tbuckley/cabot-search huggingface dataset:
BCL2 Predicts Survival in Germinal Center B-cell–like Diffuse Large B-cell Lymphoma Treated with CHOP-like Therapy and Rituximab
Authors: Javeed Iqbal, Paul N. Meyer, Lynette M. Smith, Nathalie A. Johnson, Julie M. Vose, Timothy C. Greiner, Joseph M. Connors, Louis M. Staudt, Lisa Rimsza, Elaine Jaffe, Andreas Rosenwald, German Ott, Jan Delabie, Elias Campo, Rita M. Braziel, James R. Cook, Raymond R. Tubbs, Randy D. Gascoyne, James O. Armitage, Dennis D. Weisenburger, Wing C. Chan
Journal: Clinical Cancer Research (2011)

We have previously shown the prognostic significance of BCL2 expression in the activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL) patients treated with cyclophosphamide-Adriamycin-vincristine-prednisone (CHOP) or CHOP-like therapy. However, after the inclusion of rituximab (R) in the CHOP regimen, several conflicting observations about the prognostic value of BCL2 expression have been reported.We evaluated the R-CHOP cohort of 221 DLBCL cases with gene expression profiling data. BCL2 protein (n = 169), mRNA (n = 221) expression, and t(14;18) (n = 144) were correlated with clinical outcome. The CHOP cohort (n = 181) was used for comparative analysis.BCL2 protein expression has significant impact on overall survival (OS) and event-free survival (EFS) in DLBCL (OS, P = 0.009; EFS, P = 0.001) and GCB-DLBCL (OS, P = 0.03; EFS, P = 0.002) but not in ABC-DLBCL in the R-CHOP cohort. The survival differences for EFS in GCB-DLBCL were still observed in multivariate analysis. At the mRNA level, this correlation was observed in EFS in DLBCL (P = 0.006), but only a trend was observed in GCB-DLBCL (P = 0.09). The t(14;18) was detected in 34% of GCB-DLBCL but was not associated with significant differences in survival. Gene enrichment analysis identified significant enrichment of the DLBCL "stromal-1" signatures and hypoxia-inducible factor 1 (HIF1-α) signature in BCL2(-)GCB-DLBCL, whereas T(FH) cell signatures were enriched in BCL2(+)GCB-DLBCL.The prognostic significance of BCL2 has changed after inclusion of rituximab in the treatment protocol and is observed in the GCB-DLBCL rather than the ABC-DLBCL. Although rituximab has benefited patients in both DLBCL subgroups, the BCL2(+)GCB-DLBCL seems to receive less benefit from this treatment and may require other novel therapeutic intervention.
Vasopeptidase Inhibitors
Authors: Roberto Corti, John C. Burnett Jr, Jean L. Rouleau, Frank Ruschitzka, Thomas F. Lüscher
Journal: Circulation (2001)

The cardiovascular system is regulated by hemodynamic and neurohumoral mechanisms. These regulatory systems play a key role in modulating cardiac function, vascular tone, and structure. Although neurohumoral systems are essential in vascular homeostasis, they become maladaptive in disease states such as hypertension, coronary disease, and heart failure. The clinical success of ACE inhibitors has led to efforts to block other humoral systems. Neutral endopeptidase (NEP) is an endothelial cell surface zinc metallopeptidase with similar structure and catalytic site. NEP is the major enzymatic pathway for degradation of natriuretic peptides, a secondary enzymatic pathway for degradation of kinins, and adrenomedullin. The natriuretic peptides can be viewed as endogenous inhibitors of the renin angiotensin system. Inhibition of NEP increases levels of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) of myocardial cell origin, and C-type natriuretic peptide (CNP) of endothelial cell origin as well as bradykinin and adrenomedullin. By simultaneously inhibiting the renin-angiotensin-aldosterone system and potentiating the natriuretic peptide and kinin systems, vasopeptidase inhibitors reduce vasoconstriction, enhance vasodilation, improve sodium/water balance, and, in turn, decrease peripheral vascular resistance and blood pressure and improve local blood flow. Within the blood vessel wall, this leads to a reduction of vasoconstrictor and proliferative mediators such as angiotensin II and increased local levels of bradykinin (and, in turn, nitric oxide) and natriuretic peptides. Preliminary clinical experiences with vasopeptidase inhibitors are encouraging. Thus, the combined inhibition of ACE and neutral endopeptidase is a new and promising approach to treat patients with hypertension, atherosclerosis, or heart failure.
In Vitro Assays for Recombinogenic Activity of Chemical Carcinogens and Related Compounds With &lt;italic&gt;Saccharomyces cerevisiae&lt;/italic&gt; D3&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: V F Simmon
Journal: JNCI Journal of the National Cancer Institute (1979)

A total of 101 carcinogens, noncarcinogens, metals, and promoters representing a wide variety of chemical classes was tested to determine whether they increased mitotic recombination in Saccharomyces cerevisiae D3. A metabolic activation system prepared from homogenates of livers from rats that had been pretreated with Aroclor 1254 (a mixture of polychlorinated biphenyls) was incorporated in the assay procedure. All of the ultimate carcinogens (20/20) and 38% of the procarcinogens (18/48) increased mitotic recombination. Of the noncarcinogens 29% (6/21) also increased mitotic recombination. A improved metabolic activation procedure appears to be required to increase the probability of detecting procarcinogens by this method. The carcinogens thioacetamide, natulan, auramine, safrole, and 1'-hydroxysafrole increased mitotic recombination in S. cerevisiae D3 (the last compound was marginally positive), but they were negative in assays with Salmonella typhyimurium.
An immunohistochemical procedure to detect patients with paraganglioma and phaeochromocytoma with germline SDHB, SDHC, or SDHD gene mutations: a retrospective and prospective analysis
Authors: Francien H van Nederveen, José Gaal, Judith Favier, Esther Korpershoek, Rogier A Oldenburg, Elly MCA de Bruyn, Hein FBM Sleddens, Pieter Derkx, Julie Rivière, Hilde Dannenberg, Bart-Jeroen Petri, Paul Komminoth, Karel Pacak, Wim CJ Hop, Patrick J Pollard, Massimo Mannelli, Jean-Pierre Bayley, Aurel Perren, Stephan Niemann, Albert A Verhofstad, Adriaan P de Bruïne, Eamonn R Maher, Frédérique Tissier, Tchao Méatchi, Cécile Badoual, Jérôme Bertherat, Laurence Amar, Despoina Alataki, Eric Van Marck, Francesco Ferrau, Jerney François, Wouter W de Herder, Mark-Paul FM Vrancken Peeters, Anne van Linge, Jacques WM Lenders, Anne-Paule Gimenez-Roqueplo, Ronald R de Krijger, Winand NM Dinjens
Journal: The Lancet Oncology (2009)
In vitro and in vivo analysis of the PABA test compared with the Lundh test--influence of intraluminal pH.
Authors: F J Hoek, G T Sanders, A Teunen, G N Tijtgat
Journal: Gut (1981)

Lundh test and PABA test results were compared in 50 patients. In the resulting correlation curve three areas of interest were differentiated: (1) an area with mean tryptic activity, found in the Lundh test, below 4 U/ml, where an abnormal PABA test result was also seen; (2) an intermediate area from 4 to 9 U/ml, where PABA test results may be found in discordance with the Lundh test; (3) the normal level, where PABA excretion was shown to be independent of intestinal chymotrypsin activity. In experiments in vitro on the kinetics of the hydrolysis of BTPABA by chymotrypsin the profound influence of the pH on Km and Vmax was shown. This influence of the pH explains why in the intermediate area of pancreatic dysfunction normal PABA test results were found in a number of cases. A higher mean pH level of the Lundh test aspirates was found for patients with a normal PABA test result than for patients with an abnormal PABA test.
Thioredoxin-Interacting Protein Is a Biomechanical Regulator of Src Activity
Authors: Oded N. Spindel, Ryan M. Burke, Chen Yan, Bradford C. Berk
Journal: Circulation Research (2014)

Fluid shear stress differentially regulates endothelial cell stress fiber formation with decreased stress fibers in areas of disturbed flow compared with steady flow areas. Importantly, stress fibers are critical for several endothelial cell functions including cell shape, mechano-signal transduction, and endothelial cell-cell junction integrity. A key mediator of steady flow-induced stress fiber formation is Src that regulates downstream signaling mediators such as phosphorylation of cortactin, activity of focal adhesion kinase, and small GTPases.Previously, we showed that thioredoxin-interacting protein (TXNIP, also VDUP1 [vitamin D upregulated protein 1] and TBP-2 [thioredoxin binding protein 2]) was regulated by fluid shear stress; TXNIP expression was increased in disturbed flow compared with steady flow areas. Although TXNIP was originally characterized for its role in redox and metabolic cellular functions, recent reports show important scaffold functions related to its α-arrestin structure. Based on these findings, we hypothesized that TXNIP acts as a biomechanical sensor that regulates Src kinase activity and stress fiber formation.Using en face immunohistochemistry of the aorta and cultured endothelial cells, we show inverse relationship between TXNIP expression and Src activity. Specifically, steady flow increased Src activity and stress fiber formation, whereas it decreased TXNIP expression. In contrast, disturbed flow had opposite effects. We studied the role of TXNIP in regulating Src homology phosphatase-2 plasma membrane localization and vascular endothelial cadherin binding because Src homology phosphatase-2 indirectly regulates dephosphorylation of Src tyrosine 527 that inhibits Src activity. Using immunohistochemistry and immunoprecipitation, we found that TXNIP prevented Src homology phosphatase-2-vascular endothelial cadherin interaction.In summary, these data characterize a fluid shear stress-mediated mechanism for stress fiber formation that involves a TXNIP-dependent vascular endothelial cadherin-Src homology phosphatase-2-Src pathway.
Use of a decision aid including information on overdetection to support informed choice about breast cancer screening: a randomised controlled trial
Authors: Jolyn Hersch, Alexandra Barratt, Jesse Jansen, Les Irwig, Kevin McGeechan, Gemma Jacklyn, Hazel Thornton, Haryana Dhillon, Nehmat Houssami, Kirsten McCaffery
Journal: The Lancet (2015)
Activity of a specific inhibitor, gefitinib (Iressa™, ZD1839), of epidermal growth factor receptor in refractory non-small-cell lung cancer
Authors: A. Santoro, R. Cavina, F. Latteri, P.A. Zucali, V. Ginanni, E. Campagnoli, B. Ferrari, E. Morenghi, V. Pedicini, M. Roncalli, M. Alloisio, G. Ravasi, H.J. Soto Parra
Journal: Annals of Oncology (2003)
Pathologic criteria for nonalcoholic steatohepatitis: Interprotocol agreement and ability to predict liver‐related mortality
Authors: Zobair M. Younossi, Maria Stepanova, Nila Rafiq, Hala Makhlouf, Zahra Younoszai, Ritambhara Agrawal, Zachary Goodman
Journal: Hepatology (2011)

Since the initial description of nonalcoholic steatohepatitis (NASH), several sets of pathologic criteria for its diagnosis have been proposed. However, their interprotocol agreement and ability to predict long-term liver-related mortality (LRM) have not been demonstrated. In this study, we examined patients with biopsy-proven nonalcoholic fatty liver disease (NAFLD) for whom liver biopsy slides and clinical and mortality data were available. Liver biopsy samples were evaluated for a number of pathologic features and were classified according to the presence or absence of NASH by (1) the original criteria for NAFLD subtypes, (2) the nonalcoholic fatty liver disease activity score (NAS), (3) the Brunt criteria, and (4) the current study's criteria. All NASH diagnostic criteria and individual pathologic features were tested for agreement and for their independent associations with LRM, which were determined with a Cox proportional hazards model. Two hundred fifty-seven NAFLD patients with complete data were included. The diagnoses of NASH by the original NAFLD subtypes and by the current study's definition of NASH were in almost perfect agreement (κ = 0.896). However, their agreement was moderate with NAS (κ = 0.470 and κ = 0.511, respectively) and only fair to moderate with the Brunt criteria (κ = 0.365 and κ = 0.441, respectively). Furthermore, the agreement of the Brunt criteria with NAS was relatively poor (κ = 0.178). During the follow-up (median = 146 months), 31% of the patients died (9% were LRM). After we controlled for confounders, a diagnosis of NASH by the original criteria for NAFLD subtypes [adjusted hazard ratio = 9.94 (95% confidence interval = 1.28-77.08)] demonstrated the best independent association with LRM. Among the individual pathologic features, advanced fibrosis showed the best independent association with LRM [adjusted hazard ratio = 5.68 (95% confidence interval = 1.50-21.45)].The original criteria for NAFLD subtypes and the current study's criteria for NASH were in almost perfect agreement, but their level of agreement with the NAS and Brunt criteria was lower. A diagnosis of NASH by the original criteria for NAFLD subtypes demonstrated the best predictability for LRM in NAFLD patients.
Is non-invasive ventilation (NIV) utilised appropriately outside of respiratory specialist areas?
Authors: Stephanie Harlow, Amber Lane, Paul Murray
Journal: European Respiratory Journal (2012)

Background   The British Thoracic Society (BTS) recommends regular audit of NIV practice (BTS, NIV in acute respiratory failure,  Thorax , 2002,  57 p192-211) and states inappropriate use of NIV is undesirable.   Aims and objectives   The aim of this study was to establish if inappropriate NIV could be correlated with location of set up. Proving this hypothesis would enable us to target locations to provide additional support to reduce and prevent the inappropriate use of NIV.   Methods   Data were collected prospectively from 255 consecutive patients requiring NIV from May 2009 to April 2011 using an adapted version of the BTS NIV data tool. The establishment of NIV was deemed appropriate or not as per the BTS guidelines.   Results   The impact of appropriate use of NIV on mortality is summarised.  The impact of location on appropriate use of NIV is summarised.   Conclusion   Patients commenced on NIV outside of respiratory speciality areas are more likely to receive inappropriate NIV with subsequent higher mortality rates.This may be due to the lack of expertise in non-respiratory areas. We therefore conclude that NIV should only be initiated in respiratory specialist areas within our hospital.
Dichloroacetate restores drug sensitivity in paclitaxel-resistant cells by inducing citric acid accumulation
Authors: Xiang Zhou, Ruohua Chen, Zhenhai Yu, Rui Li, Jiajin Li, Xiaoping Zhao, Shaoli Song, Jianjun Liu, Gang Huang
Journal: Molecular Cancer (2015)

The Warburg effect describes the increased reliance of tumor cells on glycolysis for ATP generation. Mitochondrial respiratory defect is thought to be an important factor leading to the Warburg effect in some types of tumor cells. Consequently, there is growing interest in developing anti-cancer drugs that target mitochondria. One example is dichloroacetate (DCA) that stimulates mitochondria through inhibition of pyruvate dehydrogenase kinase. We investigated the anti-cancer activity of DCA using biochemical and isotopic tracing methods. We observed that paclitaxel-resistant cells contained decreased levels of citric acid and sustained mitochondrial respiratory defect. DCA specifically acted on cells with mitochondrial respiratory defect to reverse paclitaxel resistance. DCA could not effectively activate oxidative respiration in drug-resistant cells, but induced higher levels of citrate accumulation, which led to inhibition of glycolysis and inactivation of P-glycoprotein. The abilityof DCA to target cells with mitochondrial respiratory defect and restore paclitaxel sensitivity by inducing citrate accumulation supports further preclinical development.
Phase II Study of Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone Immunochemotherapy Followed by Yttrium-90–Ibritumomab Tiuxetan in Untreated Mantle-Cell Lymphoma: Eastern Cooperative Oncology Group Study E1499
Authors: Mitchell R. Smith, Hailun Li, Leo Gordon, Randy D. Gascoyne, Elisabeth Paietta, Andres Forero-Torres, Brad S. Kahl, Ranjana Advani, Fangxin Hong, Sandra J. Horning
Journal: Journal of Clinical Oncology (2012)

Purpose To test the hypothesis that consolidation therapy with yttrium-90 ( 90 Y) –ibritumomab tiuxetan after brief initial therapy with four cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in patients with previously untreated mantle-cell lymphoma would be a well-tolerated regimen that would improve outcomes compared with historical R-CHOP data. Patients and Methods Patients ≥ 18 years old with histologically confirmed mantle-cell lymphoma expressing CD20 and cyclin D1 who had not received any previous therapy and had an Eastern Cooperative Oncology Group performance status of 0 to 2 and adequate organ function were eligible. The study enrolled and treated 57 patients, of whom 56 patients were eligible. Fifty-two patients (50 eligible patients) received 90 Y-ibritumomab tiuxetan. The study design required 52 eligible patients to detect a 50% improvement in the median time to treatment failure (TTF) compared with that reported for six cycles of R-CHOP. Results With 56 analyzed patients (median age, 60 years; men, 73%), the overall response rate was 82% (55% complete response/complete response–unconfirmed). With a median follow-up of 72 months, the median TTF was 34.2 months. The median overall survival (OS) has not been reached, with an estimated 5-year OS of 73% (79% for patients ≤ age 65 years v 62% for patients &gt; age 65 years; P = .08 [log-rank test]). There were no unexpected toxicities. Conclusion R-CHOP given for four cycles followed by 90 Y–ibritumomab tiuxetan compared favorably with historical results with six cycles of R-CHOP in patients with previously untreated mantle-cell lymphoma. This regimen was well tolerated and should be applicable to most patients with this disease.
Repeated B cell depletion in treatment of refractory systemic lupus erythematosus
Authors: K P Ng
Journal: Annals of the Rheumatic Diseases (2005)

<b>Objectives:</b> To report the clinical outcome and safety profile of repeated B cell depletion in seven patients with refractory systemic lupus erythematosus (SLE). <b>Methods:</b> Since June 2000, seven patients with refractory SLE had repeated cycles of B cell depletion (18 cycles in total, up to three cycles per patient) because of disease relapse. The clinical response (assessed by the British Isles Lupus Activity Guide (BILAG) activity index), duration of B cell depletion, and adverse events in these patients was reviewed. <b>Results:</b> Four patients (Nos 1, 2, 3, 6) had three cycles of treatment and three (Nos 4, 5, 7) had two cycles. Four of the seven patients (Nos 1, 3, 5, 6) improved. The mean global BILAG scores dropped from 15 to 6 at 5–7 months. The median duration of clinical response and B cell depletion was 13 months and 6 months, respectively. After the third cycle, 2/4 patients (Nos 1 and 2) improved. The median duration of clinical benefit was 12 months. Most patients tolerate re-treatment very well. <b>Conclusion:</b> Re-treatment with B cell depletion of patients with severe SLE is safe and may be effective for 6–12 months on average.
Immunohistochemical Loss of LKB1 Is a Biomarker for More Aggressive Biology in <i>KRAS</i>-Mutant Lung Adenocarcinoma
Authors: Antonio Calles, Lynette M. Sholl, Scott J. Rodig, Ashley K. Pelton, Jason L. Hornick, Mohit Butaney, Christine Lydon, Suzanne E. Dahlberg, Geoffrey R. Oxnard, David M. Jackman, Pasi A. Jänne
Journal: Clinical Cancer Research (2015)

LKB1 loss is common in lung cancer, but no assay exists to efficiently evaluate the presence or absence of LKB1. We validated an IHC assay for LKB1 loss and determined the impact of LKB1 loss in KRAS-mutant non-small cell lung cancer (NSCLC).We optimized and validated an IHC assay for LKB1 (clone Ley37D/G6) using a panel of lung cancer cell lines and tumors with known LKB1 mutations, including 2 patients with Peutz-Jeghers syndrome (PJS) who developed lung adenocarcinoma. We retrospectively analyzed tumors for LKB1 using IHC from 154 KRAS-mutant NSCLC patients, including 123 smokers and 31 never-smokers, and correlated the findings with patient and tumor characteristics and clinical outcome.LKB1 expression was lost by IHC in 30% of KRAS-mutant NSCLC (smokers 35% vs. never-smokers 13%, P = 0.017). LKB1 loss did not correlate with a specific KRAS mutation but was more frequent in tumors with KRAS transversion mutations (P = 0.029). KRAS-mutant NSCLC patients with concurrent LKB1 loss had a higher number of metastatic sites at the time of diagnosis (median 2.5 vs. 2, P = 0.01), higher incidence of extrathoracic metastases (P = 0.01), and developed brain metastasis more frequently (48% vs. 25%, P = 0.02). There was a nonsignificant trend to worse survival in stage IV KRAS-mutant NSCLC patients with LKB1 loss.LKB1 IHC is a reliable and efficient assay to evaluate for loss of LKB1 in clinical samples of NSCLC. LKB1 loss is more common in smokers, and is associated with a more aggressive clinical phenotype in KRAS-mutant NSCLC patients, accordingly to preclinical models.
MUC5B and interstitial lung disease
Authors: Yasmin Bakerally
Journal: Thorax (2013)

MUC5B and interstitial lung diseaseIn this study, the data for 2633 participants from the Framingham Heart Study were analysed to explore any association between a polymorphism in the promoter of a mucin gene (MUC5B) and radiological evidence of interstitial lung abnormalities.Data for participants were evaluated to include physical examination findings, respiratory questionnaires, spirometry including diffusion capacity for carbon monoxide, genotyping for MUC5B and thoracic CT evaluation.Participants with the MUC5B variant were significantly more likely to have radiological interstitial lung abnormalities.Seven percent of CT scans examined demonstrated evidence of interstitial lung abnormalities-these participants were observed to have reduced total lung capacity, reduced diffusion capacity and were twice as likely to describe shortness of breath and a chronic cough.This study was largely robust in its methodology and conclusions.The patient population (Framingham Heart Study) were however predominantly of European descent.Rates of radiological interstitial lung abnormalities were much higher in this cohort than previously observed rates of idiopathic lung fibrosis.It is thought that not all of these lung abnormalities will progress to idiopathic lung fibrosis.There is also likely a degree of underdiagnosis of idiopathic lung fibrosis.Idiopathic lung fibrosis is a condition of significant morbidity and mortality, and although there are known associations with advancing age and smoking, the exact mechanism of disease is largely unknown.Twenty percent of the population have been found to have the MUC5B variant, although a far smaller proportion of the population display features of idiopathic lung fibrosis.This points to the fact that the disease is multifactorial in aetiology and further research is needed into the genetics of the condition and potential environmental triggers.
From progress to regression: biomedical research funding
Authors: H. George Mandel, Elliot S. Vesell
Journal: Journal of Clinical Investigation (2004)

Despite great advances in health-related research and health care, major challenges remain regarding the causes and cures of many diseases; these may be overcome with further research. Our society is enthusiastic about fostering such investigations. However, available federal funds limit many such projects. Previously there have been sizable increases in the NIH budget, but because of the escalating cost of scientific investigation and the pressures of financing other much-needed governmental programs, recent growth in biomedical research funding has barely kept up with inflation. This article focuses on select attempts to sustain the record of scientific achievement enabled in the past by continued increasing investment and also suggests some solutions.