tbuckley/cabot-search huggingface dataset:
Functional Metabolic Screen Identifies 6-Phosphofructo-2-Kinase/Fructose-2,6-Biphosphatase 4 as an Important Regulator of Prostate Cancer Cell Survival
Authors: Susana Ros, Claudio R. Santos, Sofia Moco, Franziska Baenke, Gavin Kelly, Michael Howell, Nicola Zamboni, Almut Schulze
Journal: Cancer Discovery (2012)

Alterations in metabolic activity contribute to the proliferation and survival of cancer cells. We investigated the effect of siRNA-mediated gene silencing of 222 metabolic enzymes, transporters, and regulators on the survival of 3 metastatic prostate cancer cell lines and a nonmalignant prostate epithelial cell line. This approach revealed significant complexity in the metabolic requirements of prostate cancer cells and identified several genes selectively required for their survival. Among these genes was 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4), an isoform of phosphofructokinase 2 (PFK2). We show that PFKFB4 is required to balance glycolytic activity and antioxidant production to maintain cellular redox balance in prostate cancer cells. Depletion of PFKFB4 inhibited tumor growth in a xenograft model, indicating that it is required under physiologic nutrient levels. PFKFB4 mRNA expression was also found to be greater in metastatic prostate cancer compared with primary tumors. Taken together, these results indicate that PFKFB4 is a potential target for the development of antineoplastic agents.Cancer cells undergo several changes in their metabolism that promote growth and survival. Using an unbiased functional screen, we found that the glycolytic enzyme PFKFB4 is essential for prostate cancer cell survival by maintaining the balance between the use of glucose for energy generation and the synthesis of antioxidants. Targeting PFKFB4 may therefore present new therapeutic opportunities.
p66 <sup>ShcA</sup> Modulates Tissue Response to Hindlimb Ischemia
Authors: Germana Zaccagnini, Fabio Martelli, Pasquale Fasanaro, Alessandra Magenta, Carlo Gaetano, Anna Di Carlo, Paolo Biglioli, Marco Giorgio, Ines Martin-Padura, Pier Giuseppe Pelicci, Maurizio C. Capogrossi
Journal: Circulation (2004)

Oxidative stress plays a pivotal role in ischemia and ischemia/reperfusion injury. Because p66(ShcA)-null (p66(ShcA)-/-) mice exhibit both lower levels of intracellular reactive oxygen species and increased resistance to cell death induced by oxidative stress, we investigated whether tissue damage that follows acute ischemia or ischemia/reperfusion was altered in p66(ShcA)-/- mice.Unilateral hindlimb ischemia was induced by femoral artery dissection, and ischemia/reperfusion was induced with an elastic tourniquet. Both procedures caused similar changes in blood perfusion in p66(ShcA) wild-type (p66(ShcA)wt) and p66(ShcA)-/- mice. However, significant differences in tissue damage were found: p66(ShcA)wt mice displayed marked capillary density decrease and muscle fiber necrosis. In contrast, in p66(ShcA)-/- mice, minimal capillary density decrease and myofiber death were present. When apoptosis after ischemia was assayed, significantly lower levels of apoptotic endothelial cells and myofibers were found in p66(ShcA)-/- mice. In agreement with these data, both satellite muscle cells and endothelial cells isolated from p66(ShcA)-/- mice were resistant to apoptosis induced by simulated ischemia in vitro. Lower apoptosis levels after ischemia in p66(ShcA)-/- cells correlated with decreased levels of oxidative stress both in vivo and in vitro.p66(ShcA) plays a crucial role in the cell death pathways activated by acute ischemia and ischemia/reperfusion, indicating p66(ShcA) as a potential therapeutic target for prevention and treatment of ischemic tissue damage.
Highly Sensitive Diagnosis of 43 Monogenic Forms of Diabetes or Obesity Through One-Step PCR-Based Enrichment in Combination With Next-Generation Sequencing
Authors: Amélie Bonnefond, Julien Philippe, Emmanuelle Durand, Jean Muller, Sadia Saeed, Muhammad Arslan, Rosa Martínez, Franck De Graeve, Véronique Dhennin, Iandry Rabearivelo, Michel Polak, Hélène Cavé, Luis Castaño, Martine Vaxillaire, Jean-Louis Mandel, Olivier Sand, Philippe Froguel
Journal: Diabetes Care (2013)

OBJECTIVE Accurate etiological diagnosis of monogenic forms of diabetes and obesity is useful as it can lead to marked improvements in patient care and genetic counseling. Currently, molecular diagnosis based on Sanger sequencing is restricted to only a few genes, as this technology is expensive, time-consuming, and labor-intensive. High-throughput next-generation sequencing (NGS) provides an opportunity to develop innovative cost-efficient methods for sensitive diabetes and obesity multigene screening. RESEARCH DESIGN AND METHODS We assessed a new method based on PCR enrichment in microdroplets (RainDance Technologies) and NGS using the Illumina HiSeq2000 for the molecular diagnosis of 43 forms of monogenic diabetes or obesity. Forty patients carrying a known causal mutation for those subtypes according to diagnostic laboratories were blindly reanalyzed. RESULTS Except for one variant, we reidentified all causal mutations in each patient associated with an almost-perfect sequencing of the targets (mean of 98.6%). We failed to call one highly complex indel, although we identified a dramatic drop of coverage at this locus. In three patients, we detected other mutations with a putatively deleterious effect in addition to those reported by the genetic diagnostic laboratories. CONCLUSIONS Our NGS approach provides an efficient means of highly sensitive screening for mutations in genes associated with monogenic forms of diabetes and obesity. As cost and time to deliver results have been key barriers to uncovering a molecular cause in the many undiagnosed cases likely to exist, the present methodology should be considered in patients displaying features of monogenic diabetes or obesity.
Do the 2010 ACR/EULAR or ACR 1987 classification criteria predict erosive disease in early arthritis?
Authors: Heidi Mäkinen, Kalevi Kaarela, Heini Huhtala, Pekka J Hannonen, Markku Korpela, Tuulikki Sokka
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Background</h3> The new 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for rheumatoid arthritis (RA) aim at earlier diagnosis of RA compared to the 1987 ACR criteria. <h3>Objective</h3> To evaluate the ability of the 2010 ACR/EULAR and the 1987 ACR classification criteria to predict radiographic progression after 10 years of follow-up. <h3>Methods</h3> All early arthritis patients referred to Central Hospital in Jyväskylä from 1997 to 1999 (cases with peripheral joint synovitis, other specific diseases excluded) were included in this 10-year follow-up study. Radiographs of hands and feet were analysed according to Larsen on a scale of 0–100. <h3>Results</h3> At 10 years, 58% of the patients had an erosive disease (defined as Larsen ≥2 in at least one joint). The discriminative power of the 2010 ACR/EULAR and the 1987 ACR criteria (erosive disease at 10 years) were comparable, with area under the curve 0.72 (95% CI 0.65 to 0.79) (2010 ACR/EULAR criteria) and 0.65 (95% CI 0.58 to 0.72) (1987 ACR criteria). The respective sensitivities and specificities were 0.87 and 0.70, and 0.44 and 0.47. At 10 years, median (IQR) Larsen score was 6 (0, 15) among patients who had fulfilled both sets of criteria, 2 (0, 8) in those who met the 2010 ACR/EULAR and did not meet the ACR 1987 criteria, 0 (0, 5) in those who met ACR 1987 criteria but did not meet 2010 ACR/EULAR criteria, and 0 (0, 2) among patients who did not fulfil either of the criteria. The percentage of patients with erosions was 69%, 64%, 32% and 26%, respectively. <h3>Conclusions</h3> The ability of the 2010 ACR/EULAR and 1987 ACR classification criteria to identify erosive disease in early arthritis is low. The discriminative power of the 2010 ACR/EULAR criteria of erosiveness in 10 years is slightly better than that of the 1987 ACR criteria.
Acute Kidney Injury Leads to Inflammation and Functional Changes in the Brain
Authors: Manchang Liu, Yideng Liang, Srinivasulu Chigurupati, Justin D. Lathia, Mikhail Pletnikov, Zhaoli Sun, Michael Crow, Christopher A. Ross, Mark P. Mattson, Hamid Rabb
Journal: Journal of the American Society of Nephrology (2008)

<h3>STUDY OBJECTIVE</h3> To examine the association between exposure to environmental tobacco smoke (ETS) and demographic, lifestyle, occupational characteristics and self reported health conditions. <h3>DESIGN</h3> Cross sectional study, using data from multiphasic health checkups between 1979 and 1985. <h3>SETTING</h3> Large health plan in Northern California, USA. <h3>PARTICIPANTS</h3> 16 524 men aged 15–89 years and 26 197 women aged 15–105 years who never smoked. <h3>RESULTS</h3> Sixty eight per cent of men and 64 per cent of women reported any current ETS exposure (at home, in small spaces other than home or in large indoor areas). The exposure time from all three sources of ETS exposure correlated negatively with age. Men and women reporting high level ETS exposure were more likely to be black and never married or separated/divorced, to have no college or partial college education, to consume three alcoholic drink/day or more and to report exposure to several occupational hazards. Consistent independent relations across sexes were found between any current exposure to ETS and a positive history of hay fever/asthma (odds ratio (OR)=1.22 in men, 1.14 in women), hearing loss (OR=1.30 in men, 1.27 in women), severe headache (OR=1.22 in men, 1.17 in women), and cold/flu symptoms (OR=1.52 in men, 1.57 in women). Any current ETS exposure was also associated with chronic cough (OR=1.22) in men and with heart disease (OR=1.10) in women. Self reported stroke was inversely associated with any current ETS exposure in men (OR=0.27). No associations were noted for cancer or tumour and for migraine. <h3>CONCLUSION</h3> ETS exposure correlated with several personal characteristics potentially associated with adverse health outcomes. Although the study design precluded causal inference, ETS exposure was associated with several self reported acute and chronic medical conditions.
Visible tumour on bronchoscopy: Do we need cytology?
Authors: Muhammad Naeem, Raja Reddy
Journal: European Respiratory Journal (2013)

Introduction:   Flexible bronchoscopy has a important role in diagnosing lung cancer. Where tumor is visible on bronchoscopy, it is common practice to carry out the full complement of Forceps biopsies, washings and brushings to enable histological/cytological diagnosis 1, 2 .  The aim of this retrospective study was to determine whether routine collection of cytology samples (washings & brushings) increase the diagnostic yield as compared to biopsy alone in cases where adequate biopsies (at least five) of bronchoscopically visible tumor were obtained.   Method:   We reviewed consecutive series of 278 bronchoscopies in which biopsies were done during period of 5 years from 2008 to 2012. A total of 148 bronchoscopies met the criteria of bronchoscopically visible tumor and in 145 of these the bronchoscopist felt adequate biopsies were obtained. All these patients also had washings and brushings carried out.   Results:   In the 145 cases where adequate biopsies were obtained, overall diagnostic yield was 99.3%. Histology was positive in 144 cases whereas cytology was positive in 98. Both were negative in one patient.   Conclusion:   Additional cytology specimens didn’t add to the diagnostic yield in bronchoscopically visible tumors where adequate biopsies were obtained. Omitting routine cytological sampling could yield significant cost savings as well as reducing bronchoscopy time.   References:   1. Dobler CC, Crawford AB. Bronchoscopic diagnosis of endoscopically visible lung malignancies: should cytological examinations be carried out routinely? Intern Med J. 2009 Dec;39(12):806-11.
OX40 Ligand Contributes to Human Lupus Pathogenesis by Promoting T Follicular Helper Response
Authors: Clément Jacquemin, Nathalie Schmitt, Cécile Contin-Bordes, Yang Liu, Priya Narayanan, Julien Seneschal, Typhanie Maurouard, David Dougall, Emily Spence Davizon, Hélène Dumortier, Isabelle Douchet, Loïc Raffray, Christophe Richez, Estibaliz Lazaro, Pierre Duffau, Marie-Elise Truchetet, Liliane Khoryati, Patrick Mercié, Lionel Couzi, Pierre Merville, Thierry Schaeverbeke, Jean-François Viallard, Jean-Luc Pellegrin, Jean-François Moreau, Sylviane Muller, Sandy Zurawski, Robert L. Coffman, Virginia Pascual, Hideki Ueno, Patrick Blanco
Journal: Immunity (2015)
Intensive Group Therapy: An Effective Behavioral-Psychoanalytic Method
Authors: LEE BIRK
Journal: American Journal of Psychiatry (1974)

This paper describes the results of a clinical trial of a new method, intensive group therapy, devised explicitly to incorporate the principal advantages of three traditionally separate techniques: the intensive five-day-a-week format of psychoanalysis; the real-life quality of group therapy, which promotes social-interaction analysis and modification; and the punishment/reinforcement techniques of behavior therapy. The eight patients treated in the group all had had extensive but largely unsuccessful therapy; during the first 18 months of intensive group therapy seven of the eight made appreciable therapeutic gains.
Validation of Microarray Data by Quantitative Reverse-Transcriptase Polymerase Chain Reaction
Authors: Serge Koscielny, Stefan Michiels, Valérie Boige, Catherine Hill
Journal: Journal of Clinical Oncology (2005)

help us in decision making more than present algorithms and models do.In the meanwhile, a careful evaluation of the benefits and costs of introducing an AI in the management of any individual patient should be part of the decision making process.In fact, no one of the strategies tested so far (upfront use, sequencing, switch-ing, extended use) can be regarded as the panacea for all women.
Prevention of Lipopolysaccharide-induced Microangiopathy by gp49B1
Authors: Joseph S. Zhou, Daniel S. Friend, Anna M. Feldweg, Massoud Daheshia, Lin Li, K. Frank Austen, Howard R. Katz
Journal: The Journal of Experimental Medicine (2003)

gp49B1 is expressed on mast cells and inhibits immunoglobulin E-dependent activation and inflammation in vivo. We now show that gp49B1 is expressed on neutrophils and prevents neutrophil-dependent vascular injury in response to lipopolysaccharide (LPS). The intradermal (i.d.) injection of LPS into gp49B1-null (gp49B-/-) but not gp49B1-sufficient (gp49B+/+) mice elicited macroscopic hemorrhages by 24 h, which were preceded on microscopic analyses by significantly more intravascular thrombi (consisting of neutrophils, platelets, and fibrin) that occluded venules and by more tissue neutrophils than in gp49B+/+ mice. However, there were no differences in the number of intact (nondegranulating) mast cells or the tissue levels of mediators that promote neutrophil recruitment. Hemorrhage was prevented by depleting neutrophils, blocking beta2 integrin-intercellular adhesion molecule 1 interactions, or inhibiting coagulation. These characteristics indicate that gp49B-/- mice are exquisitely sensitive to a local Shwartzman reaction (LSR) after a single i.d. injection of LPS, whereas in the classic LSR, a second exposure is required for increased beta2 integrin function, intravascular neutrophil aggregation, formation of occlusive thrombi, and hemorrhage. Moreover, LPS increased gp49B1 expression on neutrophils in vivo. The results suggest that gp49B1 suppresses the LPS-induced increase in intravascular neutrophil adhesion, thereby providing critical innate protection against a pathologic response to a bacterial component.
Echocardiographic determination of contraction and relaxation measurements of the left ventricular wall in normal subjects and patients with muscular dystrophy.
Authors: S J Goldberg, L Feldman, C Reinecke, L Z Stern, D J Sahn, H D Allen
Journal: Circulation (1980)

Boys with Duchenne's muscular dystrophy (DMD) usually have a cardiomyopathy characterized by fibrosis of the epicardial half of the left ventricle. This cardiomyopathy is difficult to detect by noninvasive techniques. We report a technique that evaluates incremental left ventricular posterior wall thickening and thinning. High-quality left ventricular posterior wall echoes in 24 boys with DMD and 32 controls were recorded at chordal level two times 1 year apart. Endocardial and epicardial echoes and a timing ECG were digitized and analyzed by minicomputer. Left ventricular wall amplitudes were determined at standardized temporal increments during contraction and relaxation. To compare with this left ventricular assessment technique, systolic ejection times, shortening fraction and mean velocity of circumferenial fiber shortening (Vcf) were also computed in the standard way. Mean year-to-year changes were minor. Mean Vcf, the ratio of preejection period to left ventricular ejection time and shortening fraction during the first year were statistically similar to those of the controls. Shortening fraction decreased slightly during the second year and became significantly different from the control, but remained within the normal range. Left ventricular wall thickness and cavity size were significantly less in boys with DMD than in controls. Therefore, we had to normalize incremental wall thickness to determine if any significant difference occurred. To do this, we evaluated the percentage of maximal wall thickness which occurred at a given percent of systole and diastole. Using this technique, it was shown that thickening during systole was a nearly linear process with respect to time in both groups. However, relaxation was significantly different between the groups. Relaxation was found to be an alinear process, and most thinning occurred in the first 40% of diastole. The major findings of this investigation was that the left ventricular wall of boys with DMD thinned at a slower rate than that of normal subjects. This new technique appears to be sensitive and demonstrates subtle changes in the left ventricular posterior wall.
Interactions between T helper cells and dendritic cells during the rat mixed lymphocyte reaction.
Authors: J Green, R Jotte
Journal: The Journal of Experimental Medicine (1985)

This paper describes the interactions between dendritic cells (DC) and T helper (Th) cells in the rat mixed lymphocyte reaction (MLR). Th blasts that are actively proliferating were generated in a 5 d primary MLR; resting Th memory cells were derived from a 10-12 d MLR. The DC were purified from thoracic duct lymph derived from rats whose mesenteric lymph nodes had been removed. The results show that DC are the major stimulators in the primary MLR and also for the restimulation of Th blasts and Th memory cells. Th blasts rapidly formed large clusters when cultured with DC but not with Ia+ macrophages or B cells. This interaction was not dependent on a major histocompatibility complex (MHC) difference between the T blasts and the DC. Con A-activated T and B blasts also formed clusters when cultured with DC. Th memory cells formed small clusters with DC, but, in a different assay in which clusters are dispersed, we detected an antigen-specific interaction between Th memory cells and DC. The monoclonal antibodies W3/25 (anti-rat CD4) and MRC OX-6 (anti-MHC class II) blocked proliferation in the primary MLR and also inhibited the restimulation of Th memory cells. However, the restimulation of Th blasts in a secondary MLR was only blocked by MRC OX-6. These results suggest that there are different requirements for the restimulation of T blasts than for the activation of primary or memory Th cells. W3/25 and MRC OX-6 did not affect the clustering of T blasts with DC but they both inhibited the antigen-specific binding of Th memory cells to DC. The data suggest that the CD4 (W3/25) antigen is involved in antigen-specific interactions between Th cells and DC.
Comparison of Percutaneous Coronary Intervention with Medication in the Treatment of Coronary Artery Disease in Hemodialysis Patients
Authors: Kaoru Yasuda, Hirotake Kasuga, Toru Aoyama, Hiroshi Takahashi, Takanobu Toriyama, Yasumasa Kawade, Shigejiro Iwashima, Shigeki Yamada, Hirohisa Kawahara, Shoichi Maruyama, Yukio Yuzawa, Hideki Ishii, Toyoaki Murohara, Seiichi Matsuo
Journal: Journal of the American Society of Nephrology (2006)

It has been reported that percutaneous coronary intervention (PCI) is beneficial for coronary artery disease (CAD) among the general population. However, its effects in patients who are on hemodialysis (HD) remain unclear. A prospective cohort study was performed to clarify whether PCI has a therapeutic advantage over medical therapy among HD patients with CAD. A follow-up study to 5 yr was conducted among 259 HD patients with ischemic heart disease. Mean follow-up was 39 mo. Patients were divided into three groups: 122 patients without significant stenosis, 88 patients who had significant stenosis and were treated with PCI, and 49 patients who had significant stenosis and were treated with medication only. The primary end point was cardiac death, and the secondary end point was all-cause death. The results showed that the 5-yr cardiac survival rate was 41.6% in the medication group, 77.1% in the PCI group (P = 0.0006), and 84.5% in the nonstenosis group (P < 0.0001). The 5-yr all-cause survival rate was 19.3% in the medication group, 48.4% in the PCI group (P = 0.004), and 64.3% in the nonstenosis group (P < 0.0001). Even after adjustment for other risk factors, effects of PCI on the risk for cardiac and all-cause death remained significant and independent (odds ratio 0.14; 95% confidence interval 0.08 to 0.25, P = 0.0006; and odds ratio 0.37; 95% confidence interval 0.26 to 0.54, P = 0.0062, respectively). Results were consistent when the therapeutic effect of PCI or medication was analyzed using propensity-matched patients. These data suggested that PCI could improve the prognosis of HD patients with CAD. PCI would be recommended for HD patients with CAD.
The importance of leukotrienes in airway inflammation in a mouse model of asthma.
Authors: W R Henderson, D B Lewis, R K Albert, Y Zhang, W J Lamm, G K Chiang, F Jones, P Eriksen, Y T Tien, M Jonas, E Y Chi
Journal: The Journal of Experimental Medicine (1996)

Inhalation of antigen in immunized mice induces an infiltration of eosinophils into the airways and increased bronchial hyperreactivity as are observed in human asthma. We employed a model of late-phase allergic pulmonary inflammation in mice to address the role of leukotrienes (LT) in mediating airway eosinophilia and hyperreactivity to methacholine. Allergen intranasal challenge in OVA-sensitized mice induced LTB4 and LTC4 release into the airspace, widespread mucus occlusion of the airways, leukocytic infiltration of the airway tissue and broncho-alveolar lavage fluid that was predominantly eosinophils, and bronchial hyperreactivity to methacholine. Specific inhibitors of 5-lipoxygenase and 5-lipoxygenase-activating protein (FLAP) blocked airway mucus release and infiltration by eosinophils indicating a key role for leukotrienes in these features of allergic pulmonary inflammation. The role of leukotrienes or eosinophils in mediating airway hyperresponsiveness to aeroallergen could not be established, however, in this murine model.