tbuckley/cabot-search huggingface dataset:
Acute Effects of Dietary Cholic Acid and Methylazoxymethanol Acetate on Colon Epithelial Cell Proliferation; Metabolism of Bile Salts and Neutral Sterols in Conventional and Germfree SD Rats&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: W F Weidema, E E Deschner, B I Cohen, J J DeCosse
Journal: JNCI Journal of the National Cancer Institute (1985)

The acute effects of cholic acid ingestion on methylazoxymethanol acetate [(MAM) CAS: 592-62-1]-treated conventional and germfree rats were investigated. Male SD rats were divided into 4 treatment groups. The first group received control chow; the second group, control chow plus 0.5% cholic acid; the third group, control chow plus MAM; and the fourth group, control chow plus 0.5% cholic acid plus MAM. Fecal bile acids, cholesterol, cholesteral degradation products, and neutral sterols, as well as labeling indices and numbers of epithelial cells per crypt column, were measured after 6 weeks of treatment. The administration of MAM to germfree groups diminished both fecal bulk and the amount of fecal water. MAM did not affect the fecal bile acid composition. Analysis of the fecal bile acids in conventional rats fed cholic acid demonstrated that half of the bile acids were in a form of deoxycholic acid. In the germfree groups fed cholic acid, 90% of the bile acids appeared unaltered in the feces. Neither in the germfree nor in the conventional groups was an effect seen of MAM on the output of fecal neutral sterols. The addition of cholic acid to the food decreased the output of neutral sterols both in the conventional (P less than .001) and in the germfree (P less than .02) animals. The germfree animals showed a reduced amount of neutral steroid excretion (P less than .01) when compared to the findings for the conventional groups. MAM had no influence on the fecal cholesterol or coprostanol output. The consumption of 0.5% cholic acid decreased the total output of cholesterol (P less than .05). The excretion of coprostanol was significantly diminished in the conventional rats fed cholic acid (P less than .001). No difference in labeling indices was observed between conventional and germfree rats, whether treated with cholic acid, MAM, or cholic acid plus MAM. However, all germfree groups showed less epithelial cells per crypt column (P less than .001) than did conventional animals.
Abstract 109: Adiponectin Inhibits TNF-a-Induced Vascular Inflammatory Response via Caveolin-Mediated Ceramidase Recruitment and Activation
Authors: Xin Ma, Yajing Wang, Wayne Lau, Erhe Gao, Walter Koch
Journal: Circulation Research (2013)

Anti-inflammatory and vascular protective actions of adiponectin (APN) are well-recognized. However, many fundamental questions remain unanswered. The current study attempted to identify the APN receptor subtype responsible for APN’s vascular protective action, and investigate the role of ceramidase activation in APN anti-inflammatory signaling. Wild type (WT) or gene manipulated HUVEC were treated with TNFα in the presence and absence of APN. The effect of APN on TNFα-induced inflammatory and oxidative/nitrative stress was determined. In WT HUVEC, APN significantly reduced TNFα-induced ICAM-1 expression and attenuated TNFα-induced superoxide and peroxynitrite formation (P&lt;0.01). These anti-inflammatory actions were virtually abolished by AdipoR1-, but not AdipoR2-, knockdown (KD). Treatment with APN significantly increased neutral ceramidase (nCDase) activity (3.7-fold, P&lt;0.01). AdipoR1-KD markedly (P0.05), reduced APN-induced nCDase activation. More importantly, siRNA mediated nCDase-KD markedly blocked the effect of APN upon TNFα-induced ICAM-1 expression (P0.05), and modestly inhibited APN anti-inflammatory effect (P87% of APN-induced nCDase activation was lost. Whereas APN treatment failed to inhibit TNFα-induced ICAM-1 expression, treatment with S1P or SEW (S1P receptor agonist) remained effective in Cav1-KD cells in reducing TNFα-induced ICAM-1 expression (P&lt;0.01). AdipoR1 and Cav1 co-localized and co-precipitated in HUVECs. APN treatment did not affect this interaction. Moreover, re-expression of WT Cav1 in Cav1-KD cells restored nCDase activation in response to APN (P&lt;0.01 vs. vehicle), whereas re-expression of a mutated Cav1 blocking AdipoR1/Cav1 interaction failed to restore APN-mediated nCDase activation. Finally, there is weak basal Cav1/nCDase interaction, which significantly increased following APN treatment. These results demonstrate for the first time that APN inhibits TNFα-induced inflammatory response via Cav1-mediated ceramidase recruitment and activation in an AdipoR1- dependent fashion.
Characterization of the Mutational Landscape of Multiple Myeloma Using Comprehensive Genomic Profiling
Authors: Christoph Heuck, Donald Johann, Brian A Walker, Caleb K Stein, Yogesh Jethava, Rashid Z Khan, Scott Miller, Frits van Rhee, Maurizio Zangari, Ruslana Tytarenko, Phillip Farmer, Ryan Williams, Siraj Ali, Phil J Stephens, Vincent A. Miller, Gareth J Morgan, Bart Barlogie
Journal: Blood (2014)
Maximum standardized uptake (SUVmax) on initial <sup>18</sup>FDG-PET/CT as prognostic value in patients with diffuse large B-cell lymphoma.
Authors: B. Kwon, Y. Choi, Y. Soel, M. Song, S. Kim, H. Shin, J. Chung, G. Cho
Journal: Journal of Clinical Oncology (2010)

8103 Background: PET is widely used imaging tool for staging and monitoring tumor response of NHL. This study evaluate whether maximum standardized uptake values(SUVmax) on initial 18FDG-PET/CT can identify subset of patients with better or worse prognosis among patients with DLBCL. Methods: Sixty-three patients with newly diagnosed DLBCL underwent PET/CT before rituximab-containing chemotherapy. Patients were treated with six cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine,and prednisone) every 3 weeks. SUVmax determined in the coregistered PET/CT images. Results: During a median follow up period 26 months, disease progressed in24 (37%) of patients. Median time to progression was 32 months. Estimated 2-year progression free survival was 58.4%.Twelve patients died. Estimated 2 year overall survival was 75.8%. The average SUVmax was 11.4 ± 5.6(range, 3.0-30.1). Patients evaluated and divided according to their SUVmax level in three groups. Patients were divided as follows: group I (SUV<7.5, n=16), group II (SUV≥7.5 and <15, n=33), group III (SUV≥15, n=16). Early tumor response was assessed after three cycles of chemotherapy. Patients within the group I, overall response rate was 93% (CR:8, PR:7) and PD in one patient. In the group II, overall response rate was 71%(CR:15, PR:7) and PD in 6 patients within the group III showed overall response rate 93%(CR:8, PR:7) and PD in one patient. After six cycles of chemotherapy, disease progressed in 3 patients, one patient in each group. During the follow up period, relapse was four patients in the group I, five patients in the group II, two patients in the group III. We did not find a significant relationship of maximum SUV with response to treatment or PFS or OS. Conclusions: There was no prognostic value of SUVmax on initial PET/CT in patients with diffuse large B-cell Lymphoma. Maximum SUV on initial PET does not help in prediction of treatment response and relapse. No significant financial relationships to disclose.
Abstract 19383: Reduced Longitudinal and Circumferential Strains with Radial Compensation in End Stage Renal Disease Patients Despite Normal Ejection Fraction
Authors: Padmini Varadarajan, Shuja Rasool, Waqas Aftab, Ramdas G Pai
Journal: Circulation (2012)

Background: Patients with end stage renal disease (ESRD) have high prevalence of heart failure despite normal left ventricular (LV) ejection fraction (EF) leading to adverse outcomes and higher mortality. Hence, we prospectively assessed LV strain patterns in ESRD patients with normal EF. Methods: We prospectively evaluated 100 ESRD patients with normal EF and wall motion and compared them to 22 age and gender matched controls. Complete demographic, clinical and echocardiographic data were collected. LV longitudinal, circumferential and radial strains were computed using speckle tracking echocardiography and corresponding end systolic wall stresses were calculated using Mirsky’s formulae. Results: The mean age was 54 years, 41% men, 53% had diabetes, mean EF was 65% and 15% had heart failure. The global longitudinal and mid LV circumferential strains were significantly lower in patients with ESRD with normal EF compared to the age and gender matched controls (-15.7+7.9% vs -20.4+4.1%, p=0.02 and 19.8+6.2% vs 25.2+3.8%, p=0.01 respectively). However, the radial strain was marginally higher compared to the controls (26.2+15.4% vs. 17.4+9.6%, p=0.07). Normalized for the corresponding wall stresses, only the circumferential strain was lower in ESRD patients and longitudinal and radial stresses were similar between the groups. Conclusions: 1) Global longitudinal and circumferential strains are reduced accompanied by an increase in radial strain in ESRD patients with normal EF. 2) This may only partly be explained by changes in wall stress and reflects incipient LV myocardial dysfunction. 3) Evaluation and targeting of abnormalities of LV wall stress and strain in this high risk population may help obviate heart failure and its deleterious consequences.
Phase I study of trabectedin (T) in combination with docetaxel (D) in patients with advanced malignancies
Authors: M. Von Mehren, D. Buck, E. Temmer, Y. A. Elsayed, R. B. Cohen
Journal: Journal of Clinical Oncology (2006)

2068 Background: T is a novel cytotoxic agent that binds to the DNA minor groove and is active in several tumor types. The objective of this study is to determine the maximum tolerated dose (MTD) of the combination. Other objectives include safety and efficacy. Methods: Eligible patients (pts) had advanced cancer, PS 0–1 and adequate organ function. Restricted pts were limited to 1 prior cytotoxic regimen, while unrestricted pts had no limit. On day 1 of each cycle, Pts received D starting at 60 mg/m 2 over 1 hour followed by T starting at 0.4 mg/m 2 over 3 hours. Dosing was repeated q 3 weeks. Incremental doses of both drugs were explored. PK samples were collected. A standard “3+3” dose escalation, definitions of dose limiting toxicity (DLT), and dose modifications were implemented. Results: To date, 31 pts have been treated, receiving 147 cycles (Range 1–28, median 6). At dose level 2 (D 60 mg/m 2 + T 0.6 mg/m 2 ), 2/4 unrestricted pts and 3/5 restricted pts developed DLT (grade IV neutropenia and/or febrile neutropenia) requiring institution of prophylactic filgrastim. Therapy was well tolerated after institution of filgrastim and no DLTs have been observed through the current dose level 6 (D 60 mg/m 2 + T 1.3 mg/m 2 ). Most frequently related grade 3 and 4 adverse events (AE) were: neutropenia (51%), elevated liver enzymes (3.7%), DVT (3.7%), and hyponatremia (3.7%). The most frequently related grade 1and 2 AEs were: fatigue (56%), neutropenia (56%), nausea (55%), and anemia (40%). Anti-tumor activity included a complete response in a pt with peritoneal Ca and durable prolong stable disease (SD) in 2 pts with sarcoma (20 + and 10 + months) and a pt with prostate Ca (8+ months). Another pt with gastric Ca achieved SD lasting 8 months. PK evaluations of D and T are ongoing. Conclusions: The combination of T and D with filgrastim support is safe and well-tolerated. Preliminary data suggest that this regimen is active in pts with advanced cancers. Additional cohorts are planned giving D 75 mg/m 2 and T 1.3 mg/m 2 . [Table: see text]
PX-171-003-A1, an open-label, single-arm, phase (Ph) II study of carfilzomib (CFZ) in patients (pts) with relapsed and refractory multiple myeloma (R/R MM): Long-term follow-up and subgroup analysis.
Authors: D. S. D. Siegel, T. Martin, M. Wang, R. Vij, S. Lonial, V. Kukreti, N. J. Bahlis, M. Alsina, G. Somlo, F. Buadi, F. J. Reu, K. W. Song, L. A. Kunkel, A. Wong, M. Vallone, R. Z. Orlowski, A. K. Stewart, S. Singhal, S. Jagannath, A. J. Jakubowiak
Journal: Journal of Clinical Oncology (2011)

8027 Background: CFZ is a novel, highly selective epoxyketone proteasome inhibitor in development for treatment (tx) of MM. Single-agent CFZ has shown durable activity in up to 63% of pts with relapsed MM. PX-171-003-A1 was an open-label, single-arm ph 2b trial in pts with advanced refractory MM. Methods: Pts received and were refractory to ≥2 prior therapies (bortezomib [BTZ], either thalidomide or lenalidomide, and an alkylator). CFZ was given on d1, 2, 8, 9, 15, 16 of 28-day cycles (C), (20 mg/m2 in C1; 27 mg/m2 in C2–12). Primary endpoint was overall response rate (ORR). Secondary endpoints were clinical benefit response (CBR), duration of response (DOR), overall survival (OS), and safety. Cytogenetic data (if available), peripheral neuropathy (PN) history, International Staging System (ISS)/Durie-Salmon staging, and prior tx history were collected for subset analyses. Responses assessed per International Myeloma Working Group criteria were confirmed by Independent Review Committee. Results: Of 266 pts enrolled, 257 were response-evaluable. ORR was 24% with median DOR of 7.4 mo (95% CI 6.2–10.3). 71 of 229 pts had ≥1 cytogenetic abnormality and achieved an ORR of 28%, with median DOR of 7 mo (95% CI 4–10). Median OS was 15.5 mo (95% CI 12.7–19.0). The most common treatment-emergent adverse events (AEs) ≥ G3 were primarily hematologic. New-onset PN and PN ≥G3 were infrequent. 27 pts completed 12C and continued on extension protocol PX-171-010. Notably, there was no difference in DOR and TTP for pts achieving MR vs ≥PR, suggesting that distinguishing these subsets may not translate into clinically meaningful differences in the context of CFZ treatment. Conclusions: Single-agent CFZ achieved significant, durable responses in 36% of pts with BTZ and IMiD refractory MM, including those with unfavorable cytogenetics. CFZ was well-tolerated and AEs were clinically manageable with no new, unexpected, or cumulative toxicities. Baseline characteristic Total n ≥PR, % ≥MR, % Overall 257 24 36 Prior therapies <5 110 25 33 ≥5 147 24 36 Cytogenetic status Normal/favorable 158 24 37 Unfavorable 71 28 32 ISS stage I 76 32 46 II 96 25 35 III 78 18 24
Effect of Bisphosphonates, Denosumab, and Radioisotopes on Bone Pain and Quality of Life in Patients with Non–Small Cell Lung Cancer and Bone Metastases: A Systematic Review
Authors: Lizza E.L. Hendriks, Bregtje C.M. Hermans, Marieke H.J. van den Beuken—van Everdingen, Monique M.H. Hochstenbag, Anne-Marie C. Dingemans
Journal: Journal of Thoracic Oncology (2015)
Experts call for smoking ban outside pubs and restaurants
Authors: Adrian O’Dowd
Journal: BMJ (2015)

New exclusion zones that ban smoking should be established outside pubs, restaurants, parks, and schools, public health experts have claimed.

The Royal Society for Public Health, an independent health education charity, published a report on 13 August1 in which it called for an extension to the public areas that already ban smoking, in the interests of everyone’s health. The society also called for much greater use of electronic (e) cigarettes by smoking cessation services, claiming that nicotine was “no more harmful to health than caffeine.”

In its report, Stopping Smoking by Using Other Sources of Nicotine , the society’s authors said that …
Lack of correlation of neoantigens arising from tumor somatic mutations with tumor infiltrating lymphocytes (TILs) or survival in HER2-positive breast cancer (HER2+ BC).
Authors: Peter Stephen Savas, Roberto Salgado, Franco Caramia, Carsten Denkert, Sibylle Loibl, Christos Sotiriou, Fabrice Andre, Terence Paul Speed, Sherene Loi
Journal: Journal of Clinical Oncology (2015)

613 Background: We have previously shown that TILs are positively prognostic in HER2+ BC. TILs comprise mostly CD8+ T cells but the basis for antigen recognition is unclear. Here we investigated the relationship between somatic mutations and TILs. Methods: Two cohorts of HER2+ early-stage BC were analysed. Cohort 1: 50 cases from the Responsify-EU project and Cohort 2: 172 cases from The Cancer Genome Atlas with whole exome sequencing, gene expression, germline SNP (inferring HLA genotype) and survival. Cohort 1 received adjuvant trastuzumab and chemotherapy. TILs were quantified from H&E slides in both cohorts using our previously defined method. We performed computational prediction of mutant peptide neoantigens binding patient specific MHC Class I. Results: In cohorts 1 and 2, 660/2113 (31%) and 3268/10841 (30%) non-synonymous point mutations were predicted to be immunogenic mutations (iMut), with a median of 9.5 (IQR 3 – 19), and 9 (IQR 6 – 18) per sample per cohort, respectively. The number of iMut predicted was strongly correlated with the total number of mutations (Cohort 1: Rs = 0.9; Cohort 2: Rs = 0.8, both p < 0.00001). TILs were strongly and significantly correlated (Rs> 0.5, p < 0.001 for all) with gene expression surrogates of immune activation (CD8A, GRZMB, PRF1) and immunosuppression (PDL1, CTLA4, IDO1). In cohorts 1&2, there was no significant correlation between TILs and total mutation count (Rs= 0.04; Rs= 0.02, respectively), iMut (Rs= 0 for both) nor the APOBEC mutation signature (Rs= 0). There was no difference in the level of TILs between lowest and highest quartiles of iMut burden in the cohorts combined (p = 0.7). In the trastuzumab-treated cohort 1, total mutation count ( ≤ 100 vs > 100) and iMut count (0 vs ≥ 1) was not associated with invasive disease-free survival (IDFS p = 0.4; p = 0.9 respectively). The presence of a recently reported melanoma neoantigen signature (Snyder, NEJM 2014) also did not significantly correlate with the presence of TILs (Rs= 0.03) or IDFS (p = 0.6). Conclusions: In HER2+BC, predicted tumor neoantigens did not correlate with TILs or survival. Other mechanisms seem to be eliciting the anti-tumor immune response in HER2+BC.
The Right Drug for the Right Patient: Navigating Systemic Therapy Options in Metastatic Renal Cell Carcinoma and Future Directions
Authors: Toni K. Choueiri, Robert J. Motzer
Journal: Journal of the National Comprehensive Cancer Network (2015)

School as an Associate Professor of Medicine.He is interested in developing novel therapies and biomarkers in genitourinary malignancies including kidney and bladder cancers.His work is funded by ASCO, the DF/HCC Kidney SPORE, and
Ozone Exposure Increases Circulating Stress Hormones and Lipid Metabolites in Humans
Authors: Desinia B. Miller, Andrew J. Ghio, Edward D. Karoly, Lauren N. Bell, Samantha J. Snow, Michael C. Madden, Joleen Soukup, Wayne E. Cascio, M. Ian Gilmour, Urmila P. Kodavanti
Journal: American Journal of Respiratory and Critical Care Medicine (2016)

Air pollution has been associated with increased prevalence of type 2 diabetes; however, the mechanisms remain unknown. We have shown that acute ozone exposure in rats induces release of stress hormones, hyperglycemia, leptinemia, and glucose intolerance that are associated with global changes in peripheral glucose, lipid, and amino acid metabolism.To examine ozone-induced metabolic derangement in humans using serum metabolomic assessment, establish human-to-rodent coherence, and identify novel nonprotein biomarkers.Serum samples were obtained from a crossover clinical study that included two clinic visits (n = 24 each) where each subject was blindly exposed in the morning to either filtered air or 0.3 parts per million ozone for 2 hours during 15-minute on-off exercise. Serum samples collected within 1 hour after exposure were assessed for changes in metabolites using a metabolomic approach.Metabolomic analysis revealed that ozone exposure markedly increased serum cortisol and corticosterone together with increases in monoacylglycerol, glycerol, and medium- and long-chain free fatty acids, reflective of lipid mobilization and catabolism. Additionally, ozone exposure increased serum lysolipids, potentially originating from membrane lipid breakdown. Ozone exposure also increased circulating mitochondrial β-oxidation-derived metabolites, such as acylcarnitines, together with increases in the ketone body 3-hydroxybutyrate. These changes suggested saturation of β-oxidation by ozone in exercising humans.As in rodents, acute ozone exposure increased stress hormones and globally altered peripheral lipid metabolism in humans, likely through activation of a neurohormonally mediated stress response pathway. The metabolomic assessment revealed new biomarkers and allowed for establishment of rodent-to-human coherence. Clinical trial registered with www.clinicaltrials.gov (NCT 01492517).
Second cancers after hematopoietic stem cell transplantation with total body irradiation conditioning regimen in hematologic disorders.
Authors: J. Kim, M. J. Chung, J. H. Lee, B. O. Choi, S. Chung
Journal: Journal of Clinical Oncology (2011)

6548 Background: Myeloablative hematopoietic stem cell transplantation (HSCT) is the treatment of choice for several malignant hematologic disorders. Long-term survivors are increasing by the improvement of treatment protocol and supportive care. The purpose of this retrospective study was to define the incidence of second cancers in a cohort of very long term survivors treated with total body irradiation (TBI) as a part of conditioning prior to HSCT. Methods: Between 1992 and 2005, 1446 patients with hematologic disorders underwent HSCT with TBI conditioning regimen. Total 780 patients with disease free at least 5 years after HSCT were evaluated. The dose of TBI was median 12 Gy. TBI was fractionated from 1.65 to 2 Gy per fraction, twice a day. The graft-versus-host disease (GVHD) prophylaxis was cyclosporine associated to methotrexate in the majority of patients. The cumulative probability of a new malignancy was estimated by Kaplan-Meier method. The log-rank test was used for statistical comparison of potential risk factors for second malignancy. Multivariate analysis was performed using Cox proportional hazard model. Results: Median age at transplantation was 30 years (range, 2 - 66). Median duration of follow up was 9.3 years (range, 5.0 – 18.0). Second cancer occurred in 17 patients. The median time from transplantation to the diagnosis of second cancer was 5.6 years. Three tongue cancers, 1 tonsil cancer, 3 thyroid cancers, 2 breast cancers, 1 colon cancer, 1 brain tumor and 2 bone tumors were detected. The posttransplant lymphoproliferative disorders were observed in 4 patients. The experience of chronic extensive GVHD was the statistically significant factor associated with an increased risk of second cancer in univariate and multivariate analysis (p < 0.0001 and p < 0.0001, respectively). Conclusions: Long term surveillance of patients undergoing HSCT is essential to detect late-developing cancers, particularly for patients who received immunosuppressive therapy for a long period by chronic extensive GVHD. Guidelines should be developed in regard to screening and prevention of second cancers for the benefit of patients.