tbuckley/cabot-search huggingface dataset:
Phase I trial of gemcitabine and Wilms' tumor 1 peptide vaccine combination therapy in patients with advanced pancreatic or biliary tract cancer.
Authors: M. Kaida, Y. Morita-Hoshi, T. Wakeda, Y. Yamaki, A. Soeda, S. Kondo, C. Morizane, H. Ueno, T. Okusaka, Y. Heike
Journal: Journal of Clinical Oncology (2010)

e13049 Background: WT1 is expressed in various kinds of cancers and serves as a potent antigen for cancer immunotherapy. Methods: We performed a clinical phase I trial of gemcitabine (GEM) and WT1 vaccine combination therapy for advanced pancreatic cancer or biliary tract cancer. Patients with HLA-A 0201, HLA-A 0206, and/or HLA-A 2402 positive inoperable advanced pancreatic or biliary tract cancer, who has not received GEM previously were eligible. Six doses of GEM and 4 doses of WT1 vaccination were administered with the following schedule in 2 months: GEM (1000 mg/m2) was administered intravenously on days 1, 8, and 15 with 1-week rest. WT1 peptide (1 mg or 3 mg) in Montanide adjuvant was injected intradermally on day 8 and day 22. Results: Between November 2007 and September 2009, 25 patients (13 male, 12 female) were enrolled in this study. Nine patients had inoperable advanced pancreatic cancer, 8 had gallbladder cancer, 4 had intrahepatic bile duct cancer, and 4 had extrahepatic bile duct cancer. Out of 18 patients who completed the study 15 had stable disease and 3 had progressive disease at the end of this study. Seven patients could not complete the study, because of rapid disease progression (6) or patient's preference (1). Grade 1 or 2 skin reaction at the site of vaccination was observed in all patients. Patients also experienced grade 1 to 4 cytopenia, which was considered to be caused by GEM. No other adverse events above grade 3 were seen. The median survival time and disease control rate at 2 months for overall patients, pancreatic cancer, gallbladder cancer, intrahepatic bile duct cancer, and extrahepatic bile duct cancer were 275 days, 193 days, 196 days, 374 days, 225 days, and 64%, 89%, 25%, 100%, 50%, respectively. Although WT1-specific T cells were not detectable in the fresh whole blood either by multimer assay or intracellular IFN-γ staining, tetramer analysis of peptide cultured cells showed an expansion of WT1 specific T cells in 59% (13/22) of the patients. Conclusions: GEM and WT1 vaccine combination therapy is safe enough to be applied to patients with advanced pancreatic or biliary tract cancer, and that may provide a long-term survival in some patients. No significant financial relationships to disclose.
Perilipin2/adipophilin and ApoA-1 team up to combat atherosclerosis
Authors: Benoit Pourcet, Bart Staels
Journal: Cardiovascular Research (2015)

This editorial refers to ‘Enhanced atheroprotection and lesion remodelling by targeting the foam cell and increasing plasma cholesterol acceptors’ by S.-H. Son et al. , pp. 294–304. 

Atherogenesis is characterized by accumulation of lipids and immune cells in the vascular wall.1 Modified low density lipoprotein (LDL) promotes the infiltration of monocytes in the intima, where they differentiate in macrophages which scavenge cholesterol from atherogenic lipoproteins, hence inducing atherosclerotic lesion formation. In these macrophages, lipoprotein-derived cholesterol accumulates as cholesteryl esters (CEs) into lipid droplets (LDs), which are coated by specific LD-associated proteins. Current therapeutic strategies specifically aiming to limit foam cell formation are still insufficient despite extensive research.2 Liver and intestinal-produced apolipoprotein A-1 (ApoA-1) triggers cholesterol efflux from macrophages by interacting with the cholesterol transporter ATP binding cassette (ABC)A1, leading to the formation of nascent HDL, which then functionally interacts with ABCG1 to further enhance this process. HDL then returns cholesterol to the liver for excretion via the bile, a process named reverse cholesterol transport (RCT).2 Efficient enhancement of cholesterol efflux from foam cells and ensuing RCT are necessary to limit atherogenesis. Son et al . propose an innovative approach in which simultaneous limitation of cholesterol storage in lipid droplets and ApoA-1-stimulated efflux from macrophages cooperate to decrease plaque lipid-burden and, even more intriguingly, enhance plaque stability ( Figure 1 ).3 



Figure 1 
Overexpression of ApoA-1 and decrease of PLIN2 cooperate to reduce foam cell formation and stabilize atherosclerotic lesion. ( A ) In arterial …
Imaging patterns predict patient survival and molecular subtype in glioblastoma via machine learning techniques
Authors: Luke Macyszyn, Hamed Akbari, Jared M. Pisapia, Xiao Da, Mark Attiah, Vadim Pigrish, Yingtao Bi, Sharmistha Pal, Ramana V. Davuluri, Laura Roccograndi, Nadia Dahmane, Maria Martinez-Lage, George Biros, Ronald L. Wolf, Michel Bilello, Donald M. O'Rourke, Christos Davatzikos
Journal: Neuro-Oncology (2015)

MRI characteristics of brain gliomas have been used to predict clinical outcome and molecular tumor characteristics. However, previously reported imaging biomarkers have not been sufficiently accurate or reproducible to enter routine clinical practice and often rely on relatively simple MRI measures. The current study leverages advanced image analysis and machine learning algorithms to identify complex and reproducible imaging patterns predictive of overall survival and molecular subtype in glioblastoma (GB). One hundred five patients with GB were first used to extract approximately 60 diverse features from preoperative multiparametric MRIs. These imaging features were used by a machine learning algorithm to derive imaging predictors of patient survival and molecular subtype. Cross-validation ensured generalizability of these predictors to new patients. Subsequently, the predictors were evaluated in a prospective cohort of 29 new patients. Survival curves yielded a hazard ratio of 10.64 for predicted long versus short survivors. The overall, 3-way (long/medium/short survival) accuracy in the prospective cohort approached 80%. Classification of patients into the 4 molecular subtypes of GB achieved 76% accuracy. By employing machine learning techniques, we were able to demonstrate that imaging patterns are highly predictive of patient survival. Additionally, we found that GB subtypes have distinctive imaging phenotypes. These results reveal that when imaging markers related to infiltration, cell density, microvascularity, and blood–brain barrier compromise are integrated via advanced pattern analysis methods, they form very accurate predictive biomarkers. These predictive markers used solely preoperative images, hence they can significantly augment diagnosis and treatment of GB patients.
Effects of Comprehensive Lifestyle Modification on Blood Pressure Control
Authors: Lawrence J Appel, Catherine M Champagne, David W Harsha, Lawton S Cooper, Eva Obarzanek, Patricia J Elmer, Victor J Stevens, William M Vollmer, Pao-Hwa Lin, Laura P Svetkey, Sarah W Stedman, Deborah R Young
Journal: JAMA (2003)

ContextWeight loss, sodium reduction, increased physical activity, and limited alcohol intake are established recommendations that reduce blood pressure (BP). The Dietary Approaches to Stop Hypertension (DASH) diet also lowers BP. To date, no trial has evaluated the effects of simultaneously implementing these lifestyle recommendations.ObjectiveTo determine the effect on BP of 2 multicomponent, behavioral interventions.Design, Setting, and ParticipantsRandomized trial with enrollment at 4 clinical centers (January 2000-June 2001) among 810 adults (mean [SD] age, 50 [8.9] years; 62% women; 34% African American) with above-optimal BP, including stage 1 hypertension (120-159 mm Hg systolic and 80-95 mm Hg diastolic), and who were not taking antihypertensive medications.InterventionParticipants were randomized to one of 3 intervention groups: (1) "established," a behavioral intervention that implemented established recommendations (n = 268); (2) "established plus DASH,"which also implemented the DASH diet (n = 269); and (3) an "advice only" comparison group (n = 273).Main Outcome MeasuresBlood pressure measurement and hypertension status at 6 months.ResultsBoth behavioral interventions significantly reduced weight, improved fitness, and lowered sodium intake. The established plus DASH intervention also increased fruit, vegetable, and dairy intake. Across the groups, gradients in BP and hypertensive status were evident. After subtracting change in advice only, the mean net reduction in systolic BP was 3.7 mm Hg (P<.001) in the established group and 4.3 mm Hg (P<.001) in the established plus DASH group; the systolic BP difference between the established and established plus DASH groups was 0.6 mm Hg (P = .43). Compared with the baseline hypertension prevalence of 38%, the prevalence at 6 months was 26% in the advice only group, 17% in the established group (P = .01 compared with the advice only group), and 12% in the established plus DASH group (P<.001 compared with the advice only group; P = .12 compared with the established group). The prevalence of optimal BP (<120 mm Hg systolic and <80 mm Hg diastolic) was 19% in the advice only group, 30% in the established group (P = .005 compared with the advice only group), and 35% in the established plus DASH group (P<.001 compared with the advice only group; P = .24 compared with the established group).ConclusionIndividuals with above-optimal BP, including stage 1 hypertension, can make multiple lifestyle changes that lower BP and reduce their cardiovascular disease risk.
Potato Consumption and Risk of Type 2 Diabetes: Results From Three Prospective Cohort Studies
Authors: Isao Muraki, Eric B. Rimm, Walter C. Willett, JoAnn E. Manson, Frank B. Hu, Qi Sun
Journal: Diabetes Care (2015)

We aimed to elucidate whether potato consumption is associated with a higher risk of type 2 diabetes (T2D).
Benefit of treatment of latent tuberculosis infection in individual patients
Authors: Claudia C. Dobler, Andrew Martin, Guy B. Marks
Journal: European Respiratory Journal (2015)

We aimed to develop a decision aid that estimates whether treatment of latent tuberculosis infection (LTBI) is likely to have a net gain in quality-adjusted life-years for an individual. A Markov model was developed which incorporated personalised estimates for risk of tuberculosis (TB) reactivation, TB death, quality-of-life impairments and treatment side-effects. The net effect of LTBI treatment was quantified in terms of quality-adjusted life-years gained or lost. Analyses were conducted for a representative set of hypothetical patients. LTBI treatment was estimated to be beneficial when the annual risk of TB reactivation exceeded 13/100,000 to 93/100,000 for females aged 10-75 years and 15/100,000 to 119/100,000 for males aged 10-75 years; the numbers needed to treat to avoid one case of TB were 93, 77, 85 and 72, respectively, at these threshold levels. LTBI treatment was estimated to confer a positive net benefit across a broad range of patients with characteristics typically seen in a low incidence setting for TB. Use of the decision aid has the potential to facilitate and increase confidence with LTBI treatment decisions by providing clinicians and patients with personalised estimates of likely net benefit.
Genomic alterations in primary breast cancers and their sentinel lymph node metastases detected by array CGH
Authors: Chunjie Wang, Vladmir Vladmir, Vietty Wong, Stephanie Leung, Keisha Warren, Gaiane Iakovleva, Nona Arneson, Naomi Miller, Bruce Youngson, David McCready, Susan Done
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

347 

Breast cancer is a devastating disease afflicting millions of women and it is a major cause of premature mortality. It is estimated that one in eight women in North America will be diagnosed with breast cancer in their lifetime. Breast cancer kills by metastasizing. The presence and extent of axillary lymph nodes metastasis is one of the most important prognostic indicators in breast cancer. The sentinel lymph node is the first node that receives lymphatic drainage from a primary cancer within the breast. Identification of genomic alterations in sentinel lymph node metastases may allow identification of the earliest changes associated with metastatic spread. In this investigation, using array comparative genomic hybridization (aCGH), we compared the genomic profiles of primary breast carcinomas, their matched sentinel and more distal lymph node metastases and invasive breast carcinomas without nodal metastasis. All the cases studied were from a single institution, University Health Network, Toronto, ON. Prior to the study institutional Research Ethics Board approval was obtained. Nineteen cases of infiltrating duct carcinoma (IDC) were subjected to aCGH: 8 cases IDC without metastasis, 11 cases IDC with axillary lymph node metastases. Fourteen lymph node metastasis samples were studied: 9 sentinel and 5 distal. aCGH data was analyzed by correlation of raw data, cluster analysis, circular binary segmentation and moving average methods. The results showed that primary tumors and their matched sentinel lymph node metastases share high genomic similarity. However, gains at 2p24-13, 2q22-33, 9q21-31, 12q21-23, 17 q23-25 and loses at 11q23-ter, 14q23-31, 20p11-q12, 2q36-ter, 8q24-ter, 9q33-ter, 2p11-q11, and 12q13 were either preferentially or uniquely detected in IDC associated with lymph node metastasis. Two genes from each region of gain were selected for further validation by quantitative real-time PCR (Q-PCR). Amplification within the 60-63Mb region of chromosome 17 (17q23.3-24.2) was associated with large IDC size and lymph node metastasis ( p <0.05). Our findings indicate that genomic events associated with metastatic progression do occur and can be detected within primary breast cancer. Gain on 17q23-25 is a candidate region for further testing as a predictor of nodal metastasis. These results could be applied to develop novel targeted gene therapies and predict clinical prognosis.
Chondrocyte clocks make cartilage time-sensitive material
Authors: Karen M. Doody, Nunzio Bottini
Journal: Journal of Clinical Investigation (2015)

Circadian rhythms mediated by both central and tissue-specific peripheral clocks allow for the synchronization of biological processes with diurnal cycles such as activity and rest. Disruption of these rhythms can be caused by altered sleep-awake patterns or by pathological conditions and can initiate or exacerbate human disease through mechanisms that are only partially understood. In this issue, Dudek et al. identify a chondrocyte-autonomous cartilage clock and demonstrate that expression of an important circadian pacemaker, BMAL1, decreases during osteoarthritis progression. They show that chondrocyte-specific deletion of BMAL1 leads to cartilage degradation and disruption of key pathways, shifting cartilage homeostasis toward a catabolic state. These findings provide insight into the interplay between circadian rhythm and cartilage in osteoarthritis.
Growth of Multicell Spheroids in Tissue Culture as a Model of Nodular Carcinomas&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Sutherland, Robert M., McCredie, John A., Inch, W. Rodger
Journal: JNCI Journal of the National Cancer Institute (1971)

Journal Article Growth of Multicell Spheroids in Tissue Culture as a Model of Nodular Carcinomas Get access Robert M. Sutherland, Robert M. Sutherland The Ontario Cancer Treatment and Research Foundation, London Clinic, and the Departments of Therapeutic Radiology and Surgery, University of Western Ontario, London, Ontario, Canada Search for other works by this author on: Oxford Academic PubMed Google Scholar John A. McCredie, John A. McCredie The Ontario Cancer Treatment and Research Foundation, London Clinic, and the Departments of Therapeutic Radiology and Surgery, University of Western Ontario, London, Ontario, Canada Search for other works by this author on: Oxford Academic PubMed Google Scholar W. Rodger Inch W. Rodger Inch The Ontario Cancer Treatment and Research Foundation, London Clinic, and the Departments of Therapeutic Radiology and Surgery, University of Western Ontario, London, Ontario, Canada Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 46, Issue 1, January 1971, Pages 113–120, https://doi.org/10.1093/jnci/46.1.113 Published: 01 January 1971 Article history Received: 29 June 1970 Accepted: 28 September 1970 Published: 01 January 1971
Superior Performance of Aptamer in Tumor Penetration over Antibody: Implication of Aptamer-Based Theranostics in Solid Tumors
Authors: Dongxi Xiang, Conglong Zheng, Shu-Feng Zhou, Shuxi Qiao, Phuong Ha-Lien Tran, Chunwen Pu, Yong Li, Lingxue Kong, Abbas Z. Kouzani, Jia Lin, Ke Liu, Lianhong Li, Sarah Shigdar, Wei Duan
Journal: Theranostics (2015)

Insufficient penetration of therapeutic agents into tumor tissues results in inadequate drug distribution and lower intracellular concentration of drugs, leading to the increase of drug resistance and resultant failure of cancer treatment.Targeted drug delivery to solid tumors followed by complete drug penetration and durable retention will significantly improve clinical outcomes of cancer therapy.Monoclonal antibodies have been commonly used in clinic for cancer treatment, but their limitation of penetrating into tumor tissues still remains because of their large size.Aptamers, as "chemical antibodies", are 15-20 times smaller than antibodies.To explore whether aptamers are superior to antibodies in terms of tumor penetration, we carried out the first comprehensive study to compare the performance of an EpCAM aptamer with an EpCAM antibody in theranostic applications.Penetration and retention were studied in in vitro three-dimensional tumorspheres, in vivo live animal imaging and mouse colorectal cancer xenograft model.We found that the EpCAM aptamer can not only effectively penetrate into the tumorsphere cores but can also be retained by tumor sphere cells for at least 24 h, while limited tumor penetration by EpCAM antibody was observed after 4 h incubation.As observed from in vivo live animal imaging, EpCAM aptamers displayed a maximum tumor uptake at around 10 min followed by a rapid clearance after 80 min, while the signal of peak uptake and disappearance of antibody appeared at 3 h and 6 h after intravenous injection, respectively.The signal of PEGylated EpCAM aptamers in xenograft tumors was sustained for 26 h, which was 4.3-fold longer than that of the EpCAM antibody.Consistently, there were 1.67-fold and 6.6-fold higher accumulation of PEGylated aptamer in xenograft tumors than that of antibody, at 3 h and 24 h after intravenous administration, respectively.In addition, the aptamer achieved at least a 4-time better tumor penetration in xenograft tumors than that of the antibody at a 200 μm distances from the blood Ivyspring International
Kinetics of Nitrosamide Formation From Alkylureas, &lt;italic&gt;N&lt;/italic&gt;-Alkylurethans, and Alkylguanidines: Possible Implications for the Etiology of Human Gastric Cancer&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: Sidney S. Mirvish
Journal: JNCI Journal of the National Cancer Institute (1971)

The rate of methylurea nitrosation to give methylnitrosourea was proportional to the concentrations of methylurea, nitrous acid, and hydrogen ion. The reaction rate was very rapid under acidic conditions and was increased by sulfate and phosphate ions. Nitrosation of ethylurea, N-methylurethan, and N-ethylurerhan obeyed similar third-order kinetics, but proceeded at slower rates. Nitrosation of DL-citrulline gave N-δ-nitroso-DL-citrulline, with a rate constant 7% of that for methylurea nitrosation. Nitrosation of methylguanidine gave a 35% yield of methylnitrosourea, but the rate constant at pH 2 was only 0.6% of that for citrulline. A new compound, methylnitrosocyanamide, was produced at shorter times. Nitrosation of N-α-acetyl-L-arginine and L-arginine gave unidentified products with absorption spectra similar to the spectrum of nitrosocitrulline, the rate constants at pH 1 being similar to the rate constant for methylguanidine. The results explain findings by others that feeding nitrite plus alkylureas to rats induces cancer and produces 7-alkylation of guanine in tissue nucleic acids. The results also raise the possibility that intragastric nitrosamide formation could be a significant etiological factor in human gastric cancer, because some nitrosamides induce gastric cancer in animals, and some alkylureas and alkylguanidines e.g., citrulline, arginine, and methylguanidine, occur widely in food. If a man ate a 300-g meal containing 38 mg citrulline and 60 mg sodium nitrite, it was estimated that 2.7 mg citrulline might be nitrosated intragastrically. This could be a significant hazard, if nitrosocitrulline is carcinogenic.
Hepatic expression of <i>CYP3A4</i> and <i>CYP3A5</i> genes in Asians and implications for pharmacokinetic variations during chemotherapy
Authors: S. R Jada, X. Xiang, Q. Zhou, H. H Li, L. L Ooi, B. Chowbay
Journal: Journal of Clinical Oncology (2006)

13124 Background: Hepatic expression of CYP3A4 and CYP3A5 enzymes are important determinants of interindividual variability in chemotherapy. The objective of this study was to genotypically quantitate expression of CYP3A4 and CYP3A5 genes in healthy hepatic tissues from Asian cancer patients undergoing hepatectomy. Methods: Healthy Asian hepatic tissues (Chinese: N = 27; Malay: N = 1; Indian: N = 3) were obtained from the institution’s central tissue repository bank. Messenger RNA was isolated from each tissue sample and reversed transcribed to cDNA followed by real time PCR experiments. Results from these gene expression experiments were normalized against GAPDH transcripts. DNA was also extracted from the hepatocytes and genotyped for four single nucleotide polymorphisms in the CYP3A4 gene (CYP3A4*1B, *4, *5 and *6) and three in the CYP3A5 gene (CYP3A5*1, *3 and *6). Results: CYP3A4 variant forms were absent in all Asian patients. CYP3A5 was polymorphic and genotyping analysis showed that the *1/*1, *1/*3 and *3/*3 genotypes were present in 6%, 52% and 42% of the Asian liver samples, respectively. Liver tissues harbouring the *1/*1 and *1/*3 genotypes showed insignificant CYP3A5 expression pattern (P=0.160). The CYP3A5 mRNA expression levels were approximately 6-fold lower in *3/*3 samples compared with samples carrying at least one *1 allele (*1/*1 + *1/*3). Non-parametric analysis using Kruskal-Wallis test showed that the hepatic expression of CYP3A5 mRNA between liver tissues that harboured at least one *1 allele (*1/*1 + *1/*3) and those carrying homozygous *3/*3 genotype to be highly significantly different (P &lt; 0.007). Conclusions: These results show that polymorphic CYP3A4 isoforms are probably rare in Asians compared with CYP3A5 polymorphisms. This study also suggest that CYP3A5, rather than CYP3A4 could be important for interindividual variations in pharmacokinetics of CYP3A4/5 substrates during chemotherapy in Asians. No significant financial relationships to disclose.