tbuckley/cabot-search huggingface dataset:
A Large-Scale RNAi-Based Mouse Tumorigenesis Screen Identifies New Lung Cancer Tumor Suppressors That Repress FGFR Signaling
Authors: Ling Lin, Lynn Chamberlain, Magnolia L. Pak, Arvindhan Nagarajan, Romi Gupta, Lihua J. Zhu, Casey M. Wright, Kwun M. Fong, Narendra Wajapeyee, Michael R. Green
Journal: Cancer Discovery (2014)

To discover new tumor-suppressor genes (TSG), we developed a functional genomics approach in which immortalized but nontumorigenic cells were stably transduced with large-scale shRNA pools and tested for tumor formation in mice. Identification of shRNAs in resulting tumors revealed candidate TSGs, which were validated experimentally and by analyzing expression in human tumor samples. Using this approach, we identified 24 TSGs that were significantly downregulated in human lung squamous cell carcinomas (hLSCC). Amplification of fibroblast growth factor receptor 1 (FGFR1), which aberrantly increases FGFR signaling, is a common genetic alteration in hLSCCs. Remarkably, we found that 17 of the TSGs encode repressors of FGFR signaling. Knockdown of 14 of these TSGs transformed immortalized human bronchial epithelial cells and, in most cases, rendered them sensitive to FGFR inhibitors. Our results indicate that increased FGFR signaling promotes tumorigenesis in many hLSCCs that lack FGFR1 amplification or activating mutations.A functional genomics approach identifies new lung TSGs whose loss aberrantly increases FGFR signaling to promote tumorigenesis. These TSGs are frequently downregulated in hLSCCs, indicating that increased FGFR signaling promotes tumorigenesis in many hLSCCs lacking FGFR1 amplification or activating mutations.
Inhaled Nitric Oxide in Acute Respiratory Distress Syndrome
Authors: ERIC TRONCY, JEAN-PAUL COLLET, STAN SHAPIRO, JEAN-GILLES GUIMOND, LOUIS BLAIR, THIERRY DUCRUET, MARTIN FRANCOEUR, MARC CHARBONNEAU, GILBERT BLAISE
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

This pilot randomized controlled clinical trial of patients with ARDS was implemented to study the impact of inhaled nitric oxide (inhNO) on lung function, morbidity, and mortality. Thirty patients with ARDS were randomly allocated to usual care or usual care plus inhNO. The optimal dose of inhNO was determined to be between 0.5 and 40 parts-per-million daily. All therapeutic interventions were standardized. ARDS resulted mainly from sepsis (25 of the 30). During the first 24 h, the hypoxia score increased greatly in patients treated with inhNO + 70.4 mm Hg ( + 59%) versus + 14.2 mm Hg ( + 9.3%) for the control group (p = 0.02), venous admixture decreased from 25.7 to 15.2% in the inhNO group, and from only 19.4 to 14.9% in the control group (p = 0.05). After the first day of therapy no further beneficial effect of inhNO was detected. Forty percent of the patients treated with inhNO were alive and weaned from mechanical ventilation within 30 d after randomization compared with 33.3% in the control group (p = 0.83). The 30-d mortality rate was similar in the two groups; most deaths (11 of 17) were due to multiple organ dysfunction syndrome. This study shows that inhNO, in this population, may improve gas exchange but does not affect mortality.
Late-breaking abstract: Preclinical evaluation of an inhibitor of cytosolic phospholipase A2α for the treatment of asthma
Authors: Christopher Hewson, Sheena Patel, Luigino Calzetta, Hinnah Campwala, Suzanne Havard, Emma Luscombe, Philip Clarke, Peter Peachell, Maria Matera, Mario Cazzola, Clive Page, William Abraham, Cara Williams, James Clark, Nicholas Clarke, Michael Yeadon
Journal: European Respiratory Journal (2011)

Asthma is an inflammatory lung disease with considerable requirement for new and effective therapies. Cytosolic phospholipase A 2 α (cPLA 2 α) is the rate-limiting enzyme responsible for production of eicosanoids implicated in asthma. We investigated a novel cPLA 2 α inhibitor, PF-5212372, to establish the preclinical rationale for asthma. PF-5212372 potently and effectively inhibited prostaglandin D 2  (PGD 2 ) and cysteinyl leukotriene release from human lung mast cells (IC 50 s 0.29nM and 0.45nM, respectively). In a mixed human lung cell population, PF-5212372 effectively inhibited leukotriene B 4 , thromboxane A 2  and PGD 2  (IC 50 s 2.6nM, 2.6nM and 4.0nM, respectively), but was less effective against PGE 2  release (IC 50  >301nM,  p  p  p  2  IC 50  0.78nM). PF-5212372 was shown to inhibit AMP-induced constriction of ex vivo human bronchial sections (81% inhibition,  p   These data show that inhibition of cPLA 2 α using PF-5212372 is effective in a wide-range of pre-clinical asthma models and demonstrates cell retention that may yield clinical duration of action. PF-5212372 may represent a new therapeutic option for the treatment of asthma.
Amygdala Response in Patients With Acute PTSD to Masked and Unmasked Emotional Facial Expressions
Authors: Jorge L. Armony, Vincent Corbo, Marie-Hélène Clément, Alain Brunet
Journal: American Journal of Psychiatry (2005)

OBJECTIVE: This study used functional magnetic resonance imaging to investigate amygdala response in patients with acute posttraumatic stress disorder (PTSD) to emotional expressions. METHOD: Thirteen medication-free individuals with acute PTSD and no axis I psychiatric comorbidity were scanned while viewing pictures of fearful or happy faces, presented above or below consciousness, with backward masking. RESULTS: There was a significant positive correlation between the severity of PTSD and the difference in amygdala responses between masked fearful and happy faces and a corresponding negative correlation for the difference between unmasked fearful and happy faces. CONCLUSIONS: These findings suggest that functional abnormalities in brain responses to emotional stimuli observed in chronic PTSD are already apparent in its acute phase.
Cancer Therapy with a Replicating Oncolytic Adenovirus Targeting the Hypoxic Microenvironment of Tumors
Authors: Dawn E. Post, Narra Sarojini Devi, Zhenchao Li, Daniel J. Brat, Balveen Kaur, Ainsley Nicholson, Jeffrey J. Olson, Zhaobin Zhang, Erwin G. Van Meir
Journal: Clinical Cancer Research (2004)

Abstract Hypoxia plays a critical role in driving tumor malignancy and is associated with poor patient survival in many human cancers. Novel therapies targeting hypoxic tumor cells are urgently needed, because these cells hinder tumor eradication. Here we demonstrate than an anticancer strategy based on intratumoral delivery of a novel type of oncolytic adenovirus targeting tumor hypoxia is therapeutically efficient and can augment standard chemotherapy. We used a conditionally replicative adenovirus (HYPR-Ad) to specifically kill hypoxic tumor cells. Viral infection and conditional replication occurred efficiently in hypoxic/hypoxia-inducible factor-active cells in culture and in vivo, prevented tumor formation, and reduced the growth of established tumors. Combining HYPR-Ad with chemotherapy effective against normoxic cells resulted in strongly enhanced antitumor efficacy. These studies demonstrate that targeting the hypoxic microenvironment of tumors rather than an intrinsic gene expression defect is a viable and novel antitumor therapeutic strategy that can be used in combination with existing treatment regimens. The replication and oncolytic potential of this virus was made dependent on hypoxic/hypoxia-inducible factor, a transcription factor activated in the tumor hypoxic microenvironment, broadening its therapeutic use to solid tumors of any genetic make-up or tissue of origin.
Acute effects of deep diaphragmatic breathing in COPD patients with chronic respiratory insufficiency
Authors: M Vitacca, E Clini, L Bianchi, N Ambrosino
Journal: European Respiratory Journal (1998)

This study investigated the impact of deep diaphragmatic breathing (DB) on blood gases, breathing pattern, pulmonary mechanics and dyspnoea in severe hypercapnic chronic obstructive pulmonary disease (COPD) patients recovering from an acute exacerbation. Transcutaneous partial pressure of carbon dioxide (Ptc,CO2) and oxygen (Ptc,O2) and arterial oxygen saturation (Sa,O2), were continuously monitored in 25 COPD patients with chronic hypercapnia, during natural breathing and DB. In eight of these patients, breathing pattern and minute ventilation (V'E) were also assessed by means of a respiratory inductance plethysmography. In five tracheostomized patients, breathing pattern and mechanics were assessed by means of a pneumotachograph/pressure transducer connected to an oesophageal balloon. Subjective rating of dyspnoea was performed by means of a visual analogue scale. In comparison to natural breathing deep DB was associated with a significant increase in Ptc,O2 and a significant decrease in Ptc,CO2, with a significant increase in tidal volume and a significant reduction in respiratory rate resulting in increased V'E. During DB, dyspnoea worsened significantly and inspiratory muscle effort increased, as demonstrated by an increase in oesophageal pressure swings, pressure-time product and work of breathing. We conclude that in severe chronic obstructive pulmonary disease patients with chronic hypercapnia, deep diaphragmatic breathing is associated with improvement of blood gases at the expense of a greater inspiratory muscle loading.
Noninvasive genomic detection of melanoma
Authors: W. Wachsman, V. Morhenn, T. Palmer, L. Walls, T. Hata, J. Zalla, R. Scheinberg, H. Sofen, S. Mraz, K. Gross, H. Rabinovitz, D. Polsky, S. Chang
Journal: British Journal of Dermatology (2011)

Early detection and treatment of melanoma is important for optimal clinical outcome, leading to biopsy of pigmented lesions deemed suspicious for the disease. The vast majority of such lesions are benign. Thus, a more objective and accurate means for detection of melanoma is needed to identify lesions for excision.To provide proof-of-principle that epidermal genetic information retrieval (EGIR™; DermTech International, La Jolla, CA, U.S.A.), a method that noninvasively samples cells from stratum corneum by means of adhesive tape stripping, can be used to discern melanomas from naevi.Skin overlying pigmented lesions clinically suspicious for melanoma was harvested using EGIR. RNA isolated from the tapes was amplified and gene expression profiled. All lesions were removed for histopathological evaluation.Supervised analysis of the microarray data identified 312 genes differentially expressed between melanomas, naevi and normal skin specimens (P<0·001, false discovery rate q<0·05). Surprisingly, many of these genes are known to have a role in melanocyte development and physiology, melanoma, cancer, and cell growth control. Subsequent class prediction modelling of a training dataset, consisting of 37 melanomas and 37 naevi, discovered a 17-gene classifier that discriminates these skin lesions. Upon testing with an independent dataset, this classifier discerned in situ and invasive melanomas from naevi with 100% sensitivity and 88% specificity, with an area under the curve for the receiver operating characteristic of 0·955.These results demonstrate that EGIR-harvested specimens can be used to detect melanoma accurately by means of a 17-gene genomic biomarker.
Intra-articular apatite deposition in mixed connective tissue disease: crystallographic and technetium scanning characteristics.
Authors: C W Hutton, P J Maddison, A J Collins, J A Berriman
Journal: Annals of the Rheumatic Diseases (1988)

An acute arthritis in a patient with mixed connective tissue disease (MCTD) was found to be associated with intra-articular deposition of carbonated hydroxyapatite crystals. A technetium hydroxymethylene diphosphonate bone scan showed intense uptake in the delayed phase scan of the affected joints. Synovial fluid analysis demonstrated uptake of the radiopharmaceutical drug directly onto the crystals.
THE MECHANISM OF THE SYMPTOMS OF INSULIN HYPOGLYCEMIA
Authors: H. E. HIMWICH, J. P. FROSTIG, J. F. FAZEKAS, Z. HADIDIAN
Journal: American Journal of Psychiatry (1939)

1. Simultaneous observations of clinical symptoms, cerebral oxygen utilization, blood sugar level and electrical activity of the brain were made on patients with schizophrenia receiving the insulin treatment. 2. Blood sugar decreases during the first hours after the injection of insulin and then remains at a low level until termination with sugar while the clinical signs continue to develop progressively throughout the entire course of hypoglycemia. 3. The march of the symptoms is correlated with a gradual decrease of cerebral oxygen uptake and the electrical changes. 4. The regression of the symptoms is accompanied by a gradual increase of the oxygen uptake and a reduction of the delta index. The sequence of the symptoms during regression is in an order which is the reverse of their appearance. 5. During hypoglycemia the alpha waves disappear approximately at the time when the functions of the cortex are completely suppressed and reappear with the restoration of cortical functions. 6. It is therefore, concluded that as a result of the hypoglycemia caused by the administration of insulin the metabolism of the brain is diminished. This reducton of cerebral metabolism is the cause of the clinical symptoms as well as the alterations of the cerebral electrical activity of the brain. 7. These conclusions concerning the correlations between the clinical and physiological changes are to be regarded only as a working hypothesis because of the small number of the experiments performed.
Public Health England's reply to editorial on its draft report on shale gas extraction
Authors: J. Harrison, P. Cosford
Journal: BMJ (2014)

Law and colleagues comment on Public Health England’s (PHE’s) draft report on potential public health impacts of exposures to chemical and radioactive pollutants as a result of shale gas extraction.1 2 Three of the authors also reviewed health risks associated with shale gas exploitation, and their conclusions regarding risks identified and the need for further monitoring of emissions …
Comparison of cyclooxygenase 2 expression in adenocarcinomas of the gastric cardia and distal oesophagus
Authors: C J Buskens
Journal: Gut (2003)

Adenocarcinomas of the gastric cardia and distal oesophagus are at present often considered as one clinical entity because of their comparable increasing incidence, prognosis, and optimal treatment options. However, it is still a matter of debate whether these malignancies have the same pathogenesis and genotype.The aim of this study was to analyse expression of cyclooxygenase 2 (COX-2) in cardia carcinomas, and correlate this expression with clinicopathological parameters and survival. The results were compared with the prognostic value of COX-2 found for Barrett carcinomas.Tumour sections of 134 consecutive patients undergoing potentially curative surgery for an adenocarcinoma of the gastric cardia and substantially invading the distal oesophagus were immunohistochemically stained using a COX-2 monoclonal antibody. Specimens were blindly scored based on intensity and extent of COX-2 immunopositivity.COX-2 expression was negative to weak in 59% ("COX-2 low") and moderate to strong in 41% ("COX-2 high") of tumours. This was significantly lower than in Barrett carcinomas (p<0.0001). COX-2 expression was not correlated with any clinicopathological parameter. A correlation between elevated COX-2 expression and reduced survival, as described for Barrett carcinomas, was not identified for cardiac carcinomas.There is a difference in COX-2 expression with respect to intensity and prognostic significance between adenocarcinomas of the gastric cardia and distal oesophagus. This suggests a different pathogenesis and different genetic constitution of these two cancers. Based on these findings, the role of selective COX-2 inhibitors in the treatment of adenocarcinomas of the gastric cardia is less promising than in Barrett carcinomas.
Hypoglycemia and Diabetes: A Report of a Workgroup of the American Diabetes Association and The Endocrine Society
Authors: Elizabeth R. Seaquist, John Anderson, Belinda Childs, Philip Cryer, Samuel Dagogo-Jack, Lisa Fish, Simon R. Heller, Henry Rodriguez, James Rosenzweig, Robert Vigersky
Journal: Diabetes Care (2013)

To review the evidence about the impact of hypoglycemia on patients with diabetes that has become available since the past reviews of this subject by the American Diabetes Association and The Endocrine Society and to provide guidance about how this new information should be incorporated into clinical practice.Five members of the American Diabetes Association and five members of The Endocrine Society with expertise in different aspects of hypoglycemia were invited by the Chair, who is a member of both, to participate in a planning conference call and a 2-day meeting that was also attended by staff from both organizations. Subsequent communications took place via e-mail and phone calls. The writing group consisted of those invitees who participated in the writing of the manuscript. The workgroup meeting was supported by educational grants to the American Diabetes Association from Lilly USA, LLC and Novo Nordisk and sponsorship to the American Diabetes Association from Sanofi. The sponsors had no input into the development of or content of the report.The writing group considered data from recent clinical trials and other studies to update the prior workgroup report. Unpublished data were not used. Expert opinion was used to develop some conclusions.Consensus was achieved by group discussion during conference calls and face-to-face meetings, as well as by iterative revisions of the written document. The document was reviewed and approved by the American Diabetes Association's Professional Practice Committee in October 2012 and approved by the Executive Committee of the Board of Directors in November 2012 and was reviewed and approved by The Endocrine Society's Clinical Affairs Core Committee in October 2012 and by Council in November 2012.The workgroup reconfirmed the previous definitions of hypoglycemia in diabetes, reviewed the implications of hypoglycemia on both short- and long-term outcomes, considered the implications of hypoglycemia on treatment outcomes, presented strategies to prevent hypoglycemia, and identified knowledge gaps that should be addressed by future research. In addition, tools for patients to report hypoglycemia at each visit and for clinicians to document counseling are provided.
Digital necrosis with Ogilvie's syndrome
Authors: G D Wright, C D McCullagh, I K Walsh, S D Roberts
Journal: Annals of the Rheumatic Diseases (1997)

Case reportA 76 year old retired fisherman presented with a progressive four week history of cold, painful, blue fingers.Systematic enquiry was unremarkable apart from generalised lethargy over the preceding six weeks.He had osteoarthritis of his left hip and had taken indomethacin 25 mg thrice daily for five years.He was an ex-smoker of 20 cigarettes/day for 40 years.On examination he was apyrexic.There was severe ischaemia of both hands with gangrene and necrosis of the fingertips (fig 1).Both feet were cyanosed, but there was no overt ischaemia or necrosis.All peripheral pulses were palpable with a blood pressure in both arms of 160/90.There were no large vessel bruits or cardiac murmurs.Abdominal distension was noted but there was no tenderness or organomegaly.His fundi were normal.The remainder of the physical examination was unremarkable.Laboratory investigations revealed a hypochromic, normocytic anaemia with a haemoglobin of 9.4 g/dl and a white cell count of 19.1.× 10 9 with a neutrophilia.The erythrocyte sedimentation rate (Westergren) was 133 mm/1st h with a C reactive protein of 180 mg/l (normal range <10 mg/l).Urine analysis revealed 2+ protein, 3+ blood and granular casts but no red cell casts.Urine and blood cultures were sterile.The urea was 19.7 mmol/l and the serum creatinine 180 µmol/l with a creatinine clearance of 43.6 ml/min and a urinary total protein of 0.13 g/24 h.The alkaline phosphatase was 472 IU/l and the -glutamyltransferase 184 U/l with a serum albumin of 21 mmol/l.The IgG antinuclear antibody assay was positive with a titre of 1:80, but anti-double stranded DNA antibody and rheumatoid factor were not detected.Extractable nuclear antigens, antiphospholipid antibodies, and antineutrophil cytoplasmic antibodies were not detected.Plasma protein electrophoresis, serum immunoglobulins, CH50, C3, and C4 were normal.Cryoglobulins, cold agglutinins, and immune complexes were not detected.Hepatitis B and C serology was negative.Chest and sinus radiographs were normal.Echocardiography showed mild left ventricular hypertrophy but there were no vegetations.Von Willebrand factor antigen was increased >450% (normal range < 200).Upper limb arteriography revealed smooth narrowing and complete cessation of flow in the vessels entering both hands, consistent with diVuse vasculitis (fig 2).Ultrasound examina-
Bridging emotion theory and neurobiology through dynamic systems modeling
Authors: Marc D. Lewis
Journal: Behavioral and Brain Sciences (2005)

Efforts to bridge emotion theory with neurobiology can be facilitated by dynamic systems (DS) modeling. DS principles stipulate higher-order wholes emerging from lower-order constituents through bidirectional causal processes – offering a common language for psychological and neurobiological models. After identifying some limitations of mainstream emotion theory, I apply DS principles to emotion–cognition relations. I then present a psychological model based on this reconceptualization, identifying trigger, self-amplification, and self-stabilization phases of emotion-appraisal states, leading to consolidating traits. The article goes on to describe neural structures and functions involved in appraisal and emotion, as well as DS mechanisms of integration by which they interact. These mechanisms include nested feedback interactions, global effects of neuromodulation, vertical integration, action-monitoring, and synaptic plasticity, and they are modeled in terms of both functional integration and temporal synchronization. I end by elaborating the psychological model of emotion–appraisal states with reference to neural processes.
Cerebrospinal fluid–based kinetic biomarkers of axonal transport in monitoring neurodegeneration
Authors: Patrizia Fanara, Po-Yin A. Wong, Kristofor H. Husted, Shanshan Liu, Victoria M. Liu, Lori A. Kohlstaedt, Timothy Riiff, Joan C. Protasio, Drina Boban, Salena Killion, Maudi Killian, Lorrie Epling, Elisabeth Sinclair, Julia Peterson, Richard W. Price, Deborah E. Cabin, Robert L. Nussbaum, Jörg Brühmann, Roland Brandt, Chadwick W. Christine, Michael J. Aminoff, Marc K. Hellerstein
Journal: Journal of Clinical Investigation (2012)

Progress in neurodegenerative disease research is hampered by the lack of biomarkers of neuronal dysfunction. We here identified a class of cerebrospinal fluid-based (CSF-based) kinetic biomarkers that reflect altered neuronal transport of protein cargo, a common feature of neurodegeneration. After a pulse administration of heavy water (2H2O), distinct, newly synthesized 2H-labeled neuronal proteins were transported to nerve terminals and secreted, and then appeared in CSF. In 3 mouse models of neurodegeneration, distinct 2H-cargo proteins displayed delayed appearance and disappearance kinetics in the CSF, suggestive of aberrant transport kinetics. Microtubule-modulating pharmacotherapy normalized CSF-based kinetics of affected 2H-cargo proteins and ameliorated neurodegenerative symptoms in mice. After 2H2O labeling, similar neuronal transport deficits were observed in CSF of patients with Parkinson's disease (PD) compared with non-PD control subjects, which indicates that these biomarkers are translatable and relevant to human disease. Measurement of transport kinetics may provide a sensitive method to monitor progression of neurodegeneration and treatment effects.
Direct recordings of grid-like neuronal activity in human spatial navigation
Authors: Joshua Jacobs, Christoph T Weidemann, Jonathan F Miller, Alec Solway, John F Burke, Xue-Xin Wei, Nanthia Suthana, Michael R Sperling, Ashwini D Sharan, Itzhak Fried, Michael J Kahana
Journal: Nature Neuroscience (2013)