bluuebunny/crossref_metadata_2025_split huggingface dataset:
Efficacy of tomato concentrates in mouse models of dyslipidemia and cancer
Authors: Chattopadhyay Arnab , Grijalva Victor , Hough Greg , Su Feng , Mukherjee Pallavi , Farias‐Eisner Robin , Anantharamaiah G. M. , Faull Kym F. , Hwang Lin H. , Navab Mohamad , Fogelman Alan M. , Reddy Srinivasa T. 
Published: July 2015

AbstractWe previously reported that adding freeze‐dried tomato powder from transgenic plants expressing the apolipoprotein A‐I mimetic peptide 6F at 2.2% by weight to a Western diet (WD) ameliorated dyslipidemia and atherosclerosis in mice. The same dose in a human would require three cups of tomato powder three times daily. To reduce the volume, we sought a method to concentrate 6F. Remarkably, extracting the transgenic freeze‐dried tomato overnight in ethyl acetate with 5% acetic acid resulted in a 37‐fold reduction in the amount of transgenic tomato needed for biologic activity. In a mouse model of dyslipidemia, adding 0.06% by weight of the tomato concentrate expressing the 6F peptide (Tg6F) to a WD significantly reduced plasma total cholesterol and triglycerides (P < 0.0065). In a mouse model of colon cancer metastatic to the lungs, adding 0.06% of Tg6F, but not a control tomato concentrate (EV), to standard mouse chow reduced tumor‐associated neutrophils by 94 ± 1.1% (P = 0.0052), and reduced tumor burden by two‐thirds (P = 0.0371). Adding 0.06% of either EV or Tg6F by weight to standard mouse chow significantly reduced tumor burden in a mouse model of ovarian cancer; however, Tg6F was significantly more effective (35% reduction for EV vs. 53% reduction for Tg6F; P = 0.0069). Providing the same dose of tomato concentrate to humans would require only two tablespoons three times daily making this a practical approach for testing oral apoA‐I mimetic therapy in the treatment of dyslipidemia and cancer.
Pharmacology and physiology of gastrointestinal enteroendocrine cells
Authors: Mace O. J. , Tehan B. , Marshall F. 
Published: July 2015

AbstractGastrointestinal (GI) polypeptides are secreted from enteroendocrine cells (EECs). Recent technical advances and the identification of endogenous and synthetic ligands have enabled exploration of the pharmacology and physiology of EECs. Enteroendocrine signaling pathways stimulating hormone secretion involve multiple nutrient transporters and G protein‐coupled receptors (GPCRs), which are activated simultaneously under prevailing nutrient conditions in the intestine following a meal. The majority of studies investigate hormone secretion from EECs in response to single ligands and although the mechanisms behind how individual signaling pathways generate a hormonal output have been well characterized, our understanding of how these signaling pathways converge to generate a single hormone secretory response is still in its infancy. However, a picture is beginning to emerge of how nutrients and full, partial, or allosteric GPCR ligands differentially regulate the enteroendocrine system and its interaction with the enteric and central nervous system. So far, activation of multiple pathways underlies drug discovery efforts to harness the therapeutic potential of the enteroendocrine system to mimic the phenotypic changes observed in patients who have undergone Roux‐en‐Y gastric surgery. Typically obese patients exhibit ~30% weight loss and greater than 80% of obese diabetics show remission of diabetes. Targeting combinations of enteroendocrine signaling pathways that work synergistically may manifest with significant, differentiated EEC secretory efficacy. Furthermore, allosteric modulators with their increased selectivity, self‐limiting activity, and structural novelty may translate into more promising enteroendocrine drugs. Together with the potential to bias enteroendocrine GPCR signaling and/or to activate multiple divergent signaling pathways highlights the considerable range of therapeutic possibilities available. Here, we review the pharmacology and physiology of the EEC system.
Effect of CYP3A perpetrators on ibrutinib exposure in healthy participants
Authors: de Jong Jan , Skee Donna , Murphy Joe , Sukbuntherng Juthamas , Hellemans Peter , Smit Johan , de Vries Ronald , Jiao Juhui James , Snoeys Jan , Mannaert Erik 
Published: July 2015

AbstractIbrutinib (PCI‐32765), a potent covalent inhibitor of Bruton's tyrosine kinase, has shown efficacy against a variety of B‐cell malignancies. Given the prominent role of CYP3A in ibrutinib metabolism, effect of coadministration of CYP3A perpetrators with ibrutinib was evaluated in healthy adults. Ibrutinib (120 mg [Study 1, fasted], 560 mg [studies 2 (fasted), and 3 (nonfasted)]) was given alone and with ketoconazole [Study 1; 400 mg q.d.], rifampin [Study 2; 600 mg q.d.], and grapefruit juice [GFJ, Study 3]. Lower doses of ibrutinib were used together with CYP3A inhibitors [Study 1: 40 mg; Study 3: 140 mg], as safety precaution. Under fasted condition, ketoconazole increased ibrutinib dose‐normalized (DN) exposure [DN‐AUClast: 24‐fold; DN‐Cmax: 29‐fold], rifampin decreased ibrutinib exposure [Cmax: 13‐fold; AUClast: 10‐fold]. Under nonfasted condition, GFJ caused a moderate increase [DN‐Cmax: 3.5‐fold; DN‐AUC: 2.2‐fold], most likely through inhibition of intestinal CYP3A. Half‐life was not affected by CYP perpetrators indicating the interaction was mainly on first‐pass extraction. All treatments were well‐tolerated.
Pharmacodynamic assays to facilitate preclinical and clinical development of pre‐mRNA splicing modulatory drug candidates
Authors: Shi Yihui , Joyner Amanda S. , Shadrick William , Palacios Gustavo , Lagisetti Chandraiah , Potter Philip M. , Sambucetti Lidia C. , Stamm Stefan , Webb Thomas R. 
Published: July 2015

AbstractThe spliceosome has recently emerged as a new target for cancer chemotherapy and novel antitumor spliceosome targeted agents are under development. Here, we describe two types of novel pharmacodynamic assays that facilitate drug discovery and development of this intriguing class of innovative therapeutics; the first assay is useful for preclinical optimization of small‐molecule agents that target the SF3B1 spliceosomal protein in animals, the second assay is an ex vivo validated, gel‐based assay for the measurement of drug exposure in human leukocytes. The first assay utilizes a highly specific bioluminescent splicing reporter, based on the skipping of exons 4–11 of a Luc‐MDM2 construct, which specifically yields active luciferase when treated with small‐molecule spliceosome modulators. We demonstrate that this reporter can be used to monitor alternative splicing in whole cells in vitro. We describe here that cell lines carrying the reporter can be used in vivo for the efficient pharmacodynamic analysis of agents during drug optimization and development. We also demonstrate dose‐ and time‐dependent on‐target activity of sudemycin D6 (SD6), which leads to dramatic tumor regression. The second assay relies on the treatment of freshly drawn human blood with SD6 ex vivo treatment. Changes in alternative splicing are determined by RT‐PCR using genes previously identified in in vitro experiments. The Luc‐MDM2 alternative splicing bioluminescent reporter and the splicing changes observed in human leukocytes should allow for the more facile translation of novel splicing modulators into clinical application.
Preclinical evaluation of SMM‐189, a cannabinoid receptor 2‐specific inverse agonist
Authors: Presley Chaela , Abidi Ammaar , Suryawanshi Satyendra , Mustafa Suni , Meibohm Bernd , Moore Bob M. 
Published: July 2015

AbstractCannabinoid receptor 2 agonists and inverse agonists are emerging as new therapeutic options for a spectrum of autoimmune‐related disease. Of particular interest, is the ability of CB2 ligands to regulate microglia function in neurodegenerative diseases and traumatic brain injury. We have previously reported the receptor affinity of 3′,5′‐dichloro‐2,6‐dihydroxy‐biphenyl‐4‐yl)‐phenyl‐methanone (SMM‐189) and the characterization of the beneficial effects of SMM‐189 in the mouse model of mild traumatic brain injury. Herein, we report the further characterization of SMM‐189 as a potent and selective CB2 inverse agonist, which acts as a noncompetitive inhibitor of CP 55,940. The ability of SMM‐189 to regulate microglial activation, in terms of chemokine expression and cell morphology, has been determined. Finally, we have determined that SMM‐189 possesses acceptable biopharmaceutical properties indicating that the triaryl class of CB2 inverse agonists are viable compounds for continued preclinical development for the treatment of neurodegenerative disorders and traumatic brain injury.
Retraction: Poly(3‐hexylthiophene) films by electrospray deposition for crystalline silicon/organic hybrid junction solar cells
Authors: Hiate Taiga , Miyauchi Naoto , Tang Zeguo , Ishikawa Ryo , Ueno Keiji , Shirai Hajime 
Published: July 2015

AbstractThe above article, published online on 25 July 2015 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the authors, the journal Editor‐in‐Chief, Stefan Hildebrandt, and Wiley‐VCH GmbH & Co. KGaA. The retraction has been agreed since the contents of the article have already been published by the corresponding author in Jpn. J. Appl. Phys. 51, 061602 (2015) on 4 June 2015.The manuscript submitted to physica status solidi (c) was part of the E‐MRS 2015 Spring Meeting, Symposium A, Proceedings. The authors regret the dual publication and express their sincere apologies to readers. (© 2015 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Attribute‐based credentials with cryptographic collusion prevention
Authors: Hajny Jan , Dzurenda Petr , Malina Lukas 
Published: July 2015

AbstractCryptographic attribute‐based credentials (ABCs) allow users to prove their personal attributes remotely and in a privacy‐friendly way. While staying anonymous and untraceable, the users are able to prove their attributes, such as age, membership, or nationality, before using a network service. Unfortunately, there are very few practical cryptographic ABC schemes available today. Furthermore, some existing schemes rely on the hardware tamper‐resistance of smart cards to avoid collusion attacks. The trust in hardware limits the usage of such schemes on poorly protected cards and on smart phones. In this paper, we present the full cryptographic specification of an ABC scheme, which makes the collusion attacks impossible even on insecure hardware like mobile phones. Furthermore, the scheme provides features, which are difficult to achieve using existing schemes, namely the practical revocation of users, the de‐anonymization of malicious users, and the unlinkability of verification sessions. Besides the cryptographic architecture, we also present our practical implementation on a smart phone and embedded platforms. Copyright © 2015 John Wiley & Sons, Ltd.
HC-HA/PTX3 Purified From Amniotic Membrane Promotes BMP Signaling in Limbal Niche Cells to Maintain Quiescence of Limbal Epithelial Progenitor/Stem Cells
Authors: Chen Szu-Yu , Han Bo , Zhu Ying-Ting , Mahabole Megha , Huang Jie , Beebe David C. , Tseng Scheffer C. G. 
Published: July 2015

Abstract
To explore how limbal niche cells (LNCs) may control quiescence, self-renewal, and corneal epithelial lineage commitment/differentiation of limbal epithelial progenitor/stem cells (LEPCs), we have established an in vitro sphere assay by reunion between the two cell types in three-dimensional Matrigel. The resultant sphere exhibits inhibition of corneal epithelial lineage commitment/differentiation and marked clonal growth of LEPCs, of which the latter is correlated with activation of canonical Wnt signaling. Herein, we have created a similar reunion assay in immobilized heavy chain-hyaluronic acid/pentraxin 3 (HC-HA/PTX3), which is purified from amniotic membrane (AM) and consists of a complex formed by hyaluronic covalently linked to heavy chain 1 of inter-α-inhibitor and noncovalently linked to pentraxin 3. The resultant spheres exhibited similar suppression of corneal epithelial lineage commitment/differentiation but upregulation of quiescence markers including nuclear translocation of Bmi-1, and negligible clonal growth of LEPCs. This outcome was correlated with the suppression of canonical Wnt but activation of noncanonical (Planar cell polarity) Wnt signaling as well as BMP signaling in both LEPCs and LNCs. The activation of BMP signaling in LNCs was pivotal because nuclear translocation of pSmad1/5/8 was prohibited in hLEPCs when reunioned with mLNCs of conditionally deleted Bmpr1a;Acvr1DCKO mice. Furthermore, ablation of BMP signaling in LEPCs led to upregulation of cell cycle genes, downregulation of Bmi-1, nuclear exclusion of phosphorylated Bmi-1, and marked promotion of the clonal growth of LEPCs. Hence, HC-HA/PTX3 uniquely upregulates BMP signaling in LNCs which leads to BMP signaling in LEPCs to achieve quiescence, helping explain how AM transplantation is clinically useful to be used as a matrix for ex vivo expansion of LEPCs and to treat corneal blindness caused by limbal stem cells deficiency. Stem Cells 2015;33:3341–3355
Intranodal Mapping Using Carbon Dye Results in More Accurate Lymph Node Staging in Colon Cancer Patients
Authors: Weixler Benjamin , Warschkow Rene , Zettl Andreas , Riehle Hans‐Martin , Guller Ulrich , Viehl Carsten T. , Zuber Markus 
Published: July 2015

AbstractIntroductionSmall nodal tumor infiltrates (SNTI)—defined as isolated tumor cells and micrometastases—are associated with worse disease‐free and overall survival in stage I and II colon cancer patients. Their detection, however, remains challenging. The objective of the present study was to evaluate whether there is a correlation between the location of SNTI and phagocytosed carbon dye particles in sentinel lymph nodes (SLN) of colon cancer patients.Materials and MethodsIsosulfan blue and carbon dye were injected intraoperatively near the tumor to mark the SLN. Serial sections of SLN were stained with hematoxylin–eosin and immunohistochemistry. Intranodal distribution of phagocytosed carbon particles was compared to the presence of SNTI.ResultsOf a cohort of 159 patients, 24 patients had SNTI in their lymph nodes (LN). SNTI were found in a total of 116 LN of which 66 were SLN and 50 were non‐SLN. In 59, these 116 LN with SNTI phagocytosed carbon dye were found (50.9 %). Phagocytosed carbon dye was identified significantly more often in SLN (49 of 66 SNTI positive SLN) compared to 10 of 50 SNTI positive non‐SLN (p < 0.001). In 52 out of 59 LN (88.1 %), phagocytosed carbon dye was in close proximity to SNTI.ConclusionsIn the majority of patients, SNTI are located in the same SLN compartment as phagocytosed carbon dye particles. Our investigation provides evidence that the use of carbon dye facilitates SNTI detection and improves LN staging in colon cancer. Therefore, the concept of intranodal mapping—which has been previously described for melanoma—can be extended to colon cancer patients.
Comparison of Survival Outcomes Between Right Posterior Sectionectomy and Right Hepatectomy for Hepatocellular Carcinoma in Cirrhotic Liver: A Single‐Centre Experience
Authors: Yip Vincent S. K. , Poon Ronnie T. P. , Chok Kenneth S. H. , Chan Albert C. Y. , Dai Wing Chiu , Tsang Simon H. Y. , Chan See Ching , Lo Chung Mau , Cheung Tan To 
Published: July 2015

AbstractBackgroundRight hepatectomy (RH) instead of right posterior sectionectomy (RPS) is commonly performed for hepatocellular carcinoma (HCC) in cirrhotic livers located lateral to the right hepatic vein in order to ensure adequate resection margin. This potentially increased the risk of postoperative liver failure. This study aims to compare survival outcomes and surgical morbidities between RH and RPS.MethodsAll patients between 2003 and 2013 with resection for solitary HCC in cirrhotic livers at segment 6/7 were reviewed. Baseline demographics, liver function, perioperative outcomes, and overall (OS) and disease‐free survival (DFS) were compared between RH and RPS.ResultsEighty‐one patients were included in this study. Thirty‐two patients had RH and forty‐nine with RPS were selected as controls. Majority of the HCC patients (91.4 %) suffered from chronic hepatitis B. There was no significant difference in age, gender and Child‐Pugh grade between the two groups. The median tumour size of RH group was 6 vs. 4 cm in the RPS group (p < 0.0001). Both groups had no statistical difference in resection margin and their associated morbidities. The 5‐year OS for RH and RPS was 76 and 83.8 %, respectively (p = 0.766), whereas their corresponding DFS was 52.6 and 52.2 % (p = 0.859). Despite the discrepancy of tumour size among the two groups, there was no statistical difference in subgroup analysis based on their corresponding stage of disease.ConclusionRPS can achieve similar OS and DFS as RH for HCC, and should be considered as the treatment of choice in order to optimise the postoperative remnant parenchymal liver functions.
Influence of glucose fermentation on CO2 assimilation to acetate in homoacetogen Blautia coccoides GA-1
Authors: Liu Chong , Li Jianzheng , Zhang Yupeng , Philip Antwi , Shi En , Chi Xue , Meng Jia 
Published: July 2015

Abstract
Fermentation of glucose influences CO2 assimilation to acetate in homoacetogens. Blautia coccoides was investigated for a better understanding of the metabolic characteristics of homoacetogens in mixotrophic cultures. Batch cultures of the strain with H2/CO2 as a sole carbon source reached an acetate yield of 5.32 g/g dry cell weight after 240 h of incubation. Autotrophic metabolism was inhibited as glucose was added into the culture: the higher the glucose concentration the lower the autotrophic ability of the bacterium. Autotrophy was inhibited by high glucose concentration, probably due to the competition for coenzyme A between the Embden-Meyerhof-Parnas pathway and the Wood-Ljungdahl carbon fixation pathway, the energy (adenosine triphosphate) allocation for synthesis of cell carbon and reduction of CO2, in combination with the low pH caused by the accumulation of acetate.
Exploring medium-chain-length polyhydroxyalkanoates production in the engineered yeast Yarrowia lipolytica
Authors: Gao Cuijuan , Qi Qingsheng , Madzak Catherine , Lin Carol Sze Ki 
Published: July 2015

Abstract
Medium-chain-length polyhydroxyalkanoates (mcl-PHAs) are a large class of biopolymers that have attracted extensive attention as renewable and biodegradable bio-plastics. They are naturally synthesized via fatty acid de novo biosynthesis pathway or β-oxidation pathway from Pseudomonads. The unconventional yeast Yarrowia lipolytica has excellent lipid/fatty acid catabolism and anabolism capacity depending of the mode of culture. Nevertheless, it cannot naturally synthesize PHA, as it does not express an intrinsic PHA synthase. Here, we constructed a genetically modified strain of Y. lipolytica by heterologously expressing PhaC1 gene from P. aeruginosa PAO1 with a PTS1 peroxisomal signal. When in single copy, the codon optimized PhaC1 allowed the synthesis of 0.205 % DCW of PHA after 72 h cultivation in YNBD medium containing 0.1 % oleic acid. By using a multi-copy integration strategy, PHA content increased to 2.84 % DCW when the concentration of oleic acid in YNBD was 1.0 %. Furthermore, when the recombinant yeast was grown in the medium containing triolein, PHA accumulated up to 5.0 % DCW with as high as 21.9 g/L DCW, which represented 1.11 g/L in the culture. Our results demonstrated the potential use of Y. lipolytica as a promising microbial cell factory for PHA production using food waste, which contains lipids and other essential nutrients.
Spinal disulfide HMGB1, but not all-thiol HMGB1, induces mechanical hypersensitivity in a TLR4-dependent manner
Authors: Agalave N.M. , AbdelMoaty S. , Lundback P. , Andersson U. , Harris H. , Svensson C.I. 
Published: July 2015

Abstract

Aims
Increasing evidence indicates that extracellular high mobility group box-1 protein (HMGB1) is involved in the pathogenesis of inflammatory and autoimmune disease. Data from our laboratory demonstrates that HMGB1 contributes to nociceptive behavior in a model of rheumatoid arthritis-induced pain. HMGB1 binds to multiple receptors, including toll like receptor (TLR) 2, TLR4 and receptor for advanced glycation end products (RAGE). When the cysteine in position C106 is in the reduced thiol form and C23 and C45 are engaged in a disulfide bridge (disulfide HMGB1), the molecule functions as a cytokine-inducing TLR4 ligand. In contrast, when these three cysteines are all reduced (all-thiol HMGB1), HMGB1 exclusively potentiates chemotactic activity via CXCR4. It is currently not well understood which receptor and which redox form of HMGB1 that mediates pain hypersensitivity and is therefore the aim of this study.

Methods
All animal work was carried out in accordance with protocol approved by the local ethics committee for animal experiments in Sweden. Balb/c, C57B/l6 (WT), Tlr2–/–, Tlr4–/– and Rage–/– male mice were used for this study. Disulfide (ds) and all thiol (at) form of HMGB1 were injected intrathecally (1 μg) and mechanical hypersensitivity assessed by von Frey filaments. Lumbar spinal cords were collected after i.t. injection of atHMGB1 and ds HMGB1 and mRNA levels for cytokine and glia markers assessed by quantitative PCR.

Results
In Balb/c and C57Bl/6 WT mice, i.t injection of dsHMGB1, but not atHMGB1, led to a significant reduction in mechanical thresholds. dsHMGB1 induced mechanical hypersensitivity 6 h after i.t. injection, which lasted for 5 days, compared to i.t. injection of saline. When dsHMGB1 was injected i.t. to Tlr4 deficient mice it did not induce mechanical hypersensitivity. In contrast Tlr2 and Rage deficient mice were still susceptible to dsHMGB1-induced mechanical hypersensitivity. Analysis of mRNA for cytokines and glial cell-associated factors in lumbar spinal cords revealed increased levels of Tnf, Ccl2, Cxcl1, Cxcl2, Gfap and Cd11b in mice injected with dsHMGB1, but not atHMGB1, with exception for Il1β and Cxcr3 that was induced also by atHMGB1. Intrathecal injection of dsHMGB1 to Tlr4
–/– deficient mice, did not increase mRNA levels for Tnf, Il1β, Ccl2, Gfap and Cd11b.

Conclusions
We found the i.t. injection of the disulfide, but not the all-thiol, form of HMGB1 to induce pronouncedand long-lasting mechanical hypersensitivity, glial reactivity and cytokine induction in a TLR4-, but not TLR2- or RAGE-dependent manner. Thus our data indicates that, the redox state of HMGB1 is key for determining its nociceptive property and receptor usage and thus also the functional consequences of HMGB1 release. Agents interfering with extracellular HMGB1 may be considered in the development of new pain relieving therapeutics.