tbuckley/cabot-search huggingface dataset:
Combining an Aurora Kinase Inhibitor and a Death Receptor Ligand/Agonist Antibody Triggers Apoptosis in Melanoma Cells and Prevents Tumor Growth in Preclinical Mouse Models
Authors: Yan Liu, Oriana E. Hawkins, Anna E. Vilgelm, Jeffrey S. Pawlikowski, Jeffrey A. Ecsedy, Jeffrey A. Sosman, Mark C. Kelley, Ann Richmond
Journal: Clinical Cancer Research (2015)

Preclinical studies show that inhibition of aurora kinases in melanoma tumors induces senescence and reduces tumor growth, but does not cause tumor regression. Additional preclinical models are needed to identify agents that will synergize with aurora kinase inhibitors to induce tumor regression.We combined treatment with an aurora kinase A inhibitor, MLN8237, with agents that activate death receptors (Apo2L/TRAIL or death receptor 5 agonists) and monitored the ability of this treatment to induce tumor apoptosis and melanoma tumor regression using human cell lines and patient-derived xenograft (PDX) mouse models.We found that this combined treatment led to apoptosis and markedly reduced cell viability. Mechanistic analysis showed that the induction of tumor cell senescence in response to the AURKA inhibitor resulted in a decreased display of Apo2L/TRAIL decoy receptors and increased display of one Apo2L/TRAIL receptor (death receptor 5), resulting in enhanced response to death receptor ligand/agonists. When death receptors were activated in senescent tumor cells, both intrinsic and extrinsic apoptotic pathways were induced independent of BRAF, NRAS, or p53 mutation status. Senescent tumor cells exhibited BID-mediated mitochondrial depolarization in response to Apo2L/TRAIL treatment. In addition, senescent tumor cells had a lower apoptotic threshold due to decreased XIAP and survivin expression. Melanoma tumor xenografts of one human cell line and one PDX displayed total blockage of tumor growth when treated with MLN8237 combined with DR5 agonist antibody.These findings provide a strong rationale for combining senescence-inducing therapeutics with death receptor agonists for improved cancer treatment.
Denaturation of Collagen Via Heating: An Irreversible Rate Process
Authors: N.T. Wright, J.D. Humphrey
Journal: Annual Review of Biomedical Engineering (2002)

Heating therapies are increasingly used in cardiology, dermatology, gynecology, neurosurgery, oncology, ophthalmology, orthopedics, and urology, among other medical specialties. This widespread use of heating is driven primarily by the availability of new technology, not by a detailed understanding of the biothermomechanics. Without basic quantification of the underlying physical and chemical processes in terms of parameters that can be controlled clinically, identification of preferred interventions will continue to be based primarily on trial and error, thus necessitating large clinical studies and years of accumulative experience. Perusal of the literature reveals that much has been learned over the past century about the response of cells, proteins, and tissues to supra-physiologic temperatures; yet, the associated findings are reported in diverse journals and the underlying basic processes remain unidentified. In this review, we seek to contrast various findings on the kinetics of the thermal denaturation of collagen and to encourage investigators to consider the many open problems in part via a synthesis of results from the diverse literatures.
Pazopanib in advanced and platinum-resistant urothelial cancer: an open-label, single group, phase 2 trial
Authors: Andrea Necchi, Luigi Mariani, Nadia Zaffaroni, Lawrence H Schwartz, Patrizia Giannatempo, Flavio Crippa, Carlo Morosi, Rodolfo Lanocita, Teodoro Sava, Cinzia Ortega, Caterina Messina, Cosimo Sacco, Marzia Pennati, Maria G Daidone, Nicola Nicolai, Filippo De Braud, Alessandro M Gianni, Roberto Salvioni
Journal: The Lancet Oncology (2012)
DNA methyltransferase inhibitors—state of the art
Authors: J. Goffin, E. Eisenhauer
Journal: Annals of Oncology (2002)

BackgroundDNA methylation is the addition of a methyl group to the 5 position of cytosine. It is an epigenetic process with several effects, including chromatin structure modulation, transcriptional repression and the suppression of transposable elements. In malignancy, methylation patterns change, resulting in global hypomethylation with regional hypermethylation. This can lead to genetic instability and the repression of tumor suppressor genes.DesignA review of the DNA methyltransferase inhibitor literature was conducted.ResultsDNA methylation inhibitors have demonstrated the ability to inhibit hypermethylation, restore suppressor gene expression and exert antitumor effects in in vitro and in vivo laboratorymodels. Four inhibitors, which are analogs of the nucleoside deoxycitidine, have been clinically tested: 5-azacytidine, 5-aza-2′-deoxycytidine, 1-β-d-arabinofuranosyl-5-azacytosine and dihydro-5-azacytidine. The first two have demonstrated encouraging antileukemic activity but little activity in solid tumors, while the latter two are no longer under study due to lack of efficacy. A fifth agent, MG98, is an antisense oligodeoxynucleotide directed against the 3′ untranslated region of the DNA methyltransferase-1 enzyme mRNA, and is now under phase II study.ConclusionsWhile some positive clinical results with DNA methyltransferase inhibitors have been seen, a definitive clinical role for these agents will most likely require combination therapy, and good phase III studies are needed.
Antitumor Effect of Somatostatin Analogs in Neuroendocrine Tumors
Authors: Yu Jo Chua, Michael Michael, John R. Zalcberg, Rod J. Hicks, David Goldstein, Winston Liauw, Timothy Price
Journal: Journal of Clinical Oncology (2009)

TO THE EDITOR: We read with interest the report by Rinke et al 1 of the interim analysis of a randomized, placebo-controlled trial of octreotide LAR, the long-acting somatostatin analog (SSA), in metastatic midgut neuroendocrine tumors (NETs), along with the companion editorial by Oberg. 2 These results are an important contribution to our understanding of the biology of NETs. However, although scientifically provocative and supportive of the long-held belief of many clinicians in this field that SSAs have an antiproliferative effect in this heterogeneous group of diseases, the data published thus far still leave some important issues unresolved. The study planned to enroll 162 patients, but after nearly 8 years, only 85 were randomly assigned. Despite the much-reduced accrual, Rinke et al reported a marked difference in median time to progression on the basis of WHO radiologic criteria in the intent-to-treat population of 14.3 months with octreotide LAR compared with 6.0 months with placebo (hazard ratio [HR], 0.33; 95% CI, 0.20 to 0.59;P.000072). Importantly, similar benefits were demonstrated regardless of the presence or absence of carcinoid syndrome ( 40% of patients had carcinoid syndrome). As impressive as these results seem, we have concerns about whether both study arms are comparable. Notably, there was a highlystatisticallysignificantimbalanceinthetimesincediagnosis between the study arms in favor of the octreotide LAR arm, with a medianof7.5monthscomparedwith3.3monthsfortheplaceboarm (P.0096). Given the heterogeneous natural history of these tumors and the relatively small size of the analyzed population, it is unclear how this imbalance might have influenced the overall outcome of the study. A longer duration between diagnosis and treatment suggests more indolent disease; if by chance more of these patients were in the experimental treatment arm, as seems to have been the case in this trial, a longer time to progression could have ensued, whether or not the treatment was effective. Similarly, the planned subgroup analysis suggested that the benefit of octreotide LAR was greatest in patients withlimited(0%to10%)liverinvolvement(HR,0.17;95%CI,0.08to 0.40). Conceivably, those patients with a longer time since diagnosis were also those with limited liver involvement as a result of lower biologic aggressiveness. However, the explanation for the suggestion ofreducedactivityofoctreotideLARinthosepatientswithsignificant liver involvement in this trial was not discussed. If there is a proportionate increase in the overall quantity of somatostatin receptors with tumor bulk, the dose of octreotide LAR used may have been inade
Effect of Eculizumab on Hemolysis and Transfusion Requirements in Patients with Paroxysmal Nocturnal Hemoglobinuria
Authors: Peter Hillmen, Claire Hall, Judith C.W. Marsh, Modupe Elebute, Michael P. Bombara, Beth E. Petro, Matthew J. Cullen, Stephen J. Richards, Scott A. Rollins, Christopher F. Mojcik, Russell P. Rother
Journal: New England Journal of Medicine (2004)

Paroxysmal nocturnal hemoglobinuria (PNH) arises from a somatic mutation of the PIG-A gene in a hematopoietic stem cell and the subsequent production of blood cells with a deficiency of surface proteins that protect the cells against attack by the complement system. We tested the clinical efficacy of eculizumab, a humanized antibody that inhibits the activation of terminal complement components, in patients with PNH.
The Immunobiology and Pathophysiology of Primary Biliary Cirrhosis
Authors: Gideon M. Hirschfield, M. Eric Gershwin
Journal: Annual Review of Pathology Mechanisms of Disease (2013)

Primary biliary cirrhosis (PBC) is an autoimmune disease characterized by clinical homogeneity among patients, an overwhelming female predominance, production of a multilineage immune response to mitochondrial autoantigens, inflammation of small bile ducts, and in some patients the development of fibrosis and cirrhosis. The targets in this disease are small bile ducts, and the prototypic serologic response includes antimitochondrial antibodies (AMAs). Several key observations have greatly advanced our understanding of PBC. First, the multilineage immune response, including AMAs, is directed at the E2 component of the 2-oxo-dehydrogenase pathway, particularly PDC-E2. Second, such autoantibodies may be identified years before the clinical diagnosis of disease. Third, the autoreactive T cell precursor frequency for both CD4 and CD8 cells is significantly higher in liver and regional lymph node than in blood, so the multilineage antimitochondrial response may be required for the development of this disease. Fourth, the apotope of biliary cells contains intact PDC-E2; this apotope, in a setting that includes granulocyte macrophage colony–stimulating factor–stimulated macrophages and AMAs, produces an intense proinflammatory response. Fifth, several mouse models of PBC highlight the importance of loss of tolerance to PDC-E2 as well as a critical role for the interleukin (IL)-12 signaling pathway. Finally, genome-wide association studies suggest an important role for the IL-12 pathway in disease susceptibility. Taken together, these findings have resulted in a better understanding of the mechanism for selective biliary cell destruction and have also suggested unique pathways for therapeutic intervention.
A third-generation microsatellite-based linkage map of the honey bee, Apis mellifera, and its comparison with the sequence-based physical map
Authors: Michel Solignac, Florence Mougel, Dominique Vautrin, Monique Monnerot, Jean-Marie Cornuet
Journal: Genome biology (2007)

The honey bee is a key model for social behavior and this feature led to the selection of the species for genome sequencing. A genetic map is a necessary companion to the sequence. In addition, because there was originally no physical map for the honey bee genome project, a meiotic map was the only resource for organizing the sequence assembly on the chromosomes.We present the genetic (meiotic) map here and describe the main features that emerged from comparison with the sequence-based physical map. The genetic map of the honey bee is saturated and the chromosomes are oriented from the centromeric to the telomeric regions. The map is based on 2,008 markers and is about 40 Morgans (M) long, resulting in a marker density of one every 2.05 centiMorgans (cM). For the 186 megabases (Mb) of the genome mapped and assembled, this corresponds to a very high average recombination rate of 22.04 cM/Mb. Honey bee meiosis shows a relatively homogeneous recombination rate along and across chromosomes, as well as within and between individuals. Interference is higher than inferred from the Kosambi function of distance. In addition, numerous recombination hotspots are dispersed over the genome.The very large genetic length of the honey bee genome, its small physical size and an almost complete genome sequence with a relatively low number of genes suggest a very promising future for association mapping in the honey bee, particularly as the existence of haploid males allows easy bulk segregant analysis.
Optimizing Insulin Secretagogue Therapy in Patients With Type 2 Diabetes
Authors: Ole Schmitz, Sten Lund, Per Heden Andersen, Morten Jønler, Nils Pørksen
Journal: Diabetes Care (2002)

OBJECTIVE—Repaglinide, a novel antidiabetic agent that has a rapid onset and short duration of action, was developed for mealtime dosing. The purpose of this pharmacodynamic study was to validate a prandial regimen of repaglinide by comparing meal-related dosing with a regimen in which the same total daily dose was divided into only two doses at morning and evening meals. RESEARCH DESIGN AND METHODS—The study was a double-blind, randomized, parallel-group trial in 19 antidiabetic agent-naive subjects with type 2 diabetes (mean age 58 years, known duration of diabetes 3.5 years, HbA1c 7.3%, and BMI 32 kg/m2). Patients were randomly assigned to receive repaglinide either before each of the three main meals or before breakfast and before the evening meal. Patients in both groups received the same total daily dose of repaglinide. Twenty-four hour profiles of blood glucose, plasma insulin, and plasma C-peptide concentrations were measured at baseline and after 4 weeks of treatment. RESULTS—Repaglinide increased postprandial insulin levels and markedly reduced postprandial glucose levels relative to baseline in both groups. Significant reductions were also recorded in fasting blood glucose and HbA1c levels. The repaglinide regimen, in which a dose was taken before each main meal, was more effective in improving glycemic control (including postprandial glucose and HbA1c levels) than the same total dose of repaglinide divided into morning and evening mealtime doses. CONCLUSIONS—These data support the strategy of mealtime dosing with repaglinide. The improvements in glycemic control observed in these patients are encouraging. In addition to classic parameters of glycemic control, improvements in postprandial glucose excursions may prove to be important because postprandial hyperglycemia has been suggested to be an independent risk factor for cardiovascular disease in diabetes.
Leptin selectively decreases visceral adiposity and enhances insulin action.
Authors: N Barzilai, J Wang, D Massilon, P Vuguin, M Hawkins, L Rossetti
Journal: Journal of Clinical Investigation (1997)

Intraabdominal adiposity and insulin resistance are risk factors for diabetes mellitus, dyslipidemia, arteriosclerosis, and mortality. Leptin, a fat-derived protein encoded by the ob gene, has been postulated to be a sensor of energy storage in adipose tissue capable of mediating a feedback signal to sites involved in the regulation of energy homeostasis. Here, we provide evidence for specific effects of leptin on fat distribution and in vivo insulin action. Leptin (LEP) or vehicle (CON) was administered by osmotic minipumps for 8 d to pair-fed adult rats. During the 8 d of the study, body weight and total fat mass decreased similarly in LEP and in CON. However, while moderate calorie restriction (CON) resulted in similar decreases in whole body (by 20%) and visceral (by 21%) fat, leptin administration led to a specific and marked decrease (by 62%) in visceral adiposity. During physiologic hyperinsulinemia (insulin clamp), leptin markedly enhanced insulin action on both inhibition of hepatic glucose production and stimulation of glucose uptake. Finally, leptin exerted complex effects on the hepatic gene expression of key metabolic enzymes and on the intrahepatic partitioning of metabolic fluxes, which are likely to represent a defense against excessive storage of energy in adipose depots. These studies demonstrate novel actions of circulating leptin in the regulation of fat distribution, insulin action, and hepatic gene expression and suggest that it may play a role in the pathophysiology of abdominal obesity and insulin resistance.
Randomized Trial: Quitline Specialist Training in Gain-Framed vs Standard-Care Messages for Smoking Cessation
Authors: B. A. Toll, S. Martino, A. Latimer, P. Salovey, S. O'Malley, S. Carlin-Menter, J. Hopkins, R. Wu, P. Celestino, K. M. Cummings
Journal: JNCI Journal of the National Cancer Institute (2010)

Smoking accounts for a large proportion of cancer-related mortality, creating a need for better smoking cessation efforts. We investigated whether gain-framed messages (ie, presenting benefits of quitting) will be a more persuasive method to encourage smoking cessation than standard-care messages (ie, presenting both costs of smoking [loss-framed] and benefits of quitting). Twenty-eight specialists working at the New York State Smokers' Quitline (a free telephone-based smoking cessation service) were randomly assigned to provide gain-framed or standard-care counseling and print materials. Smokers (n = 2032) who called the New York State Smokers' Quitline between March 10, 2008, and June 13, 2008, were exposed to either gain-framed (n = 810) or standard-care (n = 1222) messages, and all medically eligible callers received nicotine replacement therapy. A subset of 400 call recordings was coded to assess treatment fidelity. All treated smokers were contacted for 2-week and 3-month follow-up interviews. All statistical tests were two-sided. Specialists providing gain-framed counseling used gain-framed statements statistically significantly more frequently than those providing standard-care counseling as assessed with frequency ratings for the two types of gain-framed statements, achieving benefits and avoiding negative consequences (for achieving benefits, gain-framed mean frequency rating = 3.9 vs standard-care mean frequency rating = 1.4; mean difference = −2.5; 95% confidence interval [CI] = −2.8 to −2.3; P < .001; for avoiding negative consequences, gain-framed mean frequency rating = 1.5 vs standard-card mean frequency rating = 1.0; mean difference = −0.5; 95% CI = −0.6 to −0.3; P < .001). Gain-framed counseling was associated with a statistically significantly higher rate of abstinence at the 2-week follow-up (ie, 99 [23.3%] of the 424 in the gain-framed group vs 76 [12.6%] of the 603 in the standard-care group, P < .001) but not at the 3-month follow-up (ie, 148 [28.4%] of the 522 in the gain-framed group vs 202 [26.6%] of the 760 in the standard-care group, P = .48). Quitline specialists can be trained to provide gain-framed counseling with good fidelity. Also, gain-framed messages appear to be somewhat more persuasive than standard-care messages in promoting early success in smoking cessation.
c-Jun NH2-Terminal Kinase Activating Kinase 1/Mitogen-Activated Protein Kinase Kinase 4–Mediated Inhibition of SKOV3ip.1 Ovarian Cancer Metastasis Involves Growth Arrest and p21 Up-regulation
Authors: Tamara Lotan, Jonathan Hickson, Jeffrey Souris, Dezheng Huo, Jennifer Taylor, Terry Li, Kristen Otto, Seiko Diane Yamada, Kay Macleod, Carrie W. Rinker-Schaeffer
Journal: Cancer Research (2008)

Abstract In many patients without clinical metastases, cancer cells have already escaped from the primary tumor and entered a distant organ. A long-standing question in metastasis research is why some disseminated cancer cells fail to complete steps of metastatic colonization for extended periods of time. Our laboratory identified c-Jun NH2-terminal kinase activating kinase 1/mitogen-activated protein kinase kinase 4 (JNKK1/MKK4) as a metastasis suppressor protein in a mouse xenograft model of experimental i.p. ovarian cancer metastasis. In this model, expression of JNKK1/MKK4 via activation of p38 delays formation of ≥1-mm implants and prolongs animal survival. Here, we elucidate the time course of this delay as well as the biological mechanisms underpinning it. Using the Gompertz function to model the net accumulation of experimental omental metastases, we show that MKK4-expressing implants arise, on average, 30 days later than controls. Quantitative real-time PCR shows that MKK4 expression does not have a substantial effect on the number of cancer cells initially adhering to the omentum, and terminal deoxyribonucleotidyl transferase–mediated dUTP nick end labeling analysis shows that there is no increase in apoptosis in these cells. Instead, immunohistochemical quantitation of cell cycle proteins reveals that MKK4-expressing cells fail to proliferate once they reach the omentum and up-regulate p21, a cell cycle inhibitor. Consistent with the time course data, in vitro kinase assays and in vivo passaging of cell lines derived from macroscopic metastases show that the eventual outgrowth of MKK4-expressing cells is not due to a discrete selection event. Rather, the population of MKK4-expressing cells eventually uniformly adapts to the consequences of up-regulated MKK4 signaling. [Cancer Res 2008;68(7):2166–75]
Treatment of Patients With Metastatic Urothelial Cancer “Unfit” for Cisplatin-Based Chemotherapy
Authors: Matthew D. Galsky, Noah M. Hahn, Jonathan Rosenberg, Guru Sonpavde, Thomas Hutson, William K. Oh, Robert Dreicer, Nicholas Vogelzang, Cora N. Sternberg, Dean F. Bajorin, Joaquim Bellmunt
Journal: Journal of Clinical Oncology (2011)

Cisplatin-based combination chemotherapy is considered standard first-line treatment for patients with metastatic urothelial carcinoma. However, a large proportion of patients with metastatic urothelial carcinoma are considered "unfit" for cisplatin. The purpose of this review is to define unfit patients and to identify treatment options for this subgroup of patients.In this review, the criteria used to define unfit patients are explored and the results of prospective clinical trials evaluating chemotherapeutic regimens in unfit patients are summarized.Several phase II trials and a single, large phase III trial have explored chemotherapeutic regimens for the treatment of unfit patients with metastatic urothelial carcinoma. Heterogeneous eligibility criteria have been used to define unfit patients in these studies. A uniform definition of unfit is proposed on the basis of the results of a survey of genitourinary medical oncologists. According to this definition, unfit patients would meet at least one of the following criteria: Eastern Cooperative Oncology Group performance status of 2, creatinine clearance less than 60 mL/min, grade ≥ 2 hearing loss, grade ≥ 2 neuropathy, and/or New York Heart Association Class III heart failure.Additional studies to optimize treatment for this important subset of patients are needed. A uniform definition of unfit patients will lead to more uniform clinical trials, enhanced ability to interpret the results of these trials, and a greater likelihood of developing a viable strategy for regulatory approval.