bluuebunny/crossref_metadata_2025 huggingface dataset:
Biomarker and Tumor Responses of Oral Cavity Squamous Cell Carcinoma to Trametinib: A Phase II Neoadjuvant Window-of-Opportunity Clinical Trial
Authors: Uppaluri Ravindra , Winkler Ashley E. , Lin Tianxiang , Law Jonathan H. , Haughey Bruce H. , Nussenbaum Brian , Paniello Randal C. , Rich Jason T. , Diaz Jason A. , Michel Loren P. , Wildes Tanya , Dunn Gavin P. , Zolkind Paul , Kallogjeri Dorina , Piccirillo Jay F. , Dehdashti Farrokh , Siegel Barry A. , Chernock Rebecca D. , Lewis James S. , Adkins Douglas R.
Published: November 2016

Purpose: Ras/MEK/ERK pathway activation is common in oral cavity squamous cell carcinoma (OCSCC). We performed a neoadjuvant (preoperative) trial to determine the biomarker and tumor response of OCSCC to MEK inhibition with trametinib.

Experimental Design: Patients with stage II–IV OCSCC received trametinib (2 mg/day, minimum 7 days) prior to surgery. Primary tumor specimens were obtained before and after trametinib to evaluate immunohistochemical staining for p-ERK1/2 and CD44, the primary endpoint. Secondary endpoints included changes in clinical tumor measurements and metabolic activity [maximum standardized uptake values (SUVmax) by F-18 fluorodeoxyglucose positron emission tomography/CT), and in tumor downstaging. Drug-related adverse events (AE) and surgical/wound complications were evaluated.

Results: Of 20 enrolled patients, 17 (85%) completed the study. Three patients withdrew because of either trametinib-related (n = 2: nausea, duodenal perforation) or unrelated (n = 1: constipation) AEs. The most common AE was rash (9/20 patients, 45%). Seventeen patients underwent surgery. No unexpected surgical/wound complications occurred. Evaluable matched pre- and posttrametinib specimens were available in 15 (88%) of these patients. Reduction in p-ERK1/2 and CD44 expression occurred in 5 (33%) and 2 (13%) patients, respectively. Clinical tumor response by modified World Health Organization criteria was observed in 11 of 17 (65%) evaluable patients (median 46% decrease, range 14%–74%). Partial metabolic response (≥25% reduction in SUVmax) was observed in 6 of 13 (46%) evaluable patients (median 25% decrease, range 6%–52%). Clinical-to-pathologic tumor downstaging occurred in 9 of 17 (53%) evaluable patients.

Conclusions: Trametinib resulted in significant reduction in Ras/MEK/ERK pathway activation and in clinical and metabolic tumor responses in patients with OCSCC. Clin Cancer Res; 23(9); 2186–94. ©2016 AACR.
Trifluoperazine, a Well-Known Antipsychotic, Inhibits Glioblastoma Invasion by Binding to Calmodulin and Disinhibiting Calcium Release Channel IP3R
Authors: Kang Seokmin , Hong Jinpyo , Lee Jung Moo , Moon Hyo Eun , Jeon Borami , Choi Jungil , Yoon Nal Ae , Paek Sun Ha , Roh Eun Joo , Lee C. Justin , Kang Sang Soo
Published: November 2016

Calcium (Ca2+) signaling is an important signaling process, implicated in cancer cell proliferation and motility of the deadly glioblastomas that aggressively invade neighboring brain tissue. We have previously demonstrated that caffeine blocks glioblastoma invasion and extends survival by inhibiting Ca2+ release channel inositol 1,4,5-trisphosphate receptor (IP3R) subtype 3. Trifluoperazine (TFP) is an FDA-approved antipsychotic drug for schizophrenia. Interestingly, TFP has been recently reported to show a strong anticancer effect on lung cancer, hepatocellular carcinoma, and T-cell lymphoma. However, the possible anticancer effect of TFP on glioblastoma has not been tested. Here, we report that TFP potently suppresses proliferation, motility, and invasion of glioblastoma cells in vitro, and tumor growth in in vivo xenograft mouse model. Unlike caffeine, TFP triggers massive and irreversible release of Ca2+ from intracellular stores by IP3R subtype 1 and 2 by directly interacting at the TFP-binding site of a Ca2+-binding protein, calmodulin subtype 2 (CaM2). TFP binding to CaM2 causes a dissociation of CaM2 from IP3R and subsequent opening of IP3R. Compared with the control neural stem cells, various glioblastoma cell lines showed enhanced expression of CaM2 and thus enhanced sensitivity to TFP. On the basis of these findings, we propose TFP as a potential therapeutic drug for glioblastoma by aberrantly and irreversibly increasing Ca2+ in glioblastoma cells. Mol Cancer Ther; 16(1); 217–27. ©2016 AACR.
Establishment of the In Vivo Efficacy of Pretargeted Radioimmunotherapy Utilizing Inverse Electron Demand Diels-Alder Click Chemistry
Authors: Houghton Jacob L. , Membreno Rosemery , Abdel-Atti Dalya , Cunanan Kristen M. , Carlin Sean , Scholz Wolfgang W. , Zanzonico Pat B. , Lewis Jason S. , Zeglis Brian M.
Published: November 2016

The pretargeting system based on the inverse electron demand Diels-Alder reaction (IEDDA) between trans-cyclooctene (TCO) and tetrazine (Tz) combines the favorable pharmacokinetic properties of radiolabeled small molecules with the affinity and specificity of antibodies. This strategy has proven to be an efficient method for the molecularly targeted delivery of pharmaceuticals, including isotopes for radiological imaging. Despite encouraging results from in vivo PET imaging studies, this promising system has yet to be thoroughly evaluated for pretargeted radioimmunotherapy (PRIT). Toward that end, we synthesized two novel 177Lu-labeled tetrazine-bearing radioligands. Next, we compared the usefulness of our ligands for PRIT when paired with TCO-modified 5B1—a human, anti-CA19.9 mAb—in preclinical murine models of pancreatic cancer. The exemplary ligand, 177Lu-DOTA-PEG7-Tz, showed rapid (4.6 ± 0.8% ID/g at 4 hours) and persistent (16.8 ± 3.9% ID/g at 120 hours) uptake in tumors while concurrently clearing from blood and nontarget tissues. Single-dose therapy studies using 5B1-TCO and varying amounts of 177Lu-DOTA-PEG7-Tz (400, 800, and 1,200 μCi) showed that our system elicits a dose-dependent therapeutic response in mice bearing human xenografts. Furthermore, dosimetry calculations suggest that our approach is amenable to clinical applications with its excellent dosimetric profile in organs of clearance (i.e., liver and kidneys) as well as in dose-limiting tissues, such as red marrow. This study established that a pretargeted methodology utilizing the IEDDA reaction can rapidly and specifically deliver a radiotherapeutic payload to tumor tissue, thus illustrating its excellent potential for clinical translation. Mol Cancer Ther; 16(1); 124–33. ©2016 AACR.
TAS-116, a Novel Hsp90 Inhibitor, Selectively Enhances Radiosensitivity of Human Cancer Cells to X-rays and Carbon Ion Radiation
Authors: Lee Younghyun , Sunada Shigeaki , Hirakawa Hirokazu , Fujimori Akira , Nickoloff Jac A. , Okayasu Ryuichi
Published: November 2016

Hsp90 inhibitors have been investigated as cancer therapeutics in monotherapy and to augment radiotherapy; however, serious adverse effects of early-generation Hsp90 inhibitors limited their development. TAS-116 is a novel Hsp90 inhibitor with lower adverse effects than other Hsp90 inhibitors, and here, we investigated the radiosensitizing effects of TAS-116 in low linear energy transfer (LET) X-ray and high LET carbon ion–irradiated human cancer cells and mouse tumor xenografts. TAS-116 decreased cell survival of both X-ray and carbon ion–irradiated human cancer cell lines (HeLa and H1299 cells), and similar to other Hsp90 inhibitors, it did not affect radiosensitivity of noncancerous human fibroblasts. TAS-116 increased the number of radiation-induced γ-H2AX foci and delayed the repair of DNA double-strand breaks (DSB). TAS-116 reduced the expression of proteins that mediate repair of DSBs by homologous recombination (RAD51) and nonhomologous end joining (Ku, DNA-PKcs), and suppressed formation of RAD51 foci and phosphorylation/activation of DNA-PKcs. TAS-116 also decreased expression of the cdc25 cell-cycle progression marker, markedly increasing G2–M arrest. Combined treatment of mouse tumor xenografts with carbon ions and TAS-116 showed promising delay in tumor growth compared with either individual treatment. These results demonstrate that TAS-116 radiosensitizes human cancer cells to both X-rays and carbon ions by inhibiting the two major DSB repair pathways, and these effects were accompanied by marked cell-cycle arrest. The promising results of combination TAS-116 + carbon ion radiotherapy of tumor xenografts justify further exploration of TAS-116 as an adjunct to radiotherapy using low or high LET radiation. Mol Cancer Ther; 16(1); 16–24. ©2016 AACR.
Effect of Type I Diabetes on the Proteome of Mouse Oocytes
Authors: Jiang Guangjian , Zhang Guangli , An Tian , He Zhongchen , Kang Lihua , Yang Xiuyan , Gu Yujie , Zhang Dongwei , Wang Yangang , Gao Sihua
Published: November 2016

Background: Type I diabetes is a global public health concern that affects young people of reproductive age and can damage oocytes, reducing their maturation rate and blocking embryonic development. Understanding the effects of type I diabetes on oocytes is important to facilitate the maintenance of reproductive capacity in female diabetic patients. Methods: To analyze the effects of type I diabetes on mammalian oocytes, protein profile changes in mice with streptozotocin-induced type I diabetes were investigated using proteomic tools; non-diabetic mouse oocytes were used as controls. Immunofluorescence analysis for the spindle and mitochondria of oocytes. Results: We found that type I diabetes severely disturbed the metabolic processes of mouse oocytes. We also observed significant changes in levels of histone H1, H2A/B, and H3 variants in diabetic oocytes (fold change: > 0.4 or < -0.4), with the potential to block activation of the zygotic genome and affect early embryo development. Furthermore, diabetic oocytes exhibited higher abnormal spindle formation and spatial remodeling of mitochondria than observed in the controls. Conclusion: Our results indicate that type I diabetes disrupts metabolic processes, spindle formation, mitochondria distribution and modulates epigenetic code in oocytes. Such effects could have a major impact on the reproductive dynamics of female patients with type I diabetes.
A Double-Negative Feedback Interaction between MicroRNA-29b and DNMT3A/3B Contributes to Ovarian Cancer Progression
Authors: Teng Yue , Zuo Xiaohang , Hou Meng , Zhang Yan , Li Chen , Luo Wenjuan , Li Xu
Published: November 2016

Background: Epigenetic abnormalities are increasingly observed in multiple malignancies, including epithelial ovarian cancer (EOC), and their effects can be significantly counteracted by tumor-suppressor microRNAs, namely epi-miRNAs. Here, we investigated the role of miR-29b, a well-established epi-miRNA, in the DNA methylation regulation of EOC cells. Methods: The correlation between miR-29b and DNMT3A/3B expression was evaluated by RT-qPCR, western blotting and immunohistochemical analysis. The functional roles of miR-29b and DNMT3A/3B were tested by anti-miRs and microRNA precursors. A luciferase reporter assay was employed to detect the direct binding of miR-29b to DNMT3A/3B 3′ UTRs. Co-IP was utilized for investigating Id-1 binding activity. Results: miR-29b was negatively correlated with DNMT3A/3B expression at the cellular/histological levels. miR-29b silencing was correlated with increased DNMT3A/3B levels, whereasmiR-29b over-expression caused DNMT3A/3B down-regulation. Luciferase reporter assays confirmed that the miR-29b-mediated downregulation of DNMT3A/3Boccurred through the direct targeting of theirmRNAs'3'-UTRs,whereasBGS assays found that DNMT3A/3B knockdown increased miR-29b expression via CpG island promoter hypomethylation, thus suggesting a crucial crosstalk betweenmiR-29b and DNMT3A/3B via a double-negative feedback loop. Co-IP assay confirmed direct binding between DNMT3A and Id-1. Conclusion: Taken together, our study sheds light on a novel epigenetic circuitry regulating EOC progression and may provide novel options for miR-29b-based epi-therapeutic approaches for future EOC treatment.
Diagnostic Potential of Differentially Expressed Homer1 and Homer2 in Ischemic Stroke
Authors: Zhu Man , Zuo Jiangcheng , Shen Ji , Jing Wei , Luo Ping , Li Nandi , Wen Xue , Wang Chen , Yu Mingxia , Liang Chunzi , Tu Jiancheng
Published: November 2016

Background: Ischemic stroke (IS) is an extremely heterogeneous disease with variable pathogenesis. Due to the lack of early diagnostic marker, the mortality rate of IS remains high worldwide. The family of Homer plays an important role in the pathology of atherosclerotic plaque. In this study, we have investigated its expression pattern and clinical significance in IS. Methods: RT-qPCR was performed to detect the expression of Homer1, Homer2, and Homer3. Results: We found that the mRNA levels of Homer1 (p<0.001) and Homer2 (p<0.001), but not Homer3, in large-artery atherosclerosis (LAA) strokes were significantly upregulated than those in non-LAA strokes and controls. Multinomial logistic regression analyses showed that, although none of the Homer was associated with non-LAA strokes, higher Homer1 (adjusted OR=1.337, 95% CI: 1.227-1.458) and Homer2 (adjusted OR=1.099, 95% CI: 1.062-1.138) levels showed significant associations with increased odds of having LAA stroke, compared with the controls. The receiver operating characteristic (ROC) curves showed that the combination of Homer1 and Homer2 had a better diagnostic accuracy to differentiate LAA strokes from non-LAA strokes and controls, and the sensitivity and specificity ratios were 80.5%/90.4% and 98.0%/70.3%, respectively. Conclusion: Our data suggested that Homer1 and Homer2 might be considered as novel diagnostic biomarkers for LAA stroke.
Predictive and Prognostic Value of Early Disease Progression by PET Evaluation in Advanced Non-Small Cell Lung Cancer
Authors: Banna Giuseppe Luigi , Anile Giuseppe , Russo Giorgio , Vigneri Paolo , Castaing Marine , Nicolosi Maurizio , Strano Salvatore , Gieri Stefania , Spina Rosaria , Patanè Domenico , Calcara Giacomo , Fraggetta Filippo , Marletta Francesco , Stefano Alessandro , Ippolito Massimo
Published: November 2016

Objective: To assess the predictive and prognostic value of progressive metabolic disease (PMD) by the use of early 18Fluorodeoxyglucose positron emission tomography (18FDG-PET) in patients with clinical stage IV non-small cell lung cancer (NSCLC) treated with first-line chemotherapy. Methods: An 18FDG-PET performed following the first cycle of chemotherapy (PET-1) was compared with a pretreatment 18FDG-PET (PET-0) and a computed tomography (CT) scan after the third cycle (CT-3). The primary endpoint was the positive predictive value (PPV) of PMD. Secondary endpoints included the prognostic value of PMD. Results: Eleven of 38 patients (29%) had a PMD by PET-1, and 15 (39%), including all patients with a PMD, experienced a progressive disease by CT-3. The PPV of PMD was 100% according to both the European Organization for Research and Treatment of Cancer (EORTC) criteria and the PET Response Criteria In Solid Tumors (PERCIST) (p value for both, <0.0001). Patients with a PMD by PET-1 had a median overall survival of 7.0 months versus 14.0 months for those without a PMD (p = 0.04, according to the EORTC criteria). Conclusions: Early 18FDG-PET assessment deserves further investigation for the identification of NSCLC patients who do not benefit from first-line chemotherapy.
Elaidic Acid, a Trans-Fatty Acid, Enhances the Metastasis of Colorectal Cancer Cells
Authors: Ohmori Hitoshi , Fujii Kiyomu , Kadochi Yui , Mori Shiori , Nishiguchi Yukiko , Fujiwara Rina , Kishi Shingo , Sasaki Takamitsu , Kuniyasu Hiroki
Published: November 2016

The effects of trans-fatty acids (TFAs) on cardiovascular disorders have been extensively studied, and the effect of TFAs on cancers has recently been recognized. This study examined the effects of elaidic acid (EA), a TFA, on colorectal cancer (CRC) progression. We demonstrated that EA enhanced the growth, survival, and invasion of the CRC cell lines, CT26, and HT29. Tumor growth and metastasis in the lung, liver, and peritoneum were significantly more enhanced in CRC cells treated with EA than those treated with the cis form of EA, oleic acid (OA), or vehicle. Spheres of CRC cells were formed at more pronounced numbers in EA-treated cells than in OA-treated cells. Compared to OA, EA treatment also induced expression of the stemness factors, nucleostemin, CD133, and Oct4. Moreover, spheres of EA-treated CRC cells were larger and more proliferative than spheres of OA-treated cells. Oral intake of EA also enhanced liver metastasis and CD133 expression of CRC cells in a dose-dependent manner. EA intake also increased resistance to 5-fluorouracil. Inhibition of Wnt and ERK1/2 abrogated EA-induced enhancement of metastasis. Our findings demonstrate that EA might provide prominent metastatic potential to CRC cells, which shows important implications for the treatment of CRC.
Gulo Acts as a de novo Marker for Pronephric Tubules in Xenopus laevis
Authors: Xie Yajun , Liu Yuhang , Zhao Ya , Wang Hui , Liu Yamin , Wang Honglian , Li Mi , Zhao Hui , Zhou Qin , Lv Xiaoyan
Published: November 2016

Backgrounds/Aims: Vitamin C is an antioxidant and acts as a cofactor for several key enzymatic catalytic reactions in animals. Amphibians produce vitamin C in their kidneys, as opposed to mammals that produce vitamin C in their liver. Gulo serves as a crucial enzyme for vitamin C synthesis in mammals, but the characteristics and localization of its homologous genes during kidney development in Xenopus laevis, an amphibian, remains unknown. Methods: We aligned amino acid sequences of Gulo across different species by using bioinformatics methods and detected patterns of expression for Gulo during kidney development by using RT-PCR and in situ hybridization. Results: We identified a new site on the X. laevis genome, LOC495407. Sequence alignment analysis indicated this fragment is highly conserved and homologous to gulo genes in mammals. RT-PCR and in situ hybridization results reveal that X. laevis gulo is maternally expressed during the early stages of embryonic development, particularly, in the tubules of the pronephros from the middle tail-bud stage and onward in embryos. Conclusion: Gulo is a novel specific marker for pronephros tubules in X. laevis, and may be used as a potential marker for kidney development studies and disease diagnosis in mammals.
Extracellular Volume Overload and Increased Vasoconstriction in Patients With Recurrent Intradialytic Hypertension
Authors: Van Buren Peter Noel , Zhou Yunyun , Neyra Javier A. , Xiao Guanghua , Vongpatanasin Wanpen , Inrig Jula , Toto Robert
Published: November 2016

Background/Aims: Intradialytic hypertension (IH) occurs frequently in some hemodialysis patients and increases mortality risk. We simultaneously compared pre-dialysis, post-dialysis and changes in extracellular volume and hemodynamics in recurrent IH patients and controls. Methods: We performed a case-control study among prevalent hemodialysis patients with recurrent IH and hypertensive hemodialysis controls. We used bioimpedance spectroscopy and impedance cardiography to compare pre-dialysis, post-dialysis, and intradialytic change in total body water (TBW) and extracellular water (ECW), as well as cardiac index (CI) and total peripheral resistance index (TPRI). Results: The ECW/TBW was 0.453 (0.05) pre-dialysis and 0.427 (0.04) post-dialysis in controls vs. 0.478 (0.03) and 0.461 (0.03) in IH patients (p=0.01 post-dialysis). The ECW/TBW change was -0.027 (0.03) in controls and -0.013 (0.02) in IH patients (p=0.1). In controls, pre- and post-dialysis TPRI were 3254 (994) and 2469 (529) dynes/sec/cm2/m2 vs. 2983 (747) and 3408 (980) dynes/sec/cm2/m2 in IH patients (p=0.002 post-dialysis). There were between-group differences in TPRI change (0=0.0001), but not CI (p=0.09). Conclusions: Recurrent intradialytic hypertension is associated with higher post-dialysis extracellular volume and TPRI. Intradialytic TPRI surges account for the vasoconstrictive state post-dialysis, but intradialytic fluid shifts may contribute to post-hemodialysis volume expansion.
Global Overexpression of ET-1 Decreases Blood Pressure - A Systematic Review and Meta-Analysis of ET-1 Transgenic Mice
Authors: Lu Yong Ping , Tsuprykov Oleg , Vignon-Zellweger Nicolas , Heiden Susi , Hocher Berthold
Published: November 2016

Background/Aims: ET-1 has independent effects on blood pressure regulation in vivo, it is involved in tubular water and salt excretion, promotes constriction of smooth muscle cells, modulates sympathetic nerve activity, and activates the liberation of nitric oxide. To determine the net effect of these partially counteracting mechanisms on blood pressure, a systematic meta-analysis was performed. Methods: Based on the principles of Cochrane systematic reviews, we searched in major literature databases - MEDLINE (PubMed), Embase, Google Scholar, and the China Biological Medicine Database (CBM-disc) - for articles relevant to the topic of the blood pressure phenotype of endothelin-1 transgenic (ET-1+/+) mice from January 1, 1988 to March 31, 2016. Review Manager Version 5.0 (Rev-Man 5.0) software was applied for statistical analysis. In total thirteen studies reported blood pressure data. Results: The meta-analysis of blood pressure data showed that homozygous ET-1 transgenic mice (ET-1+/+ mice) had a significantly lower blood pressure as compared to WT mice (mean difference: -2.57 mmHg, 95% CI: -4.98∼ -0.16, P = 0.04), with minimal heterogeneity (P = 0.86). A subgroup analysis of mice older than 6 months revealed that the blood pressure difference between ET-1+/+ mice and WT mice was even more pronounced (mean difference: -6.19 mmHg, 95% CI: -10.76∼ -1.62, P = 0.008), with minimal heterogeneity (P = 0.91). Conclusion: This meta-analysis provides robust evidence that global ET-1 overexpression in mice lowers blood pressure in an age-dependent manner. Older ET-1+/+ mice have a somewhat more pronounced reduction of blood pressure.
Effects of Exogenous Interleukin-9 on the Growth, Proliferation and Activity of Interstitial Cells of Cajal Cultured in vitro
Authors: Huang Lei , Du Baofeng , Gong Yaoyao , Xu Hairong , Lu Jia , Si Xinmin
Published: November 2016

Objectives: To evaluate the role of exogenous interleukin-9 (IL-9) in the growth, proliferation and activity of interstitial cells of Cajal (ICCs) cultured in vitro, and to assess its role in maintaining the functions of ICCs. Methods: ICCs of murine gastric antrum were isolated and cultured in vitro. ICCs were identified with c-Kit and ANO1 immunofluorescent antibodies. Both fluorescence microscope and confocal microscopy were used to observe the effects of IL-9 on the growth, proliferation and activity of ICCs in cultured in vitro. ICCs were loaded with fluorescence probe Fluo-3/AM and the fluorescence of intracellular calcium concentration ([Ca2+]i) was measured by confocal microscopy. The effects of exogenous IL-9 on the sulfated cholecystokinin octapeptide (CCK-8S)-evoked [Ca2+]i elevation were observed by confocal microscopy. Results: Immunofluorescence results confirmed the successful separation and culture of ICCs in vitro. IL-9 in concentrations ranging from 0.02 to 1 μg/ml promoted the growth, proliferation and activity of ICCs in culture, and ICCs grew best with 0.5 mg/ml of IL-9. The presence of IL-9 could significantly increase the CCK-8S-evoked [Ca2+]i oscillation, which is probably caused by facilitating the maintenance of the functions of ICCs under suitable conditions for culture. Conclusion: IL-9 could promote the growth, proliferation and activity of ICCs, reinforce the CCK-8S-induced [Ca2+]i increment in ICCs, and facilitate the maintenance of the functions of ICCs under suitable culture condition.
Brush Cytology and AgNOR in the Diagnosis of Oral Squamous Cell Carcinoma
Authors: Jajodia Ekta , Raphael Vandana , Shunyu N. Brian , Ralte Sarah , Pala Star , Jitani Ankit Kumar
Published: November 2016

Objective: We aimed to evaluate the role of brush cytology in the screening of oral lesions with malignant suspicion and compare it with histopathology in north-eastern India. Study Design: Brush cytology samples taken from 48 patients were processed for conventional cytology (CC) and liquid-based cytology (LBC), and biopsy samples were also obtained. LBC samples were also stained to assess the argyrophilic nucleolar organizer region (AgNOR). The cytology was compared with histopathology, both individually and in combination with AgNOR. The smear quality was compared with histopathology for evaluating their diagnostic accuracy. Results: The sensitivity of diagnosing oral cavity squamous cell carcinoma by LBC and CC alone was 75 and 85%, respectively, which improved on combining with the AgNOR count, with a cutoff of 6.5. The presence of round cells on cytology was significantly associated with high-grade lesions. LBC provided clearer cytomorphology but compromised the background information in high-grade lesions. Conclusion: Brush cytology is a minimally invasive tool for screening oral lesions with malignant suspicion. LBC and CC are complementary techniques for cytological screening and combining them with AgNOR can increase the diagnostic yield. With objective criteria for assessment, cytology can be an indispensable tool for screening oral lesions in a resource-limited set-up, especially in high-incidence regions.
Cardiodoron® bei Patienten mit Schlafstörungen - Ergebnisse einer prospektiven Beobachtungsstudie
Authors: Rother Claudia , Schnelle Martin
Published: November 2016

Hintergrund: Schlafstörungen gehören zu den häufigsten gesundheitlichen Problemen der heutigen Zeit. Stress und die dadurch bedingte innere Anspannung sowie eine unrhythmische Lebensführung z.B. durch Schichtarbeit sind bekannte auslösende Faktoren. Weniger bekannt ist, dass auch funktionelle Herz-Kreislauf-Beschwerden zu Störungen des Schlafs führen können und dass deren Behandlung zu einer Verbesserung der Schlafqualität beiträgt. Ganzheitlich betrachtet geht es daher um die Wiederherstellung einer gesunden Rhythmik, insbesondere des Herz-/Atem- sowie des Schlaf-Wach-Rhythmus, die Cardiodoron®, eine Heilpflanzenkomposition aus Primula veris, Hyoscyamus niger und Onopordum acanthium, unterstützt. Patienten und Methoden: Mittels einer prospektiven, multizentrischen Beobachtungsstudie sollte ermittelt werden, wie sich funktionelle Herz-Kreislauf-Beschwerden und/oder Schlafstörungen unter der Behandlung mit Cardiodoron® (Dilution) über 3-6 Monate entwickeln. Im Zeitraum von September 2009 bis März 2012 dokumentierten 92 Ärzte 501 Patienten, von denen 380 über Schlafstörungen klagten und deren Daten in dieser Publikation näher betrachtet werden. Nach einer Aufnahmeuntersuchung erfolgte nach 90 Tagen eine Abschlussuntersuchung und bei Fortführung der Therapie nach nochmals 90 Tagen eine Follow-up-Untersuchung. Neben 30 ärztlicherseits bewerteten Symptomen beurteilten die Patienten ihr Befinden mittels Pittsburgh Sleep Quality Index (PSQI) nach Buysse und der Beschwerden-Liste nach von Zerssen (B-L und B-L'). Ergebnisse: Unter der Cardiodoron®-Therapie gingen bei guter Verträglichkeit sowohl die Ausprägung der Schlafstörungen (um 65% von 2,0 auf 0,7 Punkte) als auch die erfassten 30 Symptome (um 59% von 24,3 auf 9,9 Punkte) deutlich zurück (p < 0,01). Weiterhin reduzierten sich der PSQI und der Gesamtwert der Beschwerden-Liste signifikant (p < 0,0001) um 60% bzw. 56% (von 12,2 auf 4,8 bzw. von 25,6 auf 11,4 Punkte). Schlussfolgerungen: Bei Patienten mit Schlafstörungen (mit oder ohne funktionelle Herz-Kreislauf-Beschwerden) kann die Ausprägung der Beschwerden mit Cardiodoron® deutlich gesenkt werden. Cardiodoron® ist gut verträglich.
Contextual Factors and Mental Distress as Possible Predictors of Hazardous Drinking in Norwegian Medical Doctors: A 15-Year Longitudinal, Nationwide Study
Authors: Mahmood Javed Iqbal , Støen Grotmol Kjersti , Tesli Martin , Vaglum Per , Tyssen Reidar
Published: November 2016

Background: We have previously identified long-term individual predictors of hazardous drinking in doctors, but longitudinal studies on contextual factors (work and life stress) and mental distress being independently linked to hazardous drinking over the first 15 years of a medical career are lacking. Methods: Two nationwide cohorts of Norwegian doctors (n = 1,052) from all 4 Norwegian universities were surveyed in their final year of medical school (1993/1994 and 1999) (T1), and 4 (T2), 10 (T3), and 15 (T4) years later. Hazardous drinking was measured using a validated 9-item version of the Alcohol Use Disorder Identification Test. Work-related and other predictors were analysed using generalized estimating equations. Results: Ninety percent (947/1,052) responded at least once, and 42% (450/1,052) responded at all 4 time points. Hazardous drinking was reported by 16% at T1, 14% at T2 and T3, and 15% at T4. Life events (p = 0.009) and mental distress (p = 0.002) were adjusted predictors of hazardous drinking, in addition to male gender, no religious activity, drinking to cope with tension, and low conscientiousness. Conclusions: Doctors' work-related stress was not linked to hazardous drinking, but life events, mental distress, and drinking to cope were. Prevention should target mental distress and drinking to cope with tension.
Conventional, Doppler and Contrast-Enhanced Ultrasonography in Differential Diagnosis of Ovarian Masses
Authors: Liu Zongyu , Yang Fan , Zhang Yong , Yu Huimei , Zhu He , Yang Ruiqi , Fan Limei
Published: November 2016

Background: Differential diagnosis of ovarian masses can influence both treatment selection and prognosis of ovarian tumor patients. A comprehensive review was performed with respect to the diagnostic value of conventional ultrasonography, Doppler ultrasonography and contrast-enhanced ultrasonography (CEUS) in differentiating benign from malignant ovarian masses. Methods: Databases were searched for relevant articles. Retrieved studies were screened according to the inclusion criteria. Pooled statistics including specificity, sensitivity, positive likelihood ratios (PLR), negative likelihood ratios (NLR), diagnostic odds ratio (DOR) and area under curve (AUC) were utilized to calculate the overall diagnostic value for each diagnostic approach. Results: Sixty-seven high quality articles were finally enrolled in the present meta-analysis. The sensitivity and specificity of conventional US were 0.92 and 0.86, respectively. The corresponding sensitivity and specificity of Doppler US were 0.93 and 0.85, respectively. Additionally, these figures for CEUS were 0.97 and 0.92, respectively. Finally, the AUC values for conventional US, Doppler US and CEUS were 0.95, 0.96 and 0.99, respectively. Conclusion: All of the three US-related imaging modalities have relatively high diagnostic value in distinguishing malignant tumors from benign ones in ovarian tumors.
Activation of Hepatic Stellate Cells is Inhibited by microRNA-378a-3p via Wnt10a
Authors: Yu Fujun , Fan XuFei , Chen Bicheng , Dong Peihong , Zheng Jianjian
Published: November 2016

Background/Aims: Wnt/β-catenin pathway is involved in liver fibrosis and microRNAs (miRNAs) are considered as key regulators of the activation of hepatic stellate cells (HSCs). A recent study showed the protective role of miR-378a-3p against cardiac fibrosis. However, whether miR-378a-3p suppresses Wnt/β-catenin pathway in liver fibrosis is largely unknown. Methods: miR-378a-3p expression was detected in carbon tetrachloride-induced liver fibrosis and activated HSCs. Effects of miR-378a-3p overexpression on HSC activation and Wnt/β-catenin pathway were analyzed. Bioinformatic analysis was employed to identify the potential targets of miR-378a-3p. Serum miR-378a-3p expression was analyzed in patients with cirrhosis. Results: Reduced miR-378a-3p expression was observed in the fibrotic liver tissues and activated HSCs. Up-regulation of miR-378a-3p inhibited HSC activation including cell proliferation, α-smooth muscle actin (α-SMA) and collagen expression. Moreover, miR-378a-3p overexpression resulted in Wnt/β-catenin pathway inactivation. Luciferase reporter assays demonstrated that Wnt10a, a member of Wnt/β-catenin pathway, was confirmed to be a target of miR-378a-3p. By contrast, miR-378a-3p inhibitor contributed to HSC activation, with an increase in cell proliferation, α-SMA and collagen expression. But all these effects were blocked down by silencing of Wnt10a. Notably, sera from patients with cirrhosis contained lower levels of miR-378a-3p than sera from healthy controls. Receiver operating characteristic curve analysis suggested that serum miR-378a-3p differentiated liver cirrhosis patients from healthy controls, with an area under the curve of ROC curve of 0.916. Conclusion: miR-378a-3p suppresses HSC activation, at least in part, via targeting of Wnt10a, supporting its potential utility as a novel therapeutic target for liver fibrosis.
Cell-Derived Microparticles in Patients with Type 2 Diabetes Mellitus: a Systematic Review and Meta-Analysis
Authors: Li Sheyu , Wei Jia , Zhang Chenghui , Li Xiaodan , Meng Wentong , Mo Xianming , Zhang Qianying , Liu Qilin , Ren Kaiyun , Du Rong , Tian Haoming , Li Jianwei
Published: November 2016

Background/Aims: The aim of this study was to assess the association between circulating cell-derived microparticles (MPs) and type 2 diabetes mellitus (T2DM). Methods: A literature search was performed systematically in PubMed and Embase to identify available case-control or cross-sectional studies that compared different types of cell-derived MPs in patients with T2DM and non-diabetic controls. Pooled standardized mean differences (SMDs) of each MP type were pooled using meta-analysis. Results: Forty-eight studies involving 2,460 patients with T2DM and 1,880 non-diabetic controls were included for systematic review and 34 of which were included for quantitative study by meta-analysis. In the overall analysis, the levels of circulating total MPs (TMPs), platelet-derived MPs (PMPs), monocyte-derived MPs (MMPs) and endothelium-derived MPs (EMPs) were significantly higher in T2DM patients than those in controls (TMPs: SMD, 0.64; 95%CI, 0.12∼1.15; P=0.02; PMPs: SMD, 1.19; 95%CI, 0.88∼1.50; P <0.00001; MMPs: SMD, 0.92; 95%CI, 0.66∼1.17; P <0.00001; EMPs: SMD, 0.73; 95%CI, 0.50∼0.96; P <0.00001). Meanwhile, no significant difference was shown in leukocyte-derived MPs (LMPs) level between diabetic and non-diabetic groups (SMD, 0.37; 95%CI, -0.15∼0.89; P=0.17). Conclusions: The counts of TMPs, PMPs, MMPs and EMPs elevated in patients with T2DM. And cell-derived MPs may play a role in the pathogenesis of T2DM.
The Impact of a Standardized Oral Multinutrient Supplementation on Embryo Quality in in vitro Fertilization/Intracytoplasmic Sperm Injection: A Prospective Randomized Trial
Authors: Nouri Kazem , Walch Katharina , Weghofer Andrea , Imhof Martin , Egarter Christian , Ott Johannes
Published: November 2016

The role of micronutrients in fertility has recently gained increased attention. We aimed to test the impact of a standardized, multinutrient supplementation on outcomes after in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) in a pilot study. One hundred women undergoing IVF/ICSI were prospectively included and randomized to receive either a multinutrient supplementation named PROfertil® female that included folic acid, selenium, vitamin E, catechins, glycyrrhizin, diosgenin, damiana and omega-3-fatty acids (study group; n = 50), or 400 µg folic acid (control group; n = 50). Outcome parameters were embryo quality on day 3 after oocyte retrieval (good quality vs. poor quality) and the clinical pregnancy rate. In an intention-to-treat analyses, a higher rate of women with at least one good quality embryo (with at least 6 cells and a fragmentation rate <20%) were found for the study (29/50, 58.0%) compared to the control group (18/50, 36.0%; p = 0.045 in chi-square test; relative risk 1.611, 95% CI 1.009-2.597). In conclusion, a multinutrient supplementation that includes folic acid, selenium, vitamin E, catechins, glycyrrhizin, diosgenin, damiana and omega-3-fatty acids seems beneficial in terms of embryo quality.
Anaphylaxis to Over-the-Counter Flurbiprofen in a Child
Authors: Giovannini Mattia , Sarti Lucrezia , Barni Simona , Pucci Neri , Novembre Elio , Mori Francesca
Published: November 2016

Non-steroidal anti-inflammatory drugs are suspected to cause drug hypersensitivity very frequently in paediatric patients. In this article, we describe the first case of anaphylaxis to flurbiprofen in a child and provide insight into the possibility of severe reactions and even anaphylaxis to over-the-counter flurbiprofen. Finally, the importance of a rigorous allergy work-up in reaching a confident diagnosis and providing the patient with a safe alternative is shown.
Acute Overfeeding Does Not Alter Liver or Adipose Tissue-Derived Cytokines in Healthy Humans
Authors: Chen Miaoxin , Liu Bo , Thompson Campbell H. , Wittert Gary A. , Heilbronn Leonie K.
Published: November 2016

Background/Aims: The secretions of liver-derived cytokines angiopoietin-like 6, insulin-like growth factor 1, selenoprotein-P and C-reactive protein and adipokines, adiponectin and monocyte chemoattractant protein-1 are altered in obese individuals, and they directly induce insulin resistance in both cellular and animal models. This study is aimed at examining the effects of acute overnutrition on these cytokines in healthy individuals, and identifying association with markers of insulin resistance. Methods: Thirty-one young healthy individuals (10 men, body mass index (BMI) 22.4 ± 2.7; 21 women, BMI 23.3 ± 4.9) were enrolled for the study. Metabolic assessments were done 3 days after an energy balanced diet (30% fat) and 3 days of a high-fat overfeeding diet (+1,250 kcal/day, 45% fat), and the assessments included the fasting body weight and blood samples to analyze the selected cytokines and evaluate the insulin sensitivity by a hyperinsulinemic euglycemic clamp (80 mU/m2/min). Results: Three days of overfeeding increased the body weight, fasting glucose and insulin, and thus the homeostasis model assessment of insulin resistance. However, there were no changes in peripheral insulin sensitivity, or in the circulating cytokines assessed. Conclusions: The hepatokines and adipokines assessed were not acutely sensitive to overnutrition in healthy individuals, despite increases in markers of hepatic insulin resistance.
LPA
Gene, Ethnicity, and Cardiovascular Events
Authors: Lee Sang-Rok , Prasad Anand , Choi Yun-Seok , Xing Chao , Clopton Paul , Witztum Joseph L. , Tsimikas Sotirios
Published: November 2016

Background:

The relationship of
LPA
single nucleotide polymorphisms (SNPs), apolipoprotein(a) isoforms, and lipoprotein(a) [Lp(a)] levels with major adverse cardiovascular events (MACE) in different ethnic groups is not well known.

Methods:

LPA
SNPs, apolipoprotein(a) isoforms, Lp(a), and oxidized phospholipids on apolipoprotein B-100 (OxPL-apoB) levels were measured in 1792 black, 1030 white, and 597 Hispanic subjects enrolled in the Dallas Heart Study. Their interdependent relationships and prospective association with MACE after median 9.5-year follow-up were determined.

Results:

LPA
SNP rs3798220 was most prevalent in Hispanics (42.38%), rs10455872 in whites (14.27%), and rs9457951 in blacks (32.92%). The correlation of each of these SNPs with the major apolipoprotein(a) isoform size was highly variable and in different directions among ethnic groups. In the entire cohort, Cox regression analysis with multivariable adjustment revealed that quartiles 4 of Lp(a) and OxPL-apoB were associated with hazard ratios (95% confidence interval) for time to MACE of 2.35 (1.50–3.69,
P
<0.001) and 1.89 (1.26–2.84,
P
=0.003), respectively, versus quartile 1. Addition of the major apolipoprotein(a) isoform and the 3
LPA
SNPs to these models attenuated the risk, but significance was maintained for both Lp(a) and OxPL-apoB. Evaluating time to MACE in specific ethnic groups, Lp(a) was a positive predictor and the size of the major apolipoprotein(a) isoform was an inverse predictor in blacks, the size of the major apolipoprotein(a) isoform was an inverse predictor in whites, and OxPL-apoB was a positive predictor in Hispanics.

Conclusions:

The prevalence and association of
LPA
SNPs with size of apolipoprotein(a) isoforms, Lp(a), and OxPL-apoB levels are highly variable and ethnicity-specific. The relationship to MACE is best explained by elevated plasma Lp(a) or OxPL-apoB levels, despite significant ethnic differences in
LPA
genetic markers.
To Arm or to Ally? The Patron's Dilemma and the Strategic Logic of Arms Transfers and Alliances
Authors: Yarhi-Milo Keren , Lanoszka Alexander , Cooper Zack
Published: November 2016

How do great powers decide whether to provide arms to or form alliances with client states? This “patron's dilemma” revolves around a decision about how to best provide security to clients without becoming entrapped in unwanted conflicts. Strong commitments worsen the risk of entrapment, whereas weak commitments intensify fears of abandonment. This traditional alliance dilemma can be addressed through the provision of arms and alliances. Great power patrons primarily make such decisions on the basis of two factors: first, the extent to which the patron believes it and its client have common security interests; and second, whether the patron believes that its client has sufficient military capabilities to deter its main adversary without the patron's assistance. Patrons assess the degree of shared threat and the local balances of capabilities in determining whether to support their clients with arms, alliances, or both. As demonstrated in the U.S. provision of security goods to Taiwan and Israel during the Cold War, this strategic logic explains how great powers manage the patron's dilemma.
Separating Fact from Fiction in the Debate over Drone Proliferation
Authors: Horowitz Michael C. , Kreps Sarah E. , Fuhrmann Matthew
Published: November 2016

What are the consequences of drone proliferation for international security? Despite extensive discussions in the policy world concerning drone strikes for counterterrorism purposes, myths about the capabilities and implications of current-generation drones often outstrip reality. Understanding the impact of drones requires separating fact from fiction by examining their effects in six different contexts—counterterrorism, interstate conflict, crisis onset and deterrence, coercive diplomacy, domestic control and repression, and use by nonstate actors for the purposes of terrorism. Although current-generation drones introduce some unique capabilities into conflicts, they are unlikely to produce the dire consequences that some analysts fear. In particular, drone proliferation carries potentially significant consequences for counterterrorism operations and domestic control in authoritarian regimes. Drones could also enhance monitoring in disputed territories, potentially leading to greater stability. Given their technical limitations, however, current-generation drones are unlikely to have a large impact on interstate warfare. Assessing the consequences of drone proliferation has important implications for a range of policy issues, including the management of regional disputes, the regulation of drone exports, and defense against potential terrorist attacks on the homeland.
Emergencities
Authors: Loh Kah Seng
Published: November 2016

Western planning experts, beginning with the United Nations Mission of Experts on Tropical Housing in 1950–1951, undertook major interventions in what they described as a zone of urban crisis across Southeast Asia after the Second World War. In various ‘emergencities’, allegedly threatened by expanding squatter settlements, the experts proposed robust and immediate state action to organise a comprehensive regime of planning to replace the unauthorised areas with regulated housing. Yet, despite its scientific appearance, the planning expertise constituted a political project that sought to transfer Western ideas of the “Garden City” to unruly Southeast Asian cities. The project stressed the importance of nationhood, citizenship and democracy in urban reform and was fearful of the appeal of communism in post-colonial Southeast Asia. The expert interventions usually failed but still had significant and unpredictable outcomes. By reinforcing patronage politics, they politicised housing and extended state power into urban life. The interventions also created crisis situations of their own making and catalysed social resistance, both spontaneous and organised. Southeast Asian cities became sites of a struggle between competing forms of urban modernity. In contrast to the experts framing modernity and tradition in opposition, however, squatters demonstrated their adaptive “cultures of modernity”, utilising both old and new ways in their pursuit of a modern life.
Have Performance, Will Travel
Authors: Taylor Nora A.
Published: November 2016

This article looks at artistic exchanges in Southeast Asia that are created through person-to-person contact, rather than the circulation of objects, in the form of performance art events, re-enactments, and large travelling exhibitions. It argues that close physical contact and creative collaborations among artists have become a means of writing alternative art histories that rely on oral transmission and live recordings. The creation of networks among artists have helped develop bonds among artists, as well as foster the development of art history in the region.
Joseph’s Two Garments. The Reception of Joseph in Targum Neofiti
Authors: Niedźwiedzki Tomasz
Published: November 2016

Biblical characters underwent certain ‘transformations’ as they were received in targumic literature. Although previous studies of Joseph have considered his image in the extant Targums, it seems that scholars have passed over some of his salient features present in Targum Neofiti, such as his relationship with his father, his brothers, Esau, and the Egyptians, along with a detailed and overall evaluation of his moral conduct. On the basis of particular interpretations that appear in Targum Neofiti, it is possible to describe some of the exegetical traditions about Joseph that were circulating in early Judaism.
A new combination in Smyrnium (Apiaceae)
Authors: STINCA ADRIANO , PIGNATTI SANDRO
Published: November 2016

Recently, Raimondo et al. (2015) described a new species for Sicily and Creta, i.e. Smyrnium dimartinoi Raimondo, Mazzola & Spadaro (2015: 138). This taxon is closely related morphologically and ecologically to the aggregate of S. perfoliatum Linnaeus (1753: 262), in which two subspecies are usually recognized (cf. Hartvig 1986, Conti et al. 2005, Reduron 2008, Hand 2011): S. perfoliatum subsp. perfoliatum and S. perfoliatum subsp. rotundifolium (Miller 1768: without pagination) Bonnier & Layens (1894: 135).
World review of the genus Strongylophthalmyia Heller (Diptera: Strongylophthalmyiidae). Part I: Introduction, morphology, species groups, and review of the Strongylophthalmyia punctata subgroup
Authors: EVENHUIS NEAL L.
Published: November 2016

The Strongylophthalmyia punctata subgroup, comprising 24 species with armored fore femora, and restricted primarily to SE Asia, is reviewed. Eighteen new species, S. albisternum, n. sp. (Thailand), S. borneensis, n. sp. (Borneo), S. caestus, n. sp. (Philippines), S. darlingi, n. sp. (Sumatra), S. federeri, n. sp. (Philippines), S. hauseri, n. sp. (Thailand, Vietnam), S. indochinensis, n. sp. (Cambodia, Thailand, Vietnam), S. inundans, n. sp. (Philippines), S. laosensis, n. sp. (Laos), S. lowi, n. sp. (Peninsular Malaysia), S. malayensis, n. sp. (Peninsular Malaysia), S. nigripalpis, n. sp. (Peninsular Malaysia), S. oxybeles, n. sp. (Sumatra), S. pappi, n. sp. (Thailand), S. phillindablank, n. sp. (China), S. sichuanica, n. sp. (China), S. sumatrana, n. sp. (Sumatra), and S. thailandica, n. sp. (Thailand) are described and illustrated, S. microstyla Shatalkin and S. punctata Hennig are redescribed based on examination of the holotypes, and a key to species of the subgroup is presented. A general taxonomic overview of the genus Strongylophthalmyia is given with discussion of and keys to proposed species groups.