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PDF file - 77KB, Pharmacodynamic effects of LFA102 in the rat mammary gland

Numerous lines of evidence suggest that the polypeptide hormone prolactin (PRL) may contribute to breast and prostate tumorigenesis through its interactions with the prolactin receptor (PRLR). Here, we describe the biologic properties of LFA102, a humanized neutralizing monoclonal antibody directed against the extracellular domain of PRLR. This antibody was found to effectively antagonize PRL-induced signaling in breast cancer cells in vitro and in vivo and to block PRL-induced proliferation in numerous cell line models, including examples of autocrine/paracrine PRL activity. A single administration of LFA102 resulted in regression of PRL-dependent Nb2-11 tumor xenografts and significantly prolonged time to progression. Finally, LFA102 treatment significantly inhibited PRLR signaling as well as tumor growth in a carcinogen-induced, estrogen receptor-positive rat mammary cancer model as a monotherapy and enhanced the efficacy of the aromatase inhibitor letrozole when administered in combination. The biologic properties of LFA102, elucidated by the preclinical studies presented here, suggest that this antibody has the potential to be a first-in-class, effective therapeutic for the treatment of PRL-dependent cancers. Mol Cancer Ther; 12(3); 295–305. ©2012 AACR.

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PDF file - 55KB, Pharmacokinetic properties of LFA102 in rodents

PDF file - 71K, Spearman partial correlation coefficients between biomarkers among controls of a nested case-control study in the EPIC cohort.

PDF file - 100K, Odds Ratios with 95% Confidence Intervals (CI) of Lung Cancer for circulating levels of Tryptophan, Kynurenine and Kynurenine/Tryptophan ratio by histological type. P for trend were assessed by the base 2 logarithm of the circulating levels.

Background: Imbalances in tryptophan metabolism have been linked to cancer-related immune escape and implicated in several cancers, including lung cancer.Methods: We conducted a nested case–control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) that included 893 incident lung cancer cases and 1,748 matched controls. Circulating levels of tryptophan and six of its metabolites were measured and evaluated in relation to lung cancer risk.Results: Tryptophan (Ptrend = 2 × 10−5) and the kynurenine/tryptophan ratio (KTR; Ptrend = 4 × 10−5) were associated with lung cancer risk overall after adjusting for established risk factors. The ORs comparing the fifth and first quintiles (OR5th vs. 1st) were 0.52 [95% confidence interval (CI), 0.37–0.74] for tryptophan and 1.74 (95% CI, 1.24–2.45) for KTR. After adjusting for plasma methionine (available from previous work, which was strongly correlated with tryptophan), the associations of tryptophan (adjusted Ptrend = 0.13) and KTR (Ptrend = 0.009) were substantially attenuated. KTR was positively associated with squamous cell carcinoma, the OR5th vs. 1st being 2.83 (95% CI, 1.62–4.94, Ptrend = 3 × 10−5) that was only marginally affected by adjusting for methionine.Conclusions: This study indicates that biomarkers of tryptophan metabolism are associated with subsequent lung cancer risk. Although this result would seem consistent with the immune system having a role in lung cancer development, the overall associations were dependent on methionine, and further studies are warranted to further elucidate the importance of these metabolites in lung cancer etiology.Impact: This is the first prospective study investigating the tryptophan pathway in relation to lung cancer risk. Cancer Epidemiol Biomarkers Prev; 23(3); 461–8. ©2013 AACR.

PDF file - 113K, Odds ratios with 95% Confidence Intervals (CI) of lung cancer for circulating levels of Tryptophan, Kynurenine and Kynurenine/Tryptophan ratio by smoking status. P for trend were assessed by the base 2 logarithm of the circulating levels.

PDF file - 98K, Odds ratios with 95% Confidence Intervals (CI) of lung cancer for circulating levels of Kynurenic acid, 3-Hydroxykynurenine, Anthralinic acid, Xanthurenic acid, 3-Hydroxyantranilic acid and Neopterine. P for trend were assessed by the base 2 logarithm of the circulating levels.

A mathematical module for predicting and analysing the drawing forces is formed and verified. The process used in the current study is drawing. Geometric parameters of the deformation zone and the “selective transfer phenomenon” are also taken into consideration. The experimental verification is conducted through two tests: In the first test, the experimental blanks are cylindrical rods (steel 45, length 150 mm), and are preliminary turned, and the drawplate made of steel 9xc, are used. Regular micro-relief (RMR) hardens the working surfaces of the drawplate. In the second test, the same conditions are applied except for the samples, which represent solid cylindrical billets made of steel 45 with a complicatedly modified surface layer, including a brass film, regular microgeometry and a “servo-witte” copper film. As a result, in the first experiment, the discrepancies are in the range of -29.1% up to +23%. In the second experiment, the discrepancies are in the range of +1.38% up to +48.9%.

Background: The consumption of legumes is promoted as part of a healthy diet in many countries but associations of total and types of legume consumption with type 2 diabetes (T2D) are not well established. Analyses across diverse populations are lacking despite the availability of unpublished legume consumption data in prospective cohort studies. Objective: To examine the prospective associations of total and types of legume intake with the risk of incident T2D. Methods: Meta-analyses of associations between total legume, pulse, and soy consumption and T2D were conducted using a federated approach without physical data-pooling. Prospective cohorts were included if legume exposure and T2D outcome data were available and the cohort investigators agreed to participate. We estimated incidence rate ratios (IRRs) and CIs of associations using individual participant data including ≤42,473 incident cases among 807,785 adults without diabetes in 27 cohorts across the Americas, Eastern Mediterranean, Europe, and Western Pacific. Random-effects meta-analysis was used to combine effect estimates and estimate heterogeneity. Results: Median total legume intake ranged from 0-140 g/d across cohorts. We observed a weak positive association between total legume consumption and T2D (IRR = 1.02, 95% CI: 1.01 to 1.04) per 20 g/d higher intake, with moderately high heterogeneity (I2 = 74%). Analysis by region showed no evidence of associations in the Americas, Eastern Mediterranean, and Western Pacific. The positive association in Europe (IRR = 1.05, 95% CI: 1.01 to 1.10, I2 = 82%) was mainly driven by studies from Germany, UK, and Sweden. No evidence of associations was observed for the consumption of pulses or soy. Conclusions: These findings suggest no evidence of an association of legume intakes with T2D in several world regions. The positive association observed in some European studies warrants further investigation relating to overall dietary contexts in which legumes are consumed, including accompanying foods which may be positively associated with T2D. Funding for the InterConnect project was provided by the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement no. 602068. Additionally, investigators acknowledge funding from the following agencies: NJW, NGF, FI, and MP acknowledge funding from the Medical Research Council Epidemiology Unit (MC_UU_12015/1 and MC_UU_12015/5); NJW and NGF acknowledge support from National Institute of Health Research (NIHR) Biomedical Research Centre Cambridge: Nutrition, Diet, and Lifestyle Research Theme (IS-BRC-1215-20014). TB acknowledges funding from EUCAN-Connect under the European Union's Horizon 2020 research and innovation programme (grant agreement no. 824989). MBR and MAMG acknowledge funding from the Spanish Government Instituto de Salud Carlos III and the European Regional Development Fund (FEDER) (PI17/01795). JK acknowledges funding from the Korea Centers for Disease Control and Prevention, Ministry for Health and Welfare, Republic of Korea (4845-301 and 4851-302), and the Collaborative Genome Program for Fostering New Post-Genome Industry of the National Research Foundation (NRF) funded by the Ministry of Science and ICT (NRF-2017M3C9A6047623). RM acknowledges funding from the Tehran University of Medical Sciences (grant number: 81/15), Cancer Research UK (grant number: C20/A5860), the Intramural Research Program of the U.S. National Cancer Institute, NIH, and the International Agency for Research on Cancer. LB acknowledges that the Cohort of Swedish Men (COSM) and the Swedish Mammography Cohort (SMC) are part of the Swedish Infrastructure for Medical Population-Based Life-Course and Environmental Research (SIMPLER), which receives funding from the Swedish Research Council (2017-00644). BD is an investigator of the Brazilian National Health Technology Assessment Institute and SC received a fellowship from Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), the Brazilian National Council for Scientific and Technological Development Fund (FEDER) (PI17/01795). The Zutphen Elderly Study was funded by The Netherlands Prevention Foundation, The Hague, The Netherlands and the National Institute of Aging, Bethesda, MD, USA. The funding sources did not participate in the design or conduct of the study; collection, management, analysis, or interpretation of the data; or preparation, review, or approval of the manuscript.

The redox field generated by electrically conductive minerals is one of the main constituents of self-potentials. It can be explained by electrochemical reactions in which conductors participate. The location and outline of seafloor hydrothermal ore deposits can be detected using marine self-potential anomalies that can be approximated through a marine geobattery model. The numerical modeling of marine self-potentials could be the foundation of corresponding data inversion and interpretation and improving the application effect of the self-potential method in detecting seafloor hydrothermal ore deposits. In this study, the inert electrode model and the on-land geobattery model are introduced to build the marine geobattery model, and the finite-infinite element coupling method is derived to deal with the truncated boundary problem effectively. Also, two tests are conducted to study the effect of model parameters on ground self-potential anomalies. A seafloor sulfide deposit model is built to study the self-potential characteristics. The numerical modeling results suggest that the precision and efficiency of the coupled method are superior to that of the traditional finite element method. Self-potential anomalies are greatly affected by medium resistivity, complex terrain, and amplitudes of embedded redox fields. Gradient changes in embedded redox fields do not cause significant self-potential anomalies but lead to mutations of current sources. The self-potential anomaly from the sulfide deposit model shows that the self-potential method can be effectively used to explore seafloor hydrothermal deposits that accompany negative self-potential anomalies above the ore bodies. The coupled method is quite suitable for multi-source models such as self-potential models.

A mathematical module for predicting and analyzing the drawing force is formed and verified. The process used in the current study is drawing. Geometric parameters of the deformation zone and the “selective transfer phenomenon” are also taken into consideration. The experimental verification is conducted through two tests: In the first test, the experimental blanks are cylindrical rods (steel 45, length 150 mm), and are preliminary machined by turning, and the drawplate made of steel 9xc, are used. Regular micro-relief (RMR) hardens the working surfaces of the drawplate. In the second test, the same conditions are applied except for the samples, which represent solid cylindrical billets made of steel 45 with a complicatedly modified surface layer, including a brass film, regular microgeometry, and a “servo-witte” copper film. As a result, in the first experiment, the discrepancies are in the range of -29.1% up to +23%. In the second experiment, the discrepancies are in the range of +1.38% up to +48.9%.

The Peshawar basin is a part of the lower Himalayas that contains an enormous amount of groundwater storage. The evaluation of groundwater potential in the southern Peshawar district was done using a hydrogeological and geophysical technique. A total of 13 Vertical Electrical Sounding (VES) profiles were utilized to assess potential groundwater zones for surface resistivity studies. The aquifer system was delineated by comparing the data from five boreholes with the VES findings. It was also possible to find areas of super-saturated groundwater potential by linking metrics such as transmissivity (T), hydraulic conductivity (K), storativity (S), and the Dar Zarrouk. The examined aquifer is composed of clay, sand, gravels, boulders, and loose layers of lacustrine mud that are interlayered to form unconsolidated groundwater aquifer system. As a result, it is possible to use the aquifer for groundwater development because of its low-medium discharge.