tbuckley/cabot-search huggingface dataset:
Birth-Weight-Standardized Neonatal Mortality Rates and the Prevention of Low Birth Weight: How Does the United States Compare with Sweden?
Authors: Alfred L. Frechette, Pearl K. Russo
Journal: New England Journal of Medicine (1982)

BIRTH-WEIGHT-STANDARDIZED NEONATAL MORTALITY RATES AND THE PREVENTION OF LOW BIRTH WEIGHT: HOW DOES MASSACHUSETTS COMPARE WITH SWEDEN?Bernard Guyer, M.D., M.P.H., Lee Anne Wallach, M.D., M.P.H., and Sharon L. Rosen, PH.D.The crude infant mortality rate and crude neonatal mortality rate in the United States are often compared unfavorably with those of other industrialized Western nations, especially Sweden.1 , 2 In 1978, the United States, with an infant mortality rate of 13.8 deaths per thousand live births, ranked 17th among these nations, whereas Sweden ranked second with an infant mortality rate of 7.8. Similarly, in 1978, the neonatal mortality rate in the . . .
A phase I study of lirilumab (BMS-986015), an anti-KIR monoclonal antibody, administered in combination with ipilimumab, an anti-CTLA4 monoclonal antibody, in patients (Pts) with select advanced solid tumors.
Authors: Naiyer A. Rizvi, Jeffrey R. Infante, Geoffrey Thomas Gibney, Erin Marie Bertino, Sarah A. Cooley, Kiki Lekatis, Jon M. Wigginton, Andres A. Gutierrez, Ashok Kumar Gupta, Su Young Kim, F. Stephen Hodi
Journal: Journal of Clinical Oncology (2013)

TPS3106 Background: Immune checkpoint blockade represents a novel form of cancer immunotherapy. Killer cell immunoglobulin-like receptors (KIR) and cytotoxic T lymphocyte antigen-4 (CTLA-4) are immune receptors that down-regulate NK and T cell activity, respectively. The anti-KIR antibody, lirilumab (BMSE986015), potentiates innate immunity by blocking signaling through inhibitory KIRs and has demonstrated modest side effects in a Phase I trial. The anti-CTLA-4 antibody, ipilimumab, potentiates adaptive immunity and has demonstrated improved overall survival in pts with advanced melanoma and preliminary evidence of clinical activity in Phase I and II trials. We hypothesized that coordinate modulation of innate and adaptive immunity by combining anti-KIR and anti-CTLA4 antibodies could achieve enhanced biologic and clinical activity compared to either agent alone. Here, we describe a Phase I study of lirilumab plus ipilimumab in pts with selected advanced solid tumors. Methods: This study will be performed in two parts and enroll approximately 150 pts. During dose escalation, pts with advanced melanoma, non-small cell lung cancer and castrate resistant prostate cancer, will be enrolled. During cohort expansion, 20 pts with each tumor type will be enrolled at the maximum tolerated dose (MTD), or the maximum administered dose, if no MTD is defined. The primary study objectives are to delineate the safety and tolerability, dose limiting toxicities, and MTD of this combination. Secondary objectives are to assess preliminary anti-tumor activity, pharmacokinetics, and immunogenicity of this combination in all pts, and the pharmacodynamic effects on tumor infiltrating lymphocytes in a cohort of melanoma pts. Exploratory objectives include a thorough assessment of the modulation of innate and adaptive immunity by this combination in peripheral blood and/or tumor specimens, and preliminary evaluation of the association of these changes with clinical outcome. Clinical trial registration number: NCT01750580 Clinical trial information: NCT01750580.
Abstract 20189: Renal Denervation With Neuron Targeted Nanoparticles Attenuates the Hypertension Associated With Obesity
Authors: Lilei Yu, XiaoYa Zhou, Songyun Wang, Zhuo Wang, Bing Huang, Kai Liao, Hong Jiang
Journal: Circulation (2014)

Introduction: Obesity is associated with hypertension and increased renal sympathetic nervous activity, Our recent study indicated that autonomic denervation could be induced by nanoparticles.In addition, non-toxic fragment of tetanus toxin, known as tetanus toxin C fragment(TTC), which demonstrates extremely high affinity binding to the surfaces of neurons. Hypothesis: This study was to test the hypothesis that renal denervation with TTC-conjugated nanoparticles could attenuate hypertension associated with obesity . Methods: TTC-conjugated nanoparticles and neurotoxic agent (N-isopropylacrylamide monomer) were synthesized. We determined the hemodynamic responses to a high-fat diet in control (n = 6) and renal-denervated by nanoparticles (n = 8) chronically instrumented dogs. After a control period of 7 days, dogs were placed on a high-fat diet for 5 weeks. a modified balloon catheter will be advanced in the target renal artery segment to allow nanoparticles permeating into vascular wall, after that the moving of nanoparticles will be guided by outside magnetic filed towards renal sympathetic nerve.Blood pressure(BP),heart rate variability (HRV),serum norepinephrine (NE) were measured. Pathological examinations were performed on all retrieved samples. Results: In response to a high-fat diet, body weight increased from 17.6 ± 2.4 to 24.8 ± 1.8 kg in the control group. Heart rate increased from 92 ± 6 to 118 ± 10 beats per minute in the control group. BP increased significantly from 105 ± 5 to 139 ± 4 mm Hg in the control group. In contrast, 5 weeks of a high-fat diet in the renal denervation group did not significantly increase body weight(which went from 18.3 ± 2.5 to 19 ± 2.1 mm Hg), Heart rate (which went from 87 ± 3 to 89 ± 6 mm Hg) and BP (which went from 107 ± 3 to 109 ± 6 mm Hg). sympathetic indices of HRV, serum NE, renal sympathetic activity and the expression of c-fos protein in renal sympathetic nerve was significantly lower in the renal denervation group. A histological examination revealed the disruption of nerve fibers, necrosis of Schwann cells and neurons, and apparent denervation in denervation group. Conclusions: Our results indicate that Renal denervation by TTC-conjugated nanoparticles could attenuate hypertension associated with obesity.
Abstract 8980: Investigating Left Ventricular Torsion with 4-Dimensional Echocardiography
Authors: Daniella Ohnemus, Jill Panosian, Helene Houle, Muhammad Ashraf, David J Sahn
Journal: Circulation (2012)

Background: We investigated the relationship between left ventricular (LV) torsion, strain and stroke volume (SV) using a new 4-dimensional (4D) echocardiography strain and mechanics program developed by Siemens. Methods: We used an in vitro rotation model capable of producing torsion and longitudinal strain in 3 freshly harvested pig hearts, which were secured on a pump phantom in a water bath with the apex fixed and the base rotated 0°, 10° and 20° at SVs of 40, 50, 60 and 70 ml. 4D image loops were obtained on a Siemens Acuson SC2000 ultrasound system using a 4Z1C matrix probe. Results: As degrees of rotation increased, computed apical and basal rotation increased accordingly. There was no strong correlation between computed rotation and SV. The Siemens 3D mechanics program computed slight degrees of rotation at both the apical and basal levels, even when the phantom control system was set to 0° rotation. Conclusions: The apparent rotation measured when the rotator was set to 0° supports the hypothesis that rotation is intrinsic and originates from the helical orientation of the myocardial fibers. The 4D program tracked increasing LV rotation extremely accurately in our study.
Reduced natural selection associated with low recombination in Drosophila melanogaster.
Authors: R M Kliman, J Hey
Journal: Molecular Biology and Evolution (1993)

Synonymous codons are not used equally in many organisms, and the extent of codon bias varies among loci. Earlier studies have suggested that more highly expressed loci in Drosophila melanogaster are more biased, consistent with findings from several prokaryotes and unicellular eukaryotes that codon bias is partly due to natural selection for translational efficiency. We link this model of varying selection intensity to the population-genetics prediction that the effectiveness of natural selection is decreased under reduced recombination. In analyses of 385 D. melanogaster loci, we find that codon bias is reduced in regions of low recombination (i.e., near centromeres and telomeres and on the fourth chromosome). The effect does not appear to be a linear function of recombination rate; rather, it seems limited to regions with the very lowest levels of recombination. The large majority of the genome apparently experiences recombination at a sufficiently high rate for effective natural selection against suboptimal codons. These findings support models of the Hill-Robertson effect and genetic hitchhiking and are largely consistent with multiple reports of low levels of DNA sequence variation in regions of low recombination.
miR-34a-dependent overexpression of Per1 decreases cholangiocarcinoma growth
Authors: Yuyan Han, Fanyin Meng, Julie Venter, Nan Wu, Ying Wan, Holly Standeford, Heather Francis, Cynthia Meininger, John Greene, Jerome P. Trzeciakowski, Laurent Ehrlich, Shannon Glaser, Gianfranco Alpini
Journal: Journal of Hepatology (2016)
Combination of 6-thioguanine, capecitabine, and celecoxib with temozolomide or lomustine for recurrent high-grade glioma.
Authors: T. Walbert, M. R. Gilbert, M. D. Groves, V. K. Puduvalli, W. A. Yung, C. A. Conrad, G. C. Bobustuc, H. Colman, B. N. Bekele, V. A. Levin
Journal: Journal of Clinical Oncology (2010)

2057 Background: There is currently no standardized therapy for high-grade gliomas after recurrence. Since chemotherapy for these tumors is still dominated by alkylating agents, we evaluated the efficacy of combination chemotherapy with temozolomide (TMZ) or lomustine (CCNU) and 6-thioguanine (6-TG), capecitabine (CAP), and celecoxib (CEL). Methods: Forty-three patients with recurrent glioblastoma (GBM) and 31 patients with recurrent anaplastic glioma (AG) were enrolled in this open-label, non-comparative, study. Patients previously treated with TMZ received CCNU while all others received TMZ; all patients received 6-TG, CAP, and CEL. Endpoints were 12-month progression-free survival (PFS) for patients with AG and 6-month PFS for patients with GBM, duration of PFS, and MRI- based objective response rates (OR). Results: Results from the TMZ and CCNU treatment arms were combined in the final analysis because there was no statistically significant difference between them. 38 patients with GBM were treated with the CCNU-based regimen, and 5 received the TMZ-based regimen. For the 43 GBM patients, the OR rate was 12% and 33% had stable disease. For GBM, the 6 month PFS was 14% and median overall survival 32 weeks. For the 31 AG patients, the combined OR rate was 26% and 42% had stable disease; the 12 month PFS was 44%. Treatment was reasonably well tolerated; hematologic toxicity was most common and more frequent with CCNU. Conclusions: The combination therapy with 6-TG, CAP, and CEL plus either CCNU or TMZ does not appear to be more effective than conventional alkylating agents for patients with recurrent GBM. The combination, however, is promising for patients with recurrent AG. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Bayer, Castle Biosciences, Genentech, Merck, Novartis, Pfizer, Schering-Plough Bayer, IMEDEX, Merck, Novartis, Schering-Plough Castle Biosciences, Celgene, Genentech, Lilly, MGI Pharma, Novartis, Pfizer, Schering-Plough Schering-Plough
Effects of defibrotide on tumour adhesion and invasion in multiple myeloma, breast cancer and renal cell cancer
Authors: C. Echart, M. Distaso, I. Vlodavsky, C. Mitsiades, K. C. Anderson, P. G. Richardson, M. Iacobelli
Journal: Journal of Clinical Oncology (2008)

8600 Background: Defibrotide (DF), an polydisperse oligonucleotide, has been shown to increase in vivo sensitivity of multiple myeloma (MM) cells to conventional chemotherapy. The tumor microenvironment can influence drug response, resulting in chemoresistance, by interactions between cell surface integrins and extracellular matrix (ECM) proteins. Heparanase (HPSE) is an endoglycosidase involved in degradation and remodeling of the ECM. We investigated if the expression of adhesion molecules in human microvascular endothelial cells (HMEC) is modified by coculture with MM cells and if DF regulates the expression of these molecules. We also evaluated if DF modulates adhesion of MM cells to fibronectin. Finally, we evaluated if DF regulates the expression of HPSE in human breast carcinoma and renal adenocarcinoma (RCC) cell lines. Methods: HMEC were co-cultured with MM cells for 48h with and without DF. The expression of ICAM-1 and E-selectin in HMEC and MM cells was examined by RT-PCR and by FACS. HPSE gene expression was evaluated in RCC and breast carcinoma cells treated with DF or saline. Adhesion of MM cells to fibronectin was evaluated in 96 well plates coated with fibronectin with and without DF for 24 h. Attached MM cells were detected by calcein staining. Results: Coculture with MM cells substantially induced the expression of ICAM-1 and E-selectin (p<0.01) in HMEC cells. DF significantly downregulated ICAM-1 and E- selectin gene expression in HMEC co-cultured with MM cells (p<0.01). Furthermore, DF significantly downregulated HPSE gene expression in the RCC and breast carcinoma cell lines (p<0.01). Adhesion of MM cells to fibronectin was significantly reduced by DF (p<0.01). Conclusions: Our results demonstrate that DF downregulates the expression of adhesion molecules in MM and activated endothelial cells. DF significantly inhibited adhesion of MM cells to fibronectin. Theses findings, together with the downregulation of HPSE in human cancer cell lines, suggest that the anti-cancer activity of DF is due to its combined effects on tumour cell interactions with their microenvironment and provide a rational framework for future studies of DF in combination with other agents for the treatment of MM and other neoplasias, including breast cancer and RCC. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Gentium S.p.A. Gentium S.p.A.
Portal flow steal after liver transplantation
Authors: Bohyun Kim, Kyoung Won Kim, Gi-Won Song, Sung-Gyu Lee
Journal: Clinical and Molecular Hepatology (2015)

Portal flow steal occasionally persists even after the liver transplantation, which may reduce the portal flow and thus threaten the patients' outcome. Therefore, pre- and peri-operative detection of portal steal phenomenon requiring radiological or surgical interruption is essential for the liver transplantation candidates as well as for the recipients. Keywords: Liver transplantation; Portosystemic shunt; Portal flow steal; Doppler
Capecitabine (X) and taxanes in patients (pts) with anthracycline-pretreated metastatic breast cancer (MBC): Sequential vs. combined therapy results from a MOSG randomized phase III trial
Authors: C. Soto, L. Torrecillas, S. Reyes, M. Ramirez, L. Perez, G. Cervantes, F. Gonzalez, E. Tellez, P. Cortes, H. Benitez
Journal: Journal of Clinical Oncology (2006)

570 Introduction: Capecitabine (Xeloda [X]) shows synergy with taxanes and adding X to docetaxel (T) extends overall survival (OS), response rate (RR) and progression free-survival (PFS) beyond T alone. Sequential single-agent therapy could confer convenience benefits and may be more appropriate than combination chemotherapy for some pts. Methods: Pts with anthracycline-pretreated MBC received 3-weekly cycles of 1 of the following regimens: X→taxane (X 1250mg/m 2 bid d1–14, followed after progression (PD) by T 100mg/m 2 or paclitaxel [P] 175mg/m 2 day 1; X+P (X 825mg/m 2 bid days 1–14 + P 175mg/m 2 day 1) or X+T (X 825mg/m 2 bid days 1–14 + T 75mg/m 2 day 1). Results: Of the 368 pts enrolled, 91 are either still on therapy or not evaluable. The table shows baseline characteristics, efficacy and safety in evaluable pts. Median follow up is 15.5 months. Median doses for X in each arm (1 st cycle vs. 8 th cycle, mg/m 2 bid): 1218 vs. 1054; 948 vs. 900; 846 vs. 751. Median doses for P and T (1 st cycle vs. 8 th cycle, mg/m 2 ): 173 vs. 169 and 75 vs. 72, respectively. In the X→taxane arm, 58 pts (64%) received sequential taxane; the remainder did not receive a taxane, either because they were still on X, had CR or had rapid PD. Conclusions: RR is higher with XP and XT, but PFS and OS are similar at a median follow-up of 15.5 months. All regimens were well tolerated with minimal grade 4 AEs. Because there is no clear superiority of sequential vs. combined therapy, pt characteristics are likely to be used to decide which regimen is the most appropriate. [Table: see text] [Table: see text]
Efficacy and safety of sorafenib in patients with advanced hepatocellular carcinoma according to ECOG performance status: A subanalysis from the SHARP trial
Authors: J. Raoul, A. Santoro, M. Beaugrand, J. A. Marrero, M. Moscovici, M. Shan, A. Nadel, D. Voliotis, J. Bruix, J. M. Llovet
Journal: Journal of Clinical Oncology (2008)

4587 Background: Most patients with HCC present with advanced disease; until recently, there were no proven treatment options in this setting. In late 2007, the FDA and EMEA granted approval of sorafenib, an oral multi-kinase inhibitor, in the treatment of advanced HCC following demonstration of a significant overall survival (OS) benefit in the phase III SHARP trial. SHARP recruited patients with ECOG PS 0–2, but the influence of PS on safety and efficacy of sorafenib has not previously been reported. Here we report a subanalysis of SHARP, analyzing the effect of ECOG PS on outcomes in this trial. Methods: Patients with advanced measurable HCC, ECOG PS 0–2 and no cirrhosis or Child-Pugh status A, received either sorafenib (400mg bid) or placebo. Treatment groups were stratified according to region, ECOG PS, and extrahepatic spread or vascular invasion. Endpoints included OS, time to progression (TTP; based on independent tumor assessment), and safety. Patients were grouped according to ECOG PS 0 or 1–2 for this analysis. Results: A total of 602 patients were eligible, 325 (sorafenib=161, placebo=164) had ECOG PS 0 at baseline and 277 (sorafenib=138, placebo=139) had PS 1–2. Among patients with PS 0, median OS for sorafenib vs placebo was 13.3 vs 8.8 months (HR: 0.68; 95% CI: 0.50, 0.95) and median TTP was 5.5 vs 2.9 months (HR: 0.55; 95% CI: 0.40, 0.77). Among patients with PS 1–2, median OS for sorafenib vs placebo was 8.9 vs 5.6 months (HR: 0.71; 95% CI: 0.52, 0.96) and median TTP was 5.3 vs 2.8 months (HR: 0.61; 95% CI: 0.42, 0.88). There were no notable differences in the adverse event (AE) profile of sorafenib in patients with PS 0 compared with PS 1–2. The incidence rates for grade 3–4 drug-related AEs in the sorafenib arm for patients with PS 0 vs PS 1–2 were: diarrhea (8.8 vs 8.0%), fatigue (2.5 vs 5.1%), hand-foot skin reaction (8.8 vs 6.6%), hypertension (1.9 vs 1.5%) and pain (any event) (3.1 vs 2.9%). Conclusions: Compared with placebo, sorafenib prolonged OS and TTP in patients with advanced HCC irrespective of ECOG PS 0 or 1–2. Treatment was well tolerated. Overall, these data suggest that sorafenib extends survival in HCC patients with ECOG PS 1–2 in addition to PS 0, and further support sorafenib as the new standard of care in this setting. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bayer Bayer, Biocompatibles, Bristol-Myers Squibb, AstraZeneca, Eisai, MDS Nordion Bayer, Biocompatibles, Bracco Bayer
Phase I study of first line radiochemotherapy (RCT) with oxaliplatin (Ox), fluorouracil (FU) and folinic acid (FA) in inoperable locally advanced (LA) or metastatic (m) esophageal cancer (EC)
Authors: M. Giovannini, T. Conroy, E. François, J. Seitz, V. Boige, M. Ducreux, M. Ychou, J. P. Metges, I. Sedeki, Y. Yataghene
Journal: Journal of Clinical Oncology (2004)

4044 Background: RCT with 4 cycles (cy) FU/CDDP and 50 Gy (RTOG regimen) is the reference treatment (Tt) for patients (pts) with Inoperable EC, and is associated with 25% long-term survival.To improve these results, we assessed safety and activity of RCT using FU/FA/Ox in EC. Methods: pts with adenocarcinoma (AC), squamous cell (SC), adenosquamous carcinoma (ASC); no prior Tt; radiotherapy (RT) field < 30 cm high; primary tumor ≥5 cm high or metastases; age 18–75 yrs; PS ≤ 2. Tt: 3 RCT cy followed by 3 cy Folfox 4.RCT: Ox d1, FU bolus (b) + Continuous infusion (ci) + FA fixed dose 200 mg/m2 d1–2 q2 weeks (wks) with concurrent RT 50 Gy in 25 fractions/ 5 wks. 5 doses levels (mg/m2): Ox (50–75-85–100), FUb (300–400), FUci (400–600), then Folfox 4, 3 cy d1–2 q2 wks. First endpoint: Maximal Tolerated Dose (MTD) of Ox/FU + RT 50 Gy (dose level at which at least 3/3 or 3/6 pts experience dose limiting toxicity defined as G4 hematotoxicity or G3–4 non-hematotoxicity except esophagitis, dysphagia, nausea and vomiting).Results: 33 pts treated; 12LA/21m; 26M/7F; 10AC/4ASC/19SC; median age 58 (35–76); median cy 6 (1–10); 56 % pts completed therapy. MTD was observed at level 5 (mg/m2) Ox : 100 + FUb/ci: 400/600.Recommended doses are (mg/m2) Ox: 85 + FUb/ci: 400/600 (Folfox 4).Efficacy in 28 evaluable pts: ORR = 61 % (3CR, 14PR). Median TTP and overall survival (months): 5 [95% CI : 3- 6] and 9 [95% CI : 5- 13].Conclusions: In EC Ox/FU/FA + RT 50 Gy is safe and active; a randomised phase II/III study comparing Folfox 4 + RT 50 Gy versus RTOG regimen is starting. No significant financial relationships to disclose.
CEA as a prognostic factor in locally advanced breast cancer patients undergoing neoadjuvant chemotherapy
Authors: N. Valeri, N. Battelli, C. Mariotti, A. Santinelli, W. Siquini, P. Gusella, C. Braconi, P. Lippe, S. Cascinu Prof
Journal: Journal of Clinical Oncology (2006)

10705 Background: CEA and CA 15.3 are most commonly used to evaluate disease progression in metastatic and recurrent breast cancer. Only few significant studies showed a potential predictive role of CEA and CA 15.3 in adjuvant or neoadjuvant setting. We evaluated the correlation between tumour markers level at diagnosis and outcome in locally advanced breast cancer patients treated with neoadjuvant chemotherapy. Methods: Patients with locally advanced breast cancer (T &gt; 3.5 cm and T4) at diagnosis entered the study. All patients had to have initial negative staging (chest X-ray, abdominal ultrasonography, bone scintigraphy and CT scan), whereas all patients who developed metastatic disease in sites which were uncertain during initial staging were excluded. Tumour markers at diagnosis were considered negative if CEA was inferior to 5 ng/ml and CA 15.3 inferior to 35 U/ml. All patients received neoadjuvant chemotherapy (4–6 cycles with regimens containing Anthracyclines and Taxanes or FEC). Most of patients underwent radical mastectomy followed by sequential radiation therapy and adjuvant chemotherapy and/or hormonotherapy in hormonal responsive patients. Results: Fifty-three patients entered the study. At a median follow up of 73 months, 35 patients were disease free after adjuvant treatment (group A), whereas 18 patients developed metastatic disease during follow-up (group B). At diagnosis 14 patients had CA 15.3 greater than 34 U/ml (7 in group A and 7 in group B), 6 patients had CEA greater than 5 ng/ml (1 in group A and 5 in group B) and 18 patients had CEA or CA 15.3 greater than normal values (7 in group A and 11 in group B).We analyzed DFS and OS in patients with normal (CEA &lt; 5 ng/ml, CA15.3 &lt; 35 U/ml) and elevated (CEA ≥ 5 ng/ml, CA 15.3 ≥ 35 U/ml) tumour markers at diagnosis; DFS (p = 0.001) and OS (p = 0.03) were significantly reduced in patients with elevated CEA at diagnosis; differences were not statistically significant for CA 15.3 (p &gt; 0.05). Conclusions: CEA levels before neoadjuvant treatment could represent an important prognostic factor and may influence the choice of treatment in locally advanced breast cancer patients . No significant financial relationships to disclose.