tbuckley/cabot-search huggingface dataset:
The Dual EGFR/HER2 Inhibitor Lapatinib Synergistically Enhances the Antitumor Activity of the Histone Deacetylase Inhibitor Panobinostat in Colorectal Cancer Models
Authors: Melissa J. LaBonte, Peter M. Wilson, Will Fazzone, Jared Russell, Stan G. Louie, Anthony El-Khoueiry, Heinz-Josef Lenz, Robert D. Ladner
Journal: Cancer Research (2011)

As key molecules that drive progression and chemoresistance in gastrointestinal cancers, epidermal growth factor receptor (EGFR) and HER2 have become efficacious drug targets in this setting. Lapatinib is an EGFR/HER2 kinase inhibitor suppressing signaling through the RAS/RAF/MEK (MAP/ERK kinase)/MAPK (mitogen-activated protein kinase) and PI3K (phosphoinositide 3-kinase)/AKT pathways. Histone deacetylase inhibitors (HDACi) are a novel class of agents that induce cell cycle arrest and apoptosis following the acetylation of histone and nonhistone proteins modulating gene expression and disrupting HSP90 function inducing the degradation of EGFR-pathway client proteins. This study sought to evaluate the therapeutic potential of combining lapatinib with the HDACi panobinostat in colorectal cancer (CRC) cell lines with varying EGFR/HER2 expression and KRAS/BRAF/PIK3CA mutations. Lapatinib and panobinostat exerted concentration-dependent antiproliferative effects in vitro (panobinostat range 7.2-30 nmol/L; lapatinib range 7.6-25.8 μmol/L). Combined lapatinib and panobinostat treatment interacted synergistically to inhibit the proliferation and colony formation in all CRC cell lines tested. Combination treatment resulted in rapid induction of apoptosis that coincided with increased DNA double-strand breaks, caspase-8 activation, and PARP cleavage. This was paralleled by decreased signaling through both the PI3K and MAPK pathways and increased downregulation of transcriptional targets including NF-κB1, IRAK1, and CCND1. Panobinostat treatment induced downregulation of EGFR, HER2, and HER3 mRNA and protein through transcriptional and posttranslational mechanisms. In the LoVo KRAS mutant CRC xenograft model, the combination showed greater antitumor activity than either agent alone, with no apparent increase in toxicity. Our results offer preclinical rationale warranting further clinical investigation combining HDACi with EGFR and HER2-targeted therapies for CRC treatment.
Endothelial cell–restricted disruption of FoxM1 impairs endothelial repair following LPS-induced vascular injury
Authors: You-Yang Zhao, Xiao-Pei Gao, Yidan D. Zhao, Muhammad K. Mirza, Randall S. Frey, Vladimir V. Kalinichenko, I-Ching Wang, Robert H. Costa, Asrar B. Malik
Journal: Journal of Clinical Investigation (2006)

Recovery of endothelial integrity after vascular injury is vital for endothelial barrier function and vascular homeostasis. However, little is known about the molecular mechanisms of endothelial barrier repair following injury. To investigate the functional role of forkhead box M1 (FoxM1) in the mechanism of endothelial repair, we generated endothelial cell–restricted FoxM1-deficient mice (FoxM1 CKO mice). These mutant mice were viable and exhibited no overt phenotype. However, in response to the inflammatory mediator LPS, FoxM1 CKO mice displayed significantly protracted increase in lung vascular permeability and markedly increased mortality. Following LPS-induced vascular injury, FoxM1 CKO lungs demonstrated impaired cell proliferation in association with sustained expression of p27Kip1 and decreased expression of cyclin B1 and Cdc25C. Endothelial cells isolated from FoxM1 CKO lungs failed to proliferate, and siRNA-mediated suppression of FoxM1 expression in human endothelial cells resulted in defective cell cycle progression. Deletion of FoxM1 in endothelial cells induced decreased expression of cyclins, Cdc2, and Cdc25C, increased p27Kip1 expression, and decreased Cdk activities. Thus, FoxM1 plays a critical role in the mechanism of the restoration of endothelial barrier function following vascular injury. These data suggest that impairment in FoxM1 activation may be an important determinant of the persistent vascular barrier leakiness and edema formation associated with inflammatory diseases.
Elevated coagulation and inflammatory markers in adolescents with a history of premature adrenarche
Authors: Sarantis Livadas, Maria Dracopoulou, Karmen Vasileiadi, Christina Lazaropoulou, Maria-Alexandra Magiakou, Paraskevi Xekouki, Antonis Voutetakis, Christina Kanaka-Gantenbein, Ioannis Papassotiriou, Christodoulos Stefanadis, George P. Chrousos, Catherine Dacou-Voutetakis
Journal: Metabolism (2009)
Ca <sup>2+</sup> -Dependent Rapid Ca <sup>2+</sup> Sensitization of Contraction in Arterial Smooth Muscle
Authors: George J. Dimopoulos, Shingo Semba, Kazuyo Kitazawa, Masumi Eto, Toshio Kitazawa
Journal: Circulation Research (2006)

Ca(2+) ion is a universal intracellular messenger that regulates numerous biological functions. In smooth muscle, Ca(2+) with calmodulin activates myosin light chain (MLC) kinase to initiate a rapid MLC phosphorylation and contraction. To test the hypothesis that regulation of MLC phosphatase is involved in the rapid development of MLC phosphorylation and contraction during Ca(2+) transient, we compared Ca(2+) signal, MLC phosphorylation, and 2 modes of inhibition of MLC phosphatase, phosphorylation of CPI-17 Thr38 and MYPT1 Thr853, during alpha(1) agonist-induced contraction with/without various inhibitors in intact rabbit femoral artery. Phenylephrine rapidly induced CPI-17 phosphorylation from a negligible amount to a peak value of 0.38+/-0.04 mol of Pi/mol within 7 seconds following stimulation, similar to the rapid time course of Ca(2+) rise and MLC phosphorylation. This rapid CPI-17 phosphorylation was dramatically inhibited by either blocking Ca(2+) release from the sarcoplasmic reticulum or by pretreatment with protein kinase C inhibitors, suggesting an involvement of Ca(2+)-dependent protein kinase C. This was followed by a slow Ca(2+)-independent and Rho-kinase/protein kinase C-dependent phosphorylation of CPI-17. In contrast, MYPT1 phosphorylation had only a slow component that increased from 0.29+/-0.09 at rest to the peak of 0.68+/-0.14 mol of Pi/mol at 1 minute, similar to the time course of contraction. Thus, there are 2 components of the Ca(2+) sensitization through inhibition of MLC phosphatase. Our results support the hypothesis that the initial rapid Ca(2+) rise induces a rapid inhibition of MLC phosphatase coincident with the Ca(2+)-induced MLC kinase activation to synergistically initiate a rapid MLC phosphorylation and contraction in arteries with abundant CPI-17 content.
Neutrophil preservation: the effect of short-term storage on in vivo kinetics.
Authors: T H Price, D C Dale
Journal: Journal of Clinical Investigation (1977)

A rabbit model was developed to study the in vivo viability of neutrophils stored in vitro for up to 72 h. Acid-citrate-dextrose anticoagulated whole blood was obtained from rabbits previously injected with tritiated thymidine ([3H]thymidine), stored under varying conditions, and then injected into recipient rabbits. Neutrophil viability and function were assessed by measuring the ability of the tagged neutrophils to circulate and to migrate into subcutaneous polyvinyl sponges. Unstored neutrophils disappeared exponentially from the circulation with a t1/2 of 3.2 h and gave a zero time recovery of 30.5%. Storage of cells at either room temperature or 4 degrees C for 24 h or longer resulted in temporary sequestration of cells from active circulation. With cells stored for up to 72 h at 4 degrees C, recovery returned to normal values after 1-2 h. Room temperature stored cells, in contrast, showed evidence of irreversible damage at 48-h storage with low recovery for the entire time span studied. With unstored blood, 8.1+/-0.9% of the injected neutrophil label was present in the subcutaneous sponges. The accumulated label progressively decreased as cell storage time increased reaching at 72 h 5.1+/-0.6 and 2.6+/-0.3% for 4 degrees C and room temperature-stored cells, respectively. The results of this study indicate that 4 degrees C storage of rabbit neutrophils is superior to storage at room temperature. The data suggest that it may be feasible to store neutrophils at least a few days without loss of in vivo functions.
Characteristics of Patients With Nonalcoholic Steatohepatitis Who Develop Hepatocellular Carcinoma
Authors: Kohichiroh Yasui, Etsuko Hashimoto, Yasuji Komorizono, Kazuhiko Koike, Shigeki Arii, Yasuharu Imai, Toshihide Shima, Yoshihiro Kanbara, Toshiji Saibara, Takahiro Mori, Sumio Kawata, Hirofumi Uto, Shiro Takami, Yoshio Sumida, Toshinari Takamura, Miwa Kawanaka, Takeshi Okanoue
Journal: Clinical Gastroenterology and Hepatology (2011)

Nonalcoholic steatohepatitis (NASH) can progress to hepatocellular carcinoma (HCC). We aimed to characterize the clinical features of NASH patients with HCC.In a cross-sectional multicenter study in Japan, we examined 87 patients (median age, 72 years; 62% male) with histologically proven NASH who developed HCC. The clinical data were collected at the time HCC was diagnosed.Obesity (body mass index ≥25 kg/m(2)), diabetes, dyslipidemia, and hypertension were present in 54 (62%), 51 (59%), 24 (28%), and 47 (55%) patients, respectively. In nontumor liver tissues, the degree of fibrosis was stage 1 in 10 patients (11%), stage 2 in 15 (17%), stage 3 in 18 (21%), and stage 4 (ie, liver cirrhosis) in 44 (51%). The prevalence of cirrhosis was significantly lower among male patients (21 of 54, 39%) compared with female patients (23 of 33, 70%) (P = .008).Most patients with NASH who develop HCC are men; the patients have high rates of obesity, diabetes, and hypertension. Male patients appear to develop HCC at a less advanced stage of liver fibrosis than female patients.
Coronary arteritis complicating rheumatoid arthritis.
Authors: G A van Albada-Kuipers, J A Bruijn, M L Westedt, F C Breedveld, F Eulderink
Journal: Annals of the Rheumatic Diseases (1986)

The case is described of a patient with rheumatoid arthritis (RA) who developed heart failure and vasculitis and died of a myocardial infarction. Autopsy showed vasculitis of several major epicardial coronary arteries. Coronary arteritis in a patient with RA is seldom diagnosed during their lifetime but should be suspected when such a patient develops ischaemic heart disease.
Speech and language delays in preschool children
Authors: J. Boyle
Journal: BMJ (2011)

Parents need information about the range of development, so they can spot early problems’

Speech and language delays affect 6-7% of children at school entry and can result in problems in one or more areas, such as understanding vocabulary and grammar, inferring meaning, expressive language, sound production, voice, fluency and articulation, and the use of language in social contexts.1 For some children, language problems are markers for—and secondary to—conditions such as autism, sensory impairment, or more general developmental disabilities. For others, they are the result of primary delay that cannot be accounted for by low non-verbal ability, hearing impairment, behaviour problems, emotional problems, or neurological impairments. Environmental factors such as limited opportunities for learning language or learning English as an additional language may also overlap with primary and secondary delay. In the linked cluster randomised trial (doi:10.1136/bmj.d4741), Wake and colleagues assess the effects of a low intensity parent-toddler language promotion programme delivered to toddlers identified as slow to talk on screening in universal services.2 

Language delay that persists until school entry can have adverse effects on literacy, behaviour, social development, and mental health into adulthood, with receptive language and secondary delay particular risk factors.3 4 5 6 But the case …
Pharmacogenetics of methotrexate: toxicity among marrow transplantation patients varies with the methylenetetrahydrofolate reductase C677T polymorphism
Authors: Cornelia M. Ulrich, Yutaka Yasui, Rainer Storb, Mark M. Schubert, John L. Wagner, Jeannette Bigler, Kiley S. Ariail, Cassie L. Keener, Sue Li, Hao Liu, Federico M. Farin, John D. Potter
Journal: Blood (2001)
Final Trial Report of Sentinel-Node Biopsy versus Nodal Observation in Melanoma
Authors: Donald L. Morton, John F. Thompson, Alistair J. Cochran, Nicola Mozzillo, Omgo E. Nieweg, Daniel F. Roses, Harold J. Hoekstra, Constantine P. Karakousis, Christopher A. Puleo, Brendon J. Coventry, Mohammed Kashani-Sabet, B. Mark Smithers, Eberhard Paul, William G. Kraybill, J. Gregory McKinnon, He-Jing Wang, Robert Elashoff, Mark B. Faries
Journal: New England Journal of Medicine (2014)

Sentinel-node biopsy, a minimally invasive procedure for regional melanoma staging, was evaluated in a phase 3 trial.
Malignant peritoneal mesothelioma: a multicenter study on 81 cases
Authors: V. de Pangher Manzini, L. Recchia, M. Cafferata, C. Porta, S. Siena, L. Giannetta, F. Morelli, F. Oniga, A. Bearz, V. Torri, M. Cinquini
Journal: Annals of Oncology (2009)
Renal Phenotype of UT-A Urea Transporter Knockout Mice
Authors: Robert A. Fenton, Anneliese Flynn, Adetola Shodeinde, Craig P. Smith, Jurgen Schnermann, Mark A. Knepper
Journal: Journal of the American Society of Nephrology (2005)

The urea transporters UT-A1 and UT-A3 mediate rapid transepithelial urea transport across the inner medullary collecting duct (IMCD). In a previous study, using a new mouse model in which both UT-A1 and UT-A3 were genetically deleted from the IMCD (UT-A1/3(-/-) mice), we investigated the role of these transporters in the function of the renal inner medulla. Here the authors report a new series of studies investigating more generally the renal phenotype of UT-A1/3(-/-) mice. Pathologic screening of 33 tissues revealed abnormalities in both the testis (increased size) and kidney (decreased size and vascular congestion) of UT-A1/3(-/-) mice. Total urinary nitrate and nitrite (NOx) excretion rates in UT-A1/3(-/-) mice were more than double those in wild-type mice. Total renal blood flow was not different between UT-A1/3(-/-) and wild-type mice but underwent a greater percentage decrease in response to NG-Nitro-L-arginine methyl ester hydrochloride (L-NAME) infusion. Whole kidney GFR (FITC-inulin clearance) was not different in UT-A1/3(-/-) mice compared with controls and underwent a similar increase in response to a greater dietary protein intake. Fractional urea excretion was markedly elevated in UT-A1/3(-/-) mice on a 40% protein diet, reaching 102.4 +/- 8.8% of the filtered load, suggesting that there may be active urea secretion somewhere along the renal tubule. Although there was a marked urinary concentrating defect in UT-A1/3(-/-) mice, there was no decrease in aquaporin 2 or aquaporin 3 expression. Furthermore, although urea accumulation in the inner medulla was markedly attenuated, there was no decrease in sodium ion concentration in tissue from outer medulla or two levels of the inner medulla. These results support our conclusion that the urinary concentrating defect in UT-A1/3(-/-) mice is caused by a failure of urea transport from the IMCD lumen to the inner medullary interstitium, resulting in osmotic diuresis.
The complete genome, comparative and functional analysis of Stenotrophomonas maltophilia reveals an organism heavily shielded by drug resistance determinants
Authors: Lisa C Crossman, Virginia C Gould, J Maxwell Dow, Georgios S Vernikos, Aki Okazaki, Mohammed Sebaihia, David Saunders, Claire Arrowsmith, Tim Carver, Nicholas Peters, Ellen Adlem, Arnaud Kerhornou, Angela Lord, Lee Murphy, Katharine Seeger, Robert Squares, Simon Rutter, Michael A Quail, Mari-Adele Rajandream, David Harris, Carol Churcher, Stephen D Bentley, Julian Parkhill, Nicholas R Thomson, Matthew B Avison
Journal: Genome biology (2008)

Abstract Background Stenotrophomonas maltophilia is a nosocomial opportunistic pathogen of the Xanthomonadaceae. The organism has been isolated from both clinical and soil environments in addition to the sputum of cystic fibrosis patients and the immunocompromised. Whilst relatively distant phylogenetically, the closest sequenced relatives of S. maltophilia are the plant pathogenic xanthomonads. Results The genome of the bacteremia-associated isolate S. maltophilia K279a is 4,851,126 bp and of high G+C content. The sequence reveals an organism with a remarkable capacity for drug and heavy metal resistance. In addition to a number of genes conferring resistance to antimicrobial drugs of different classes via alternative mechanisms, nine resistance-nodulation-division (RND)-type putative antimicrobial efflux systems are present. Functional genomic analysis confirms a role in drug resistance for several of the novel RND efflux pumps. S. maltophilia possesses potentially mobile regions of DNA and encodes a number of pili and fimbriae likely to be involved in adhesion and biofilm formation that may also contribute to increased antimicrobial drug resistance. Conclusion The panoply of antimicrobial drug resistance genes and mobile genetic elements found suggests that the organism can act as a reservoir of antimicrobial drug resistance determinants in a clinical environment, which is an issue of considerable concern.
Exhaled NO may predict the decline in lung function in bronchiolitis obliterans syndrome
Authors: O. Brugiere
Journal: European Respiratory Journal (2005)

Bronchiolitis obliterans syndrome (BOS) remains the leading cause of morbidity/mortality following lung transplantation. In recipients with BOS, markers predicting the decline in lung function are needed. The aim of this longitudinal study was to determine whether exhaled nitric oxide fraction (<i>F</i><sub>eNO</sub>) measurements provide useful information for discriminating patients with unstable BOS from those with stable BOS. During a 14-month period, 145 <i>F</i><sub>eNO</sub> measurements were performed in 50 lung transplant recipients. Among them, 16 recipients with BOS (32 <i>F</i><sub>eNO</sub> measurements) were analysed. For each <i>F</i><sub>eNO</sub> measurement, the patients were classified into three groups according to the decline in forced expiratory volume in one second (FEV<sub>1</sub>) within the following 6 months: 1) stable BOS free; 2) stable BOS (decline in FEV<sub>1</sub> of &lt;5%); and 3) unstable BOS (decline in FEV<sub>1</sub> of ≥15%). The mean <i>F</i><sub>eNO</sub> in patients with unstable BOS was significantly increased compared with that in stable BOS-free patients (18.4±5.7 <i>versus</i> 9.7±3.7 ppb) and that in patients with stable BOS (18.4±5.7 <i>versus</i> 9.7±3.3 ppb). The present findings suggest that, in patients with bronchiolitis obliterans syndrome, a raised exhaled nitric oxide fraction may predict the development of worrisome functional impairment during long-term follow-up.
Decreased expression of Fas (APO‐1/CD95) on peripheral blood CD4+ T lymphocytes in cutaneous T‐cell lymphomas
Authors: O. Dereure, P. Portales, J. Clot, J‐J. Guilhou
Journal: British Journal of Dermatology (2000)

The usually protracted and indolent course of cutaneous T-cell lymphoma (CTCL) is consistent with an accumulation of lymphocytes rather than being a true proliferative disorder, perhaps as the result of defective lymphocyte apoptosis. Fas (CD95) is the main signalling membrane molecule involved in postactivation T-lymphocyte apoptosis.To evaluate expression of Fas on circulating CD4+ lymphocytes in patients with CTCL.Fas expression on peripheral blood CD4+ T cells in 16 patients with mycosis fungoides (patch and infiltrated plaque stages) and in four patients with Sézary syndrome was compared with that in 25 matched patients with lymphocyte-mediated cutaneous benign inflammatory disorders and in 15 subjects without inflammatory cutaneous diseases.Fas expression on peripheral CD4+ lymphocytes was significantly lower in patients with CTCL compared with subjects with benign inflammatory cutaneous disorders and with healthy donors.This pattern supports the hypothesis that a defect in T-cell apoptosis may play a part in the pathophysiology of CTCL, perhaps through abnormalities of the Fas/Fas ligand system. Alternatively, this decrease could be the result of the presence of the soluble Fas ligand molecule in the sera of patients with CTCL.
Coadministration of Ritonavir Strongly Enhances the Apparent Oral Bioavailability of Docetaxel in Patients with Solid Tumors
Authors: Roos L. Oostendorp, Alwin Huitema, Hilde Rosing, Robert S. Jansen, Rob ter Heine, Marianne Keessen, Jos H. Beijnen, Jan H.M. Schellens
Journal: Clinical Cancer Research (2009)

Abstract Purpose: To enhance the systemic exposure to oral docetaxel by coadministration of ritonavir, an efficacious inhibitor of CYP 3A4 with minor P-glycoprotein inhibiting effects, in patients with cancer. Experimental Design: A proof-of-concept study was carried out in 12 patients with solid tumors. The first cohort of patients (n = 4) received 10 mg and the subsequent cohort (n = 8) 100 mg of oral docetaxel, coadministered with 100 mg oral ritonavir randomized simultaneously or ritonavir given 60 minutes before docetaxel on days 1 and 8. On day 15 or 22, patients received 100 mg i.v. docetaxel. Results: The area under the plasma concentration-time curve in patients who received 10 mg oral docetaxel in combination with ritonavir was low, and the dose could safely be increased to 100 mg. The area under the plasma concentration-time curve in patients who received 100 mg oral docetaxel combined with ritonavir simultaneously or ritonavir given 60 minutes before docetaxel was 2.4 ± 1.5 and 2.8 ± 1.4 mg/h/L, respectively, compared with 1.9 ± 0.4 mg/h/L after i.v. docetaxel. The apparent oral bioavailability of docetaxel combined with ritonavir simultaneously or ritonavir given 60 minutes before docetaxel was 131% ± 90% and 161% ± 91%, respectively. The oral combination of docetaxel and ritonavir was well tolerated. Conclusion: Coadministration of ritonavir significantly enhanced the apparent oral bioavailability of docetaxel. These data are promising and form the basis for further development of a clinically applicable oral formulation of docetaxel combined with ritonavir.