, Sakis Themistoclakis, Antonio Rossillo, Aldo Bonso, Andrea Natale
Journal: JAMA (2005)

Treatment with antiarrhythmic drugs and anticoagulation is considered first-line therapy in patients with symptomatic atrial fibrillation (AF). Pulmonary vein isolation (PVI) with radiofrequency ablation may cure AF, obviating the need for antiarrhythmic drugs and anticoagulation.To determine whether PVI is feasible as first-line therapy for treating patients with symptomatic AF.A multicenter prospective randomized study conducted from December 31, 2001, to July 1, 2002, of 70 patients aged 18 to 75 years who experienced monthly symptomatic AF episodes for at least 3 months and had not been treated with antiarrhythmic drugs.Patients were randomized to receive either PVI using radiofrequency ablation (n=33) or antiarrhythmic drug treatment (n=37), with a 1-year follow-up.Recurrence of AF, hospitalization, and quality of life assessment.Two patients in the antiarrhythmic drug treatment group and 1 patient in the PVI group were lost to follow-up. At the end of 1-year follow-up, 22 (63%) of 35 patients who received antiarrhythmic drugs had at least 1 recurrence of symptomatic AF compared with 4 (13%) of 32 patients who received PVI (P<.001). Hospitalization during 1-year follow-up occurred in 19 (54%) of 35 patients in the antiarrhythmic drug group compared with 3 (9%) of 32 in the PVI group (P<.001). In the antiarrhythmic drug group, the mean (SD) number of AF episodes decreased from 12 (7) to 6 (4), after initiating therapy (P = .01). At 6-month follow-up, the improvement in quality of life of patients in the PVI group was significantly better than the improvement in the antiarrhythmic drug group in 5 subclasses of the Short-Form 36 health survey. There were no thromboembolic events in either group. Asymptomatic mild or moderate pulmonary vein stenosis was documented in 2 (6%) of 32 patients in the PVI group.Pulmonary vein isolation appears to be a feasible first-line approach for treating patients with symptomatic AF. Larger studies are needed to confirm its safety and efficacy.
Phase II Trial of Concurrent Radiation and Weekly Cisplatin Followed by VIPD Chemotherapy in Newly Diagnosed, Stage IE to IIE, Nasal, Extranodal NK/T-Cell Lymphoma: Consortium for Improving Survival of Lymphoma Study
Authors: Seok Jin Kim, Kihyun Kim, Byung Soo Kim, Chul Yong Kim, Cheolwon Suh, Jooryung Huh, Sang-Wook Lee, Jin Seok Kim, Jaeho Cho, Gyeong-Won Lee, Ki Mun Kang, Hyeon Seok Eom, Hong Ryull Pyo, Yong Chan Ahn, Young Hyeh Ko, Won Seog Kim
Journal: Journal of Clinical Oncology (2009)

Purpose On the basis of the benefits of frontline radiation in early-stage, extranodal, natural killer (NK)/T-cell lymphoma (ENKTL), we conducted a phase II trial of concurrent chemoradiotherapy (CCRT) followed by three cycles of etoposide, ifosfamide, cisplatin, and dexamethasone (VIPD). Patients and Methods Thirty patients with newly diagnosed, stages IE to IIE, nasal ENKTL received CCRT (ie radiation 40 to 52.8 Gy and cisplatin 30 mg/m 2 weekly). Three cycles of VIPD (etoposide 100 mg/m 2 days 1 through 3, ifosfamide 1,200 mg/m 2 days 1 through 3, cisplatin 33 mg/m 2 days 1 through 3, and dexamethasone 40 mg days 1 through 4) were scheduled after CCRT. Results All patients completed CCRT, which resulted in 100% response that included 22 complete responses (CRs) and eight partial responses (PRs). The CR rate after CCRT was 73.3% (ie, 22 of 30 responses; 95% CI, 57.46 to 89.13). Twenty-six of 30 patients completed the planned three cycles of VIPD, whereas four patients did not because they withdrew (n = 2) or because they had an infection (n = 2). The overall response rate and the CR rate were 83.3% (ie; 25 of 30 responses; 95% CI, 65.28 to 94.36) and 80.0% (ie, 24 of 30 responses; 95% CI, 65.69 to 94.31), respectively. Only one patient experienced grade 3 toxicity during CCRT (nausea), whereas 12 of 29 patients experienced grade 4 neutropenia. The estimated 3-year, progression-free and overall survival rates were 85.19% (95% CI, 72.48 to 97.90) and 86.28% (95% CI, 73.97 to 98.59), respectively. Conclusion Patients with newly diagnosed, stages IE to IIE, nasal ENKTL are best treated with frontline CCRT.
The occurrence of type 1 diabetes in patients with dermatitis herpetiformis and their first-degree relatives
Authors: K. Hervonen, M. Viljamaa, P. Collin, M. Knip, T. Reunala
Journal: British Journal of Dermatology (2004)

Background The increased prevalence of type 1 diabetes (T1D) is well documented in patients with coeliac disease, whereas evidence is scanty in patients with dermatitis herpetiformis (DH). Objectives To assess the prevalence of T1D in patients with DH and their first-degree relatives, and to study how DH patients with associated T1D respond to a gluten-free diet (GFD) treatment. Methods A series of 1104 consecutive patients with DH was recorded and a specific questionnaire sent to 341 of these for familial disease surveillance. Sex- and age-matched patients with isolated DH served as controls in the diet treatment analysis. Results Twenty-five (2·3%) patients with DH were affected by T1D and three (3·0%) of their first-degree relatives also were affected by T1D, the frequencies being significantly higher than in the general population. Most DH patients with T1D and with isolated DH could adhere strictly to the GFD. The response was good or moderate in 84% of the DH patients with T1D and in 94% of the patients with isolated DH. Conclusions The prevalence of T1D is increased in patients with DH and their first-degree relatives. The rash in DH patients with T1D responds to a GFD in a way similar to that seen in patients with isolated DH.
Immunotype and Immunohistologic Characteristics of Tumor-Infiltrating Immune Cells Are Associated with Clinical Outcome in Metastatic Melanoma
Authors: Gulsun Erdag, Jochen T. Schaefer, Mark E. Smolkin, Donna H. Deacon, Sofia M. Shea, Lynn T. Dengel, James W. Patterson, Craig L. Slingluff
Journal: Cancer Research (2012)

Immune cells infiltrating the microenvironment of melanoma metastases may either limit or promote tumor progression, but the characteristics that distinguish these effects are obscure. In this study, we systematically evaluated the composition and organization of immune cells that infiltrated melanoma metastases in human patients. Three histologic patterns of immune cell infiltration were identified, designated immunotypes A, B, and C. Immunotype A was characterized by no immune cell infiltrate. Immunotype B was characterized by infiltration of immune cells limited only to regions proximal to intratumoral blood vessels. Immunotype C was characterized by a diffuse immune cell infiltrate throughout a metastatic tumor. These immunotypes represented 29%, 63%, and 8% of metastases with estimated median survival periods of 15, 23, and 130 months, respectively. Notably, from immunotypes A to C, there were increasing proportions of B cells and decreasing proportions of macrophages. Overall, the predominant immune cells were T cells (53%), B cell lineage cells (33%), and macrophages (13%), with natural killer and mature dendritic cells only rarely present. Whereas higher densities of CD8(+) T cells correlated best with survival, a higher density of CD45(+) leukocytes, T cells, and B cells also correlated with increased survival. Together, our findings reveal striking differences in the immune infiltrate in melanoma metastases in patients, suggesting microenvironmental differences in immune homing receptors and ligands that affect immune cell recruitment. These findings are important, not only by revealing how the immune microenvironment can affect outcomes but also because they reveal characteristics that may help improve individualized therapy for patients with metastatic melanoma.