tbuckley/cabot-search huggingface dataset:
Radioprotection of <i>IDH1</i>-Mutated Cancer Cells by the IDH1-Mutant Inhibitor AGI-5198
Authors: Remco J. Molenaar, Dennis Botman, Myrthe A. Smits, Vashendriya V. Hira, Sanne A. van Lith, Jan Stap, Peter Henneman, Mohammed Khurshed, Krissie Lenting, Adri N. Mul, Dionysia Dimitrakopoulou, Cornelis M. van Drunen, Ron A. Hoebe, Tomas Radivoyevitch, Johanna W. Wilmink, Jaroslaw P. Maciejewski, W. Peter Vandertop, William P. Leenders, Fonnet E. Bleeker, Cornelis J. van Noorden
Journal: Cancer Research (2015)

Abstract Isocitrate dehydrogenase 1 (IDH1) is mutated in various types of human cancer to IDH1R132H, a structural alteration that leads to catalysis of α-ketoglutarate to the oncometabolite D-2-hydroxyglutarate. In this study, we present evidence that small-molecule inhibitors of IDH1R132H that are being developed for cancer therapy may pose risks with coadministration of radiotherapy. Cancer cells heterozygous for the IDH1R132H mutation exhibited less IDH-mediated production of NADPH, such that after exposure to ionizing radiation (IR), there were higher levels of reactive oxygen species, DNA double-strand breaks, and cell death compared with IDH1 wild-type cells. These effects were reversed by the IDH1R132H inhibitor AGI-5198. Exposure of IDH1 wild-type cells to D-2-hydroxyglutarate was sufficient to reduce IDH-mediated NADPH production and increase IR sensitivity. Mechanistic investigations revealed that the radiosensitivity of heterozygous cells was independent of the well-described DNA hypermethylation phenotype in IDH1-mutated cancers. Thus, our results argue that altered oxidative stress responses are a plausible mechanism to understand the radiosensitivity of IDH1-mutated cancer cells. Further, they offer an explanation for the relatively longer survival of patients with IDH1-mutated tumors, and they imply that administration of IDH1R132H inhibitors in these patients may limit irradiation efficacy in this setting. Cancer Res; 75(22); 4790–802. ©2015 AACR.
Guidelines for the validation and application of typing methods for use in bacterial epidemiology
Authors: A. van Belkum, P.T. Tassios, L. Dijkshoorn, S. Haeggman, B. Cookson, N.K. Fry, V. Fussing, J. Green, E. Feil, P. Gerner-Smidt, S. Brisse, M. Struelens
Journal: Clinical Microbiology and Infection (2007)
Type of acute hamstring strain affects flexibility, strength, and time to return to pre-injury level
Authors: C Askling, T Saartok, A Thorstensson
Journal: British Journal of Sports Medicine (2005)

Objectives: To investigate possible links between aetiology of acute, first time hamstring strains in sprinters and dancers and recovery of flexibility, strength, and function as well as time to return to pre-injury level. Methods: Eighteen elite sprinters and 15 professional dancers with a clinically diagnosed hamstring strain were included. They were clinically examined and tested two, 10, 21, and 42 days after the acute injury. Range of motion in hip flexion and isometric strength in knee flexion were measured. Self estimated and actual time to return to pre-injury level were recorded. Hamstring reinjuries were recorded during a two year follow up period. Results: All the sprinters sustained their injuries during high speed sprinting, whereas all the dancers were injured while performing slow stretching type exercises. The initial loss of flexibility and strength was greater in sprinters than in dancers (p&lt;0.05). At 42 days after injury, both groups could perform more than 90% of the test values of the uninjured leg. However, the actual times to return to pre-injury level of performance were significantly longer (median 16 weeks (range 6–50) for the sprinters and 50 weeks (range 30–76) for the dancers). Three reinjuries were noted, all in sprinters. Conclusion: There appears to be a link between the aetiologies of the two types of acute hamstring strain in sprinters and dancers and the time to return to pre-injury level. Initially, sprinters have more severe functional deficits but recover more quickly.
Targeting VEGF-A to Treat Cancer and Age-Related Macular Degeneration
Authors: Napoleone Ferrara, Robert D. Mass, Claudio Campa, Robert Kim
Journal: Annual Review of Medicine (2006)

Inhibiting angiogenesis is a promising strategy to treat cancer and several other disorders, including intraocular neovascular syndromes. The identification of vascular endothelial growth factor (VEGF)-A as a major regulator of normal and pathological angiogenesis has enabled significant progress toward effective treatments for such disorders. Several VEGF inhibitors have been recently approved by the U.S. Food and Drug Administration for the treatment of cancer and the neovascular form of age-related macular degeneration. This review summarizes the basic biology of VEGF-A and illustrates the clinical progress in targeting this molecule.
Tumor-Driven Paracrine Platelet-Derived Growth Factor Receptor α Signaling Is a Key Determinant of Stromal Cell Recruitment in a Model of Human Lung Carcinoma
Authors: Max L. Tejada, Lanlan Yu, Jianying Dong, Kenneth Jung, Gloria Meng, Franklin V. Peale, Gretchen D. Frantz, Linda Hall, XiaoHuan Liang, Hans-Peter Gerber, Napoleone Ferrara
Journal: Clinical Cancer Research (2006)

Activated fibroblasts are thought to play important roles in the progression of many solid tumors, but little is known about the mechanisms responsible for the recruitment of fibroblasts in tumors. Using several methods, we identified platelet-derived growth factor A (PDGFA) as the major fibroblast chemoattractant and mitogen from conditioned medium generated by the Calu-6 lung carcinoma cell line. In addition, we showed that Calu-6 tumors express significant levels of PDGFC, and that the levels of expression of these two PDGFRalpha ligands correlate strongly with the degree of stromal fibroblast infiltration into the tumor mass. The most intense expression of PDGFRalpha was observed in fibroblasts in the tumor outer rim. We subsequently showed that disrupting PDGFRalpha-mediated signaling results in significant inhibition of tumor growth in vivo. Furthermore, analysis of a compendium of microarray data revealed significant expression of PDGFA, PDGFC, and PDGFRalpha in human lung tumors. We propose that therapies targeting this stromal cell type may be effective in treating certain types of solid tumors.
Medicolegal neglect? The case for physical activity promotion and Exercise Medicine
Authors: Richard Weiler, Peter Feldschreiber, Emmanuel Stamatakis
Journal: British Journal of Sports Medicine (2011)

Whether measured subjectively or objectively, a large proportion of the population are living sedentary and physically inactive lives.1 ,2 This should be a major public health focus given the overwhelming evidence demonstrating that physical inactivity increases an individual's risk for all-cause mortality and may be one of the leading causes of non-communicable chronic disease in the world, responsible for about 60% of worldwide deaths3,–,6 and probably more in developed countries.

Pandemic levels of physical inactivity result in a huge burden of unhealthy consequences within populations and for society, across all socioeconomic classes, all ethnicities and phenotypes.

However, attempts to explain the precise causes of chronic diseases and resultant deaths, for each individual, are very difficult. We are all exposed to multiple risk factors in variable quantities throughout our lives and, currently, these are virtually impossible to measure. Consequently, despite our remarkable growth in the medical field, explanations for precise causes of death remain speculative. To attribute causal status of risk factors for non-communicable disease is fraught with difficulty both clinically and medicolegally. For example, it is baffling that despite scientific progress since Richard Doll's landmark findings 60 years ago, strongly linking smoking with lung cancer,7 causation of smoking and lung cancer has still not been upheld in a court of law.8

Duty of care is a legal obligation imposed on a doctor requiring, via the Bolam test,9 that their actions conform to those of a responsible body of professional opinion, even if others have a different opinion. More recently, the Bolitho v City and Hackney Health Authority case, entitled a judge to choose between two bodies of expert opinion and reject an opinion, which is ‘logically indefensible’. …
Functional Subtyping of Breast Cancer
Authors: Roderick L. Beijersbergen, René Bernards
Journal: Cancer Discovery (2011)

Abstract Breast cancers can be subdivided in several different ways. In this issue, Brough and colleagues describe a functional subtyping of breast cancers based on their responses to specific perturbations. Cancer Discovery; 1(3); 205–6. © 2011 AACR. Commentary on Brough et al., p. 260.
Prevention of vein graft failure: potential applications for gene therapy
Authors: A Baker
Journal: Cardiovascular Research (1997)

The use of gene therapy in the clinical setting is believed to be a realistic option for the future. Many clinical trials are underway for treatment of disorders as diverse as cancer, peripheral vascular disease, and numerous monogenic diseases. However, gene therapy for vein graft failure may be more distant due to the highly complex, multifactorial aetiology of the disease. Although many of the cellular mechanisms involved in vein graft failure have been reported, important barriers still need to be overcome before gene therapy could become a clinical reality. Further understanding of the molecular mechanisms involved in graft failure will lead to the identification of appropriate therapeutic genes. Moreover, limitations in the current delivery systems need to be overcome to allow efficient, safe delivery and expression of transgenes for the required length of time in vivo. However, currently available gene delivery vectors are extremely useful tools to help in our understanding of vein graft failure. In this review, we address the issues surrounding gene therapy with particular emphasis on its future potential to ameliorate long term vein graft occlusion.
Microfabrication of complex porous tissue engineering scaffolds using 3D projection stereolithography
Authors: Robert Gauvin, Ying-Chieh Chen, Jin Woo Lee, Pranav Soman, Pinar Zorlutuna, Jason W. Nichol, Hojae Bae, Shaochen Chen, Ali Khademhosseini
Journal: Biomaterials (2012)
Asthenoazoospermia in patients receiving anti-tumour necrosis factor agents
Authors: G L. Montagna
Journal: Annals of the Rheumatic Diseases (2005)

hydrocephalus (fig 1).Because of the hydrocephalus, it was neurologically advisable not to perform a cerebrospinal fluid puncture.There was no indication of tuberculosis (chest x ray examination, tuberculin test, sputum culture) or any other infection.The neoplasia investigation was also negative.An anamnestic investigation showed that there was no need to use ibuprofen or sulindac.When the situation became life threatening we initiated immunosuppressive treatment with cyclophosphamide (100 mg/day), as well as intravenous steroids (100 mg) initially.The initial intravenous cortisone treatment relieved the headache symptoms.Follow up examinations for up to 1 year (every 3 months) showed remission of clinical and MRI findings with this treatment (fig 2).Stable partial remission occurred after 8 months, and oral administration of cyclophosphamide was stopped.Treatment to preserve remission was changed to azathioprine (100 mg).The prednisone dose was finally reduced to 5 mg.
Trastuzumab in the treatment of advanced breast cancer: Single-center experience
Authors: M. Mrsić, M. Grgić, Z. Budišić, P. Podolski, V. Bogdanić, B. Labar, J. Jakić-Razumović, N. Restek-Samaržija, M. Gošev
Journal: Annals of Oncology (2001)
Physical Activity Energy Expenditure Predicts Progression Toward the Metabolic Syndrome Independently of Aerobic Fitness in Middle-Aged Healthy Caucasians
Authors: Ulf Ekelund, Søren Brage, Paul W. Franks, Susie Hennings, Sue Emms, Nicholas J. Wareham
Journal: Diabetes Care (2005)

OBJECTIVE—To examine over a period of 5.6 years the prospective associations between physical activity energy expenditure (PAEE), aerobic fitness (Vo2max), obesity, and the progression toward the metabolic syndrome in a population-based cohort of middle-aged men and women (n = 605) who were free of the metabolic syndrome at baseline. RESEARCH DESIGN AND METHODS—PAEE was measured objectively by individually calibrated heart rate against energy expenditure. Vo2max was predicted from a submaximal exercise stress test. Fat mass and fat-free mass were assessed by bio-impedance. A metabolic syndrome score was computed by summing the standardized values for obesity, hypertension, hyperglycemia, insulin resistance, hypertriglyceridemia, and the inverse level of HDL cholesterol and expressed as a continuously distributed outcome. Generalized linear models were used to examine the independent prospective associations between PAEE and Vo2max and the metabolic syndrome score after adjusting for sex, baseline age, smoking, socioeconomic status, follow-up time, and baseline phenotypes. RESULTS—PAEE predicted progression toward the metabolic syndrome, independent of baseline metabolic syndrome, body fat, Vo2max, and other confounding factors (standardized β = −0.00085, P = 0.046). This association was stronger when excluding the adiposity component from the metabolic syndrome (standardized β = −0.0011, P = 0.035). Vo2max was not an independent predictor of the metabolic syndrome after adjusting for physical activity (standardized β = 0.00011, P = 0.93). CONCLUSIONS—PAEE predicts progression toward the metabolic syndrome independent of aerobic fitness, obesity, and other confounding factors. This finding underscores the importance of physical activity for metabolic disease prevention even when an improvement in aerobic fitness is absent.
Five-Year Survival Rates for Treatment-Naive Patients With Advanced Melanoma Who Received Ipilimumab Plus Dacarbazine in a Phase III Trial
Authors: Michele Maio, Jean-Jacques Grob, Steinar Aamdal, Igor Bondarenko, Caroline Robert, Luc Thomas, Claus Garbe, Vanna Chiarion-Sileni, Alessandro Testori, Tai-Tsang Chen, Marina Tschaika, Jedd D. Wolchok
Journal: Journal of Clinical Oncology (2015)

There is evidence from nonrandomized studies that a proportion of ipilimumab-treated patients with advanced melanoma experience long-term survival. To demonstrate a long-term survival benefit with ipilimumab, we evaluated the 5-year survival rates of patients treated in a randomized, controlled phase III trial.A milestone survival analysis was conducted to capture the 5-year survival rate of treatment-naive patients with advanced melanoma who received ipilimumab in a phase III trial. Patients were randomly assigned 1:1 to receive ipilimumab at 10 mg/kg plus dacarbazine (n = 250) or placebo plus dacarbazine (n = 252) at weeks 1, 4, 7, and 10 followed by dacarbazine alone every 3 weeks through week 22. Eligible patients could receive maintenance ipilimumab or placebo every 12 weeks beginning at week 24. A safety analysis was conducted on patients who survived at least 5 years and continued to receive ipilimumab as maintenance therapy.The 5-year survival rate was 18.2% (95% CI, 13.6% to 23.4%) for patients treated with ipilimumab plus dacarbazine versus 8.8% (95% CI, 5.7% to 12.8%) for patients treated with placebo plus dacarbazine (P = .002). A plateau in the survival curve began at approximately 3 years. In patients who survived at least 5 years and continued to receive ipilimumab, grade 3 or 4 immune-related adverse events were observed exclusively in the skin.The additional survival benefit of ipilimumab plus dacarbazine is maintained with twice as many patients alive at 5 years compared with those who initially received placebo plus dacarbazine. These results demonstrate a durable survival benefit with ipilimumab in advanced melanoma.
Transcriptional Activation by pRB and Its Coordination with SWI/SNF Recruitment
Authors: Stephen Flowers, George R. Beck, Elizabeth Moran
Journal: Cancer Research (2010)

A central question in cancer biology is why most tumor susceptibility genes are linked with only limited types of cancer. Human germ-line mutation of the retinoblastoma susceptibility gene Rb1 is closely linked with just retinoblastoma and osteosarcoma, although the gene is universally expressed. Functional analysis of pRB and its close relatives, p107 and p130, has largely focused on their roles in repression of proliferation across all tissue types, but genetic evidence indicates an active requirement for pRB in osteoblast differentiation that correlates more directly with osteosarcoma susceptibility. Still, potential promoter targets of pRB and its role in normally differentiating osteoblasts remain insufficiently characterized. Here, an early marker of osteoblast differentiation, alkaline phosphatase, is identified as a direct promoter activation target of pRB. One role of pRB on this promoter is to displace the histone lysine demethylase KDM5A, thereby favoring trimethylation of H3K4, a promoter activation mark. A major new aspect of pRB-mediated transcriptional activation revealed in this promoter analysis is its role in recruitment of an activating SWI/SNF chromatin-remodeling complex. SWI/SNF is a critical coordinator of tissue-specific gene expression. In osteoblasts, SWI/SNF complexes containing the BRM ATPase repress osteoblast-specific genes to maintain the precursor state, whereas the alternative ATPase BRG1 distinguishes an activating SWI/SNF complex necessary for RNA polymerase-II recruitment. A switch from BRM to BRG1 on the alkaline phosphatase promoter marks the onset of differentiation and is accomplished in a precise two-step mechanism. Dissociation of BRM-containing SWI/SNF depends on p300, and association of BRG1-containing SWI/SNF depends on pRB.
Decreased collagen accumulation by a prolyl hydroxylase inhibitor in pig serum-induced fibrotic rat liver
Authors: Kenji Fujiwara, Itsuro Ogata, Yasuhiko Ohta, Shigeki Hayashi, Shunji Mishiro, Katsuyoshi Takatsuki, Yuzuru Sato, Shinwa Yamada, Keichi Hirata, Hiroshi Oka, Toshitsugu Oda, Hisanori Kawaji, Shinobu Matsuda, Yasuhiko Niiyama, Ryoichi Tsukuda
Journal: Hepatology (1988)

Hepatic fibrosis was induced in rats by repeated i.p. injections of pig serum. The hepatic hydroxyproline content increased to 2.1 times the normal control level at 6 weeks and to 3.2 times at 10 weeks. When P-1894B, an inhibitor of prolyl hydroxylase, was administered, there was a dose-dependent inhibition of the increase to nearly normal control levels at 6 and 10 weeks. There was also by histology a dose-dependent reduction in the degree of hepatic fibrosis. Hepatocellular damage was minimal and its extent did not vary with the degree of fibrosis or the treatment. P-1894B dose dependently reduced the hydroxylation of peptidyl proline in the fibrotic liver. These data suggest that P-1894B inhibited hepatic fibrogenesis by direct action on collagen but not by protection against hepatocellular damage leading to collagen formation. A prolyl hydroxylase inhibitor may be a candidate for use in treatment of hepatic fibrosis.
Comparison of the Associations of Apolipoprotein B and Low-Density Lipoprotein Cholesterol With Other Cardiovascular Risk Factors in the Insulin Resistance Atherosclerosis Study (IRAS)
Authors: Ken Williams, Allan D. Sniderman, Naveed Sattar, Ralph D’Agostino, Lynne E. Wagenknecht, Steven M. Haffner
Journal: Circulation (2003)

Risk factors for vascular disease include obesity, dyslipidemia, hypertension, dysglycemia, insulin resistance, inflammation, thrombosis, and subclinical atherosclerosis. This study compares the associations of apolipoprotein B (apoB) and LDL cholesterol (LDLC) with a wide array of measures of these risk factors.In 1522 individuals in the Insulin Resistance Atherosclerosis Study, anthropometric measures and measures of lipids, apoB, C-reactive protein, fibrinogen, plasminogen activator inhibitor-1 (PAI-1), fasting and postglucose load glucose and insulin concentrations, and carotid artery intima-media thickness (IMT) were taken and insulin sensitivity was determined by frequently sampled intravenous glucose tolerance test. There were significant differences in measures of abdominal obesity, dyslipidemia, hyperinsulinemia, and thrombosis between subjects with elevated apoB but normal LDLC versus those with elevated LDLC but normal apoB. In each statistically significant comparison, the elevated-apoB group had higher associated risk than the elevated-LDLC group. Moreover, apoB is highly significantly (P<0.0001) correlated with each measure in the direction of higher risk, whereas LDLC was significantly correlated (P<0.05) only with blood pressure, triglyceride, fibrinogen, and C-reactive protein. After further adjustment for LDLC, apoB correlations remained significant, whereas several LDLC correlations adjusted for apoB became significant in the direction of lower risk.Elevated apoB is more strongly associated than LDLC with other risk factors, including measures in the National Cholesterol Education Program guidelines for lipid treatment and other more recently established risk factors. This may provide new insight into why apoB is a better predictor of vascular risk than LDLC.
Light chain editors of anti-DNA receptors in human B cells
Authors: Olga Kalinina, Yue Wang, Kevin Sia, Marko Radic, Pierre-André Cazenave, Martin Weigert
Journal: The Journal of Experimental Medicine (2014)

Receptor editing is a mechanism of self-tolerance used in newly generated B cells. The expressed heavy (H) or light (L) chain of an autoreactive receptor is replaced by upstream V genes which eliminate or modify autoreactivity. Editing of anti-DNA receptors has been characterized in anti-DNA transgenic mouse models including 3H9, 3H9/56R, and their revertant 3H9GL. Certain L chains, termed editors, rescue anti-DNA B cells by neutralizing or modifying DNA binding of the H chain. This editing mechanism acts on the natural H chain repertoire; endogenous H chains with anti-DNA features are expressed primarily in combination with editor L chains. We ask whether a similar set of L chains exists in the human repertoire, and if so, do they edit H chains with anti-DNA signatures? We compared the protein sequences of mouse editors to all human L chains and found several human L chains similar to mouse editors. These L chains diminish or veto anti-DNA binding when expressed with anti-DNA H chains. The human H chains expressed with these L chains also have relatively high arginine (Arg) content in the H chain complementarity determining region (H3), suggesting that receptor editing plays a role in establishing tolerance to DNA in humans.
New Therapies for Gout
Authors: Daria B. Crittenden, Michael H. Pillinger
Journal: Annual Review of Medicine (2013)

Gout prevalence is increasing, yet management remains suboptimal. Fortunately, new insights into gout biology are permitting the development of novel, potentially more effective strategies for both gouty inflammation and urate lowering. Colchicine, a drug long used for gout, has been recently approved (for the first time ever) by the FDA, based on a new, safer dosing regimen. The recently appreciated centrality of IL-1β in acute gouty inflammation has prompted studies of agents blocking the IL-1β receptor or soluble IL-1β signaling (canakinumab, rilonacept, anakinra). Novel approaches to urate lowering have led to mechanism-based therapies such as urate synthesis inhibitors (febuxostat is already FDA approved and BCX4208 is in development), URAT-1 inhibitors promoting renal uric acid excretion (lesinurad), and recombinant uricase to directly catabolize urate (pegloticase). These new treatments do not obviate the need for lifestyle and dietary management, another area in which significant scientific and clinical progress has recently been made.