tbuckley/cabot-search huggingface dataset:
A New Tumor Suppressor Gene, Selective for Lung Cancer
Authors: M. B. Sporn
Journal: JNCI Journal of the National Cancer Institute (2007)

sion of this gene occurred in human lung (among more than a dozen human tissues examined), and, moreover, the important observation was made that GPRC5A mRNA was expressed at only very low levels in human lung cancer cells (three of five head and neck squamous cell carcinoma and four of six non – small cell lung cancer cell lines). The authors hypothesized that this decrease in mRNA expression might be associated with the malignant transformation of airway epithelium. The article by Tao et al. ( 2 ) in the current issue of the Journal now provides excellent, detailed experimental evidence for this hypothesis. The key experimental tool in this article has been the use of mice (B6/129sv) in which the Gprc5a gene has been knocked out by homologous recombination. The Lotan group is not the fi rst to have used knockout technology to study the biology of Gprc5a in the mouse lung. Thus, in an elegant study, Xu et al. ( 3 ) used classical recombinant technology to show that Gprc5a is expressed abundantly and specifi cally in the lung during embryonic development and in adult mice. These authors found that the onset of Gprc5a expression in the embryonic mouse lung coincided with the onset of differentiation in the lung, and they suggested that this gene plays an important role in lung maturation and differentiation. The loss of such a differentiating function during carcinogenesis is in accord with classical concepts of cancer as a disease of differentiation ( 4 , 5 ). However, most notably, the lungs of 3-month-old Gprc5a − / − mice appeared histologically normal in spite of the fact that this gene is expressed at high levels in Gprc5a +/+ mice of this age, in both type I and type II pneumocytes. The reason for this lack of phenotype at 3 months of age is unclear, but the authors suggest that the expression of a related gene that regulates G protein signaling (Raig3, also known as Gprc5c) may
Sildenafil in the Treatment of Raynaud’s Phenomenon Resistant to Vasodilatory Therapy
Authors: Roland Fries, Kaveh Shariat, Hubertus von Wilmowsky, Michael Böhm
Journal: Circulation (2005)

Background— Vasodilatory therapy of Raynaud’s phenomenon represents a difficult clinical problem because treatment often remains inefficient and may be not tolerated because of side effects. Methods and Results— To investigate the effects of sildenafil on symptoms and capillary perfusion in patients with Raynaud’s phenomenon, we performed a double-blinded, placebo-controlled, fixed-dose, crossover study in 16 patients with symptomatic secondary Raynaud’s phenomenon resistant to vasodilatory therapy. Patients were treated with 50 mg sildenafil or placebo twice daily for 4 weeks. Symptoms were assessed by diary cards including a 10-point Raynaud’s Condition Score. Capillary flow velocity was measured in digital nailfold capillaries by means of a laser Doppler anemometer. While taking sildenafil, the mean frequency of Raynaud attacks was significantly lower (35±14 versus 52±18, P =0.0064), the cumulative attack duration was significantly shorter (581±133 versus 1046±245 minutes, P =0.0038), and the mean Raynaud’s Condition Score was significantly lower (2.2±0.4 versus 3.0±0.5, P =0.0386). Capillary blood flow velocity increased in each individual patient, and the mean capillary flow velocity of all patients more than quadrupled after treatment with sildenafil (0.53±0.09 versus 0.13±0.02 mm/s, P =0.0004). Two patients reported side effects leading to discontinuation of the study drug. Conclusions— Sildenafil is an effective and well-tolerated treatment in patients with Raynaud’s phenomenon.
Retraction of “Concomitant measurement of copeptin and high-sensitivity troponin for fast and reliable rule out of acute myocardial infarction”
Authors: Yonathan Freund, Camille Chenevier-Gobeaux, Yann-Erick Claessens, François Leumani, Benoit Doumenc, Pascale Bonnet, Jean-Christophe Allo, Claudine Cosson, Bruno Riou, Patrick Ray
Journal: Intensive Care Medicine (2012)
Elevated CEA levels in sera in patients with allergic bronchopulmonary aspergillosis (ABPA)
Authors: Hirotaka Matsuzaki, Wakae Tanaka, Yasuhiro Kojima, Masaki Kawakami, Masaru Suzuki, Yoshio Sakamoto, Tadashi Horiuchi
Journal: European Respiratory Journal (2011)

Background:  ABPA is an allergic disease associated with peripheral blood eosinophilia and elevated total IgE in serum. It sometimes accompanies with bronchiectasis filled with mucus plug detected by chest X-ray- or CT films or fiberotic bronchoscopy. Mucus plug is not infrequently misdiagnosed as lung tumor. Carcinoembryonic antigen (CEA) is one of tumor markers and measured as a diagnostic as well as surrogate marker of bronchogenic carcinoma. It has been reported that some patients with ABPA demonstrated elevated CEA levels in their sera.   Aim:  To evaluate clinical significance of serum CEA level in patients with ABPA.   Methods:  Ten patients (6 women), aged from 39 to 78 (median; 67) with ABPA were evaluated. All patients were never smokers or ex-smokers. Serum CEA level, eosinophil number, total IgE,  Aspergillus fumigatus  ( Af )-specific IgE- and precipitating antibodies were measured. Chest roentgenogram and or CT were examined when blood test was performed. For comparison, serum CEA levels were also evaluated in patients with bronchiectasis (n=20).   Results:  Among 10 patients with ABPA, five demonstrated elevated serum CEA levels (6.2–140.0 ng/ml; normal range ≤5 ng/ml). Massive mucus plugs were demonstrated in four out of five patients on chest CT or X-ray films. Two out of five patients were treated with systemic glycocorticosteroids resulting in the decrease in CEA levels. Another patient showed the decrease in CEA spontaneously in parallel with the decrease in eosinophil number.   Conclusion:  Massive mucus plug may induce CEA synthesis from airway epithelial cells lining on the ectasic bronchi.
The corpus callosum: More than a passive “corpus”
Authors: Kenneth Hugdahl
Journal: Behavioral and Brain Sciences (1998)

Fitch &amp; Denenberg provide excellent evidence for the existence of dynamically complex interactions between the structural and functional development of the nervous system. They are to be congratulated for showing how subtle social variables (e.g., handling) may not only influence hormonal “cascade effects” on the developing nervous system, but may also alter the structure of brain tissue, such as the corpus callosum.
Treatment of acute promyelocytic leukemia with arsenic trioxide without ATRA and/or chemotherapy
Authors: A. Ghavamzadeh, K. Alimoghaddam, S.H. Ghaffari, S. Rostami, M. Jahani, R. Hosseini, A. Mossavi, E. Baybordi, A. Khodabadeh, M. Iravani, B. Bahar, Y. Mortazavi, M. Totonchi, N. Aghdami
Journal: Annals of Oncology (2005)
Endogenous generation and protective effects of nitro-fatty acids in a murine model of focal cardiac ischaemia and reperfusion
Authors: Volker Rudolph, Tanja K. Rudolph, Francisco J. Schopfer, Gustavo Bonacci, Steven R. Woodcock, Marsha P. Cole, Paul R.S. Baker, Ravi Ramani, Bruce A. Freeman
Journal: Cardiovascular Research (2009)

AimsNitrated fatty acids (NO 2 -FA) have been identified as endogenous anti-inflammatory signalling mediators generated by oxidative inflammatory reactions.Herein the in vivo generation of nitro-oleic acid (OA-NO 2 ) and nitro-linoleic acid (LNO 2 ) was measured in a murine model of myocardial ischaemia and reperfusion (I/R) and the effect of exogenous administration of OA-NO 2 on I/R injury was evaluated. Methods and resultsIn C57/BL6 mice subjected to 30 min of coronary artery ligation, endogenous OA-NO 2 and LNO 2 formation was observed after 30 min of reperfusion, whereas no NO 2 -FA were detected in sham-operated mice and mice with myocardial infarction without reperfusion.Exogenous administration of 20 nmol/g body weight OA-NO 2 during the ischaemic episode induced profound protection against I/R injury with a 46% reduction in infarct size (normalized to area at risk) and a marked preservation of left ventricular function as assessed by transthoracic echocardiography, compared with vehicle-treated mice.Administration of OA-NO 2 inhibited activation of the p65 subunit of nuclear factor kB (NFkB) in I/R tissue.Experiments using the NFkB inhibitor pyrrolidinedithiocarbamate also support that protection lent by OA-NO 2 was in part mediated by inhibition of NFkB.OA-NO 2 inhibition of NFkB activation was accompanied by suppression of downstream intercellular adhesion molecule 1 and monocyte chemotactic protein 1 expression, neutrophil infiltration, and myocyte apoptosis. ConclusionThis study reveals the de novo generation of fatty acid nitration products in vivo and reveals the anti-inflammatory and potential therapeutic actions of OA-NO 2 in myocardial I/R injury.
No Association Between Novelty Seeking and the Type 4 Dopamine Receptor Gene (<b><i>DRD4</i></b>) in Two New Zealand Samples
Authors: P F Sullivan, W J Fifield, M A Kennedy, R T Mulder, J D Sellman, P R Joyce
Journal: American Journal of Psychiatry (1998)

OBJECTIVE: In 1986 and 1987, Cloninger postulated the existence of the heritable behavioral trait of novelty seeking and its putative underpinnings in the dopaminergic systems of the ventral midbrain. Two widely reported studies found significant associations between novelty seeking and the type 4 dopamine receptor gene (DRD4), although a more recent study did not. The authors' objective was to investigate this association in two New Zealand samples. METHOD: The authors studied two nonoverlapping samples: subjects in a depression treatment trial (N=86) and subjects from 14 pedigrees dense with alcoholism (N=181). DRD4 genotyping was based on a standard protocol. RESULTS: Novelty seeking and DRD4 were not statistically associated. CONCLUSIONS: In these samples, there was no suggestion that the DRD4 polymorphism contributed to individual differences in the behavioral trait of novelty seeking. (Am J Psychiatry 1998; 155:98–101)
Calibration of aerosol output from the Mefar dosimeter: implications for epidemiological studies
Authors: JH Dennis, AJ Avery, EH Walters, DJ Hendrick
Journal: European Respiratory Journal (1992)

Standardized methods for the measurement of airway responsiveness may use the Mefar MB3 inhalation dosimeter to generate standard doses of methacholine aerosol. The manufacturer provides calibrated output data for every nebulizer, so that a standard output may be achieved by varying nebulization time. This output is, however, measured by weight loss (WL), which may over-estimate true aerosol output (AO) because of concomitant evaporation. We have used a chemical (fluoride) tracer method to measure AO directly from two batches of Mefar nebulizers (batch 1 n = 5, batch 2 n = 10) and compared results with manufacturer's quoted WL. Mean AO from batch 1 was 10.56 mg.s-1 (range 9.50-11.63, SD = 0.92 mg.s-1), and mean AO from batch 2 was 5.66 mg.s-1 (range 4.92-6.58, SD = 0.57 mg.s-1), implying that AO varied little within, but substantially between, the two nebulizer batches. Manufacturer's quoted WL does not reflect this near two fold difference: mean WL batch 1 = 14.0 mg.s-1 (range 13-15 mg.s-1); mean WL batch 2 = 11.1 mg.s-1 (range 11-12 mg.s-1). The median aerosol fractions (AO/WL) for batches 1 and 2 were 76% (range 65-83%) and 50% (range 43-60%), respectively. Similar results were obtained with our own measurement of weight loss. This implies that if the median nebulizers of batches 1 and 2 were calibrated (as recommended) by the manufacture's WL to deliver a presumed 100 micrograms methacholine dose, the actual doses delivered would be 76 micrograms and 50 micrograms, the range for all 15 nebulizers being 43-83 micrograms.(ABSTRACT TRUNCATED AT 250 WORDS)
Comparative efficacy of tandem autologous versus autologous followed by allogeneic hematopoietic cell transplantation in patients with newly diagnosed multiple myeloma: a systematic review and meta-analysis of randomized controlled trials
Authors: Mohamed A Kharfan-Dabaja, Mehdi Hamadani, Tea Reljic, Taiga Nishihori, William Bensinger, Benjamin Djulbegovic, Ambuj Kumar
Journal: Journal of Hematology & Oncology (2013)

Despite advances in understanding of clinical, genetic, and molecular aspects of multiple myeloma (MM) and availability of more effective therapies, MM remains incurable. The autologous-allogeneic (auto-allo) hematopoietic cell transplantation (HCT) strategy is based on combining cytoreduction from high-dose (chemo- or chemoradio)-therapy with adoptive immunotherapy. However, conflicting results have been reported when an auto-allo HCT approach is compared to tandem autologous (auto-auto) HCT. A previously published meta-analysis has been reported; however, it suffers from serious methodological flaws.A systematic search identified 152 publications, of which five studies (enrolling 1538 patients) met inclusion criteria. All studies eligible for inclusion utilized biologic randomization.Assessing response rates by achievement of at least a very good partial response did not differ among the treatment arms [risk ratio (RR) (95% CI) = 0.97 (0.87-1.09), p = 0.66]; but complete remission was higher in the auto-allo HCT arm [RR = 1.65 (1.25-2.19), p = 0.0005]. Event-free survival did not differ between auto-allo HCT group versus auto-auto HCT group using per-protocol analysis [hazard ratio (HR) = 0.78 (0.58-1.05)), p = 0.11] or using intention-to-treat analysis [HR = 0.83 (0.60-1.15), p = 0.26]. Overall survival (OS) did not differ among these treatment arms whether analyzed on per-protocol [HR = 0.88 (0.33-2.35), p = 0.79], or by intention-to-treat [HR = 0.80 (0.48-1.32), p = 0.39] analysis. Non-relapse mortality (NRM) was significantly worse with auto-allo HCT [RR (95%CI) = 3.55 (2.17-5.80), p < 0.00001].Despite higher complete remission rates, there is no improvement in OS with auto-allo HCT; but this approach results in higher NRM in patients with newly diagnosed MM. At present, totality of evidence suggests that an auto-allo HCT approach for patients with newly diagnosed myeloma should not be offered outside the setting of a clinical trial.
Global Hypomethylation of Genomic DNA in Cancer-Associated Myofibroblasts
Authors: Le Jiang, Tamas A. Gonda, Mary V. Gamble, Martha Salas, Venkatraman Seshan, Shuiping Tu, William S. Twaddell, Peter Hegyi, Gyorgy Lazar, Islay Steele, Andrea Varro, Timothy C. Wang, Benjamin Tycko
Journal: Cancer Research (2008)

Abstract Global hypomethylation has long been recognized as a feature of the malignant epithelial component in human carcinomas. Here we show evidence for this same type of epigenetic alteration in cancer-associated stromal myofibroblasts. We used methylation-sensitive SNP array analysis (MSNP) to profile DNA methylation in early-passage cultures of stromal myofibroblasts isolated from human gastric cancers. The MSNP data indicated widespread hypomethylation in these cells, with rare focal gains of methylation, conclusions that were independently validated by bisulfite sequencing and by a methylation-sensitive cytosine incorporation assay. Immunohistochemistry with anti–5-methylcytosine (anti–5-methyl-C) in a series of gastrectomy specimens showed frequent loss of methylation in nuclei of both the malignant epithelial cells and α-smooth muscle actin (ASMA)–positive stromal myofibroblasts of both intestinal-type and diffuse carcinomas. We confirmed this phenomenon and established its onset at the stage of noninvasive dysplastic lesions by immunohistochemistry for anti–5-methyl-C in a transgenic mouse model of multistage gastric carcinogenesis. These findings indicate similar general classes of epigenetic alterations in carcinoma cells and their accompanying reactive stromal cells and add to accumulating evidence for biological differences between normal and cancer-associated myofibroblasts. [Cancer Res 2008;68(23):9900–8]
An Experimental Model of Cachexia Induced by a Xenografted Human Tumor
Authors: Alastair J. Strain, Gerald C. Easty, A. Munro Neville
Journal: JNCI Journal of the National Cancer Institute (1980)

A hypernephroma removed from a male patient who had lost 30 kg in weight in the 2 months preceding surgery was established in immunosuppressed CBA/Lac mice as a nonmetastasizing transplantable xenograft. The xenografted tumors, although comprising less than 5% of the total body weight of the mice, produced considerable weight loss (greater than 25%). A slight reduction in food intake of tumor-bearing mice was noted, but some animals bearing mouse or human tumors not inducing cachexia had equally low food intake without accompanying weight losses. No obvious defects in gastrointestinal histology or absorption were observed. The precise mechanism(s) producing the severe cachexia remains to be established.
[18F]Galacto-RGD Positron Emission Tomography for Imaging of αvβ3 Expression on the Neovasculature in Patients with Squamous Cell Carcinoma of the Head and Neck
Authors: Ambros J. Beer, Anca-Ligia Grosu, Janette Carlsen, Andreas Kolk, Mario Sarbia, Isabelle Stangier, Petra Watzlowik, Hans-Jürgen Wester, Roland Haubner, Markus Schwaiger
Journal: Clinical Cancer Research (2007)

Abstract Purpose: [18F]Galacto-RGD has been developed for positron emission tomography (PET)–imaging of αvβ3 expression, a receptor involved in angiogenesis and metastasis. Our aim was to study the feasibility of PET imaging with [18F]Galacto-RGD in patients with squamous cell carcinoma of the head and neck (SCCHN). Experimental Design: Eleven patients with primary diagnosis of SCCHN were examined. After injection of 140 to 200 MBq [18F]Galacto-RGD, static emission scans 60 min post injection from the head to the abdomen (n = 11) and dynamic scans &amp;gt;60 min covering the tumor region (n = 6) for kinetic modeling were acquired. Standardized uptake values (SUV) were measured in tumors, muscle and oral mucosa. Immunohistochemistry was done using an αvβ3-specific antibody (n = 7). Image fusion with magnetic resonance imaging and/or computed tomography (CT) scans (n = 8) and calculation of tumor subvolumes based on SUVs was done using the iPlan software (BrainLAB). Results: [18F]Galacto-RGD PET identified 10 of 12 tumors, with SUVs ranging from 2.2 to 5.8 (mean, 3.4 ± 1.2). Two tumors &amp;lt;5 mm were missed. Tumor/blood and tumor/muscle ratios were 2.8 ± 1.1 and 5.5 ± 1.6, respectively. Tumor kinetics was consistent with a two-tissue compartmental model with reversible specific binding. Immunohistochemistry confirmed αvβ3 expression in all tumors with αvβ3 being located on the microvessels in all specimens and additionally on tumor cells in one specimen. Image fusion of [18F]Galacto-RGD PET with magnetic resonance imaging/multislice CT and definition of tumor subvolumes was feasible in all cases. Conclusions: [18F]Galacto-RGD PET allows for specific imaging of αvβ3 expression in SCCHN with good contrast. Image fusion and definition of tumor subvolumes is feasible. This technique might be used for the assessment of angiogenesis and for planning and response evaluation of αvβ3-targeted therapies.
Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and pharmacological and psychosocial management
Authors: Katharine Bushby, Richard Finkel, David J Birnkrant, Laura E Case, Paula R Clemens, Linda Cripe, Ajay Kaul, Kathi Kinnett, Craig McDonald, Shree Pandya, James Poysky, Frederic Shapiro, Jean Tomezsko, Carolyn Constantin
Journal: The Lancet Neurology (2009)
How fast does the Grim Reaper walk? Receiver operating characteristics curve analysis in healthy men aged 70 and over
Authors: F. F. Stanaway, D. Gnjidic, F. M. Blyth, D. G. L. Couteur, V. Naganathan, L. Waite, M. J. Seibel, D. J. Handelsman, P. N. Sambrook, R. G. Cumming
Journal: BMJ (2011)

To determine the speed at which the Grim Reaper (or Death) walks.Population based prospective study.Older community dwelling men living in Sydney, Australia.1705 men aged 70 or more participating in CHAMP (Concord Health and Ageing in Men Project).Walking speed (m/s) and mortality. Receiver operating characteristics curve analysis was used to calculate the area under the curve for walking speed and determine the walking speed of the Grim Reaper. The optimal walking speed was estimated using the Youden index (sensitivity + specificity-1), a common summary measure of the receiver operating characteristics curve, and represents the maximum potential effectiveness of a marker.The mean walking speed was 0.88 (range 0.15-1.60) m/s. The highest Youden index (0.293) was observed at a walking speed of 0.82 m/s (2 miles (about 3 km) per hour), corresponding to a sensitivity of 63% and a specificity of 70% for mortality. Survival analysis showed that older men who walked faster than 0.82 m/s were 1.23 times less likely to die (95% confidence interval 1.10 to 1.37) than those who walked slower (P = 0.0003). A sensitivity of 1.0 was obtained when a walking speed of 1.36 m/s (3 miles (about 5 km) per hour) or greater was used, indicating that no men with walking speeds of 1.36 m/s or greater had contact with Death.The Grim Reaper's preferred walking speed is 0.82 m/s (2 miles (about 3 km) per hour) under working conditions. As none of the men in the study with walking speeds of 1.36 m/s (3 miles (about 5 km) per hour) or greater had contact with Death, this seems to be the Grim Reaper's most likely maximum speed; for those wishing to avoid their allotted fate, this would be the advised walking speed.
Unexpectedly uneven: posttransplant skeletal distribution of hematopoietic stem cell clones
Authors: Elliott J. Hagedorn, Leonard I. Zon
Journal: The Journal of Experimental Medicine (2014)

INSIGHTS|TheJournalofExperimentalMedicineInhibition of DNA synthesis is a keystone of cancer therapy.The purine and pyrimidine precursors of DNA are obtained either by the de novo pathway (DNP) or the nucleotide salvage pathway (NSP).The DNP generates nucleotides that are reduced to the corresponding deoxynucleotide by ribonucleotide reductase (RNR).Thymidine, a potent inhibitor of de novo synthesis, acts by specific inhibition of RNR.The NSP salvages circulating deoxynucleosides released from dead cells or from the liver and converts them to deoxynucleotides, a process that is catalyzed by deoxycytidine kinase (dCK) and thymidine kinase 1 (TK1).In this issue, Nathanson et al. provide an elegant dissection of the roles of the DNP and NSP in leukemic cells and propose that the combined inhibition of both pathways offers a new therapeutic approach.Using multiple tumor models, including human-to-mouse xenografts and mouse models, they showed that the NSP is required to generate deoxycytidine triphosphate (dCTP) to compensate when de novo dCTP synthesis is blocked using thymidine, which may explain why using thymidine alone to target the DNP has shown limited efficacy in clinical trials.The availability of a fluorinated analogue of deoxycytidine allowed the authors, in prior work, to track the effect of DI-39-a potent small molecule inhibitor of dCK activity-in vivo using positron emission tomography.Crystallographic studies of DI-39 bound to dCK showed that it inhibits dCK activity by binding to the nucleoside-binding site.Using DI-39 in combination with thymidine (to inhibit de novo synthesis) profoundly decreased dCTP levels, leading to regression of T and B cell acute lympho blastic leukemia in mice, with no significant toxicity to normal hematopoiesis.Although thymidine was the chosen inhibitor for de novo synthesis in this study, there may be better compounds to inhibit RNR, specifically hydroxyurea.Could this strategy work in humans?This study offers important insights into how cells generate dCTP and convincingly demonstrates the clinical potential of a dual inhibition strategy for cancer therapy that targets both de novo dCTP synthesis and the salvage pathway.Further work will establish the basic pharmacology (kinetics, bioavailability, and toxicology) of dCK inhibitors and identify which human tumors are most sensitive to this strategy of combined inhibition.