tbuckley/cabot-search huggingface dataset:
Epiregulin increases the severity of cancer-predisposing colitis in the IL10 mouse model
Authors: Christina Paniccia, Daekee Lee, David W. Threadgill
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

1976 

Inflammatory Bowel Disease (IBD), which includes ulcerative colitis and Crohn′s disease, affects nearly 1 million Americans and is a major predisposing factor for colorectal cancer. Although there are no highly efficacious cures for this disease, significant insight has been gained into the molecular causes of IBD initiation and progression. Mouse models have played a significant role in understanding IBD and how this disease contributes to cancer susceptibility. A widely used model for IBD-related colorectal cancer is the interleukin-10 (Il10) knockout mouse; Il10-deficient mice spontaneously develop colitis and have a heightened susceptibility to colorectal cancer. Il10-deficient mice do not manifest disease under germ-free conditions, showing that the inflammatory response causing IBD is initiated by enteric bacterial flora. Using the dextran sulfate sodium chemical model of colitis we show that epiregulin (Ereg), an epidermal growth factor receptor ligand, is required for normal intestinal homeostasis and protection from chemically-induced colitis. Furthermore, Ereg-deficient mice do not show altered susceptibility to polyp formation in the Min model. To further investigate the role of Ereg in intestinal homeostasis and its potential role in colitis-associated colorectal cancer, double mutant mice were generated that are deficient for both Ereg and Il10. Contrary to expectations from the DSS, the severity of inflammation-related intestinal damage in the Ereg, Il10 double mutant mice was greatly reduced. Despite the reduced colitis, there was no change in IL10-mediated colorectal cancer suggesting that growth factors that can dramatically alter inflammation severity have different effects on cancer susceptibility.
Breastcancer Profilechip: Utilization of microarray technology to predict prognosis and improve clinical management of breast cancer
Authors: N. Borie, D. Birnbaum, F. Bertucci, P. Viens, J. Jacquemier, T. Bachelot, S. Deraco, S. Debono, F. Hermitte, A. Koki
Journal: Journal of Clinical Oncology (2004)

9658
Cultivation and Characterization of BALB/cfC3H Mammary Tumor Cell Lines23
Authors: Mary Jane Vagi
Journal: JNCI Journal of the National Cancer Institute (1973)

Cell lines and sublines initiated from BALB/cfC3H mammary adenocarcinomas exhibited varying morphologies during the 15- to 21-month culture periods. Two epithelial cell lines, FUKU and MJY, continued to form the hemicysts and mounds characteristic of primary cell cultures. Subline MJY-alpha did not form these structures. Instead, the cells varied from polygonal to fusiform within each passage level and, when confluent, the monolayers continually released viable cells into the culture fluid. When introduced into isogeneic hosts, FUKU rapidly established adenocarcinomas with acinar areas, though MJY-alpha yielded only slow-growing carcinosarcomas. 3H-uridine incorporation revealed the constant release of virions from the cell lines and subline. Immunodiffusion assays of virus purified from the culture fluids indicated that FUKU released a mixture of virions containing both mammary tumor virus (MTV) and murine leukemia virus (MuLV) antigens; MJY-alpha virions, on the other hand, were positive for only MTV antigens. Electron microscopic examination of the cell lines and purified virions substantiated this finding. Immunofluorescence detected a shift in the localization of MTV antigens in fixed cell layers of long-term cultures. With increasing passage levels, the cytoplasmic fluorescence typical of primary cultures was replaced by a cell membrane-associated staining pattern. By the fourth to sixth passage level, only cell-surface fluorescence was observed with use of anti-MTV antisera.
Abstract 12654: The Dual Roles of the PCSK9 Active Site: Evidence for an Intermolecular Proteolytic Mechanism and a Separate Secretion Signal Encoded After Proteolytic Maturation
Authors: John S Chorba, Kevan Shokat
Journal: Circulation (2013)

Background: The protease proprotein subtilisin kexin type 9 (PCSK9) raises serum LDL cholesterol (LDL-C) by binding to the LDL receptor (LDL-R) on the cell surface and targeting it for degradation,...
Phase II pilot study of neoadjuvant docetaxel and cisplatin followed by adjuvant erlotinib in patients with stage I-III non-small cell lung cancer (NSCLC)
Authors: K. A. Gold, J. J. Lee, D. Rice, W. Tse, D. Stewart, I. Wistuba, R. S. Herbst, S. M. Lippman, W. K. Hong, E. S. Kim
Journal: Journal of Clinical Oncology (2009)

7566 Background: Pts with early stage NSCLC, especially with nodal disease, have a poor prognosis despite curative intent therapy. It is unclear which pts may derive the benefit of chemotherapy. The primary endpoint of the study was to assess the tolerability of the regimen. In addition, the clinical response of the chemotherapy regimen as well as tumor biomarkers modulation will be examined. Methods: Pts had previously untreated, potentially surgically resectable, stage I-III NSCLC with ECOG performance status (PS) 0–1 and adequate laboratory parameters. After baseline tissue was obtained, chemotherapy was administered (docetaxel [T] 75 mg/m2 and cisplatin [P] 80 mg/m2 every 3 wks) for 3 cycles. Subsequently, pts underwent restaging, then planned definitive therapy with surgical resection. Pts were then offered treatment for 1 year with erlotinib (E) 150 mg PO daily. Bronchoscopic biopsies were performed at 6 months and 1 year post- surgery. Results: 41 pts were enrolled between 2/07 and 11/08. 3 were not eligible and did not receive treatment. Of the 38 eligible pts: median age was 65 years (42–80); 24 (63.2%) were male; 26 (68%) were PS 1. Stage IB 18% (7), IIB 37% (14), IIIA 39% (15), IIIB 5% (2). 31 pts completed all 3 cycles (35 pts completed at least 2 cycles). 32 pts underwent definitive surgical resection with 1 pt pending for surgery. 5 others did not undergo surgery: pneumonia (1), progressive disease (1), definitive chemo-radiation (3). For pts completing at least 2 cycles of chemotherapy, the radiographic response rate was 57% (20) by RECIST criteria with 40% (14) having stable disease. 1 pt had a complete pathologic response. 16 pts have started adjuvant E, 4 have completed 1 yr of treatment. Grade 3/4 toxicities included neutropenia (6 pts) and hypokalemia (4 pts). Blood and tissue specimens will be analyzed to assess sensitivity to chemotherapy. Conclusions: Neoadjuvant T and P is a tolerable and active regimen with an encouraging response rate in stage I- III resectable NSCLC. In addition to clinical characteristics, determining which patients will benefit from chemotherapy by analyzing their tumor biomarkers may help improve overall outcomes of curative lung cancer pts. Supported by grant DoD# W81XWH-07–1-0306. [Table: see text]
Colistin-resistant Escherichia coli harbouring mcr-1 isolated from food animals in Hanoi, Vietnam
Authors: Surbhi Malhotra-Kumar, Basil Britto Xavier, Anupam J Das, Christine Lammens, Ha Thi Thu Hoang, Ngoc Thi Pham, Herman Goossens
Journal: The Lancet Infectious Diseases (2016)
Factors affecting chemotherapy use and delay (≥ 8 weeks) after colorectal cancer surgery and the impact of chemotherapy delay on survival.
Authors: Ik Yong Kim, Young Wan Kim
Journal: Journal of Clinical Oncology (2015)

784 Background: To date, reasons for adjuvant chemotherapy (AC) omission and delay have not been extensively studies. This study aimed to evaluate factors affecting chemotherapy use and delay (≥8 weeks) after colorectal cancer surgery and their impact on survival. Methods: Between 2008 and 2013, consecutive 584 patients undergoing major resection for stage II and III colorectal cancer in a single tertiary referral center. Results: Among 584 patients with stage II and III diseases, AC was performed in 460 (78.8%) patients. Regimens included fluorouracil with folinic acid (n=257, 55.9%), FOLFOX (n=134, 29.1%), capecitabline (n=62, 13.5%), and tegafur-uracil (n=7, 1.5%). Factors affecting not receiving AC were older age (&gt;80 years), American Society of Anesthesiologists score (≥3), presence of postoperative complication, and not receiving preoperative chemoradiation. Overall survival was 87.2% (AC +) and 58.5% (no AC, p&lt;0.001) in stage II disease, and 79.5% (AC +) and 24.6% (no AC, p&lt;0.001) in stage III disease, respectively. Recurrence-free survival was 83.7% (AC +) and 61.9% (no AC, p=0.003) in stage II disease, and 60.5%(AC +) and 21.8% (no AC, p&lt;0.001) in stage III disease, respectively. Among 460 patients undergoing AC, AC was initiated within 8 weeks in 438 patients (95.2%) and after 8 weeks in 22 patients (4.8%). Factors affecting AC delay were male gender, rectal primary, intraoperative blood loss (&gt;100ml), and presence of postoperative complications. Overall survival was 90.8% (AC +) and 40.0% (no AC, p=0.111) in stage II disease, and 82% (AC +) and 35.6% (no AC, p=0.275) in stage III disease, respectively. Recurrence-free survival 80.1% (AC +) and 54.5% (no AC, p=0.133) in stage II disease, and 64.4% (AC +) and 0.0% (no AC, p=0.014), respectively. Conclusions: In stage II, III patients, it appears that use of AC is more closely related patient’s survival rather than the time of AC initiation. To improve oncologic outcomes after curative resection, it is important to increase the proporation of AC use.
Phase I Pharmacologic Study of Oral Topotecan and Intravenous Cisplatin: Sequence-Dependent Hematologic Side Effects
Authors: Maja J. A. de Jonge, Walter J. Loos, Hans Gelderblom, André S. Th. Planting, Maria E. L. van der Burg, Alex Sparreboom, Eric Brouwer, Vera van Beurden, Marijke A. Mantel, Eddie Doyle, Solange Hearn, Graham Ross, Jaap Verweij
Journal: Journal of Clinical Oncology (2000)

PURPOSE: In in vitro studies, synergism and sequence-dependent effects were reported for the combination of topotecan and cisplatin. Recently, an oral formulation of topotecan became available. This phase I study was performed to assess the feasibility of the combination of oral topotecan and cisplatin, the pharmacokinetic interaction, and sequence-dependent effects. PATIENTS AND METHODS: Topotecan was administered orally (PO) daily for 5 days in escalating doses and cisplatin was given intravenously (IV) at a fixed dose of 75 mg/m 2 either before topotecan administration on day 1 (sequence CT) or after topotecan administration on day 5 (sequence TC) once every 3 weeks. Patients were treated in a randomized cross-over design. RESULTS: Forty-nine patients were entered onto the study; one patient was not eligible. Sequence CT induced significantly more severe myelosuppression than did sequence TC, and the maximum-tolerated dosage of topotecan in sequence CT was 1.25 mg/m 2 /d × 5. In sequence TC, the maximum-tolerated dosage of topotecan was 2.0 mg/m 2 /d × 5. Dose-limiting toxicity consisted of myelosuppression and diarrhea. Pharmacokinetics of topotecan and cisplatin were linear over the dose range studied; no sequence-dependent effects were observed. In addition, topotecan did not influence the protein binding of cisplatin or the platinum-DNA adduct formation in peripheral leukocytes in either sequence. CONCLUSION: The recommended dosages for phase II studies involving patients like the patients in our study are topotecan 1.25 mg/m 2 /d PO × 5 preceded by cisplatin 75 mg/m 2 IV day 1 once every 3 weeks, and topotecan 2.0 mg/m 2 /d PO followed by cisplatin 75 mg/m 2 IV day 5. No pharmacokinetic interaction could be discerned in our study. The antitumor efficacy of both schedules should be evaluated in a randomized phase II study.
Global variations in reimbursement of new cancer therapeutics: Improving access through risk-sharing agreements.
Authors: P. K. Cheema, S. Gavura, B. Godman, L. Yeung, M. E. Trudeau
Journal: Journal of Clinical Oncology (2010)

6050 Background: The cost of cancer treatments are rising globally. We examined access to new cancer therapeutics among various countries to identify innovative strategies to increase reimbursement when cost is a concern. Methods: We surveyed England (ENG), Scotland (SCO), France (FRA), Italy (ITA), Germany (DEU), Netherlands (NLD), Finland (FIN), Sweden (SWE), Australia (AUS), New Zealand (NZL) and Canada (Province of Ontario) (CAN), regarding their respective reimbursement decisions for 10 cancer therapeutics (Bevacizumab, Bortezomib, Cetuximab, Erlotinib, Imatinib, Pemetrexed, Rituximab, Sorafenib, Sunitinib and Traztuzumab) to determine access as of December 31, 2009, indications reimbursed and new approaches to purchasing, e.g., risk-sharing arrangements (RSAs). RSAs were defined as either price volume agreements, volume caps, patient access schemes involving free drug, or payment by results based on outcomes. If health authorities quoted ‘special pricing arrangements’ (SPAs) for reasons of confidentiality, this was taken to include RSAs. Results: 67% of countries implemented a RSA for ≥ 1 cancer therapeutic studied. ENG, SCO, FRA, ITA, AUS implemented them nationally. SWE and CAN implemented them regionally/provincially. Countries that factor disease severity in reimbursement decisions (FIN, FRA, and SWE) and/or strong price negotiations or rebates (FRA, ITA, DEU) reimbursed a median average of 100% (range 90%, 100%) of 42 identified licensed indications (FRA 90%; ITA, FIN, DEU and SWE 100%). Countries/provinces where the main driver for reimbursement is cost effectiveness, reimbursed a median average of 49% (range 26%, 88%) (NLD 88%; AUS 55%; CAN 52%; ENG 45%; SCO 40%; NZL 26%). Health authorities in 5 of these countries had a high rate of rejecting initial submissions due to excessive costs (NZL 87%; AUS 71%; SCO 61%; ENG and CAN 50%). Applying RSAs to the rejected submissions led to approval of 2 indications in SCO, 3 in ENG, and SPAs led to approval of 4 indications in CAN and 9 in AUS. Conclusions: Access to innovative cancer therapeutics is highly variable globally. RSAs appear to enhance reimbursement where there are concerns with costs for new cancer agents. No significant financial relationships to disclose.
Abstract P234: Diabetes as Risk Factor for Coronary Heart Disease in Women Compared with Men
Authors: Sanne A Peters, Rachel R Huxley, Mark Woodward
Journal: Circulation (2014)

Introduction: A previous pooled analysis suggested that women with diabetes are at substantially increased risk of fatal coronary heart disease (CHD) compared with affected men. Additional findings from larger and more contemporary studies have since published on the sex-specific associations between diabetes and incident CHD. We performed a systematic review with meta-analysis so as to provide the most reliable evidence of any sex difference in the effect of diabetes on subsequent risk of CHD. Methods: PubMed MEDLINE was systematically searched for prospective population-based cohort studies published between on January 1, 1966 and February 13, 2013. Eligible studies had to have reported sex-specific estimates of the relative risk (RR) for incident CHD associated with diabetes, and its associated variability. Random effects meta-analyses with inverse variance weighting were used to obtain sex-specific RRs and their ratio (RRR). Results: Data from 64 cohorts including 858,507 individuals and 28,203 incident CHD events were included. The RR for incident CHD associated with diabetes compared with no diabetes was 2.83 (95% confidence interval [CI]: 2.37, 3.38) in women and 2.11 (95% CI: 1.79, 2.50) in men. The multiple-adjusted RRR for incident CHD was 44% greater in women with diabetes than it was in men with diabetes (95% CI: 27; 63) with no significant heterogeneity between studies (I2=20%). Conclusions: Women with diabetes have more than a 40% greater risk of incident CHD compared with men with diabetes. Sex disparities in pharmacotherapy are unlikely to explain the excess risk in women. Instead, a greater deterioration in cardiovascular risk profile combined with more prolonged exposure to adverse levels of cardiovascular risk factors among pre-diabetic women compared with their male equivalents may be responsible for the excess risk of diabetes-related CHD in women. Future studies are warranted elucidate the mechanisms responsible for the substantial sex-difference in diabetes-related risk of CHD.
Osteoblast-derived VEGF regulates osteoblast differentiation and bone formation during bone repair
Authors: Kai Hu, Bjorn R. Olsen
Journal: Journal of Clinical Investigation (2016)

Osteoblast-derived VEGF is important for bone development and postnatal bone homeostasis. Previous studies have demonstrated that VEGF affects bone repair and regeneration; however, the cellular mechanisms by which it works are not fully understood. In this study, we investigated the functions of osteoblast-derived VEGF in healing of a bone defect. The results indicate that osteoblast-derived VEGF plays critical roles at several stages in the repair process. Using transgenic mice with osteoblast-specific deletion of Vegfa, we demonstrated that VEGF promoted macrophage recruitment and angiogenic responses in the inflammation phase, and optimal levels of VEGF were required for coupling of angiogenesis and osteogenesis in areas where repair occurs by intramembranous ossification. VEGF likely functions as a paracrine factor in this process because deletion of Vegfr2 in osteoblastic lineage cells enhanced osteoblastic maturation and mineralization. Furthermore, osteoblast- and hypertrophic chondrocyte-derived VEGF stimulated recruitment of blood vessels and osteoclasts and promoted cartilage resorption at the repair site during the periosteal endochondral ossification stage. Finally, osteoblast-derived VEGF stimulated osteoclast formation in the final remodeling phase of the repair process. These findings provide a basis for clinical strategies to improve bone regeneration and treat defects in bone healing.
Preoperative erlotinib in clinical stage I and II non-small cell lung cancer.
Authors: J. L. Port, D. Yankelevitz, P. C. Lee, C. Spinelli, N. K. Altorki
Journal: Journal of Clinical Oncology (2010)

e13639 Background: Epidermal growth factor TKI inhibitors have demonstrable efficacy in the treatment of advanced non- small cell lung cancer (NSCLC). Little is known about their role in early-stage disease. The purpose of this study was to determine the response rate and treatment toxicity to preoperative erlotinib in stage I/II NSCLC. Methods: Patients with biopsy proven clinical stages I/II NSCLC were administered erlotinib 150 mg/day for 21 days in this single-arm open-label phase II trial. The study population was not enriched using clinical or molecular criteria. CT imaging was obtained at baseline and within 1 week after completion of erlotinib treatment. Surgical resection was performed after a one week washout period. Target accrual was 30 patients. Results: Twenty-two patients were enrolled between 10/06 and 11/08, 72% of whom had stage 1 NSCLC. Median age was 71 and the majority (77%) had adenocarcinoma. All patients completed preoperative erlotinib therapy. One patient had grade 3 rash and none had grade 4 toxicity. There were no treatment-related deaths. A partial response by RECIST was observed in one patient (5%), a never-smoking African American woman with adenocarcinoma. Seven patients had ≥25% reduction in tumor volume including four patients with > 40%, one of whom had a 75% reduction in volume and met RECIST criteria for partial response. Conclusions: Erlotinib can be delivered safely in patients with early stage NSCLC. In this study 32% experienced a reduction in tumor volume despite the fact that only one patient met RECIST criteria of response. Tumor volume measurements may allow for determination more subtle, but potentially important, responses to short-term targeted therapy. Variable Median age 71 Gender Male 11 Female 11 Ethnicity Caucasian 20 African American 2 Cell type Adenocarcinoma 15 Squamous 4 Mixed 1 Adenocarcinoma/BAC 2 Clinical stage IA 9 IB 7 IIA 1 IIB 5 Smoking status Former 16 Current 4 Never 2 No significant financial relationships to disclose.
Abstract 17649: Inhibition of Src Homology 2 Domain-containing Phosphatase 1 (SHP-1) Increases Insulin Sensitivity in High-fat Diet-induced Insulin Resistant C57black6 Mice
Authors: Janine Krüger, Markus Dagnell, Philipp Stawowy, Evren Caglayan, Arne Östman, Ulrich Kintscher, Kai Kappert
Journal: Circulation (2014)

Background: Insulin resistance plays a crucial role in the development of type 2 diabetes, and exerts great impact on vascular inflammation and remodeling. At the molecular level a post-insulin receptor (IR) defect in insulin signaling has been suggested to contribute to insulin resistance. IR signaling is antagonized and tightly controlled by protein tyrosine phosphatases (PTPs). The precise role of PTPs in insulin resistance, however, has not been explored. Results: Male C57BL/6J mice were fed a high-fat diet (HFD, 60% kcal from fat) to induce insulin resistance, or a low-fat diet (LFD, 10% kcal from fat) for 10 weeks. Afterwards, HFD mice were treated with PTP-inhibitors for additional 6 weeks. Mice under HFD exhibited a significant increase in body weight as well as decreased respiratory quotient and adiponectin levels, and were characterized by impaired insulin- and glucose tolerance. Organ-based gene expression analyses in insulin-resistant mice demonstrated upregulation of SHP-1, PTP1B, LAR, and DEP-1 in insulin-sensitive organs. SHP-1 was further explored in vitro. Insulin stimulation in murine liver cells induced site-selective hyper-phosphorylation at IR tyrosine-sites Y1158, and Y1361 after inhibition of SHP-1. Furthermore, SHP-1 impairment time-dependently enhanced insulin-induced Akt- and Erk-phosphorylation, and resulted in elevated glucose uptake in skeletal muscle cells. Administration of a SHP-1 inhibitor (Sodium Stibogluconate) and a brought pan-PTP inhibitor (BMOV) in HFD mice led to improvement of both insulin- and glucose tolerance. In accordance, PTP-activity was significantly impaired in epididymal fat, skeletal muscle, and liver under BMOV treatment, being confirmed by reduced ex vivo dephosphorylation of a radioactive labelled peptide (AEEEIYGEFEAKKKK). Finally, BMOV- and SHP-1 treatment also resulted in reduced body weight. Conclusions: IR-antagonizing PTPs were organ-specifically regulated in insulin resistance. The results indicate a central role of PTPs and, in particular, of SHP-1 as endogenous antagonists of the IR. Taken together targeting PTPs led to beneficial effects in insulin resistance, and may thus improve metabolic diseases as well as cardiovascular morbidity and mortality.