bluuebunny/crossref_metadata_2025 huggingface dataset:
Degradation of TRPML1 in Neurons Reduces Neuron Survival in Transient Global Cerebral Ischemia
Authors: Wang Yang , Jiang Shao-wei , Liu Xuan , Niu Lei , Ge Xiao-li , Zhang Jin-cheng , Wang Hai-rong , Fei Ai-hua , Gao Cheng-jin , Pan Shu-ming
Published: December 2018

Postcardiac arrest syndrome yields poor neurological outcomes, but the mechanisms underlying this condition remain poorly understood. Autophagy plays an important role in neuronal apoptosis induced by ischemia. However, whether autophagy is involved in neuron apoptosis induced by cardiac arrest has been less studied. This study found that TRPML1 participates in cerebral ischemic reperfusion injury. Primary neurons were isolated and treated with mucolipin synthetic agonist 1 (ML‐SA1), as well as infected with the recombinant lentivirus TRPML1 overexpression vector in vitro. ML‐SA1 was delivered intracerebroventricularly in transient global ischemia model. Protein expression levels were determined by western blot. Neurological deficit score and the infarct volume were analyzed for the detection of neuronal damage. We found that TRPML1 was significantly downregulated in vivo and in vitro ischemic reperfusion model. We also observed that TRPML1 overexpression or treatment with the ML‐SA1 attenuated neuronal death in primary neurons and ameliorated neurological dysfunction in vivo. Our findings suggested that autophagy and apoptosis were activated after transient global ischemia. Administration of ML‐SA1 before transient global ischemia ameliorated neurological dysfunction possibly through the promotion of autophagy and the inhibition of apoptosis.
Mindfulness Meditation Is Related to Long-Lasting Changes in Hippocampal Functional Topology during Resting State: A Magnetoencephalography Study
Authors: Lardone Anna , Liparoti Marianna , Sorrentino Pierpaolo , Rucco Rosaria , Jacini Francesca , Polverino Arianna , Minino Roberta , Pesoli Matteo , Baselice Fabio , Sorriso Antonietta , Ferraioli Giampaolo , Sorrentino Giuseppe , Mandolesi Laura
Published: December 2018

It has been suggested that the practice of meditation is associated to neuroplasticity phenomena, reducing age-related brain degeneration and improving cognitive functions. Neuroimaging studies have shown that the brain connectivity changes in meditators. In the present work, we aim to describe the possible long-term effects of meditation on the brain networks. To this aim, we used magnetoencephalography to study functional resting-state brain networks in Vipassana meditators. We observed topological modifications in the brain network in meditators compared to controls. More specifically, in the theta band, the meditators showed statistically significant (p corrected = 0.009) higher degree (a centrality index that represents the number of connections incident upon a given node) in the right hippocampus as compared to controls. Taking into account the role of the hippocampus in memory processes, and in the pathophysiology of Alzheimer’s disease, meditation might have a potential role in a panel of preventive strategies.
Intervertebral Disc-Derived Stem/Progenitor Cells as a Promising Cell Source for Intervertebral Disc Regeneration
Authors: Hu Binwu , He Ruijun , Ma Kaige , Wang Zhe , Cui Min , Hu Hongzhi , Rai Saroj , Wang Baichuan , Shao Zengwu
Published: December 2018

Intervertebral disc (IVD) degeneration is considered to be the primary reason for low back pain. Despite remarkable improvements in both pharmacological and surgical management of IVD degeneration (IVDD), therapeutic effects are still unsatisfactory. It is because of the fact that these therapies are mainly focused on alleviating the symptoms rather than treating the underlying cause or restoring the structure and biomechanical function of the IVD. Accumulating evidence has revealed that the endogenous stem/progenitor cells exist in the IVD, and these cells might be a promising cell source in the regeneration of degenerated IVD. However, the biological characteristics and potential application of IVD-derived stem/progenitor cells (IVDSCs) have yet to be investigated in detail. In this review, the authors aim to perform a review to systematically discuss (1) the isolation, surface markers, classification, and biological characteristics of IVDSCs; (2) the aging- and degeneration-related changes of IVDSCs and the influences of IVD microenvironment on IVDSCs; and (3) the potential for IVDSCs to promote regeneration of degenerated IVD. The authors believe that this review exclusively address the current understanding of IVDSCs and provide a novel approach for the IVD regeneration.
Risk Factors Predicting Complications of Transvenous Lead Extraction
Authors: Jacheć Wojciech , Polewczyk Anna , Polewczyk Maciej , Tomasik Andrzej , Janion Marianna , Kutarski Andrzej
Published: December 2018

Objective. Transvenous lead extraction (TLE) is the gold standard in the management of patients with cardiac implantable electronic devices (CIED)-related complications. Knowledge of TLE risk factors is very important.Methods. Clinical data from 1915 patients undergoing TLE at the Reference Center between 2006 and 2015 were analyzed. The effects of clinical and procedure-related factors on the development of major (MJC) and minor (MIC) complications and survival after TLE were evaluated.Results. MJC were caused mainly by lead implant duration, presence of abandoned leads, multiple procedures preceding TLE, and any technical problem during TLE. Of clinical factors female gender and anemia increased the risk of MJC. MIC were reported in patients with the first implantation of CIED under the age of 30 and after sternotomy analysis of 30-day survival after procedure demonstrated a significant effect of clinical factors and lead dwell times, previous unsuccessful TLE, and MIC.Conclusions. Efficacy and safety of TLE depend mainly on procedure-related factors. This knowledge is essential for preventing MJC and MIC. Mortality at 30 days following TLE is mainly associated with the clinical factors; however, there was also a significant effect of lead dwell time and periprocedural complications on the short-term prognosis of patients undergoing TLE.
Hybrid Random Regret Minimization and Random Utility Maximization in the Context of Schedule-Based Urban Rail Transit Assignment
Authors: Li Dewei , Gao Yufang , Li Ruoyi , Zhou Weiteng
Published: December 2018

Route choice is one of the most critical passenger behaviors in public transit research. The utility maximization theory is generally used to model passengers’ route choice behavior in a public transit network in previous research. However, researchers have found that passenger behavior is far more complicated than a single utility maximization assumption. Some passengers tend to maximize their utility while others would minimize their regrets. In this paper, a schedule-based transit assignment model based on the hybrid of utility maximization and regret minimization is proposed to study the passenger route choice behavior in an urban rail transit network. Firstly, based on the smart card data, the space-time expanded network in an urban rail transit was constructed. Then, it adapts the utility maximization (RUM) and the regret minimization theory (RRM) to analyze and model the passenger route choice behavior independently. The utility values and the regret values are calculated with the utility and the regret functions. A transit assignment model is established based on a hybrid of the random utility maximization and the random regret minimization (RURM) with two kinds of hybrid rules, namely, attribute level hybrid and decision level hybrid. The models are solved by the method of successive algorithm. Finally, the hybrid assignment models are applied to Beijing urban rail transit network for validation. The result shows that RRM and RUM make no significant difference for OD pairs with only two alternative routes. For those with more than two alternative routes, the performance of RRM and RUM is different. RRM is slightly better than RUM in some of the OD pairs, while for the other OD pairs, the results are opposite. Moreover, it shows that the crowd would only influence the regret value of OD pair with more commuters. We conclude that compared with RUM and RRM, the hybrid model RURM is more general.
The WNT10B Network Is Associated with Survival and Metastases in Chemoresistant Triple-Negative Breast Cancer
Authors: El Ayachi Ikbale , Fatima Iram , Wend Peter , Alva-Ornelas Jackelyn A. , Runke Stephanie , Kuenzinger William L. , Silva Julio , Silva Wendy , Gray Joseph K. , Lehr Stephan , Barch Hilaire C. , Krutilina Raisa I. , White Andrew C. , Cardiff Robert , Yee Lisa D. , Yang Lily , O'Regan Ruth M. , Lowry William E. , Seagroves Tiffany N. , Seewaldt Victoria , Krum Susan A. , Miranda-Carboni Gustavo A.
Published: December 2018

Triple-negative breast cancer (TNBC) commonly develops resistance to chemotherapy, yet markers predictive of chemoresistance in this disease are lacking. Here, we define WNT10B-dependent biomarkers for β-CATENIN/HMGA2/EZH2 signaling predictive of reduced relapse-free survival. Concordant expression of HMGA2 and EZH2 proteins is observed in MMTV-Wnt10bLacZ transgenic mice during metastasis, and Hmga2 haploinsufficiency decreased EZH2 protein expression, repressing lung metastasis. A novel autoregulatory loop interdependent on HMGA2 and EZH2 expression is essential for β-CATENIN/TCF-4/LEF-1 transcription. Mechanistically, both HMGA2 and EZH2 displaced Groucho/TLE1 from TCF-4 and served as gatekeepers for K49 acetylation on β-CATENIN, which is essential for transcription. In addition, we discovered that HMGA2-EZH2 interacts with the PRC2 complex. Absence of HMGA2 or EZH2 expression or chemical inhibition of Wnt signaling in a chemoresistant patient-derived xenograft (PDX) model of TNBC abolished visceral metastasis, repressing AXIN2, MYC, EZH2, and HMGA2 expression in vivo. Combinatorial therapy of a WNT inhibitor with doxorubicin synergistically activated apoptosis in vitro, resensitized PDX-derived cells to doxorubicin, and repressed lung metastasis in vivo. We propose that targeting the WNT10B biomarker network will provide improved outcomes for TNBC.

Significance:

These findings reveal targeting the WNT signaling pathway as a potential therapeutic strategy in triple-negative breast cancer.
Early Loss of Histone H2B Monoubiquitylation Alters Chromatin Accessibility and Activates Key Immune Pathways That Facilitate Progression of Ovarian Cancer
Authors: Hooda Jagmohan , Novak Marián , Salomon Matthew P. , Matsuba Chikako , Ramos Romela I. , MacDuffie Emily , Song Melissa , Hirsch Michelle S. , Lester Jenny , Parkash Vinita , Karlan Beth Y. , Oren Moshe , Hoon Dave S. , Drapkin Ronny
Published: December 2018

Recent insights supporting the fallopian tube epithelium (FTE) and serous tubal intraepithelial carcinomas (STIC) as the tissue of origin and the precursor lesion, respectively, for the majority of high-grade serous ovarian carcinomas (HGSOC) provide the necessary context to study the mechanisms that drive the development and progression of HGSOC. Here, we investigate the role of the E3 ubiquitin ligase RNF20 and histone H2B monoubiquitylation (H2Bub1) in serous tumorigenesis and report that heterozygous loss of RNF20 defines the majority of HGSOC tumors. At the protein level, H2Bub1 was lost or downregulated in a large proportion of STIC and invasive HGSOC tumors, implicating RNF20/H2Bub1 loss as an early event in the development of serous ovarian carcinoma. Knockdown of RNF20, with concomitant loss of H2Bub1, was sufficient to enhance cell migration and clonogenic growth of FTE cells. To investigate the mechanisms underlying these effects, we performed ATAC-seq and RNA-seq in RNF20 knockdown FTE cell lines. Loss of RNF20 and H2Bub1 was associated with a more open chromatin conformation, leading to upregulation of immune signaling pathways, including IL6. IL6 was one of the key cytokines significantly upregulated in RNF20- and H2Bub1-depleted FTE cells and imparted upon these cells an enhanced migratory phenotype. These studies provide mechanistic insight into the observed oncogenic phenotypes triggered by the early loss of H2Bub1.

Significance:

Loss of RNF20 and H2Bub1 contributes to transformation of the fallopian tube epithelium and plays a role in the initiation and progression of high-grade serous ovarian cancer.
Performance of Single-Nucleotide Polymorphisms in Breast Cancer Risk Prediction Models: A Systematic Review and Meta-analysis
Authors: Fung Si Ming , Wong Xin Yi , Lee Shi Xun , Miao Hui , Hartman Mikael , Wee Hwee-Lin
Published: December 2018

Background:

SNP risk information can potentially improve the accuracy of breast cancer risk prediction. We aim to review and assess the performance of SNP-enhanced risk prediction models.

Methods:

Studies that reported area under the ROC curve (AUC) and/or net reclassification improvement (NRI) for both traditional and SNP-enhanced risk models were identified. Meta-analyses were conducted to compare across all models and within similar baseline risk models.

Results:

Twenty-six of 406 studies were included. Pooled estimate of AUC improvement is 0.044 [95% confidence interval (CI), 0.038–0.049] for all 38 models, while estimates by baseline models ranged from 0.033 (95% CI, 0.025–0.041) for BCRAT to 0.053 (95% CI, 0.018–0.087) for partial BCRAT. There was no observable trend between AUC improvement and number of SNPs. One study found that the NRI was significantly larger when only intermediate-risk women were included. Two other studies showed that majority of the risk reclassification occurred in intermediate-risk women.

Conclusions:

Addition of SNP risk information may be more beneficial for women with intermediate risk.

Impact:

Screening could be a two-step process where a questionnaire is first used to identify intermediate-risk individuals, followed by SNP testing for these women only.
Nuclear–Cytoplasmic Transport Is a Therapeutic Target in Myelofibrosis
Authors: Yan Dongqing , Pomicter Anthony D. , Tantravahi Srinivas , Mason Clinton C. , Senina Anna V. , Ahmann Jonathan M. , Wang Qiang , Than Hein , Patel Ami B. , Heaton William L. , Eiring Anna M. , Clair Phillip M. , Gantz Kevin C. , Redwine Hannah M. , Swierczek Sabina I. , Halverson Brayden J. , Baloglu Erkan , Shacham Sharon , Khorashad Jamshid S. , Kelley Todd W. , Salama Mohamed E. , Miles Rodney R. , Boucher Kenneth M. , Prchal Josef T. , O'Hare Thomas , Deininger Michael W.
Published: December 2018

Purpose:

Myelofibrosis is a hematopoietic stem cell neoplasm characterized by bone marrow reticulin fibrosis, extramedullary hematopoiesis, and frequent transformation to acute myeloid leukemia. Constitutive activation of JAK/STAT signaling through mutations in JAK2, CALR, or MPL is central to myelofibrosis pathogenesis. JAK inhibitors such as ruxolitinib reduce symptoms and improve quality of life, but are not curative and do not prevent leukemic transformation, defining a need to identify better therapeutic targets in myelofibrosis.

Experimental Design:

A short hairpin RNA library screening was performed on JAK2V617F-mutant HEL cells. Nuclear–cytoplasmic transport (NCT) genes including RAN and RANBP2 were among top candidates. JAK2V617F-mutant cell lines, human primary myelofibrosis CD34+ cells, and a retroviral JAK2V617F-driven myeloproliferative neoplasms mouse model were used to determine the effects of inhibiting NCT with selective inhibitors of nuclear export compounds KPT-330 (selinexor) or KPT-8602 (eltanexor).

Results:

JAK2V617F-mutant HEL, SET-2, and HEL cells resistant to JAK inhibition are exquisitely sensitive to RAN knockdown or pharmacologic inhibition by KPT-330 or KPT-8602. Inhibition of NCT selectively decreased viable cells and colony formation by myelofibrosis compared with cord blood CD34+ cells and enhanced ruxolitinib-mediated growth inhibition and apoptosis, both in newly diagnosed and ruxolitinib-exposed myelofibrosis cells. Inhibition of NCT in myelofibrosis CD34+ cells led to nuclear accumulation of p53. KPT-330 in combination with ruxolitinib-normalized white blood cells, hematocrit, spleen size, and architecture, and selectively reduced JAK2V617F-mutant cells in vivo.

Conclusions:

Our data implicate NCT as a potential therapeutic target in myelofibrosis and provide a rationale for clinical evaluation in ruxolitinib-exposed patients with myelofibrosis.
PRE-surgical Metformin In Uterine Malignancy (PREMIUM): a Multi-Center, Randomized Double-Blind, Placebo-Controlled Phase III Trial
Authors: Kitson Sarah J. , Maskell Zoe , Sivalingam Vanitha N. , Allen Jennifer L. , Ali Saad , Burns Sean , Gilmour Kyle , Latheef Rahamatulla , Slade Richard J. , Pemberton Philip W. , Shaw Joseph , Ryder W. David , Kitchener Henry C. , Crosbie Emma J.
Published: December 2018

Purpose:

Endometrioid endometrial cancer is strongly associated with obesity and insulin resistance. Metformin, an insulin sensitizer, reduces endometrial tumor growth in vitro. Presurgical window studies allow rapid in vivo assessment of antitumor activity. Previous window studies found metformin reduced endometrial cancer proliferation but these lacked methodological rigor. PREMIUM measured the anti-proliferative effect of metformin in vivo using a robust window study design.

Patients and Methods: A multicenter, double-blind, placebo-controlled trial randomized women with atypical hyperplasia or endometrioid endometrial cancer to receive metformin (850 mg daily for 3 days, and twice daily thereafter) or placebo for 1 to 5 weeks until surgery. The primary outcome was posttreatment IHC expression of Ki-67. Secondary outcomes investigated the effect of metformin on markers of the PI3K–Akt–mTOR and insulin signaling pathways and obesity.

Results:

Eighty-eight women received metformin (n = 45) or placebo (n = 43) and completed treatment. There was no overall difference in posttreatment Ki-67 between the metformin and placebo arms, in an ANCOVA analysis adjusting for baseline Ki-67 expression (mean difference −0.57%; 95% CI, −7.57%–6.42%; P = 0.87). Metformin did not affect expression of markers of the PI3K–Akt–mTOR or insulin signaling pathways, and did not result in weight loss.

Conclusions:

Short-term treatment with standard diabetic doses of metformin does not reduce tumor proliferation in women with endometrioid endometrial cancer awaiting hysterectomy. This study does not support a biological effect of metformin in endometrial cancer and casts doubt on its potential application in the primary and adjuvant treatment settings.
ER Translocation of the MAPK Pathway Drives Therapy Resistance in BRAF-Mutant Melanoma
Authors: Ojha Rani , Leli Nektaria M. , Onorati Angelique , Piao Shengfu , Verginadis Ioannis I. , Tameire Feven , Rebecca Vito W. , Chude Cynthia I. , Murugan Sengottuvelan , Fennelly Colin , Noguera-Ortega Estela , Chu Charleen T. , Liu Shujing , Xu Xiaowei , Krepler Clemens , Xiao Min , Xu Wei , Wei Zhi , Frederick Dennie T. , Boland Genevieve , Mitchell Tara C. , Karakousis Giorgos C. , Schuchter Lynn M. , Flaherty Keith T. , Zhang Gao , Herlyn Meenhard , Koumenis Constantinos , Amaravadi Ravi K.
Published: December 2018

Resistance to BRAF and MEK inhibitors (BRAFi + MEKi) in BRAF-mutant tumors occurs through heterogeneous mechanisms, including ERK reactivation and autophagy. Little is known about the mechanisms by which ERK reactivation or autophagy is induced by BRAFi + MEKi. Here, we report that in BRAF-mutant melanoma cells, BRAFi + MEKi induced SEC61-dependent endoplasmic reticulum (ER) translocation of the MAPK pathway via GRP78 and KSR2. Inhibition of ER translocation prevented ERK reactivation and autophagy. Following ER translocation, ERK exited the ER and was rephosphorylated by PERK. Reactivated ERK phosphorylated ATF4, which activated cytoprotective autophagy. Upregulation of GRP78 and phosphorylation of ATF4 were detected in tumors of patients resistant to BRAFi + MEKi. ER translocation of the MAPK pathway was demonstrated in therapy-resistant patient-derived xenografts. Expression of a dominant-negative ATF4 mutant conferred sensitivity to BRAFi + MEKi in vivo. This mechanism reconciles two major targeted therapy resistance pathways and identifies druggable targets, whose inhibition would likely enhance the response to BRAFi + MEKi.

Significance:

ERK reactivation and autophagy are considered distinct resistance pathways to BRAF + MEK inhibition (BRAFi + MEKi) in BRAFV600E cancers. Here, we report BRAFi + MEKi–induced ER translocation of the MAPK pathway is necessary for ERK reactivation, which drives autophagy. The ER translocation mechanism is a major druggable driver of resistance to targeted therapy.

This article is highlighted in the In This Issue feature, p. 305
Late-Stage Tumor Regression after PD-L1 Blockade Plus a Concurrent OX40 Agonist
Authors: Polesso Fanny , Weinberg Andrew D. , Moran Amy E.
Published: December 2018

The protective capability of tumor antigen–specific T cells is regulated by costimulatory and inhibitory signals. Current approaches in cancer immunotherapy seek to restore the function of unresponsive T cells by blocking inhibitory pathways. In contrast, providing exogenous costimulatory signals to T cells also enhances antitumor functionality. By combining these two clinical approaches, we demonstrate the synergy of targeting PD-L1 together with the costimulatory molecule OX40, to enhance antitumor immunity. Concurrently blocking PD-L1 and providing a costimulatory agonist to OX40 increased the presence and functionality of tumor antigen–specific CD8+ T cells with simultaneous enhancement of T-helper type 1 (Th1)-skewed CD4+ T cells. This shift was functionally supported by increased glucose metabolism of antigen-specific CD8+ T cells and the acquisition of granzyme B by regulatory T cells. Together, this mechanism promoted tumor regression of late-stage tumors beyond that achieved by either blockade as monotherapy. These findings indicate that targeting both T-cell intrinsic (OX40) and extrinsic (PD-L1) regulatory molecules increases the bioenergetic potential of T cells, thereby expanding functional and tumor antigen–specific T cells.
Lactate-Mediated Acidification of Tumor Microenvironment Induces Apoptosis of Liver-Resident NK Cells in Colorectal Liver Metastasis
Authors: Harmon Cathal , Robinson Mark W. , Hand Fiona , Almuaili Dalal , Mentor Keno , Houlihan Diarmaid D. , Hoti Emir , Lynch Lydia , Geoghegan Justin , O'Farrelly Cliona
Published: December 2018

Colorectal cancer is the third most common malignancy worldwide, with 1.3 million new cases annually. Metastasis to the liver is a leading cause of mortality in these patients. In human liver, metastatic cancer cells must evade populations of liver-resident natural killer (NK) cells with potent cytotoxic capabilities. Here, we investigated how these tumors evade liver NK-cell surveillance. Tissue biopsies were obtained from patients undergoing resection of colorectal liver metastasis (CRLM, n = 18), from the tumor, adjacent tissue, and distal resection margin. The number and phenotype of liver-resident NK cells, at each site, were analyzed by flow cytometry. Tumor-conditioned media (TCM) was generated for cytokine and metabolite quantification and used to treat healthy liver-resident NK cells, isolated from donor liver perfusate during transplantation. Liver-resident NK cells were significantly depleted from CRLM tumors. Healthy liver-resident NK cells exposed to TCM underwent apoptosis in vitro, associated with elevated lactate. Tumor-infiltrating liver-resident NK cells showed signs of mitochondrial stress, which was recapitulated in vitro by treating liver-resident NK cells with lactic acid. Lactic acid induced apoptosis by decreasing the intracellular pH of NK cells, resulting in mitochondrial dysfunction that could be prevented by blocking mitochondrial ROS accumulation. CRLM tumors produced lactate, thus decreasing the pH of the tumor microenvironment. Liver-resident NK cells migrating toward the tumor were unable to regulate intracellular pH resulting in mitochondrial stress and apoptosis. Targeting CRLM metabolism provides a promising therapeutic approach to restoring local NK-cell activity and preventing tumor growth.
Benign Breast Tumours - Diagnosis and Management
Authors: Paepke Stefan , Metz Stephan , Brea Salvago Anika , Ohlinger Ralf
Published: December 2018

With improvements in breast imaging, mammography, ultrasound and minimally invasive interventions, the detection of early breast cancer, non-invasive cancers, lesions of uncertain malignant potential, and benign lesions has increased. However, with the improved diagnostic capabilities comes a substantial risk of false-positive benign lesions and vice versa false-negative malignant lesions. A statement is provided on the manifestation, imaging, and diagnostic verification of isolated benign breast tumours that have a frequent manifestation, in addition to general therapy management recommendations. Histological evaluation of benign breast tumours is the most reliable diagnostic method. According to the S3 guideline and information gained from analysis of the literature, preference is to be given to core biopsy for each type of tumour as the preferred diagnostic method. An indication for open biopsy is also to be established should the tumour increase in size in the follow-up interval, after recurring discrepancies in the vacuum biopsy results, or at the request of the patient. As an alternative, minimally invasive procedures such as therapeutic vacuum biopsy, cryoablation or high-intensity focused ultrasound are also becoming possible alternatives in definitive surgical management. The newer minimally invasive methods show an adequate degree of accuracy and hardly any restrictions in terms of post-interventional cosmetics so that current requirements of extensive breast imaging can be thoroughly met.
Study on Therapeutic Action and Mechanism of TMZ Combined with RITA Against Glioblastoma
Authors: Wu Qinghua , Cao Zhongxu , Xiao Weiwei , Zhu Li , Xie Qian , Li Ling , Zhang Bao  , Zhao Wei
Published: December 2018

Background/Aims: Glioblastoma multiforme (GBM) is a malignant and aggressive central nervous system (CNS) tumor with high mortality and low survival rate. Effective treatment of GMB is a challenge worldwide. Temozolomide (TMZ) is a drug used to treat GBM, while the survival period of GBM patients with positive treatment remains less than 15 months. Reactivating p53 and Inducing Tumor Apoptosis (RITA) is a novel potential anti-cancer small molecular drug. Thus, it is essential to discover novel targets or develop effective drugs combination strategy to treat GBM. Methods: The U87 cells and U251 cells (p53 mutated) were treated with DMSO and 1, 5,10, 20 μM RITA, TMZ, RITA+TMA or PFT-α. The cell proliferation was measured using the MTS cell proliferation assay. The cell apoptosis was analyzed by Annexin V-FITC/PI Apoptosis Detection Kit. The key protein expression level was evaluated by WB. Molecular docking and molecular dynamics (MD) simulation methods were applied to simulate the interaction between RITA and ASK1. Results: Herein, we found that combination RITA and TMZ effectively inhibited the proliferation of U87 cells and promoted the apoptosis of U87 cells. Then the mechanism of RITA and TMZ treating GBM were further studied by detecting the expression of the proteins associating with p53 pathway, such as ASK1, Bax, and so on. RITA bound to the amino acids residues in the activation domain of the ASK1, then induced the conformation change of ASK1 receptor, activated ASK1 and caused a series of signal transduction, further resulted in the physiological effects. Conclusion: Taken together, the RITA suppressed the cell proliferation in glioblastoma via targeting ASK1.
Artemisinin Ameliorates Osteoarthritis by Inhibiting the Wnt/β-Catenin Signaling Pathway
Authors: Zhong Gang , Liang Ruiming , Yao Jun , Li Jia , Jiang Tongmeng , Liu Jianwei , Le Yiguan , Shen Chong , Long Huiping , Lu Huiping , Ma Shiting , Luo Jun , Miao Zhikang , Su Wei  , Zheng Li , Zhao Jinmin
Published: December 2018

Background/Aims: Current drug therapies for osteoarthritis (OA) are not practical because of the cytotoxicity and severe side-effects associated with most of them. Artemisinin (ART), an antimalarial agent, is well known for its safety and selectivity to kill injured cells. Based on its anti-inflammatory activity and role in the inhibition of OA-associated Wnt/β-catenin signaling pathway, which is crucial in the pathogenesis of OA, we hypothesized that ART might have an effect on OA. Methods: The chondro-protective and antiarthritic effects of ART on interleukin-1-beta (IL-1β)-induced and OA patient-derived chondrocytes were investigated in vitro using cell viability assay, glycosaminoglycan secretion, immunofluorescence, quantitative reverse transcription-polymerase chain reaction, and western blotting. We also used OA model rats constructed by anterior cruciate ligament transection and medial meniscus resection (ACLT+MMx) in the joints to investigate the effects of ART on OA by gross observation, morphological staining, immunohistochemistry, and enzyme-linked immunosorbent assay. Results: ART exhibited potent anti-inflammatory effects by inhibiting the expression of proinflammatory chemokines and cytokines, including interleukin (IL)-1β, IL-6, tumor necrosis factor alpha, and matrix metallopeptidase-13. It also showed favorable chondro-protective effect as evidenced by enhanced cell proliferation and viability, increased glycosaminoglycan deposition, prevention of chondrocyte apoptosis, and degeneration of cartilage. Further, ART inhibited OA progression and cartilage degradation via the Wnt/β-catenin signaling pathway, suggesting that it might serve as a Wnt/β-catenin antagonist to reduce inflammation and prevent cartilage degradation. Conclusion: In conclusion, ART alleviates IL-1β-mediated inflammatory response and OA progression by regulating the Wnt/β-catenin signaling pathway. Thereby, it might be developed as a potential therapeutic agent for OA.
Wnt-5a Promotes Neural Development and Differentiation by Regulating CDK5 via Ca2+/Calpain Pathway
Authors: Shu Yang , Xiang Min , Zhang Pei , Qi Guangjian , He Feng , Zhang Qian , Zhang Zheng , Lv Zexi , Peng Xiang , Cai Hongwei , Tian Bo 
Published: December 2018

Background/Aims: The Wnt signaling pathway has essential functions in the central nervous system, where it regulates the major physiological functions of neurons, including development, differentiation, and plasticity. Wnt signaling controls these cellular events; however, how Wnt pathways integrate into a coherent developmental program remains unclear. Methods: The expression and secretion of different WNT ligands (Wnt-1, Wnt-3a, Wnt-4, Wnt-5a, Wnt-11), and the levels and activities of cyclin-dependent kinases (CDK2, CDK4, CDK6/cyclin D, cyclin E) or CDK5 (CDK5/p35 and p25) were measured in Rat cortex at different embryonic stages, and in RA/BDNF-induced differentiated SH-SY5Y cell model, by Quantitative real-time PCR (qPCR), western blotting, ELISA, and in vitro CDK5 kinase assays. MAP2-BrdU double staining was used to assess cell differentiation and cell cycle exit in an RA/BDNF-induced differentiated SH-SY5Y cell model. The effects of CDK5 and Ca2+/calpain signaling were assessed using specific chemical inhibitors. Results: We found that Wnt-1 was unchanged and Wnt-3a was attenuated, whereas Wnt-4, Wnt-5a, and Wnt-11 were markedly up-regulated, during the development of neurons and differentiated SH-SY5Y cells. Simultaneously, the activity of CDK5 was elevated. Furthermore, we describe crosstalk between non-canonical Wnt signaling and CDK5 in the development of neurons and differentiated SH-SY5Y cells. Wnt-5a, a non-canonical Wnt ligand, regulated CDK5 via Ca2+/calpain signaling in both neuronal development and differentiation. Inhibition of Wnt-5a diminished CDK5 kinase activity via the Ca2+/calpain pathway, thereby attenuating RA-BDNF induced SH-SY5Y cell differentiation. Conclusion: Wnt-5a signaling is a significant regulator of neuronal development and differentiation and upregulates CDK5 kinase activity via Ca2+/calpain signaling.
Long Noncoding RNA HOTTIP Promotes Mouse Hepatic Stellate Cell Activation via Downregulating miR-148a
Authors: Li Zhiqin , Wang Jia , Zeng Qinglei , Hu Chunling , Zhang Jiajia , Wang Hongyan , Yan Jingya , Li Hua , Yu Zujiang
Published: December 2018

Background/Aims: HOTTIP is a critical modulator in human diseases including liver cancer, but its role and molecular biological mechanisms in liver fibrosis are still unclear. Methods: The expression profile of HOTTIP during the progression of liver fibrosis was detected in human liver samples and in CCl4-treated mice using qRT-PCR. The expressing sh-HOTTIP adenoviral vector was used to reduce HOTTIP levels in vivo. Dual-Luciferase Reporter Assay was performed to validate the interaction between miR-148a and HOTTIP, TGFBR1, or TGFBR2. Results: HOTTIP expressions in fibrotic liver samples and cirrhotic liver samples were significantly upregulated compared with healthy liver controls, and cirrhotic samples exhibited the highest levels of HOTTIP. Moreover, HOTTIP expressions were substantially induced in the liver tissues and hepatic stellate cells (HSC) of CCl4-treated mice. Ad-shHOTTIP delivery could alleviate CCl4- induced liver fibrosis in mice. Down-regulation of HOTTIP inhibited the viability and activation of HSCs in vitro, and HOTTIP negatively regulated miR-148a expression in HSCs. miR-148a had a negative effect on HSC activation by targeting TGFBR1 and TGFBR2. Conclusion: HOTTIP is involved in the progression of liver fibrosis by promoting HSC activation. The high level of HOTTIP downregulates miR-148a, thus to increase the level of TGFBR1 and TGFBR2 and contribute to liver fibrosis.
lncRNA MEG3 Suppresses the Tumorigenesis of Hemangioma by Sponging miR-494 and Regulating PTEN/ PI3K/AKT Pathway
Authors: Dai Yuxin , Wan Yongkun , Qiu Mingke , Wang Shuqing , Pan Chang , Wang Yang , Ou Jingmin
Published: December 2018

Background/Aims: Dysregulation of long noncoding RNAs (lncRNAs) is associated with the proliferation and metastasis in a variety of cancers, of which lncRNA maternally expressed gene 3 (MEG3) has been indicated as a tumor suppressor in multiple malignancies. However, the underlying mechanisms by which MEG3 contributes to human hemangiomas (HAs) remain undetermined. Methods: qRT-PCR analysis was performed to examine the expression levels of MEG3 and VEGF in proliferating or involuting phase HAs. MTT, colony formation assay, flow cytometry analysis and a subcutaneous xenograft tumor model were conducted to assess the effects of MEG3 on the HAs tumorigenesis. The interaction between MEG3 and miRNAs or their downstream pathways was evidenced by bioinformatic analysis, luciferase report assays, RNA immunoprecipitation (RIP) assay. and Western blot analysis. Results: The expression of MEG3 was substantially decreased and had a negative correlation with VEGF expression in proliferating phase HAs, as compared with the involuting phase HAs and normal skin tissues. Ectopic expression of MEG3 suppressed cell proliferation, colony formation and induced cycle arrest in vitro and in vivo, followed by the downregulation of VEGF and cyclinD1, but knockdown of MEG3 reversed these effects. Furthermore, MEG3 was verified to act as a sponge of miR-494 in HAs cells, and miR-494 counteracted MEG3-caused anti-proliferative effects by regulating PTEN/PI3K/AKT pathway, and exhibited the negative correlation with MEG3 and PTEN expression in proliferating phase HAs. Conclusion: Our findings suggested that lncRNA MEG3 inhibited HAs tumorigenesis by sponging miR-494 and regulating PTEN/PI3K/AKT pathway.
Preliminary Experience Using Motion Compensated CINE Magnetic Resonance Imaging to Visualise Fetal Congenital Heart Disease
Authors: Roy Christopher W. , Marini Davide , Lloyd David F. A. , Mawad Wadi , Yoo Shi-Joon , Schrauben Eric M. , Jaeggi Edgar , Seed Mike , Macgowan Christopher K.
Published: December 2018

Background:

Recent advances in cardiovascular magnetic resonance (CMR) imaging have facilitated CINE imaging of the fetal heart. In this work, a preliminary investigation of the utility of multislice CINE CMR for assessing fetal congenital heart disease is performed and compared with echocardiography.

Methods and Results:

Multislice CINE CMR and echocardiography images were acquired in 25 pregnant women wherein the fetus had a suspected congenital heart defect based on routine obstetric ultrasound. Pathognomonic images were identified for each subject for qualitative comparison of CMR and echocardiography. Quantitative comparison of CMR and echocardiography was then performed by 2 reviewers using a binary scoring of 9 fetal cardiac anatomic features (identifiable/not-identifiable). Pathognomonic images demonstrated the ability of CMR to visualize a variety of congenital heart defects. Overall CMR was able to identify the majority of the 9 assessed fetal cardiac anatomic features (reviewer 1, 7.1±2.1; reviewer 2, 6.7±2.3). Although both reviewers identified more anatomic features with echocardiography (reviewer 1, 7.8±2.3; reviewer 2, 7.5±2.4;
P
=0.01), combining information from both modalities enabled identification of additional anatomic features across subjects (reviewer 1, 8.4±1.3; reviewer 2, 8.4±1.2). The primary limiting factor for CMR was inadequate coverage of the fetal cardiac anatomy or noncontiguous slices because of gross fetal movement.

Conclusions:

CINE CMR enables visualization of fetal congenital heart disease. This work demonstrates the potential of CMR for diagnosing congenital heart disease in utero in conjunction with echocardiography during late gestation.
First-in-Human Studies of [
18
F] Fluorohydroxyphenethylguanidines
Authors: Raffel David M. , Jung Yong-Woon , Koeppe Robert A. , Jang Keun Sam , Gu Guie , Scott Peter J.H. , Murthy Venkatesh L. , Rothley Jill , Frey Kirk A.
Published: December 2018

Background:

Disease-induced damage to cardiac autonomic nerve populations is associated with an increased risk of sudden cardiac death. The extent of cardiac sympathetic denervation, assessed using planar scintigraphy or positron emission tomography, has been shown to predict the risk of arrhythmic events in heart failure patients staged for implantable cardioverter defibrillator therapy. The goal of this study was to perform first-in-human evaluations of 4-[
18
F]fluoro-meta-hydroxyphenethylguanidine and 3-[
18
F]fluoro-para-hydroxyphenethylguanidine, 2 new positron emission tomography radiotracers developed for quantifying regional cardiac sympathetic nerve density.

Methods and Results:

Cardiac positron emission tomography studies with 4-[
18
F]fluoro-meta-hydroxyphenethylguanidine and 3-[
18
F]fluoro-para-hydroxyphenethylguanidine were performed in normal subjects (n=4 each) to assess their imaging properties and organ kinetics. Patlak graphical analysis of their myocardial kinetics was evaluated as a technique for generating nerve density metrics. Whole-body biodistribution studies (n=4 each) were acquired and used to calculate human radiation dosimetry estimates. Patlak analysis proved to be an effective approach for quantifying regional nerve density. Using 960 left ventricular volumes of interest, across-subject Patlak slopes averaged 0.107±0.010 mL/min per gram for 4-[
18
F]fluoro-meta-hydroxyphenethylguanidine and 0.116±0.010 mL/min per gram for 3-[
18
F]fluoro-para-hydroxyphenethylguanidine. Tracer uptake was highest in heart, liver, kidneys, and salivary glands. Urinary excretion was the main elimination pathway.

Conclusions:

4-[
18
F]fluoro-meta-hydroxyphenethylguanidine and 3-[
18
F]fluoro-para-hydroxyphenethylguanidine each produce high-quality positron emission tomography images of the distribution of sympathetic nerves in human heart. Patlak analysis provides reproducible measurements of regional cardiac sympathetic nerve density at high spatial resolution. Further studies of these tracers in heart failure patients will be performed to identify the best agent for clinical development.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT02385877.
Days Alive and Out of Hospital: Exploring a Patient-Centered, Pragmatic Outcome in a Clinical Trial of Patients With Acute Coronary Syndromes
Authors: Fanaroff Alexander C. , Cyr Derek , Neely Megan L. , Bakal Jeffery , White Harvey D. , Fox Keith A.A. , Armstrong Paul W. , Lopes Renato D. , Ohman E. Magnus , Roe Matthew T.
Published: December 2018

Background

Cardiovascular clinical trials have traditionally incorporated separate time-to-first-event analyses for their primary efficacy and safety comparisons, but this framework has a number of limitations, including limited patient-centeredness and a traditional requirement for central adjudication. Days alive and out of the hospital (DAOH) has the potential to provide additional insight.

Methods and Results

TRILOGY ACS (Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes) was a randomized, multinational clinical trial that compared the effect of prasugrel versus clopidogrel in patients stabilized after non-ST segment elevation acute coronary syndrome treated without revascularization; the trial had a neutral result. DAOH was calculated for each patient using site-submitted adverse event reporting data. We described patterns of DAOH overall, and among younger adults (<75 years old), older adults (≥75 years old), and frail/prefrail patients over 12 months follow-up and used Poisson regression to compare DAOH for patients randomized to prasugrel versus clopidogrel. Of 9249 patients in the overall trial population, 500 (5.4%) died, and 2504 (27.1%) were hospitalized 4150 times over 12 months’ follow-up; the mean±SD DAOH was 317±86. The distribution of DAOH over 12 months was left-skewed, with median DAOH 363 days. Among younger adults, older adults, and frail/prefrail patients, mean DAOH were 323, 293, and 304 days, respectively. There were no differences in DAOH by treatment arm in the overall population (rate ratio, 1.00; 95% CI, 0.99–1.01) or any subgroup.

Conclusions

These results support the feasibility of determining DAOH, a patient-centered outcome that can potentially overcome many of the disadvantages of the traditional time-to-composite-event framework in the clinical trial setting.

Clinical Trial Registration

URL:
https://www.clinicaltrials.gov.
Unique identifier: NCT00699998.
Redescription of Haploniscus rostratus (Menzies, 1962) (Crustacea: Peracarida: Isopoda) with observations on the postmarsupial development, size ranges and distribution
Authors: BRÖKELAND WIEBKE
Published: December 2018

Haploniscus rostratus (Menzies, 1962) is redescribed from material obtained during deep-sea expeditions to the southeast Atlantic basins. The species is immediately recognizable by its rostrum and the unique shape of the posterior body. Specimens of all developmental stages were present in the material and are briefly described. Information on body length and body width is given and an identification key to the ontogenetic stages is provided. Development and distribution of the species are discussed. Populations of H. rostratus found north and south of the Walvis Ridge have the same morphology and do not represent cryptic species; therefore it is likely that H. rostratus is able to cross the Walvis Ridge, which has been postulated as potential barrier for benthic species by other authors.
The Elachistinae (Lepidoptera: Gelechioidea: Elachistidae) of Ecuador with descriptions of five new species
Authors: SRUOGA VIRGINIJUS
Published: December 2018

The occurrence of seven species of Elachistinae is reported from Ecuador, including the descriptions of five new species: Elachista adunca sp. n., E. laxa sp. n., E. lata sp. n. and E. phiala sp. n. One species is documented, but not named pending the availability of additional material. The new species are diagnosed and illustrated with photographs of the adults and genitalia. Elachista saccharella (Busck) is reported for the first time from Ecuador and a new host plant is recorded for this species.
Two new synonymies and lectotype designation in Trachyderini (Insecta: Coleoptera: Cerambycidae)
Authors: MONNÉ MARCELA L. , BOTERO JUAN PABLO , QUINTINO HINGRID Y.
Published: December 2018

The subfamily Cerambycinae includes, at present 716 genera and 3889 species in the Neotropical region (Monné & Bezark, 2009). Trachyderini Dupont, 1836, one of the largest tribes of Cerambycinae, is widely distributed in the Americas, especially in the Neotropics where 441 species belonging to 133 genera are recorded, about 11% of the diversity of the subfamily (Monné & Bezark, 2009; Eya, 2010).
On the distinction of Harmothoe globifera (G.O. Sars, 1873) and some other easily confused polynoids in the NE Atlantic, with the description of a new species of Acanthicolepis Norman in McIntosh, 1900 (Polychaeta, Polynoidae)
Authors: BARNICH RUTH , FIEGE DIETER
Published: December 2018

In the Northeast Atlantic several polynoid species have been confused in the past due to similarities in their elytral characters: Harmothoe globifera (G.O.Sars, 1873), Eunoe nodosa (M. Sars, 1861), Eunoe oerstedi Malmgren, 1866, Leucia nivea (M. Sars, 1863), and Acanthicolepis zibrowii n. sp., a new species from deep cold-water corals. The five species are redescribed and figured based on type and additional material. An identification key allowing also the identification of juveniles and anterior fragments and a synoptic table listing the major distinguishing characters of the species covered are provided.
The genus Conocephalus (Orthoptera, Tettigonioidea) in China
Authors: ZHOU MIN , BI WEN-XUAN , LIU XIA-WEI
Published: December 2018

A revision of Conocephalus Thunberg and its relatives from China is reported. One new combination Conocephalus brevivalva (Shi et al., 2005), one new Chinese record Conocephalus oceanicus (Le Guillou, 1841) and one new species Conocephalus shanghaiensis sp. nov. are presented. The type specimens are deposited in the Shanghai Entomological Museum, CAS.
A New Mayfly Species of Epeorus (Caucasiron) from Southwestern China (Ephemeroptera: Heptageniidae)
Authors: CHEN PING , WANG YU-YU , ZHOU CHANG-FA
Published: December 2018

The mayflies of the subgenus Epeorus (Caucasiron) are lotic aquatic insects in Heptageniidae. They are unique in the family because their gills form a disc, gills 1 are strongly expanded anteriorly and contiguous under thorax, gills 7 have a longitudinal fold and are contiguous under apex of abdomen and the pairs of gill 2–6 or 7 have a distinct projection on anterior-dorsal side of leading margin as well as imaginal tubular, diverging penis lobes with titillators. A new species, Epeorus (Caucasiron) extraordinarius sp. nov., collected from southwestern China, is described here. The strongly expanded anterior portion and the concave lateral margins of the nymphal head capsule, the color pattern of nymphs and imagos, and the structure of the male genitalia with relatively small titillators distinguish the new species from previously described members of the subgenus.
Glyptothorax malabarensis, a new catfish (Teleostei: Sisoridae) from the Western Ghats of Kerala, India
Authors: GOPI K. C.
Published: December 2018

Glyptothorax malabarensis, a new species of the Asian catfish family Sisoridae, is described from a hill stream of an upper tributary of the west-flowing Valappattanam River drainage of Kerala State, India. It is distinguished from its congeners in Peninsular India by the following combination of characters: body depth 19.6–9.9% SL, caudal peduncle length 14.3–14.7% SL and caudal peduncle depth 12.4–12.7% SL (caudal peduncle depth 86.4–88.1% of its length); thoracic adhesive apparatus approximately pentagonal, as long as broad, without a median depression; skin of head and body minutely granulated; and a coloration in life consisting of a black background with three flesh-red or orange transverse bands on body, in preservative changing to dark grey with black mottling and three yellowish-white transverse bands.