bluuebunny/crossref_metadata_2025 huggingface dataset:
Subclinical Hypothyroidism in PCOS: Impact on Presentation, Insulin Resistance, and Cardiovascular Risk
Authors: Yu Qun , Wang Jin-Bei
Published: July 2016

Aim of Study. To assess status of thyroid function and thyroid disorders particularly subclinical hypothyroidism (SCH) in subjects with polycystic ovarian syndrome (PCOS) and impact of SCH on various clinical and biochemical parameters and cardiovascular risk in PCOS.Methods. Hundred females diagnosed with PCOS as per Rotterdam criteria and 100 normal controls were recruited and were subjected to elaborate anthropometric, clinical, and biochemical assessment.Results. Notable findings included significantly higher frequency of subjects with subclinical hypothyroidism (p=0.0002), autoimmune thyroiditis (p<0.001), and goitre (p=0.02) in polycystic ovarian syndrome subjects compared to control subjects. Further SCH PCOS subjects were found to harbor significantly higher HOMA-IR (p<0.05) and frequency of subjects with dyslipidemia (p<0.05) compared to both euthyroid PCOS and euthyroid control subjects. Though frequency of subjects with cardiovascular risk factors was higher in SCH PCOS group than euthyroid PCOS group, it failed to reach statistical significance.Conclusion. We concluded that PCOS is associated with high incidence of SCH and AIT compared to normal population and SCH poses increased risk of cardiovascular disorder in PCOS.
Iatrogenic Radial Nerve Palsy following Closed Reduction of a Simple Diaphyseal Humeral Fracture: Beware the Perfect X-Ray
Authors: Jones Morgan , Kang Hean Wu , O’Neill Christopher , Maginn Paul
Published: July 2016

Radial nerve injury is a recognised complication associated with humeral shaft fracture. A case of iatrogenic radial nerve injury is presented following fracture reduction. The relevant anatomy, challenges in management of humeral fractures with associated radial nerve injury, and the importance of detailed clinical assessment and documentation are discussed.
The Association between Sleep Problems, Sleep Medication Use, and Falls in Community-Dwelling Older Adults: Results from the Health and Retirement Study 2010
Authors: Min Yaena , Nadpara Pramit A. , Slattum Patricia W.
Published: July 2016

Background. Very few studies have assessed the impact of poor sleep and sleep medication use on the risk of falls among community-dwelling older adults. The objective of this study was to evaluate the association between sleep problems, sleep medication use, and falls in community-dwelling older adults.Methods. The study population comprised a nationally representative sample of noninstitutionalized older adults participating in the 2010 Health and Retirement Study. Proportion of adults reporting sleep problems, sleep medication use, and fall was calculated. Multiple logistic regression models were constructed to examine the impact of sleep problems and sleep medication use on the risk of falls after controlling for covariates.Results. Among 9,843 community-dwelling older adults, 35.8% had reported a fall and 40.8% had reported sleep problems in the past two years. Sleep medication use was reported by 20.9% of the participants. Older adults who do have sleep problems and take sleep medications had a significant high risk of falls, compared to older adults who do not have sleep problems and do not take sleep medications. The other two groups also had significantly greater risk for falls.Conclusion. Sleep problems added to sleep medication use increase the risk of falls. Further prospective studies are needed to confirm these observed findings.
Smoking Cessation Carries a Short-Term Rising Risk for Newly Diagnosed Diabetes Mellitus Independently of Weight Gain: A 6-Year Retrospective Cohort Study
Authors: Sung Yi-Ting , Hsiao Cheng-Ting , Chang I-Jen , Lin Yu-Chih , Yueh Chen-Yu
Published: July 2016

Background.The effects of smoking on human metabolism are complex. Although smoking increases risk for diabetes mellitus, smoking cessation was also reported to be associated with weight gain and incident diabetes mellitus. We therefore conducted this study to clarify the association between smoking status and newly diagnosed diabetes mellitus.Methods. An analysis was done using the data of a mass health examination performed annually in an industrial park from 2007 to 2013. The association between smoking status and newly diagnosed diabetes mellitus was analyzed with adjustment for weight gain and other potential confounders.Results.Compared with never-smokers, not only current smokers but also ex-smokers in their first two years of abstinence had higher odds ratios (ORs) for newly diagnosed diabetes mellitus (never-smokers 3.6%, OR as 1; current smokers 5.5%, OR = 1.499, 95% CI = 1.147–1.960, andp=0.003; ex-smokers in their first year of abstinence 7.5%, OR = 1.829, 95% CI = 0.906–3.694, andp=0.092; and ex-smokers in their second year of abstinence 9.0%, OR = 2.020, 95% CI = 1.031–3.955, andp=0.040).Conclusion.Smoking cessation generally decreased risk for newly diagnosed diabetes mellitus. However, increased odds were seen within the first 2 years of abstinence independently of weight gain.
Life Threatening Severe QTc Prolongation in Patient with Systemic Lupus Erythematosus due to Hydroxychloroquine
Authors: O’Laughlin John P. , Mehta Parag H. , Wong Brian C.
Published: July 2016

We present a case of a syncopal episode resulting from significant QT interval prolongation in a patient on hydroxychloroquine for the treatment of systemic lupus erythematosus and end stage renal disease. The patient had been treated with hydroxychloroquine for two years prior to presentation. After thorough workup for secondary causes of QT interval prolongation hydroxychloroquine was discontinued and the patient’s QT interval shortened. The patient was treated with mexiletine to prevent sudden ventricular arrhythmias, which was unique compared to other documented cases in which lidocaine was used. The patient was noted to have mild prolongation of the QT interval on electrocardiogram prior to initiation of hydroxychloroquine therapy which was exacerbated by its use and may have been caused due to toxicity from underlying renal failure.
[Retracted] Protective Effects of Soy Oligopeptides in Ultraviolet B‐Induced Acute Photodamage of Human Skin
Authors: Zhou Bing-rong , Ma Li-wen , Liu Juan , Zhang Jia-an , Xu Yang , Wu Di , Permatasari Felicia , Luo Dan
Published: July 2016

Aim. We explored the effects of soy oligopeptides (SOP) in ultraviolet B‐ (UVB‐) induced acute photodamage of human skin in vivo and foreskin ex vivo. Methods. We irradiated the forearm with 1.5 minimal erythemal dose (MED) of UVB for 3 consecutive days, establishing acute photodamage of skin, and topically applied SOP. Erythema index (EI), melanin index, stratum corneum hydration, and transepidermal water loss were measured by using Multiprobe Adapter 9 device. We irradiated foreskin ex vivo with the same dose of UVB (180 mJ/cm2) for 3 consecutive days and topically applied SOP. Sunburn cells were detected by using hematoxylin and eosin staining. Apoptotic cells were detected by using terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Cyclobutane pyrimidine dimers (CPDs), p53 protein, Bax protein, and Bcl‐2 protein were detected by using immunohistochemical staining. Results. Compared with UVB group, UVB‐irradiated skin with topically applied SOP showed significantly decreased EI. Compared with UVB group, topical SOP significantly increased Bcl‐2 protein expression and decreased CPDs‐positive cells, sunburn cells, apoptotic cells, p53 protein expression, and Bax protein expressions in the epidermis of UVB‐irradiated foreskin. Conclusion. Our study demonstrated that topical SOP can protect human skin against UVB‐induced photodamage.
Preparation of Nanosized LaCoO3through Calcination of a Hydrothermally Synthesized Precursor
Authors: Tepech-Carrillo L. , Escobedo-Morales A. , Pérez-Centeno A. , Chigo-Anota E. , Sánchez-Ramírez J. F. , López-Apreza E. , Gutiérrez-Gutiérrez J.
Published: July 2016

A method for obtaining nanosized LaCoO3crystals from calcination of a precursor powder synthesized by a hydrothermal route is reported. Details concerning the evolution of the microstructure and formation mechanism of the perovskite phase were studied by powder X-ray diffraction, scanning electron microscopy, energy dispersive X-ray spectroscopy, Raman spectroscopy, and thermal analysis. It was found that the morphology of the sample progressively turns from a mix of fibers and rods to interconnected nanocrystals. It is determined that LaCoO3phase is produced by a reaction of cobalt and lanthanum oxides, the latter produced by a two-step dehydration process of La(OH)3. Finally, it was found that nearly stoichiometric LaCoO3nanocrystals can be obtained at temperatures as low as 850°C. Nevertheless, whether higher calcination temperatures are used, appropriate reaction times and a controlled atmosphere are required in order to avoid formation of lanthanum carbonates and high density of lattice defects.
Demographics and Personality Factors Associated with Burnout among Nurses in a Singapore Tertiary Hospital
Authors: Ang Shin Yuh , Dhaliwal Satvinder S. , Ayre Tracy Carol , Uthaman Thendral , Fong Kuan Yok , Tien Choo Eng , Zhou Huaqiong , Della Phillip
Published: July 2016

Background. The aim of the study was to evaluate the prevalence and extent of burnout among nurses in Singapore and investigate the influence of demographic factors and personal characteristics on the burnout syndrome.Methods. A cross-sectional survey design was adopted. All registered nurses working in Singapore General Hospital were approached to participate. A questionnaire eliciting data on demographics, burnout (measured using the Maslach Burnout Inventory, MBI), and personality profile (measured using the NEO Five-Factor Inventory, NEO-FFI) was used.Results. 1830 nurses out of 3588 responded (response rate: 51%). Results from 1826 respondents were available for analysis. The MBI identified 39% to have high emotional exhaustion (EE, cut-off score of >27), 40% having high depersonalization (DP, cut-off score of >10), and 59% having low personal accomplishment (PA, cut-off score of <33). In multivariable analysis, age, job grade, and neuroticism were significantly associated with each of the 3 components of the MBI. Staff nurses less than 30 years with high to very high neuroticism were more likely to experience high EE, high DP, and low PA.Conclusion. Younger nurses in Singapore are at increased risk of burnout. Personality traits also played a significant role in the experience of burnout.
Interferon-Gamma Improves Macrophages Function against M. tuberculosis in Multidrug-Resistant Tuberculosis Patients
Authors: Khan Taj Ali , Mazhar Humaira , Saleha Shamim , Tipu Hamid Nawaz , Muhammad Niaz , Abbas Muhammad Nasser
Published: July 2016

Background. Mycobacterium tuberculosis (M. tuberculosis) that causes tuberculosis (TB) kills millions of infected people annually especially multidrug-resistant tuberculosis (MDR-TB). On infection, macrophages recognize the mycobacteria by toll-like receptor (TLR) followed by phagocytosis and control of mycobacteria. In addition, macrophages also secrete IL-12 to induce IFN-γ production by T, which, in turn, increases the phagocytosis and oxidative burst. Individuals with defects in innate or adaptive immunity exhibit increased susceptibility to M. tuberculosis. Understanding these immunologic mechanisms will help in TB control. We aimed to investigate the immunopathologic mechanisms in MDR-TB and role of recombinant human interferon-gamma (rhIFN-γ). Study Design and Methods. Monocyte-derived macrophages (MDMs) were generated from peripheral blood mononuclear cells of MDR-TB patients and healthy subjects and were investigated for immunologic response by ELISA and flow cytometry. Results. Different functional and molecular anomalies were observed in macrophages. In addition, a defective immune response to M. tuberculosis from the patient’s MDMs was characterized, which in turn improved by pretreatment with rhIFN-γ. Conclusion. This work highlights the fact that rhIFN-γ improves macrophages function against M. tuberculosis and treatment of patients with poor responsiveness to TB therapy may be needed in future to include IFN-γ as adjuvant therapy after the full characterization of pathological and molecular mechanisms in these and in other more multidrug-resistant TB patients.
Corticotropin-Releasing Factor and Toll-Like Receptor Gene Expression Is Associated with Low-Grade Inflammation in Irritable Bowel Syndrome Patients with Depression
Authors: Jizhong Song , Qiaomin Wang , Chao Wang , Yanqing Li
Published: July 2016

The mechanism of low-grade inflammation in irritable bowel syndrome (IBS) is unclear; our research concentrates on the involvement of the corticotropin-releasing factor (CRF) and Toll-like receptor (TLR) gene expression in the process of low-grade inflammation in IBS patients with depression. This study suggests more IBS patients are presenting with the states of depression and anxiety. IBS patients with depression have shown a lower grade inflammatory response and an imbalance of the inflammatory response. CRF1, CRF2, TLR2, and TLR4 in IBS patients with depression are significantly higher than those without depression and controls. Thus, activation of the CRF-TLR associated pathways produces an inflammatory reaction, which can concurrently affect the digestive tract and the CNS and induce the corresponding digestive and psychiatric symptoms.
Chaos Control on a Duopoly Game with Homogeneous Strategy
Authors: Bai Manying , Gao Yazhou
Published: July 2016

We study the dynamics of a nonlinear discrete-time duopoly game, where the players have homogenous knowledge on the market demand and decide their outputs based on adaptive expectation. The Nash equilibrium and its local stability are investigated. The numerical simulation results show that the model may exhibit chaotic phenomena. Quasiperiodicity is also found by setting the parameters at specific values. The system can be stabilized to a stable state by using delayed feedback control method. The discussion of control strategy shows that the effect of both firms taking control method is better than that of single firm taking control method.
An Exhaustive Study of Possibility Measures of Interval-Valued Intuitionistic Fuzzy Sets and Application to Multicriteria Decision Making
Authors: Dammak Fatma , Baccour Leila , Alimi Adel M.
Published: July 2016

This work is interested in showing the importance of possibility theory in multicriteria decision making (MCDM). Thus, we apply some possibility measures from literature to the MCDM method using interval-valued intuitionistic fuzzy sets (IVIFSs). These measures are applied to a decision matrix after being transformed with aggregation operators. The results are compared between each other and concluding remarks are drawn.
Evaluation of the Degradation on a COTS Linear CCD Induced by Total Ionizing Dose Radiation Damage
Authors: Wang Zujun , He Baoping , Ma Wuying , Yao Zhibin , Huang Shaoyan , Liu Minbo , Sheng Jiangkun
Published: July 2016

The evaluation of the degradation on a COTS linear Charge Coupled Device (CCD) induced by total ionizing dose (TID) radiation damage was presented. The radiation experiments were carried out at a60Coγ-ray source. The parameters of DALSA’s linear CCD were measured at the CCD test systems as the EMVA1288 standard before and after the radiation. The dark current, dark signal nonuniformity (DSNU), photo response nonuniformity (PRNU), saturation output, full-well capacity (FWC), quantum efficiency (QE), and responsivity versus the TID were analyzed. The behavior of the tested CCD had shown a remarkable degradation after radiation. The degradation mechanisms of the CCD induced by TID damage were also discussed.
Maxillofacial Changes in Melnick-Needles Syndrome
Authors: Albuquerque do Nascimento Leilane Larissa , Salgueiro Monica da Consolação Canuto , Quintela Mariana , Teixeira Victor Perez , Mota Ana Carolina Costa , Godoy Camila Haddad Leal de , Bussadori Sandra Kalil
Published: July 2016

Background. Melnick-Needles Syndrome is rare congenital hereditary skeletal dysplasia caused by mutations in the FLNA gene, which codifies the protein filamin A. This condition leads to serious skeletal abnormalities, including the stomatognathic region.Case Presentation. This paper describes the case of a 13-year-old girl diagnosed with Melnick-Needles Syndrome presenting with different forms of skeletal dysplasia, such as cranial hyperostosis, short upper limbs, bowed long bones, metaphyseal thickening, genu valgum (knock-knee), shortened distal phalanges, narrow pelvis and shoulders, rib tapering and irregularities, elongation of the vertebrae, kyphoscoliosis, micrognathia, hypoplastic coronoid processes of the mandible, left stylohyoid ligament suggesting ossification, and dental development anomalies.Conclusion. Knowledge of this rare syndrome on the part of dentists is important due to the fact that this condition involves severe abnormalities of the stomatognathic system that cause an impact on the development of the entire face as well as functional and esthetic impairments.
Tumor-Induced NETosis as a Risk Factor for Metastasis and Organ Failure
Authors: Cedervall Jessica , Zhang Yanyu , Olsson Anna-Karin
Published: July 2016

A large proportion of cancer-related deaths are caused by thrombosis and general organ failure. One example is acute renal failure, a major cause of morbidity and mortality in cancer patients. Surprisingly, however, little is known about the situation in organs that are not targets for metastasis or affected by the primary tumor. Recently, neutrophil extracellular traps (NET) were implicated in tumor-induced effects on distant organs unaffected by the actual tumor cells. Formation of NETs (NETosis) was identified a decade ago as a mechanism by which the innate immune system protects us from infections, especially in situations with sepsis. NETs are formed when neutrophils externalize their nuclear DNA together with antimicrobial granule proteins and form a web-like structure that can trap and kill microbes. It is now becoming increasingly clear that NETs also form under noninfectious inflammatory conditions like cancer, thrombosis, autoimmunity, and diabetes and significantly contribute to disease development. The existence of NET-dissolving drugs like heparin and DNase I, already in clinical use, and recent development of specific inhibitors of protein-arginine deiminase 4 (PAD4), an enzyme required for NET formation, should enable clinical targeting of NETosis. Preventing NETosis in cancer could provide a strategy to counteract tumor-induced thrombosis and organ failure as well as to suppress metastasis. Cancer Res; 76(15); 4311–5. ©2016 AACR.
RPL23 Links Oncogenic RAS Signaling to p53-Mediated Tumor Suppression
Authors: Meng Xuan , Tackmann Nicole R. , Liu Shijie , Yang Jing , Dong Jiahong , Wu Congying , Cox Adrienne D. , Zhang Yanping
Published: July 2016

The ribosomal protein (RP)–MDM2 interaction is a p53 response pathway critical for preventing oncogenic c-MYC–induced tumorigenesis. To investigate whether the RP-MDM2-p53 pathway is a broad antioncogenic mechanism, we crossed mice bearing an MDM2C305F mutation, which disrupts RPL11 binding to MDM2, with mice expressing an oncogenic HrasG12V transgene. Interestingly, the MDM2C305F-mutant mice, which are hypersensitive to c-MYC–induced tumorigenesis, are not hypersensitive to oncogenic HrasG12V-induced tumorigenesis. Unlike c-MYC, which induces expression of RPL11, RAS overexpression leads to an increase in RPL23 mRNA and protein whereas RPL11 expression remains unchanged. The induction of RPL23 involves both MEK and PI3K signaling pathways and requires mTOR function. Increased expression of RPL23, which maintains binding to MDM2C305F mutant, correlates with increased p53 expression in MDM2C305F cells. Furthermore, RAS overexpression can induce p53 in the absence of p19ARF, and the induction can be abolished by downregulation of RPL23. Thus, although the RPL11–MDM2–p53 pathway coordinates with the p19ARF–MDM2–p53 pathway against oncogenic c-MYC–induced tumorigenesis, the RPL23–MDM2–p53 pathway coordinates with the p19ARF–MDM2–p53 pathway against oncogenic RAS-induced tumorigenesis. Cancer Res; 76(17); 5030–9. ©2016 AACR.
HTLV-1 Viral Factor HBZ Induces CCR4 to Promote T-cell Migration and Proliferation
Authors: Sugata Kenji , Yasunaga Jun-ichirou , Kinosada Haruka , Mitobe Yuichi , Furuta Rie , Mahgoub Mohamed , Onishi Chiho , Nakashima Kazutaka , Ohshima Koichi , Matsuoka Masao
Published: July 2016

Human T-cell leukemia virus type 1 (HTLV-1) causes adult T-cell leukemia-lymphoma (ATL) and other inflammatory diseases in infected individuals. However, a complete understanding of how HTLV-1 transforms T cells is lacking. Expression of the chemokine receptor CCR4 on ATL cells and HTLV-1–infected cells suggested the hypothesis that CCR4 may mediate features of ATL and inflammatory diseases caused by HTLV-1. In this study, we show that the constitutively expressed HTLV-1 bZIP factor (HBZ) encoded by HTLV-1 is responsible for inducing CCR4 and its ability to promote T-cell proliferation and migration. Ectopic expression of HBZ was sufficient to stimulate expression of CCR4 in human and mouse T cells. Conversely, HBZ silencing in ATL cell lines was sufficient to inhibit CCR4 expression. Mechanistic investigations showed that HBZ induced GATA3 expression in CD4+ T cells, thereby activating transcription from the CCR4 promoter. In an established air pouch model of ATL, we observed that CD4+ T cells of HBZ transgenic mice (HBZ-Tg mice) migrated preferentially to the pouch, as compared with those in nontransgenic mice. Migration of CD4+ T cells in HBZ-Tg mice was inhibited by treatment with a CCR4 antagonist. Proliferating (Ki67+) CD4+ T cells were found to express high levels of CCR4 and CD103. Further, CD4+ T-cell proliferation in HBZ-Tg mice was enhanced by coordinate treatment with the CCR4 ligands CCL17 and 22 and with the CD103 ligand E-cadherin. Consistent with this finding, we found that ATL cells in clinical skin lesions were frequently positive for CCR4, CD103, and Ki67. Taken together, our results show how HBZ activates CCR4 expression on T cells to augment their migration and proliferation, two phenomena linked to HTLV-1 pathogenesis. Cancer Res; 76(17); 5068–79. ©2016 AACR.
BATON-CRC: A Phase II Randomized Trial Comparing Tivozanib Plus mFOLFOX6 with Bevacizumab Plus mFOLFOX6 in Stage IV Metastatic Colorectal Cancer
Authors: Benson Al B. , Kiss Igor , Bridgewater John , Eskens Ferry A.L.M. , Sasse Carolyn , Vossen Sandra , Chen Jihong , Van Sant Chip , Ball Howard A. , Keating Anne , Krivoshik Andrew
Published: July 2016

Purpose: Tivozanib, a selective inhibitor of VEGFR-1, -2, and -3, plus mFOLFOX6 in an advanced gastrointestinal cancer phase Ib study had encouraging antineoplastic activity and a tolerable safety profile. This randomized, open-label, phase II trial of tivozanib/mFOLFOX6 versus bevacizumab/mFOLFOX6 in patients with previously untreated metastatic colorectal cancer (mCRC) evaluated tivozanib activity versus bevacizumab.

Experimental Design: Treatment-naïve patients received mFOLFOX6 every 2 weeks of each 28-day cycle plus either tivozanib orally 1.5 mg once daily for 21 days or bevacizumab intravenously 5 mg/kg every 2 weeks. Investigator-assessed progression-free survival (PFS) was the primary endpoint; some secondary endpoints included safety, overall survival, overall response rate (ORR), duration of response, time to treatment failure, and biomarker subgroup analyses.

Results: A prespecified interim futility analysis demonstrated that the futility boundary for superiority of tivozanib/mFOLFOX6 over bevacizumab/mFOLFOX6 for PFS in the intent-to-treat population was crossed; median PFS was 9.4 versus 10.7 months [HR = 1.091; confidence interval (CI), 0.693–1.718; P = 0.706]. Tivozanib/mFOLFOX6 resulted in PFS and ORR comparable with bevacizumab/mFOLFOX6; interim analyses biomarker results revealed no significant PFS association. Post hoc final analyses demonstrated a potential difference in tivozanib-specific PFS in patients with low neuropilin-1 (NRP-1), but not in patients with high NRP-1. Tivozanib/mFOLFOX6 was tolerable and adverse events were comparable with both bevacizumab/mFOLFOX6 and previous tivozanib studies.

Conclusions: The efficacy of tivozanib/mFOLFOX6 was comparable with but not superior to bevacizumab/mFOLFOX6 in patients with previously untreated mCRC. Since data from the prespecified interim analysis did not demonstrate superiority, this resulted in discontinuation of the study. The safety and tolerability profile of tivozanib/mFOLFOX6 was consistent with other tivozanib trials. NRP-1 is a potential predictive biomarker for tivozanib activity, but these results require further validation. Clin Cancer Res; 22(20); 5058–67. ©2016 AACR.
Expression of Vascular Endothelial Growth Factor in Ovarian Cancer Inhibits Tumor Immunity through the Accumulation of Myeloid-Derived Suppressor Cells
Authors: Horikawa Naoki , Abiko Kaoru , Matsumura Noriomi , Hamanishi Junzo , Baba Tsukasa , Yamaguchi Ken , Yoshioka Yumiko , Koshiyama Masafumi , Konishi Ikuo
Published: July 2016

Purpose: High VEGF expression in ovarian cancer is an unfavorable prognostic factor. However, the role of VEGF in tumor immunity remains unclear. Here, we examined the impact of VEGF on local immunity, including induction of myeloid-derived suppressor cells (MDSC), in ovarian cancer.

Experimental Design: High-grade serous ovarian cancer (HGSOC) cases were analyzed by gene expression microarray and IHC for VEGF, CD8, and CD33. VEGF receptor (VEGFR) 1 and VEGFR2 expression levels on MDSCs were analyzed in a mouse model, and the direct effects of VEGF-A on MDSC expansion were investigated. Gr1+ MDSCs and lymphocyte frequencies were analyzed in control tumors and tumors derived from cells harboring short hairpin RNA targeting Vegf-a. In addition, the therapeutic effects of anti-Gr-1 antibodies were examined.

Results: Microarray analysis revealed the upregulation of several myeloid cell chemoattractants and the downregulation of lymphocyte-related pathways in cases with high VEGF expression. In immunohistochemical analysis, VEGF expression in peritoneal dissemination correlated with MDSC infiltration. Cases with high MDSC infiltration, which was inversely correlated with intratumoral CD8+ T-cell infiltration, exhibited shorter overall survival. In a mouse model, intratumoral MDSCs expressed both VEGFR1 and VEGFR2. MDSC migration and differentiation were augmented by VEGF signaling. Vegf-a knockdown in tumor cells resulted in decreased MDSC infiltration and increased CD8+ T-cell infiltration. Moreover, treatment with anti-Gr-1 antibodies delayed the growth of control tumors, whereas Vegf-a-knockdown tumors were unaffected by anti-Gr-1 antibody treatment.

Conclusions: VEGF expression in ovarian cancer induced MDSCs, inhibited local immunity, and contributed to poor prognosis. Clin Cancer Res; 23(2); 587–99. ©2016 AACR.
Endothelial Nitric Oxide Synthase Traffic Inducer (NOSTRIN) is a Negative Regulator of Disease Aggressiveness in Pancreatic Cancer
Authors: Wang Jian , Yang Shouhui , He Peijun , Schetter Aaron J. , Gaedcke Jochen , Ghadimi B. Michael , Ried Thomas , Yfantis Harris G. , Lee Dong H. , Gaida Matthias M. , Hanna Nader , Alexander H. Richard , Hussain S. Perwez
Published: July 2016

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is refractory to available treatments. Delineating critical pathways, responsible for disease aggressiveness and therapeutic resistance, may identify effective therapeutic targets. We aimed to identify key pathways contributing to disease aggressiveness by comparing gene expression profiles of tumors from early-stage PDAC cases with extremely poor survival (≤7 months) and those surviving 2 years or more following surgical resection.

Experimental Design: Gene expression profiling was performed in tumors in a test cohort of PDAC (N = 50), which included short (≤7 months, N = 11) and long surviving (≥2 years, N = 14) patients, using affymetrix GeneChip Human 1.0 ST array. Key genes associated with disease aggressiveness were identified, using Cox regression, Kaplan–Meier, and pathway analyses with validations in independent cohorts for mechanistic and functional analyses.

Results: Gene expression profiling identified 1,820 differentially expressed genes between short and long survival groups with inflammatory gene network ranking first. Lower expression of endothelial nitric oxide synthase traffic inducer (NOSTRIN) was associated with worst survival indicating its potential inhibitory role in disease progression. NOSTRIN overexpression suppressed migration and invasion of pancreatic cancer cells and enhanced sensitivity to chemotherapeutic drug gemcitabine. NOSTRIN inhibited production of nitric oxide (NO) by suppressing the activation of endothelial nitric oxide synthase (eNOS). Furthermore, miR-221, bound to the 3′UTR of NOSTRIN and suppressed its expression, and an increased miR-221 expression associated with poor survival in PDAC.

Conclusions: Our findings showed that NOSTRIN is a potential negative regulator of disease aggressiveness, which may be targeted for designing improved treatment strategy in PDAC. Clin Cancer Res; 22(24); 5992–6001. ©2016 AACR.
FDA Approval: Uridine Triacetate for the Treatment of Patients Following Fluorouracil or Capecitabine Overdose or Exhibiting Early-Onset Severe Toxicities Following Administration of These Drugs
Authors: Ison Gwynn , Beaver Julia A. , McGuinn W. David , Palmby Todd R. , Dinin Jeannette , Charlab Rosane , Marathe Anshu , Jin Runyan , Liu Qi , Chen Xiao Hong , Ysern Xavier , Stephens Olen , Bai Ge , Wang Yaning , Dorff Sarah E. , Cheng Joyce , Tang Shenghui , Sridhara Rajeshwari , Pierce William , McKee Amy E. , Ibrahim Amna , Kim Geoffrey , Pazdur Richard
Published: July 2016

On December 11, 2015, the FDA approved uridine triacetate (VISTOGARD; Wellstat Therapeutics Corporation) for the emergency treatment of adult and pediatric patients following a fluorouracil or capecitabine overdose regardless of the presence of symptoms, and of those who exhibit early-onset, severe, or life-threatening toxicity affecting the cardiac or central nervous system, and/or early onset, unusually severe adverse reactions (e.g., gastrointestinal toxicity and/or neutropenia) within 96 hours following the end of fluorouracil or capecitabine administration. Uridine triacetate is not recommended for the nonemergent treatment of adverse reactions associated with fluorouracil or capecitabine because it may diminish the efficacy of these drugs, and the safety and efficacy of uridine triacetate initiated more than 96 hours following the end of administration of these drugs has not been established. The approval is based on data from two single-arm, open-label, expanded-access trials in 135 patients receiving uridine triacetate (10 g or 6.2 g/m2 orally every 6 hours for 20 doses) for fluorouracil or capecitabine overdose, or who exhibited severe or life-threatening toxicities within 96 hours following the end of fluorouracil or capecitabine administration. Ninety-six percent of patients met the major efficacy outcome measure, which was survival at 30 days or survival until the resumption of chemotherapy, if prior to 30 days. The most common adverse reactions were vomiting, nausea, and diarrhea. This article summarizes the FDA review of this New Drug Application, the data supporting approval of uridine triacetate, and the unique regulatory situations encountered by this approval. Clin Cancer Res; 22(18); 4545–49. ©2016 AACR.
Dysregulation of EGFR Pathway in EphA2 Cell Subpopulation Significantly Associates with Poor Prognosis in Colorectal Cancer
Authors: De Robertis Mariangela , Loiacono Luisa , Fusilli Caterina , Poeta Maria Luana , Mazza Tommaso , Sanchez Massimo , Marchionni Luigi , Signori Emanuela , Lamorte Giuseppe , Vescovi Angelo Luigi , Garcia-Foncillas Jesus , Fazio Vito Michele
Published: July 2016

Purpose: EphA2 receptor is involved in multiple cross-talks with other cellular networks, including EGFR, FAK, and VEGF pathways, with which it collaborates to stimulate cell migration, invasion, and metastasis. Colorectal cancer (CRC) EphA2 overexpression has also been correlated to stem-like properties of cells and tumor malignancy. We investigated the molecular cross-talk and miRNAs modulation of the EphA2 and EGFR pathways. We also explored the role of EphA2/EGFR pathway mediators as prognostic factors or predictors of cetuximab benefit in patients with CRC.

Experimental Design: Gene expression analysis was performed in EphA2high cells isolated from CRC of the AOM/DSS murine model by FACS-assisted procedures. Six independent cohorts of patients were stratified by EphA2 expression to determine the potential prognostic role of a EphA2/EGFR signature and its effect on cetuximab treatment response.

Results: We identified a gene expression pattern (EphA2, Efna1, Egfr, Ptpn12, and Atf2) reflecting the activation of EphA2 and EGFR pathways and a coherent dysregulation of mir-26b and mir-200a. Such a pattern showed prognostic significance in patients with stage I–III CRC, in both univariate and multivariate analysis. In patients with stage IV and WT KRAS, EphA2/Efna1/Egfr gene expression status was significantly associated with poor response to cetuximab treatment. Furthermore, EphA2 and EGFR overexpression showed a combined effect relative to cetuximab resistance, independently from KRAS mutation status.

Conclusions: These results suggest that EphA2/Efna1/Egfr genes, linked to a possible control by miR-200a and miR-26b, could be proposed as novel CRC prognostic biomarkers. Moreover, EphA2 could be linked to a mechanism of resistance to cetuximab alternative to KRAS mutations. Clin Cancer Res; 23(1); 159–70. ©2016 AACR.
Tumor-associated Lymphatic Endothelial Cells Promote Lymphatic Metastasis By Highly Expressing and Secreting SEMA4C
Authors: Wei Jun-Cheng , Yang Jie , Liu Dan , Wu Ming-Fu , Qiao Long , Wang Jun-Nai , Ma Quan-Fu , Zeng Zhen , Ye Shuang-Mei , Guo En-Song , Jiang Xue-Feng , You Lan-Ying , Chen Ying , Zhou Li , Huang Xiao-Yuan , Zhu Tao , Meng Li , Zhou Jian-Feng , Feng Zuo-Hua , Ma Ding , Gao Qing-Lei
Published: July 2016

Purpose: Lymphatic vessels are mainly regarded as passive conduits for the dissemination of cancer cells. In this study, we investigate whether and how the tumor-associated lymphatic vessels may play an active role in tumor metastasis.

Experimental Design: In situ laser capture microdissection of lymphatic vessels followed by cDNA microarray analysis was used to determine the expression profiling of lymphatic endothelial cells (LEC). Gene expression levels and activity of signaling pathways were measured by real-time RT-PCR, ELISA, or immunoblotting. Lymphangiogenesis was assessed by IHC. Lymph node metastasis was measured using fluorescence imaging. The effects of SEMA4C on lymphangiogenesis in vitro were evaluated using migration assay and tube-formation assay of LECs.

Results: Tumor-associated LECs are molecularly and functionally different from their normal counterparts. In addition to expressing high levels of membrane-bound SEMA4C, tumor-associated LECs also produced soluble SEMA4C (sSEMA4C). Increased serum sSEMA4C was detected in patients with breast cancer and cervical cancer. Patients with metastasis had much higher levels of serum sSEMA4C. sSEMA4C promoted lymphangiogenesis by activating PlexinB2-ERBB2 signaling in LECs, and promoted the proliferation and migration of tumor cells by activating PlexinB2-MET signaling, thus promoting lymphatic metastasis. Although the SEMA4C signaling pathways differ between LECs and tumor cells, RHOA activation was necessary for the effects of SEMA4C in both types of cells.

Conclusions: Tumor-associated LECs produce sSEMA4C to promote lymphatic metastasis of tumors. Our results suggest that SEMA4C and RHOA might be potential therapeutic targets, and that higher serum sSEMA4C could be a marker for breast cancer and cervical cancer. Clin Cancer Res; 23(1); 214–24. ©2016 AACR.
Integrated Analysis of Multiple Biomarkers from Circulating Tumor Cells Enabled by Exclusion-Based Analyte Isolation
Authors: Sperger Jamie M. , Strotman Lindsay N. , Welsh Allison , Casavant Benjamin P. , Chalmers Zachery , Horn Sacha , Heninger Erika , Thiede Stephanie M. , Tokar Jacob , Gibbs Benjamin K. , Guckenberger David J. , Carmichael Lakeesha , Dehm Scott M. , Stephens Philip J. , Beebe David J. , Berry Scott M. , Lang Joshua M.
Published: July 2016

Purpose: There is a critical clinical need for new predictive and pharmacodynamic biomarkers that evaluate pathway activity in patients treated with targeted therapies. A microscale platform known as VERSA (versatile exclusion-based rare sample analysis) was developed to integrate readouts across protein, mRNA, and DNA in circulating tumor cells (CTC) for a comprehensive analysis of the androgen receptor (AR) signaling pathway.

Experimental Design: Utilizing exclusion-based sample preparation principles, a handheld chip was developed to perform CTC capture, enumeration, quantification, and subcellular localization of proteins and extraction of mRNA and DNA. This technology was validated across integrated endpoints in cell lines and a cohort of patients with castrate-resistant prostate cancer (CRPC) treated with AR-targeted therapies and chemotherapies.

Results: The VERSA was validated in cell lines to analyze AR protein expression, nuclear localization, and gene expression targets. When applied to a cohort of patients, radiographic progression was predicted by the presence of multiple AR splice variants and activity in the canonical AR signaling pathway. AR protein expression and nuclear localization identified phenotypic heterogeneity. Next-generation sequencing with the FoundationOne panel detected copy number changes and point mutations. Longitudinal analysis of CTCs identified acquisition of multiple AR variants during targeted treatments and chemotherapy.

Conclusions: Complex mechanisms of resistance to AR-targeted therapies, across RNA, DNA, and protein endpoints, exist in patients with CRPC and can be quantified in CTCs. Interrogation of the AR signaling pathway revealed distinct patterns relevant to tumor progression and can serve as pharmacodynamic biomarkers for targeted therapies. Clin Cancer Res; 23(3); 746–56. ©2016 AACR.
Gas1 Inhibits Metastatic and Metabolic Phenotypes in Colorectal Carcinoma
Authors: Li Qingguo , Qin Yi , Wei Ping , Lian Peng , Li Yaqi , Xu Ye , Li Xinxiang , Li Dawei , Cai Sanjun
Published: July 2016

Growth arrest–specific 1 (Gas1) plays a critical role in growth suppression. Previous study indicated that Gas1 was closely associated with survival in patients with colorectal cancer; however, the underlying molecular mechanism remains unclear. In this study, we sought to determine the role of Gas1 in tumorigenesis and metastasis, and elucidate the possible mechanism. First, Gas1 was determined as a negative regulator of oncogenesis and metastasis in colorectal cancer. Mechanistically, Gas1 negatively regulated the aerobic glycolysis, a process that contributed to tumor progression and metastasis by providing energy source and building blocks for macromolecule synthesis. To further consolidate the role of Gas1 in glycolysis, the impact of Gas1 in the transcription of key glycolytic enzymes for glucose utilization was examined. As expected, GLUT4, HK2, and LDHB exhibited a decreased expression pattern. Consistent with this observation, an in vivo subcutaneous xenograft mouse model also confirmed the hypothesis that Gas1 is a negative regulator of glycolysis as reflected by the decreased 18FDG uptake in PET/CT system. Moreover, Gas1 negatively regulated the AMPK/mTOR/p70S6K signaling axis, a well-established cascade that regulates malignant cancer cell behaviors including proliferation, metastasis, and aberrant cancer metabolism. In the end, it was determined that Gas1 is a transcriptional target of FOXM1, whose role in colorectal cancer has been widely studied. Taken together, these studies establish Gas1 as a negative regulator in colorectal cancer.

Implications: Gas1 suppresses cell proliferation, invasion, and aerobic glycolysis of colorectal cancer both in vitro and in vivo. Mechanistically, Gas1 inhibited EMT and the Warburg effect via AMPK/mTOR/p70S6K signaling, and Gas1 itself was directly regulated by the transcription factor FOXM1. Mol Cancer Res; 14(9); 830–40. ©2016 AACR.
Renal Function Predicts Outcomes in Patients with Ischaemic Stroke and Haemorrhagic Stroke
Authors: Snarska Katarzyna , Kapica-Topczewska Katarzyna , Bachórzewska-Gajewska Hanna , Małyszko Jolanta
Published: July 2016

Background/Aims: We evaluated renal function and the impact of renal function on in-hospital outcomes in patients with ischaemic and haemorrhagic stroke. Methods: We collected data from 766 patients with stroke; 637 (83.2 %) with ischaemic and 129 with haemorrhagic one. Results: The mean serum creatinine on admission in patients with both types of stroke, who died, was significantly higher than in those who survived. Multivariate analysis showed that independent predictors of mortality in patients with ischaemic stroke were: ischemic heart disease or prior myocardial infarction, diabetes, admission glucose and eGFR on admission. Also, multivariate analysis showed that independent predictors of mortality in patients with haemorrhagic stroke were: age and admission glucose. Conclusions: Patients with haemorrhagic stroke, in particular with acute kidney injury during hospitalisation had significantly worse outcomes than patients with ischaemic stroke. Assessment of kidney function is prerequisite to employ the necessary measures to decrease the risk of in-hospital mortality among patients with acute stroke. Appropriate approach to patients with renal dysfunction (adequate hydration, avoidance of nephrotoxic drugs, drug dose adjustment etc) should be considered as preventive and therapeutic strategies in the management of acute stroke.
Risk of Ophthalmic Adverse Effects in Patients Treated with MEK Inhibitors: A Systematic Review and Meta-Analysis
Authors: Alves Carlos , Ribeiro Inês , Penedones Ana , Mendes Diogo , Batel Marques Francisco
Published: July 2016

Objectives: This meta-analysis aims to evaluate the risk of ophthalmic adverse effects associated with MEK inhibitors. Methods: A literature search was conducted in PubMed and the Cochrane Library to identify randomized clinical trials (RCTs) which have been designed to evaluate the efficacy and safety of MEK inhibitors. Overall risk of ophthalmic adverse effects, chorioretinopathy, retinal detachment, blurred vision, uveitis, and eye haemorrhage were the assessed outcomes. Peto odds ratios (ORs) with their 95% confidence intervals (CIs) were pooled. Between-study heterogeneity was assessed using I2 statistics. Results: Thirteen RCTs were included in this meta-analysis. Overall, MEK inhibitors were associated with an increased risk of ophthalmic adverse effects (OR 2.24; 95% CI 1.75-2.87; p < 0.0001; I2 = 86.5%). An increased risk was also estimated for chorioretinopathy (OR 5.44; 95% CI 2.89-10.23; p < 0.0001; I2 = 0%), retinal detachment (OR 6.54; 95% CI 3.28-13.03; p < 0.0001; I2 = 0%), and blurred vision (OR 2.30; 95% CI 1.50-3.54; p < 0.0001; I2 = 60.1%), but not for uveitis (OR 0.99; 95% CI 0.14-7.03; p = 0.991; I2 = 2.9%) or eye haemorrhage (OR 0.72; 95% CI 0.04-12.39; p = 0.824; I2 = 29.8%). Conclusions: Treatment with MEK inhibitors seems to increase the risk of ophthalmic adverse effects. A need for monitoring the safety of this class of drugs exists. Regulators, clinicians, and other health care professionals must, together, be involved in this process.
Nodular Cutaneous Amyloidosis at the Temple
Authors: Schucht Kathrin , Schröder Josef , Siegmund Heiko , Grafe Claudia , Schreml Stephan
Published: July 2016

A 52-year-old woman presented with a large partially yellow and erythematous tumor on her right temple. She reported that it had grown over the last 4 years. Regional lymph nodes were impalpable. A punch biopsy showed eosinophilic material in the dermis and subcutis. Immunohistochemistry showed positive staining for kappa and lambda light chains. Electron microscopy showed the typical amyloid fibrils (7–10 nm in diameter). There was no evidence of systemic amyloidosis, paraproteinemia or underlying plasmacytoma. The tumor was completely removed via curettage. At follow-up, the patient presented in good health with no signs of relapse.
Clinical Trial of the Protein Farnesylation Inhibitors Lonafarnib, Pravastatin, and Zoledronic Acid in Children With Hutchinson-Gilford Progeria Syndrome
Authors: Gordon Leslie B. , Kleinman Monica E. , Massaro Joe , D’Agostino Ralph B. , Shappell Heather , Gerhard-Herman Marie , Smoot Leslie B. , Gordon Catherine M. , Cleveland Robert H. , Nazarian Ara , Snyder Brian D. , Ullrich Nicole J. , Silvera V. Michelle , Liang Marilyn G. , Quinn Nicolle , Miller David T. , Huh Susanna Y. , Dowton Anne A. , Littlefield Kelly , Greer Maya M. , Kieran Mark W.
Published: July 2016

Background:

Hutchinson-Gilford progeria syndrome is an extremely rare, fatal, segmental premature aging syndrome caused by a mutation in
LMNA
yielding the farnesylated aberrant protein progerin. Without progerin-specific treatment, death occurs at an average age of 14.6 years from an accelerated atherosclerosis. A previous single-arm clinical trial demonstrated that the protein farnesyltransferase inhibitor lonafarnib ameliorates some aspects of cardiovascular and bone disease. This present trial sought to further improve disease by additionally inhibiting progerin prenylation.

Methods:

Thirty-seven participants with Hutchinson-Gilford progeria syndrome received pravastatin, zoledronic acid, and lonafarnib. This combination therapy was evaluated, in addition to descriptive comparisons with the prior lonafarnib monotherapy trial.

Results:

No participants withdrew because of side effects. Primary outcome success was predefined by improved per-patient rate of weight gain or carotid artery echodensity; 71.0% of participants succeeded (
P
<0.0001). Key cardiovascular and skeletal secondary variables were predefined. Secondary improvements included increased areal (
P
=0.001) and volumetric (
P
<0.001–0.006) bone mineral density and 1.5- to 1.8-fold increases in radial bone structure (
P
<0.001). Median carotid artery wall echodensity and carotid-femoral pulse wave velocity demonstrated no significant changes. Percentages of participants with carotid (5% to 50%;
P
=0.001) and femoral (0% to 12%;
P
=0.13) artery plaques and extraskeletal calcifications (34.4% to 65.6%;
P
=0.006) increased. Other than increased bone mineral density, no improvement rates exceeded those of the prior lonafarnib monotherapy treatment trial.

Conclusions:

Comparisons with lonafarnib monotherapy treatment reveal additional bone mineral density benefit but likely no added cardiovascular benefit with the addition of pravastatin and zoledronic acid.

Clinical Trial Registration:

URL:
http://www.clinicaltrials.gov
. Unique identifiers: NCT00879034 and NCT00916747.