tbuckley/cabot-search huggingface dataset:
Cancer Stem Cell Hypothesis and Trastuzumab in HER2-Negative Tumors
Authors: R. S. Tuma
Journal: JNCI Journal of the National Cancer Institute (2012)

the researchers did the opposite experiment and used trastuzumab to block HER2 activity in HER2-amplified cell lines, they saw the proportion of ALDH-positive cells dropped. Based on those experiments, the team concluded that trastuzumab’s clinical efficacy is due to its ability to reduce the cancer stem cell population in patients with HER2-positive tumors. Following on that work and the clinical data hinting that women with HER2-negative tumors benefit from adjuvant trastuzumab, Wicha’s group started looking for HER2-expressing cells in breast cancer cell lines and tumors clinically characterized as HER2 negative. By definition, these tumors express little or no HER2 and lack gene amplification. However, in some of those cell lines, the team uncovered a subpopulation of cells that expressed HER2, and many of those HER2-expressing cells also expressed the stem cell marker ALDH. As would have been expected previously, trastuzumab treatment had little effect on the overall cell line population. However, when the team examined the effect of trastuzumab using cancer stem cell criteria, they revealed a different story: The treated cell lines lacked the rare ALDH-expressing cells and the ability to form spheroids
m:Explorer: multinomial regression models reveal positive and negative regulators of longevity in yeast quiescence
Authors: Jüri Reimand, Anu Aun, Jaak Vilo, Juan M Vaquerizas, Juhan Sedman, Nicholas M Luscombe
Journal: Genome biology (2012)

We developed m:Explorer for identifying process-specific transcription factors (TFs) from multiple genome-wide sources, including transcriptome, DNA-binding and chromatin data. m:Explorer robustly outperforms similar techniques in finding cell cycle TFs in Saccharomyces cerevisiae. We predicted and experimentally tested regulators of quiescence (G0), a model of ageing, over a six-week time-course. We validated nine of top-12 predictions as novel G0 TFs, including Δmga2, Δcst6, Δbas1 with higher viability and G0-essential TFs Tup1, Swi3. Pathway analysis associates longevity to reduced growth, reprogrammed metabolism and cell wall remodeling. m:Explorer (http://biit.cs.ut.ee/mexplorer/) is instrumental in interrogating eukaryotic regulatory systems using heterogeneous data.
Sustained virological response prevents the development of insulin resistance in patients with chronic hepatitis C
Authors: Alessio Aghemo, Gian Maria Prati, Maria Grazia Rumi, Roberta Soffredini, Roberta D'Ambrosio, Emanuela Orsi, Stella De Nicola, Elisabetta Degasperi, Valeria Grancini, Massimo Colombo
Journal: Hepatology (2012)

Hepatitis C virus (HCV) infection is associated with insulin resistance (IR), which is a condition known to influence the progression of liver fibrosis and the response to pegylated interferon (PEG-IFN)/ribavirin (RBV) therapy. We aimed to assess whether a sustained virological response (SVR) after antiviral therapy prevents the development of IR in the long term. Members of the Milan Safety Tolerability study cohort, who received PEG-IFNα2a/RBV or PEG-IFNα2b/RBV, underwent a homeostasis model assessment (HOMA) at the baseline and 24 months after treatment completion. For all patients (n = 431), a liver biopsy sample was scored for grading, staging (Ishak), and steatosis. At the baseline, IR (HOMA value > 2) was detected in 48 patients (12%), and it was associated with body weight (P = 0.03), an HCV load < 0.6 × 10(6) IU/L (P = 0.006), fibrosis staging ≥ 4 (P = 0.01), and moderate to severe steatosis (P = 0.03). IR did not influence the rates of end-of-treatment response (75% versus 69%, P = 0.4), SVR (63% versus 60%, P = 0.8), or relapse (19% versus 24%, P = 0.5). After treatment, IR developed in 49 of the 384 nondiabetic patients (14%). Although the mean baseline and posttreatment HOMA values were similar in SVR patients (1.11 ± 0.8 versus 1.18 ± 1.1, P = 0.25), patients experiencing treatment failure showed a significant increase in the mean HOMA value at the follow-up visit (1.20 ± 0.85 versus 1.49 ± 1.3, P = 0.007), and there was an increased rate of de novo IR in non-SVR patients versus SVR patients (17% versus 7%, P = 0.007). According to a logistic regression analysis, treatment failure (odds ratio = 2.81, 95% confidence interval = 1.39-5.67, P = 0.004) and a 10% body mass index increase (odds ratio = 6.42, 95% confidence interval = 1.69-24.3, P = 0.006) were significantly associated with the development of de novo IR.In nondiabetic patients with chronic HCV, the achievement of SVR with PEG-IFN and RBV prevents the development of de novo IR.
Afatinib (A) Plus Paclitaxel (P) Following Progression on a Monotherapy in Patients (PTS) with Metastatic Non–Small-Cell Lung Cancer (NSCLC) Who Previously Benefited From Erlotinib (E)/Gefitinib (G): a Global Randomised Phase Iii Trial–Lux-Lung 5 (LL5)
Authors: M. Schuler, J.C.-H. Yang, K. Park, V.K. Chand, B. Wang, D. Planchard
Journal: Annals of Oncology (2015)
An imbalance in plasma prostanoids in patients with Raynaud′s phenomenon and pulmonary vasospasm
Authors: K Sakamoto, I Houya, K Inoue, M Tanaka, T Suzuki, Y Sakamoto, H Matsuo
Journal: European Respiratory Journal (1999)

Raynaud's phenomenon has been suggested as a predisposing factor for pulmonary vasospasm which may lead to pulmonary hypertension, but the occurrence of cold stimulus-induced pulmonary vasospasm has been inconsistent. Such inconsistent pulmonary vascular responses may be caused by differences in the production of endogenous vasodilators and vasoconstrictors among patients. Fourteen patients with Raynaud's phenomenon associated with mixed connective tissue disease (n=10) or systemic sclerosis (n=4) participated in the study. Right heart catheterization was performed before and after a cold pressor test, immersing a hand in cold water (15 degrees C) for 5 min. Plasma levels of 6-keto prostaglandin (PG)F1alpha, thromboxane (TX)B2 and endothelin (ET)-1 in the mixed venous blood were measured. Mean pulmonary artery pressure increased after the cold pressor test in five of 14 patients, and the patients were divided into those with pulmonary vasospasm (responders) and those without vasospasm (nonresponders). After the cold pressor test, levels of 6-keto PGF1alpha increased significantly in nonresponders (p&lt;0.01) and decreased significantly in responders (p&lt;0.05). The ratios of 6-keto PGF1alpha to TXB2 significantly increased in nonresponders (p&lt;0.01) but not in responders and the difference between responders and nonresponders after the cold pressor test was also statistically significant (p&lt;0.05). No significant change in plasma ET-1 levels occurred in either responders or nonresponders. The results suggest that an impaired production of prostaglandin I2 and an imbalance between prostaglandin I2 and thromboxane A2 are associated with the occurrence of pulmonary vasospasm induced by Raynaud's phenomenon.
Prototypes and portability in artificial neural network models
Authors: Thomas R. Shultz
Journal: Behavioral and Brain Sciences (2000)

The Page target article is interesting because of apparent coverage of many psychological phenomena with simple, unified neural techniques. However, prototype phenomena cannot be covered because the strongest response would be to the first-learned stimulus in each category rather than to a prototype stimulus or most frequently presented stimuli. Alternative methods using distributed coding can also achieve portability of network knowledge.
Tivantinib for second-line treatment of advanced hepatocellular carcinoma: a randomised, placebo-controlled phase 2 study
Authors: Armando Santoro, Lorenza Rimassa, Ivan Borbath, Bruno Daniele, Stefania Salvagni, Jean Luc Van Laethem, Hans Van Vlierberghe, Jörg Trojan, Frank T Kolligs, Alan Weiss, Steven Miles, Antonio Gasbarrini, Monica Lencioni, Luca Cicalese, Morris Sherman, Cesare Gridelli, Peter Buggisch, Guido Gerken, Roland M Schmid, Corrado Boni, Nicola Personeni, Ziad Hassoun, Giovanni Abbadessa, Brian Schwartz, Reinhard Von Roemeling, Maria E Lamar, Yinpu Chen, Camillo Porta
Journal: The Lancet Oncology (2012)
Effects of the oral converting enzyme inhibitor, SQ 14225, in a model of low cardiac output in dogs.
Authors: R H Freeman, J O Davis, G M Williams, J M DeForrest, A A Seymour, B P Rowe
Journal: Circulation Research (1979)

Dogs with thoracic caval constriction retain sodium and develop ascites and edema. The role of the renin-angiotensin-aldosterone system in this model of low output failure was evaluated before, during, and after administration of the new orally active converting enzyme inhibitor, 2-D-methyl-3-mercaptopropanoyl-L-proline (SQ 14225). The acute response to the initial oral dose of SQ 14225 (10 mg/kg) consisted of a striking fall in plasma aldosterone concentration (PAC) from 22.7 and 29.9 ng% to 10.7, 11.9, and 11.0 ng% (P less than 0.05) after 67.5, 112.5, and 157.5 minutes; sodium excretion increased from 1.9 and 1.9 mu Eq/min to 19.9, 22.4, and 17.8 mu Eq/min. Arterial pressure and filtration fraction decreased (P less than 0.05), and plasma renin activity (PRA) increased (P less than 0.05) after the initial dose of SQ 14225; clearance of paraaminohippuric acid (PAH) and creatinine did not change significantly. The daily responses for 3-4 days to SQ 14225 (35 mg/kg per day, given as doses of 10, 10, and 15 mg/kg) were a decrease in PAC from 50 +/- 15 and 32 +/- 10 ng% to 10 +/- 4 ng% on the 4th day, a value not statistically different from normal (P greater than 0.05), and an increase in sodium excretion from 2.9 to 2.0 mEq/day to 5.7, 10.0, 32.4, and 32.9 mEq/day on a sodium intake of 35 mEq/day (P less than 0.05 for the last 2 days). Arterial pressure and creatinine clearance decreased (P less than 0.05). PRA increased transiently on day 1 of SQ 14225 and then returned toward control levels, and clearance of PAH was unchanged. These data demonstrate an important role for aldosterone and the renin-angiotensin system in the retention of sodium and in ascites formation in dogs with thoracic caval constriction.
Epigenetic and Chromatin Modifiers As Targeted Therapy of Hematologic Malignancies
Authors: Kapil N. Bhalla
Journal: Journal of Clinical Oncology (2005)

Epigenetic regulation of gene expression is mediated through alterations in the DNA methylation status, covalent modifications of core nucleosomal histones, rearrangement of histones, and by RNA interference. It is now abundantly clear that deregulation of epigenetic mechanisms cooperates with genetic alterations in the development and progression of cancer and leukemia. Epigenetic deregulation affects several aspects of tumor cell biology, including cell growth, cell cycle control, differentiation, DNA repair, and cell death. This raises the strong possibility that reversing deregulated epigenetic mechanisms may be an effective treatment strategy for leukemia and cancer. This treatment strategy may either be designed to separately or collectively target the specific perturbations in the epigenetic mechanisms found in human hematologic malignancies. The following review describes our current understanding of the important deregulated epigenetic mechanisms and the preclinical and clinical development of epigenetic and chromatin modifiers in the therapy of these disorders.
Achilles tendon rupture.
Authors: N Maffulli
Journal: British Journal of Sports Medicine (1995)

The Achilles tendon (AT) is the largest tendon in the human body, but it is also the one that frequently undergoes a complete subcutaneous tear. Men are more frequently affected than women, in particular between 30–40 years old. An AT tear is usually the end result of an asymptomatic process of failed heling typical of tendinopathy. The diagnosis of acute tear of the AT is clinical, based on careful history taking and detailed clinical examination. Operative management of acute AT ruptures provides lower re-rupture rate, early functional treatment, less calf atrophy, and better functional results, in particular in athletes. Minimally invasive Achilles tendon repair provides many advantages and should be considered in young and active patients. Simple parameters as single-legged concentric strengthening, range of motion, and calf circumference can be used to predict the ability to return to activity. On the basis of current evidence-based studies, the routine use of PRP to improve tendon AT healing is not recommended.
Next year's pay rises for doctors should be 2% or less, government says
Authors: Adrian O'Dowd
Journal: BMJ (2005)

Next year's pay rises for doctors should be 2% or less 116, 218Pay rises for doctors and other healthcare staff in Britain should not be above 2% next year, the government said last week.The chancellor of the exchequer, Gordon Brown, used his pre-budget report to urge restraint on pay increases so that inflation stays around 2%.Mr Brown said that the health secretary, Patricia Hewitt, would be asking for a 2% rise in her evidence to the various pay review bodies for NHS staff.Ms Hewitt is due to give oral evidence to the Review Body on Doctors' and Dentists' Remuneration next week in line with Mr Brown's wishes.Mr Brown, in his pre-budget report this week, described the current year as "the toughest and most challenging year for the economy" but was confident that inflation was on course to meet its 2% target this year, next year, and the year after that.The BMA, however, is seeking a 4.5% increase in doctors' pay for next year.
Intracoronary β-Irradiation With a Rhenium-188–Filled Balloon Catheter
Authors: Martin Höher, Jochen Wöhrle, Markus Wohlfrom, Joachim Kamenz, Thorsten Nusser, Olaf C. Grebe, Hartmut Hanke, Matthias Kochs, Sven N. Reske, Vinzenz Hombach, Jörg Kotzerke
Journal: Circulation (2003)

Restenosis requiring reintervention is the main limitation of coronary angioplasty. Intracoronary irradiation reduces neointimal proliferation. We studied the efficacy of a self-centering liquid rhenium-188-filled balloon catheter for coronary beta-brachytherapy.After successful coronary angioplasty with or without stenting, 225 patients (71% de novo lesions) were randomly assigned to receive 22.5 Gy intravascular beta-irradiation in 0.5-mm tissue depth (n=113) or to receive no additional intervention (n=112). Clinical and procedural data did not differ between the groups except a higher rate of stenting in the control group (63%) compared with the rhenium-188 group (45%, P<0.02). After 6 months of follow-up, late loss was significantly lower in the irradiated group compared with the control group, both of the target lesion (0.11+/-0.54 versus 0.69+/-0.81 mm, P<0.0001) and of the total segment (0.22+/-0.67 versus 0.70+/-0.82 mm, P<0.0001). This was also evident in the subgroup of patients with de novo lesions and independent from stenting. Binary restenosis rates were significantly lower at the target lesion (6.3% versus 27.5%, P<0.0001) and of the total segment (12.6% versus 28.6%, P<0.007) after rhenium-188 brachytherapy compared with the control group. Target vessel revascularization rate was significantly lower in the rhenium-188 (6.3%) compared with the control group (19.8%, P=0.006).Intracoronary beta-brachytherapy with a rhenium-188 liquid-filled balloon is safe and efficiently reduces restenosis and revascularization rates after coronary angioplasty.
Enhanced Capillary Formation Stimulated by a Chimeric Vascular Endothelial Growth Factor/Vascular Endothelial Growth Factor-C Silk Domain Fusion Protein
Authors: Salla Keskitalo, Tuomas Tammela, Johannes Lyytikka, Terhi Karpanen, Michael Jeltsch, Johanna Markkanen, Seppo Yla-Herttuala, Kari Alitalo
Journal: Circulation Research (2007)

Vascular endothelial growth factor (VEGF)-C and VEGF-D require proteolytic cleavage of the carboxy terminal silk-homology domain for activation. To study the functions of the VEGF-C propeptides, we engineered a chimeric growth factor protein, VEGF-CAC, composed of the amino- and carboxy-terminal propeptides of VEGF-C fused to the receptor-activating core domain of VEGF. Like VEGF-C, VEGF-CAC underwent proteolytic cleavage, and like VEGF, it bound to and activated VEGF receptor-1 and VEGF receptor-2, but not the VEGF-C receptor VEGF receptor-3. VEGF-CAC also bound to neuropilins in a heparin-dependent manner. Strikingly, when VEGF-CAC was expressed via an adenovirus vector in the ear skin of immunodeficient mice, it proved to be a more potent inducer of capillary angiogenesis than VEGF. The VEGF-CAC–induced vessels differed greatly from those induced by VEGF, as they formed a very dense and fine network of pericyte and basement membrane–covered capillaries that were functional, as shown by lectin perfusion experiments. VEGF-CAC could prove useful in proangiogenic therapies in patients experiencing tissue ischemia.
The TCCTG Haplotype (-613C>T, -549T>C, -441C>T, -197T>C and -95G>T) of PTGDR Gene is Associated with Allergic Sensitization
Authors: I.J. Davila, C. Sanz, M. Isidoro-Garcia, V. Garcia-Solaesa, D. Benito-Pescador, L. Hernandez-Hernandez, E. Moreno, F.J. Muñoz-Bellido, E. Laffond, F. Lorente
Journal: Journal of Allergy and Clinical Immunology (2011)
Constitutive Activation of the Src Family Kinase Hck Results in Spontaneous Pulmonary Inflammation and an Enhanced Innate Immune Response
Authors: Matthias Ernst, Melissa Inglese, Glen M. Scholz, Kenneth W. Harder, Fiona J. Clay, Steven Bozinovski, Paul Waring, Rima Darwiche, Tom Kay, Peter Sly, Rachel Collins, Debra Turner, Margaret L. Hibbs, Gary P. Anderson, Ashley R. Dunn
Journal: The Journal of Experimental Medicine (2002)

To identify the physiological role of Hck, a functionally redundant member of the Src family of tyrosine kinases expressed in myelomonocytic cells, we generated Hck(F/F) "knock-in" mice which carry a targeted tyrosine (Y) to phenylalanine (F) substitution of the COOH-terminal, negative regulatory Y(499)-residue in the Hck protein. Unlike their Hck(-/-) "loss-of-function" counterparts, Hck(F/F) "gain-of-function" mice spontaneously acquired a lung pathology characterized by extensive eosinophilic and mononuclear cell infiltration within the lung parenchyma, alveolar airspaces, and around blood vessels, as well as marked epithelial mucus metaplasia in conducting airways. Lungs from Hck(F/F) mice showed areas of mild emphysema and pulmonary fibrosis, which together with inflammation resulted in altered lung function and respiratory distress in aging mice. When challenged transnasally with lipopolysaccharide (LPS), Hck(F/F) mice displayed an exaggerated pulmonary innate immune response, characterized by excessive release of matrix metalloproteinases and tumor necrosis factor (TNF)alpha. Similarly, Hck(F/F) mice were highly sensitive to endotoxemia after systemic administration of LPS, and macrophages and neutrophils derived from Hck(F/F) mice exhibited enhanced effector functions in vitro (e.g., nitric oxide and TNFalpha production, chemotaxis, and degranulation). Based on the demonstrated functional association of Hck with leukocyte integrins, we propose that constitutive activation of Hck may mimic adhesion-dependent priming of leukocytes. Thus, our observations collectively suggest an enhanced innate immune response in Hck(F/F) mice thereby skewing innate immunity from a reversible physiological host defense response to one causing irreversible tissue damage.
Fyn and PTP-PEST–mediated Regulation of Wiskott-Aldrich Syndrome Protein (WASp) Tyrosine Phosphorylation Is Required for Coupling T Cell Antigen Receptor Engagement to WASp Effector Function and T Cell Activation
Authors: Karen Badour, Jinyi Zhang, Fabio Shi, Yan Leng, Michael Collins, Katherine A. Siminovitch
Journal: The Journal of Experimental Medicine (2004)

Involvement of the Wiskott-Aldrich syndrome protein (WASp) in promoting cell activation requires its release from autoinhibitory structural constraints and has been attributed to WASp association with activated cdc42. Here, however, we show that T cell development and T cell receptor (TCR)-induced proliferation and actin polymerization proceed normally in WASp−/− mice expressing a WASp transgene lacking the cdc42 binding domain. By contrast, mutation of tyrosine residue Y291, identified here as the major site of TCR-induced WASp tyrosine phosphorylation, abrogated induction of WASp tyrosine phosphorylation and its effector activities, including nuclear factor of activated T cell transcriptional activity, actin polymerization, and immunological synapse formation. TCR-induced WASp tyrosine phosphorylation was also disrupted in T cells lacking Fyn, a kinase shown here to bind, colocalize with, and phosphorylate WASp. By contrast, WASp was tyrosine dephosphorylated by protein tyrosine phosphatase (PTP)-PEST, a tyrosine phosphatase shown here to interact with WASp via proline, serine, threonine phosphatase interacting protein (PSTPIP)1 binding. Although Fyn enhanced WASp-mediated Arp2/3 activation and was required for synapse formation, PTP-PEST combined with PSTPIP1 inhibited WASp-driven actin polymerization and synapse formation. These observations identify key roles for Fyn and PTP-PEST in regulating WASp and imply that inducible WASp tyrosine phosphorylation can occur independently of cdc42 binding, but unlike the cdc42 interaction, is absolutely required for WASp contributions to T cell activation.
Novel Nonsense Mutation in the Na+/HCO3 - Cotransporter Gene (SLC4A4) in a Patient with Permanent Isolated Proximal Renal Tubular Acidosis and Bilateral Glaucoma
Authors: TAKASHI IGARASHI, JUN INATOMI, TAKASHI SEKINE, GEORGE SEKI, MITSUNOBU SHIMADZU, FUMIKO TOZAWA, YASUHIRO TAKESHIMA, TORU TAKUMI, TOSHIKAZU TAKAHASHI, NORISHIGE YOSHIKAWA, HAJIME NAKAMURA, HITOSHI ENDOU
Journal: Journal of the American Society of Nephrology (2001)

Abstract. Permanent isolated proximal renal tubular acidosis (pRTA) with ocular abnormalities is a systemic disease involving short stature, isolated pRTA, mental retardation, and ocular abnormalities. Kidney Na + /HCO 3 - cotransporter (kNBC1) cDNA from peripheral lymphocytes from a patient with permanent isolated pRTA and bilateral glaucoma was screened, and a novel homozygous mutation, namely a cytosine-to-thymine transition at nucleotide 234, which resulted in the formation of a stop codon at codon 29, was identified. This homozygous mutation, Q29X, was identified in the unique 5′-end of the kNBC1 gene ( SLC4A4 ) of the patient. Cosegregation of this Q29X mutation with the disease and heterozygosity in the parents of the affected patient were observed. The absence of this mutation in 156 alleles from 78 Japanese individuals indicates that this mutation is directly related to the disease and is not a common DNA sequence polymorphism. This nonsense mutation predicts a truncated kNBC1 protein that lacks the 1007 amino acids of the carboxyl-terminus, and the effect on kNBC1 cotransport activity is likely to be a loss of function. In contrast, the pancreatic Na + /HCO 3 - cotransporter of the patient is not likely to be affected by this nonsense mutation. These results have implications for understanding the role of kNBC1 in the pathophysiologic processes of pRTA associated with ocular abnormalities and mental retardation.