bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacokinetics of oral neratinib during co‐administration of ketoconazole in healthy subjects
Authors: Abbas Richat , Hug Bruce A. , Leister Cathie , Burns Jaime , Sonnichsen Daryl 
Published: November 2010

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Neratinib is a potent, low‐molecular‐weight, orally administered, irreversible pan‐ErbB (ErbB‐1, ‐2, ‐4) receptor tyrosine kinase inhibitor that has shown anti‐tumour activity in patients with advanced ErbB‐2‐positive breast cancer both with and without prior trastuzumab exposure.• Neratinib is in phase III development for the treatment of patients with ErbB‐2‐positive breast cancer.• Preclinical data suggest that neratinib is predominantly metabolized by CYP3A4. WHAT THIS STUDY ADDS • The pharmacokinetic profile of neratinib was evaluated in healthy subjects after a single oral administration of neratinib with and without the potent CYP3A4 inhibitor, ketoconazole.• Exposure to neratinib increased more than 3‐fold during co‐administration of ketoconazole, indicating that neratinib is a substrate of CYP3A and is susceptible to interactions with potent CYP3A inhibitors and, thus, dose adjustments may be needed if neratinib is administered with such compounds.AIM The primary objective was to evaluate the pharmacokinetics of a single dose of neratinib, a potent, low‐molecular‐weight, orally administered, irreversible pan‐ErbB (ErbB‐1, ‐2, ‐4) receptor tyrosine kinase inhibitor, during co‐administration with ketoconazole, a potent CYP3A4 inhibitor.METHODS This was an open‐label, randomized, two‐period, crossover study. Fasting healthy adults received a single oral dose of neratinib 240 mg alone and with multiple oral doses of ketoconazole 400 mg. Blood samples were collected up to 72 h after each neratinib dose. Plasma concentration data were analyzed using a noncompartmental method. The least square geometric mean ratios [90% confidence interval (CI)] of Cmax(neratinib+ketoconazole) : Cmax(neratinib alone), and AUC(neratinib+ketoconazole) : AUC(neratinib alone) were assessed.RESULTS Twenty‐four subjects were enrolled. Compared with neratinib administered alone, co‐administration of ketoconazole increased neratinib Cmax by 3.2‐fold (90% CI: 2.4, 4.3) and AUC by 4.8‐fold (3.6, 6.5). Median tmax was 6.0 h with both regimens. Ketoconazole decreased mean apparent oral clearance of neratinib from 346 l h−1 to 87.1 l h−1 and increased mean elimination half‐life from 11.7 h to 18.0 h. The incidence of adverse events was comparable between the two regimens (50% neratinib alone, 65% co‐administration with ketoconazole).CONCLUSION Co‐administration of neratinib with ketoconazole, a potent CYP3A inhibitor, increased neratinib Cmax by 3.2‐fold and AUC by 4.8‐fold compared with administration of neratinib alone. These results indicate that neratinib is a substrate of CYP3A and is susceptible to interaction with potent CYP3A inhibitors and, thus, dose adjustments may be needed if neratinib is administered with such compounds.
CD2‐mediated stimulation of the naive CD4+ T‐cell subset promotes the development of skin‐associated cutaneous lymphocyte antigen‐positive memory cells
Authors: LIU L. , FOER A. , SESTERHENN J. , REINHOLD U. 
Published: November 2010

SummaryDirected migration of lymphocytes from blood into lymph nodes and organ‐associated lymphatic tissue, also referred to as homing, is initiated by T‐cell adhesion to specialized high endothelial cells of postcapillary vessels. Here, we demonstrate that selective signal transduction pathways specifically modulate the expression of the cutaneous lymphocyte antigen (CLA), the putative skin‐homing receptor, during naive to memory transition of CD4+ T cells in vitro. The results show that the expression of CLA is strongly induced by activation via CD2 [T11.1+T11.2 monoclonal antibodies (mAb)]. Addition of transforming growth factor‐β1 (TGF‐β1), interleukin‐6 (IL‐6), and, to a lesser extent, IL‐2 further enhanced the generation of CLA+ T cells, whereas the induction of this antigen was markedly inhibited by IL‐4. Periodic restimulation via CD2 and long‐term culture of activated cells in the presence of IL‐2 and TGF‐β1 resulted in stable expression of CLA during a culture period of more than 100 days. In contrast, activation of naive CD4+ T cells via CD3, CD28 or by mitogens induced a rapid naive to memory phenotype transition but a much lower percentage of CLA+ T cells showing only weak expression of the antigen. Furthermore, activation of purified CD4+ memory T cells by CD2 strongly induced expression of activation‐related antigens CD25 and HLA‐DR, but failed to up‐regulate CLA expression. Our results show that primary stimulation conditions highly modulate the development of skin‐associated T cells and indicate a new functional role for costimulatory adhesion pathways in regulating the expression of molecules associated with T‐cell homing.
Alloantigen‐specific T‐cell anergy induced by human keratinocytes is abrogated upon loss of cell‐cell contact
Authors: OTTEN H. G. , BOR B. , VERVERS C. , VERDONCK L. F. , DE BOER M. , DE GAST G. C. 
Published: November 2010

SummaryThe activation of primary human T cells largely depends on the expression of both major histocompatibility complex (MHC) class II and B7 molecules on antigen‐presenting cells (APC), whereas APC expressing HLA class II but not B7 antigens are expected to induce anergy. According to this concept, interferon‐γ (IFN‐γ)‐activated keratinocytes (KC) expressing HLA class II but not B7 costimulatory antigens should be able to induce anergy. However, in terms of anergy versus activation contradicting data have been published on the outcome of interaction between T cells and human KC. In addition, it has been shown that human KC can express a B7‐like molecule with unknown function, whereas MHC expression may be functionally impaired. To evaluate this item we transfected the human A431 KC cell line with B7‐1 coding sequences and up‐regulated HLA‐DR by treatment with IFN‐γ, yielding A431DR,B7‐1 cells. Irradiated A431DR,B7‐1 cells were found to be capable of inducing vigorous proliferative primary T‐cell responses in resting allogeneic T cells, whereas A431DR cells could induce proliferation only when interleukin‐2 (IL‐2) was added. These data indicate that KC can present alloantigens, and that lack of costimulatory molecules on KC is the main reason why these cells cannot induce primary T‐cell responses. Surprisingly, however, no evidence could be obtained of stable anergy induction by A431DR cells, as T cells contacted with A431DR cells and then transferred to A431DR,B7‐1 cells clearly demonstrated alloresponsiveness. T‐cell non‐responsiveness was maintained only when T cells remained in contact with A431DR cells. These data indicate that, despite expression of HLA class II in the absence of B7 costimulatory molecules, human KC cannot induce stable anergy but rather induce short‐term anergy in primary resting T cells.
Sensitization of T‐cell receptor‐αβ+ T cells recovered from long‐term T‐cell receptor downmodulation
Authors: OMOTO K. , KONG Y.‐Y. , NOMOTO K. , UMESUE M. , MURAKAMI Y. , ETO M. , NOMOTO K. 
Published: November 2010

SummaryAlthough the survival of fully allogeneic skin grafts was prominently prolonged by adult thymectomy in anti‐T‐cell receptor‐αβ monoclonal antibody (TCR‐αβ mAb)‐treated mice compared with that of non‐adult thymectomized (ATX) mice, the skin allografts were eventually rejected. In the anti‐TCR‐αβ mAb‐treated ATX mice, as shown in the present study, most of TCR‐αβ+ cells were promptly activated on day 2 and then rapidly disappeared by day 7, but some TCR‐αβ− Thy‐1+ cells remained at that time. These TCR‐αβ− Thy‐1+ cells which have downmodulated their TCR‐αβ expression may be refractory to depletion events by the mAb treatment. Although these downmodulated T cells re‐expressed their TCR‐αβ on day 50, they could not respond to stimuli via TCR such as TCR cross‐linking or alloantigens. However, they recovered the reactivity to donor antigens on day 85. These results indicate that the downmodulated T cells by anti‐TCR‐αβ mAb treatment are long‐lived and re‐express their TCR‐αβ at a late stage to be sensitized to donor antigen, which suggests that additional regimens may be required to get permanent, or very long‐term, graft acceptance.
Tumour necrosis factor receptor II (p75) signalling is required for the migration of Langerhans' cells
Authors: WANG B. , KONDO S. , SHIVJI G. M. , FUJISAWA H. , MAK T. W. , SAUDER D. N. 
Published: November 2010

SummaryLangerhans' cells (LC) represent the major antigen‐presenting cells within the epidermis. Following exposure of the skin to antigen, LC take up antigen, migrate into draining lymph nodes (DLN) and present processed antigen to T lymphocytes, thereby initiating an immune response. The molecular mechanisms responsible for LC migration remain unclear. Cytokines, in particular tumour necrosis factor‐α (TNF‐α) have been suggested to influence LC migration. There are two distinct membrane receptors for TNF‐α, TNF receptor I (TNF‐R1, p55) and TNF receptor II (TNF‐R2, p75), thought to be responsible for distinct TNF‐α activities. It is believed that most of TNF biological activities are mediated via TNF‐R1. In order to examine the role of TNF‐R1 signalling in LC migration, we utilized TNF‐R1 gene‐targeted mutant mice. Following application of the hapten fluorescein isothiocyanate (FITC), FITC‐bearing cells in DLN were examined by flow cytometry. A normal number of FITC+/Ia+ cells (LC) were found in DLN from TNF‐R1‐deficiency mice, suggesting that TNF‐R1‐dependent signalling is not crucial for LC migration. To investigate the possibility of signalling through TNF‐R2, blocking studies using a neutralizing anti‐TNF‐α antibody were performed. The results revealed that anti‐TNF‐α antibody significantly inhibited LC accumulation in DLN in TNF‐R1‐deficient mice, thus suggesting that TNF‐R2 signalling is involved in LC migration from skin to DLN and that murine LC express TNF‐R2.
CD27/CD70 interaction directly induces natural killer cell killing activity
Authors: YANG F.C. , AGEMATSU K. , NAKAZAWA T. , MORI T. , ITO S. , KOBATA T. , MORIMOTO C. , KOMIYAMA A. 
Published: November 2010

SummaryThe CD27 molecule is expressed on a portion of natural killer (NK) cells as well as T and B cells. To provide the functional capacity of CD27 molecule on NK cells, we here highly purified CD3− CD56+ NK cells by flow cytometry (purity >98%), and investigated their NK cell activity via CD27/CD70 interaction using a CD70‐transfectant by a 4h 51Cr‐release assay. The enhancement of NK activity by purified NK cells in the presence of interleukin‐2 (IL‐2) or interleukin‐12 (IL‐12) against CD70/Nalm‐6 was not recognized as compared to against mock/Nalm‐6. However, after a coculture with the fixed CD70/300‐19, the purified NK cells increased the NK cell activity against K562, the value being 10 to 20% higher than coculture with the mock/300‐19 in the presence of IL‐2 or IL‐12. The enhancement of NK activity was blocked by the addition of anti‐CD70 monoclonal antibody (mAb). In addition, conjugation of NK cells to the target was increased by coculture with the CD70/300‐19 without increased expression of adhesion molecules. In the parallel experiment, there was no increase in the killing capacity of NK cells. These results strongly show that CD27/CD70 interaction directly enhances NK activity in the presence of IL‐2 or IL‐12 by increasing the effector and target conjugate formation, indicating that CD27/CD70 interaction plays an important role in the cytotoxic function of NK cells.
Analysis of recombinant human tumour necrosis factor‐α‐induced CD4 expression on human eosinophils
Authors: HOSSAIN M. , OKUBO Y. , HORIE S. , SEKIGUCHI M. 
Published: November 2010

SummaryWe examined the hypothesis that one of the pro‐inflammatory cytokines, tumour necrosis factor‐α (TNF‐α), could induce expression of the adhesion molecule CD4 on human eosinophils. We further examined the effector function of CD4 and the mechanisms regulating CD4 expression.Human eosinophils were cultured with various concentrations of recombinant human TNF‐α (rhTNF‐α) with or without various drugs for 24 hr. After culture, eosinophils were stained for CD4 using a monoclonal antibody and then analysed by flow cytometry. Eosinophil‐derived neurotoxin (EDN) release as eosinophil degranulation was examined by cross‐linking of CD4 on eosinophils.The rhTNF‐α induced CD4 expression on human eosinophils in a dose‐ and time‐dependent fashion; rhTNF‐α‐induced CD4 expression was significantly inhibited by 10−6 M cycloheximide, 10−8M dexamethasone, or 10−6M herbimycin A. Recombinant human interferon‐γ inhibited rhTNF‐α‐induced CD4 expression in a dose‐dependent manner. However, cross‐linking of CD4 on eosinophils did not evoke EDN release, suggesting that newly expressed CD4 molecules on human eosinophils do not play any role in triggering degranulation. Our data indicate that TNF‐α‐induced CD4 expression on human eosinophils is dependent on protein synthesis and may be dependent on tyrosine kinase activity.
Acerola and cashew apple as sources of antioxidants and dietary fibre
Authors: Rufino Maria do Socorro M. , Pérez‐Jiménez Jara , Tabernero María , Alves Ricardo E. , De Brito Edy S. , Saura‐Calixto Fulgencio 
Published: November 2010

SummarySeveral tropical fruits have been described as natural sources of dietary fibre (DF) and phenolic compounds, associated with different health effects. The aim of this work was to ascertain the DF, phenolic compounds content (including non‐extractable polyphenols, mostly associated with DF) and antioxidant capacity in acerola fruits and cashew apples from selected clones. ‘BRS 236’ acerola fruits presented a high antioxidant capacity because of the combination of both extractable polyphenols and l‐ascorbic acid (providing together a Folin value of 170 kg−1 g d.m.). ‘CCP 76’ cashew apples contained 28 g kg−1 d.m. of extractable polyphenols and 13 g kg−1 d.m. of ascorbic acid as well as a high amount of non‐extractable condensed tannins (52 g kg−1 d.m.). DF content was of 260 g kg−1 d.m. in acerola fruit and of 209 g kg−1 d.m. in cashew apple. Acerola fruits and cashew apple should therefore be considered as new natural sources of DF and phenolic compounds.
Solvent effects on antioxidant properties of persimmon (Diospyros kaki L. cv. Daebong) seeds
Authors: Akter Mst. Sorifa , Ahmed Maruf , Eun Jong‐Bang 
Published: November 2010

SummaryThe aim of this study was to investigate the antioxidant activities of persimmon seed extracts (PSE) using different solvents such as ethanol, methanol, acetone, and their aqueous 80% solvents. The EC50 values of the extracts from absolute ethanol (EE) and methanol (ME) in 2, 2‐diphenyl‐1‐picrylhydrazyl (DPPH) radical–scavenging assay were 49.71 and 51.15 μg mL−1, respectively, while the EC50 of butylated hydroxyanisole (BHA) was 70.82 μg mL−1. However, the EC50 value of reducing power for the absolute acetone extract (AE) was higher (210.06 μg mL−1) than that of BHA (212.67 μg mL−1). Although the absolute ME had the highest antioxidant activity, it exhibited the lowest total phenolics and flavonoids. In contrast, the antioxidant activities of the aqueous solvent extracts showed a good correlation with total phenolics and flavonoids when compared to the absolute solvent extracts. The results showed that PSE could potentially be used as an inexpensive source of natural antioxidant in food and pharmaceutical industries.
Effect of fermentation on biochemical and sensory characteristics of millet flour supplemented with whey protein
Authors: Mallasy Limya O. , El Tinay Abdullahi H. , Elkhalifa Abd Elmoneim O. , Ali Maha A. M. , Mohiedeen Iman E. , Yousif Nabila E. 
Published: November 2010

SummaryPearl millet like other cereals shows qualitative and quantitative deficiency in protein. The main objective of this study was to obtain the food of high nutritive value with high protein content and biological value by supplementing pearl millet, with whey protein. Two levels of whey protein were considered (20% and 25% protein content). Supplemented samples and control were fermented in the presence of starter for 14 h according to the traditional method utilised in Sudan. The pH, crude protein, in vitro protein digestibility (IVPD) and protein fractions of the fermented and supplemented pearl millet were determined at 2‐ h intervals. Supplementation of whey protein resulted in significant increase in protein content compared to the control, i.e. 14.8%, 23.9% and 28.7% for Ashana control (AC), Ashana plus whey protein (20% protein content) (AW1) and Ashana plus whey protein (25% protein content) (AW2), respectively. Fermentation was found to cause a highly significant (P ≤ 0.05) improvement in IVPD for AC, AW1 and AW2. The major protein fraction in the whey protein supplemented doughs was the globulin. This would indicate an improvement in the nutritional quality of pearl millet. Sensory evaluation revealed higher acceptability for whey protein supplemented formulas compared to control.
Improving acetic acid production of Acetobacter pasteurianus AC2005 in hawthorn vinegar fermentation by using beer for seed culture
Authors: Zheng Yu , Zhang Keping , Wang Chunxia , Liu Hongxiang , Luo Jianmei , Wang Min 
Published: November 2010

SummaryFruit vinegar can be obtained biologically from the fermentation of fruit wine using species of the genera Acetobacter. However, the productivity of vinegar is generally low because of the inhibition by substrate ethanol and product acetic acid. In this research, the yield of acetic acid, as well as the cell growth, in hawthorn vinegar fermentation was enhanced using beer for seed preparation. The higher yield of acetic acid of AC2005 was because of the higher alcohol dehydrogenase and aldehyde dehydrogenase activities caused by using beer for seed preparation. Furthermore, Acetobacter pasteurianus AC2005 showed acid stability during the fed‐batch fermentation of hawthorn vinegar.
Glutamine‐enriched enteral nutrition in very low birthweight infants and allergic and infectious diseases at 6 years of age
Authors: Van Zwol Annelies , Moll Henriëtte A. , Fetter Willem P. F. , Van Elburg Ruurd M. 
Published: November 2010

Summaryvan Zwol A, Moll HA, Fetter WPF, van Elburg RM. Glutamine‐enriched enteral nutrition in very low birthweight infants and allergic and infectious diseases at 6 years of age. Paediatric and Perinatal Epidemiology 2010.In a previous randomised controlled trial, we found that glutamine‐enriched enteral nutrition in 102 very low birthweight (VLBW) infants decreased both the incidence of serious infections in the neonatal period and the risk of atopic dermatitis during the first year of life. We hypothesised that glutamine‐enriched enteral nutrition in VLBW infants in the neonatal period influences the risk of allergic and infectious disease at 6 years of age. Eighty‐eight of the 102 infants were eligible for the follow‐up study (13 died, 1 chromosomal abnormality). Doctor‐diagnosed allergic and infectious diseases were assessed by means of validated questionnaires. The association between glutamine‐enriched enteral nutrition in the neonatal period and allergic and infectious diseases at 6 years of age was based on univariable and multivariable logistic regression analyses. Seventy‐six of the 89 (85%) infants participated, 38 in the original glutamine‐supplemented group and 38 in the control group. After adjustment, we found a decreased risk of atopic dermatitis in the glutamine‐supplemented group: adjusted odds ratio (aOR) 0.23 [95% CI 0.06, 0.95]. No association between glutamine supplementation and hay fever, recurrent wheeze and asthma was found. A decreased risk of gastrointestinal tract infections was found in the glutamine‐supplemented group (aOR) 0.10 [95% CI 0.01, 0.93], but there was no association with upper respiratory, lower respiratory or urinary tract infections. We concluded that glutamine‐enriched enteral nutrition in the neonatal period in VLBW infants decreased the risk of atopic dermatitis and gastrointestinal tract infections at 6 years of age.
Hodgkin disease relapse discovered at the time of liver transplant for acute liver failure
Authors: Hope B. C. , Chau K. Y. , Evans H. M. , Mouat S. , Munn S. , Yeong M. L. , Chin S. E. 
Published: November 2010

Hope BC, Chau KY, Evans HM, Mouat S, Munn S, Yeong ML, Chin SE. Hodgkin disease relapse discovered at the time of liver transplant for acute liver failure.  Pediatr Transplantation 2012: 16: E10–E14. © 2010 John Wiley & Sons A/S.Abstract:  Lymphoma is a recognized cause of liver damage and in rare instances presents as ALF. In such cases, the underlying malignancy is often difficult to detect. Historically, the prognosis has been poor. Cure has occasionally been achieved with chemotherapy alone. LT in this setting is controversial, but has contributed to successful outcomes, as in the case of the five‐yr‐old girl reported here.
Iron deficiency anaemia and delayed diagnosis of colorectal cancer: a retrospective cohort study
Authors: Damery S. , Ryan R. , Wilson S. , Ismail T. , Hobbs R. ,   On behalf of the Improving Colorectal Outcomes (ICOS) Group
Published: November 2010

AbstractAim  The extent to which different referral pathways following a primary care diagnosis of iron deficiency anaemia (IDA) are associated with delay in diagnosis of colorectal cancer (CRC) was determined.Method  Eligible patients aged 40 or more years, with IDA diagnosed in primary care, and a subsequent diagnosis of CRC, were studied retrospectively. Referral pathways were identified using the specialty of first recorded GP referral following IDA diagnosis. Differences in time to diagnosis of CRC were assessed by referral specialty. Differences in the proportion of cases referred before and after the re‐issue of the NICE urgent referral guidelines for suspected lower gastrointestinal (GI) cancer were also assessed.Results  Of 628 882 eligible patients, 3.1% (n = 19 349) were diagnosed with IDA during the study period; 3.0% (n = 578) were subsequently diagnosed with CRC. Two hundred and fifty‐nine (44.8%) patients had no recorded referral or a referral unrelated to anaemia or the GI tract. Only 35% (n = 201) of patients were referred to a relevant specialty. Median time to CRC diagnosis ranged from 2.5 months (referral to a relevant surgical specialty) to 31.9 months (haematology). Time to diagnosis was longer in patients referred to a medical compared with a relevant surgical specialty (P = 0.024). There was no significant difference in time to CRC diagnosis before and after the NICE guidelines were re‐issued in 2005.Conclusion  Significant differences exist between referral specialties in time to CRC diagnosis following a primary care diagnosis of IDA. Despite NICE referral recommendations, a significant proportion of patients are still not managed within recommended care pathways to CRC diagnosis.