tbuckley/cabot-search huggingface dataset:
ATPS-14KETOGENIC DIET-INDUCED INCREASE IN MCT1 FACILITATES KETONE BODY OXIDATION IN RAT GLIOMAS
Authors: Henk De Feyter, Kevin Behar, Kevan Ip, Fahmeed Hyder, Lester Drewes, Robin de Graaf, Douglas Rothman
Journal: Neuro-Oncology (2015)

The dependence of brain tumor cells on glucose is the target of the ketogenic diet (KD), which creates a plasma nutrient profile similar to fasting: increased levels of ketone bodies and reduced plasma glucose concentrations. The use of KDs as therapy has been of particular interest for brain tumors because they reportedly cannot oxidize ketone bodies and therefore would be starved. However, in vivo studies assessing the ability of tumors to oxidize ketone bodies are lacking. We investigated ketone body oxidation in vitro and vivo using 13C magnetic resonance spectroscopy in combination with infusion of the 13C-labeled ketone body, beta-hydroxybutyrate (BHB) in two rodent glioma models (9L & RG2). The detection of 13C in glutamate following the infusion of [2,4-13C]-BHB was the primary outcome parameter and proof of oxidative 13C-BHB metabolism in the rat gliomas. Steady-state metabolic modeling was applied to further characterize the 13C-BHB metabolism. The level of glutamate 13C-labeling and 13C-BHB oxidation in 9L and RG2 rat gliomas was similar to that of contralateral brain. In addition, when glioma-bearing animals were fed a KD, immunohistochemistry showed that the ketone body transporter MCT1 was upregulated, facilitating uptake and doubling oxidation of ketone bodies in gliomas. These results demonstrate that rat gliomas can easily oxidize ketone bodies and indicate an adaptation through upregulation of ketone body transport when fed a KD. These data are not supporting the hypothesis that brain tumors are metabolically inflexible. Furthermore, there are indications that KDs in humans could also induce an increase in MCT1. MCT1 is a drug target for which an inhibitor is currently investigated in a clinical trial. Overall, these results indicate that the use of KDs as therapy targeting brain tumor metabolism and the effect of such diets on MCT1 needs further investigation, particularly in patients.
Dual c-Jun<i>N</i>-terminal kinase-cyclin D1 and extracellular signal-related kinase-c-Jun disjunction in human melanoma
Authors: G. Pathria, B. Garg, K. Garg, C. Wagner, S.N. Wagner
Journal: British Journal of Dermatology (2016)

Activity of both c-Jun and cyclin D1 is deemed critical for melanoma cell proliferation. This functionality is corroborated by frequently elevated expression and activity of these proteins in human melanomas. Correspondingly, alleviating c-Jun and cyclin D1 function is vital to the success of antimelanoma therapeutics.To understand the role of the c-Jun N-terminal kinase (JNK) signalling pathway in melanoma cell proliferation and survival.The effect of JNK inhibitors SP600125 and JNK-IN-8 on the proliferation and survival of genetically highly representative human melanoma cell lines was studied in assays of proliferation and apoptosis. Changes in c-Jun and cyclin D1 protein and mRNA levels in response to JNK and mitogen-activated protein kinase kinase (MEK) inhibition were investigated through immunoblotting and quantitative reverse-transcription polymerase chain reaction. The effects of JNK and MEK inhibitors on cell-cycle distribution were assessed by flow cytometry.We demonstrate the requirement of JNK signalling in melanoma cell proliferation and survival. While JNK inhibition suppressed the expression and activity of c-Jun, it failed to suppress cyclin D1 levels. Consistently with its inability to downregulate cyclin D1, JNK inhibition failed to induce G1 arrest. In contrast, the blockade of MEK-extracellular signal-regulated kinase (ERK) signalling, although unable to suppress c-Jun activity and expression, paradoxically abated cyclin D1 levels and triggered G1 arrest. This previously unreported dual disconnect between JNK-cyclin D1 and ERK-c-Jun levels was confirmed by concomitant JNK and BRAF inhibition, which suppressed both c-Jun and cyclin D1 levels and exhibited a heightened antiproliferative response.Dual disjunction between JNK-cyclin D1 and ERK-c-Jun signalling forms the basis for further investigation of combined JNK and MAPK signalling blockade as a more effective therapeutic approach in human melanoma.
&lt;italic&gt;Brief Communication:&lt;/italic&gt; Correlation Between the Carcinogenicities of Nitrofuran Derivatives and Their Destructive Actions on Sebaceous Glands of Mouse Skin&lt;xref ref-type="fn" rid="fn2"&gt;2&lt;/xref&gt;
Authors: H Takizawa, M Hozumi, T Sugimura, G T Bryan
Journal: JNCI Journal of the National Cancer Institute (1975)

The effects of six nitrofuran derivatives (including a formerly used food preservative) on mouse skin sebaceous glands were investigated. A close correlation was found between the carcinogenicities and destructive activities of nitrofuran derivatives on the sebaceous glands. 5-Nitro-2-furaldehyde semicarbazone and 4-methyl-1-[(5-nitrofurfurylidene)amino]-2-imidazolidinone, which are carcinogenic, caused marked destruction of the glands at a dose of 1-5 mg/mouse. 2-(5-Nitro-2-furfurylidene)-aminoethanol almost completely destroyed the glands at a dose of 5 mg/mouse; its carcinogenicity has not yet been investigated. 1-[(5-Nitrofurfurylidene)amino]-carcinogenic, did not affect the glands, even at a dose of 5 mg/mouse. 2-(2-Furyl)-3-(5-nitro-2-furyl)acrylamide, which is a potent mutagen but not carcinogenic, had no effect on the glands at a dose of 5 mg/mouse. Under similar conditions, the potent carcinogen 7,12-dimethylbenz(alpha)athracene almost completely destroyed the sebaceous glands at a dose of 0.05 mg/mouse, but dimethyl sulfoxide (used as solvent for the test compounds) had no effect.
Carcinoma of Unknown Primary: Focused Evaluation
Authors: Gauri R. Varadhachary
Journal: Journal of the National Comprehensive Cancer Network (2011)

The management of carcinoma of unknown primary (CUP) has evolved over the past decade, with the advent of sophisticated imaging and pathologic tests. Especially in the era of tailored therapeutics, this presents both an opportunity and a challenge. For the initial workup of a patient with CUP, a focused search for the primary cancer based on clinical presentation is recommended. Exhaustive use of unnecessary imaging, invasive studies, and pathologic tests adds to patient discomfort, is associated with significant cost, and often has a low yield for detection of a primary cancer. Physicians should be able to justify the need for ancillary tests and how results may impact the comprehensive management of patients. Over the next several years, physicians also need to focus their efforts on refining CUP subsets (e.g., isolated nodal, osseous, carcinomatosis presentations) and leveraging selective genomics and proteomics techniques to eventually deliver validated new therapeutic approaches to patients. This will require creative approaches to clinical studies, including establishment of international CUP cooperative groups and innovative designs. Just as physicians need to be selective in their diagnostic approach, they also need to be selective in their research efforts as they continue to impact quality of life and survival for patients with CUP.
Poly-gamma-glutamic acid from Bacillus subtilis upregulates pro-inflammatory cytokines while inhibiting NLRP3, NLRC4 and AIM2 inflammasome activation
Authors: Huijeong Ahn, Seung Goo Kang, Sung-il Yoon, Pyeung-Hyeun Kim, Doo Kim, Geun-Shik Lee
Journal: Cellular and Molecular Immunology (2016)
Resected pancreatic cancer (PC): Impact of adjuvant therapy (Rx) at a high-volume center (HVC) on overall survival (OS).
Authors: Margaret T Mandelson, Vincent J. Picozzi
Journal: Journal of Clinical Oncology (2016)

191 Background: Surgical outcomes for resected PC are known to be superior at HVCs. However, the impact of adjuvant (Rx) performed at HVCs is less studied. We examined the impact of site of adjuvant Rx administration on our resected patients (pts). Methods: Eligible pts were diagnosed 2003-2014 and resected at HVC. Pts were excluded for neoadjuvant Rx, synchronous cancer, death/lost to follow-up within 3 months or contraindications (e.g. morbidity) to adjuvant Rx.. Pts were also excluded if they refused adjuvant treatment or if a community oncologist (CC) was not identified in the medical record or in the western Washington population-based cancer registry. Pt and tumor characteristics were compared in univariate analysis and survival was calculated from date of diagnosis to death or last follow-up. Five year OS was estimated by the Kaplan Meier method and compared using Cox proportional hazards modeling to evaluate the impact of HVC adjuvant Rx on OS while adjusting for potential confounding factors. Results: 245 pts were eligible for study: 139 (57%) treated at HVC, 106 (43%) treated at CC. HVC and CC pts were similar with respect to stage and tumor size, nodal status, resection margins and average distance travelled to HVC. They differed by age (HVC: 63.1, CC: 68.2 p &lt; 0.01). Median and 5-yr OS was 36 mos and 33%. Median OS for HVC vs CC was 44 mos vs. 28 mos (p &lt; 0.01), and 5yr OS was 38.6% vs. 24.8% (p &lt; 0.01), adjustment for age did not alter our findings. Conclusions: 1) With respect to adjuvant Rx for resected PC, HVC and CC pts differed with respect to age only. 2) Both median and 5- yr OS was statistically superior at HVC vs CC. 3) Our study supports the use of HVCs for all Rx components for PC treated with curative intent. 4) Ongoing investigation of patterns of care and their impact on OS in PC is warranted.
Website of the Week: Cardiovascular diseases
Authors: Giulio Bognolo
Journal: BMJ (2003)

Two articles in this week's BMJ analyse the impact and cost effectiveness of defibrillators in public places (p 1312 and p 1316) and argue that there are better strategies for preventing unexpected death. Another two papers assess the use of aspirin after coronary surgery (p 1322) and its effect when given with ibuprofen (p 1298).

Cardiovascular diseases are a major burden in the United Kingdom, and prevention is even more important than treatment. Now adding to the vast array of websites on cardiovascular health comes the National electronic Library for Health's (NeLH) cardiovascular diseases specialist library (http://rms.nelh.nhs.uk/cardiovascular/). It is a welcome addition. Launched last week, the site is part of the wider NeLH programme developed in conjunction with the NHS and providing information in a range of fields from cancer to women's health.

The cardiovascular diseases specialist library aims to support the professional community, patients, and public alike. Well designed and extremely user friendly, the site provides much information that can be used for clinical decision making by doctors and that can advise patients about the risks of smoking, for example.

From a drop down menu users can rapidly gain access to guidelines, systematic reviews, bibliographies, a clinical database, and reviewed internet sites. A search option is available for the specialist section and the complete NeLH electronic library, and there is access to the full text version of nearly 1000 medical journals.

A useful feature is “hot off the press,” which highlights the most important papers published on cardiovascular diseases, with hyperlinks to the journal pages. Information is available on multiple conditions, causes and risk factors, diagnosis and management, and policies and prevention.

Should you need to access other branches of the NHS, the National Institute for Clinical Excellence (NICE), and the National Patient Safety Agency, there are direct links to them. There are also quick links to the main organisations that may be of use, so you do not have to look around for their home pages.
Renal function in patients receiving long-term cyclosporine therapy.
Authors: D H Van Buren, J F Burke, R M Lewis
Journal: Journal of the American Society of Nephrology (1994)

The site at which the vasomotor effects of cyclosporine are associated with acute nephrotoxicity appears to be the afferent arteriole. Proposed mechanisms mediating these effects include sympathetic nerve stimulation, disruption of the balance between vasodilating and vasoconstricting prostaglandins, hypersensitivity to vasoactive peptides, and endothelin release. These mechanisms mediate cyclosporine-associated intrarenal vasoconstriction, yet the causal relationship between these changes and the obliterative vasculopathy seen in association with chronic progressive renal allograft dysfunction is uncertain. Histologic findings seen in chronic progressive renal dysfunction are nonspecific and cannot be correlated solely with cyclosporine use. Retrospective studies analyzing both aggregate serial serum creatinine and reciprocal creatinine determinations did not report a pattern of progressive attrition consequent to toxic nephropathy. Prospective studies with serial GFR determinations with various reference substances found no progressive deterioration in allograft function. Both the retrospective and prospective studies indicate that the attrition of renal allograft function associated with cyclosporine use reflect the chronic effects of immunologic injury. Renal function in extrarenal transplant recipients immunosuppressed with cyclosporine can be characterized by an initial decline in native renal function followed by subsequent stabilization beyond the first 6 months. There does not appear to be an inordinate rate of progression to ESRD.
Initial biopsy procedure for breast cancer diagnosis influences number of surgical procedures and cost of care
Authors: W. B. Al-Refaie, J. N. Cormier, Y. Xing, K. K. Hunt, G. Fearmonti, R. Ghandi, H. M. Kuerer, F. Meric-Bernstam, I. Bedrosian, A. Lucci
Journal: Journal of Clinical Oncology (2006)

598 Background: Excisional biopsy (ExB) and percutaneous needle biopsy (PB) are both accurate methods for diagnosing breast cancer. However, comprehensive breast cancer staging requires surgical assessment of the primary tumor and regional nodes. This study was designed to examine surgical and financial implications for breast cancer patients undergoing either ExB or PB. Methods: We evaluated 2,459 women with invasive breast cancer enrolled in a comprehensive database from 2000 to 2005. Clinical and treatment factors were compared for patients who had ExB versus PB. Total costs, facility fees (operating rooms, radiology suites, and pathology processing), and professional fees were estimated. A multivariate logistic regression was performed to determine factors associated with biopsy type. Results: PB was utilized in 1817 (74%) patients and ExB in 642 (26%). Of ExB patients, 86% were performed prior to referral. Patients undergoing ExB required a greater number of surgical procedures for margin control and lymph node assessment compared to PB (median 2.0 vs. 1.0, respectively). ExB exacted a cost increase 1.7 times that of PB, with a difference of &gt;$3400 at our institution. After adjusting for age, tumor size and year of diagnosis, ExB was significantly associated with an increased number of surgical procedures required for definitive treatment compared to PB (OR = 166.7, p &lt; 0.001). Conclusions: Excisional biopsy for breast cancer diagnosis results in an increased need for return trips to the operating room and higher cost of care. Percutaneous biopsy should be considered as the preferred approach in the diagnosis of breast cancer. No significant financial relationships to disclose.
Intra- and Inter-Patient Comparison of Efficacy Between Two Phase Ii Studies of Trabectedin (T) in Patients (Pts) with Translocation-Related Sarcomas (Trs); a Randomized Comparative Study (Study-C) and a Single Arm Study (Study-S)
Authors: T. Yonemoto, S. Takahashi, N. Araki, H. Sugiura, T. Ueda, M. Takahashi, H. Morioka, H. Hiraga, T. Hiruma, T. Kunisada, A. Matsumine, A. Kawai
Journal: Annals of Oncology (2014)
APOL1 renal-risk genotypes associate with longer hemodialysis survival in prevalent nondiabetic African American patients with end-stage renal disease
Authors: Lijun Ma, Carl D. Langefeld, Mary E. Comeau, Jason A. Bonomo, Michael V. Rocco, John M. Burkart, Jasmin Divers, Nicholette D. Palmer, Pamela J. Hicks, Donald W. Bowden, Janice P. Lea, Jenna O. Krisher, Margo J. Clay, Barry I. Freedman
Journal: Kidney International (2016)
Heartbeat OCT and Motion-Free 3D In Vivo Coronary Artery Microscopy
Authors: Tianshi Wang, Tom Pfeiffer, Evelyn Regar, Wolfgang Wieser, Heleen van Beusekom, Charles T. Lancee, Geert Springeling, Ilona Krabbendam-Peters, Antonius F.W. van der Steen, Robert Huber, Gijs van Soest
Journal: JACC. Cardiovascular imaging (2016)
Response to Zakkar et al
Authors: William S. Weintraub, Kirk N. Garratt
Journal: Circulation (2016)

Do we have sufficient information to guide our choice of therapy for chronic total occlusions (CTOs)?The articles by Weintraub and Garratt ("we" in this rebuttal) and Zakker et al are complementary.Zakker et al are highly critical of technical limitations and outcomes of percutaneous coronary intervention for CTOs, stressing the technical advantages of coronary artery bypass graft (CABG) for CTOs, covering a number of the same studies as Weintraub and Garratt.We placed less emphasis on technical ability to perform CABG for CTOs and more on case selection, the importance of viable myocardium, and clinical outcomes.We stressed that the literature concerning outcomes of CABG for CTOs is limited and that additional studies are needed.Overall comparisons of CABG to percutaneous coronary intervention, such as the Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery (SYNTAX) trial, or of percutaneous coronary intervention to medical therapy, such as the Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial, cannot directly address the issue of whether to perform CABG for CTOs.The only randomized comparison of CABG to percutaneous coronary intervention was in a subset of the SYNTAX trial that included 543 CTOs, which found more complete revascularization with CABG.Complete revascularization is a surrogate; presumably, this SYXTAX subset was too small to compare clinical outcomes.We also learned little from nonrandomized comparative effectiveness studies of CABG for CTOs.Even excellent uncontrolled observational studies, such as the one by Holzhey et al, can only tell us that CABG for total occlusions can be performed; it cannot tell us whether CABG improved outcomes.We think it can be agreed that our data are inadequate and that randomized trials would offer considerably better information to guide clinical decisions.In the meantime, careful case selection, preferably with assessment of viability, is appropriate.
Cellular Toxicity of Pancreatic Carcinogens&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: P F Zucker, A M Chan, M C Archer
Journal: JNCI Journal of the National Cancer Institute (1986)

Azaserine (CAS: 115-02-6), streptozocin (CAS: 18883-66-4; streptozotocin), and N-nitrosobis(2-oxopropyl)amine [(BOP) CAS: 60599-38-4] produce different types of pancreatic tumors in rodents. We have investigated the toxic effects of these compounds on pancreatic tissues from Wistar rats and Syrian hamsters. Inhibition of protein synthesis was used as a measure of toxicity. Pancreatic islets and acinar cells from rat and hamster were labeled with [3H]leucine for 60 minutes in vitro in the presence of the various carcinogens. Azaserine, which produces acinar cell tumors in the rat, inhibited synthesis by all tissues; rat acinar cells, however, were most sensitive. Glutamine, but not serine, provided some protection against azaserine toxicity. Streptozocin inhibited synthesis by islets of both species and acinar cells from hamster; islets were the most sensitive. BOP and N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine, which induce ductal tumors in the hamster, had no effect on any of the tissues examined. These results indicate that the specificities of the cellular toxicities of the pancreatic carcinogens parallel, to some degree, their tumorigenic effects.
Identification of the BRD1 interaction network and its impact on mental disorder risk
Authors: Tue Fryland, Jane H. Christensen, Jonatan Pallesen, Manuel Mattheisen, Johan Palmfeldt, Mads Bak, Jakob Grove, Ditte Demontis, Jenny Blechingberg, Hong Sain Ooi, Mette Nyegaard, Mads E. Hauberg, Niels Tommerup, Niels Gregersen, Ole Mors, Thomas J. Corydon, Anders L. Nielsen, Anders D. Børglum
Journal: Genome Medicine (2016)

The bromodomain containing 1 (BRD1) gene has been implicated with transcriptional regulation, brain development, and susceptibility to schizophrenia and bipolar disorder. To advance the understanding of BRD1 and its role in mental disorders, we characterized the protein and chromatin interactions of the BRD1 isoforms, BRD1-S and BRD1-L. Stable human cell lines expressing epitope tagged BRD1-S and BRD1-L were generated and used as discovery systems for identifying protein and chromatin interactions. Protein-protein interactions were identified using co-immunoprecipitation followed by mass spectrometry and chromatin interactions were identified using chromatin immunoprecipitation followed by next generation sequencing. Gene expression profiles and differentially expressed genes were identified after upregulating and downregulating BRD1 expression using microarrays. The presented functional molecular data were integrated with human genomic and transcriptomic data using available GWAS, exome-sequencing datasets as well as spatiotemporal transcriptomic datasets from the human brain. We present several novel protein interactions of BRD1, including isoform-specific interactions as well as proteins previously implicated with mental disorders. By BRD1-S and BRD1-L chromatin immunoprecipitation followed by next generation sequencing we identified binding to promoter regions of 1540 and 823 genes, respectively, and showed correlation between BRD1-S and BRD1-L binding and regulation of gene expression. The identified BRD1 interaction network was found to be predominantly co-expressed with BRD1 mRNA in the human brain and enriched for pathways involved in gene expression and brain function. By interrogation of large datasets from genome-wide association studies, we further demonstrate that the BRD1 interaction network is enriched for schizophrenia risk. Our results show that BRD1 interacts with chromatin remodeling proteins, e.g. PBRM1, as well as histone modifiers, e.g. MYST2 and SUV420H1. We find that BRD1 primarily binds in close proximity to transcription start sites and regulates expression of numerous genes, many of which are involved with brain development and susceptibility to mental disorders. Our findings indicate that BRD1 acts as a regulatory hub in a comprehensive schizophrenia risk network which plays a role in many brain regions throughout life, implicating e.g. striatum, hippocampus, and amygdala at mid-fetal stages.
Reply to the letter by Dr Graham concerning ethical and interpretation issues with vonoprazan-containing <i>H. pylori</i> eradication therapy
Authors: Kazunari Murakami, Yuuichi Sakurai, Madoka Shiino, Nobuo Funao, Akira Nishimura, Masahiro Asaka
Journal: Gut (2016)

We thank Dr Graham for his interest in our article.1 ,2 In Japan, 7 days administration of PPI+amoxicillin+clarithromycin is standard treatment for Helicobacter pylori eradication3 and is the only approved treatment as first-line therapy in Japan. Therefore, there is no ethical issue in increasing sample size to match the current eradication rate. In a blinded interim analysis, the overall eradication rate was 81.6%, which was a lower rate than 90% that …