tbuckley/cabot-search huggingface dataset:
Imbalance of immune response functional phenotype and alveolar macrophages phenotype in COPD
Authors: Svetlana Lyamina, Igor Malyshev
Journal: European Respiratory Journal (2014)

Due to the role of macrophages in immune reactions and the concept of M1/M2 programming and Th1/Th2 paradigm alveolar macrophages (AM) phenotype greatly influence immune response disorders in the lungs. Objective: assessment of immune response functional phenotype imbalance and AM phenotype in COPD. Methods: Generalized analysis of AM phenotype and functional phenotype of immune response was performed by flow cytometry (Beckman Coulter FC500) by expression of M1/M2 AM phenotypes CD markers (CD25, CD80/CD163, CD206, respectively) and cytokine production of proinflammatory M1, anti-inflammatory M2 and M1/M2 cytokines in culture medium (CM) of AM and bronchoalveolar lavage fluid (BALF) in patients with stage 1-3 COPD (1: n=12, 2: n=15, 3: n=14; 32-60 y.o.) and healthy volunteers (HV) (n=10, 35-58 y.o.). Results: M1/M2 ratio of AM CD markers expression progressively increased from stage 1 to 3 COPD (2.6, 3.2 and 4.0 times, respectively, p<0.05) as compared to HV. In stage 1-3 COPD M1/M2 indices of CM cytokine production was increased 8.1, 15.24 and 1.45 times, respectively vs. HV (p<0.05). Generalized M1/M2 BALF cytokine index in 1-2 stage COPD was decreased (0.5 and 0.4 times, respectively, p<0.05) and 1.8 times increased in stage 3 COPD (p<0.05). Conclusions: Genuine AM phenotype in stage 1-3 COPD significantly shifted towards M1 phenotype vs healthy. Functional phenotype of immune response in stage 1-2 COPD drifted towards M2 phenotype, whereas in stage 3 COPD – to M1 phenotype vs healthy volunteers. Imbalance of immune response functional phenotype and alveolar macrophages phenotype in stage 1-2 COPD most likely indicate compensatory reaction of the innate immune response.
Abstract 12820: Arrhythmias on Home Intravenous Inotropic Therapy in Advanced Heart Failure
Authors: Kumar Sanam, Marina I Revilla Martinez, Taimoor Hashim, Charity J Morgan, Jose A Tallaj, Salpy V Pamboukian, Renzo Y Loyaga-Rendon, James F George, Deepak Acharya
Journal: Circulation (2014)

Introduction: Although home inotropes improve hemodynamics and symptoms in low-output congestive heart failure (CHF), they were associated with arrhythmias in prior trials. However, these studies were performed before routine use of implantable cardioverter defibrillators (ICDs), cardiac resynchronization, beta blockers, and aldosterone antagonists in CHF. Although concern for arrhythmias limits inotrope use, arrhythmia risks with inotropes on modern therapies are not well known. Methods: We collected arrhythmia data at baseline and post-inotrope on 197 consecutive patients discharged from our institution between January 2007 and March 2013 on intravenous inotropes. Patients were followed until they died, received a transplant or left ventricular assist device, were weaned off inotropes, or remained on inotropes at the end of the study. Results: All patients had advanced CHF, with mean baseline NYHA 3.7, cardiac index 1.7 L/min/m2, left ventricular ejection fraction (LVEF) 17%. At baseline, 39% had a hist...
Final results from an EORTC (GU Group)/NCRI randomized phase III trial of adjuvant interleukin-2, interferon alpha, and 5-fluorouracil in patients with a high risk of relapse after nephrectomy for renal cell carcinoma (RCC).
Authors: M. Aitchison, C. A. Bray, H. Van Poppel, R. Sylvester, J. Graham, C. Innes, L. McMahon, P. A. Vasey
Journal: Journal of Clinical Oncology (2011)

4505 Background: Despite an apparently curative resection, 30% of patients with RCC will develop metastases. Histological risk factors can predict those at highest risk. The role of adjuvant treatment remains unclear. The aim of the present study was to determine if triple therapy improves disease free (DFS) or overall survival (OS). Methods: Patients 8 weeks post nephrectomy for RCC without macroscopic residual disease with stage T3b-c,T4 or any pT and pN 1 or pN 2 or positive microscopic margins or microscopic vascular invasion, and no metastases were randomised to receive either adjuvant treatment (regimen in table below) or to observation only. Quality of life was assessed by EORTC QLQ C-30. Treatment delivery and toxicity were monitored. The trial was designed to detect an increase in 3 year DFS from 50 % in controls to 65 % on treatment (hazard ratio (HR) = 0.63) with 90% power and 2-sided alpha = 0.05; this required 308 patients and 200 events. The actual power achieved was 87%. Results: From 1998 to 2007, 309 patients were randomized (68% male), 155 to the control arm (median age 55) and 154 to treatment (median age 57). 35% did not complete the treatment, primarily due to toxicity (92% of patients experienced > grade 2, 41%> grade 3). There were no statistically significant differences between the two arms at 6 months in any QoL parameters. There was however a suggestion of a persistent deficit in fatigue and physical function (p = 0.06). Median follow-up time was 5.9 years (maximum 12.1 years). 182 patients relapsed with 3 year DFS of 50% with control versus 61% with treatment (overall HR 0.84, 95% confidence interval (CI) 0.63-1.12). 124 patients died. OS at 5 years is 63% for control and 70% with treatment (HR 0.86, 95% CI 0.60 -1.22). Conclusions: The treatment is associated with significant toxicity. There is no statistically significant benefit for the regimen in terms of disease free or overall survival. Adjuvant treatment regimen. Drug Dose Weeks Days IL-2 s.c. (MIU/m2) 20 1,4 3,4,5 5 2,3 1,3,5 IFN-α s.c. (MIU/m2) 6 1,4 1 6 2,3 1,3,5 9 5-8 1,3,5 5-FU i.v. bolus (mg/m2) 750 5-8 1
Analysis of association between carcinoid heart disease and mesenteric fibrosis in patients with midgut carcinoid tumour
Authors: K. Desai, S. Bhattacharya, R. Srirajaskanthan, L. Morgan-Rowe, C. Toumpanakis, T. Meyer, M. Caplin
Journal: Journal of Clinical Oncology (2009)

e15650 Background: Valvular heart disease in patients with carcinoid syndrome is due to development of fibrosis and endocardial thickening in the heart. The most accepted theory relating to development of heart disease is secretion of serotonin (5- hydroxy tryptamine) by the tumour or metastases. Mesenteric fibrosis develops as a result of peptides e.g.TGF beta released by local metastases. Both complications cause significant morbidity and mortality in patients with carcinoid syndrome. Aim: to evaluate the relationship of carcinoid heart disease and mesenteric fibrosis. Methods: We analysed retrospectively all patients (n=200) who had metastatic (liver metatstasis) neuroendocrine tumour and carcinoid syndrome with the primary clearly identified within the small bowel or caecum. We aimed to evaluate clinically symptoms of mesenteric ischemia and small bowel obstruction and also radiological presence of desmoplasia and small bowel dilatation. All patients underwent clinical and echocardiographic cardiovascular assessment to determine the presence of carcinoid heart disease. Results: Of 200 patients 42 had echocardiographic evidence of carcinoid heart disease. 4 patients had evidence of both mesenteric desmoplasia and carcinoid heart disease. 38 patients had carcinoid heart disease alone. Of the remaining 158 patients who had no evidence of carcinoid heart disease, 24 of them had evidence of desmoplasia and/or clinical evidence of sub-acute bowel obstruction where no other cause could be found. The remaining 134 patients had none of these complications. Comparing the relationship of Carcinoid heart disease and mesenteric fibrosis using two tailed exact Fisher's test, p value is 0.45, demonstrating they are statistically independent. We are currently assessing the effect on mortality. Conclusions: Carcinoid heart disease and mesenteric fibrosis (and its effects) are important determinants in morbidity and mortality of patients with midgut neuroendocrine tumour. Although carcinoid heart disease and mesenteric fibrosis are part of the same patho-physiologic process affecting patients with midgut neuroendocrine tumour, the results suggest that progression of these complications is independent of each other. No significant financial relationships to disclose.
BRCA1 large genomic rearrangement identified in an Ashkenazi Jewish woman.
Authors: E. A. Schalles, C. A. Cullinane
Journal: Journal of Clinical Oncology (2010)

e12029 Background: Germline mutations in BRCA1 and BRCA2 are associated with an increased risk of breast and ovarian cancer. Successfully identifying BRCA1/2 mutation carriers is imperative so effective cancer risk medical management options may be implemented. There are numerous reports of individuals initially classified as not having an identifiable deleterious point mutation who were later discovered to carry a large genomic rearrangement (deletion or duplication). We report a woman of Ashkenazi Jewish ancestry diagnosed with invasive ductal carcinoma of the right breast at age 33 and invasive ductal carcinoma of the left breast at age 51 who was ultimately identified as being a carrier of a BRCA1 large genomic rearrangement. Methods: Over a five year period (from 2003 to 2008) the following genetic testing was performed: mutation analysis for 187delAG and 5385insC within BRCA1 and 6174delT within BRCA2, BRCA1/2 full gene sequencing and a comprehensive rearrangement test of both BRCA1 and BRCA2 by quantitative PCR analysis and sequence analysis of the CHK2 gene. Results: The patient was found to carry the germline BRCA1 mutation del exon 1-2. The 1100delC mutation was not detected within the CHK2 gene for this individual. Conclusions: Previous investigations have estimated the prevalence of genomic rearrangements in different populations and commented on the selection process of individuals specifically for large genomic rearrangement testing. It has been suggested that genomic rearrangement testing should be considered in non-Ashkenazi Jewish women with a significant personal and family history of breast and ovarian cancer. Our patient is of Ashkenazi Jewish ancestry and did not report a strong family cancer history (mother, maternal grandmother and paternal grandmother all with post-menopausal breast cancer). Restrictive testing guidelines may hinder identifying BRCA mutation carriers and impede medical interventions such as enhanced cancer screening and/or risk reduction strategies. Therefore, if there is sufficient support for BRCA1/2 full gene sequencing and a point mutation is not identified then large genomic rearrangement testing should automatically be included for all individuals regardless of ethnicity. No significant financial relationships to disclose.
A prospective validation of a direct tumor xenograft model in pancreatic ductal adenocarcinoma (PDA)
Authors: A. Jimeno, A. Solomon, C. Karikari, I. Garrido-Laguna, D. Trusty, R. Hruban, R. Schulick, J. Cameron, A. Maitra, M. Hidalgo
Journal: Journal of Clinical Oncology (2008)

4500 Background: While many agents have been tested in patients (pts) with PDA very few have demonstrated clinical activity. Furthermore, most drugs are effective in small groups of patients suggesting that biomarkers predictive of efficacy are important. New preclinical models predictive of clinical outcome that can be used for drug screening and biomarker discovery are needed. We have developed the PancXenoBank, a preclinical model that uses surgically resected PDAs to generate xenografted cancers as a platform for drug evaluation and marker discovery. This study prospectively evaluated the ability of this model to predict clinical patient outcome. Methods: PDAs surgically resected at Johns Hopkins Hospital are implanted and propagated in nude mice. A battery of 5 approved and 5 investigational agents are then tested in mice bearing a xenograft and ranked based on activity against each pts tumor while the pt undergoes standard adjuvant treatment. This information is used to guide pt treatment at the time of progression. Results: From Nov 2005 to Dec 2007 207 pts were consented, 190 operated and 90 were xenografted. Major causes for not xenografting were other histologies/no cancer (40), unresectable disease (17) or too little tissue (16). Of the 90 xenografted cases, 18 failed to engraft, 32 have grown and 40 are still at the implantation phase (< 6 months). We have generated complete efficacy data on 16 patients for whom a tailored-made set of standard and investigational agents with activity against their tumors has been defined. Thus far we have applied the information to one patient predicted to be resistant to gemcitabine (G) and sensitive to mitomycin C (MMC). The patient progressed after 2 cycles of G, and had a complete response after second line treatment with MMC (CA19–9 dropped from 100,000 to 10, and the pt remains progression-free at 18+ months). Conclusions: The proposed approach is feasible and will lead to the validation (or lack of) of this model as predictive of clinical outcome. The PancXenoBank is the only available preclinical model for which this important question can be directly answered. Drug efficacy results, further statistical data and an update on the clinical trial will be presented. No significant financial relationships to disclose.
UGT1A1,A7 and A9 genotyping and pharmacokinetics of irinotecan-containing chemotherapy in patients with advanced cancer
Authors: B. Valenzuela, R. Nalda, M. Duart, V. Escudero, J. Perez-Ruixo, E. Martinez-Navarro, J. Rebollo, R. Gonzalez, A. Brugarolas
Journal: Journal of Clinical Oncology (2009)

e14563 Background: To the best of our knowledge only one previous report in asian lung cancer patients (pts) assesed UGT1A1, A7 and A9 genotypes along with irinotecan pharmacokinetics (Han et al. JCO 2006; 24: 2237–44). We set out to evaluate UGT1A1, A7 and A9 genotypes in caucasian cancer patients and their relationship with both irinotecan toxicity and irinotecan pharmacokinetics. Methods: UGT1A1, A7 and A9 genotypes were obtained from blood genomic DNA by direct sequencing. The area under the time-concentration curve (AUC) of SN-38 and SN-38G were calculated. The ratio between these AUCs (AUC SN-38G /AUC SN-38) was also calculated. Associations between pharmacokinetics parameters and the UGT1A genotypes were assessed by univariate analysis. Toxicity was collected using standard NCI grading criteria. Statistical correlation between presence of grade III and IV toxicity and UGT1A1,A7 and A9 genotypes was done by Pearson's Chi square. At least 80 patients (with both genotype and pharmacokinetics) are needed to achieve enough statistical power. Results: At the time of writing this abstract, complete genotyping and toxicity data from 59 patients were available. Sex (females 17, males 42). Median age 60 (range 25–88). Pathology (no. pts): lung (26), colon (17), others (16). 21 pts. (35.59%) had received previous chemotherapy. All but 5 pts received doses of irinotecan between 120 and 150 mg/m2. Median no. of cycles 6 (range 1–15). The frequencies of the different UGT1A1, A7 and A9 genotypes are similar to those previously reported. At least one episode of grade III or IV leukopenia was present in 19 pts. (32.2%), and grade III diarrea in 11 pts (18.6%). No statistically significant correlation was found between presence of leukopenia grades III and IV, and the genotypes UGT1A1,A7, and A9 (P=0.687, P=0.156 and P=0.476, respectively). Diarrea grade III was not statistically significantly associated with UGT1A1 (P=0.318), A7 (P=0.318) and A9 (P=0.158). 21 out of 59 pts. had pharmacokinetics (PK) data available. In genotype-PK association analysis, UGT1A1,A7 and A9 were not statistically associated with AUC SN-38G / AUC SN-38 ratios (P=0.844, P=0.911, P=0.431, respectively). Conclusions: Patients are still being accrued to achieve the targeted size. No significant financial relationships to disclose.
Membranes of Normal Hamster Lymphocytes and Lymphoid Cells Neoplastically Transformed by Simian Virus 40. I. High-Yield Purification of Plasma Membrane Fragments2
Authors: R. Schmidt Ullrich, D. F. H. Wallach, F. D. G. Davis
Journal: JNCI Journal of the National Cancer Institute (1976)

In this first paper of a series comparing the membranes of normal lymphocyte populations from male outbred Syrian hamsters with those of neoplastic transformants (GD 248) induced by simian virus 40, a method is described for the isolation of representative plasma membrane (PM) fragments from both cell types. Multiple criteria were used to monitor the purity and yield of PM material after cell disruption by nitrogen cavitation and after membrane fractionation by a combination of differential centrifugation and isopyknic ultracentrifugation in dextran density gradients. Lactoperoxidase-catalyzed radioiodination before cell disruption was used as an extrinsic surface marker; Na+,K+-activated ATPase, as well as alkaline phosphatase, was used as intrinsic functional PM markers. The distribution of nuclei, mitochondria, lysosomes, and endoplasmic reticulum (ER) during fractionation was monitored by the measurement of DNA, succinate dehydrogenase and monoamine oxidase, beta-glucuronidase and glucose-6-phosphatase, and NADH:lipoamide oxidoreductase, respectively. According to the three PM markers employed, a 15- to 20-fold purification (over homogenate) and a PM yield of about 65% were obtained for both cell categories, with negligible contamination by DNA, mitochondria, lysosomes, and er. The procedure also allowed recovery of 60% of the mitochondria free of other cell elements.
The transient receptor potential vanilloid 4 channel modulates uterine tone during pregnancy
Authors: Lihua Ying, Margaux Becard, Deirdre Lyell, Xiaoyuan Han, Linda Shortliffe, Cristiana Iosef Husted, Cristina M. Alvira, David N. Cornfield
Journal: Science Translational Medicine (2015)

TRPV4 channel activity determines myometrial tone and may be a target for treating preterm labor.
Our experiences in cases with breast cancer
Authors: E. Gocen, A. Mayadagli, S. K. Gul, F. Oruc, C. Parlak
Journal: Journal of Clinical Oncology (2008)

11579 Background: Breast cancer is the most common malignancy among women. Although its incidence reveals a trend toward incline, mortality associated with breast cancer is gradually decreasing. In the present study, epidemiological features of cases of breast cancer, which had been followed up regularly between years 1996 and 2006, were assessed retrospectively. Methods: A total of 622 patients with the diagnosis of breast cancer, which had been followed up in our clinic at regular intervals between years 1996 and 2006, were evaluated in terms of their demographic features, stages and prognostic features. Results: Median age was 53 (25–92). There were 277 cases at the age ≤ 50, and 345 cases were older than 50. Most of the cases were postmenopausal (n:459, 73.7%), and tumor was localized in the upper lateral quadrant in 505 cases (81.2%). Median follow-up time was 31.2 months (1–249.4). Median age at menarche and first pregnancy were 13 years (12–16) and 20 years (15–40), respectively. Median number of pregnancy was 4 (0–12). TNM stages were stage I in 70 patients, stage II in 313 patients, stage III in 201 patients and stage IV in 38 patients. Most common histopathological type was invasive ductal carcinoma in 576 cases (92.7%), invasive lobular carcinoma in 18 cases (2.8%), medullary carcinoma in 11 cases (1.8%) and others in 17 cases (2.7%). All cases were operable except 37 cases. MRM was the predominant surgical approach (n:469, 75.4%) while breast conserving surgery was performed to 118 cases. Adjuvant RT was given to 72.5% of cases, and most common KT regimen employed was FEC (55.7%). Either tamoxifen or an aromatase inhibitor was given as HT agent in 57.9% of cases. Most common site of metastasis was bone (11.9), and liver was the most common solid organ site for metastasis. Median survival time was 96.93 months (95% CI: 80.9–112.9), and 96 patients died during the follow-up period. Five-year DFS and OS were 69.5% and 72.6%, respectively. Conclusions: Our results were comparable with the literature. No significant financial relationships to disclose.
A genomic strategy for targeting therapy in castration-Independent Prostate Cancer
Authors: P. Mendiratta, A. Tewari, J. Guinney, A. Porrello, W. T. Barry, P. G. Febbo
Journal: Journal of Clinical Oncology (2008)

5067 Background: Response to secondary hormonal manipulations and cytotoxic therapy is variable in men with castration resistant prostate cancer (CRPC). Androgen receptor (AR) signaling persists in CRPC but there are no established biomarkers which facilitate the choice between continued hormonal manipulations or initiation of cytotoxic therapy in CRPC. Methods: A transcription-based AR activity signature was developed using established analytic methods from an androgen-sensitive prostate cancer cell line (LNCaP). The AR signature assigns a probability of AR activity to individual samples (range 0 to 1) and was applied to independent datasets of LNCaP cells and human prostate samples with known androgen status. The AR signature was subsequently applied to multiple human prostate cancer datasets to determine if AR activity in individual tumor specimens correlates with clinical and molecular phenotypes. Results: A robust expression-based signature of AR activity can accurately predict the AR activity status of independent LNCaP samples, anticipates the hormonal status of individuals (castrate v non-castrate), and assigns an AR activity score that correlates with intraprostatic androgen levels in human biopsy specimens (two-tail Spearman p=0.022 for dihydrotestosterone). The mean difference between AR activity between replicates was minimal (5%) and intra-individual consistency across different metastatic sites was also consistent. In two independent datasets, AR activity was predicted to be higher in local, untreated prostate tumors (mean 0.80 ± 0.23, n=16 and 0.72 ± 0.21, n=10) and decreased but more heterogeneous in CRPC (0.42 ± 0.33, n=32 and 0.40 ± 0.33, n=10)(Mann Whitney P=0.0001 and 0.036, respectively). Low probability of AR activity correlated strongly with predicted SRC activity in local (p = 0.006, n=79) and metastatic (p=0.059, n=32) prostate tumors and predicted sensitivity to dasatinib, a src-targeting kinase inhibitor. Conclusions: Determining the level of AR activity in an individual’s CRPC has the potential to identify patients most likely to benefit from continued hormonal manipulation versus those who are more likely to benefit from other biologically targeted or cytotoxic therapies. No significant financial relationships to disclose.