tbuckley/cabot-search huggingface dataset:
Detection of fatty acid synthase inhibition by magnetic resonance spectroscopy
Authors: James Ross, Kumar Kaluarachi, William Tong, Sabrina Ronen
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

4492 

Introduction . Fatty acid synthase (FASN) is the key enzyme responsible for de novo synthesis of long-chain fatty acids (FA). FASN expression is significantly increased in cancer cells and is associated with poor prognosis, particularly in breast and prostate cancer. Furthermore, inhibition of FASN results in cell cycle arrest and apoptosis. We therefore became interested in using magnetic resonance spectroscopy (MRS) to study the metabolic consequences of FASN inhibition and to identify pharmacodynamic markers of FASN inhibition.

M&M For metabolic studies by MRS, PC3 human prostate cancer cells were grown in DMEM/F-12 with 1-13C labeled glucose (to monitor FA synthesis) and 1,2-13C labeled choline (to monitor choline metabolism). FASN was inhibited for 24 and 48 h with 30 μM orlistat. The effect of treatment on cell proliferation was determined by cell count. The effect on FASN activity was determined using a spectrophotometric assay. For MR studies cells were extracted using the dual-phase extraction method and spectra recorded on an Avance DRX500 Bruker spectrometer using a flip angle of 30o and repetition delays of 5s, 3.5s and 4.5 s for  1H 13C and 31P MRS respectively. Metabolite concentrations were determined by integration and normalization to reference and cell number. Choline kinase activity was determined by monitoring PCho synthesis in a cell lysate by MRS.

Results FASN activity decreased by 51±10% (n=3) at 24 h and 83±11% (n=2) at 48 h following treatment with orlistat. This was associated with inhibition in cell proliferation by 32±21% (n=3) at 24 h and 63±7% (n=3) at 48 h relative to control. 13C and 31P MRS data indicated progressive inhibition of de novo synthesis of FA, PtdCho and PCho by 47±29%, 64±32% and 28±7%, respectively at 24 h (n=3) and by 84±1%, 66±5% and 47±23%, respectively, at 48 h (n=2). This was followed by a progressive decrease in their total pools down to 39±8%, 68±4% and 58±4% at 48 h, respectively. In addition, all membrane phospholipids decreased by 48 h. Importantly, significant correlations were found between inhibition of FASN and de novo synthesized pools of FA, PtdCho and PCho. Furthermore, FASN inhibition correlated with total PCho levels (R2=0.9987). Preliminary results also indicate that choline kinase activity was reduced by 64% (n=1) in orlistat treated cells relative to control.

Discussion and Conclusions As expected, inhibition of FASN by orlistat decreased de novo FA synthesis. We hypothesize that this led to the downstream inhibition in synthesis of PtdCho as well as the synthesis of its precursor PCho. We show here that (i) the metabolic consequences of FASN inhibition on cellular metabolism and (ii) mechanistic information can be studied in detail by combining 1H, 13C and 31P MRS.

Acknowledgments We would like to acknowledge the NCI Cancer Center Support Grant CA016672 for the support of Core NMR facility.
Advanced breast cancer: a phase II trial with gemcitabine.
Authors: J Carmichael, K Possinger, P Phillip, M Beykirch, H Kerr, J Walling, A L Harris
Journal: Journal of Clinical Oncology (1995)

PURPOSE In this phase II study, the efficacy and tolerability of gemcitabine were studied in 44 patients with locally advanced or metastatic breast cancer. PATIENTS AND METHODS Of 40 patients assessable for response, 14 were chemotherapy-naive, seven had received adjuvant chemotherapy, and 19 had received one prior chemotherapy regimen for metastatic disease. Gemcitabine was administered as a 30-minute intravenous infusion once a week for 3 weeks followed by a 1-week rest every 4 weeks. The mean number of completed cycles administered was 2.7 and the mean dosage delivered was 725 mg/m2 per injection. Eighty-one percent of doses were delivered as scheduled. RESULTS There were three complete responses and seven partial responses, for an overall response rate of 25.0% (95% confidence interval [CI], 12.7% to 41.2%). Four patients were not assessable for efficacy (one had insufficient therapy, two had no bidimensionally measurable disease, and one had neither). All responses were independently validated by an external oncology review board. Responses were observed early in treatment, with a median time to response of 1.9 months. The median survival duration for all 40 assessable patients was 11.5 months. Hematologic toxicity was generally mild, with World Health Organization (WHO) grade 3 and 4 leukopenia occurring in 6.8% and 2.3% of patients and neutropenia in 23.3% and 7.0%, of patients, respectively. The only other grade 4 toxicities were infection and nausea and vomiting in one patient each. One patient was withdrawn due to shortness of breath, possibly drug-related. Flu-like symptoms, which were mild, transient, and treatable with acetominophen, were reported in 6.8% of patients. Only one patient developed alopecia of severity greater than WHO grade 2. CONCLUSION In view of the single-agent activity seen in advanced breast cancer, modest toxicity profile, and novel mechanism of action, gemcitabine deserves evaluation in breast cancer and is an ideal candidate for combination therapy.
To ascertain usefulness of chester step test in pulmonary rehabilitation programmes
Authors: Seher Zaidi, Jamie Rylance, Samantha Roberts, James Finnerty, Ian Benton, Aravind Ponnuswamy, Kevin Sykes, Stephen Scott
Journal: European Respiratory Journal (2013)

Background  The Chester Step Test assesses aerobic capacity in healthy subjects. It has not been tested in patients with COPD pre and post rehabilitation.  Aim  To ascertain the utility of the Chester Step Test (CST) in measuring exercise capacity in patients with COPD, by comparison with a validated Incremental Shuttle Walk Test (ISWT) which is shown to reflect peak exercise capacity.  Method  Thirty-two patients with stable COPD underwent each exercise test, before and after completion of a 6 week pulmonary rehabilitation programme. Tests were conducted by a blinded assessor who recorded data including heart rate, oxygen saturations.  Results  Baseline mean characteristics were as follows: age 66 years (SD 8.5); SpO2 94.5 (SD 2.40); FEV1 52% predicted (SD 17.7%). Participants completed a mean 171.3m (SD 75.65) of the ISWT, and 157seconds (SD 92.3) of the CST.  Seventeen patients completed the rehabilitation programme. Correlation by linear regression (r2) between each ISWT and CST was 0.31 before rehab (p=0.001), and 0.25 afterwards (p=0.039). Pre and post rehab percentage change was significant for ISWT (p  Conclusions  Although these two tests correlate significantly at each visit, the ISWT appears more sensitive to change following rehab, but sensitivity can potentially be increased with a modification of the protocol. Further studies are required to explore this.
Cigarette smoke down-regulates the expression of β-catenin in primary human lung fibroblasts
Authors: Nicola Miglino, Seidel Petra, Michael Roth, Charlotte Sadowski-Cron, Didier Lardinois, Michael Tamm, Pieter Borger
Journal: European Respiratory Journal (2011)

Rationale:  Cigarette smoke is the major cause of COPD/emphysema but the etiology of these diseases is still unknown. β-catenin is a signaling molecule which is regulated through degradation/stabilization mechanism, and which promotes cell proliferation via the Wnt signaling pathway. Decreased β-catenin signaling may be involved in the parenchymal tissue destruction leading to emphysema.   Objectives:  Investigate the effect of cigarette smoke on the expression of β-catenin and cell proliferation in primary human lung fibroblasts (n=6).   Methods:  Fibroblasts were exposed to cigarette smoke conditioned medium (20%, 24 hours). Expression of β-catenin was determined by immuno-blotting. Proliferation was determined by [3H]-thymidine incorporation.   Results:  Cigarette smoke significantly down-regulated β-catenin expression and reduced proliferation of primary lung fibroblasts.   Conclusions:  Cigarette smoke down-regulates β -catenin and reduces cell proliferation in lung fibroblasts which may underlie the impaired tissue repair leading to parenchymal destruction in the lung of COPD/emphysema patients.
The antigenic landscape of multiple myeloma: mass spectrometry (re)defines targets for T-cell–based immunotherapy
Authors: Simon Walz, Juliane S. Stickel, Daniel Johannes Kowalewski, Heiko Schuster, Katja Weisel, Linus Backert, Stefan Kahn, Annika Nelde, Tatjana Stroh, Martin Handel, Oliver Kohlbacher, Lothar Kanz, Helmut Rainer Salih, Hans-Georg Rammensee, Stefan Stevanović
Journal: Blood (2015)
Targeting transcription factor STAT3 for cancer prevention and therapy
Authors: Edna Zhi Pei Chai, Muthu K. Shanmugam, Frank Arfuso, Arunasalam Dharmarajan, Chao Wang, Alan Prem Kumar, Ramar Perumal Samy, Lina H.K. Lim, Lingzhi Wang, Boon Cher Goh, Kwang Seok Ahn, Kam Man Hui, Gautam Sethi
Journal: Pharmacology & Therapeutics (2016)
Twice-Daily Insulin Regimens in Management of Severe Diabetes
Authors: Nigel Oakley, Hugh Mather, Lindsay Hadley, Janice Lynch, Thomas Pilkington
Journal: Journal of the Royal Society of Medicine (1981)

Diurnal glucose profiles have been compared in ten insulin dependent diabetics receiving, firstly, a twice-daily soluble insulin (SI): isophane insulin (NPHI) insulin (30% SI, 70% NPHI). For each patient the two regimens gave similar profiles though nocturnal blood glucose control was better on Mixtard. HbA1 values were similar on the two regimens. The findings show that, using highly purified formulations, small changes in insulin proportions in twice-daily SI: NPHI regimens may be irrelevant to diabetic control; they also suggest that highly purified NPHI may have a substantially shorter duration of action than its older counterpart and that the convenient regimen of twice-daily Mixtard is usually as good as any more complicated 'tailormade' regimen of highly purified insulins.
Nuclear NF-kb/p65 expression and response to neoadjuvant chemotherapy in breast cancer.
Authors: R. L. Jones, F. G. Rojo, R. A'Hern, N. Villena, J. Corominas, S. Servitja, A. Rovira, J. S. Reis-Filho, M. Dowsett, J. Albanell
Journal: Journal of Clinical Oncology (2010)

611 Background: NF-kB is a potential therapeutic target in breast cancer and other tumor types. However, studies assessing its significance in a clinical setting are as yet limited. The aim of this study was to evaluate clinicopathological associations and predictive value of the transcription factor NF-kB in a large series of breast cancer patients that received neoadjuvant systemic treatment. Methods: A retrospective search of a prospectively maintained database was performed to identify patients. Immunohistochemistry was employed to asses the p65 subunit of NF-kB using nuclear staining, as a surrogate of activation. Results: Nuclear NF-kB expression (n = 133) was found in 26.3% (n = 35) of cases. Nuclear NF-kB staining was associated with high histological grade (p = 0.05), ER negativity (p = 0.01) and high Ki67 index (p = 0.002). Patients with nuclear NF-kB staining had a higher pathological complete response (pCR) rate compared to those without (26.5% vs. 6.0% respectively, p = 0.004); there were no significant associations with clinical response or outcome. In a subset analysis, in HER2+ and/or ER- tumors combined (n = 42) there was no significant association between nuclear NF-kB staining and pCR rate (p = 014) and clinical response (p = 0.39). In contrast, in ER+/HER2- tumors (n = 43), those with nuclear NF-kB staining had a significantly less clinical responses compared to negative cases (14.3% vs. 61%; p = 0.038). There were no pCRs in ER+/ HER2- tumors. Conclusions: Nuclear NF-kB/p65 expression is associated with ER negativity, high Ki67 index and tumor grade. In the entire series, it was associated to increased pCRs but not to clinical response to neoadjuvant chemotherapy. A subset analysis revealed that nuclear NF-kB/p65 expression was linked to chemoresistance in ER+/HER2- tumors. No significant financial relationships to disclose.
Common Sequence Variation in the VEGFC Gene Is Associated with Diabetic Retinopathy and Diabetic Macular Edema
Authors: Georgia Kaidonis, Kathryn P. Burdon, Mark C. Gillies, Sotoodeh Abhary, Rohan W. Essex, John H. Chang, Bishwanath Pal, Maria Pefkianaki, Mark Daniell, Stewart Lake, Nikolai Petrovsky, Alex W. Hewitt, Alicia Jenkins, Ecosse L. Lamoureux, Jonathan M. Gleadle, Jamie E. Craig
Journal: Ophthalmology (2015)
The Role of Inflammatory Processes in Airway Hyperresponsiveness
Journal: Thorax (1990)

This book is the outcome of a meeting, in Florida in 1988, of a select group of academics and research workers with an interest in the pathophysiology of asthma.The work is divided into seven chapters, though they are really sections, under the headings of: clini- cal presentation, pathology, diagnostic procedures, physiology, cellular mechanisms, pharmacology and therapeutics, and epidemiology.Each section is com- posed of contributions from three to five different authors, who obviously bring their own particular interests and slant.That leads to a rather disjointed
Pulmonary tuberculosis and cigarette smoking
Authors: Houda Gharsalli, Wided Ben Hamed, Samira Aouadi, Aida Bayoudh, Emna Mhiri, Ali Ben Kheder, Sonia Maalej
Journal: European Respiratory Journal (2013)

Introduction: Smoking and tuberculosis represent two major world health issues particularly in developing countries.Tobacco has a significant impact on the risk of tuberculosis.

Aim: Describe the relationship between tobacco consumption and pulmonary tuberculosis infection.

Materials and methods: It’s a comparative study between two groups of patients hospitalized in our department for pulmonary tuberculosis between January 2010 to December 2011. A first group made by 25 smokers patients was compared to a second group consists of 25 non smokers patients.

Results: The most frequent symptoms in both groups were cough and loss of weight. Compared to the non smokers patients, the smokers patients had a longer delay of diagnosis (p=0.004), more nodular lesions (64% vs 24%, p=0.004) and more bilateral lesions (58.2 % vs 41.8%, p=0.045) in the chest X ray, a longer delay of sputum negativity (1.99 vs 1.12 months, p=0.004) and more frequent pulmonary sequelae (70.8% vs 29.2%, p=0.02). Evolution after antituberculosis treatment was favourable for all patients.

Conclusion: Tobacco may delay the diagnosis, the recovery of pulmonary tuberculosis and may induce pulmonary sequelae in spite of correctly antituberculosis treatment. Smoking cessation represents an essential means of controlling tuberculosis epidemic.
Patterns of Referral to a Menopause Clinic
Authors: T Garnett, A Mitchell, J Studd
Journal: Journal of the Royal Society of Medicine (1991)

One hundred and fifty new patients attending the Menopause Clinic at Dulwich Hospital were questioned on their attitudes and fears about hormone replacement therapy and the perceived attitudes of their general practitioner. The majority of patients attending the clinic had initiated referral themselves and many had travelled from outside the health authority area in order to be seen. The waiting list for an appointment was often unacceptable. We conclude that specialist menopause clinics in teaching hospitals are unable to cope with the demand for information about the menopause and hormone replacement from post-menopausal women and suggest alternative means for providing this service.
TBCRC 001: EGFR inhibition with cetuximab added to carboplatin in metastatic triple-negative (basal-like) breast cancer
Authors: L. A. Carey, H. S. Rugo, P. K. Marcom, W. Irvin, M. Ferraro, E. Burrows, X. He, C. M. Perou, E. P. Winer
Journal: Journal of Clinical Oncology (2008)

1009 Background: Basal-like breast cancer (BBC) has low expression of ER, PR, and HER2, and is thus often called triple negative (TN). Preclinical studies suggest that BBC depend on EGFR/HER1 for proliferation. TBCRC 001 is a multicenter randomized phase II study of cetuximab (C) alone and combined with carboplatin (P) in TN metastatic BrCa (MBC). Methods: Eligibility required measurable disease, ≤ 3 prior chemotherapy, no prior platinum or EGFR inhibitor. Patients (pts) in Arm 1 received C alone (400 mg/m2, then 250 mg/m2 weekly) with P (AUC 2, 3 of 4 weeks) added upon progression (PD). Pts in Arm 2 received C+P throughout. Primary endpoint was objective response (RR, CR+PR). Results: 102 TN patients were enrolled; Arm 1 = 31 pts (closed in 3/07), Arm 2 = 71 (closed 10/07). Mean age 51, 68% white, 26% African American. 87% received prior adjuvant chemo, 54% prior chemo for MBC (24% > 1 prior). Arm 1: PR 6% (2 pts, > 40 weeks), stable disease (SD) 4%, and clinical benefit (CB=PR or SD > 6mos) 10%. Arm 2: RR 18% (13 pts), SD 9% (6), and CB 27% (19). PR did not appear to differ by line of therapy: 14% 1st-line, 31% 2nd-line, 17% 3rd-line. Most pts progressed rapidly; median PFS was 2.0 months. The regimen was tolerable, grade 3 toxicity occurring in > 5% pts were: Arm 1 - rash only (10% pts); Arm 2 - rash (6%), fatigue (6%), and N/V (6%). Two grade 4 infusion reactions occurred in Arm 2. Biopsies from 16 mets confirmed subtype: basal-like (13), claudin-low (2), HER2+/ER- (1). Preliminary pharmacodynamics on paired biopsies (before/after 1–2 weeks therapy) in 9 pts reveal that 7 had gene expression evidence of activity across the EGFR pathway: 2 decreased with treatment (1PR, 1SD); 5 had no change or increased activity with treatment (1SD, 4 PD). Final response rates and further correlative endpoints will be presented. Conclusions: C alone was well tolerated but has low activity in TN MBC. C+P has 18% RR and 27% CB. Many pts progressed rapidly, consistent with the aggressive behavior of this tumor subtype. Serial biopsies offer insight into EGFR pathway modulation by therapy. Translational studies confirming molecular subtype, identifying biologic effects of EGFR inhibition and platinum, evaluating circulating tumor cells, and studying the BRCA1 pathway are ongoing. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bristol-Myers Squibb
Neoadjuvant docetaxel and capecitabine in patients with high risk/locally advanced prostate cancer: Preliminary results of a phase II study
Authors: J. D. Friedman, U. Vaishampayan, J. Montie, R. Shah, F. Sarkar, D. Smith, M. Hussain
Journal: Journal of Clinical Oncology (2005)

4742 Background: Prostate cancers (PCa) express high levels of thymidine phosphorylase (TP), an enzyme responsible for activation of capecitabine to 5 -fluorouracil (5-FU). In pre-clinical studies, docetaxel increases the activity of TP, and when combined with capecitabine demonstrates synergistic anti-tumor effect. Alone, docetaxel is active in hormone refractory PCa. This study is designed to assess the activity and safety of neoadjuvant docetaxel and capecitabine in patients (pts) with high risk/locally advanced PCa. Intra-tumoral changes in 5-FU metabolizing enzymes and molecular markers (apoptosis, gene expression profile) of response to chemotherapy will be evaluated. Methods: Pts with either clinical stage >T2, or PSA >15, or Gleason ≥8 receive 3–6 cycles of docetaxel (36 mg/m2 IV over 30 minutes on days 1, 8, and 15) and capecitabine (1250 mg/m2/day PO BID, on days 5–18) q 28 days, followed by local therapy. The primary endpoint is a ≥50% decline in PSA. Tissue and serum samples pre and post chemotherapy are collected for histology, 5-FU related enzymes, apoptosis, and tissue microarray profile. Results: Thus far, 10 pts have been enrolled (median age 57 years). One pt had a clinical stage T1c, 2 T2a, 4 T2b, 3 T2c. Biopsy Gleason score was ≥8 in 8 pts. Median PSA prior to chemotherapy was 20.3 ng/mL (6.9–282). Five pts met 1 entry criteria and 5 met 2. Of the 10 pts, 9 completed 3 or more cycles, and are evaluable for response (1 pt recently began cycle 1). High grade toxicity (G 3 and 4) was seen in 3 pts with diarrhea and 1 with neutropenia. 3/9 pts had a ≥50% PSA decline (2 of which a ≥70% decline). The remaining 6 pts had stable or < 50% decline in PSA. Testosterone levels did not change post chemotherapy. Seven patients chose surgery. Three pts had a pathological stage T3b, 3 T3a, 1 T2a. Two patients had involved lymph nodes. Microarray profile and 5-FU related enzyme data will be presented. Conclusions: Docetaxel and capecitabine in the neoadjuvant setting is feasible. Evidence for clinical activity and effects on biologic correlates await further patient accrual. This research is supported in part by a grant from Aventis. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Aventis
Smoking habits and erlotinib response in non-small-cell lung cancer (NSCLC) treatment
Authors: Regina Monteiro, Ana Antunes, Ivone Gonçalves, Cristina Lima, Ana Barroso, Sofia Neves, Sara Conde, Barbara Parente
Journal: European Respiratory Journal (2011)

Background: Erlotinib is a tyrosine kinase inhibitor (TKI) approved for 2nd or 3rd line treatment of advanced NSCLC.  Aim: Evaluate the smoking impact on objective response (OR) and survival of pts treated with erlotinib.  Method: Retrospective analysis of OR, overall and post-erlotinib (PE) survival in pts treated with this TKI from 2006 til December 2010, taking into account the gender, smoking status, histology and epidermal growth factor receptor (EGFR) gene mutational status.  Results: Over the past 5 years, 104 pts (57 males) began treatment with erlotinib: 66 adenocarcinomas (AC), 18 squamous cell carcinomas (SCC) and 20 NSCLC. Smoking status: 48 non-smokers (NS); 31 ex-smokers (ES) and 25 active smokers (AS). Median overall survival of 23 months (m). There was no significant difference in overall survival among pts of different gender, staging or smoking status. Median PE survival of 6m. The PE survival was higher in NS (12 vs 6m in ES and 4m in AS; p=0.077), AC (10 vs 5m in SCC and 3m in NSCLC; p=0.013) and in mutated pts (14 vs 6m in non-mutated; p=0.003). Analyzing by histologic subtypes, in AC survival remains higher in NS (21 vs 10m in ES and 2m in AS; p=0.021). Analyzing by mutational status, smoking habits lose significance. Assessing the OR to erlotinib, 50 pts had disease progression and 48 disease control (DC). DC was more frequent in NS (54.2% vs 45.8%; OR=0.476; 95%CI:0.212-1.070) and mutated pts (67.5% vs 32.5%; OR=1.685; 95%CI:0.603-4.707).  Conclusion: Smoking habits have a major impact on survival of AC pts treated with erlotinib. This impact loses significance when analyzed by mutational status.
Antenatal Care in High-Risk Pregnancies
Authors: Q M Al-Nahi, J W Dale, E R Brown, J A D Anderson
Journal: Journal of the Royal Society of Medicine (1984)

A retrospective analysis of the antenatal records of women who gave birth to live babies was conducted in the three Districts of the East Sussex Health Area in 1977. A high-risk group was identified and the antenatal care for them was compared with that given to mothers in general. Comparison was also made between Districts. Women in the high-risk group were similar to those in the general group with respect to the number of antenatal visits. Overall this was also found with respect to when the last visit was made, but there were differences among those with short or long gestations. Pregnant women at high risk were more likely to be supervised by the hospital team exclusively during the antenatal period than those in the general group. Maternal characteristics which might have been used to identify high-risk pregnancies were often not recorded. High-risk mothers more frequently had infants with Apgar scores of less than 5 at one minute and birth weights of 2500 g or less than did women in the general group. However, it would appear that District policy on health care varied significantly since various aspects of care were found to be more dependent on the District concerned than on the risk group involved.