tbuckley/cabot-search huggingface dataset:
DACH1 Inhibits breast cancer cell growth and invasion through down-regulaing cyclin D1 kinase activity
Authors: Kongming Wu, Anping Li, Mahadev Rao, Luis E. Dettin, Manran Liu, Chenguang Wang, Elena Tilli, Ying Yang, Priscilla A. Furth, Ales Cvekl, Robert G. Russell, Richard G. Pestell
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

2581 

In Drosophila , synergistic expression of sine oculis(so), eyes absent(eya) and dachshund (dac) controls eye formation. The highly conserved vertebrate homologues Six, Eya and Dach respectively, are co-expressed in multiple organs, and regulate precursor cell proliferation and surviving. Dach1 null mice die during the first 24 hours after birth and the biological functions of Dach1 is poorly understood. Dach1 interacts with Smad/Sin3A complex to control BMPs and TGF-β signals. The phosphatase function of Eya switches the function of Six1-Dach from repression to activation. The role of Six/Eya/Dach network in mammary gland development and oncogenesis is not clear. We found that DACH1, Six1 and cyclin D1 were differently expressed during mouse mammary gland development by immuno-histochemical study. Semi-quantitative analysis of immuno-histochemical stains of human breast tissue arrays showed that DACH1 was detected in normal epithelium; DACH1 expression was decreased or lost in 124 invasive cancers. Reduced expression of DACH1 was inversely correlated with increased cyclin D1 in invasive cancer. DACH1 inhibited mammary epithelial cell proliferation and contact-dependent growth. DACH1 inhibited colony formation in vitro. Expressing of DACH1 significantly reduced tumor growth by 50% in athymic female nude mice compared with vehicle control. DACH1 expression decreased cell migration in wound closure assays and transwell chamber, and decreased invasion in matrigel assays. DACH1 induction in MDA-MB-231 cells by ponasteron A decreased cyclin D1 and phospho-RB, increased p21CIP1 and p27 KIP1. DACH1 inhibited S phase by FACS analysis and DNA syntheses by H3-TdR incorporation in 3T3 wild type cells and in p21CIP1 KO or p27KIP1 KO cells, but not in cyclin D1 KO cells. Our data suggest that cyclin D1 kinase activity is a key target of DACH1 repression of cell proliferation. Reduced expression of DACH1 maybe has an important role in breast cancer proliferation and invasion.
Smoking during pregnancy.
Authors: D M Fergusson, L J Horwood, F T Shannon
Journal: BMJ (1968)

PointersTransfusion and Perforation: Perforation of colon occurred in four neonates after exchange transfusion for haemolytic disease, and was thought to be the result of disturbances in the portal circulation.All recovered after laparotomy and antibiotics (p.345).Six further cases are reported, the pathological findings resembling acute necrotizing enterocolitis (p.349).Leader at p. 340.Prognosis in Nephrotic Syndrome: A study of 400 nephrotics suggests that in children aged 1 to 5 years differential protein clearance tests can obviate renal biopsy (p.352).Leader at p. 343.Folate Siatus in Pregnancy: Report confirms previous findings that 300 "g.folic acid daily is a suitable supplement (p.356).Myocardial Infarction: Oxygen therapy prob- ably worth while since tissue oxygenation appears to be improved by it, despite reduction it causes in cardiac output (p.360).Ventricular Dysrhythmias: Occurred after recovery from infarction in 11 out of 142 patients, and proved fatal in seven (p. 364).Vasodilator in Infarction: Controlled trial did not show any benefit from treatment with dipyridamole (p.366).Case Reports: Oedema of legs from bladder distension (p.369).Bandaging causing sternal depression with associated cardiac arrhythmia (p.369).Schizophrenia: Coping with patient in the home environment (p.371).
Phase II trial of patupilone in patients (pts) with breast cancer brain metastases (BCBM) progressing or recurring after whole brain radiation therapy (WBXRT)
Authors: A. K. Conlin, G. D'Andrea, C. A. Hudis, M. E. Robson, P. Drullinsky, M. Theodoulou, E. Lis, T. Y. Kang, D. M. Peereboom, A. D. Seidman
Journal: Journal of Clinical Oncology (2008)

1086 Background: BCBM are increasing in frequency possibly due to improved systemic therapies and few effective agents that cross the blood-brain barrier (BBB). Patupilone is a novel epothilone that penetrates the BBB in animal models and has activity against brain metastases from non-small cell lung cancer (Abrey et al, ASCO/ECCO 2007). We therefore evaluate patupilone in patients with BCBM. Methods: This dual-center, open-label, phase II study aims to enroll 45 pts with measurable, BCBM progressing despite prior WBXRT with a secondary group of 10 pts with leptomeningeal or asymptomatic, unirradiated brain metastases. Patupilone is given as a single 20-min intravenous infusion, 10mg/m2 every 3 weeks without steroid premedication until disease progression or unacceptable toxicity. The primary endpoint is 3-month central nervous system (CNS) progression free survival (PFS). Secondary endpoints include toxicity, systemic disease response rate, and overall survival. Results: 17 pts have enrolled since February 2007 including 14 in the primary study group. The median age is 55 (43–68 yrs). All have had prior chemotherapy: 94% taxanes and 69% anthracyclines. At baseline 30% (5 pts) had KPS 60–70, and 70% (12 pts) had KPS 80–100. The most common toxicity encountered is diarrhea: 5/17 NCI CTC grade 1 (29%), 2 grade 2 (12%) and 2 grade 3 (12%). Fatigue is the next most common with 6 grade 2 (35%) and no grade 3. In total 6 grade 3 (35%) and no grade 4 adverse events have occurred; 1 death occurred on study. Three pts have had 25% dose reductions (myalgia, diarrhea/hypokalemia, GI ulcer). To date, best responses have been: 1 partial response, 2 stable disease, 10 progressive disease. Two pts are awaiting first assessment, 1 pt withdrew before assessment and 1 pt died before assessment, possibly related to therapy. At this juncture, the 3-month PFS in the CNS is 1/12 (8%). One pt suspected of radiographic progression on MRI and who went to craniotomy had only necrotic tissue without viable tumor upon resection. Conclusions: Patupilone has preliminary activity and is well tolerated as systemic therapy for pts with previously irradiated BCBM. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis Novartis
Proliferative and Metastatic Potential of Exfoliated Colorectal Cancer Cells
Authors: B Fermor, H C Umpleby, J V Lever, M O Symes, R C Williamson
Journal: JNCI Journal of the National Cancer Institute (1986)

Exfoliated colorectal carcinoma cells were obtained by lavage of 27 freshly resected tumor-bearing segments of human bowel with the use of either Hartmann's solution or medium 199. The tumor cells were isolated from the lavage fluid on Nycodenz (Nyegaard, Oslo, Norway) columns. Their proliferative and metastatic potentials were investigated by their ability to incorporate tritiated thymidine ([3H]dThd) and by their ability to form experimental pulmonary tumors following iv injection into immune-deprived stain A mice. Tumor cells from 7 of 12 patients incorporated [3H]dThd as detected by autoradiography of the cells. Pulmonary nodules of colorectal carcinoma were seen in a single mouse after iv injection of tumor cells from 6 of 17 patients and were histologically distinct from spontaneous lung cancers seen in 3 other animals. No tumors were seen in 12 immune-deprived mice receiving tissue culture medium 199 only. Thus exfoliated colorectal carcinoma cells can undergo further division and might give rise to implantation metastases in humans.
Diffusion of brachytherapy for localized prostate cancer across SEER sites from 1992 to 2001
Authors: Y.-N. Wong, F. Wan, D. Penson, M. Putt, C. Montagnet, K. Armstrong
Journal: Journal of Clinical Oncology (2005)

4660 Background: Introduced in 1972, brachytherapy (BT) came into wider use in the late 1980’s through the development of transperineal implantation. It’s use increased significantly in the 1990’s, either alone or in conjunction with external beam radiation (EB) or androgen depravation therapy. It’s role in intermediate risk localized prostate cancer (LPC) is unclear. However, over 30% of LPC patients are now being treated with a regimen that includes BT. Little is known about what factors have influenced the rapid uptake of this technology. Methods: We analyzed data from the Surveillance, Epidemiology and End Results Registry (SEER) for men diagnosed LPC from 1992 to 2001. We limited the analysis to the seven largest SEER sites: San Francisco-Oakland, Connecticut, Detroit (DT), Seattle (SE), Iowa, Atlanta (AT) and Los Angeles.(LA) Logistic regression was used to identify predictors of rate of change in BT (+/− EB) use. Results: BT usage increased more rapidly in AT and SE than other SEER during the time period analyzed. In AT, usage increased from 7.2% of cases in 1992 to 38.1% in 2001. Usage in SE increased from 5% to 25.8%. In DT and LA, the two largest sites, BT usage increased from .63% to 14.2% and 4.2% to 8% respectively. Similar slower rates of increase were seen in other sites (see table 1). (p value for the interaction between site and year <.001) Rates of increase in the use of BT was similar for blacks and whites. Conclusions: The rate of diffusion of BT technology differs significantly among sites. Whether the presence of thought leaders in the region drives patient interest and encourages earlier adoption of new technology is unclear. Further research in both prostate cancer and other disease sites is needed to determine what factors influence the diffusion of technology in different areas of the country and help to clarify regional variations in acquisition of new technology, overall costs of care and patient outcomes. No significant financial relationships to disclose.
Letter by Wasfy et al Regarding Article, “Facility Level Variation in Hospitalization, Mortality, and Costs in the 30 Days After Percutaneous Coronary Intervention: Insights on Short-Term Healthcare Value From the Veterans Affairs Clinical Assessment, Reporting, and Tracking System (VA CART) Program”
Authors: Jason H. Wasfy, Francesca Dominici, Robert W. Yeh
Journal: Circulation (2016)
Athletes with implantable cardioverter defibrillators: can they return to competitive sports?
Authors: Jordan M Prutkin, Michael J Ackerman, Jonathan A Drezner
Journal: British Journal of Sports Medicine (2016)

An 18-year-old man, African-American college basketball player is seen for pre-participation cardiovascular screening. He reports no cardiovascular symptoms and has no family history of juvenile sudden cardiac death or heritable cardiac disease. A screening ECG shows T wave inversion preceded by ST segment elevation in V3-V4 and abnormal T wave inversion in the lateral leads V5-V6, I and aVL (figure 1). An echocardiogram is performed showing concentric left ventricular hypertrophy with prominent apical thickening with a maximal septal measurement of 24 mm, posterior wall thickness of 12–13 mm, left ventricular internal diameter in diastole of 4.8 cm, and normal left ventricular systolic and diastolic function without outflow tract obstruction. Cardiac MRI demonstrates asymmetric thickening of the mid and apical septum with a maximal measurement of 31 mm, as well as several adjacent dense foci of delayed gadolinium enhancement in the mid inferior septum; findings consistent with a diagnosis of hypertrophic cardiomyopathy (HCM). Subsequent exercise treadmill testing and ambulatory ECG monitoring show no abnormalities. The patient receives an implantable cardioverter defibrillator (ICD) for primary prevention of sudden death because his maximal wall thickness is >30 mm (class IIa). Should he be allowed to return to competitive sports?



Figure 1 
Screening ECG with abnormal T wave inversion in the lateral leads.



ICDs have demonstrated a mortality benefit in many cardiac conditions by reducing sudden death from ventricular arrhythmias. ICDs are indicated for high-risk patients with cardiomyopathies and channelopathies where the potential benefit outweighs the risk of complications. High-risk patients are typically defined as having a prior cardiac arrest, ventricular tachycardia, left …
Effect of itraconazole and rifampin on the pharmacokinetics of olaparib tablet formulation in patients with advanced solid tumours: Phase I open-label studies.
Authors: Elizabeth R. Plummer, Henk M.W. Verheul, Sylvie Rottey, Karin Leunen, Guy Heinrich Maria Jerusalem, Christian D. Rolfo, Dorte L. Nielsen, L Rhoda Molife, Rebecca Kristeleit, Judith de Vos-Geelen, Morten Mau-Sørensen, Patricia M.M.B. Soetekouw, Carla van Herpen, Helen Swaisland, Anitra Fielding, Karen So, Wendy Bannister, Luc Dirix
Journal: Journal of Clinical Oncology (2015)

2565 Background: The metabolism of olaparib (Lynparza) is mediated predominantly by CYP3A4/5 enzymes. Two Phase I studies are reported here investigating pharmacokinetic interactions between olaparib (tablet formulation) and itraconazole, a potent CYP3A4 inhibitor (Study 1, NCT01900028), and rifampin, a potent CYP3A4 inducer (Study 2, NCT01929603). Methods: In Study 1, 59 eligible patients (pts) received a single oral dose of olaparib 100 mg on Day 1 and olaparib 100 mg plus itraconazole 200 mg on Day 9; itraconazole 200 mg was administered once daily (qd) on Days 5–11. In Study 2, 22 pts received a single oral dose of olaparib 300 mg on Day 1 and single oral dose olaparib 300 mg plus rifampin 600 mg on Day 14; rifampin 600 mg qd was administered on Days 5–17. Results: Co-administration with itraconazole in Study 1 resulted in a significant increase in mean Cmax (treatment ratio 1.42; 90% CI: 1.33, 1.52) and mean AUC (treatment ratio 2.70; CI: 2.44, 2.97) compared with olaparib alone. Olaparib absorption was slightly slower in the presence of itraconazole (median [range] tmax, 1.50 [0.5–12] hours) vs olaparib alone (1.03 [0.5–8.25] hours). In Study 2, a significant decrease in olaparib bioavailability was observed when co-administered with rifampin (decrease of 71% in Cmax [treatment ratio: 0.29; 90% CI: 0.24, 0.33] and 87% in AUC [0.13; 90% CI: 0.11, 0.16]) vs olaparib alone. Median tmax, was reduced in the presence of rifampin (0.78 [0.27–5.95] hours compared with 1.49 [0.57–3.05] hours for olaparib alone). In both studies, the majority of adverse events were of mild or moderate severity; safety data were consistent with the known safety profile of olaparib. Conclusions: It is recommended that potent CYP3A enzyme inhibitors (eg. itraconazole, telithromycin, clarithromycin, ketoconazole, voriconazole, nefazodone, posaconazole, ritinovir, lopinavir, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir) or inducers (eg. phenytoin, rifampin, carbamazepine, St John’s Wort) be avoided during olaparib treatment. Clinical trial information: NCT01900028/NCT01929603.
A pro-inflammatory role for the Frizzled-8 receptor in chronic bronchitis
Authors: Anita I R Spanjer, Mark H Menzen, Akkelies E Dijkstra, Maarten van den Berge, H Marike Boezen, David C Nickle, Don D Sin, Yohan Bossé, Corry-Anke Brandsma, Wim Timens, Dirkje S Postma, Herman Meurs, Irene H Heijink, Reinoud Gosens
Journal: Thorax (2016)

We have previously shown increased expression of the Frizzled-8 receptor of the Wingless/integrase-1 (WNT) signalling pathway in COPD. Here, we investigated if the Frizzled-8 receptor has a functional role in airway inflammation associated with chronic bronchitis.Acute cigarette-smoke-induced airway inflammation was studied in wild-type and Frizzled-8-deficient mice. Genetic association studies and lung expression quantitative trait loci (eQTL) analyses for Frizzled-8 were performed to evaluate polymorphisms in FZD8 and their relationship to tissue expression in chronic bronchitis. Primary human lung fibroblasts and primary human airway epithelial cells were used for in vitro studies.Cigarette-smoke-exposure induced airway inflammation in wild-type mice, which was prevented in Frizzled-8-deficient mice, suggesting a crucial role for Frizzled-8 in airway inflammation. Furthermore, we found a significant genetic association (p=0.009) between single nucleotide polymorphism (SNP) rs663700 in the FZD8 region and chronic mucus hypersecretion, a characteristic of chronic bronchitis, in a large cohort of smoking individuals. We found SNP rs663700 to be a cis-eQTL regulating Frizzled-8 expression in lung tissue. Functional data link mesenchymal Frizzled-8 expression to inflammation as its expression in COPD-derived lung fibroblasts was regulated by pro-inflammatory cytokines in a genotype-dependent manner. Moreover, Frizzled-8 regulates inflammatory cytokine secretion from human lung fibroblasts, which in turn promoted MUC5AC expression by differentiated human airway epithelium.These findings indicate an important pro-inflammatory role for Frizzled-8 and suggest that its expression is related to chronic bronchitis. Furthermore, our findings indicate an unexpected role for fibroblasts in regulating airway inflammation in COPD.
<i>CDH-1</i> germ line mutations in diffuse gastric and infiltrating ductal breast cancer
Authors: A. P. Efremidis, F. Fostira, C. Panopoulos, K. Papademitriou, N. Pistalmazian, N. Tsoukalas, D. Yannoukakos
Journal: Journal of Clinical Oncology (2009)

e22218 Background: Hereditary Diffuse Gastric Cancer (HDGC) syndrome is characterized by the predisposition to gastric cancer of the diffuse type and to breast cancer of the lobular type. The autosomal dominantly inherited germline mutations of the E- cadherin (CDH1) gene are the defects underlying the HDGC syndrome. The median age of onset for diffuse gastric cancer is 38 years. CDH1 mutations are highly penetrant, conferring a cumulative risk of diffuse gastric cancer of 75%. Methods: Genomic DNA was purified from peripheral blood leukocytes following standard chloroform extraction. The complete coding sequences of the CDH1-gene, including splice junctions, were amplified by Polymerase Chain Reaction (PCR) and electrophorized in an ABI Prism 310 Genetic Analyzer. Results: A pathogenic mutation located on exon 7 of the CDH1 gene was identified in a female patient diagnosed with bilateral breast cancer at the age of 36. She underwent bilateral mastectomy for an infiltrating ductal adenocarcinoma of the left breast and in situ lobular of the right breast. At the age of 45 the patient underwent gastrectomy for diffuse type gastric adenocarcinoma. She had a positive family history for breast and gastric cancer from both sides, but without meeting the absolute clinical criteria for hereditary diffuse gastric cancer syndrome. The nonsense mutation found was probably maternally inherited, since the maternal grandmother was diagnosed with breast cancer at the age of 38. Conclusions: The selection process of patients for genetic testing for the HDGC syndrome is not quite clear at the moment, as it is apparent that more types of breast cancer and not only lobular, can be associated with the syndrome. Criteria should be more flexible in respects to the histopathology of the cancer type. This is the first CDH1 mutation identified in a Greek patient. No significant financial relationships to disclose.
Phase I evaluation of recombinant interleukin-2 in patients with advanced malignant disease.
Authors: M B Atkins, J A Gould, M Allegretta, J J Li, R A Dempsey, R A Rudders, D R Parkinson, S Reichlin, J W Mier
Journal: Journal of Clinical Oncology (1986)

Seventeen patients with refractory malignant tumors were treated with recombinant human interleukin-2 (IL-2) administered by weekly bolus intravenous (IV) injection in a phase I dose escalation trial. Patients received 10,000 to 1,000,000 U/m2 per injection over a course of 3 to 33 weeks. Toxicity was dose related and consisted primarily of fever, chills, nausea, and vomiting. Hypotension was observed at doses of 500,000 U/m2 or higher and in one instance was sufficiently severe to require pressors. No tumor regression was seen and all patients eventually developed progressive disease. Blood levels of cortisol, ACTH, prolactin, and growth hormone as well as the acute phase reactant C-reactive protein (CRP) increased after the administration of IL-2 in most patients. Serum IL-2 levels in excess of 250 U/mL were detected five minutes after an IV injection of 1,000,000 U/m2, after which the levels declined with a half-life of approximately 25 minutes. No alteration in lymphocyte surface phenotype or enhancement in natural cell-mediated cytotoxicity against natural killer (NK)-sensitive and resistant tumor cell lines was observed when these parameters were measured weekly just before the IL-2 injections. However, a dramatic but transient decline in circulating lymphocytes and NK activity was noted within hours of receiving IL-2. This effect was independent of fever and was not abrogated by pretreatment with ibuprofen or metyrapone. The majority of patients developed serum IgG antibodies of IL-2 detectable with a sensitive enzyme-linked immunosorbent assay (ELISA) and a nitrocellulose dot blot assay. The development of anti-IL-2 antibodies was not associated with symptoms suggestive of serum sickness, reductions in serum complement levels, or deterioration in lymphocyte tumoricidal activity. This investigation provides insight into the in vivo actions of this potent biological response modifier and will assist in the design of future studies with IL-2 administered alone or in conjunction with other treatment modalities.
Acute lymphoid leukemia in adolescents: clinical and biologic features predict a poor prognosis--a Pediatric Oncology Group Study.
Authors: W Crist, J Pullen, J Boyett, J Falletta, J van Eys, M Borowitz, J Jackson, B Dowell, C Russell, F Quddus
Journal: Journal of Clinical Oncology (1988)

Analysis of remission induction rates for 1,768 children (1.5 to 11 years) and 425 adolescents (greater than or equal to 11 years) with acute lymphoid leukemia (ALL), and of event-free survival times for 570 children and 147 adolescents, disclosed that adolescents fared significantly worse by both measures of treatment outcome (P = .0001). Adolescents with either T cell or non-T cell ALL entered remission significantly less often than did children (P = less than .02 and P = less than .001, respectively). Within each of the major immunophenotypes of ALL, adolescents had shorter duration of continuous complete remission: early pre-B (non-B, non pre-B, non-T) (P = .001), pre-B (P = .05), and T (P = .027). We compared the clinical characteristics of adolescents and children, and lymphoblast characteristics present at diagnosis to account for the inferior prognosis of adolescent patients. Adolescents had a higher incidence of T cell ALL (P = .0001) and thus a higher incidence of all T cell-associated characteristics. Adolescents with non-T, non-B ALL were more likely to be male (P = .044), and to have higher leukocyte counts (P = .002) and lower levels of IgG (P = .0003), IgA (P = .0001), and IgM (P = .002). Their leukemic cells had lower PAS scores (P = .0001), a higher incidence rate of L2 morphology by French-American-British (FAB) criteria (P = .001), common ALL antigen negativity (P = .0001), and hypodiploid or pseudodiploid karyotypes (P = .004). These findings clearly indicate an increased incidence of prognostically unfavorable clinical and biologic features in adolescents with ALL, providing a biologic explanation for their poor prognosis.
Who benefits from high-dose therapy for multiple myeloma?
Authors: K C Anderson
Journal: Journal of Clinical Oncology (1995)

Article Tools Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.1995.13.6.1291 Journal of Clinical Oncology - published online before print September 21, 2016 PMID: 7751873 Who benefits from high-dose therapy for multiple myeloma? K C AndersonxK C AndersonSearch for articles by this author https://doi.org/10.1200/JCO.1995.13.6.1291 First Page PDF © 1995 by American Society of Clinical Oncology