tbuckley/cabot-search huggingface dataset:
Advanced Hodgkin disease (clinical stages IIIB and IV): Low relapse rate after brief chemotherapy followed by high‐dose total lymphoid irradiation
Authors: P. Colonna, J. M. Andrieu, R. Ghouadni, Z. Zouaoui‐Benhadji, M. Afiane, P. Kubisz, J. M. Tourani, K. Belhadj‐Merzoug, C. Krisch, A. Laugier
Journal: American Journal of Hematology (1989)

Abstract From January 1980 to September 1986, 50 patients with Hodgkin disease, clinical stages (CS) IIIB (26 cases) and IVB (24 cases) were treated by three cycles of mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) chemotherapy, followed by high‐dose (40 Gy) (sub)total lymphoid irradiation, including the spleen. Ten patients (2 CS IIIB, 8 CS IVB) were in failure, and seven (4 CS IIIB, 3 CS IVB) died during their first complete remission (2 from treatment‐related complications, 1 from unknown cause, 4 from insufficient supportive care and/or a shortage of health supplies); three patients (CS IIIB) relapsed (2 alive in second complete remission, 1 deceased). After 7 years, actuarial survival and relapse‐free duration were, respectively, 64% for the 50 patients and 89% for the 40 patients in complete remission. Unfavourable outcome was observed in patients with pelvic nodal involvement. The low relapse rate (none in CS IVB) was the most striking result after brief chemotherapy followed by total lymphoid irradiation.
Ribonucleotide Reductase Large Subunit (<i>RRM1</i>) Gene Expression May Predict Efficacy of Adjuvant Mitotane in Adrenocortical Cancer
Authors: Marco Volante, Massimo Terzolo, Martin Fassnacht, Ida Rapa, Antonina Germano, Silviu Sbiera, Fulvia Daffara, Paola Sperone, Giorgio Scagliotti, Bruno Allolio, Mauro Papotti, Alfredo Berruti
Journal: Clinical Cancer Research (2012)

Mitotane is the most broadly used systemic therapy for adrenocortical carcinoma (ACC), but its mechanism of action and possible predictors of treatment response are currently poorly defined. Our aim was to evaluate the gene expression of ribonucleotide reductase large subunit 1 (RRM1) and excision repair cross-complementation group 1 (ERCC1) in ACC as potential biomarkers for clinical outcome and response to mitotane.Forty-five and 47 tissue samples from two cohorts (Orbassano, Italy; Wuerzburg, Germany) of completely resected ACC were centrally analyzed using real-time PCR for RRM1 and ERCC1 expression. Fifty-four patients received surgery alone and 38 received adjuvant mitotane after surgery. Clinical and pathologic features were highly comparable in the two series. H295R and SW-13 ACC cell lines were also used for pharmacologic tests.ERCC1 gene expression was not associated to clinical outcome. In contrast, high RRM1 gene expression was associated to shorter disease-free survival (DFS) and overall survival at both univariate and multivariate analysis. In patients with low RRM1 gene expression, adjuvant mitotane was associated with improved DFS, whereas this effect was lost in cases with high RMM1 expression. In vitro mitotane induced strong up regulation of RRM1 transcription (up to 25-fold increase) in mitotane-insensitive SW-13 but not in mitotane-sensitive H295R cells. Furthermore, RRM1 silencing in SW-13 cells induced sensitivity to mitotane.Our in vitro and in vivo data indicate that RRM1 gene expression is functionally associated to mitotane sensitivity and support a possible role of RRM1 determination as a novel molecular biomarker predicting response to adjuvant mitotane in ACC.
Additional Autoimmune Disease Found in 33% of Patients at Type 1 Diabetes Onset
Authors: Taylor M. Triolo, Taylor K. Armstrong, Kim McFann, Liping Yu, Marian J. Rewers, Georgeanna J. Klingensmith, George S. Eisenbarth, Jennifer M. Barker
Journal: Diabetes Care (2011)

We sought to define the prevalence of nonislet, organ-specific autoantibodies at diagnosis of type 1 diabetes and to determine the prevalence of comorbid autoimmune diseases.Children (n = 491) diagnosed with type 1 diabetes at the Barbara Davis Center for Childhood Diabetes were screened for autoimmune thyroid disease (thyroid peroxidase autoantibodies [TPOAb]), celiac disease (tissue transglutaminase autoantibodies [TTGAb]), and Addison disease (21-hydroxylase autoantibodies [21OHAb]).Of the 491 children, 161 had at least one nonislet autoantibody, and of these, 122 (24.8%) were positive for TPOAb, and 15 of the 122 (12.3%) had autoimmune thyroid disease. There were 57 (11.6%) who were positive for TTGAb, of whom 14 (24.6%) had celiac disease. Five (1.0%) were positive for 21OHAb, of whom one had Addison disease.Many autoantibody-positive subjects present with additional autoimmune disorders. Detection of these autoantibodies at type 1 diabetes onset may prevent complications associated with delayed diagnosis of these disorders.
Preoperative Chemotherapy Plus Surgery Versus Surgery Plus Adjuvant Chemotherapy Versus Surgery Alone in Early-Stage Non–Small-Cell Lung Cancer
Authors: Enriqueta Felip, Rafael Rosell, José Antonio Maestre, José Manuel Rodríguez-Paniagua, Teresa Morán, Julio Astudillo, Guillermo Alonso, José Manuel Borro, José Luis González-Larriba, Antonio Torres, Carlos Camps, Ricardo Guijarro, Dolores Isla, Rafael Aguiló, Vicente Alberola, José Padilla, Abel Sánchez-Palencia, José Javier Sánchez, Eduardo Hermosilla, Bartomeu Massuti
Journal: Journal of Clinical Oncology (2010)

To address whether preoperative chemotherapy plus surgery or surgery plus adjuvant chemotherapy prolongs disease-free survival compared with surgery alone among patients with resectable non-small-cell lung cancer.In this phase III trial, 624 patients with stage IA (tumor size > 2 cm), IB, II, or T3N1 were randomly assigned to surgery alone (212 patients), three cycles of preoperative paclitaxel-carboplatin followed by surgery (201 patients), or surgery followed by three cycles of adjuvant paclitaxel-carboplatin (211 patients). The primary end point was disease-free survival.In the preoperative arm, 97% of patients started the planned chemotherapy, and radiologic response rate was 53.3%. In the adjuvant arm, 66.2% started the planned chemotherapy. Ninety-four percent of patients underwent surgery; surgical procedures and postoperative mortality were similar across the three arms. Patients in the preoperative arm had a nonsignificant trend toward longer disease-free survival than those assigned to surgery alone (5-year disease-free survival 38.3% v 34.1%; hazard ratio [HR] for progression or death, 0.92; P = .176). Five-year disease-free survival rates were 36.6% in the adjuvant arm versus 34.1% in the surgery arm (HR 0.96; P = .74).In early-stage patients, no statistically significant differences in disease-free survival were found with the addition of preoperative or adjuvant chemotherapy to surgery. In this trial, in which the treatment decision was made before surgery, more patients were able to receive preoperative than adjuvant treatment.
Fibroblast Growth Factor-23 and Incident Atrial Fibrillation
Authors: Jehu S. Mathew, Michael C. Sachs, Ronit Katz, Kristen K. Patton, Susan R. Heckbert, Andrew N. Hoofnagle, Alvaro Alonso, Michel Chonchol, Rajat Deo, Joachim H. Ix, David S. Siscovick, Bryan Kestenbaum, Ian H. de Boer
Journal: Circulation (2014)

Fibroblast growth factor-23 (FGF-23) is a hormone that promotes urinary phosphate excretion and regulates vitamin D metabolism. Circulating FGF-23 concentrations increase markedly in chronic kidney disease and are associated with increased risk of clinical cardiovascular events. FGF-23 may promote atrial fibrillation (AF) by inducing left ventricular hypertrophy and diastolic and left atrial dysfunction.
Anti-TIM3 Antibody Promotes T Cell IFN-γ–Mediated Antitumor Immunity and Suppresses Established Tumors
Authors: Shin Foong Ngiow, Bianca von Scheidt, Hisaya Akiba, Hideo Yagita, Michele W. L. Teng, Mark J. Smyth
Journal: Cancer Research (2011)

Abstract Strategies to activate and rescue exhausted tumor-specific T cells, including the use of monoclonal antibodies (mAb) that block the negative costimulatory receptors CTLA-4 and PD-1 are proving very effective, but TIM3 has been relatively neglected as a target. Here we report an extensive characterization of the therapeutic activity and mechanism of action of an anti-mouse TIM3 mAb against experimental and carcinogen-induced tumors. For the first time we specifically define the mechanism of antitumor action of anti-TIM3 requiring IFN-γ producing CD8+ T cells and CD4+ T cells, and a higher ratio of tumor infiltrating CD8+:CD4+ T cells correlating with therapeutic success. Interestingly, in some models, anti-TIM3 appeared to be effective sometime before the appearance and accumulation of significant TIM3+PD-1+ T cell populations in tumor bearing mice. Anti-TIM3 displayed modest prophylactic and therapeutic activity against a small fraction of carcinogen-induced sarcomas, but comparative and combination studies of anti-TIM3 with anti-CTLA-4 and anti–PD-1 against experimental and carcinogen-induced tumors suggested that these agents might be well-tolerated and very effective in combination. Cancer Res; 71(10); 3540–51. ©2011 AACR.
Cytokines and their receptors
Authors: A Ray, P B Sehgal
Journal: Journal of the American Society of Nephrology (1992)

Recent years have seen the discovery and molecular characterization of a bewildering array of cytokines and hematopoietic growth factors--and an even more complex description of their overlapping functions. The molecular cloning of a wide array of the cell-surface receptors for these cytokines has led to the recognition of classes of structurally related receptor superfamilies. The functional receptors for many of these cytokines (e.g., interleukin (IL)-2R and IL-6R) involve two distinct subunits; strikingly, the same beta subunit can interact with distinct alpha subunits to constitute the receptor for different cytokines (e.g., those for IL-3, IL-5, and granulocyte monocyte colony-stimulating factor). Considerable progress has also been made in defining the molecular mechanisms that underlie clinically relevant cytokine-related phenomena. As an example, the molecular mechanism by which glucocorticoids inhibit IL-6 gene expression has been shown to include the occlusion of the inducible enhancer and the basal promoter elements in the IL-6 promoter. Acute rejection episodes in renal transplant patients are accompanied by increases in serum IL-6 levels; the administration of glucocorticoids during these episodes leads to a rapid and marked decrease in IL-6 levels. It appears that the serum IL-6 level may be a useful diagnostic and prognostic indicator in the transplant patient.
Primary cutaneous infection with <i>Mycobacterium avium intracellulare</i> complex resembling lupus vulgaris
Authors: P. KULLAVANIJAYA, S. SIRIMACHAN, S. SURARAK
Journal: British Journal of Dermatology (1997)

We describe a 56-year-old woman with Mycobacterium avium complex infection of the skin. She presented with a granulomatous plaque studded with pustules and crusts on the cheeks and bridge of the nose. The appearance resembled lupus vulgaris. The lesion responded well to antituberculous treatment within 9 months. An association of Mycobacterium avium complex with squamous cell carcinoma of the cervix is emphasized.
Association Between Elevated Blood Glucose and Outcome in Acute Heart Failure
Authors: Alexandre Mebazaa, Etienne Gayat, Johan Lassus, Taly Meas, Christian Mueller, Aldo Maggioni, Frank Peacock, Jindrich Spinar, Veli-Pekka Harjola, Roland van Kimmenade, Atul Pathak, Thomas Mueller, Luigi Tavazzi, Salvatore diSomma, Marco Metra, Domingo Pascual-Figal, Said Laribi, Damien Logeart, Semir Nouira, Naoki Sato, Jiri Parenica, Nicolas Deye, Riadh Boukef, Corinne Collet, Greet Van den Berghe, Alain Cohen-Solal, James L. Januzzi
Journal: Journal of the American College of Cardiology (2013)
Constitutive Activation of Akt by Flt3 Internal Tandem Duplications Is Necessary for Increased Survival, Proliferation, and Myeloid Transformation
Authors: Christian H. Brandts, Bülent Sargin, Miriam Rode, Christoph Biermann, Beate Lindtner, Joachim Schwäble, Horst Buerger, Carsten Müller-Tidow, Chunaram Choudhary, Martin McMahon, Wolfgang E. Berdel, Hubert Serve
Journal: Cancer Research (2005)

Abstract Up to 30% of patients with acute myeloid leukemia (AML) harbor internal tandem duplications (ITD) within the FLT3 gene, encoding a receptor tyrosine kinase. These mutations induce constitutive tyrosine kinase activity in the absence of the natural Flt3 ligand and confer growth factor independence, increased proliferation, and survival to myeloid precursor cells. The signaling pathways and downstream nuclear targets mediating leukemic transformation are only partly identified. Here, we show that the presence of Flt3-ITD constitutively activates Akt (PKB), a key serine-threonine kinase within the phosphatidylinositol 3-kinase pathway. Constitutive activation of Akt phosphorylated and inhibited the transcription factor Foxo3a. Restored Foxo3a activity reversed Flt3-ITD–mediated growth properties and dominant-negative Akt prevented Flt3-ITD–mediated cytokine independence. Conditional Akt activation targeted to the cell membrane induced cytokine-independent survival, cell cycle progression, and proliferation. Importantly, Akt activation was sufficient to cause in vitro transformation of 32D myeloid progenitor cells and in vivo promoted the development of a leukemia-like myeloid disease. Akt phosphorylation was found in myeloid blasts of 86% of AML patients, suggesting an important role in leukemogenesis. In summary, Akt is necessary for increased survival, proliferation, and leukemic transformation by Flt3-ITD, possibly by inactivation of Foxo transcription factors. These findings indicate that Akt and Foxo transcription factors are attractive targets for therapeutic intervention in AML.
The cognitive defects of neonatally irradiated mice are accompanied by changed synaptic plasticity, adult neurogenesis and neuroinflammation
Authors: Stefan J Kempf, Arianna Casciati, Sonja Buratovic, Dirk Janik, Christine von Toerne, Marius Ueffing, Frauke Neff, Simone Moertl, Bo Stenerlöw, Anna Saran, Michael J Atkinson, Per Eriksson, Simonetta Pazzaglia, Soile Tapio
Journal: Molecular Neurodegeneration (2014)

Epidemiological evidence suggests that low doses of ionising radiation (≤1.0 Gy) produce persistent alterations in cognition if the exposure occurs at a young age. The mechanisms underlying such alterations are unknown. We investigated the long-term effects of low doses of total body gamma radiation on neonatally exposed NMRI mice on the molecular and cellular level to elucidate neurodegeneration. Significant alterations in spontaneous behaviour were observed at 2 and 4 months following a single 0.5 or 1.0 Gy exposure. Alterations in the brain proteome, transcriptome, and several miRNAs were analysed 6–7 months post-irradiation in the hippocampus, dentate gyrus (DG) and cortex. Signalling pathways related to synaptic actin remodelling such as the Rac1-Cofilin pathway were altered in the cortex and hippocampus. Further, synaptic proteins MAP-2 and PSD-95 were increased in the DG and hippocampus (1.0 Gy). The expression of synaptic plasticity genes Arc, c-Fos and CREB was persistently reduced at 1.0 Gy in the hippocampus and cortex. These changes were coupled to epigenetic modulation via increased levels of microRNAs (miR-132/miR-212, miR-134). Astrogliosis, activation of insulin-growth factor/insulin signalling and increased level of microglial cytokine TNFα indicated radiation-induced neuroinflammation. In addition, adult neurogenesis within the DG was persistently negatively affected after irradiation, particularly at 1.0 Gy. These data suggest that neurocognitive disorders may be induced in adults when exposed at a young age to low and moderate cranial doses of radiation. This raises concerns about radiation safety standards and regulatory practices.
Primary Prophylaxis With Hematopoietic Colony Stimulating Factor: Insights From a Canadian Cost-Effectiveness Analysis
Authors: S. A. Strassels, M. Dickson, L. B. Norris, C. L. Bennett
Journal: JNCI Journal of the National Cancer Institute (2013)

To identify disease etiology and its consequences, epidemiologists compare disease rates in different populations, geographic areas, and time periods.These statistical comparisons become difficult when diseases are relatively rare (eg, most cancers), and this problem is often resolved by broadening the definition of the groups (eg, all Asians or Pacific Islanders), geographic areas (eg, many
Levofloxacin Inhalation Solution (MP-376) in Patients with Cystic Fibrosis with <i>Pseudomonas aeruginosa</i>
Authors: David E. Geller, Patrick A. Flume, Doris Staab, Rainald Fischer, Jeffery S. Loutit, Douglas J. Conrad
Journal: American Journal of Respiratory and Critical Care Medicine (2011)

Rationale: Lower respiratory tract infection with Pseudomonas aeruginosa (PA) is associated with increased morbidity in patients with cystic fibrosis (CF). Current treatment guidelines for inhaled antibiotics are not universally followed due to the perception of decreased efficacy, increasing resistance, drug intolerance, and high treatment burden with current aerosol antibiotics. New treatment options for CF pulmonary infections are needed.Objectives: This study assessed the efficacy and safety of a novel aerosol formulation of levofloxacin (MP-376, Aeroquin) in a heavily treated CF population with PA infection.Methods: This study randomized 151 patients with CF with chronic PA infection to one of three doses of MP-376 (120 mg every day, 240 mg every day, 240 mg twice a day) or placebo for 28 days. The primary efficacy endpoint was the change in sputum PA density. Secondary endpoints included changes in pulmonary function, the need for other anti-PA antimicrobials, changes in patient-reported symptom scores, and safety monitoring.Measurements and Main Results: All doses of MP-376 resulted in reduced sputum PA density at Day 28, with MP-376 240 mg twice a day showing a 0.96 log difference compared with placebo (P = 0.001). There was a dose-dependent increase in FEV1 for MP-376, with a difference of 8.7% in FEV1 between the 240 mg twice a day group and placebo (P = 0.003). Significant reductions (61–79%) in the need for other anti-PA antimicrobials were observed with all MP-376 treatment groups compared with placebo. MP-376 was generally well tolerated relative to placebo.Conclusions: Nebulized MP-376was well tolerated and demonstrated significant clinical efficacy in heavily treated patients with CF with PA lung infection.Clinical trial registered with www.clinicaltrials.gov (NCT00677365).
Molecular characterization of clinical grade in breast cancer (BC) challenges the existence of “grade 2” tumors
Authors: C. Sotiriou, P. Wirapati, S. Loi, C. Desmedt, A. L. Harris, J. Bergh, J. Smeds, F. Cardoso, M. Delorenzi, M. Piccart
Journal: Journal of Clinical Oncology (2005)

506 Background: Histological grade (HG) in BC provides important prognostic information. Grade 2 tumors are observed to have an intermediate clinical outcome if compared to grade 1 (good prognosis) and grade 3 (poor prognosis) tumors. A major problem is the lack of inter-observer consistency, particularly for grade 2 tumors. The aim of this study was to correlate gene expression profiles (GEP) with HG and clinical outcome. Methods: GEP from 137 early BC patients receiving only locoregional therapy at 2 institutions was performed using Affymetrix U133 A chips. Median follow-up was 6.8 years. Differentially expressed genes were identified by contrasting grade 1 and grade 3 determined by the local pathologist using a stratified t-test. Central pathology review is ongoing. False discovery proportion was done using 10,000 permutations. A multiple independent validation was performed using three publicly available datasets from Van’t Veer et al. 2002, Sorlie et al. 2001 and Sotiriou et al. 2003 (total=281 tumor samples). Results: Grade 1 and 3 tumors were associated with distinct GEP. A “genetic grade index” (GGI) based on the 80 most significant genes was computed. Interestingly, grade 2 tumors were found to have GGI similar to either grade 1 or 3 tumors. At 50% cutoff, GGI segregated grade 2 tumors into two distinct subgroups namely grade 1- and grade 3-like with statistically different relapse free survival (RFS; HR: 3.89, p=0.013) and distant metastasis free survival (DMFS; HR: 4.67, p=0.049), similar to those observed in HG 1 and 3 tumors respectively (RFS; HR: 2.61, p=0.019 and DMFS; HR: 3.59, p=0.026). We then applied the 80-gene list to 3 independent publicly available datasets. Similarly in all three, grade 2 tumors were divided into grade 1- and 3-like subgroups with statistically distinct clinical outcome. Conclusions: HG 1 and 3 in BC is associated with distinctive GEP. GEP reveals grade 2 tumors to consist of either grade 1 or 3 molecular signatures, associated with different prognoses. This has been independently confirmed in multiple validation sets across different microarray platforms and could have important implications for optimal patient management. No significant financial relationships to disclose.
Mitochondrial trifunctional protein deficiency. Catalytic heterogeneity of the mutant enzyme in two patients.
Authors: T Kamijo, R J Wanders, J M Saudubray, T Aoyama, A Komiyama, T Hashimoto
Journal: Journal of Clinical Investigation (1994)

We examined the enzyme protein and biosynthesis of human trifunctional protein harboring enoyl-CoA hydratase, 3-hydroxyacyl-CoA dehydrogenase, and 3-ketoacyl-CoA thiolase activity in cultured skin fibroblasts from two patients with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. The following results were obtained. (a) In cells from patient 1, immunoblot analysis and pulse-chase experiments indicated that the content of trifunctional protein was < 10% of that in control cells, due to a very rapid degradation of protein newly synthesized in the mitochondria. The diminution of trifunctional protein was associated with a decreased activity of enoyl-CoA hydratase, 3-hydroxyacyl-CoA dehydrogenase, and 3-ketoacyl-CoA thiolase, when measured using medium-chain to long-chain substrates. (b) In cells from patient 2, the rate of degradation of newly synthesized trifunctional protein was faster than that in control cells, giving rise to a trifunctional protein amounting to 60% of the control levels. The 3-hydroxy-acyl-CoA dehydrogenase activity with medium-chain to long-chain substrates was decreased drastically, with minor changes in activities of the two other enzymes. These data suggest a subtle abnormality of trifunctional protein in cells from patient 2. Taken together, the results obtained show that in both patients, long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency is caused by an abnormality in the trifunctional protein, even though there is a heterogeneity in both patients.