tbuckley/cabot-search huggingface dataset:
Atrial natriuretic factor does not improve the outcome of cadaveric renal transplantation.
Authors: J M Sands, J F Neylan, R A Olson, D P O'Brien, J D Whelchel, W E Mitch
Journal: Journal of the American Society of Nephrology (1991)

Atrial natriuretic factor (ANF) ameliorates renal damage in animal models of acute ischemic renal failure. Consequently, ANF could blunt acute tubular necrosis related to ischemia that occurs frequently in cadaveric renal transplants. Ten pairs of cadaveric kidneys were transplanted into 20 recipients. Paired recipients received either alpha-human ANF (hANF) or vehicle alone in a prospective, double-blind protocol. Upon revascularization of the allograft, either hANF or vehicle was administered intravenously as a 50-micrograms bolus, followed by a 4-h infusion (0.1 microgram/kg/min). Glomerular filtration rate ([125I]iothalamate clearance) was measured between 4 and 7 days posttransplant and again between 14 and 21 days posttransplant. Serum creatinine was measured daily when patients were in the hospital, then twice weekly as patients were examined in the outpatient clinic. Between the groups, there was no significant difference in age of the recipients or donors, cold ischemia time, or histocompatibility leukocyte antigen match. Infusion of hANF had no adverse effects. When subjects receiving hANF were compared with those treated with vehicle alone, there were no significant differences in serum creatinine or glomerular filtration rate. Three hANF and four vehicle recipients required dialysis postoperatively. At 1 month posttransplant, 19 of 20 patients had functioning allografts; an allograft from one hANF recipient never functioned. It was concluded that hANF, when given by the protocol of this study, had no beneficial effect on the outcome of cadaveric renal transplantation in humans.
Bevacizumab Plus Irinotecan Versus Temozolomide in Newly Diagnosed O<sup>6</sup>-Methylguanine–DNA Methyltransferase Nonmethylated Glioblastoma: The Randomized GLARIUS Trial
Authors: Ulrich Herrlinger, Niklas Schäfer, Joachim P. Steinbach, Astrid Weyerbrock, Peter Hau, Roland Goldbrunner, Franziska Friedrich, Veit Rohde, Florian Ringel, Uwe Schlegel, Michael Sabel, Michael W. Ronellenfitsch, Martin Uhl, Jaroslaw Maciaczyk, Stefan Grau, Oliver Schnell, Mathias Hänel, Dietmar Krex, Peter Vajkoczy, Rüdiger Gerlach, Rolf-Dieter Kortmann, Maximilian Mehdorn, Jochen Tüttenberg, Regine Mayer-Steinacker, Rainer Fietkau, Stefanie Brehmer, Frederic Mack, Moritz Stuplich, Sied Kebir, Ralf Kohnen, Elmar Dunkl, Barbara Leutgeb, Martin Proescholdt, Torsten Pietsch, Horst Urbach, Claus Belka, Walter Stummer, Martin Glas
Journal: Journal of Clinical Oncology (2016)

In patients with newly diagnosed glioblastoma that harbors a nonmethylated O(6)-methylguanine-DNA methyltransferase promotor, standard temozolomide (TMZ) has, at best, limited efficacy. The GLARIUS trial thus explored bevacizumab plus irinotecan (BEV+IRI) as an alternative to TMZ.In this phase II, unblinded trial 182 patients in 22 centers were randomly assigned 2:1 to BEV (10 mg/kg every 2 weeks) during radiotherapy (RT) followed by maintenance BEV (10 mg/kg every 2 weeks) plus IRI(125 mg/m(2) every 2 weeks) or to daily TMZ (75 mg/m(2)) during RT followed by six courses of TMZ (150-200 mg/m(2)/d for 5 days every 4 weeks). The primary end point was the progression-free survival rate after 6 months (PFS-6).In the modified intention-to-treat (ITT) population, PFS-6 was increased from 42.6% with TMZ (95% CI, 29.4% to 55.8%) to 79.3% with BEV+IRI (95% CI, 71.9% to 86.7%; P <.001). PFS was prolonged from a median of 5.99 months (95% CI, 2.7 to 7.3 months) to 9.7 months (95% CI, 8.7 to 10.8 months; P < .001). At progression, crossover BEV therapy was given to 81.8% of all patients who received any sort of second-line therapy in the TMZ arm. Overall survival (OS) was not different in the two arms: the median OS was 16.6 months (95% CI, 15.4 to 18.4 months) with BEV+IRI and was 17.5 months (95% CI, 15.1 to 20.5 months) with TMZ. The time course of quality of life (QOL) in six selected domains of the European Organisation for Research and Treatment of Cancer Quality-of-Life Questionnaire (QLQ) -C30 and QLQ-BN20 (which included cognitive functioning), of the Karnofsky performance score, and of the Mini Mental State Examination score was not different between the treatment arms.BEV+IRI resulted in a superior PFS-6 rate and median PFS compared with TMZ. However, BEV+IRI did not improve OS, potentially because of the high crossover rate. BEV+IRI did not alter QOL compared with TMZ.
Non-&lt;italic&gt;H-2&lt;/italic&gt;-Linked Control of in Vivo Growth of SJL/J-Derived Reticulum Cell Sarcoma in Recombinant Inbred Strains Between BALB/cKe and SJL/J Mice&lt;xref ref-type="fn" rid="FN1"&gt;2&lt;/xref&gt;
Authors: T Sakano, S M Wilbur, B Bonavida, M Cohn
Journal: JNCI Journal of the National Cancer Institute (1985)

This report investigated the growth of reticulum cell sarcoma (RCS) in several congenic and recombinant inbred strains between BALB/cKe female (H-2d) and SJL/J male (H-2s) mice. SJA20 mice congenic with SJL/J except at the Igh locus supported RCS growth. Recombinant mice of the H-2d haplotype did not support RCS growth. However, recombinant inbred mice of the H-2s haplotype varied in their susceptibility to permit RCS growth in vivo. These results supported the role of non-H-2 gene(s) controlling the growth of RCS. Since the recombinant strains of mice exhibited different immunologic characteristics and since RCS tumor growth depended on the ability of the mice to develop a strong antitumor proliferative response, the findings reported here suggested that non-H-2 genes control the magnitude of the syngeneic proliferative response and consequently regulate RCS growth in vivo.
A phase I study of IPH2101, a novel anti-inhibitory KIR monoclonal antibody, in patients with multiple myeloma.
Authors: D. M. Benson, S. Padmanabhan, C. C. Hofmeister, C. E. Bakan, R. Abonour, A. Suvannasankha, Y. A. Efebera, P. J. Squiban, M. A. Caligiuri, S. Farag
Journal: Journal of Clinical Oncology (2010)

8139 Background: A natural killer (NK) cell immune response against MM has been well documented; however, this process is impaired by upregulation of MHC class I antigens on MM cells which serve as ligands to NK cell inhibitory killer immunoglobulin-like receptors (KIR). In allogeneic transplantation, KIR/MHC mismatch has improved outcomes in MM by disrupting this relationship. Preclinical data (Blood. 2009;114:2667) demonstrate that IPH2101 (formerly 1-7F9), a human IgG4 monoclonal antibody recognizing common inhibitory KIR, mimics this effect in the autologous setting by enhancing the NK cell vs MM effect. We present results of a phase I study of IPH2101 in patients with MM. Methods: A 7-cohort, open-label, single-agent, dose-escalation, safety and tolerability study was conducted in patients with heavily pre-treated MM. IPH2101 was dose-escalated from 0.0003 to 3 mg/kg IV q28 D for up to 4 cycles in a standard 3+3 trial design. Re-dosing was based on safety data from the prior cycle and data on KIR occupancy, pharmacokinetics (PK), pharmacodynamics (PD), and comprehensive biological effects of IPH2101 were collected. A 7 patient (pt) extension phase of the trial is nearing completion currently at the 3 mg/kg dose level in pts with one prior therapy. Results: Data from 24 treated pts are available at present. 13 pts have received at least 2 doses of IPH2101. No DLT has been observed. One pt at dose level 1 was replaced and dose level 4 was expanded to 6 pts due to SAE (acute renal failure deemed possibly related to IPH2101). To date, IPH2101 has been well tolerated with AEs related to IPH2101 observed in 4 pts (17%). Full KIR occupancy through the majority of the dosing interval was observed at the 1 mg/kg dose with a clear relationship between Cmax and KIR occupancy. PK and PD data closely approximate predicted values and preliminary analyses suggest 3 pts have had disease stabilization with IPH2101. Conclusions: IPH2101 enhances the NK cell vs. MM effect by blocking inhibitory KIR and appears to be safe and well tolerated. Clinical results will be presented, including data from the final, dose extension phase of the study. This immunotherapeutic approach holds promise for the treatment of MM, and further study is warranted. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Innate Pharma Innate Pharma
Skin mottling score as a predictor of 28-day mortality in patients with septic shock
Authors: Edmilson Bastos de Moura, Fábio Ferreira Amorim, Alfredo Nicodemos da Cruz Santana, Gabriel Kanhouche, Lucas Garcia de Souza Godoy, Lucila de Jesus Almeida, Thais Almeida Rodrigues, Carlos Darwin Gomes da Silveira, Marcelo de Oliveira Maia
Journal: Intensive Care Medicine (2015)
Abstract MP041: Menopausal Age, Reproductive Lifespan And Type 2 Diabetes Risk: A Case-cohort Study (InterAct)
Authors: Judith Brand, Yvonne T van der Schouw, N C Onland-Moret, Stephen Sharp, Ken Ong, Eva Ardanaz, Kay-Tee Khaw, Nicholas J Wareham
Journal: Circulation (2012)

Background: Early menopause and estrogen deficiency are important determinants of future health outcomes. While experimental data suggest a role for estrogens in glucose homeostasis, the relationship between menopausal age and type 2 diabetes (T2D) risk is relatively unexplored. Objective: To investigate associations of menopausal age and reproductive lifespan (defined as menopausal age minus age at menarche) with T2D risk. Methods: A case cohort study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC), including 3691 incident T2D cases and a random subcohort of 4408 postmenopausal women (including 235 incident diabetes cases). Prentice weighted Cox regression and random effect meta-analyses were used to investigate the associations between menopausal age, reproductive lifespan and T2D risk. Results: Earlier age at menopause was associated with an increased T2D risk. After adjustment for reproductive and classical T2D risk factors, the HRs across categories of menopausal age (&lt; 40, 40–44, 45–49, 50–54 and ≥ 55 years) were 1.31 (1.01–1.69), 1.10 (0.91–1.34), 1.00 (0.88–1.13), 1.00 (reference) and 0.86 (0.70–1.05) respectively ( P trend = 0.01). The association between reproductive lifespan and T2D risk was weaker: HRs across quartiles of reproductive lifespan were 1.18 (0.98–1.41), 1.02 (0.86–1.22), 0.96 (0.81–1.14) and 1.00 (reference) respectively ( P trend = 0.02). No effect modification with body mass index, waist circumference or smoking status was observed ( P interaction all &gt; 0.05). Conclusion: Earlier age at menopause and a shorter reproductive lifespan are associated with an increased T2D risk, supporting a protective role for estrogens in metabolic disease risk.
Single-copy DNA distance between two congeneric sea urchin species exhibiting radically different modes of development.
Authors: M J Smith, J D Boom, R A Raff
Journal: Molecular Biology and Evolution (1990)

We have investigated the differences between nuclear genomes of two purportedly congeneric species of sea urchin that differ radically in early development. Heliocidaris tuberculata develops by means of a typical pluteus larva, whereas H. erythrogramma develops directly from an egg that is 100-fold the volume of the H. tuberculata egg. Reassociation kinetic analysis shows that the kinetic components of the genomic DNA from the two species are essentially the same. No single repeat component explains the 30% difference between the H. erythrogramma and H. tuberculata genomes. Reciprocal hybridization of tracer-labeled single-copy DNA fractions between these species indicates that approximately 50% of the single-copy DNA is sufficiently similar to form hybrids at standard hybridization criterion. Thermal denaturation profiles of the hybridized single-copy DNA sequence yields median (T50H) values of 13.8 degrees-16.5 degrees C. This result suggests a divergence time of 10-13 Mya, which is comparable to divergence times between congeneric sea urchin species in other genera that do not differ significantly in development. Radical differences in early developmental processes can evolve rapidly between closely related forms.
Breast cancer and oral contraceptives: findings in Royal College of General Practitioners' study.
Authors: Clifford Kay, M Vessey, Klim Mcpherson, Richard Doll
Journal: BMJ (1981)

The incidence of breast cancer was studied among women taking part in the continuing cohort study organised by the Royal College of General Practitioners. An overall relative risk of 1.19 (not significant) was found in those who had used oral contraceptives. The risk ratio in women under 35 years old was 2.81, but this too was not significant. There was evidence that the estimated increased risk for younger women could be a chance occurrence. No convincing evidence of any adverse effects of oral contraceptives on breast cancer has been shown, but because of the long latent period of this tumour there is a need for longer observation.
Review: In patients with chest pain, risk scores better predict high risk for ACS than individual risk factors
Authors: Eric R. Bates
Journal: Annals of Internal Medicine (2016)

Source Citation Fanaroff AC, Rymer JA, Goldstein SA, Simel DL, Newby LK. Does this patient with chest pain have acute coronary syndrome?: the rational clinical examination systematic review. JAMA. 2015;314:1955-65. 26547467
Uptake of atrial natriuretic peptide and production of cGMP in cultured human glomerular endothelial cells.
Authors: D F Green, V A Duruibe, G Blyden, R E Laskey, J J Bourgoignie
Journal: Journal of the American Society of Nephrology (1994)

Interactions between human glomerular endothelial cells and atrial natriuretic peptide (ANP) were studied with 125I-alpha-human-ANP binding and intracellular accumulation of cGMP. Uptake for alpha-hANP (1-28 or 5-28) by homogeneous cultures of human glomerular endothelial cells was dose and time dependent with optimal uptake occurring after 30 min of incubation at 37 degrees C. Scatchard analysis of the specific binding data with a two-compartmental model identified both high (Kd = 0.3 nM)- and low (Kd = 10 nM)-affinity receptors, with a binding site density of 12,000 and 18,060 receptors per cell, respectively. alpha-hANP markedly stimulated glomerular endothelial cell-associated cGMP. After a 2-min incubation, cGMP increased 1.3-fold (from 17.88 +/- 1.29 to 23.33 +/- 3 pmol/mg of protein), in the presence of 1 nM ANP, to more than threefold (from 21 +/- .1 to 80.5 +/- 14.5 pmol/mg of protein) with 1 microM ANP (P < 0.05). In contrast, a 10 microM concentration of the clearance receptor C-ANP4-23 increased cGMP by 1.6 +/- 0.6 fold. ANP stimulation of intracellular cGMP was 100 times more sensitive in human glomerular endothelial than in mesangial cells. In comparison, higher doses of bradykinin were necessary to evoke similar responses in glomerular endothelial cells. In the presence of 10 microM bradykinin, cellular cGMP increased by 1.75 +/- 0.6-fold versus control cells. However, unlike ANP, bradykinin-stimulated cGMP synthesis was significantly inhibited by prior treatment with oxyhemoglobin (10(-5) M), an inhibitor of soluble guanylate cyclase, and NG-nitro-L-arginine (NO2Arg), a specific inhibitor of endothelial-derived relaxing factor (EDRF).(ABSTRACT TRUNCATED AT 250 WORDS)
First death by voluntary euthanasia in Quebec is confirmed
Authors: Owen Dyer
Journal: BMJ (2016)

A terminally ill patient’s life has been ended by a physician’s injection in a Quebec City hospital, the first case of legal voluntary euthanasia ever carried out by a doctor in North America. Quebec legalised voluntary euthanasia in December.1

The case was confirmed to CBC News by a spokeswoman for the Quebec City regional health authority, who said that a second patient’s request is being reviewed. No details about either case will be released.

Georges L’Esperance, a physician and president of the Quebec Association for the Right to Die with Dignity, told the National Post that he had been informed of two other cases of euthanasia this month, both in the Montreal area.

He said that …
Alkylation of Rat Liver Nucleic Acids Not Related to Carcinogenesis by &lt;italic&gt;N&lt;/italic&gt;-Nitrosamines&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;&lt;xref ref-type="fn" rid="FN3"&gt;3&lt;/xref&gt;
Authors: W Lijinsky, A E Ross
Journal: JNCI Journal of the National Cancer Institute (1969)

The supposed relationship between carcinogenesis by N-nitrosamines and their conversion in vivo to an alkylating agent that alkylates nucleic acids in target organs was investigated. Rats were given single treatments with tritium-labeled nitrosoazetidine, nitrosohexamethyleneimine, nitrosomethylaniline, and nitrosomethylcyclohexylamine. DNA and RNA were isolated from liver and hydrolyzed in acid and the products separated by ion-exchange chromatography. The fractions were assayed for radioactivity and a peak of radioactivity was sought that did not correspond with guanine or adenine, as evidence of alkylation. None of the DNA's contained an alkylated base derived from the nitrosamine. Such an alkylated base was in the liver RNA from animals treated with the liver carcinogen nitrosoazetidine, but the liver RNA from animals treated with the liver carcinogen nitrosohexamethyleneimine contained no such alkylated base. On the other hand, nitrosomethylcyclohexylamine, though not a liver carcinogen, did give rise to an alkylated base in liver RNA, and this base was identified as 7-methylguanine by mass spectrometry. No alkylated base was detected in liver RNA of rats treated with nitrosomethylaniline. These results suggest that in vivo alkylation of nucleic acids by cyclic N-nitrosamines might be unrelated to carcinogenesis by these compounds.
Isolation of Epstein-Barr Virus (EBV)-Specific Cytotoxic T Lymphocytes That Lyse Reed-Sternberg Cells: Implications for Immune-Mediated Therapy of EBV+ Hodgkin's Disease
Authors: Amy P. Sing, Richard F. Ambinder, Doley J. Hong, Michael Jensen, Wendy Batten, Effie Petersdorf, Philip D. Greenberg
Journal: Blood (1997)

Abstract A subset of Hodgkin's disease (HD) patients have detectable Epstein-Barr virus (EBV) genomes in the malignant Reed-Sternberg (R-S) cells. R-S cells express only a limited set of latent EBV proteins, but only LMP1 and LMP2 can potentially elicit a CD8+ cytotoxic T-lymphocyte (CTL) response. We have evaluated if either of these proteins could be used as targets for specific adoptive T-cell therapy for EBV-positive (EBV+) HD. The success of this strategy requires that R-S cells are susceptible to lysis by CD8+ CTL, and that CTL specific for LMP1 and LMP2 can be detected and potentially amplified in HD patients. Antigen presentation and CTL sensitivity was evaluated with an in vitro maintained, phenotypically representative R-S cell line, HDLM-2. The R-S cells were able to process and present viral proteins, and to be efficiently lysed by specific CTL in a Class I–restricted manner. Since CTL responses to LMP1 and LMP2 do not represent the dominant responses to EBV, we examined if CTL clones specific for these proteins could be isolated despite the presence of weak or nondetectable responses in polyclonal T-cell lines. LMP-specific clones were generated from individuals either by cloning from the polyclonal EBV-reactive T-cell lines or by direct stimulation of peripheral blood mononuclear cells (PBMC) with cells expressing LMP1 or LMP2 as the only EBV protein. Our ability to isolate CTL specific for LMP proteins from individuals with HD and the sensitivity of R-S cells for CTL-mediated lysis suggest that the pursuit of specific adoptive immunotherapy represents a viable strategy for the subset of HD patients with EBV+ tumors.
Caring for Coronary Artery Disease in China
Authors: David Blumenthal, William Hsiao, Daniel M. Blumenthal
Journal: JAMA Internal Medicine (2016)

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PWE-120 High rate of false positives for advanced fibrosis when simple non-invasive fibrosis tests are used in older patients (≥ 65 years) with nafld
Authors: S Mcpherson, T Hardy, E Henderson, M Allison, V Ratziu, S Francque, AD Burt, C Day, QM Anstee
Journal: Gut (2015)

<h3>Introduction</h3> Simple non-invasive fibrosis scores, such as the FIB-4 and NAFLD fibrosis scores (NFS), are now widely used to identify/exclude advanced fibrosis in patients with NAFLD. Use of these scores in primary care provides a simple objective method to identify patients who need further investigation for advanced fibrosis. Few older patients (≥ 65 years) were included in previous studies, but older patients represent a large proportion of patients with NAFLD in the community. The aim of this study was to assess the performance of simple non-invasive fibrosis tests in older patients (≥65 years old) with biopsy-proven NAFLD. <h3>Method</h3> Patients with biopsy proven NAFLD were recruited from 4 specialist fatty liver clinics. The diagnostic performance of the AST/ALT ratio, FIB-4 and NFS were assessed using liver biopsy as the standard. <h3>Results</h3> From a total of 634 patients, 76 were ≥65 years (mean age 69 ± 3 years, 35% male, 58% diabetic). 60 (79%) of the older patients had steatohepatitis and 30 (39%) had advanced fibrosis (stage 3–4). In older patients the AUROCs for a diagnosis of advanced fibrosis were 0.73, 0.81 and 0.81 for the AST/ALT ratio, FIB-4 and NFS respectively, which was similar to younger patients (0.69, 0.80 and 0.82 respectively). However the specificity for advanced fibrosis using the FIB-4 and NFS was much lower in the older patients than younger patients (FIB-4 35% vs 79%; NFS 20% vs 66%), leading to a high false positive rate. New cut-offs for older patients were derived to improve the specificity to 70% and did not adversely affect the sensitivity (FIB-4 2.0, sensitivity 77%; NFS 0.12, sensitivity 80%). <h3>Conclusion</h3> The diagnostic accuracy for advanced fibrosis using the NFS and FIB-4 score was similar in older and younger patients. However, the specificity for advanced fibrosis was low in older patients (≥ 65 years), resulting in a high false positive rate, which may result in patients undergoing unnecessary further investigations. Adoption of our new cut-offs could reduce the proportion of older patients being referred from primary care for further investigation. <h3>Disclosure of interest</h3> None Declared.
Bromodomain inhibitor OTX015 in patients with lymphoma or multiple myeloma: a dose-escalation, open-label, pharmacokinetic, phase 1 study
Authors: Sandy Amorim, Anastasios Stathis, Mary Gleeson, Sunil Iyengar, Valeria Magarotto, Xavier Leleu, Franck Morschhauser, Lionel Karlin, Florence Broussais, Keyvan Rezai, Patrice Herait, Carmen Kahatt, François Lokiec, Gilles Salles, Thierry Facon, Antonio Palumbo, David Cunningham, Emanuele Zucca, Catherine Thieblemont
Journal: The Lancet Haematology (2016)