tbuckley/cabot-search huggingface dataset:
Abstract 1499: Gene therapy in a mouse model for malignant melanoma: Combining the activities of the p53/Arf and interferon pathways
Authors: Christian A. Merkel, Bryan E. Strauss
Journal: Cancer Research (2010)

Abstract Background: Malignant melanoma cells typically maintain wild-type p53 in a non-functional state, due in part to the loss of ARF (p14ARF in humans, p19ARF in mice). Data have shown that interferon-β (IFNβ) can activate the transcription of p53 and interact with the ARF pathway as well. By using a p53-driven adenovirus, we sought to combine the action and regulation of p53, p19ARF and IFNβ for the treatment of malignant melanoma in an immunocompetent mouse model. Methods: p53-responsive AdPG adenoviral vectors (Bajgelman and Strauss, 2008) containing p53, p19ARF and IFNβ were produced and expression verified by immunofluorescence and ELISA. In vitro evaluation of the antiproliferative effect of single or co-transduction of B16F10 cells (B16, p53 wild-type) was done by FACS after annexin/PI staining. C57/Bl6 mice were injected subcutaneously with B16 cells and tumors were allowed to develop (∼0.5 cm2). At this point, three consecutive intra-tumor injections (3 day interval between injections) of individual or combined adenoviral vectors were performed. Animals were then sacrificed and tumors collected and analyzed. Results: The combination of IFNβ and p19ARF proved to be more effective in inhibiting proliferation of B16 cells than either treatment alone, both in vitro and in vivo. In vitro we observed that neither AdPGp19 nor AdPGIFNβ alone altered the cell cycle, though co-transduction with these vectors resulted in extensive cell death. Annexin-V staining was also increased by the combined, but not individual, treatments. Cell death was observed only after 90-120h of incubation, yet prior to this event, indicators of senescence (positive SA-βGal staining, loss of histone H3 acetylatation at Lys9) were revealed in both single and combined vector treatments. In vivo, we observed that the combined gene transfer strategy led to reduced tumor volume, reduced incorporation of BrdU and increased staining by TUNEL in the primary tumor. Assays are in progress to determine if the combined treatment is effective in reducing metastases and prolonging survival. Conclusion: The use of p53-responsive vectors for the restoration of ARF expression in the presence of IFNβ represents a potential strategy for melanoma tumor suppression. While mechanistic studies are underway, we propose that the complementation of the p53/ARF and interferon pathways in the primary tumor may lead to reduction of metastases. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1499.
Adjuvant Tamoxifen Plus Ovarian Function Suppression Versus Tamoxifen Alone in Premenopausal Women With Early Breast Cancer: Patient-Reported Outcomes in the Suppression of Ovarian Function Trial
Authors: Karin Ribi, Weixiu Luo, Jürg Bernhard, Prudence A. Francis, Harold J. Burstein, Eva Ciruelos, Meritxell Bellet, Lorenzo Pavesi, Ana Lluch, Marilena Visini, Vani Parmar, Carlo Tondini, Pierre Kerbrat, Antonia Perelló, Patrick Neven, Roberto Torres, Davide Lombardi, Fabio Puglisi, Per Karlsson, Thomas Ruhstaller, Marco Colleoni, Alan S. Coates, Aron Goldhirsch, Karen N. Price, Richard D. Gelber, Meredith M. Regan, Gini F. Fleming
Journal: Journal of Clinical Oncology (2016)

The Suppression of Ovarian Function trial showed improved disease control for tamoxifen plus ovarian function suppression (OFS) compared with tamoxifen alone for the cohort of premenopausal patients who received prior chemotherapy. We present the patient-reported outcomes.The quality-of-life (QoL) analysis includes 1,722 of 2,045 premenopausal patients with hormone receptor-positive breast cancer randomly assigned to receive adjuvant treatment with 5 years of tamoxifen plus OFS or tamoxifen alone. Chemotherapy use before enrollment was optional. Patients completed a QoL form consisting of global and symptom indicators at baseline, every 6 months for 24 months, and annually during years 3 to 6. Differences in the change of QoL from baseline between the two treatments were tested at 6, 24, and 60 months with mixed models for repeated measures with and without chemotherapy and overall.Patients on tamoxifen plus OFS were more affected than patients on tamoxifen alone by hot flushes at 6 and 24 months, by loss of sexual interest and sleep disturbance at 6 months, and by vaginal dryness up to 60 months. Without prior chemotherapy, patients on tamoxifen alone reported more vaginal discharge over the 5 years than patients on tamoxifen plus OFS. Symptom-specific treatment differences at 6 months were less pronounced in patients with prior chemotherapy. Changes in global QoL indicators from baseline were small and similar between treatments over the whole treatment period.Overall, OFS added to tamoxifen resulted in worse endocrine symptoms and sexual functioning during the first 2 years of treatment, with variable magnitudes of treatment differences. Short-term differences in symptom-specific QoL, treatment burden, and coping effort between treatment groups were less pronounced for patients with prior chemotherapy, the cohort that benefited most from OFS in terms of disease control.
The TGFBR1*6A/9A Polymorphism Is Not Associated with Differential Risk of Breast Cancer.
Authors: N. McInerney, N. McInerney, G. Colleran, A. Rowan, E. Barclay, A. Jones, C. Curran, N. Miller, I. Tomlinson, E. Sawyer, E. Sawyer, M. Kerin
Journal: Cancer Research (2009)

Abstract Background: A polymorphic 9-bp deletion in exon 1 of TGFBR1 (TGFBR1*6A) has been identified as a low-penetrance cancer susceptibility allele. The strongest association in the initial studies was with breast cancer; however these studies included patients with different types of cancer, including colon, cervical and breast carcinomas, with only a small proportion being breast cancer patients. In subsequent case-control studies focussing on breast cancer alone, the results have been equivocal. Methods: In order to clarify whether TGFBR1*6A is associated with breast cancer risk, we have genotyped this polymorphism in 988 breast cancer cases and 1016 controls form the West of Ireland and also performed a meta-analysis of previously published data (5150 cases and 6344 controls). All statistical analyses were undertaken using STATA 9.2.Results: In our series from the West of Ireland, we found no association (genotypic odds ratio (OR) under a dominant model= 0.93, 95% confidence interval (CI) 0.73-1.19, p=0.57; allelic OR=0.93, 95% CI 0.74-1.15, p=0.49). Meta-analysis showed evidence of heterogeneity among studies. Using the random effects model, there was no evidence of an association of the *6A allele with breast cancer (genotypic OR under a dominant model= 1.10, 95% CI = 0.94 to 1.28, p=0.24, allelic OR=1.12, 95%CI 0.97-1.31, p=0.13) with breast cancer. Conclusions: This study confirms that TGFBR1*6A is not associated with breast cancer and highlights the problems associated with small case-control studies, especially where minor allele frequencies are low. It remains to be seen whether the association with other cancer types, including colorectal cancer, can be validated in large case-control series. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3062.
THU0399 Effects of 12-Month Etanercept Therapy on Disease Activity, Bone Turnover Markers and Peripheral QCT Bone Mineral Density in Patients with Ankylosing Spondylitis
Authors: S. Szántó, K. Gulyás, N. Bodnár, Á. Horváth, Z. Pethö, B. Juhász, E. Végh, F. Balázs, L. Pogácsás, H. P. Bhattoa, Z. Szekanecz
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Ankylosing spondylitis (AS) is a chronic inflammatory disease with elevated risk of vertebral fractures. Several factors play role in fracture rate in these patients including age, body mass index, immobility, spinal inflammation and high disease activity. <h3>Objectives</h3> The aim of our study was to investigate the relationship of bone mineral density (BMD) with some measures ofdisease activity and functional ability. In addition, we wished to determine the effects of 12-month etanercept (ETN) therapy on disease activity, bone markers, as well as bone density assessed by DEXA and peripheral qCT. <h3>Methods</h3> We assessed 17 AS patients (14 males, 3 females) with a mean age of 42.6 years and a mean disease duration of 7.2 years. 50mg weekly ETN therapy was administered and patients were assessed at baseline and after 3, 6 and 12 months of treatment. Disease activity was determined by BASDAI. BMD was evaluated by DEXA and by radius pQCT, a method capable of total, trabecular and cortical density assessment. In addition, serum osteocalcin, CTX, 25-hydroxy-D3 vitamin (25-OH-D3) and P1NP levels were also determined. <h3>Results</h3> BASDAI values improved significantly during the one-year anti-TNFα therapy (6.14, 2.26, 1.82 and 1.25 mean BASDAI at baseline and after 3, 6 and 12 months, respectively). DEXA and most bone markers showed no significant changes in BMD at the lumbar spine or femur region. However, peripheral qCT revealed increased total (852 mg/cm<sup>3</sup>) and trabecular density (279 mg/cm<sup>3</sup>) after 12 months of anti-TNF therapy in comparison to baseline values (773 mg/cm<sup>3</sup> and 256 mg/cm<sup>3</sup>, respectively). In addition, 25-OH-D3 levels increased from 60 to 73 nmol/l (normal value: &gt;75 nmol/l) upon one-year ETN treatment. <h3>Conclusions</h3> One-year ETNtherapy may prevent further bone loss in AS. Biologic treatment may have beneficial effects on the trabecular bone. ETN therapy may also restore 25-OH-D3 levels. <h3>Disclosure of Interest</h3> None Declared
Noninvasive Regional Myocardial Perfusion with Radioactive Potassium
Authors: Barry L. Zaret, H. William Strauss, Neil D. Martin, Harry P. Wells, M. D. Flamm
Journal: New England Journal of Medicine (1973)

Myocardial perfusion imaging after intravenously administered radioactive potassium (43K) was used to delineate noninvasively areas of myocardial infarction and left ventricular regions that become transiently ischemic during angina pectoris. Forty-three subjects were studied at rest and during maximal treadmill exercise. In 12 normal subjects 43K distribution was homogeneous both at rest and during exercise. In 13 of 15 patients with previous myocardial infarction studied at rest, regions of decreased radionuclide accumulation corresponded to the anatomic location of the infarct. In 16 of 19 patients with angina pectoris, regions of relatively decreased 43K accumulation were identified when the tracer was administered during exercise, but were not present at rest. These zones of relative hypo-perfusion corresponded to regions supplied by angiographically demonstrable stenotic coronary arteries in all patients so studied. 43K myocardial imaging thus provides a safe and simple noninvasive means of assessing regional myocardial perfusion at rest, with exercise and during angina pectoris. (N Engl J Med 288:809–812, 1973)
SAT0412 Arthralgia Occurring under Aromatase Inhibitor Treatment for Breast Cancer. A Prospective Controlled Study.
Authors: D. Wendling, H. Letho-Gyselinck, X. Guillot, C. Prati, X. Pivot
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Treatment with third generation aromatase inhibitors (AI) is associated with occurrence of arthralgia, with an incidence ranging from 25 to 45 %. In these patients, arthralgia may also be related to other conditions such as osteoarthritis, common tendinitis or auto immune diseases. <h3>Objectives</h3> The aim of this study was to study patients treated with AI and reporting arthralgia, and comparing patients with new onset to patients with pre existing arthralgia and exacerbation under AI, to look for associated etiologic factors. <h3>Methods</h3> Patients followed in a tertiary oncology center for breast cancer treated with AI and reporting arthralgia were prospectively screened for rheumatologic clinical evaluation, as well as biologic (ESR, CRP, RF, ANA, ACPA) or imaging (X-Rays of symptomatic regions) investigation. Type of cancer, duration, treatment, type of AI, duration of AI treatment. Patients were divided in two groups : patients with new onset of arthralgia under AI, and patients with pre existing and exacerbation of arthralgia under AI. The two groups are compared using t test for quantitative variables (significance : p less than 0.05). <h3>Results</h3> Seventy five women were included, mean age (SD): 64.8 (9.2) years, time from cancer diagnosis : 34 (25) months. Adjuvant chemotherapy and/or radiotherapy were noted in respectively 52 and 64 cases. AI was Anastrozole (n = 6), Letrozole (55), Exemestane (14). Mean duration AI treatment since onset or exacerbation of arthralgia : 179 (224) days. Mean number of painful joints : 7.6 (9.7); locations (number of patients) :shoulder 36, elbow 22, wrist 25, MCP 27, PIP 26, knee 26, MTP28. Mean ESR : 29 (25)mm/h; CRP : 3 (7.6) mg/l). New onset arthralgia : n = 38; pre existing and exacerbation of arthralgia : n = 37. No statistical differences were found between these two groups for type of cancer, presence of chemotherapy or radiotherapy, presence of metastases, duration and type of AI treatment, VAS pain, number and distribution of tender joints, ESR, CRP, ANA, RF, ACPA positivity, and radiographic findings. Positive lymph nodes and radiographic signs of rotator cuff dysfunction were statistically more frequent in the pre existing and exacerbation group. Some specific diagnoses were done after evaluation : 2 CREST syndrome (one in each group), 1 RA and 1 Sjögren syndrome in the new onset symptom group. <h3>Conclusions</h3> Arthralgia under AI treatment is frequent. Our study argues for an absence of specificity of these arthralgia, without particular difference between new onset or exacerbation of pre existing arthralgia, auto immune disease seem more frequent in the new onset symptom group, and thus possibly related to anti aromatase therapy. <h3>Disclosure of Interest</h3> None Declared
Studies of the Cardiovascular System in the Hypotension of Liver Failure
Authors: M. L. Mashford, W. Mahon, T. C. Chalmers
Journal: New England Journal of Medicine (1962)

AS a result of improvements in treatment of the bleeding, infections and coma complicating severe liver disease it has become relatively common for patients with cirrhosis to die in a state characterized by hypotension, which is not due to bleeding, and by oliguria with a rising blood nonprotein nitrogen concentration.1, This syndrome may last for a week or more and is an almost certain portent of death. Its pathogenesis is obscure, and hemodynamic measurements have been reported in only a few patients. A patient described by Hecker and Sherlock3 had a high cardiac output and low total peripheral resistance . . .
Effect of Transferrin Saturation on Iron Absorption in Man
Authors: Munsey S. Wheby, Genoveva Umpierre
Journal: New England Journal of Medicine (1964)

IN a previous report1 data were presented indicating that the level of transferrin saturation was not important in regulating iron absorption from the gastrointestinal tract during short-term experiments. These data conflicted with other reports, which concluded that the level of transferrin saturation played a major part in regulating iron absorption.2 3 4 The latter studies were based on serial isotopic analysis of peripheral blood after ingestion of radioactive iron, thus entailing the assumption that peripheral blood radioactivity accurately reflected portal blood radioactivity, even when high levels of transferrin saturation were achieved. This assumption was shown to be false by our studies utilizing . . .
P4-01-04: Effects of CYP2D6 Phenotype and Drug Adherence on Tamoxifen Metabolite Levels.
Authors: BA Sousa, S Nasim, DE Cole, BY Wong, K Hill, KI Pritchard, M Trudeau, S Verma, R Dent, T Petrella, S Gandhi, S Ueng, U Vandenberghe, A Romaschin, E Warner
Journal: Cancer Research (2011)

Abstract Background Although the activity of cytochrome P450 2D6 (CYP2D6), the enzyme responsible for conversion of tamoxifen (TAM) to its most important active metabolite endoxifen, varies significantly with genotype. Routine genotype testing in patients on TAM has recently been discouraged. Conflicting results in publications regarding the prognostic utility of this test remain unexplained. Confounding factors could be lack of predicted correlation between CYP2D6 genotype and TAM active metabolites, or variability of patient compliance Methods: Consecutive breast cancer patients on TAM were asked to enroll in a study to examine the relationship between CYP 2D6 phenotype, patient-reported treatment adherence, and TAM metabolites levels. Patients were genotyped for CYP2D6 polymorphisms using long-range PCR allele-specific amplification and single-nucleotide primer extension assay. From the genotypes, four phenotype groups were defined: Ultra rapid Metabolizer (UM), Extensive Metabolizer (EM), Intermediate Metabolizer (IM) and Poor Metabolizer (PM). Plasma was collected after at least 6 weeks of TAM (20 mg daily). The parent drug TAM, as well as 4-hydroxy N-desmethyl tamoxifen (endoxifen), 4 hydroxy tamoxifen (4OHtam) and N-desmethyl-tamoxifen (NDtam), were determined by Liquid Chromatography tandem mass-spectrometry (LC-MS/MS). Patients also completed a questionnaire about ethinicity, side effects, concurrent medications and tamoxifen adherence. Correlation between metabolite/TAM ratio and phenotype was tested by Spearman correlation test. Relationship between metabolite levels and adherence was tested by Wilcoxon rank sum test. Chi square test was used to compare proportions. Results: Of the 100 patients enrolled there were 62 Caucasians, 25 Asians, 4 Africans and 6 Unknown. We found a strong correlation between ratio of endoxifen/TAM and phenotype (p &amp;lt;.0001) (Table 1) Over a 2 week period 68 never missed a TAM dose, 25 missed 1–2 times, 2 missed 3–5 times and 2 &amp;gt; 5times (2 missing data). In EM group we found significantly lower levels of TAM (p &amp;lt;.0001), NDtam (p=.008), 4OHtam (p=.003) in less adherent patients. A trend to decreased levels was also shown for endoxifen (p=.081). No associations were found between adherence or phenotype activity and side effects. Conclusions: Our data suggests the predicted association between endoxifen levels and genotype. However, non-adherence may have a significant confounding effect. Prospective studies to evaluate the prognostic impact of CYP2D6 variants for patients on adjuvant tamoxifen should be done but results could be confounded by variable drug adherence if this is not measured concurrently. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-01-04.
Attenuation by prostaglandins of the facilitatory effect of angiotensin II at adrenergic prejunctional sites in the isolated Krebs-perfused rat heart.
Authors: S M Lanier, K U Malik
Journal: Circulation Research (1982)

In the isolated rat heart prelabeled with [ 3 H]norepinephrine ([ 3 H]NE) and perfused with oxygenated Krebs-Ringer bicarbonate solution, we studied the effect of angiotensin II (All) on the overflow of tritium before and during electrical stimulation of the cardiac sympathetic nerve plexus in the presence and absence of prostaglandin synthesis inhibitors (indomethacin, sodium meclofenamate) and also during infusion of PGE2 and PGI 2 .Stimulation of the cardiac nerve plexus increased the overflow of tritium, which was most likely due to excitation of adrenergic nerve fibers because it was blocked by tetrodotoxin, guanethidine, or by removal of calcium from the perfusion medium.Infusion of All (9 nM) into the heart did not alter the basal tritium overflow but increased that elicited by nerve stimulation.The All-induced increase in the electrically evoked tritium overflow consisted primarily of intact [ 3 H]NE and was most likely due to enhanced transmitter release because it was not reduced by inhibitors of neuronal (cocaine) and extraneuronal (normetanephrine) uptake.Moreover, All had no effect on the uptake of [ 3 H]NE by the heart, whereas cocaine markedly reduced it.All infusion into the heart increased the output of PGE2 and 6-keto PGFi n (the stable metabolite of PGI2), and this increase was abolished during infusion of either indomethacin (1.4 /XM) or sodium meclofenamate (6.3 JIM).The cyclooxygenase inhibitors enhanced the All-induced increase in tritium overflow elicited by nerve stimulation, and this increment was minimized by infusion of either PGE2 or PGI 2 (27-85 nM) into the heart.These data suggest that one or more products of arachidonic acid, presumably PGI2 and/or PGE2, synthesized in the rat heart act to attenuate the effect of All at prejunctional sites to enhance adrenergic transmitter release elicited by nerve impulses.
Abstract P6-05-08: Significant heterogeneity in ERalpha and PR receptor status in different distant breast cancer metastases of the same patient
Authors: LDC Hoefnagel, P van der Groep, JE Broers, E van der Wall, PJ van Diest
Journal: Cancer Research (2012)

Abstract Purpose: Receptor conversion for estrogen receptor alpha (ERα), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) in single distant breast cancer metastases has been described before. However, most patients develop multiple metastases. Heterogeneity in receptor status between different metastases of the same patient has not been studied, probably since such material is very rare. The consequence of such heterogeneity would mean that as many metastases as possible need to be biopsied to re-assess receptor status. We therefore aimed to study heterogeneity of receptor status between different distant metastases of the same patient in a relatively large group by re-staining all primary tumors and metastases with current optimal immunohistochemical methods on full sections. Material and methods: Formalin fixed paraffin embedded tissue of primary breast carcinomas and corresponding multiple (≥2) distant metastases from 38 female patients were collected from several pathology departments in The Netherlands and stained for ERα, PR and HER2 by IHC. We evaluated the heterogeneity of receptor status between the metastases and the correlation with the primary tumor. Results: In the 4 cases that showed ER conversion, 2 (50%) showed heterogeneity in receptor expression between different metastases of the same patient. Of the 17 cases that showed PR conversion, 12 cases (71%) showed heterogeneity in expression between metastases. There were no changes in the receptor profile of primary breast cancer to their metastases for HER2 in this group. Conclusion: In a significant number of metastatic breast cancer patients, there is heterogeneity in ER and PR receptor status between different breast cancer metastases of the same patient. This implies that as many metastases as possible need to be biopsied to re-assess receptor status and set the optimal indication for hormonal therapy in these patients. Alternatively, non-invasive assessment of the receptor status by molecular imaging may be an easier future way to assess receptor status of all metastatic lesions. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-05-08.