tbuckley/cabot-search huggingface dataset:
Peripheral blood absolute lymphocyte/monocyte ratio recovery during ABVD treatment cycles predicts clinical outcomes in classical Hodgkin lymphoma
Authors: L F Porrata, K M Ristow, T M Habermann, W R Macon, T E Witzig, J P Colgan, D J Inwards, S M Ansell, I N Micallef, P B Johnston, G Nowakowski, C A Thompson, S N Markovic
Journal: Blood Cancer Journal (2013)

The peripheral blood absolute lymphocyte/monocyte count ratio at diagnosis (ALC/AMC-DX) predicts survival in classical Hodgkin lymphoma (cHL). However, a limitation of the ALC/AMC-DX is the inability to assess sequentially the host/tumor interaction during treatment. Therefore, we retrospectively examined the ALC/AMC ratio, as a surrogate marker of host immunity (ALC) and tumor microenvironment (AMC), at each adriamycin, bleomycin, vinblastine and dacarbazine treatment cycle as a predictor for clinical outcomes. From 1990 until 2008, 190 cHL patients were diagnosed, treated and followed at Mayo Clinic Rochester and qualified for the study. The ALC/AMC ratio at each treatment cycle was a predictor for overall survival (OS) and progression-free survival (PFS). An ALC/AMC ratio 1.1 versus ALC/AMC <1.1 during treatment cycles was an independent predictor for OS (hazard ratio (HR)=0.14; 95% confidence interval (CI): 0.04-0.40; P<0.0002) and for PFS (HR=0.19; 95% CI: 0.05-0.82; P<0.03). The ALC/AMC ratio during treatment cycles is a predictor for survival and provides a platform to develop therapeutic modalities to manipulate the ALC/AMC ratio during chemotherapy to improve clinical outcomes in cHL.
Tumorigenesis and Aberrant Signaling in Transgenic Mice Expressing the Human Herpesvirus-8 K1 Gene
Authors: O. Prakash
Journal: JNCI Journal of the National Cancer Institute (2002)

Background: The K1 gene of human herpesvirus-8 (HHV-8; also known as Kaposi's sarcoma-associated herpesvirus) encodes a transmembrane signaling protein that elicits cellular activation events. To evaluate the potential role of K1 in HHV-8-associated pathogenesis, we produced transgenic mice expressing the HHV-8 K1 gene under the transcriptional control of the simian virus 40 promoter. Methods: Three independent heterozygous transgenic K1 mouse lines were generated from founder mice. Mouse splenic and thymic lymphocytes and tumor tissues were analyzed for the expression of cytokines involved in inflammatory and immune responses, including tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), basic fibroblast growth factor (bFGF), and interleukin 12 (IL-12); for the activation of the transcription factors nuclear factor-κB (NF-κB) and the B cell-specific transcription factor Oct-2; and for the activation of the Src and Syk family kinases, components of B-cell receptor-induced signal-transduction pathways. Results: Expression of bFGF was increased in K1-transgenic mice as compared with nontransgenic mice, whereas expression of TNF-α and IL-6 did not differ using reverse transcriptase–polymerase chain reaction. K1-transgenic mice showed substantially less serum IL-12 induction than did nontransgenic mice when challenged with a lipopolysaccharide. B lymphocytes from K1-transgenic mice but not from nontransgenic mice showed constitutive activation of NF-κB and Oct-2. K1 expression in human B lymphocytes stimulated NF-κB-dependent promoter activity. B lymphocytes from K1-transgenic mice also showed increased phosphorylation of Lyn, a Src family tyrosine kinase, and enhanced Lyn activity. Tumors in K1-transgenic mice showed features indicative of a spindle-cell sarcomatoid tumor and a malignant plasmablastic lymphoma. The pattern of cytokine, transcription factor, and Lyn kinase activity in the lymphoma was similar to that in B lymphocytes from K1-transgenic mice. Conclusion: K1 may be involved in the activation of NF-κB signaling. The enhanced NF-κB activity in nonmalignant lymphocytes of K1 mice and its persistence in lymphoma tumors of these mice suggest that the K1 mouse may be a model of premalignancy.
Exogenously Administered Growth Hormone and Insulin-like Growth Factor-I Alter Intracellular Ca <sup>2+</sup> Handling and Enhance Cardiac Performance
Authors: Hinrik Strömer, Antonio Cittadini, Pamela S. Douglas, James P. Morgan
Journal: Circulation Research (1996)

It has been proposed that chronic treatment with growth hormone (GH) or insulin-like growth factor-I (IGF-I) in the rat may enhance cardiac function in vivo. To confirm these findings and elucidate the mechanisms by which cardiac function is modulated, we studied isolated buffer-perfused rat hearts after 4 weeks of treatment with high doses of GH and IGF-I alone or in combination. Mechanical parameters were measured at 50% of the intracardiac balloon volume at which maximal developed pressure (DevP) occurred. EC 50 of the force-Ca 2+ relationship and maximal Ca 2+ -activated systolic wall stress (max σ s ) were assessed by increasing Ca 2+ in the perfusate in a stepwise fashion and plotting systolic wall stress (σ s ) versus intracellular peak systolic Ca 2+ , measured by the aequorin bioluminescence method. We found a marked increase of systolic pressure (P s ), DevP, and (+dP/dt)/DevP in the treated groups compared with the control group. The combination group showed a blunted effect. σ s was increased in all treated groups for a perfusate Ca 2+ concentration of &gt;1.5 mmol/L. The enhanced systolic performance can be explained by an increase of the overall Ca 2+ responsiveness due to an increased maximal response to Ca 2+ even though the EC 50 of the Ca 2+ -dose response was also slightly increased. P s was further enhanced by an increase of the relative wall thickness induced by the treatment. Diastolic pressure, diastolic Ca 2+ , and the amplitude and time course of the Ca 2+ transient were not influenced by any treatment protocol. All treatments caused increases of body and heart weight. These data support the hypothesis that both IGF-I and GH directly affect cardiac performance by altering cardiac geometry as well as by enhancing max σ s .
On the Nature of Gene Innovation: Duplication Patterns in Microbial Genomes
Authors: S. D. Hooper
Journal: Molecular Biology and Evolution (2003)

Gene duplication is considered a major force in gene family expansion and gene innovation. As gene copies assume novel functions, they must avoid periods of neutrality or be deleted from the genome. Current opinions state that copies avoid neutrality through gene dosage effects. These copies are therefore selected from an early stage. This study concentrates on the flow of copies from recent duplication to gene innovation. We have studied 21 microbial genomes using amino acid divergence to describe paralog evolution in the long-term perspective. Five of these were studied in closer detail using nucleotide divergence for a shorter perspective. It was found that rates of duplication and deletion are high, with only a small fraction of duplications retained and apparently selected. This leads to a steady accumulation of paralogs, which seems to be of a similar magnitude in most of the genomes. Furthermore, it is found that genes of high expression level, as measured by their codon bias, are strongly underrepresented among the most recent duplications. Based on these and other observations, it is suggested that gene innovation is driven by amplification of weak, ancillary functions rather than strong, established functions.
Reply to P.G. Tsoutsou et al, O. Kaidar-Person et al, and A. Courdi et al
Authors: Kevin S. Hughes, Lauren A. Schnaper, Jennifer R. Bellon, Constance T. Cirrincione, Donald A. Berry, Beryl McCormick, Hyman B. Muss, Barbara L. Smith, Clifford A. Hudis, Eric P. Winer, William C. Wood
Journal: Journal of Clinical Oncology (2013)

Hughes et al 1 recently reported the long-term results of the Cancer and Leukemia Group B (CALGB) 9343 study about the impact of radiation therapy (RT) in patients age 70 years or older with breast cancer.The rate of locoregional-free survival was 98% in the group treated with RT plus tamoxifen versus 90% in patients receiving only tamoxifen (P Ͻ .001),with no significant difference in overall survival (OS), time to mastectomy, time to distant metastases, and cancer-specific survival.The authors' conclusion is that treatment with tamoxifen only is a reasonable option for these patients.The accompanying editorial 2 emphasizes that life expectancy, comorbidity, compliance with endocrine therapy, and tumor grade are factors to consider before deciding to omit RT.We wish to provide some additional comments.First, Figure 2 in the article by Hughes et al 1 depicts locoregional-free survival with 10-year rates of 90% and 98% in the absence or presence of RT, respectively.However, in the text, the authors state that 90% and 98% of patients were free from locoregional recurrence, respectively.In a Kaplan-Meier analysis of locoregional-free survival, the event should not only be the occurrence of recurrence, but also mortality. 3 If it is stated that patients were free of locoregional recurrence, it means that mortality was not considered.If the analysis was conducted with locoregional recurrence as the sole event, then the correct presentation would be an ascending curve with the ordinate labeled as "locoregional recurrence rate."Second, whatever the presentation, the interpretation of the results depends on whether we see the glass as half empty or half full.The authors stated that they observed a small improvement in locoregional recurrence with the addition of RT.It can also be stated that there is five-fold increase in locoregional recurrence: from 2% to 10%, if RT is omitted.This relative increase is not likely to be perceived as small.Third, RT is a local treatment, and its main aim is to sterilize potential tumor cells in the irradiated volume, so the rate of local recurrence is an end point that should prevail over OS, which is a late event that depends on other factors aside from local control.Fourth, as opposed to head and neck cancer, for instance, in which relapse is closely followed by mortality, a slowly growing breast cancer is characterized by a long time interval between the onset of recurrence and recurrence-related mortality.Provided that sufficient time is allowed, mortality will be increased.
Raynaud's phenomenon as initial manifestation of cutaneous polyarteritis nodosa.
Authors: J L Andreu-Sanchez, J M Martin-Santos, C Isasi-Zaragoza, A Trujillo-Castellanos, E Cuende-Quintana, J Mulero
Journal: Annals of the Rheumatic Diseases (1991)

The case of a 45 year old man with cutaneous polyarteritis nodosa and Raynaud9s phenomenon as initial manifestation of the disease is reported. Although peripheral vascular disease is a well characterised extracutaneous manifestation of cutaneous polyarteritis nodosa, to our knowledge this is the first reported case in which Raynaud9s phenomenon was the initial and sole manifestation of the disease for a long time.
Diseases of the Reticuloendothelial System and Haematology
Authors: Lionel Whitby
Journal: Annual Review of Medicine (1953)

CD40 is a cell-surface member of the TNF (tumor necrosis factor) receptor superfamily. Upon activation, CD40 can license dendritic cells to promote antitumor T cell activation and re-educate macrophages to destroy tumor stroma. Numerous agonist CD40 ...Read More
Vitamin D Deficiency Is Associated With Retinopathy in Children and Adolescents With Type 1 Diabetes
Authors: Harleen Kaur, Kim C. Donaghue, Albert K. Chan, Paul Benitez-Aguirre, Stephen Hing, Margaret Lloyd, Janine Cusumano, Alison Pryke, Maria E. Craig
Journal: Diabetes Care (2011)

To examine the hypothesis that vitamin D deficiency (VDD) is associated with an increased prevalence of microvascular complications in young people with type 1 diabetes.In a cross-sectional study of 517 patients, 25-hydroxyvitamin D was measured. Retinopathy was assessed by 7-field stereoscopic retinal photography, peripheral neuropathy by thermal and vibration threshold testing, and microalbuminuria by albumin excretion rate or albumin-to-creatinine ratio.Retinopathy prevalence was higher in cases with VDD versus sufficiency (18 vs. 9%, P = 0.02); deficiency was not associated with microalbuminuria or neuropathy. In logistic regression, retinopathy was associated with VDD (odds ratio 2.12 [95% CI 1.03-4.33]), diabetes duration (1.13, 1.05-1.23), and HbA(1c) (1.24, 1.02-1.50).VDD is associated with an increased prevalence of retinopathy in young people with type 1 diabetes. The inflammatory and angiogenic effects of VDD may contribute to early retinal vascular damage; however, further investigations are warranted.
Respiratory symptoms in relation to indoor exposure to mite and cat allergens and endotoxins
Authors: U. Gehring, J. Heinrich, B. Jacob, K. Richter, B. Fahlbusch, G. Schlenvoigt, W. Bischof, H-E. Wichmann
Journal: European Respiratory Journal (2001)

The authors investigated the relationship between respiratory symptoms in adults and exposure to mite and cat allergens, the role of endotoxins in house dust, the effects of mixtures of several allergens, and interactions between allergen exposure and allergic sensitization. Within a nested case-control study, 405 subjects aged 25–50 yrs from two German cities answered a standardized questionnaire. Allergen-specific immunoglobulin-E was measured. Dust samples were taken from the subjects' homes to determine exposure to mite ( Dermatophagoides pteronyssinus antigen 1 Der p 1) and ( D. farinae antigen 1 Der f 1) and cat (cat antigen d1 Fel d 1) allergen and endotoxin content in settled house dust. Exposure to Der f 1 and Der p 1 plus Der f 1 &gt;10 µg·g −1 of mattress dust, respectively, increased the risk of wheeze and breathlessness (odds ratios (OR): 4.04, 95% confidence interval (CI): 1.53–10.64, OR: 2.78, 95% CI: 1.06–7.28). Fel d 1 &gt;8 µg·g −1 was positively associated with cough at night (OR: 2.74, 95% CI: 1.22–6.17), noteworthy also in the nonsensitized subjects. Subjects exposed to elevated concentrations of more than one allergen had an up to seven-fold increase in the risk of respiratory symptoms, compared to nonexposed subjects. Sensitized subjects exposed to elevated concentrations of Der f 1 or Fel d 1 were found to have the highest risk of asthma attacks and respiratory symptoms. No statistically significant association was found between exposure to endotoxins and respiratory health. Indoor exposure to Dermatophagoides farinae antigen 1 and cat antigen d1 is a risk factor for respiratory symptoms in adults, and for cat antigen d 1 even in nonsensitized subjects. The risk is increased if subjects are exposed to a mixture of allergens or if they are sensitized in addition to high exposure.
Transcriptome Analysis of Recurrently Deregulated Genes across Multiple Cancers Identifies New Pan-Cancer Biomarkers
Authors: Bogumil Kaczkowski, Yuji Tanaka, Hideya Kawaji, Albin Sandelin, Robin Andersson, Masayoshi Itoh, Timo Lassmann, Yoshihide Hayashizaki, Piero Carninci, Alistair R.R. Forrest
Journal: Cancer Research (2015)

Abstract Genes that are commonly deregulated in cancer are clinically attractive as candidate pan-diagnostic markers and therapeutic targets. To globally identify such targets, we compared Cap Analysis of Gene Expression profiles from 225 different cancer cell lines and 339 corresponding primary cell samples to identify transcripts that are deregulated recurrently in a broad range of cancer types. Comparing RNA-seq data from 4,055 tumors and 563 normal tissues profiled in the The Cancer Genome Atlas and FANTOM5 datasets, we identified a core transcript set with theranostic potential. Our analyses also revealed enhancer RNAs, which are upregulated in cancer, defining promoters that overlap with repetitive elements (especially SINE/Alu and LTR/ERV1 elements) that are often upregulated in cancer. Lastly, we documented for the first time upregulation of multiple copies of the REP522 interspersed repeat in cancer. Overall, our genome-wide expression profiling approach identified a comprehensive set of candidate biomarkers with pan-cancer potential, and extended the perspective and pathogenic significance of repetitive elements that are frequently activated during cancer progression. Cancer Res; 76(2); 216–26. ©2015 AACR.
Sodium current deficit and arrhythmogenesis in a murine model of plakophilin-2 haploinsufficiency
Authors: Marina Cerrone, Maartje Noorman, Xianming Lin, Halina Chkourko, Feng-Xia Liang, Roel van der Nagel, Thomas Hund, Walter Birchmeier, Peter Mohler, Toon A. van Veen, Harold V. van Rijen, Mario Delmar
Journal: Cardiovascular Research (2012)

AimsThe shRNA-mediated loss of expression of the desmosomal protein plakophilin-2 leads to sodium current (INa) dysfunction. Whether pkp2 gene haploinsufficiency leads to INa deficit in vivo remains undefined. Mutations in pkp2 are detected in arrhythmogenic right ventricular cardiomyopathy (ARVC). Ventricular fibrillation and sudden death often occur in the 'concealed phase' of the disease, prior to overt structural damage. The mechanisms responsible for these arrhythmias remain poorly understood. We sought to characterize the morphology, histology, and ultrastructural features of PKP2-heterozygous-null (PKP2-Hz) murine hearts and explore the relation between PKP2 abundance, INa function, and cardiac electrical synchrony.
Phase I Study of Dovitinib (TKI258), an Oral FGFR, VEGFR, and PDGFR Inhibitor, in Advanced or Metastatic Renal Cell Carcinoma
Authors: Eric Angevin, Jose A. Lopez-Martin, Chia-Chi Lin, Jürgen E. Gschwend, Andrea Harzstark, Daniel Castellano, Jean-Charles Soria, Paramita Sen, Julie Chang, Michael Shi, Andrea Kay, Bernard Escudier
Journal: Clinical Cancer Research (2013)

Signaling through the fibroblast growth factor (FGF) pathway may account for tumor resistance to antiangiogenic therapies targeting the VEGF pathway. Here, dovitinib (TKI258), a potent oral inhibitor of FGF receptor, VEGF receptor (VEGFR), and platelet-derived growth factor receptor tyrosine kinases, is studied in a dose escalation trial.Patients with advanced or metastatic renal cell carcinoma (RCC) with predominant clear cell histology were treated with oral dovitinib 500 or 600 mg/day (5-days-on/2-days-off schedule).Twenty heavily pretreated patients (median 3 prior regimens) were enrolled, with 16, 11, and 12 patients having previously received at least 1: VEGFR inhibitor, mTOR inhibitor, and immunotherapy, respectively. Fifteen and 5 patients were treated in 500- and 600-mg cohorts, respectively. Three patients experienced dose-limiting toxicities: grade 2 bradycardia (500 mg), grade 4 hypertensive crisis (600 mg), and grade 3 asthenia with grade 2 nausea and vomiting (600 mg). The most common adverse events related to dovitinib were nausea (75%), diarrhea (70%), vomiting (70%), and asthenia (50%), the majority of which were mild (grade 1 or 2), with grade 3 events 5% or less (except asthenia, 15%) and only one grade 4 event (hypertensive crisis). Two patients achieved a partial response (500 mg), and 12 patients had stable disease, including 2 patients with long lasting disease stabilizations (>1 year) in the 500-mg cohort.Dovitinib was tolerable and showed antitumor activity at a maximum tolerated dose of 500 mg on a 5-days-on/2-days-off schedule in heavily pretreated RCC patients.
P248 Associations of depression, fatigue and quality of life in adult non-CF bronchiectasis
Authors: H. Batchelor, S. Brill, J. S. Brown, J. R. Hurst
Journal: Thorax (2011)

<h3>Introduction</h3> Non-cystic fibrosis bronchiectasis is a chronic lung condition characterised by persistent cough, excessive sputum and recurrent chest infections. Symptoms also include dyspnoea, haemoptysis, depression and fatigue. The latter can have a major impact on patients9 physical and psychosocial well-being. We investigated disease- and patient-related factors associated with quality of life, fatigue and depression in bronchiectasis. <h3>Method</h3> Patients were recruited from the London Bronchiectasis Cohort. A clinical diagnosis of bronchiectasis was confirmed by review of previous CT imaging. A full medical history including exacerbations and aetiology, spirometry, and the SGRQ (for quality of life), CESD (depression), and FACIT (fatigue) questionnaires were completed at a baseline appointment. Statistics were analysed using SPSS. <h3>Results</h3> 31 patients (25 female) were studied with a mean (SD) age of 58.8 (SD 12.0) years. The commonest aetiologies were post-infectious (15/31) and idiopathic (11/31). The median (IQR) self-reported exacerbation frequency was 3.0 (1.9–5.6)/year. Frequent exacerbations were associated with poorer quality of life: there was a significant association between exacerbation frequency and the SGRQ score (r=0.46, p=0.013). Frequent exacerbations were also associated with greater baseline breathlessness (r=0.40, p=0.038), but not with lung function, depression or fatigue. Patients with greater disease severity (lower FEV<sub>1</sub>) also had more breathlessness (MRC: r=−0.38, p=0.046), and poorer quality of life (SGRQ: r=−0.50, p=0.005) but not greater depression or fatigue. The depression scale was not related to any of the disease or patient-related factors. The only patient or disease-related variable associated with fatigue was breathlessness (MRC: r=−0.57, p=0.002). <h3>Conclusion</h3> The determinants of quality of life, depression and fatigue in non-CF bronchiectasis are different. Depression in this population appears to be independent of markers of disease severity such as FEV<sub>1</sub>, exacerbation frequency and MRC dyspnoea score.
Opposing effects of glucagon and triiodothyronine on the hepatic levels of messenger ribonucleic acid S14 and the dependence of such effects on circadian factors.
Authors: W B Kinlaw, H L Schwartz, H C Towle, J H Oppenheimer
Journal: Journal of Clinical Investigation (1986)

We have studied the effect of glucagon on the expression of a triiodothyronine (T3) and carbohydrate-inducible mRNA sequence (mRNA-S14) in rat liver that undergoes a threefold diurnal variation (peak, 2200 h; nadir, 0800 h). Glucagon injection into euthyroid rats (25 micrograms/100 g body wt i.p., three doses at 15-min intervals) during the nocturnal plateau of mRNA-S14 caused a monoexponential disappearance of this sequence (t1/2, 90 min) accompanied by a 90% reduction in the transcriptional rate in a nuclear run-off assay, indicative of a near total reduction of synthesis. This effect was markedly attenuated in rats treated with T3 (200 micrograms/100 g body wt i.p.) 24 h before glucagon injection. When T3 was given 15 min after glucagon, the glucagon-initiated decline in mRNA-S14 was reversed within 90 min, suggesting a rapid interaction between the two hormones in the evening. Curiously, administration of T3 alone at this hour did not affect a significant increase in mRNA-S14. At 0800 h, however, T3 caused the expected brisk induction of this sequence, whereas glucagon was without effect. In essence, glucagon affected mRNA-S14 synthesis only in the evening, while T3 increased levels of this sequence above the baseline only in the morning. T3, however, reversed the effect of prior glucagon injection at night. The observed alterations in hormonal responsivity could underly the diurnal variation of mRNA-S14 expression. Moreover, the data suggest the hypothesis that T3 may act on S14 gene expression by antagonizing factors that inhibit its transcription.