tbuckley/cabot-search huggingface dataset:
Immunotherapy advances for glioblastoma
Authors: D. A. Reardon, G. Freeman, C. Wu, E. A. Chiocca, K. W. Wucherpfennig, P. Y. Wen, E. F. Fritsch, W. T. Curry, J. H. Sampson, G. Dranoff
Journal: Neuro-Oncology (2014)

Survival for patients with glioblastoma, the most common high-grade primary CNS tumor, remains poor despite multiple therapeutic interventions including intensifying cytotoxic therapy, targeting dysregulated cell signaling pathways, and blocking angiogenesis. Exciting, durable clinical benefits have recently been demonstrated for a number of other challenging cancers using a variety of immunotherapeutic approaches. Much modern research confirms that the CNS is immunoactive rather than immunoprivileged. Preliminary results of clinical studies demonstrate that varied vaccine strategies have achieved encouraging evidence of clinical benefit for glioblastoma patients, although multiple variables will likely require systematic investigation before optimal outcomes are realized. Initial preclinical studies have also revealed promising results with other immunotherapies including cell-based approaches and immune checkpoint blockade. Clinical studies to evaluate a wide array of immune therapies for malignant glioma patients are being rapidly developed. Important considerations going forward include optimizing response assessment and identifiying correlative biomarkers for predict therapeutic benefit. Finally, the potential of complementary combinatorial immunotherapeutic regimens is highly exciting and warrants expedited investigation.
Synergy between a plasminogen cascade and MMP-9 in autoimmune disease
Authors: Zhi Liu, Ning Li, Luis A. Diaz, Michael Shipley, Robert M. Senior, Zena Werb
Journal: Journal of Clinical Investigation (2005)

Extracellular proteolysis by the plasminogen/plasmin (Plg/plasmin) system and MMPs is required for tissue injury in autoimmune and inflammatory diseases. We demonstrate that a Plg cascade synergizes with MMP-9/gelatinase B in vivo during dermal-epidermal separation in an experimental model of bullous pemphigoid (BP), an autoimmune disease. BP was induced in mice by antibodies to the hemidesmosomal antigen BP180. Mice deficient in MMP-9 were resistant to experimental BP, while mice deficient in Plg and both tissue Plg activator (tPA) and urokinase Plg activator (uPA) showed delayed and less intense blister formation induced by antibodies to BP180. Plg-deficient mice reconstituted locally with Plg or the active form of MMP-9 (actMMP-9), but not the proenzyme form of MMP-9 (proMMP-9), developed BP. In contrast, proMMP-9 or actMMP-9, but not Plg, reconstituted susceptibility of MMP-9–deficient mice to the skin disease. In addition, MMP-3–deficient mice injected with pathogenic IgG developed the same degree of BP and expressed levels of actMMP-9 in the skin similar to those of WT controls. Thus, the Plg/plasmin system is epistatic to MMP-9 activation and subsequent dermal-epidermal separation in BP.
Inhibition of HIF-1alpha activity by homeodomain-interacting protein kinase-2 correlates with sensitization of chemoresistant cells to undergo apoptosis
Authors: Lavinia Nardinocchi, Rosa Puca, Ada Sacchi, Gabriella D'Orazi
Journal: Molecular Cancer (2009)

Abstract Background Homeodomain-interacting protein kinase-2 (HIPK2), a transcriptional co-repressor with apoptotic function, can affect hypoxia-inducible factor 1 (HIF-1) transcriptional activity, through downmodulation of its HIF-1α subunit, in normoxic condition. Under hypoxia, a condition often found in solid tumors, HIF-1α is activated to induce target genes involved in chemoresistance, inhibition of apoptosis and tumor progression. Here, we investigated whether the HIPK2 overexpression could downregulate HIF-1α expression and activity in tumor cells treated with hypoxia-mimicking condition, and evaluated whether HIPK2-dependent downregulation of HIF-1α could sensitize chemoresistant tumor cells to adriamycin (ADR)-induced apoptosis. Methods Tumor cell lines carrying wild-type p53, siRNA p53, or mutant p53 were overexpressed with HIPK2 (full length or catalytic inactive mutant) and treated with cobalt chloride (CoCl 2 ) to mimic hypoxia, in the presence or absence of ADR treatment. HIF-1α expression was measured by semiquantitative reverse-transcriptase (RT)-PCR and Western immunoblotting and HIF-1 activity was evaluated by luciferase assay using reporter plasmid containing hypoxia response elements (HREs) upstream of luciferase gene. HIF-1 target genes, including multidrug resistance 1 (MDR1) and the antiapoptotic Bcl2 were determined by RT-PCR. Cell survival and apoptosis were measured by colony assay and cleavage of the caspase-3 substrate PARP, respectively. Results Overexpression of HIPK2 resulted in downmodulation of cobalt-stabilized HIF-1α protein and HIF-1α mRNA levels, with subsequent inhibition of HIF-1 transcriptional activity. MDR1 and Bcl-2 gene expression was downmodulated by HIPK2 overexpression in cobalt-treated cells. Inhibition of HIF-1 transcriptional activity was dependent on HIPK2 catalytic activity. HIPK2 overexpression did not induce per se apoptosis of cobalt-treated cells, on the contrary it sensitized cobalt-treated cells to ADR-induced apoptosis, regardless of their p53 status. Conclusion The ability of HIPK2 to restore the apoptosis-inducing potential of chemotherapeutic drug in hypoxia-mimicking condition and therefore to sensitize chemoresistant tumor cells suggests that HIPK2 may induce fundamental alterations in cell signaling pathways, involving or not p53 function. Thus potential use of HIPK2 is promising for cancer treatment by potentiating cytotoxic therapies, regardless of p53 cell status.
Wide Dispersion and Diversity of Clonally Related Inhibitory Interneurons
Authors: Corey C. Harwell, Luis C. Fuentealba, Adrian Gonzalez-Cerrillo, Phillip R.L. Parker, Caitlyn C. Gertz, Emanuele Mazzola, Miguel Turrero Garcia, Arturo Alvarez-Buylla, Constance L. Cepko, Arnold R. Kriegstein
Journal: Neuron (2015)
How well does B-type natriuretic peptide predict death and cardiac events in patients with heart failure: systematic review
Authors: Jenny A Doust, Eva Pietrzak, Annette Dobson, Paul Glasziou
Journal: BMJ (2005)

<h3>Abstract</h3> <b>Objective</b> To assess how well B-type natriuretic peptide (BNP) predicts prognosis in patients with heart failure. <b>Design</b> Systematic review of studies assessing BNP for prognosis in patients with heart failure or asymptomatic patients. <b>Data sources</b> Electronic searches of Medline and Embase from January 1994 to March 2004 and reference lists of included studies. <b>Study selection and data extraction</b> We included all studies that estimated the relation between BNP measurement and the risk of death, cardiac death, sudden death, or cardiovascular event in patients with heart failure or asymptomatic patients, including initial values and changes in values in response to treatment. Multivariable models that included both BNP and left ventricular ejection fraction as predictors were used to compare the prognostic value of each variable. Two reviewers independently selected studies and extracted data. <b>Data synthesis</b> 19 studies used BNP to estimate the relative risk of death or cardiovascular events in heart failure patients and five studies in asymptomatic patients. In heart failure patients, each 100 pg/ml increase was associated with a 35% increase in the relative risk of death. BNP was used in 35 multivariable models of prognosis. In nine of the models, it was the only variable to reach significance—that is, other variables contained no prognostic information beyond that of BNP. Even allowing for the scale of the variables, it seems to be a strong indicator of risk. <b>Conclusion</b> Although systematic reviews of prognostic studies have inherent difficulties, including the possibility of publication bias, the results of the studies in this review show that BNP is a strong prognostic indicator for both asymptomatic patients and for patients with heart failure at all stages of disease.
Progesterone Receptor Loss Correlates with Human Epidermal Growth Factor Receptor 2 Overexpression in Estrogen Receptor–Positive Breast Cancer
Authors: Hyun-Jung Kim, Xiaojiang Cui, Susan G. Hilsenbeck, Adrian V. Lee
Journal: Clinical Cancer Research (2006)

Abstract Response to endocrine therapy in breast cancer correlates with estrogen receptor (ER) and progesterone receptor (PR) status. It was originally hypothesized that the ability of PR to predict response to endocrine therapy was due to the fact that PR is an estrogen-regulated gene and that its levels represented a marker of functional ER activity. However, it is now known that loss of PR can occur via multiple mechanisms, many of which do not include ER function, e.g., hypermethylation of the PR promoter and loss of heterozygosity of the PR gene. We have shown that growth factor signaling pathways can directly down-regulate PR levels via the phosphatidylinositol 3′-kinase (PI3K)/Akt/mTOR pathway, and that this can occur independent of ER. For example, overexpression of myr-Akt in MCF-7 cells causes complete loss of PR protein and mRNA but does not reduce ER levels or activity, thus generating ER+/PR− MCF-7 cells. Therefore, the absence of PR may not simply reflect a lack of ER activity but rather may reflect hyperactive cross-talk between ER and growth factor signaling pathways. Consistent with this hypothesis, several recent clinical studies have found that ER+/PR− breast cancers overexpress human epidermal growth factor receptor (HER) 1 and HER2 compared with ER+/PR+ breast cancers. Although HER receptors can lower ER levels, one study showed that loss of PR correlated with high HER2 levels in a multivariate analysis. Furthermore, loss of PTEN, a negative regulator of the PI3K/Akt signaling pathway, has been shown to be associated with specific loss of PR and no change in ER levels. Given the well-recognized resistance of ER+/PR− breast cancer to antiestrogens, more studies are needed to better understand the etiology of ER+/PR− breast cancer, particularly the analysis of other growth factor receptors and their downstream signaling intermediates with respect to PR status.
SOME IMPLICATIONS OF CONDITIONAL REFLEX STUDIES FOR PLACEBO RESEARCH
Authors: LESTER H. GLIEDMAN, W. HORSLEY GANTT, HARRY A. TEITELBAUM
Journal: American Journal of Psychiatry (1957)

Three separate groups of conditional reflex studies were presented to illustrate their implication for the general problem of reaction to placebo. The first demonstrates how the effect of a person can be conditioned and thereby makes it possible for the expectations of patients from a therapeutic situation to be realized. The second emphasizes the importance of "central excitatory states" for conditioning and suggests that the ability of doctors to produce these may make patients amenable to their doctors' expectations of them. The third describes the pertinence of the state of the organism and the principles of extinction to patient responses to placebo. It is suggested that placebo effects may be more explicable when considered in terms of learning concepts.
Histological appearances of oesophagus, antrum and duodenum and their correlation with symptoms in patients with a duodenal ulcer.
Authors: R J Earlam, J Amerigo, T Kakavoulis, D J Pollock
Journal: Gut (1985)

Clinical data and histology from the oesophagus, gastric antrum, and duodenum were collected from 36 patients undergoing surgery for duodenal ulcer. Gastritis was present in 94% of the patients (25% of atrophic type), oesophagitis in 72% and duodenitis in 39%. Abnormal biopsies were present from all three sites in 33% of the patients. Only one patient showed three normal biopsies. The low incidence of duodenitis does not support the theory that duodenitis is part of the same spectrum as duodenal ulcer. Heartburn was related to the presence of gastritis (100%) and oesophagitis (76%) but not to duodenitis (52%). No relationship was found between the length of history, severity of pain, and histological abnormalities.
Arachidonic acid and docosahexaenoic acid are increased in human colorectal cancer.
Authors: J P Neoptolemos, D Husband, C Imray, S Rowley, N Lawson
Journal: Gut (1991)

Increased arachidonic acid concentrations in experimental rodent colonic cancer have been described recently. In humans, a reduced erythrocyte stearic acid to oleic acid ratio has been reported in patients with colorectal cancer and it has been proposed that similar changes exist in the cancer tissue. The long chain fatty acids in the cancers of 15 patients with colorectal cancer were measured and compared with values in the unaffected mucosa. The values were expressed as mean (SD) mg fatty acid/g tissue and compared by analysis of variance. In the cancer tissue arachidonic acid was increased (0.703 (0.109) mg/g v 0.603 (0.127) mg/g, p less than 0.05) as was docosahexaenoic acid (0.211 (0.066) mg/g v 0.148 (0.039) mg/g, p less than 0.001). In contrast, the stearic acid to oleic acid ratio in the cancer tissue was increased rather than decreased, as previously suggested (0.36 (0.05) v 0.29 (0.7), p less than 0.01). Increased arachidonic acid and docosahexaenoic acid concentrations may be related to reduced lipid peroxidation, which is a feature of rapidly growing cells. Alternatively, the increased arachidonic acid values could be due to enhanced desaturase activity upon linoleic and linolenic acid, leading perhaps to increased formation of prostaglandins and other lipoxygenase products.
Correlations of Vibrio fischeri bacteria test data with bioassay data for other organisms.
Authors: K L Kaiser
Journal: Environmental Health Perspectives (1998)

Linear relationships of the median lethal concentrations of several hundreds of chemicals for a variety of organisms with Vibrio fischeri median effective concentrations are investigated. Significant correlations can be developed for many aquatic species including the fishes fathead minnow, bluegill, catfish, goldfish, goldorfe, guppy, killifish, rainbow trout, sheepshead minnow, and zebrafish; the water flea Daphnia sp.; such crustaceans as Artemia sp. and Crangon sp.; the ciliate Tetrahymena pyriformis; and algae, such as Chlorella sp. These interspecies relationships can be used to estimate order-of-magnitude type toxic effects of many substances for these aquatic organisms. Highly significant relationships can be obtained when selecting compounds on a chemical basis, such as alcohols, ketones, aromatics, etc., which allow the calculation of the compounds' toxicities to the corresponding aquatic species with increased accuracy and confidence. Analogous correlations with mammalian (rat and mouse) oral, intraperitoneal, and intravenous median lethal dose (LD50) data are much weaker than those for most aquatic species. However, there are significant differences between these three routes of administration and the intravenous LD50 data show the best relationship with the Vibrio data.
Occlusive thrombi arise in mammals but not birds in response to arterial injury: evolutionary insight into human cardiovascular disease
Authors: Alec A. Schmaier, Timothy J. Stalker, Jeffrey J. Runge, Dooyoung Lee, Chandrasekaran Nagaswami, Patricia Mericko, Mei Chen, Simon Cliché, Claude Gariépy, Lawrence F. Brass, Daniel A. Hammer, John W. Weisel, Karen Rosenthal, Mark L. Kahn
Journal: Blood (2011)
Low-dose Metronomic Combined with Intermittent Bolus-dose Cyclophosphamide Is an Effective Long-term Chemotherapy Treatment Strategy
Authors: Yuval Shaked, Urban Emmenegger, Giulio Francia, Limor Chen, Christina R. Lee, Shan Man, Armen Paraghamian, Yaacov Ben-David, Robert S. Kerbel
Journal: Cancer Research (2005)

Abstract Metronomic chemotherapy refers to the close, regular administration of comparatively low doses of cytotoxic drugs, with minimal or no drug-free breaks, over prolonged periods. It is thought to have an antiangiogenic basis. However, whereas surprisingly durable and potent tumor responses have been observed in a number of preclinical tumor models, relapses usually eventually occur using this type of treatment strategy. We therefore decided to test modified metronomic chemotherapy regimens that might significantly delay such relapses, but still maintain modest and acceptable toxicity profiles. Here, we show that repeated administration of bolus doses (BDs) of cyclophosphamide every 3 or 6 weeks, combined with a daily oral low-dose metronomic (LDM) regimen (20 mg/kg/d cyclophosphamide), improves efficacy and significantly delays progression of transplanted PC-3 human prostate cancer xenografts, syngeneic transplanted EMT-6 breast tumors, and “spontaneous” murine erythroleukemia. Efficacy was superior whereas toxicity was mild and comparable to the LDM regimen, the latter assessed by body weight, neutrophil, lymphocyte, and total white blood counts. Antiangiogenic activity, measured by reduction in circulating endothelial precursor cells, revealed that the greatest degree of suppression occurred using the combination treatment. Overall, our results indicate that the administration of intermittent BD combined with chronic oral LDM cyclophosphamide is a potent treatment regimen for controlling tumor growth, which has a low toxicity profile, over prolonged periods of time.
Perioperative chemotherapy with docetaxel, cisplatin and capecitabine (DCX) in gastro-oesophageal adenocarcinoma: a phase II study of the Arbeitsgemeinschaft Internistische Onkologie (AIO)
Authors: P.C. Thuss-Patience, R.D. Hofheinz, D. Arnold, A. Florschütz, S. Daum, A. Kretzschmar, L. Mantovani-Löffler, D. Bichev, K. Breithaupt, M. Kneba, G. Schumacher, M. Glanemann, P. Schlattmann, P. Reichardt, B. Gahn
Journal: Annals of Oncology (2012)
Expression Profiling of T-Cell Lymphomas Differentiates Peripheral and Lymphoblastic Lymphomas and Defines Survival Related Genes
Authors: Beatriz Martinez-Delgado, Barbara Meléndez, Marta Cuadros, Javier Alvarez, Jose Maria Castrillo, Ana Ruiz de la Parte, Manuela Mollejo, Carmen Bellas, Ramon Diaz, Luis Lombardía, Fatima Al-Shahrour, Orlando Domínguez, Alberto Cascon, Mercedes Robledo, Carmen Rivas, Javier Benitez
Journal: Clinical Cancer Research (2004)

Abstract Purpose: T-Cell lymphomas constitute heterogeneous and aggressive tumors in which pathogenic alterations remain largely unknown. Expression profiling has demonstrated to be a useful tool for molecular classification of tumors. Experimental Design: Using DNA microarrays (CNIO-OncoChip) containing 6386 cancer-related genes, we established the expression profiling of T-cell lymphomas and compared them to normal lymphocytes and lymph nodes. Results: We found significant differences between the peripheral and lymphoblastic T-cell lymphomas, which include a deregulation of nuclear factor-κB signaling pathway. We also identify differentially expressed genes between peripheral T-cell lymphoma tumors and normal T lymphocytes or reactive lymph nodes, which could represent candidate tumor markers of these lymphomas. Additionally, a close relationship between genes associated to survival and those that differentiate among the stages of disease and responses to therapy was found. Conclusions: Our results reflect the value of gene expression profiling to gain insight about the molecular alterations involved in the pathogenesis of T-cell lymphomas.
Outcomes after thoracoscopic versus open lobectomy
Authors: Ulrik Sartipy
Journal: Thorax (2012)

Outcomes after thoracoscopic versus open lobectomyIn this national database study from the USA, the short-term outcomes following thoracoscopic lobectomy were compared with open thoracotomy lobectomy.From the Nationwide Inpatient Sample database, maintained by the Agency for Healthcare Research and Quality, all adult patients who underwent lobectomy as the principal procedure, by either thoracoscopy or thoracotomy during 2007 and 2008, were included.Patients with prior thoracotomy, or if both thoracoscopic and open lobectomy were listed as the approach, were excluded.All 68 350 patients were included, and 15% underwent a thoracoscopic lobectomy.Propensity score matching was used to reduce confounding by indication, and 10 173 thoracoscopic lobectomy patients were matched to 30 866 patients in the open lobectomy group.There was no difference regarding in-hospital mortality between the open lobectomy group and the thoracoscopic lobectomy group (2.3% vs 1.6%).There were modest differences regarding postoperative complications, and 2 days shorter in hospital stay, favouring thoracoscopic lobectomy.Interestingly, about one-third of the minimally invasive lobectomies were performed at non-teaching centres, implying that the technique was not limited to highly specialised academic centres.Limitations acknowledged by the authors were lack of clinical or pathological staging data, including tumour size and location, and other inherent weaknesses when using administrative databases for outcomes research.Although this large national study suggests that thoracoscopic lobectomy was associated with less in-hospital morbidity compared with open lobectomy, the role of minimally invasive lobectomy is still unclear.Importantly, the long-term oncological efficacy needs to be ascertained before widespread use, because early stage lung cancer patients are referred for surgery with curative intent.
Brain buffering is restored in hyponatremic rats by correcting their plasma sodium concentration.
Authors: S Adler, J G Verbalis, D Williams
Journal: Journal of the American Society of Nephrology (1994)

Previous studies from this laboratory showed that both acute and chronic hyponatremia impaired active brain buffering. These studies were performed to determine whether correcting the plasma sodium restored normal buffering in hyponatremic rats. Acute (1- and 2-day) and chronic (7- and 14-day) hyponatremia was induced in male Sprague-Dawley rats by constant desmopressin administration combined with a liquid diet. Plasma sodium was corrected by stopping desmopressin for 6 h, substituting solid chow, and allowing free access to water. Studies were performed 24 h later. Uncorrected hyponatremic rats who continued to receive desmopressin and liquid diet served as controls. Brain pH was determined by [31P]NMR in rats anesthetized with N2O and paralyzed with pancuronium. Brain buffering was determined by the response to CO2 loading. Resting brain pH was the same in corrected and uncorrected rats, but the two groups responded differently to CO2 loading. Thus, 55 min after ventilation with 20% CO2, corrected rat brain pH was 0.13 pH units higher than in uncorrected rats despite statistically similar changes in CO2 tension and arterial pH in both groups. Moreover, 15 min into recovery from CO2 exposure, brain pH in corrected rats overshot resting pH by 0.07, whereas no overshoot occurred in uncorrected rats. Buffering in corrected rats was identical to that shown previously in normonatremic rats. The complete restoration of late-phase buffering achieved by normalizing the plasma sodium of hyponatremic rats indicates that at least some portion of active hydrogen ion transport is sodium dependent in the brain.
Combination of romidepsin with cyclophosphamide, doxorubicin, vincristine, and prednisone in previously untreated patients with peripheral T-cell lymphoma: a non-randomised, phase 1b/2 study
Authors: Jehan Dupuis, Franck Morschhauser, Hervé Ghesquières, Hervé Tilly, Olivier Casasnovas, Catherine Thieblemont, Vincent Ribrag, Céline Bossard, Fabien Le Bras, Emmanuel Bachy, Bénédicte Hivert, Emmanuelle Nicolas-Virelizier, Fabrice Jardin, Jean-Noel Bastie, Sandy Amorim, Julien Lazarovici, Antoine Martin, Bertrand Coiffier
Journal: The Lancet Haematology (2015)