tbuckley/cabot-search huggingface dataset:
The mRNA-Destabilizing Protein Tristetraprolin Is Suppressed in Many Cancers, Altering Tumorigenic Phenotypes and Patient Prognosis
Authors: Sarah E. Brennan, Yuki Kuwano, Nadim Alkharouf, Perry J. Blackshear, Myriam Gorospe, Gerald M. Wilson
Journal: Cancer Research (2009)

AU-rich element-binding proteins (ARE-BP) regulate the stability and/or translational efficiency of mRNAs containing cognate binding sites. Many targeted transcripts encode factors that control processes such as cell division, apoptosis, and angiogenesis, suggesting that dysregulated ARE-BP expression could dramatically influence oncogenic phenotypes. Using several approaches, we evaluated the expression of four well-characterized ARE-BPs across a variety of human neoplastic syndromes. AUF1, TIA-1, and HuR mRNAs were not systematically dysregulated in cancers; however, tristetraprolin mRNA levels were significantly decreased across many tumor types, including advanced cancers of the breast and prostate. Restoring tristetraprolin expression in an aggressive tumor cell line suppressed three key tumorgenic phenotypes: cell proliferation, resistance to proapoptotic stimuli, and expression of vascular endothelial growth factor mRNA. However, the cellular consequences of tristetraprolin expression varied across different cell models. Analyses of gene array data sets revealed that suppression of tristetraprolin expression is a negative prognostic indicator in breast cancer, because patients with low tumor tristetraprolin mRNA levels were more likely to present increased pathologic tumor grade, vascular endothelial growth factor expression, and mortality from recurrent disease. Collectively, these data establish that tristetraprolin expression is frequently suppressed in human cancers, which in turn can alter tumorigenic phenotypes that influence patient outcomes.
CCR5 blockade in rheumatoid arthritis: a randomised, double-blind, placebo-controlled clinical trial
Authors: Arno W R van Kuijk, Clarissa E Vergunst, Danielle M Gerlag, Barry Bresnihan, Juan J Gomez-Reino, Regine Rouzier, Patrick C Verschueren, Christiaan van de Leij, Mario Maas, Maarten C Kraan, Paul P Tak
Journal: Annals of the Rheumatic Diseases (2010)

Objective C-C chemokine receptor type 5 (CCR5), a chemokine receptor expressed on T cells and macrophages, and its ligands are found in inflamed synovial tissue (ST) of patients with rheumatoid arthritis (RA). The rationale for testing CCR5 blockade in patients with RA was supported by the effects of a CCR5 antagonist in collagen-induced arthritis in rhesus monkeys. The effects of CCR5 blockade in patients with active RA were explored. Methods In this phase Ib randomised, placebo-controlled trial, treatment with an oral CCR5 inhibitor (SCH351125) in patients with active RA was evaluated. Clinical efficacy was assessed using European League Against Rheumatism and American College of Rheumatology response criteria. ST biopsies were taken before and after 28 days of treatment, and analysed for CCR5+ cells. In a subset of patients, MRIs of an inflamed joint were obtained before and after treatment. Results In all, 32 patients were included; 20 received SCH351125 and 12 placebo. Three patients who received SCH351125 did not complete the study due to adverse events; none of these were serious. No improvement was observed in the active treatment group compared to placebo. Results were consistent for clinical evaluation, ST analysis and MRI. Conclusion This proof of concept study does not support the use of CCR5 blockade as a therapeutic strategy in patients with active RA.
mTORC1 Inhibition Is Required for Sensitivity to PI3K p110α Inhibitors in <i>PIK3CA</i> -Mutant Breast Cancer
Authors: Moshe Elkabets, Sadhna Vora, Dejan Juric, Natasha Morse, Mari Mino-Kenudson, Taru Muranen, Jessica Tao, Ana Bosch Campos, Jordi Rodon, Yasir H. Ibrahim, Violeta Serra, Vanessa Rodrik-Outmezguine, Saswati Hazra, Sharat Singh, Phillip Kim, Cornelia Quadt, Manway Liu, Alan Huang, Neal Rosen, Jeffrey A. Engelman, Maurizio Scaltriti, José Baselga
Journal: Science Translational Medicine (2013)

Persistent mTORC1 signaling correlates with resistance to PI3K p110α inhibition in breast cancer, which can be overcome by inhibiting mTORC1.
<b><i>Ran</i></b>, a Small GTPase Gene, Encodes Cytotoxic T Lymphocyte (CTL) Epitopes Capable of Inducing HLA-A33–restricted and Tumor-Reactive CTLs in Cancer Patients
Authors: Koichi Azuma, Tetsuro Sasada, Hiroko Takedatsu, Hiroki Shomura, Makoto Koga, Yoshiaki Maeda, Akihisa Yao, Tatsuya Hirai, Arimichi Takabayashi, Shigeki Shichijo, Kyogo Itoh
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The purpose is to identify a gene coding for tumor-associated antigen and peptide capable of inducing CTLs reactive to tumor cells with a HLA-A33–restricted fashion to provide scientific basis for specific immunotherapy to HLA-A33+ cancer patients. Experimental Design: An expression gene-cloning method was used to identify the tumor-associated antigen gene. Northern blot analysis and immunohistochemistry were used to examine the mRNA and protein expression levels in various cells and tissues, respectively. Synthetic peptides were examined for their ability to induce HLA-A33+ tumor-reactive CTLs in peripheral blood mononuclear cells from cancer patients. Result: A gene of small GTPase, Ran, which controls the cell cycle through the regulation of nucleocytoplasmic transport, mitotic spindle organization, and nuclear envelope formation, was found to encode epitopes recognized by the HLA-A33–restricted CTLs established from T cells infiltrating into gastric adenocarcinoma. The expression of the Ran gene was increased in most cancer cell lines and cancer tissues at both the mRNA and protein levels. However, it was not enhanced in the surrounding normal cells or tissues. It was also undetectable in normal tissues as far as tested. Ran-derived peptides at positions 48–56 and 87–95 could induce CD8+ peptide-specific CTLs reactive to tumor cells from HLA-A33+ epithelial cancer patients in a HLA class I-restricted manner. Conclusions: Because of its increased expression in cancer cells and involvement in malignant transformation and/or the enhanced proliferation of cancer cells, the two Ran-directed peptides could be potent candidates in use for specific immunotherapy against HLA-A33+ epithelial cancers.
Randomized Study of Basal-Bolus Insulin Therapy in the Inpatient Management of Patients With Type 2 Diabetes (RABBIT 2 Trial)
Authors: Guillermo E. Umpierrez, Dawn Smiley, Ariel Zisman, Luz M. Prieto, Andres Palacio, Miguel Ceron, Alvaro Puig, Roberto Mejia
Journal: Diabetes Care (2007)

We sought to study the optimal management of hyperglycemia in non-intensive care unit patients with type 2 diabetes, as few studies thus far have focused on the subject.We conducted a prospective, multicenter, randomized trial to compare the efficacy and safety of a basal-bolus insulin regimen with that of sliding-scale regular insulin (SSI) in patients with type 2 diabetes. A total of 130 insulin-naive patients were randomized to receive glargine and glulisine (n = 65) or a standard SSI protocol (n = 65). Glargine was given once daily and glulisine before meals at a starting dose of 0.4 units x kg(-1) x day(-1) for blood glucose 140-200 mg/dl or 0.5 units x kg(-1) x day(-1) for blood glucose 201-400 mg/dl. SSI was given four times per day for blood glucose >140 mg/dl.The mean admission blood glucose was 229 +/- 6 mg/dl and A1C 8.8 +/- 2%. A blood glucose target of <140 mg/dl was achieved in 66% of patients in the glargine and glulisine group and in 38% of those in the SSI group. The mean daily blood glucose between groups ranged from 23 to 58 mg/dl, with an overall blood glucose difference of 27 mg/dl (P < 0.01). Despite increasing insulin doses, 14% of patients treated with SSI remained with blood glucose >240 mg/dl. There were no differences in the rate of hypoglycemia or length of hospital stay.Treatment with insulin glargine and glulisine resulted in significant improvement in glycemic control compared with that achieved with the use of SSI alone. Our study indicates that a basal-bolus insulin regimen is preferred over SSI in the management of non-critically ill, hospitalized patients with type 2 diabetes.
Has the brain evolved to answer “binding questions” or to generate likely hypotheses about complex and continuously changing environments?
Authors: Birgitta Dresp, Jean Charles Barthaud
Journal: Behavioral and Brain Sciences (2006)

We question the ecological plausibility as a general model of cognition of van der Velde's &amp; de Kamps's combinatorial blackboard architecture, where knowledge-binding in space and time relies on the structural rules of language. Evidence against their view of the brain and an ecologically plausible, alternative model of cognition are brought forward.
Overexpression of Glut4 protein in muscle increases basal and insulin-stimulated whole body glucose disposal in conscious mice.
Authors: J M Ren, B A Marshall, M M Mueckler, M McCaleb, J M Amatruda, G I Shulman
Journal: Journal of Clinical Investigation (1995)

The effect of increased Glut4 protein expression in muscle and fat on the whole body glucose metabolism has been evaluated by the euglycemic hyperinsulinemic clamp technique in conscious mice. Fed and fasting plasma glucose concentrations were 172 +/- 7 and 78 +/- 7 mg/dl, respectively, in transgenic mice, and were significantly lower than that of nontransgenic littermates (208 +/- 5 mg/dl in fed; 102 +/- 5 mg/dl in fasting state). Plasma lactate concentrations were higher in transgenic mice, (6.5 +/- 0.7 mM in the fed and 5.8 +/- 1.0 mM in fasting state) compared with that of non-transgenic littermates (4.7 +/- 0.3 mM in the fed and 4.2 +/- 0.5 mM in fasting state). In the fed state, the rate of whole body glucose disposal was 70% higher in transgenic mice in the basal state, 81 and 54% higher during submaximal and maximal insulin stimulation. In the fasting state, insulin-stimulated whole body glucose disposal was also higher in the transgenic mice. Hepatic glucose production after an overnight fast was 24.8 +/- 0.7 mg/kg per min in transgenic mice, and 25.4 +/- 2.7 mg/kg per min in nontransgenic mice. Our data demonstrate that overexpression of Glut4 protein in muscle increases basal as well as insulin-stimulated whole body glucose disposal. These results suggest that skeletal muscle glucose transport is rate-limiting for whole body glucose disposal and that the Glut4 protein is a potential target for pharmacological or genetic manipulation for treatment of patients with non-insulin-dependent diabetes mellitus.
Tissue Engineering of Vascularized Cardiac Muscle From Human Embryonic Stem Cells
Authors: Oren Caspi, Ayelet Lesman, Yaara Basevitch, Amira Gepstein, Gil Arbel, Irit Huber Manhal Habib, Lior Gepstein, Shulamit Levenberg
Journal: Circulation Research (2007)

Transplantation of a tissue-engineered heart muscle represents a novel experimental therapeutic paradigm for myocardial diseases. However, this strategy has been hampered by the lack of sources for human cardiomyocytes and by the scarce vasculature in the ischemic area limiting the engraftment and survival of the transplanted muscle. Beyond the necessity of endothelial capillaries for the delivery of oxygen and nutrients to the grafted muscle tissue, interactions between endothelial and cardiomyocyte cells may also play a key role in promoting cell survival and proliferation. In the present study, we describe the formation of synchronously contracting engineered human cardiac tissue derived from human embryonic stem cells containing endothelial vessel networks. The 3D muscle consisted of cardiomyocytes, endothelial cells (ECs), and embryonic fibroblasts (EmFs). The formed vessels were further stabilized by the presence of mural cells originating from the EmFs. The presence of EmFs decreased EC death and increased EC proliferation. Moreover, the presence of endothelial capillaries augmented cardiomyocyte proliferation and did not hamper cardiomyocyte orientation and alignment. Immunostaining, ultrastructural analysis (using transmission electron microscopy), RT-PCR, pharmacological, and confocal laser calcium imaging studies demonstrated the presence of cardiac-specific molecular, ultrastructural, and functional properties of the generated tissue constructs with synchronous activity mediated by action potential propagation through gap junctions. In summary, this is the first report of the construction of 3D vascularized human cardiac tissue that may have unique applications for studies of cardiac development, function, and tissue replacement therapy.
Neurosignals – Incorporating CNS electrophysiology into cognitive process
Authors: James F. Pagel
Journal: Behavioral and Brain Sciences (2005)

This commentary reviews electrophysiological research suggesting that oscillatory electrical potentials recorded by the EEG could have function at cellular and DNA levels. Evidence supporting the potential functional significance of sleep-state-specific frequencies includes psychoactive neurochemical alteration of CNS electrophysiology, and sleep-state-specific alteration of dreaming. As Walker proposes, physiologic electrical fields are likely to have a functional role in the consolidation of memory.
Addition of an oral histamine antagonist to reduce adverse events associated with fumaric acid esters in the treatment of psoriasis: a randomized double-blind placebo-controlled trial
Authors: D.M.W. Balak, S. Fallah-Arani, C.M. Venema, H.A.M. Neumann, H.B. Thio
Journal: British Journal of Dermatology (2014)

Fumaric acid esters (FAEs) are considered an effective and safe long-term treatment for psoriasis. However, 30-40% of patients need to discontinue FAE treatment due to intolerable adverse events.To assess whether the addition of cetirizine, an oral histamine-1 receptor antagonist, to FAEs would reduce the incidence of adverse events.In a randomized, double-blind, placebo-controlled trial, patients with psoriasis with a Psoriasis Area and Severity Index ≥ 10 starting an FAE up to a dose of dimethylfumarate 720 mg per day were randomized 1 : 1 to receive either additional cetirizine 10 mg once daily (n = 25) or placebo (n = 25) for 12 weeks. Randomization and treatment allocation were done at our hospital trial pharmacy. Primary outcomes were the incidence of adverse events and the proportion of patients discontinuing treatment.Fifty patients (33 male, 17 female; median age 44 years) were enrolled. Addition of cetirizine did not reduce the incidence of adverse events compared with placebo (84% vs. 84%, P = 1·00). The types of adverse events were not different between the cetirizine and placebo groups, the most common being gastrointestinal complaints (68% vs. 64%) and flushes (60% vs. 48%). The proportion of patients discontinuing treatment was not statistically different between the cetirizine and placebo groups (24% vs. 32%, P = 0·53).Addition of oral cetirizine 10 mg once daily to FAE treatment did not reduce adverse events in patients with psoriasis during the first 12 weeks of treatment. The mechanisms underlying FAE-induced gastrointestinal and flushing symptoms likely involve mediators other than histamine.
Late Pelvic Toxicity After Bladder-Sparing Therapy in Patients With Invasive Bladder Cancer: RTOG 89-03, 95-06, 97-06, 99-06
Authors: Jason A. Efstathiou, Kyounghwa Bae, William U. Shipley, Donald S. Kaufman, Michael P. Hagan, Niall M. Heney, Howard M. Sandler
Journal: Journal of Clinical Oncology (2009)

In selected patients with muscle-invasive bladder cancer, combined-modality therapy (transurethral resection bladder tumor [TURBT], radiation therapy, chemotherapy) with salvage cystectomy, if necessary, can achieve survival rates similar to radical cystectomy. We investigated late pelvic toxicity after chemoradiotherapy for patients treated on prospective protocols.
Inhibition of Multiple Vascular Endothelial Growth Factor Receptors (VEGFR) Blocks Lymph Node Metastases but Inhibition of VEGFR-2 Is Sufficient to Sensitize Tumor Cells to Platinum-Based Chemotherapeutics
Authors: Patrizia Sini, Ivana Samarzija, Fabienne Baffert, Amanda Littlewood-Evans, Christian Schnell, Andreas Theuer, Sven Christian, Anja Boos, Holger Hess-Stumpp, John A. Foekens, Buddy Setyono-Han, Jeanette Wood, Nancy E. Hynes
Journal: Cancer Research (2008)

Abstract Vascular endothelial growth factor receptors (VEGFR) have important roles in cancer, affecting blood and lymphatic vessel functionality as well as tumor cells themselves. We compared the efficacy of a VEGFR tyrosine kinase inhibitor, PTK787/ZK222584 (PTK/ZK), which targets the three VEGFRs, with blocking antibodies directed against VEGFR-2 (DC101) or VEGF-A (Pab85618) in a metastatic melanoma model. Although all inhibitors exerted comparable effects on primary tumor growth, only PTK/ZK significantly reduced lymph node metastasis formation. A comparable decrease in lymphatic vessel density following blockade of VEGFR-2 (DC101) or the three VEGFRs (PTK/ZK) was observed in the metastases. However, the functionality of lymphatics surrounding the primary tumor was more significantly disrupted by PTK/ZK, indicating the importance of multiple VEGFRs in the metastatic process. The antimetastatic properties of PTK/ZK were confirmed in a breast carcinoma model. B16/BL6 tumor cells express VEGF ligands and their receptors. Blockade of a VEGFR-1 autocrine loop with PTK/ZK inhibited tumor cell migration. Furthermore, the tumor cells also showed enhanced sensitivity to platinum-based chemotherapy in combination with PTK/ZK, indicating that autocrine VEGFRs are promoting tumor cell migration and survival. In summary, our results suggest that, in addition to blocking angiogenesis, combined inhibition of the three VEGFRs may more efficiently target other aspects of tumor pathophysiology, including lymphatic vessel functionality, tumor cell dissemination, survival pathways, and response to chemotherapeutic compounds. [Cancer Res 2008;68(5):1581–92]
FLAVINE AND BRILLIANT GREEN, POWERFUL ANTISEPTICS WITH LOW TOXICITY TO THE TISSUES: THEIR USE IN THE TREATMENT OF INFECTED WOUNDS
Authors: C. H. Browning, R. Gulbransen, E. L. Kennaway, L. H. D. Thornton
Journal: BMJ (1917)

From the Blanci-Suitton Inistituto of Pathology, the Middllcsce HIospital
From Estrogen-Centric to Aging and Oxidative Stress: A Revised Perspective of the Pathogenesis of Osteoporosis
Authors: Stavros C. Manolagas
Journal: Endocrine Reviews (2010)

Estrogen deficiency has been considered the seminal mechanism of osteoporosis in both women and men, but epidemiological evidence in humans and recent mechanistic studies in rodents indicate that aging and the associated increase in reactive oxygen species (ROS) are the proximal culprits. ROS greatly influence the generation and survival of osteoclasts, osteoblasts, and osteocytes. Moreover, oxidative defense by the FoxO transcription factors is indispensable for skeletal homeostasis at any age. Loss of estrogens or androgens decreases defense against oxidative stress in bone, and this accounts for the increased bone resorption associated with the acute loss of these hormones. ROS-activated FoxOs in early mesenchymal progenitors also divert ß-catenin away from Wnt signaling, leading to decreased osteoblastogenesis. This latter mechanism may be implicated in the pathogenesis of type 1 and 2 diabetes and ROS-mediated adverse effects of diabetes on bone formation. Attenuation of Wnt signaling by the activation of peroxisome proliferator-activated receptor γ by ligands generated from lipid oxidation also contributes to the age-dependent decrease in bone formation, suggesting a mechanistic explanation for the link between atherosclerosis and osteoporosis. Additionally, increased glucocorticoid production and sensitivity with advancing age decrease skeletal hydration and thereby increase skeletal fragility by attenuating the volume of the bone vasculature and interstitial fluid. This emerging evidence provides a paradigm shift from the “estrogen-centric” account of the pathogenesis of involutional osteoporosis to one in which age-related mechanisms intrinsic to bone and oxidative stress are protagonists and age-related changes in other organs and tissues, such as ovaries, accentuate them.
Oligo-astheno-teratozoospermia in mice lacking Cnot7, a regulator of retinoid X receptor beta
Authors: Takahisa Nakamura, Ryoji Yao, Takehiko Ogawa, Toru Suzuki, Chizuru Ito, Naoki Tsunekawa, Kimiko Inoue, Rieko Ajima, Takashi Miyasaka, Yutaka Yoshida, Atsuo Ogura, Kiyotaka Toshimori, Toshiaki Noce, Tadashi Yamamoto, Tetsuo Noda
Journal: Nature Genetics (2004)
The Canadian clinician-scientist training program must be reinstated
Authors: David D.W. Twa, Jordan W. Squair, Michael A. Skinnider, Jennifer X. Ji
Journal: Journal of Clinical Investigation (2015)

Clinical investigators within the Canadian and international communities were shocked when the Canadian Institutes of Health Research (CIHR) announced that their funding for the MD/PhD program would be terminated after the 2015-2016 academic year. The program has trained Canadian clinician-scientists for more than two decades. The cancellation of the program is at odds with the CIHR's mandate, which stresses the translation of new knowledge into improved health for Canadians, as well as with a series of internal reports that have recommended expanding the program. Although substantial evidence supports the analogous Medical Scientist Training Program in the United States, no parallel analysis of the MD/PhD program has been performed in Canada. Here, we highlight the long-term consequences of the program's cancellation in the context of increased emphasis on translational research. We argue that alternative funding sources cannot ensure continuous support for students in clinician-scientist training programs and that platform funding of the MD/PhD program is necessary to ensure leadership in translational research.