bluuebunny/crossref_metadata_2025 huggingface dataset:
Tumor Radiosensitization by Monomethyl Auristatin E: Mechanism of Action and Targeted Delivery
Authors: Buckel Lisa , Savariar Elamprakash N. , Crisp Jessica L. , Jones Karra A. , Hicks Angel M. , Scanderbeg Daniel J. , Nguyen Quyen T. , Sicklick Jason K. , Lowy Andrew M. , Tsien Roger Y. , Advani Sunil J.
Published: February 2015

Intrinsic tumor resistance to radiotherapy limits the efficacy of ionizing radiation (IR). Sensitizing cancer cells specifically to IR would improve tumor control and decrease normal tissue toxicity. The development of tumor-targeting technologies allows for developing potent radiosensitizing drugs. We hypothesized that the anti-tubulin agent monomethyl auristatin E (MMAE), a component of a clinically approved antibody-directed conjugate, could function as a potent radiosensitizer and be selectively delivered to tumors using an activatable cell-penetrating peptide targeting matrix metalloproteinases and RGD-binding integrins (ACPP–cRGD–MMAE). We evaluated the ability of MMAE to radiosensitize both established cancer cells and a low-passage cultured human pancreatic tumor cell line using clonogenic and DNA damage assays. MMAE sensitized colorectal and pancreatic cancer cells to IR in a schedule- and dose-dependent manner, correlating with mitotic arrest. Radiosensitization was evidenced by decreased clonogenic survival and increased DNA double-strand breaks in irradiated cells treated with MMAE. MMAE in combination with IR resulted in increased DNA damage signaling and activation of CHK1. To test a therapeutic strategy of MMAE and IR, PANC-1 or HCT-116 murine tumor xenografts were treated with nontargeted free MMAE or tumor-targeted MMAE (ACPP–cRGD–MMAE). While free MMAE in combination with IR resulted in tumor growth delay, tumor-targeted ACPP-cRGD-MMAE with IR produced a more robust and significantly prolonged tumor regression in xenograft models. Our studies identify MMAE as a potent radiosensitizer. Importantly, MMAE radiosensitization can be localized to tumors by targeted activatable cell-penetrating peptides. Cancer Res; 75(7); 1376–87. ©2015 AACR.
Stem Cell Transplantation Reverses Chemotherapy-Induced Cognitive Dysfunction
Authors: Acharya Munjal M. , Martirosian Vahan , Chmielewski Nicole N. , Hanna Nevine , Tran Katherine K. , Liao Alicia C. , Christie Lori-Ann , Parihar Vipan K. , Limoli Charles L.
Published: February 2015

The frequent use of chemotherapy to combat a range of malignancies can elicit severe cognitive dysfunction often referred to as “chemobrain,” a condition that can persist long after the cessation of treatment in as many as 75% of survivors. Although cognitive health is a critical determinant of therapeutic outcome, chemobrain remains an unmet medical need that adversely affects quality of life in pediatric and adult cancer survivors. Using a rodent model of chemobrain, we showed that chronic cyclophosphamide treatment induced significant performance-based decrements on behavioral tasks designed to interrogate hippocampal and cortical function. Intrahippocampal transplantation of human neural stem cells resolved all cognitive impairments when animals were tested 1 month after the cessation of chemotherapy. In transplanted animals, grafted cells survived (8%) and differentiated along neuronal and astroglial lineages, where improved cognition was associated with reduced neuroinflammation and enhanced host dendritic arborization. Stem cell transplantation significantly reduced the number of activated microglia after cyclophosphamide treatment in the brain. Granule and pyramidal cell neurons within the dentate gyrus and CA1 subfields of the hippocampus exhibited significant reductions in dendritic complexity, spine density, and immature and mature spine types following chemotherapy, adverse effects that were eradicated by stem cell transplantation. Our findings provide the first evidence that cranial transplantation of stem cells can reverse the deleterious effects of chemobrain, through a trophic support mechanism involving the attenuation of neuroinflammation and the preservation host neuronal architecture. Cancer Res; 75(4); 676–86. ©2015 AACR.
Stromal CD8+ T-cell Density—A Promising Supplement to TNM Staging in Non–Small Cell Lung Cancer
Authors: Donnem Tom , Hald Sigurd M. , Paulsen Erna-Elise , Richardsen Elin , Al-Saad Samer , Kilvaer Thomas K. , Brustugun Odd Terje , Helland Aslaug , Lund-Iversen Marius , Poehl Mette , Olsen Karen Ege , Ditzel Henrik J. , Hansen Olfred , Al-Shibli Khalid , Kiselev Yury , Sandanger Torkjel M. , Andersen Sigve , Pezzella Francesco , Bremnes Roy M. , Busund Lill-Tove
Published: February 2015

Purpose: Immunoscore is a prognostic tool defined to quantify in situ immune cell infiltrates, which appears to be superior to the tumor–node–metastasis (TNM) classification in colorectal cancer. In non–small cell lung cancer (NSCLC), no immunoscore has been established, but in situ tumor immunology is recognized as highly important. We have previously evaluated the prognostic impact of several immunological markers in NSCLC, yielding the density of stromal CD8+ tumor-infiltrating lymphocytes (TIL) as the most promising candidate. Hence, we validate the impact of stromal CD8+ TIL density as an immunoscore in NSCLC.

Experimental Design: The prognostic impact of stromal CD8+ TILs was evaluated in four different cohorts from Norway and Denmark consisting of 797 stage I–IIIA NSCLC patients. The Tromso cohort (n = 155) was used as training set, and the results were further validated in the cohorts from Bodo (n = 169), Oslo (n = 295), and Denmark (n = 178). Tissue microarrays and clinical routine CD8 staining were used for all cohorts.

Results: Stromal CD8+ TIL density was an independent prognostic factor in the total material (n = 797) regardless of the endpoint: disease-free survival (P < 0.001), disease-specific survival (P < 0.001), or overall survival (P < 0.001). Subgroup analyses revealed significant prognostic impact of stromal CD8+ TIL density within each pathologic stage (pStage). In multivariate analysis, stromal CD8+ TIL density and pStage were independent prognostic variables.

Conclusions: Stromal CD8+ TIL density has independent prognostic impact in resected NSCLC, adds prognostic impact within each pStage, and is a good candidate marker for establishing a TNM-Immunoscore. Clin Cancer Res; 21(11); 2635–43. ©2015 AACR.
Human Chorionic Gonadotropin Improves Endometriosis Through Downregulation of Leptin Expression in Rats
Authors: Wu Ling-Ling , Pang Rui-Ping , Yin Yu-Zhu , Shen Kai-Feng , Zhang Pei-Zhen
Published: February 2015

Objective: To investigate whether and how human chorionic gonadotropin (HCG) treatment ameliorates endometriosis in an endometriotic rat model. Methods: Twenty-four endometriosis rats were established and were randomly divided into four groups, and then the rats were treated with 19.4, 25.8, and 51.6 IU/100 g weight/day of HCG, respectively. The control group was treated with 0.9% NaCl. After 15 days (3 estrous cycles), the ectopic lesion volume and the expression of leptin protein in eutopic and ectopic endometrium were investigated. Results: After HCG treatment, the volumes of endometriotic lesions were significantly smaller than those before treatment. During endometriosis development, the expression of leptin protein in eutopic and ectopic endometrium was remarkably increased. HCG administration reversed leptin upregulation in endometriotic tissues. Conclusion: HCG therapy appears to be an effective treatment for endometriosis in rats through down-regulation of leptin expression in eutopic and ectopic endometrium.
Thrombotic Responses of Endothelial Outgrowth Cells to Protein-Coated Surfaces
Authors: Anderson Deirdre E.J. , McKenna Kathryn A. , Glynn Jeremy J. , Marzec Ulla , Hanson Stephen R. , Hinds Monica T.
Published: February 2015

There is significant clinical need for viable small-diameter vascular grafts. While there are many graft biomaterials in development, few have been clinically successful. Evaluation of grafts with a clinically relevant model is needed to drive development. This work examined extracellular matrix coatings on the thrombotic phenotype of endothelial outgrowth cells (EOCs). EOCs were tested on flat plates and tubular grafts. Flat plate studies examined collagen I, collagen IV, fibronectin and α-elastin coatings. EOCs attached or proliferated more readily on collagen I and fibronectin surfaces as determined by total DNA. The production of activated protein C (APC) by EOCs was also dependent on the surface coating, with collagen I and fibronectin displaying a higher activity than both collagen IV and α-elastin on flat plate studies. Based on these results, only collagen I and fibronectin coatings were tested on expanded polytetrafluoroethylene (ePTFE) in the ex vivo model. Tubular samples showed significantly greater tissue factor pathway inhibitor gene expression on collagen I than on fibronectin. Platelet adhesion was not significantly different, but EOCs on collagen I produced significantly lower APC than on fibronectin, suggesting that differences exist between the flat plate and tubular cultures. Overall, while the hemostatic phenotype of EOCs displayed some differences, cell responses were largely independent of the matrix coating. EOCs adhered strongly to both fibronectin- and collagen-I-coated ePTFE grafts under ex vivo (100 ml/min) flow conditions suggesting the usefulness of this clinically relevant cell source, testing modality, and shunt model for future work examining biomaterials and cell conditioning before implantation.
LRAT Overexpression Diminishes Intracellular Levels of Biologically Active Retinoids and Reduces Retinoid Antitumor Efficacy in the Murine Melanoma B16F10 Cell Line
Authors: Amann Philipp M. , Czaja Katharina , Bazhin Alexandr V. , Rühl Ralph , Eichmüller Stefan B. , Merk Hans F. , Baron Jens M.
Published: February 2015

Background/Aim: Vitamin A (all-trans-retinol, ATRol) serves as a precursor for all-trans-retinoic acid (ATRA), a ligand for the retinoic acid receptor (RAR), representing a potent regulator for many physiological processes. While murine melanoma cells are highly sensitive to retinoid treatment, human melanoma cells have developed still unidentified mechanisms that mediate cellular retinoid resistance. One of the key retinoid metabolizing enzymes is lecithin retinol acyltransferase (LRAT), which catalyzes the transformation of ATRol into inactive retinyl esters. LRAT is highly expressed in human melanoma cells. The aim of this study was to identify the mechanisms in retinol metabolism that are responsible for cellular retinoid sensitivity in the murine melanoma cell line B16F10. Methods: mRNA expression analysis, cell viability assessment and determination of intracellular retinoid levels using HPLC analysis of a generated LRAT-overexpressing B16F10 cell line compared to the control B16F10 cell line. Results: We found that the murine retinoid-sensitive B16F10 cell line does not express the enzyme LRAT. LRAT overexpression decreased the antiproliferative effects of retinoid treatment in these melanoma cells. The RAR-regulated enzyme Cyp26a1 showed a significantly lower expression in LRAT-overexpressing B16F10 cells. Cyp26a1 expression was restored after ATRA incubation. HPLC analysis revealed that the level of inactive retinyl ester increased after ATRol treatment, and levels of the substrate ATRol and biologically active ATRA significantly decreased in LRAT-overexpressing murine melanoma. Consistently with this, levels of 4-oxo-retinoic acid, an ATRA metabolite and Cyp26a1 product, were also decreased in LRAT-overexpressing cells. Conclusion: Our results revealed a direct link between LRAT expression and regulation of ATRA levels indicating that the absence of LRAT-catalyzed retinol esterification is important for mediating retinoid sensitivity in murine melanoma cells. Thus, our data suggest that LRAT overexpression represents a novel mechanism by which tumor cells can escape high supplementary ATRA levels that mediate tumor-suppressive RAR signaling.
HLA-B Alleles B*15:01 and B*15:02: Opposite Association with Hepatitis C Virus Infection in Chinese Voluntary Blood Donors
Authors: Xiong Huaping , Huang Jieting , Rong Xia , Zhang Ming , Huang Ke , Xu Ru , Wang Min , Li Chengyao , Liao Qiao , Xia Wenjie , Luo Guangping , Ye Xin , Lu Ling , Fu Yongshui , Guo Tai , Nelson Kenrad
Published: February 2015

Background: Although human leukocyte antigens (HLA) have been shown in association with the outcomes of hepatitis C virus (HCV) infection among different ethnic groups, such studies remain absent in China, where the HCV prevalence is higher than the global average. Methods: In this study, 426 HCV-infected and 709 uninfected blood donors were analyzed, among whom the HLA alleles were sequenced using a high-resolution genotyping method. Results: At the 2-digit level, none of the alleles showed a statistical difference between the HCV-infected and uninfected groups. However, at the 4-digit level, the HLA-B alleles B*15:01 and B*15:02 showed an opposite association with HCV infection, i.e. B*15:01 was significantly higher in the HCV-infected group (odds ratio, OR = 1.561, p = 0.010), while B*15:02 was significantly higher in the uninfected group (OR = 0.778, p = 0.016). We also identified a higher frequency of B*13:02 in the HCV-infected group (OR = 1.515, p = 0.009) and a higher frequency of B*07:05 in the uninfected group (OR = 0.299, p = 0.001). Conclusions: The frequencies of four HLA alleles, B*07:05, B*13:02, B*15:01, and B*15:02, were found to be significantly different between the HCV-infected and uninfected blood donors in China, revealing an inverse relation of B*15:01 and B*15:02 with HCV infection. This finding suggests that the ethnic genetic variations of HLA may greatly affect the host immune responses against HCV.
Chronic Obstructive Pulmonary Disease and Diabetes Mellitus: A Systematic Review of the Literature
Authors: Gläser Sven , Krüger Stefan , Merkel Martin , Bramlage Peter , Herth Felix J.F.
Published: February 2015

The objective of this systematic review was to discuss our current understanding of the complex relationship between chronic obstructive pulmonary disease (COPD) and type-2 diabetes mellitus (T2DM). We performed a systematic search of the literature related to both COPD and diabetes using PubMed. Relevant data connecting both diseases were compiled and discussed. Recent evidence suggests that diabetes can worsen the progression and prognosis of COPD; this may result from the direct effects of hyperglycemia on lung physiology, inflammation or susceptibility to bacterial infection. Conversely, it has also been suggested that COPD increases the risk of developing T2DM as a consequence of inflammatory processes and/or therapeutic side effects related to the use of high-dose corticosteroids. In conclusion, although there is evidence to support a connection between COPD and diabetes, additional research is needed to better understand these relationships and their possible implications.
Prognostic Factors for the Selection of Patients Eligible for Second-Line Chemotherapy in Advanced Biliary Tract Cancer
Authors: Kang Eun Joo , Choi Yoon Ji , Kim Jung Sun , Park Kyong Hwa , Oh Sang Chul , Seo Jae Hong , Kim Hong Jun , Kang Ka-won , Yu Eun Sang , Shin Sang W. , Kim Yeul H. , Kim Jun Suk
Published: February 2015

Background: The efficacy of second-line chemotherapy (CT2) after the failure of first-line chemotherapy (CT1) for advanced biliary tract cancer (BTC) has not been established. We investigated the favorable prognostic factors for CT2 to determine which patients could be expected to benefit from CT2. Methods: From a total of 168 patients who were treated with chemotherapy at our institution between January 2003 and December 2012, we retrospectively reviewed 50 patients who received CT2. Patients were treated with various chemotherapeutic combinations as CT1 and CT2. Results: The median overall survival (OS) of patients who received and CT2 was 10.2 and 5.5 months, respectively. Good performance status (PS), a serum albumin level >3.5 g/dl and metastasis to only 1 organ were independent prognostic factors that affected the OS of the patients who received CT2. Patients who had only 1 metastastic organ, a good PS and a serum albumin level >3.5 g/dl at the beginning of CT2 demonstrated prolonged survival compared to patients who did not exhibit these 3 factors (9.5 vs. 4.3 months, p < 0.005). Conclusions: CT2 should be considered for patients with advanced BTC, especially for those who have only 1 metastatic organ and remain in generally good medical condition after the failure of CT1.
Effects of Microtubule and Actin Inhibitors on Cryptococcus neoformans Examined by Scanning and Transmission Electron Microscopy
Authors: Kopecká Marie
Published: February 2015

Background:Cryptococcus neoformans is one of the most important human fungal pathogens. Its cells contain rich microtubules required for nuclear division and rich F-actin cytoskeletons for cell division. Disruption of microtubules by a microtubule inhibitor should block nuclear division, and disruption of F-actin by an actin inhibitor should block cell division. We investigated the effects of microtubule and actin inhibitors to find out whether the cytoskeletons of C. neoformans can become a new anti-fungal target for the inhibition of cell division, when examined at the ultrastructural level. Methods: Cells treated with the microtubule inhibitors vincristine (VIN) and methyl benzimidazole-2-ylcarbamate (BCM) and the actin inhibitor latrunculin A (LA), in yeast extract peptone dextrose medium, were examined by scanning (SEM) and transmission electron microscopy (TEM), and the cell number was counted using a Bürker chamber. Results: After 2 days of inhibition with VIN, BCM or LA, the cells did not divide, but later, resistant, proliferating cells appeared in all samples. With combined microtubule and actin inhibitors (VIN + LA or BCM + LA), cells did not divide during 6 or even 14 days, and no resistant cells originated. TEM showed that the inhibited cells were without cytoplasm and were dead; only empty cell walls persisted with reduced capsules, shown on SEM. Conclusion: Combined microtubule and actin inhibitors (VIN + LA or BCM + LA), have lethal effects on C. neoformans cells and no resistant cells originate.
Narrative Discourse Impairments in Persian-Speaking Persons with Traumatic Brain Injury: A Pilot Study
Authors: Ghayoumi Anaraki Zahra , Marini Andrea , Yadegari Fariba , Mahmoodi Bakhtiari Behrooz , Fakharian Esmaeil , Rahgozar Mehdi , Rassouli Maryam
Published: February 2015

Objective: Studies have shown the presence of narrative discourse difficulties in persons with traumatic brain injury (TBI), even in those who do not suffer from aphasia. Yet, there still exist inconsistencies between the results of different studies, in particular at the microlinguistic level. Moreover, a limited number of languages have been studied in this regard. Therefore, this study aimed at examining these skills in Persian-speaking individuals with TBI. The purpose of this pilot study was to analyse the microlinguistic and macrolinguistic skills of these individuals to determine impaired linguistic measures at different levels of narrative discourse. Participants and Methods: Fourteen non-aphasic Persian-speaking persons with TBI (9 with severe TBI and 5 with moderate TBI), aged 19-40 years (mean = 25.84, SD = 5.69), and 61 age-matched healthy adults completed a narrative task. Measures of language productivity, clause density, verbal error ratio, and cohesion ratio were calculated. Also, test-retest and inter-rater reliability coefficients were analysed. Results: The TBI group was impaired in some microlinguistic and all macrolinguistic measures compared to their control peers. Conclusion: The results of this study suggest that multi-level narrative discourse analyses of Persian-speaking individuals with TBI may be useful for speech/language pathologists wishing to evaluate communication disorders in persons with TBI.
The Bethesda System for Reporting Thyroid Fine-Needle Aspiration Cytology: A Kuwaiti Experience - A Cytohistopathological Study of 374 Cases
Authors: Kapila Kusum , Qadan Laila , Ali Rola H. , Jaragh Mohammed , George Sara S. , Haji Bahiya E.
Published: February 2015

Introduction: The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) identifies 6 diagnostic categories in which the risk of malignancy increases respectively. The aim of our study was to assess TBSRTC reporting in our hospital and to evaluate its specificity based on cytohistological correlation. Methods: A histological diagnosis was available in 374 (110 males and 264 females) out of 7,809 thyroid aspirates examined at Mubarak Al-Kabeer Hospital, Kuwait, from 2004 to 2012. The aspirates were classified in accordance with TBSRTC. Results: Thyroid aspirates were classified as nondiagnostic (n = 18; 4.8%), benign (n = 114; 30.5%); atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS; n = 59; 15.8%), follicular neoplasm/suspicious for follicular neoplasm (FN/SFN; n = 17; 4.5%), suspicious for malignancy (SM; n = 80; 21.4%), or malignant (n = 86; 23.0%). In 75 of 86 malignant cases, a papillary carcinoma was detected. There were 3 (1.6%) false-positive aspirates and the sensitivity, specificity, negative predictive value, and positive predictive value were 91.0, 61.9, 84.2, and 75.3%, respectively. Conclusions: Our results are fairly comparable to those of various previous studies in the SM, AUS/FLUS, and SFN categories. The higher rates observed in the nondiagnostic and benign categories were possibly due to limited guided aspirations and a lack of on-site evaluation for all cases.
Outcomes and Postoperative Complications of Robot-Assisted Laparoscopic Hysterosacropexy: Initial Experience
Authors: Cerruto Maria Angela , D'Elia Carolina , Cavicchioli Francesca Maria , Cavalleri Stefano , Balzarro Matteo , Porcaro Antonio Benito , Curti Pierpaolo , Artibani Walter
Published: February 2015

Background: Pelvic organ prolapse is a common condition, affecting about 50% of women with children. The aim of our study was to evaluate results and complication rates in a consecutive series of female patients undergoing robot-assisted laparoscopic hysterosacropexy (RALHSP). Materials and Methods: We performed a medical record review of female patients with uterine prolapse who had consecutively undergone RALHSP from February 2010 to 2013 at our department. Results: Fifteen patients were included in the analysis. All patients had uterine prolapse stage ≥II and urodynamic stress urinary incontinence. The mean age was 58.26 years. According to the Clavien-Dindo system, 4 out of 15 patients (26.6%) had grade 1 early complications and 1 patient had a grade 2 complication. At a median follow-up of 36 months, there was a significant prolapse relapse rate of 20% (3/15). Conclusion: In our hands RALHSP is easy to perform, with satisfying mid-term outcomes and a low complication rate.
In vitro Anticancer Activity of Myricanone in Human Lung Adenocarcinoma A549 Cells
Authors: Dai Guanhai , Tong Yeling , Chen Xuan , Ren Zeming , Yang Feng
Published: February 2015

Background: Lung cancer is the leading cause of cancer-related mortality worldwide. Despite the new chemotherapy regimens and cytotoxic combinations investigated in multiple clinical trials in recent years, no significant improvement in the prognosis of patients with lung cancer has been achieved. Recently, scientists have focused on the potential role of extracts of traditional Chinese medicinal herbs as alternative and complementary medications for cancer treatment. Myricanone, a typical large ring of cyclic diarylheptanoids, is abundant in the bark of Myrica. Our studies have found that myricanone exerts potent anticancer activity. This study aimed to investigate the underlying mechanism of the effect of myricanone on A549 cells in vitro. Methods: A549 cells were treated with different concentrations of myricanone for the following assays. Tritiated thymidine incorporation was used to measure growth inhibition. Flow cytometry was used to detect apoptosis and cell cycle progression, and colony formation was performed to observe the effect of myricanone on the A549 proliferation rate. Results: Myricanone induced significant dose-dependent growth inhibitory effects on A549 cells with an IC50 of 3.22 µg/ml. A significant decrease in colony formation was observed. This decrease induced cell apoptosis, G1 phase arrest and the emergence of the sub-G₀ peak in A549 cells. Conclusions: These results suggest that myricanone exhibits anticancer activity and may be applicable in the clinical prevention and treatment of lung cancer in the future.
Preoperative Neutrophil-to-Lymphocyte Ratio Has a Better Predictive Capacity in Diagnosing Tubo-Ovarian Abscess
Authors: Yildirim Melahat , Turkyilmaz Esengul , Avsar Ayse Filiz
Published: February 2015

Background: The aim of this study is to identify the inflammatory markers which predict a tubo-ovarian abscess (TOA) in the most accurate way. Methods: This study involves 312 women. Preoperative inflammatory markers in the study group were compared with those in the healthy control group to identify the most efficient predictor of TOA with a high sensitivity and specificity. The recommended cutoff values of the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), white blood cell count, and red cell distribution width were determined using receiver operating characteristic curve (ROC) analyses. Results: The area under the curve (AUC = 0.99) in the ROC analysis was found to be statistically significant for NLR (p < 0.001) with a cutoff value of ≥4.15 (95% CI 0.97-1.00, sensitivity 95.2%, specificity 99.4%). The positive predictive value of NLR was 99.2%, and the negative predictive value was 96.7% (p < 0.001). The recommended threshold for PLR was found to be 164.37 (AUC = 0.95, 95% CI 0.93-0.98, sensitivity 86.7%, specificity 92%), and the cutoff point of the white blood cell count in the ROC analysis was 9.55 × 103/μl (AUC = 0.90, 95% CI 0.87-0.95, sensitivity 78.68%, specificity 96.68%). Conclusion: Preoperative NLR and PLR improve the predictive value of serum markers for the presence of TOA.
The RANKL-RANK Story
Authors: Nagy Vanja , Penninger Josef M.
Published: February 2015

Receptor activator of nuclear factor κB (RANK) and its ligand (RANKL) have originally been described for their key roles in bone metabolism and the immune system. Subsequently, it has been shown that the RANKL-RANK system is critical in the formation of mammary epithelia in lactating females and the thermoregulation of the central nervous system. RANKL and RANK are under the tight control of the female sex hormones estradiol and progesterone. A reduction of the circulating female sex hormones leading to an increase in RANKL-RANK signaling is the leading cause of osteoporosis in postmenopausal women. Denosumab, a human monoclonal anti-RANKL antibody, has been approved for the treatment of postmenopausal osteoporosis, where it is showing great promise. In addition, RANKL-RANK signaling also plays a critical role in other bone pathologies, bone metastasis or hormone-driven breast cancer. This review will highlight some of the functions of RANKL-RANK in bone turnover, the immune system and brain with a focus on the regulatory role of the female sex hormones.
Interleukin-17A Promotes Arginase-1 Production and 2,4-Dinitrochlorobenzene-Induced Acute Hyperinflammation in Human Papillomavirus E7 Oncoprotein-Expressing Skin
Authors: Tran Le Son , Mittal Deepak , Mattarollo Stephen R. , Frazer Ian H.
Published: February 2015

Human papillomaviruses (HPVs) have evoked numerous mechanisms to subvert host innate immunity and establish a local immunosuppressive environment to facilitate persistent virus infection. Topical application of 2,4-dinitrochlorobenzene (DNCB) was speculated to overcome this immunosuppressive environment and was employed in the immunotherapy of HPV-associated lesions. We have previously shown that DNCB treatment of skin expressing HPV16.E7 protein, the major oncogenic protein expressed in HPV-associated premalignant cervical epithelium, results in a hyperinflammatory response, with an associated induction of Th2 cytokines and infiltration of myeloid cells producing arginase-1, which also contributes to the hyperinflammation. However, the molecular mechanisms underlying arginase-1 induction and arginase-mediated hyperinflammation in K14.E7 skin have not been elucidated. Here, we show that HPV16.E7 protein expression as a transgene in skin is associated with enhanced IL-17A production by macrophages exposed to DNCB. Interestingly, induction of arginase-1 by DNCB is not seen in K14.E7 animals unable to express IL-17A. Further, blockade of either IL-17A or arginase activity alleviates DNCB-induced hyperinflammation through reduced recruitment of neutrophils, as a consequence of decreased CXCL1 and CXCL5 chemokine production. Thus, our findings suggest that increased IL-17A expression by macrophages in E7-expressing skin exposed to DNCB promotes arginase-1 induction and contributes directly to the observed hyperinflammation.
Tyrosine Kinase Inhibitor Induced Isolated Pericardial Effusion
Authors: Agrawal Vineet , Christenson Eric S. , Showel Margaret M.
Published: February 2015

Long-term therapy with tyrosine kinase inhibitors (TKI) has resulted in improved outcomes for patients suffering from Bcr-Abl fusion protein-harboring leukemias. As a result, a growing population of patients on TKI therapy present to their primary care providers. In this case, we report on the case of a 62-year-old male who presented with a symptomatic pericardial effusion. After pericardiocentesis, malignancy and infectious etiologies were excluded. The pericardial effusion was attributed to his TKI, with a transition of this medication to a different TKI. A repeat evaluation 1 month following the withdrawal of the offending agent showed no recurrence of his pericardial effusion on echocardiogram. In this report, we will highlight a rare but important side effect of TKI therapy before discussing its purported mechanisms and differing incidence rates. Early recognition of serosal inflammation related to long-term TKI therapy by primary care providers is important in preventing patient morbidity and mortality.
Body Mass Index and Heart Failure Among Patients With Type 2 Diabetes Mellitus
Authors: Li Weiqin , Katzmarzyk Peter T. , Horswell Ronald , Zhang Yonggang , Wang Yujie , Johnson Jolene , Hu Gang
Published: February 2015

Background—

Epidemiological data on the association between body mass index (BMI) and heart failure (HF) risk among diabetic patients are rare.

Methods and Results—

We performed a prospective cohort study of risk for HF among 31 155 patients with type 2 diabetes mellitus (11 468 men and 19 687 women). Cox proportional hazards regression models were used to estimate the association of different levels of BMI with HF risk. During a mean follow-up of 7.8 years, 5834 subjects developed HF (2379 men and 3455 women). The multivariable-adjusted (age, race, smoking, income, and type of insurance) hazard ratios of HF associated with BMI levels (18.5–22.9, 23–24.9, 25–29.9 [reference group], 30–34.9, 35–39.9, and ≥40 kg/m
2
) at baseline were 0.95, 1.00, 1.00, 1.16, 1.64, and 2.02 (
P
trend
<0.001) for men and 1.16, 1.16, 1.00, 1.23, 1.55, and 2.01 (
P
nonlinear
<0.001) for women, respectively. When we used an updated mean value of BMI, the association of HF risk with BMI did not change. When stratified by age, race, smoking status, and use of antidiabetic drugs, the positive associations among men and the J-shaped associations among women were still present.

Conclusions—

Our study suggests a positive association between BMI and HF risk among men and a J-shaped association between BMI and HF risk among women with type 2 diabetes mellitus.
Vorapaxar in Patients With Diabetes Mellitus and Previous Myocardial Infarction
Authors: Cavender Matthew A. , Scirica Benjamin M. , Bonaca Marc P. , Angiolillo Dominick J. , Dalby Anthony J. , Dellborg Mikael , Morais Joao , Murphy Sabina A. , Ophuis Ton Oude , Tendera Michal , Braunwald Eugene , Morrow David A.
Published: February 2015

Background—

Vorapaxar reduces cardiovascular death, myocardial infarction (MI), or stroke in patients with previous MI while increasing bleeding. Patients with diabetes mellitus (DM) are at high risk of recurrent thrombotic events despite standard therapy and may derive particular benefit from antithrombotic therapies. The Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events-TIMI 50 trial was a randomized, double-blind, placebo-controlled trial of vorapaxar in patients with stable atherosclerosis.

Methods and Results—

We examined the efficacy of vorapaxar in patients with and without DM who qualified for the trial with a previous MI. Because vorapaxar is contraindicated in patients with a history of stroke or transient ischemic attack, the analysis (n=16 896) excluded such patients. The primary end point of cardiovascular death, MI, or stroke occurred more frequently in patients with DM than in patients without DM (rates in placebo group: 14.3% versus 7.6%; adjusted hazard ratio, 1.47;
P
<0.001). In patients with DM (n=3623), vorapaxar significantly reduced the primary end point (11.4% versus 14.3%; hazard ratio, 0.73 [95% confidence interval, 0.60–0.89];
P
=0.002) with a number needed to treat to avoid 1 major cardiovascular event of 29. The incidence of moderate/severe bleeding was increased with vorapaxar in patients with DM (4.4% versus 2.6%; hazard ratio, 1.60 [95% confidence interval, 1.07–2.40]). However, net clinical outcome integrating these 2 end points (efficacy and safety) was improved with vorapaxar (hazard ratio, 0.79 [95% confidence interval, 0.67–0.93]).

Conclusions—

In patients with previous MI and DM, the addition of vorapaxar to standard therapy significantly reduced the risk of major vascular events with greater potential for absolute benefit in this group at high risk of recurrent ischemic events.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00526474.
Taxonomic review of the chironomid genus Cricotopus v.d. Wulp (Diptera: Chironomidae) from Australia: keys to males, females, pupae and larvae, description of ten new species and comments on Paratrichocladius Santos Abreu
Authors: DRAYSON NICK , CRANSTON PETER S. , KROSCH MATT N.
Published: February 2015

The Australian species of the Orthocladiinae genus Cricotopus Wulp (Diptera: Chironomidae) are revised for larval, pupal, adult male and female life stages. Eleven species, ten of which are new, are recognised and keyed, namely Cricotopus acornis Drayson & Cranston sp. nov., Cricotopus albitarsis Hergstrom sp. nov., Cricotopus annuliventris (Skuse), Cricotopus brevicornis Drayson & Cranston sp. nov., Cricotopus conicornis Drayson & Cranston sp. nov., Cricotopus hillmani Drayson & Cranston, sp. nov., Cricotopus howensis Cranston sp. nov., Cricotopus parbicinctus Hergstrom sp. nov., Cricotopus tasmania Drayson & Cranston sp. nov., Cricotopus varicornis Drayson & Cranston sp. nov. and Cricotopus wangi Cranston & Krosch sp. nov. Using data from this study, we consider the wider utility of morphological and molecular diagnostic tools in untangling species diversity in the Chironomidae. Morphological support for distinguishing Cricotopus from Paratrichocladius Santo-Abreu in larval and pupal stages appears lacking for Australian taxa and brief notes are provided concerning this matter.
Taxonomic implications of morphological variation in three species of Trinomys (Rodentia: Echimyidae) from eastern Brazil
Authors: DALAPICOLLA JERONYMO , LEITE YURI L. R.
Published: February 2015

Trinomys is a genus of terrestrial spiny rats from the Atlantic Forest, and three species occur in the state of Espírito Santo, eastern Brazil: T. gratiosus, T. paratus, and T. setosus. The levels of morphological variation within and among these species are virtually unknown, and their geographic ranges have not been properly assessed. These three species are externally very similar, hampering their identification in surveys and ecological studies that are not based on voucher specimens. We evaluated 162 specimens of Trinomys spp. from eastern Brazil, especially from the state of Espírito Santo, and used data from skulls, skins, and bacula to examine morphological variation and its taxonomic implications. We found extensive morphological variation in the skins and skulls even when diagnostic characters were examined, such as the number of dental lophs and bones contributing to the postorbital process. We also found variation in bacular shape among and within species, including polymorphism among individuals from the same population. The geographic range of each species in Espírito Santo was well defined: T. setosus occurred on the left (north) bank of the Doce River, and the other two species, T. gratiosus and T. paratus, occurred on the right (south) bank of this river; however, T. gratiosus was found at altitudes above 500 m, whereas T. paratus occurred below 580 m. Despite difficulties in species identification, the results of morphological and morphometric analyses are compatible with the current classification of these three species. In addition, the level of morphological variation found in specimens identified as T. g. panema—including types—falls within the range of T. g. gratiosus, confirming the taxonomic status of the former as a junior synonym of the latter.
Two new stygobiotic species of Elaphoidella (Crustacea: Copepoda: Harpacticoida) with comments on geographical distribution and ecology of harpacticoids from caves in Thailand
Authors: WATIROYRAM SANTI , BRANCELJ ANTON , SANOAMUANG LA-ORSRI
Published: February 2015

Elaphoidella thailandensis sp. nov. and E. jaesornensis sp. nov., collected during an investigation of cave-dwelling copepod fauna in the northern part of Thailand, are described and figured herein. The new species were collected from pools filled by percolating water from the unsaturated zone of a karstic aquifer in Phitsanulok and Lampang Provinces, respectively. Elaphoidella thailandensis, from Tham Khun cave, is distinguished from its congeners by the two-segmented endopod of pediger 1, the absence of endopod on pediger 4, and the setal formula 4, 5, 6 for the distal exopodal segment of pedigers 2–4. Elaphoidella jaesornensis, from Tham Phar Ngam cave, is distinguished from its most closely related species, E. namnaoensis Brancelj, Watiroyram & Sanoamuang, 2010, by the armature formula of the endopod of pedigers 2–5. The geographical distribution and ecology of Harpacticoida from Thai caves is also presented.
Revision of the status of some genus-level water mite taxa in the families Pionidae Thor, 1900, Aturidae Thor, 1900, and Nudomideopsidae Smith, 1990 (Acari: Hydrachnidiae)
Authors: SMITH IAN M. , COOK DAVID R. , GERECKE REINHARD
Published: February 2015

A number of changes to the status of genus group names in water mites are proposed to foster a more consistent and phylogenetically defensible approach to the ranking of taxa at this level of the classification. The water mite taxa Acercopsis Viets, 1926 (Pionidae: Tiphyinae), Madawaska Habeeb, 1954 (Pionidae: Foreliinae), Brachypodopsis Piersig, 1903, Cubanaxonopsis Orghidan & Gruia, 1981, Hexaxonopsis Viets, 1926, Paraxonopsis Motaş & Tanasachi, 1947, Vicinaxonopsis Cook, 1974, Parabrachypoda Viets, 1929, and Ocybrachypoda Cook, 1974 (Aturidae: Axonopsinae), Ameribrachypoda Smith, 1991 (Aturidae: Aturinae), and Allomideopsis Smith, 1990 (Nudomideopsidae) are elevated in rank from subgenera to full genera to reflect current knowledge of their species diversity, morphological distinctness, relationships and apparent age. In light of the above changes in the subfamily Axonopsinae, the subgenera Kalobrachypoda Viets, 1929 and Navinaxonopsis Cook, 1967 are transferred from the genus Axonopsis to the genus Brachypodopsis, the subgenus Plesiobrachypoda Viets, 1942 is transferred from the genus Axonopsis to the genus Hexaxonopsis, and the species formerly placed in the subgenus Hemibrachypoda Viets, 1937 are transferred from the genus Brachypoda to the genus Parabrachypoda Viets, 1929, and Hemibrachypoda is placed in synonymy with Parabrachypoda. The family group taxa to which all of these genera belong are reviewed to provide context for the proposed changes.
Redescription of Alitta succinea (Leuckart, 1847) and reinstatement of A. acutifolia (Ehlers, 1901) n. comb. based upon morphological and molecular data (Polychaeta: Nereididae)
Authors: VILLALOBOS-GUERRERO TULIO F. , CARRERA-PARRA LUIS F.
Published: February 2015

The nereidid worm Alitta succinea (Leuckart, 1847), described from Western Germany, has been considered by some authors as a widespread and alien invasive species, or else as a group of morphologically indistinguishable species. Neither idea has yet been supported by critical taxonomic revisions of relevant material. Most characterizations of A. succinea were based upon a mixture of morphological features from specimens from the type locality and from other regions. Moreover, four species described from America are considered junior synonyms of A. succinea, including Nereis acutifolia Ehlers, 1901, described from the eastern tropical Pacific. The type material of the latter species has not been reviewed since its description. We re-examined type and topotype materials of A. succinea and N. acutifolia including atokous and epitokous specimens. In addition, newly collected specimens were used to evaluate genetic divergence between both species using the mitochondrial gene COI. Alitta succinea is redescribed from type material and specimens from Germany. We rejected the recent placement of the species in Neanthes and we transferred it to Alitta. Further, we refuse the synonymy of N. acutifolia with A. succinea due to morphological and molecular differences. Consequently, we regard Alitta acutifolia n. comb. as a valid species, and the supposed introduction and the alien status of A. succinea along the Mexican and Central American Pacific shores are rejected.
Impacts of Mesoscale Wind on Turbulent Flow and Ventilation in a Densely Built-up Urban Area
Authors: Park Seung-Bu , Baik Jong-Jin , Lee Sang-Hyun
Published: February 2015

Turbulent flow in a densely built-up area of Seoul, South Korea, for 0900–1500 LST 31 May 2008 is simulated using the parallelized large-eddy simulation model (PALM) coupled to a mesoscale model (Weather Research and Forecasting Model). Time-varying inflow that is composed of mesoscale wind and turbulent signals induces different mean flows and turbulence structures depending on time. Sweeps induced by upper flow are distinct for 0900–0910 LST, and strong ejections and weaker sweeps are dominant for 1450–1500 LST at height z = 200 m. To investigate pedestrian wind environment and ventilation, mean wind velocity and turbulent kinetic energy at 2.5 m above streets are analyzed. The reference mean wind speed at z = 600 m continuously increases after 1010 LST. The pedestrian mean streamwise velocity tends to decrease after 1100 LST, although the pedestrian mean wind speed tends to slowly increase. Whereas the temporal velocity variations related to mesoscale wind are distinct in a street canyon and an intersection, the variations induced by mesoscale wind disappear in a dense building area, indicating strong decoupling from mesoscale wind. The velocity ratio of the pedestrian mean wind speed to the reference mean wind speed, representing a measure of ventilation in urban areas, is high on broad streets and at intersections and is low in dense building areas. Vortices in street canyons and winding flows around tall buildings seem to induce high velocity ratio there. The velocity ratio is shown to be linearly proportional to the pedestrian mean streamwise velocity.
Cluster Analysis of A-Train Data: Approximating the Vertical Cloud Structure of Oceanic Cloud Regimes
Authors: Bankert Richard L. , Solbrig Jeremy E.
Published: February 2015

Moderate Resolution Imaging Spectroradiometer (MODIS) data continue to provide a wealth of two-dimensional, cloud-top information and derived environmental products. In addition, the A-Train constellation of satellites presents an opportunity to combine MODIS data with coincident vertical-profile data collected from sensors on CloudSat and Cloud–Aerosol Lidar and Infrared Pathfinder Satellite Observations (CALIPSO). Approximating the vertical structure of clouds in data-sparse regions can be accomplished through a two-step process that consists of cluster analysis of MODIS data and quantitative analysis of coincident vertical-profile data. Daytime data over the eastern North Pacific Ocean are used in this study for both the summer (June–August) and winter (December–February) seasons in separate cluster analyses. A-Train data from 2006 to 2009 are collected, and a K-means cluster analysis is applied to selected MODIS data that are coincident with single-layer clouds found in the CloudSat/CALIPSO (“GEOPROF-lidar”) data. The resultant clusters, 16 in both summer and winter, are quantified in terms of average cloud-base height, cloud-top height, and normalized cloud water content profile. A cluster and its quantified characteristics can then be assigned to a given pixel in near real-time MODIS data, regardless of its proximity to the observed vertical-profile data. When applied to a two-dimensional MODIS dataset, these assigned clusters can provide an approximate three-dimensional representation of the cloud scene.
Estimating Lorenz’s Reference State in an Ocean with a Nonlinear Equation of State for Seawater
Authors: Saenz Juan A. , Tailleux Rémi , Butler Edward D. , Hughes Graham O. , Oliver Kevin I. C.
Published: February 2015

The study of the mechanical energy budget of the oceans using the Lorenz available potential energy (APE) theory is based on knowledge of the adiabatically rearranged Lorenz reference state of minimum potential energy. The compressible and nonlinear character of the equation of state for seawater has been thought to cause the reference state to be ill defined, casting doubt on the usefulness of APE theory for investigating ocean energetics under realistic conditions. Using a method based on the volume frequency distribution of parcels as a function of temperature and salinity in the context of the seawater Boussinesq approximation, which is illustrated using climatological data, the authors show that compressibility effects are in fact minor. The reference state can be regarded as a well-defined one-dimensional function of depth, which forms a surface in temperature, salinity, and density space between the surface and the bottom of the ocean. For a very small proportion of water masses, this surface can be multivalued and water parcels can have up to two statically stable levels in the reference density profile, of which the shallowest is energetically more accessible. Classifying parcels from the surface to the bottom gives a different reference density profile than classifying in the opposite direction. However, this difference is negligible. This study shows that the reference state obtained by standard sorting methods is equivalent to, though computationally more expensive than, the volume frequency distribution approach. The approach that is presented can be applied systematically and in a computationally efficient manner to investigate the APE budget of the ocean circulation using models or climatological data.