tbuckley/cabot-search huggingface dataset:
Substitutions at BRCA1 promoter region: Clustering of variations in related Brazilian haplotypes
Authors: J. Bines, E. C. C. B. Costa, F. R. Vargas, M. Â. M. Moreira, A. S. Moreira, C. H. Costa, E. M. B. Teixeira, M. C. M. Maia, F. Coura, C. H. D. Silva
Journal: Journal of Clinical Oncology (2005)

9590 Background: Previous studies showed that biallelic polymorphism at BRCA1 locus define two haplotype classes highly prevalent in human populations. Analyses of markers comprising the genomic region between RNU2 and BRCA1 suggest a linkage disequilibrium, and mutations found in BRCA1 were found to be not randomly distributed in respect to different alleles. The goal of this study is to search variations at BRCA1 promoter region and their relationship with genetic markers in probands selected for hereditary breast cancer. Methods: A total of 77 probands, tested negative for BRCA1/2 mutations at coding regions, were selected and promoter region analyzed by PCR, SSCP, DNA cloning, and sequencing. The polymorphism 3565-C>G [GenBank L78833] was used for distinction of haplotypes I (allele C) and II (allele G), and homozygotes (CC or GG) were selected for characterization with the microsatellite markers (D17S1325, D17S1326 and D17S855). Results: The substitutions found were: two 3800-C>T in exon 1B, one 3988-A>C in exon 1B, one 3777-G>A in Estrogen-Receptor (ERE)-binding-motif; and one proband with three substitutions in cis: 3292-T>C at promoter a, 3593-G>A at promoter b, and 3800-C>T in exon 1B. This last substitution was previously described as a low frequency allele. The remaining substitutions have not been previously described. All these substitutions were associated in cis with the allele 3565-G (haplotype II). Microsatellite analyses for 3565-C>G homozygous individuals showed association of D17S1326 alleles ranging from 91pb to 105pb with haplotype II (N=25) and haplotype I (N=17) with alleles ranging from 107bp - 115bp (69% vs. 47%, p>0,05). Conclusions: These results suggest that the different variations found are not randomly associated with the different haplotypes defined by markers 3565-C>G and D17S1326. Additionally, these variations must be tested in a promoter functional assay to verify their influence at the transcriptional level. No significant financial relationships to disclose.
A phase 1–2 clinical study of a second generation oral MEK inhibitor, PD 0325901 in patients with advanced cancer
Authors: P. Lorusso, S. Krishnamurthi, J. R. Rinehart, L. Nabell, G. Croghan, M. Varterasian, S. S. Sadis, S. S. Menon, J. Leopold, M. B. Meyer
Journal: Journal of Clinical Oncology (2005)

3011 Background: Oral PD 0325901 is a potent inhibitor of the dual-specificity kinases, MEK1/2 (MAPK/ERK/Kinase), thereby preventing phosphorylation and subsequent activation of mitogen-activated protein kinase (pMAPK/pERK). Methods: The Phase 1 component of this Phase 1–2 study tested oral PD 0325901 administered QD or BID for 21 days repeated every 4 weeks in patients with breast, colon, nonsmall cell lung cancer (NSCLC) or melanoma. Tumor tissue was assessed by immunohistochemistry (IHC) for pERK at baseline (BL) and Day 15 of Cycle 1. Pharmacokinetic (PK) samples were obtained on Days 1 and 21 in all patients and also on Day 1 of Cycle 2 in patients participating in a 2-way crossover food effect component. Due to elevated serum phosphorus with corresponding soft tissue mineralization observed in rats, serum Ca, P and (Ca x P) product were monitored closely. Results: From February through November 2004, 30 patients received 74 (range 1–8) cycles of PD 0325901 administered at 1mg QD, or at 1mg, 2mg, 4mg, 8mg, 15mg, 20mg or 30mg BID. In decreasing frequency, common toxicities included rash, fatigue, diarrhea, nausea, and vomiting. Acneiform rash involving face, trunk and arms was dose limiting (DLT) in one patient at 30mg BID. Transient and reversible visual effects including blurred vision and halos occurred in 5 patients receiving ≥15mg BID. There was no notable effect on serum (C x P) product. Mean Cmax and AUC increased with dose and administration of PD 0325901 with food appeared to delay Tmax, decrease Cmax, and had a variable effect on AUC. Doses ≥ 2mg BID consistently suppressed tumor pERK by an average of 84% relative to BL and doses ≥15 mg BID yielded average steady state plasma concentrations >270ng/ml predicted necessary for near maximal pERK suppression in xenograft models. Responses included 1 PR (melanoma) and 5 SD (4 melanoma, 1 NSCLC). Conclusion: PD 0325901 is well tolerated, suppresses pERK in tumor tissue, and demonstrated objective response in melanoma. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Pfizer Pfizer
Prognosis and outcome of patients with pancreatic metastases from renal cell carcinoma: When the site matters.
Authors: Paolo Grassi, Ludovic S. Doucet, Viktor Grünwald, Bohuslav Melichar, Luca Galli, Ugo De Giorgi, Annalisa Guida, Cinzia Ortega, Matteo Santoni, Aristotelis Bamias, Elena Verzoni, Roberto Iacovelli, Lisa Derosa, Hana Studentova, Monica Pacifici, Filippo G. De Braud, Bernard J. Escudier, Giuseppe Procopio
Journal: Journal of Clinical Oncology (2015)

484 Background: Pancreatic metastases from renal cell carcinoma (PmRCC) are uncommon and their prognostic value in the era of targeted terapies (TTs) is not well defined. We evaluated the outcome of a cohort of PmRCC patients (pts) who were treated with either surgery and TTs. Methods: PmRCC pts treated between 1993 and 2014 were identified from the databases of 10 European centers. Clinical records were retrospectively reviewed and pts characteristics, including demographics and clinical outcome, were analyzed. Kaplan-Meier methods and log-rank test were used to evaluate progression-free survival (PFS) and overall survival (OS). Cox’s proportional hazard models were used for OS analysis. Results: A total of 232pts were evaluated. Median age was 61 years, sex ratio M/F was 147/85, and PmRCC were synchronous in 69 pts (30%). Pts treated with pancreatic surgery (including radiosurgery) were 67 (29%), while patients receiving systemic treatment were 210 (91%). Pts with only PmRCC were 23 (11%), whereas in the other 201 cases: lung (25%), lymphnodes (16%), and liver (13%) were the most common metastatic sites. The majority of pts (94%) received nephrectomy (Nx). Median time from Nx to PmRCC occurrence was 92 months (IQR 50-143). First-line TTs included: sunitinib (42%), sorafenib (12%), pazopanib (9%), interferon+bevacizumab (8%), and temsirolimus (1%), 30% of pts received cytokines and 65% of pts received subsequent lines of TTs. Best response to first-line treatment were complete response (5%), partial response (41%), and stable disease (36%) with a disease control rate (DCR) of 82% and a median PFS of 12 months (IQR 9-13). Median OS (calculated from the time of PmRCC occurrence to death) was 73 months (IQR 61-90) with a 5-yr OS of 59%. Median OS for pts treated with surgical resection was 114 months (IQR 90-204) with a 5-year OS of 81%. At univariate analysis only Motzer/Heng prognostic score were significantly associated with OS (p=0.006). Conclusions: PmRCC are associated with long-term survival, usually occur many years after Nx and seem to lead to a less aggressive disease. Surgery should be considered in oligometastatic disease as it can be associated with prolonged survival. TTs are active in these pts and achieve high DCR.
In Vivo and In Vitro Studies on the Morphogenesis of Tumors Induced by Murine Sarcoma Virus (Harvey) 2
Authors: W. R. Thomas, E. J. Aw, J. M. Papadimitriou, P. J. Simons
Journal: JNCI Journal of the National Cancer Institute (1973)

Journal Article In Vivo and In Vitro Studies on the Morphogenesis of Tumors Induced by Murine Sarcoma Virus (Harvey) Get access W. R. Thomas, W. R. Thomas Departments of Microbiology and Pathology, University of Western Australia, Perth Medical Centre, Shenton Park, Western Australia 6008 Search for other works by this author on: Oxford Academic PubMed Google Scholar E. J. Aw, E. J. Aw Departments of Microbiology and Pathology, University of Western Australia, Perth Medical Centre, Shenton Park, Western Australia 6008 Search for other works by this author on: Oxford Academic PubMed Google Scholar J. M. Papadimitriou, J. M. Papadimitriou Departments of Microbiology and Pathology, University of Western Australia, Perth Medical Centre, Shenton Park, Western Australia 6008 Search for other works by this author on: Oxford Academic PubMed Google Scholar P. J. Simons P. J. Simons Departments of Microbiology and Pathology, University of Western Australia, Perth Medical Centre, Shenton Park, Western Australia 6008 Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 51, Issue 5, November 1973, Pages 1541–1549, https://doi.org/10.1093/jnci/51.5.1541 Published: 01 November 1973 Article history Received: 30 March 1973 Accepted: 02 July 1973 Published: 01 November 1973
Phase I dose finding study of Genexol-PM (G-PM) in Asian cancer patients
Authors: Z. Wang, S. Lal, E. Sandanaraj, W. T. Lim, S. S. Leong, E. H. Tan, B. Chowbay
Journal: Journal of Clinical Oncology (2008)

13512 Background: G-PM, a polymeric micelle formulated paclitaxel free of Cremophor-EL has been proven to have significantly greater in-vivo antitumor efficacy than conventional paclitaxel with the delivery of higher doses without additional toxicity. The objective of this phase I study was to asses the pharmacokinetics and the maximum tolerated dose (MTD) of G-PM in Asian patients with advanced solid tumors. Methods: G-PM was administered intravenously over 1h without premedications at dose levels of 80, 100, 120, 140, 160, 180, 200 mg/m2 according to a 3+3 design. The patients were administered G-PM on a weekly basis for three weeks followed by a rest week. Blood samplings for pharmacokinetic parameter estimations were done at 0, 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 24 h after the start of G-PM infusion. Non-compartmental analysis was performed to estimate the pharmacokinetic parameters of G-PM and its metabolites, p-3’- hydroxypaclitaxel and 6α-hydroxypaclitaxel using WinNonlin. Results: 26 patients were recruited for this dose escalation phase I study. The median G-PM AUC0-inf and Cmax were 4.9mghL−1 and 2.7mgL−1, respectively. The increment in G-PM exposure levels (AUC0-inf and Cmax) followed a linear trend across dose levels of 80 to 180mg/m2. The AUC0-inf and Cmax of G-PM showed a 3.4 fold increase across 80 to 180mg/m2. The median clearance of G-PM was observed to be 44.8Lh−1 and the median Vd and t1/2 was 532.2L and 7.9h, respectively. The median AUC0-inf and Cmax of the major metabolite 6α-hydroxypaclitaxel were 122mghL−1 and 52.6mgL−1, respectively. The median AUC0-inf and Cmax of p- 3’-hydroxypaclitaxel were 75.0mghL−1 and 37.4mgL−1, respectively. The half-lives (t1/2) of both 6α-hydroxypaclitaxel and p-3’-hydroxypaclitaxel were 1.2h and 1.3h, respectively, suggesting a rapid conversion of these metabolites to dihydroxypaclitaxel. The MTD of G-PM was identified to be 180mg/m2. Conclusions: The weekly regimen of Genexol-PM displayed a linear pharmacokinetics up to 180mg/m2. The recommended phase II dose of weekly G-PM in Asian cancer patients is 180mg/m2. No significant financial relationships to disclose.
Differences in Purine Metabolizing Enzyme Activities in Human Leukemia T-Cell, B-Cell, and Null Cell Lines: Brief Communication 2
Authors: George L. Tritsch, Jun Minowada
Journal: JNCI Journal of the National Cancer Institute (1978)

Clear metabolic differences between T- and B-cells were demonstrated. Both adenosine deaminase (ADA) and nucleoside phosphorylase (NP) activities increased during logarithmic growth and then decreased in T-cells, but remained essentially constant during the growth cycle of B-cells. When these enzyme activities were examined In a number of T-cell, B-cell, and null cell lines, ADA activity was clearly higher in T-cells as compared to all others. With NP, the opposite appeared to be true, although the differences were much smaller and not statistically significant in all instances. No clear differences were found in the isoenzyme distributions of both enzymes in the various cell types.
Abstract P130: Weight Maintenance after a Worksite Nutrition and Exercise Program: A Randomized Controlled Trial
Authors: Anne N Thorndike, Lillian Sonnenberg, Erica Healey, Khinlei Myint-U, Joseph C Kvedar, Susan Regan
Journal: Circulation (2012)

Background: To address rising healthcare costs associated with obesity, many employers are providing programs to help employees lose weight and make lifestyle changes. Improving health outcomes and reducing costs will depend on whether employees sustain these changes, but few studies have evaluated worksite interventions to maintain a reduction in weight and cardiovascular risk factors over time. Methods: At a large hospital in Boston, MA, we conducted a randomized controlled trial to determine if a 9-month maintenance program immediately following a 10-week team-based worksite exercise and nutrition program would improve weight and cardiovascular risk factor outcomes at 1 year. In 2008, 330 employees from 24 teams completed a 10-week program and were randomized by team to the maintenance intervention or control (usual care) for 9 months. The maintenance intervention included both 1) Internet support with a website for individualized goal-setting and self-monitoring of weight and exercise and 2) minimal personal support with optional individual nutrition and exercise training sessions. Main outcome measures were weight loss, percentage weight loss, waist circumference, fasting lipids, and blood pressure at 1 year. For participants who did not follow up, we used a baseline observation carried forward method for 1 year outcomes. We used random-effects regression models adjusted for clustering within team, and the intervention effect was modeled as the interaction of study arm and time. Results: At 1 year, 238 subjects (72%) completed follow-up assessments. Mean baseline BMI was 27.6 and did not differ between intervention and control. Compared to baseline, both groups lost weight during the 10-week program and maintained 65% of weight loss at 1 year (p&lt;.001). There was no difference in weight loss between intervention and control groups at end of the 10-week program (4.8 lbs vs. 4.3 lbs, p=.53 for group x time interaction) or end of maintenance at 1 year (3.4 lbs vs. 2.5 lbs., p=.40 for group x time interaction). All subjects had significant reductions in percentage weight loss, waist circumference, total cholesterol, and LDL cholesterol at 1 year but did not differ by group. Conclusions: A 10-week worksite nutrition and exercise program resulted in significant reductions in weight and cardiovascular risk factors at 1 year, and participation in an Internet-based maintenance program did not improve these outcomes. Worksite programs to maintain weight loss and lifestyle changes may require more resource-intensive behavioral counseling or incentives to engage participation and improve long-term effectiveness.
Intra-articular hip injections: is there a role for ultrasound?
Authors: Kevin Lian, Bruce Forster
Journal: British Journal of Sports Medicine (2016)

Injection of medications such as corticosteroids, local anaesthetics and viscosupplements are becoming increasingly important means of diagnosis and local, targeted treatment of various hip pathologies, in particular, osteoarthritis.1 ,2 Obtaining needle access to the hip joint is challenging due to its deep anatomic location and proximity to neurovascular structures, and therefore, imaging guidance is often advocated. Fluoroscopy has been the traditional method of choice for needle placement; sonography offers additional benefits in visualisation of neurovascular structures, lack of ionising radiation, portability and possibly decreased cost. In the typical practitioner office setting, ultrasound-guided injection is the only alternative to landmark-guided injection. Comparisons of accuracy between these two methods, however, have not been directly evaluated. Hoeber et al ’s3 meta-analysis compares the accuracy of these two injection methods.

Ultrasound-guided procedures have shown substantial growth in the last decade, increasing by 100.8% from 2004 to 2010, with non-radiologists accounting for 72.2% of this growth.4 Yet the …
Prediction of response to treatment in superficial bladder carcinoma through pattern of interleukin-2 gene expression.
Authors: R Kaempfer, L Gerez, H Farbstein, L Madar, O Hirschman, R Nussinovich, A Shapiro
Journal: Journal of Clinical Oncology (1996)

PURPOSE Superficial bladder carcinoma, treated by resection and intravesical administration of bacillus Calmette-Guérin (BCG), yields a remission rate that approaches 70%. We examined whether expression of interleukin-2 (IL-2) or interferon-gamma (IFN-gamma) genes can serve to predict response. PATIENTS AND METHODS During BCG treatment, we analyzed induction of IL-2 and IFN-gamma mRNA in peripheral-blood mononuclear cells (PBMC) from 73 patients: 51 with papillary tumors and 22 with carcinoma-in-situ (CIS). Results were correlated with remission, relapse, or tumor persistence over a 4-year follow-up period. RESULTS Independent of tumor type, induction of IL-2 mRNA was observed for patients who responded with remission, but not for those who relapsed (P = .0001). Multivariate logistic analysis showed that inducibility of IL-2 mRNA is the discriminating parameter, which yields a predictive value of 97% for remission. Of 23 patients with relapse/persistence, 22 lacked inducibility of IL-2 mRNA (sensitivity, 95.6%), while 35 of 50 patients in remission exhibited inducibility (specificity, 70%). For patients with carcinoma-in-situ, in which remission or failure depends solely on response to BCG, sensitivity and specificity were 88% and 86%, respectively; for patients with papillary tumors, they were 100% and 64%. IFN-gamma mRNA, by contrast, was clearly inducible in PBMC from all patients (P = .51). The disease-free interval increased progressively with inducibility of IL-2 mRNA; this trend was highly significant (P = .0001). CONCLUSION IL-2 gene expression is essential for mounting an antitumor response in superficial bladder carcinoma. Inducibility of IL-2 mRNA is an independent prognostic parameter and useful predictive indicator of remission versus relapse.
Tritiated Thymidine Incorporation Into Epithelial Cells of Normal-Appearing Colorectal Mucosa of Cancer Patients2
Authors: Alain P. Maskens, Eleanor E. Deschner
Journal: JNCI Journal of the National Cancer Institute (1977)

A radioautographic analysis of the number and position of labeled epithelial nuclei after in vitro incorporation of tritiated thymidine ([3H]TDR) was carried out with 30 specimens of histologically normal colorectal mucosa from 26 patients, of whom 13 were being treated for rectal or sigmoid cancer and 13 were controls. A higher mean labeling index was found in the cancer than in the control group (9.8% +/- 1.2 and 7.9% +/- 0.9, respectively). Because of wide individual variations, this difference was not statistically significant. However, a highly significant upward shift of the proliferating cell compartment was observed in the cancer group, resulting in a specific modification of the [3H]TDR labeling pattern in 6 of 17 specimens. DNA synthesis predominated in the middle or middle and upper thirds of the crypts of Lieberkühn rather than in the lower third as observed in controls. The patchy alteration of epithelial cell renewal frequently accompanying colorectal cancer was suggestive of a defect in the regulatory control mechanism. This in vitro [3H]TDR incorporation assay could provide a valuable discriminatory parameter in studies of high-risk populations.
No link between macrolide antibiotics and ventricular arrhythmias, study finds
Authors: Michael McCarthy
Journal: BMJ (2016)

Use of macrolide antibiotics in older adults is not associated with an increased risk of ventricular arrhythmias, a large retrospective cohort study has found.1

The findings contradicted those of a previous study that found an increased risk of cardiovascular death and all cause mortality in patients prescribed the macrolide antibiotic azithromycin compared with patients prescribed amoxicillin or no antibiotic at all.2

That study and other reports of arrhythmias linked to the use of macrolide antibiotics …
Elevation of the Serum Fas Ligand in Patients With Hemophagocytic Syndrome and Diamond-Blackfan Anemia
Authors: Daiichiro Hasegawa, Seiji Kojima, Eiji Tatsumi, Akira Hayakawa, Yoshiyuki Kosaka, Hajime Nakamura, Masahiro Sako, Yuko Osugi, Shigekazu Nagata, Kimihiko Sano
Journal: Blood (1998)
Lack of Association of Serologically Detectable Human Melanoma-Associated Antigens With Beta2 Microglobulin: Serologic and Immunochemical Evidence23
Authors: Richard P. McCabe, Francesco Indiveri, Darrell R. Galloway, Soldano Ferrone, Ralph A. Reisfeld
Journal: JNCI Journal of the National Cancer Institute (1980)

Serologic and immunochemical assays showed that human melanoma-associated antigens (MAA) identified with operationally specific xenoantisera were neither spatially nor structurally associated with β2-microglobulin (β2-μ), the light chain of the HLA-A,B antigen molecular complex; i.e., cultured melanoma cells coated with a specific anti-β2-μ xenoantiserum maintained their reactivity with anti-MAA xenoantisera. Furthermore, soluble MAA were not bound by a β2-μ immunoadsorbent. Finally, MAA were shed into the culture medium of melanoma cells and then were immunoprecipitated with specific anti-MAA xenoantisera; analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, they appeared as two distinct structures with molecular weights of 240,000 and 94,000 but comprised no structure with the characteristic 12,000 molecular weight of β2-μ. Conversely, immunoprecipitates obtained by the reaction of spent culture medium of [3H]valine-labeled melanoma cells with anti-β2-μ xenoantiserum had the 12,000-molecular-weight component but no structures with the molecular weights established for MAA. Thus the data refute the contention that serologically detectable MAA have a molecular structure similar to that of HLA antigens.