bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract A23: Novel approach for targeting hepatocellular carcinoma cell survival: OSU-2S/Sorafenib combination
Authors: Omar Hany A. , Tolba Mai F. , Hung Jui-Hsiang , Al-Tel Taleb H.
Published: January 2017

Background: OSU-2S is a novel non-immunosuppressant anticancer agent that was designed and developed using fingolimod (Gilenya®) as a scaffold. OSU-2S was reported to have a substantial anticancer activity against hepatocellular carcinoma (HCC) through different mechanisms. The effectiveness of HCC treatment is often poor due to acquired resistance during the course of therapy. The current work was aimed to test the possible therapeutic synergy between OSU-2S and sorafenib, the multi-kinase inhibitor which is used as standard first-line systemic treatment for advanced HCC. Mechanistically, such combination can achieve optimal anticancer activity through synergistic targeting of the cancer cell survival signaling pathways.

Methods: The synergistic combination between OSU-2S and sorafenib was tested on three different HCC cell lines (Hep3B, Huh-7, HepG2) using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium) assay, colony formation, invasion, migration, immunofluorescence, and Western blot analysis.

Results: The combination incidences for OSU-2S/ Sorafenib obtained from MTT and colony formation assays were in the range of 0.4-0.8 at different dose levels which indicated synergistic anticancer activity. This synergy was confirmed by enhanced ability to activate apoptosis and to hinder several cell survival signaling pathways such as mitogen-activated protein kinase (MAPK) pathway. The synergy was mediated through the activation of the pro-apoptotic kinase, PKCδ and the augmentation of reactive oxygen species generation.

Conclusion: OSU-2S/ Sorafenib combination represents a novel therapeutically relevant approach to be introduced in HCC chemotherapeutic protocols which should effectively target cancer cells and improve the survival of HCC patients.

Citation Format: Hany A. Omar, Mai F. Tolba, Jui-Hsiang Hung, Taleb H. Al-Tel. Novel approach for targeting hepatocellular carcinoma cell survival: OSU-2S/Sorafenib combination. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr A23.
Abstract A31: 14-3-3 binding sites in full-length and splice variant forms of BRAF V600E modulate the response to RAF inhibitors
Authors: Vido Michael J. , Le Kaitlyn , Rock Justin , Hartsough Edward J. , Dadpey Neda , Aplin Andrew E.
Published: January 2017

The serine/threonine kinase BRAF is mutated in 7% of human cancers, the most frequent alteration being a valine to glutamic acid substitution at amino acid 600 (V600E). BRAF V600E melanomas are highly sensitive to RAF inhibitors but the expression of aberrantly spliced BRAF V600E (BRAF V600E ΔEx) isoforms are associated with resistance in 13-30% of progressing patients. Compared to full-length BRAF V600E, BRAF V600E ΔEx exhibit enhanced dimerization and signaling via ERK1/2 during RAF inhibitor therapy; however, much remains unknown regarding their mechanism of action. The 14-3-3 protein binding sites, serine 365 (S365) and serine 729 (S729), play a complex role in regulating the activity and dimerization of RAF isoforms. All reported BRAF V600E ΔEx isoforms lose the N-terminal 14-3-3 binding site (S365) but retain the C-terminal site (S729); therefore, we analyzed the involvement of 14-3-3 binding sites in response to RAF inhibitor therapy. In full-length BRAF V600E, mutation of S365 to alanine promotes elevated MEK-ERK1/2 signaling and growth in the presence of RAF inhibitor. BRAF V600E ΔEx exhibits increased phosphorylation on S729 during RAF inhibitor therapy. Mutation of S729 to alanine renders the BRAF V600E ΔEx isoforms sensitive to RAF inhibitor, measured by reduced ERK1/2 phosphorylation and cell growth in vitro and in vivo. These data highlight the importance of BRAF V600E 14-3-3 binding sites in mediating targeted therapy resistance in mutant BRAF-driven melanoma.

Citation Format: Michael J. Vido, Kaitlyn Le, Justin Rock, Edward J. Hartsough, Neda Dadpey, Andrew E. Aplin. 14-3-3 binding sites in full-length and splice variant forms of BRAF V600E modulate the response to RAF inhibitors. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr A31.
Abstract A33: Discovery of novel anti-cancer therapeutic agents for Notch activation complex kinase (NACK) targeting the Notch pathway
Authors: Zhu Xiaoxia , Wang Zhiqiang , Jin Ke , Astudillo Luisana , Zhou Wen , Chen Jinshui , Buchwald Peter , Schürer Stephan C. , Capobianco Anthony J.
Published: January 2017

The Notch signaling pathway has been found to play an important role in multiple human cancers by regulating transcriptional programs. However, the mechanism by which Notch drives target gene transcription is still elusive. In our previous study, we have identified and characterized a novel Notch activation complex kinase, NACK, which acts as a Notch transcriptional co-activator and an essential regulator of Notch-mediated tumorigenesis and development. In this regard, NACK could become a putative drug target in anti-cancer therapies.

The lack of three-dimensional (3D) structure of NACK hinders the designing of potential drug inhibitors. Therefore, computational methods are adopted to elucidate the structural and functional features of NACK, which further aid in designing new NACK inhibitors. Molecule docking (Glide) is utilized to obtain potential hit inhibitors for NACK, which will be validated using in-vitro and in-vivo assays. This will open avenues for the development of new therapies for Notch-dependent cancers.

Citation Format: Xiaoxia Zhu, Zhiqiang Wang, Ke Jin, Luisana Astudillo, Wen Zhou, Jinshui Chen, Peter Buchwald, Stephan C. Schürer, Anthony J. Capobianco. Discovery of novel anti-cancer therapeutic agents for Notch activation complex kinase (NACK) targeting the Notch pathway. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr A33.
Abstract A35: Olaparib causes premature loss of cohesion in cancer cells
Authors: Kukolj Eva , Kaufmann Tanja , Dick Amalie E. , Zeillinger Robert , Gerlich Daniel W. , Slade Dea
Published: January 2017

Although it has been decades since PARP inhibitors were initially discovered and various clinical trials have been performed, their mode of action in killing tumor cells subsequent to PARP inhibition is still not fully understood. We have recently identified poly(ADP-ribosyl)ation (PARylation) as a new post-translational modification of the cohesin complex, a key player in chromosome segregation during mitosis. We investigated the effect of PARP inhibition on mitosis in a panel of cells of cancer (cervical, breast, ovarian) and normal tissue origin. We treated cancerous and non-cancerous cell lines labelled with chromatin markers with a selected set of PARP inhibitors and imaged them with fluorescence live microscopy.

Out of 5 tested inhibitors, a well-known and clinically relevant PARP inhibitor olaparib, induced strongest perturbations in mitotic progression. Olaparib induced a delay in entering anaphase, problems aligning chromosomes at the metaphase plate and premature loss of cohesion (cohesion fatigue) after a prolonged metaphase arrest. Cohesion fatigue, leading to cell death, was observed in cancer cell lines exhibiting S-phase stalling or G2/M arrest with increased protein levels of PARP1. Olaparib is known to entrap PARP1 at replication forks and thereby perturb replication fork movement. While its addition before the onset of mitosis did not result in mitotic defects, addition of olaparib only in S-phase was sufficient to cause mitotic phenotypes. Our results indicate that PARP inhibition by olaparib in S phase has downstream effects on mitotic progression. PARP1 RNAi in addition to olaparib treatment rescues the cohesion fatigue phenotype, suggesting that entrapment of PARP1 at the replication fork upon its inhibition is the main cause of cohesion fatigue. Cohesion fatigue was observed only in highly aneuploid cancer cells that are described to have an increased rate of chromosome mis-segregation.

In conclusion, higher susceptibility of aneuploid cancer to cohesion fatigue and cell death upon olaparib treatment relative to normal cells would support its use as anti-mitotic chemotherapy.

Citation Format: Eva Kukolj, Tanja Kaufmann, Amalie E. Dick, Robert Zeillinger, Daniel W. Gerlich, Dea Slade. Olaparib causes premature loss of cohesion in cancer cells. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr A35.
Abstract A44: A landscape of pharmacogenomic interactions in cancer
Authors: Iorio Francesco , Knijnenburg Theo , vis Daniel , Bignell Graham , Menden Michael , Wessels Lodewyk , Saez-Rodriguez Julio , McDermott Ultan , Garnett Mathew
Published: January 2017

Systematic studies of cancer genomes are providing unprecedented insights into the molecular nature of human cancer. Using this information to guide the development and application of therapies in the clinic is challenging. Here we report how cancer-driving alterations identified in 11,289 tumors from 29 tissues (integrating mutations, copy-number alterations, methylation and gene expression) correlate with response to 265 compounds profiled in 1,001 human cancer cell-lines. We find that cell-lines faithfully recapitulate oncogenic aberrations identified in tumors, and that many of these associate with drug sensitivity or resistance. Logic-based modeling uncovers combinations of aberrations that specifically sensitize to drugs, while machine-learning demonstrates the redundancy of different molecular data types in predicting drug response. Our comprehensive analysis and associated datasets are rich resources to identify novel therapeutic options for selected cancer sub-populations.

Citation Format: Francesco Iorio, Theo Knijnenburg, Daniel vis, Graham Bignell, Michael Menden, Lodewyk Wessels, Julio Saez-Rodriguez, Ultan McDermott, Mathew Garnett. A landscape of pharmacogenomic interactions in cancer. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr A44.
Abstract B21: Brd4 modulates S-phase checkpoint response and sensitizes ovarian cancer cells to ATR inhibition
Authors: Zhang Jingwen , Chen Huawei , Dulak Austin
Published: January 2017

The BET (bromodomain and extra terminal domain) family proteins function as chromatin readers through interactions with acetylated lysine residues on both histones and transcription factors. BRD4 is the most well-studied member of this group that promotes tumorigenesis by regulating expression of core transcriptional programs; however, the role of Brd4 in other cellular processes is not entirely clear. Here, we show using small molecule inhibition of the BET proteins that Brd4 is required to maintain S-phase checkpoint signaling. Treatment of high-grade serous ovarian and osteosarcoma cancer cell lines with BET inhibitors, AZD5153 and JQ1, results in the accumulation of gH2AX and 53BP1 foci formation, which is suggestive of elevated DNA damage levels. The induction of DNA damage caused by both inhibitors corresponds with cell cycle arrest at the G1/S boundary. Displacement of Brd4 in cell lines under intrinsic or exogenous replication stress led to a time-dependent reduction in phospho-Chk1 first detected within 30 minutes of AZD5153 treatment in U2OS cells. The decrease in Chk1 phosphorylation was observed without a concomitant decrease in total Chk1, and this was not replicated by treatment with pan-transcriptional inhibitors, suggesting a non-transcriptional mechanism linked to Brd4. Furthermore, Brd4 interacts with core DNA replication machinery during S-phase and inhibition of Brd4 leads to aberrant DNA replication without decreasing ATR phosphorylation. Consistent with a role in S-phase signaling, Brd4 inhibition sensitizes replicating cells to replication stress-inducing agents. Finally, we observed that ovarian cancer cell lines are highly-sensitive to the combination of Brd4 and ATR (AZD6738) inhibitors. Concurrent treatment with AZD5153 and AZD6738 induces DNA damage and apoptosis in a synergistic manner. Together, these findings highlight a novel function for Brd4 and provide evidence to support further evaluation of Brd4i combinations with DNA damage repair agents.

Citation Format: Jingwen Zhang, Huawei Chen, Austin Dulak. Brd4 modulates S-phase checkpoint response and sensitizes ovarian cancer cells to ATR inhibition. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr B21.
Abstract B28: Induced expression of Sprouty4 in breast invasive ductal carcinoma cells inhibits ERK MAP kinase and reduces malignant phenotype
Authors: Jackson Ryan M. , Brock Ethan J. , Shah Seema , Sameni Mansoureh , Sloane Bonnie F. , Li Quanwen , Mattingly Raymond R.
Published: January 2017

Our previous work has identified increased expression of Sprouty4 in 3D models of breast ductal carcinoma in situ (DCIS). Sprouty4 in other systems has been shown to function as a negative regulator of the mitogen activated protein kinase (MAPK/ERK) pathway. We hypothesize that Sprouty4 is an endogenous inhibitor of ERK/MAPK signaling in DCIS, and that its loss or reduced expression is one mechanism by which triple-negative lesions progress toward invasive ductal carcinoma (IDC). Using immunohistochemistry our labs have found that Sprouty4 was highly expressed in some human premalignant breast tissue samples, and that this expression was reduced in malignant triple-negative samples. These results correspond with immunoblot data from our 3D culture model of breast cancer progression in which Sprouty4 expression was higher during DCIS than in the IDC stage. Efficient over-expression of Sprouty4 reduced both MAPK/ERK activity as well as the aggressive phenotype of MCF10.CA1d IDC cells. Immunofluorescence experiments done in IDC cells overexpressing Sprouty4 revealed relocation of E-cadherin back to the cell surface and the restoration of adherens junctions. To determine if these effects were due to changes in MAPK/ERK signaling, IDC cells were treated with MEK162, an allosteric MEK inhibitor. Nanomolar concentrations of drug restored an epithelial-like phenotype similar to that produced by Sprouty4 over-expression. From these data we conclude that Sprouty4 may act to control MAPK/ERK signaling in a subset of DCIS, thus limiting the progression of these premalignant breast cancers. Further, if in vivo data correspond with our in vitro work, this may argue for the investigation of MEK inhibitors as an adjunct treatment in triple-negative disease, where options are limited.

Citation Format: Ryan M. Jackson, Ethan J. Brock, Seema Shah, Mansoureh Sameni, Bonnie F. Sloane, Quanwen Li, Raymond R. Mattingly. Induced expression of Sprouty4 in breast invasive ductal carcinoma cells inhibits ERK MAP kinase and reduces malignant phenotype. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr B28.
Negotiating Complexity: A Bioecological Systems Perspective on Literacy Development
Authors: Jaeger Elizabeth L.
Published: January 2017

Background/Aims: Urie Bronfenbrenner's bioecological systems model is well regarded in the field of child development. Although this model is not commonly used by literacy researchers, I argue that Bronfenbrenner's emphasis on the roles of personal characteristics, proximal processes, contextual systems, and historical time has explanatory power in the area of literacy. Methods: I review this body of literature and describe a visual representation that clarifies the relevant aspects of the theory. Results: Adoption of Bronfenbrenner's model increases the likelihood that literacy development will be understood as occurring at the site of transaction between cognitive processes and social practices. Literacy researchers who have applied this theory differ in the degree to which they have attended to Bronfenbrenner's guidance relative to adequate research practice and, as such, findings from this research range from less to more theoretically sound and useful. Conclusion: As contemporary literacy researchers consider employing Bronfenbrenner's theory to frame their work, it is necessary for them to account for all aspects of his rich and complex model.
Integrating Development and Evolution in Psychological Science: Evolutionary Developmental Psychology, Developmental Systems, and Explanatory Pluralism
Authors: Witherington David C. , Lickliter Robert
Published: January 2017

New attempts in psychological science at integrating developmental (individual-level) and evolutionary (population-level) accounts of phenotypic stability and variability have achieved increasing prominence of late. Foremost among such attempts is the field of evolutionary developmental psychology (EDP). EDP proposes that selective pressures in evolution inform psychological development through a synthesis of the Darwinian/neo-Darwinian selectionist perspective embraced by evolutionary psychology and the developmental dynamics perspective endorsed by developmental systems theory. We examine the theoretical assumptions behind selectionist and developmental perspectives and argue that both perspectives are ontologically incompatible. We provide an alternative framework for integrating developmental and evolutionary explanations that transcend this ontological division of selectional and developmental perspectives. This framework promotes a pluralistic approach that moves beyond traditional antecedent/consequent, mechanistic views of causality and embraces both functional (part-to-whole) and structural (whole-to-part) modes of explanation as distinct, equally legitimate, and simultaneously applicable perspectives in understanding phenotypic stability and variability over time.
Skin Surface Topography and Texture Analysis of Sun-Exposed Body Sites in View of Sunscreen Application
Authors: Korn Verena , Surber Christian , Imanidis Georgios
Published: January 2017

Background/Aims: To determine the roughness of the surface of human skin at highly sun-exposed anatomical sites in a wide age range in order to derive consequences for sunscreen application. Methods: The forehead, cheek, nose, shoulder, and dorsal hand of 4 age groups (0-9, 20-39, 40-59, and >60 years) were investigated by replica formation, and areal topography was determined by confocal chromatic imaging. The arithmetic mean height as a roughness parameter and the void volume of the surface profile were calculated. Results: Age and site had a significant effect on roughness. Both the dorsal hand and nose exhibited the greatest roughness over the age of 40, and the forehead of the youngest age group exhibited the smallest roughness. Differentiation between sites progressed with age, whereas roughness increased significantly with age for the dorsal hand and nose but not for the other sites. The void volume was smaller than the volume corresponding to the typically recommended amount of sunscreen application except for the cases of largest roughness. Conclusions: Different site-age combinations show significant variation of skin surface roughness. The application of sunscreen may in some instances need to be adjusted to take into account the increased roughness of highly sun-exposed anatomical sites.
Development of a Normative Database for Multifocal Electroretinography in the Context of a Multicenter Clinical Trial
Authors: Simão Sílvia , Costa Miguel Ângelo , Sun Jennifer K. , Cunha-Vaz José , Simó Rafael ,   on behalf of the European Consortium for the Early Treatment of Diabetic Retinopathy (EUROCONDOR)
Published: January 2017

Purpose: The aim of this study is to present the largest normative database using multifocal electroretinography (mfERG) in the context of a multicenter clinical trial. Methods: This investigational study included 156 eyes from 78 Caucasian subjects aged 45-70 years without known ophthalmic disease or diabetes mellitus; the subjects were recruited from 11 clinical sites in the setting of the EUROCONDOR project. Standardized mfERG acquisition (103 hexagons per eye) was established based on the International Society of Clinical Electrophysiology in Vision. At least one technician per site received both specialized training and certification. The main variables that could have influenced the results were considered in the analyses. Results: The normative database was based on 111 eyes. The overall mean P1-implicit time (IT) was 33.94 ± 1.70 ms, and the mean P1 amplitude was 30.58 ± 5.20 nV/deg2. Age and gender were independently related to predictors of P1-IT but not of P1 amplitude. The responses that were averaged for the 6 rings showed a longer P1-IT time in the fovea, decreasing progressively to the parafovea and perifovea. By contrast, P1 amplitude values sharply decreased with retinal eccentricity. Conclusions: This normative database can be used as a comparative index of expected normal values in the clinical setting and for examining the effect of studies testing neuroprotective agents.
Current Status of Exposed Endoscopic Full-Thickness Resection and Further Development of Non-Exposed Endoscopic Full-Thickness Resection
Authors: Mori Hirohito , Rahman Asadur , Kobara Hideki , Fujihara Shintaro , Nishiyama Noriko , Ayaki Maki , Matsunaga Tae , Murakami Masanori , Masaki Tsumomu
Published: January 2017

Endoscopic full-thickness resection (EFTR) is a procedure that makes it possible to access the lesions that are on the wall of the digestive tract via the shortest distance through the mouth. Because of the ultra-minimal invasive nature of the treatment, pure EFTR is a highly promising surgical procedure that allows the radical excision of full-thickness layers of digestive tract tumors using only a flexible endoscope. There are 2 types of EFTR methods: exposed and non-exposed. Considering the risks of contracting infection and intraperitoneal dissemination of tumor cells, non-exposed EFTR is an ideal method. However, a number of issues remain unresolved, including the method for performing a full-thickness suture under endoscopic view and the challenge of securing the operating field in the case of gastrointestinal tract collapse. Moreover, advances in the development of equipment such as full-thickness suturing devices would be helpful to make this therapeutic procedure the most minimally invasive endoscopic surgery ever.
Microbiota Plays a Key Role in Non-Steroidal Anti-Inflammatory Drug-Induced Small Intestinal Damage
Authors: Otani Koji , Tanigawa Tetsuya , Watanabe Toshio , Shimada Sunao , Nadatani Yuji , Nagami Yasuaki , Tanaka Fumio , Kamata Noriko , Yamagami Hirokazu , Shiba Masatsugu , Tominaga Kazunari , Fujiwara Yasuhiro , Arakawa Tetsuo
Published: January 2017

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) damage the small intestine by causing multiple erosions and ulcers. However, to date, no established therapies and prophylactic agents are available to treat such damages. We reviewed the role of intestinal microbiota in NSAID-induced intestinal damage and identified potential therapeutic candidates. Summary: The composition of the intestinal microbiota is an important factor in the pathophysiology of NSAID-induced small intestinal damage. Once mucosal barrier function is disrupted due to NSAID-induced prostaglandin deficiency and mitochondrial malfunction, lipopolysaccharide from luminal gram-negative bacteria and high mobility group box 1 from the injured epithelial cells activate toll-like receptor 4-signaling pathway and nucleotide-binding oligomerization domain-like receptor family, pyrin domain-containing 3 inflammasome; this leads to the release of proinflammatory cytokines such as tumor necrosis factor-α and interleukin-1β. Proton pump inhibitors (PPIs) are often used for the prevention of NSAID-induced injuries to the upper gastrointestinal tract. However, several studies indicate that PPIs may induce dysbiosis, which may exacerbate the NSAID-induced small intestinal damage. Our recent research suggests that probiotics and rebamipide could be used to prevent NSAID-induced small intestinal damage by regulating the intestinal microbiota. Key Messages: Intestinal microbiota plays a key role in NSAID-induced small intestinal damage, and modulating the composition of the intestinal microbiota could be a new therapeutic strategy for treating this damage.
Frequent Presence of Lymphovascular Invasion in Small Rectal Neuroendocrine Tumors on Immunohistochemical Analysis
Authors: Kitagawa Yoshiyasu , Ikebe Dai , Suzuki Takuto , Hara Taro , Itami Makiko , Yamaguchi Taketo
Published: January 2017

Rectal neuroendocrine tumors (RNETs) have become common in recent years and are good candidates for endoscopic resection (ER). To achieve clear resection margins, more advanced techniques such as endoscopic submucosal dissection, endoscopic submucosal resection with a ligation device, and cap-assisted endoscopic mucosal resection are available for ER. After ER, lymphovascular invasion (LVI) is regarded as an important predictor of nodal metastasis. Previous studies have shown that small RNETs with LVI were uncommon (0-8.3%). However, using immunohistochemical analysis, a recent study revealed the frequent occurrence of LVI in small RNETs in a systematic manner (46.7%). There is a possibility that the actual detection rate of LVI in small RNETs is not always evaluated accurately because of the limited detection sensitivity of conventional hematoxylin-eosin staining. In addition, the correlation between LVI detected using immunohistochemical analysis and the development of metastasis remains unclear. Further prospective studies are required to clarify the role of LVI detected using immunohistochemical analysis.
Gender Difference of Gastric Emptying in Healthy Volunteers and Patients with Functional Dyspepsia
Authors: Mori Hideki , Suzuki Hidekazu , Matsuzaki Juntaro , Taniguchi Kanami , Shimizu Toshiyuki , Yamane Tsuyoshi , Masaoka Tatsuhiro , Kanai Takanori
Published: January 2017

Background and Aim: Delayed gastric emptying is one of the reasons why functional dyspepsia (FD) occurs. The 13C-acetate breath test is widely used to evaluate gastric emptying. Nevertheless, the standard value of 13C-acetate breath test has not taken into account the gender difference of gastric emptying among healthy individuals. The main aim of this study was to readjust the standard value of 13C-acetate breath test in the light of gender differences. In addition, we clarified the prevalence and clinical characteristics of delayed gastric emptying in patients with FD using the modified standard values of 13C-acetate breath test. Methods: Fifty-two healthy individuals and 126 patients with patients with FD were enrolled. Gastric emptying was evaluated by the 13C-acetate breath test. The cut-off points of Tmax for the diagnosis of delayed gastric emptying were determined on the basis of results from healthy individuals making a distinction of genders. Gastroesophageal reflux symptoms, dyspeptic symptoms, scores of anxiety and depression, age, body mass index (BMI), smoking and alcohol consumption were compared between the delayed gastric emptying group and the non-delayed gastric emptying group. Results: Since gastric emptying was delayed in healthy women compared with that in healthy men (Tmax, 53.6 ± 19.3 vs. 42.7 ± 16.9 min, p = 0.04), we set the cut-off points of Tmax at 60 min in men and at 75 min in women. In patients with FD, the prevalence of delayed gastric emptying was not different between men and women with the modified standard values of 13C-acetate breath test. (31.0 vs. 27.4%, p = 0.68). BMI was lower in the delayed gastric emptying group than in the non-delayed group among the male patients. Reflux symptoms were more severe in delayed gastric emptying group than in the non-delayed group among the female patients. Conclusion: The standard values of 13C-acetate breath test should be modified bearing the gender difference in mind. It provides us more appropriate information to understand the mechanisms of FD.
Yogurt Containing Lactobacillus gasseri Mitigates Aspirin-Induced Small Bowel Injuries: A Prospective, Randomized, Double-Blind, Placebo-Controlled Trial
Authors: Suzuki Takayoshi , Masui Aya , Nakamura Jun , Shiozawa Hirokazu , Aoki Jun , Nakae Hirohiko , Tsuda Shingo , Imai Jin , Hideki Ozawa , Matsushima Masashi , Mine Tetsuya , Tamura Akira , Ohtsu Toshihiro , Asami Yukio , Takagi Atsushi
Published: January 2017

Background: Although there is evidence about the beneficial effects of probiotics, their effects on aspirin-induced small bowel injuries have not been well examined. We evaluated the effects of the probiotic Lactobacillus gasseri OLL2716 (LG) on aspirin-induced small intestinal lesions, such as ulcers, erosions, reddened lesions, and bleeding. Summary: This study enrolled 64 patients who received aspirin for more than 1 month and provided written informed consent to be part of the study. The patients received 112 ml of yogurt containing LG or placebo twice daily for 6 weeks. Small bowel injuries were evaluated by capsule endoscopy before and after consuming the yogurt. The effect of LG on patient symptoms was also assessed using the Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease (FSSG) and Gastrointestinal Symptom Rating Scale (GSRS) questionnaires before and after 6 weeks of treatment. There was no significant difference in any baseline characteristics and the number of small bowel mucosal breaks between the 2 groups. In contrast with the placebo group, the LG group had significantly fewer small bowel mucosal breaks and reddened lesions after 6 weeks (p < 0.01). The FSSG and GSRS scores were also significantly improved in the LG group but not in the placebo group. Key Messages: This double-blind, placebo-controlled study found that LG may be useful in reducing aspirin-induced small bowel injuries and in mitigating gastrointestinal symptoms.
Evaluation for the Clinical Efficacy of Colon Capsule Endoscopy in the Detection of Laterally Spreading Tumors
Authors: Igawa Atsushi , Oka Shiro , Tanaka Shinji , Otani Ichiro , Kunihara Sayoko , Chayama Kazuaki
Published: January 2017

Background and Aim: The manner in which colorectal lesions are being detected with PillCam COLON2 capsule endoscopy (CCE2) has markedly improved in recent days. However, limited data are available on CCE2 for detecting laterally spreading tumors (LSTs). The aim of this study was to compare CCE2 with optical colonoscopy (OC), which is currently the gold standard used in the detection of LSTs. Methods: We performed a prospective, single-academic center study comparing CCE2 with OC in patients with LSTs diagnosed using OC, which was performed during the 3-month period prior to CCE2. We focused on the sensitivity and specificity of CCE2 for detecting LSTs. LSTs were classified into the LST-granular type (LST-G) or the LST-non-granular type (LST-NG). Results: Thirty patients (mean age 59.5 years) were enrolled. Of them, 21 LSTs (7 LST-Gs and 14 LST-NGs) were evaluated in this study. The mean diameter of the LSTs was 27 ± 15 mm (range 10-60 mm). Histopathological diagnoses of the LSTs were as follows: tubular adenoma, 12 cases (57%); sessile serrated adenoma/polyp (SSA/P), 4 cases (19%); Tis carcinoma, 1 case (5%); and T1 carcinoma, 4 cases (19 LSTs were found in the following locations: cecum, 1 case (5%); ascending colon, 6 cases (29%); transverse colon, 6 cases, (29%); descending colon, 1 case (5%); sigmoid colon, 3 cases (13%); and rectum, 4 cases (19%). The colon cleansing level was adequate in all cases. The sensitivity and specificity of CCE2 for detecting LSTs were 81 and 100% respectively. For detecting LST-Gs and LST-NGs, the sensitivity and specificity were 71 and 100%, and 86 and 100%, respectively. There were 4 false-negative cases (LST-G (18 mm), cecum; LST-G (20 mm), sigmoid colon; LST-NG (25 mm), transverse colon; LST-NG (20 mm), transverse colon). Conclusions: The sensitivity for detecting LSTs is lower with CCE2 than it is with OC, especially for LSTs located on the right colon or for SSA/P.
Prevalence of Gastric Non-Helicobacter pylori-Helicobacters in Japanese Patients with Gastric Disease
Authors: Øverby Anders , Murayama Somay Y. , Michimae Hirofumi , Suzuki Hidekazu , Suzuki Masayuki , Serizawa Hiroshi , Tamura Ryo , Nakamura Shinichi , Takahashi Shinichi , Nakamura Masahiko
Published: January 2017

Background: Non-Helicobacter pylori-helicobacters (NHPH) compose a group of gram negative zoonotic bacteria that may induce in humans gastric diseases including gastritis, gastroduodenal ulcer and MALT lymphoma. Their prevalence in the general population has previously been reported to 0.1-6.2%, although such reports still remain less in number. Aims: This study aimed at estimating the prevalence of gastric NHPH in Japanese people, and further aimed at linking this to different gastric diseases and co-infection with H. pylori. Methods: Endoscopically obtained biopsy samples from 280 Japanese patients with various gastric diseases were collected. Samples were analyzed by immunohistochemistry and by species-specific PCR for detection of gastric helicobacters. Results: The total prevalence of gastric NHPH among 280 Japanese patients was 6.1%, and the prevalence of H. pylori was 65.7%. There was no significant difference in prevalence of either NHPH or H. pylori when infected with H. pylori or NHPH, respectively. NHPH infection was found to be the highest in patients with gastric MALT lymphoma and duodenal ulcer, the former being independent of co-infection with H. pylori and the latter being dependent. Conclusions: This study reports a total prevalence of 6.1% of gastric NHPH in Japanese patients, and further highlights gastric MALT lymphoma and duodenal ulcer (when co-infected with H. pylori) as important related diseases.
The Feasibility of Conservative Management for Morbidly Adherent Placenta Accidentally Encountered after Vaginal Delivery
Authors: Cui Ran , Lu Junli , Zhang Zhenyu , Bai Huimin
Published: January 2017

Objective: To evaluate the feasibility of conservative management for patients with morbidly adherent placenta (MAP) accidentally encountered after term vaginal delivery. Methods: Medical records of patients with MAP who were accidentally encountered after term vaginal delivery and treated in our hospital from January 2009 to December 2015 were retrospectively reviewed. Results: A total of 8 eligible patients were included in this analysis. Primary postpartum hemorrhage occurred in 5 (62.5%) cases. Emergent uterine artery embolization, intrauterine balloon occlusion, and blood transfusion were performed in 5 (62.5%), 2 (25%), and 2 (25%) cases, respectively. Placentas were left in situ in all these 8 cases. Subsequent adjunctive medication treatments, including methotrexate, mifepristone, and traditional Chinese medicine, were administered in 7 (87.5%), 4 (50%), and 3 (37.5%) cases, respectively. The retained placenta spontaneously passed out in 4 (50%) patients. Additional curettage operation was performed in 3 (37.5%) patients. Emergent hysterectomy was performed in 1 (12.5%) patient due to cardiac insufficiency and acute pulmonary edema caused by sepsis. No other severe adverse events were identified. Conclusions: Conservative management is feasible for patients with MAP accidentally encountered after vaginal delivery with close follow-up.
Asian Perspectives on Diagnostic and Therapeutic Strategies in Inflammatory Bowel Disease: Report and Analysis of a Survey with Questionnaires
Authors: Yoshida Atsushi , Ueno Fumiaki , Morizane Toshio , Joh Takashi , Kamiya Takeshi , Takahashi Shin''ichi , Tokunaga Kengo , Iwakiri Ryuichi , Kinoshita Yoshikazu , Suzuki Hidekazu , Naito Yuji , Uchiyama Kazuhiko , Fukodo Shin , Chan Francis K.L. , Halm Ki-Baik , Kachintorn Udom , Fock Kwong Ming , Rani Abdul Aziz , Syam Ari Fahrial , Sollano Jose D. , Zhu Qi ,   The International Gastroenterology Consensus Symposium Study Group
Published: January 2017

Background: Diagnostic and therapeutic strategies in inflammatory bowel disease (IBD) vary among countries in terms of availability of modalities, affordability of health care resource, health care policy and cultural background. This may be the case in different countries in Eastern Asia. The aim of this study was to determine and understand the differences in diagnostic and therapeutic strategies of IBD between Japan and the rest of Asian countries (ROA). Methods: Questionnaires with regard to clinical practice in IBD were distributed to members of the International Gastroenterology Consensus Symposium Study Group. The responders were allowed to select multiple items for each question, as multiple modalities are frequently utilized in the diagnosis and the management of IBD. Dependency and independency of selected items for each question were evaluated by the Bayesian network analysis. Results: The selected diagnostic modalities were not very different between Japan and ROA, except for those related to small bowel investigations. Balloon-assisted enteroscopy and small bowel follow through are frequently used in Japan, while CT/MR enterography is popular in ROA. Therapeutic modalities for IBD depend on availability of such modalities in clinical practice. As far as modalities commonly available in both regions are concerned, there seemed to be similarity in the selection of each therapeutic modality. However, evaluation of dependency of separate therapeutic modalities by Bayesian network analysis disclosed some difference in therapeutic strategies between Japan and ROA. Conclusion: Although selected modalities showed some similarity, Bayesian network analysis elicited certain differences in the clinical approaches combining multiple modalities in various aspects of IBD between Japan and ROA.
Transforming Activity of Murine Herpesvirus 68 Putative Growth Factor Is Related to the Ability to Change Cytoskeletal Structure
Authors: Lachová Veronika , Svetlíková Darina , Golais František , Šupolíková Miroslava , Turianová Lucia , Betáková Tatiana
Published: January 2017

Murine herpesvirus 68 (MHV-68) can transform cells in vitro and in vivo. We investigated putative murine herpesvirus growth factors (MHGFs) obtained by the separation of cell-free media from MHV-68-transformed cells on an FPLC Sephadex G15 column. The transforming activity of the MHGFA fraction was related to depolymerization of actin, disruption of the microtubule network, and punctate-reticular changes of the Golgi. The MHGFW fraction had only repressing activity on the transformed phenotype. Incubation of MRC-5 cells with MHGFW resulted in reticular changes of the Golgi apparatus, minor depolymerization of actin filaments, and no detectable changes of the microtubule network. Reorganization of the actin cytoskeleton is associated with oncogenesis. Further study of the MHGFs from herpesviruses and proteins responsible for changes in the organization of the cytoskeleton could give insight into the cell transformation mechanism and oncogenesis.
Is Overnight Fasting before Surgery Too Much or Not Enough? How Basic Aging Research Can Guide Preoperative Nutritional Recommendations to Improve Surgical Outcomes: A Mini-Review
Authors: Longchamp Alban , Harputlugil Eylul , Corpataux Jean-Marc , Ozaki C. Keith , Mitchell James R.
Published: January 2017

Dietary restriction (DR) is best known for extending lifespan in experimental model organisms, but also increases resistance to a variety of clinically relevant stressors, including those associated with surgery. Extended periods of DR, lasting months to years, are required for optimal longevity benefits in rodents, but short-term dietary preconditioning (less than 1 week) remarkably protects from acute injury. Here, we discuss recent advances in our understanding of the mechanistic basis of short-term DR and fasting in the context of surgical stress resistance, including upstream amino acid sensing by the GCN2 and mTORC1 pathways, and downstream effector mechanisms including increased insulin-dependent prosurvival signaling and elevated endogenous hydrogen sulfide production. We also review the current trend in preoperative nutrition away from preoperative fasting and towards carbohydrate loading. Finally, we discuss the rationale for the nonmutually exclusive use of brief DR or pharmacological DR mimetics to precondition against the stress and potential complications of surgery.
Establishment and Characterization of an SV40 Large T Antigen-Transduced Porcine Colonic Epithelial Cell Line
Authors: Kaiser Bastian , Böttner Martina , Wedel Thilo , Brunner Ronald M. , Goldammer Tom , Lesko Szilvia , Gäbel Gotthold , Gleich Alexander , Pfannkuche Helga
Published: January 2017

Continuous cell lines have become indispensable tools that have enabled investigations into cellular mechanisms by increasing experimental reproducibility and sample availability, and decreasing the use of experimental animals. To facilitate studies of epithelial barrier function of the porcine colon, we aimed to establish an epithelial cell line with an extended replicative capacity. Cells were isolated from the proximal colon of a 3-week-old piglet and transduced using a recombinant retroviral vector construct containing the simian virus 40 large T antigen (SV40 TAg). We established a clonal epithelial cell line, referred to as PoCo83-3, that stably expressed the SV40 TAg, verified at mRNA and protein levels. PoCo83-3 showed epithelial cell-specific features, such as cobblestone-like morphology, dome structure formation, the presence of apical microvilli, and the expression of keratin 18, E-cadherin and the tight junction-associated proteins zonula occludens-1, occludin, and claudin-1. To validate PoCo83-3 as an in vitro model in epithelial barrier research, proinflammatory cytokine-inducible alterations in barrier integrity were demonstrated by incubating the cells with TNF-α and IFN-γ for 48 h. These cytokine treatments promoted a decreased transepithelial electrical resistance. In summary, PoCo83-3 exhibited an extended life span and a differentiated phenotype while maintaining epithelial characteristics. Based on these results, we present this cell line as a valuable in vitro model for investigations of epithelial barrier function in the porcine colon.
Disrupted Brain Activation and Deactivation Pattern during Semantic Verbal Fluency Task in Patients with Major Depression
Authors: Takamura Masahiro , Okamoto Yasumasa , Okada Go , Toki Shigeru , Yamamoto Tetsuya , Yamamoto Osamu , Jitsuiki Hiroaki , Yokota Norio , Tamura Tatsuji , Kurata Akiko , Kaichi Yoko , Akiyama Yuji , Awai Kazuo , Yamawaki Shigeto
Published: January 2017

Background: Patients with major depressive disorder (MDD) exhibit cognitive impairment, and evidence suggests that the semantic version of the verbal fluency task is a reliable cognitive marker of the disorder. Here, using functional magnetic resonance imaging (fMRI), we investigated the dysfunction of neural processing in acute depression and examined the effects of a 6-week pharmacological intervention. Methods: Sixteen patients with MDD participated in 2 fMRI sessions, and 16 healthy control (HC) subjects participated in 1 fMRI session. During each fMRI session, the participants performed a semantic verbal fluency task. Brain activity during the task was compared between groups (MDD 1st fMRI vs. HC) and times (MDD 1st fMRI vs. 2nd fMRI). Results: Significant brain hypoactivation was observed in MDD patients at the prefrontal, lateral parietal, and limbic regions compared to HC, and MDD patients exhibited hyperactivation at the left precuneus compared to HC. Hypoactivity of the left dorsolateral prefrontal cortex (DLPFC) and hyperactivity of the precuneus were normalized with treatment. Conclusions: Hypoactivation of the left DLPFC and hyperactivation of the precuneus should be considered as dysregulation of anticorrelated brain networks during a cognitive demanding task. This failure of network regulation may be an important factor in the pathophysiology of MDD.
Unknown Primary Melanoma: Worldwide Survey on Clinical Management
Authors: Ribero Simone , Pampena Riccardo , Bataille Veronique , Moscarella Elvira , Thomas Luc , Quaglino Pietro , Potenza Concetta , Van Akkooi Alexander C.J. , Testori Alessandro , Nathan Paul , Puig Susana , Zalaudek Iris , Argenziano Giuseppe , Longo Caterina
Published: January 2017

Background: How to deal with melanoma of unknown primary (MUP) origin is a debated topic in the literature. Objective: We performed a worldwide survey to inquire what clinical and investigational workup is performed as well as the physicians' perception of this disease. Methods: A questionnaire was sent via mail to clinicians involved in melanoma care from December 2015 to April 2016 using the International Dermoscopy Society website. Results: 119 physicians from 47 different countries answered the questionnaire. The most reported examination was skin examination followed by CT and/or PET scans. All the participants declared asking about previous excisions of skin lesions with 81% of them asking for a histopathological slide review of previous biopsies. Half of the participants checked for a possible vitiligo phenomenon that may explain regression of the primary lesion. BRAF, cKIT, and GNAQ mutations were screened by 32% of participants. The majority of participants (76%) applied the same treatment protocols for MUP as patients with known primary melanomas of the same AJCC stage. Conclusion: Strong heterogeneity was found between physicians dealing with MUP. Thus, a consensus document should be strongly encouraged.
Transmembrane Mucins: Signaling Receptors at the Intersection of Inflammation and Cancer
Authors: van Putten Jos P.M. , Strijbis Karin
Published: January 2017

Mucosal surfaces line our body cavities and provide the interaction surface between commensal and pathogenic microbiota and the host. The barrier function of the mucosal layer is largely maintained by gel-forming mucin proteins that are secreted by goblet cells. In addition, mucosal epithelial cells express cell-bound mucins that have both barrier and signaling functions. The family of transmembrane mucins consists of diverse members that share a few characteristics. The highly glycosylated extracellular mucin domains inhibit invasion by pathogenic bacteria and can form a tight mesh structure that protects cells in harmful conditions. The intracellular tails of transmembrane mucins can be phosphorylated and connect to signaling pathways that regulate inflammation, cell-cell interactions, differentiation, and apoptosis. Transmembrane mucins play important roles in preventing infection at mucosal surfaces, but are also renowned for their contributions to the development, progression, and metastasis of adenocarcinomas. In general, transmembrane mucins seem to have evolved to monitor and repair damaged epithelia, but these functions can be highjacked by cancer cells to yield a survival advantage. This review presents an overview of the current knowledge of the functions of transmembrane mucins in inflammatory processes and carcinogenesis in order to better understand the diverse functions of these multifunctional proteins.