bluuebunny/crossref_metadata_2025 huggingface dataset:
Bax Targeted by miR-29a Regulates Chondrocyte Apoptosis in Osteoarthritis
Authors: Miao Guiqiang , Zang Xuehui , Hou Huige , Sun Hui , Wang Lihui , Zhang Ting , Tan Yongtao , Liu Wenzhou , Ye Pei , Gao Lihua , Zha Zhengang
Published: March 2019

Osteoarthritis (OA) is a chronic degenerative joint disease, where chondrocyte apoptosis is responsible for cartilage degeneration. Bax is a well-known proapoptotic protein of the Bcl-2 family, involved in a large number of physiological and pathological processes. However, the regulation mechanisms of Bax underlying chondrocyte apoptosis in OA remain unknown. In the present study, we determined the role of Bax in human OA and chondrocyte apoptosis. The results showed that Bax was upregulated in chondrocytes from the articular cartilage of OA patients and in cultured chondrocyte-like ATDC5 cells treated by IL-1β. Bax was identified to be the direct target of miR-29a by luciferase reporter assay and by western blotting. Inhibition of miR-29a by the mimics protested and overexpression by miR-29a inhibitors aggravated ATDC5 apoptosis induced by IL-1β. These data reveal that miR-29a/Bax axis plays an important role in regulating chondrocyte apoptosis and suggest that targeting the proapoptotic protein Bax and increasing expression levels of miR-29a emerge as potential approach for protection against the development of OA.
Sulfur Hexafluoride (SF6) versus Perfluoropropane (C3F8) in the Intraoperative Management of Macular Holes: A Systematic Review and Meta-Analysis
Authors: Hecht Idan , Mimouni Michael , Blumenthal Eytan Z. , Barak Yoreh
Published: March 2019

Purpose. A systematic literature search was conducted to identify and review studies comparing SF6 to C3F8 as a tamponade agent in the intraoperative management of macular holes. Methods. Publications up to October 2018 that focused on macular hole surgery in terms of primary closure, complications, and clinical outcomes were included. Forest plots were created using a weighted summary of proportion meta-analysis. Analysis was performed separately for SF6 and C3F8. A random effects model was used, and corresponding I2 heterogeneity estimates were calculated. Results. Nine pertinent publications studying a total of 4,715 patients were identified in 2000 to 2017, including two randomized studies (n=206), two prospective studies (n=170), and five retrospective or registry-based studies. Similar rates of closure between SF6 and C3F8 were reported in eight out of nine studies, regardless of subgroup analyses. All studies reporting visual outcomes showed similar results when comparing SF6 to C3F8 at one to six months of follow-up. Neither agent was clearly associated with increased risk of ocular hypertension, cataract formation, or other adverse events. Meta-analytic pooling of the closure rates in the SF6 group resulted in 91.73% (95% confidence interval: 88.40 to 94.55, I2: 38.03%), and for C3F8, the closure rate was 88.36% (95% confidence interval: 85.88 to 90.63, I2: 0.0%). Conclusions. Both SF6 and C3F8 appear to have achieved similar visual outcomes and primary closure rates and neither was associated with an increased risk of adverse events. Considering the more rapid visual recovery with SF6, there appears to be no evidence to support C3F8 as the tamponade agent of choice for macular hole surgery.
Identification and Characterization of theOCT4Upstream Regulatory Region inSus scrofa
Authors: Kim Seung-Hun , Choi Kwang-Hwan , Lee Dong-Kyung , Lee Mingyun , Hwang Jae Yeon , Lee Chang-Kyu
Published: March 2019

OCT4plays pivotal roles in maintaining pluripotency during early mammalian embryonic development and in embryonic stem cells. It is essential to establish a reporter system based on theOCT4promoter region to study pluripotency. However, there is still a lack of information about the porcineOCT4upstream reporter system. To improve our understanding of the porcineOCT4regulatory region, we identified conserved regions in the porcineOCT4promoter upstream region by sequence-based comparative analysis using various mammalian genome sequences. The similarity of nucleotide sequences in the 5′upstream region was low among mammalian species. However, theOCT4promoter and four regulatory regions, including distal and proximal enhancer elements, had high similarity. Next, a functional analysis of the porcineOCT4promoter region was conducted. Luciferase reporter assay results indicated that the porcineOCT4distal enhancer and proximal enhancer were highly activated in mouse embryonic stem cells and embryonic carcinoma cells, respectively. A comparison analysis of naïve and primed state marker gene expression in a dual-reporter assay showed that the expression levels of naïve and primed markers differed in fluorescence signal between high-expressing cells and low-expressing cells. Similar toOCT4upstream-based reporter systems derived from other species, the porcineOCT4upstream region-based reporter constructs showed exclusive expression patterns depending on the state of pluripotency. This work provides basic information about the porcineOCT4upstream region and various porcineOCT4fluorescence reporter constructs, which can be applied to study species-specific pluripotency in early embryo development and the establishment of embryonic stem cells in pigs.
Pentraxin-3 Levels Relate to the Wells Score and Prognosis in Patients with Acute Pulmonary Embolism
Authors: Yang Haotian , Zhang Jun , Huan Ying , Xu Yawei , Guo Rong
Published: March 2019

Objective. To investigate the value of the PTX-3 test in evaluating the prognosis of acute pulmonary embolism (APE). Method. 117 APE patients were selected and divided into two groups according to plasma PTX-3 levels, including the group in which PTX−3≥3.0 ng/mL (n=42) and the group in which PTX−3<3.0 ng/mL (n=75). Patients were stratified into high-risk, medium-risk, and low-risk groups according to the Wells scores, and the PTX-3 levels were compared among the groups. Patients had been followed-up as well. Results. According to the Wells scores, 11 patients were classified as high-risk (9.4%) and 68 were medium-risk (58.1%), while 38 were low-risk (32.5%). The PTX-3 levels in different risk groups were statistically different (all P<0.05). During the follow-up period, 6 deaths occurred in the group with elevated PTX-3 (≥3.0 ng/mL), while 2 deaths occurred in the group with nonelevated PTX-3 (<3.0 ng/mL). The difference between the two groups was statistically significant (P<0.01). 13 patients were hospitalized due to recurrent pulmonary embolism, of which 12 were in the group with elevated PTX-3 (≥3.0 ng/mL), while 1 patient was in the group with nonelevated PTX-3 (<3.0 ng/mL). The difference was statistically significant (P<0.01). Conclusion. The plasma PTX-3 level in APE patients is correlated with PE risk stratification. There is a significant correlation between PTX-3 levels and PE-related cardiac deaths, as well as the prognosis of recurrent PE. PTX-3 can be used as a clinical indicator of PE prognosis.
Bilevel Programming Model of Urban Public Transport Network under Fairness Constraints
Authors: Hao Jingjing , Liu Xinquan , Shen Xiaojing , Feng Nana
Published: March 2019

In this paper, the bilevel programming model of the public transport network considering factors such as the per capita occupancy area and travel cost of different groups was established, to alleviate the urban transportation equity and optimize the urban public transport network under fairness constraints. The upper layer minimized the travel cost deprivation coefficient and the road area Gini coefficient as the objective function, to solve the optimization scheme of public transport network considering fairness constraints; the lower layer was a stochastic equilibrium traffic assignment model of multimode and multiuser, used to describe the complex selection behavior of different groups for different traffic modes in the bus optimization scheme given by the upper layer. The model in addition utilised the noninferior sorting genetic algorithm II to validate the model via a simple network. The results showed that (1) the travel cost deprivation coefficient of the three groups declined from 33.42 to 26.51, with a decrease of 20.68%; the Gini coefficient of the road area declined from 0.248 to 0.030, with a decrease of 87.76%; it could be seen that the transportation equity feeling of low-income groups and objective resource allocation improved significantly; (2) before the optimization of public transport network, the sharing rate of cars, buses, and bicycles was 42%, 47%, and 11%, respectively; after the optimization, the sharing rate of each mode was 7%, 82%, and 11%, respectively. Some of the high and middle income users who owned the car were transferred to the public transportation. It could be seen that the overall travel time of the optimized public transport network reduced, enhancing the attraction of the public transport network to various travel groups. The model improves the fairness of the urban public transport system effectively while ensuring the travel demand of the residents. It provides theoretical basis and model foundation for the optimization of public transit network, and it is a new attempt to improve the fairness of the traffic planning scheme.
Porous Silicon as a Platform for Radiation Theranostics Together with a Novel RIB-Based Radiolanthanoid
Authors: Jakobsson Ulrika , Mäkilä Ermei , Airaksinen Anu J. , Alanen Osku , Etilé Asenath , Köster Ulli , Ranjan Sanjeev , Salonen Jarno , Santos Hélder A. , Helariutta Kerttuli
Published: March 2019

Mesoporous silicon (PSi) is biocompatible and tailorable material with high potential in drug delivery applications. Here, we report of an evaluation of PSi as a carrier platform for theranostics by delivering a radioactive ion beam- (RIB-) based radioactive lanthanoid into tumors in a mouse model of prostate carcinoma. Thermally hydrocarbonized porous silicon (THCPSi) wafers were implanted with 159Dy at the facility for radioactive ion beams ISOLDE located at CERN, and the resulting [159Dy]THCPSi was postprocessed into particles. The particles were intratumorally injected into mice bearing prostate cancer xenografts. The stability of the particles was studied in vivo, followed by ex vivo biodistribution and autoradiographic studies. We showed that the process of producing radionuclide-implanted PSi particles is feasible and that the [159Dy]THCPSi particles stay stable and local inside the tumor over seven days. Upon release of 159Dy from the particles, the main site of accumulation is in the skeleton, which is in agreement with previous studies on the biodistribution of dysprosium. We conclude that THCPSi particles are a suitable platform together with RIB-based radiolanthanoids for theranostic purposes as they are retained after administration inside the tumor and the radiolanthanoid remains embedded in the THCPSi.
Transverse Momentum Dependence in Double Parton Scattering
Authors: Gaunt Jonathan R. , Kasemets Tomas
Published: March 2019

In this review, we describe the status of transverse momentum dependence (TMD) in double parton scattering (DPS). The different regions of TMD DPS are discussed, and expressions are given for the DPS cross section contributions that make use of as much perturbative information as possible. The regions are then combined with each other as well as single parton scattering to obtain a complete expression for the cross section. Particular emphasis is put on the differences and similarities to transverse momentum dependence in single parton scattering. We further discuss the status of the factorisation proof for double colour singlet production in DPS, which is now on a similar footing to the proofs for TMD factorisation in single Drell-Yan, discuss parton correlations, and give an outlook on possible research on DPS in the near future.
Research on Structural Characteristics of Dynamic Nuclear Zone in Dynamic System of Coal and Rock
Authors: Rong Hai , Liang Bing , Zhang Hongwei , Zhu Feng
Published: March 2019

In order to calculate the concrete scale range of coal and rock mass in rockburst of different degrees of danger and to prevent and control rockburst in coal mines, the concept of dynamic system of coal and rock is put forward in this paper. The model of the relationship between the occurrence of rockburst and dynamic system is built at the same time, which could be used to analyze the rockburst risk of coal and rock in different scales. The calculation method of dynamic nuclear zone scale and its evaluation system and quantitative indicators are put forward based on the energy release process of dynamic system of coal and rock. Combined with the fracturing technology of liquid CO2, the accuracy of the calculation method for the radius of dynamic nuclear zone is verified in a coal mine in Shanxi Province. The degree of coincidence between the results of the two methods is 96.9%∼97.5%, which shows that the calculation method for the radius of dynamic nuclear zone has high reliability and practicability. This method can be widely used in forecasting the risk of rockburst. The liquid CO2 fracturing method can be well used to simulate the blasting source of rockburst at the same time and can be applied to more mines in the future.
Repetition of Prediabetes Enhances the Risk of Developing Diabetes
Authors: Numata Yoshihiro , Ohya Toshihide , Nitta Yasuhiko , Yoshinaka Yumiko , Shogakiuchi Azusa , Toyota Akihiro
Published: March 2019

We attempted to clarify the severity of the risk of diabetes mellitus (DM) in the individuals who repeatedly fulfill the criteria for prediabetes in both fasting plasma glucose (FPG) and hemoglobin A1c (HbA1c). The subjects were 2347 individuals who underwent annual health checkup at our hospital. They were classified as normal glucose tolerance or prediabetes as their yearly status of glucose tolerance for three years; furthermore, the individuals classified as prediabetes were subclassified into 3 groups. Among them, we focused the individuals who fulfilled the criteria for prediabetes in both FPG and HbA1c, and this group was named as PD3. Similarly, all subjects were categorized into 4 groups by the frequency of the status of PD3 during three years. Moreover, all subjects were categorized into 8 patterns when PD3 status was positive. Then, we surveyed the development of diabetes for 5 years, and the incidence rates (IRs) and the age- and sex-adjusted odds ratios (ORs) were obtained. A total of 188 subjects developed diabetes. The individuals in the group of PD3 showed the highest IR of DM (33.6%). The values of ORs were 11.5, 20.0, and 63.5 when the frequencies of PD3 were one, two, and three, respectively. In the group whose frequency of PD3 was two, the individuals who had repeated the status of PD3 twice then moved to the status other than PD3 showed smaller risk of DM than the others in the same group. In conclusion, individuals who fulfill the criteria for prediabetes in both FPG and HbA1c were at a high risk of developing DM, and the risk was enhanced by repeating this status. On the other hand, changing the status from PD3 to others might reduce the risk of DM.
Multiple Faces of Chronic Lymphocytic Leukaemia: A Patient with Renal, Cardiac, and Skeletal Complications
Authors: Htet Zay Myo , Gomez Cesar , Ali Ahsan , Nair Sunil , Karim Mahzuz
Published: March 2019

We describe a patient who had chronic lymphocytic leukaemia (CLL) Binet stage A at presentation with further evidence of disease at multiple sites but who initially required no treatment. However, several years later, her peripheral blood lymphocyte count started to increase, and soon after that she suffered an acute myocardial infarct (in the absence of coronary atheroma) together with proteinuric renal failure due to membranoproliferative glomerulonephritis. Her renal function improved markedly following anti-CLL chemotherapy. We postulate that her cardiac and renal disease were both complications of her CLL. In patients with CLL who develop new clinical signs or symptoms (even if apparently unrelated), consideration should be given as to whether these may be disease complications as this may serve as an indication to commence anti-CLL therapy; close liaison between different specialties is vital.
Effect of Garnet Characteristics on Abrasive Waterjet Cutting of Hard Granite Rock
Authors: Oh Tae-Min , Joo Gun-Wook , Cha Yohan , Cho Gye-Chun
Published: March 2019

Abrasive waterjet cutting technology has come back into use in the field of rock excavation (such as for tunneling) due to the need for precision construction with low vibration. Because the abrasive particles play an important role in efficient erosion during the cutting process, the abrasive characteristics strongly affect the rock cutting performance. In this study, rock cutting tests were performed with five different coarse (40 mesh) garnets to explore the effect of the abrasive feed rate, physical properties, and particle size distribution on rock cutting performance. In addition, garnet particle disintegration was investigated with garnet characteristics for the abrasive waterjet. The test results indicate that the particle size distribution, garnet purity, specific gravity, and hardness are the most important parameters for rock cutting performance. This study offers better understanding of coarse garnet performance and efficiency according to the garnet characteristics. This should provide assistance in selection of the garnet needed to achieve the desired performance for hard rock cutting.
Patellar Tendon Avulsion with Tibial Tuberosity Sleeve Fragment
Authors: Isaka Akira , Ichihara Satoshi , Homma Yasuhiro , Hirose Tomohiko , Kajihara Hajime
Published: March 2019

Rupture of the patellar tendon is relatively rare. We report a case of patellar tendon avulsion with a tibial tuberosity sleeve fragment in pediatric patient. In pediatric patient, diagnosis is sometimes difficult due to uncompleted ossification. In the present case, which involved the presence of a small fleck of bone from tibia, we were able to attain a diagnosis using the Koshino-Sugimoto index and MRI and easily determine the optimal treatment with the use of the suture anchor and tension band wiring method.
Kidney Injury Molecule 1 (KIM-1) as an Early Predictor for Acute Kidney Injury in Post-Cardiopulmonary Bypass (CPB) in Open Heart Surgery Patients
Authors: Khreba Nora A. , Abdelsalam Mostafa , Wahab A. M. , Sanad Mohammed , Elhelaly Rania , Adel Mohammed , El-Kannishy Ghada
Published: March 2019

Introduction. Postoperative acute kidney injury is associated with a higher mortality, a more complicated hospital course with longer hospital stay. Urinary kidney injury molecule 1 may play an important role as an early predictor of acute kidney injury post-cardiopulmonary in open heart surgery. Methods. We evaluated 45 patients who underwent open heart surgery from January 2016 to June 2016. Both urinary kidney injury molecule 1 and serum creatinine were evaluated before operation and 3hs and 24hs after operation. Acute kidney injury was diagnosed according to Kidney Disease: Improving Global Outcomes, 2012 guidelines. Results. In this study, 27 patients developed acute kidney injury. The three hour-post-surgery urinary kidney injury molecule 1 was significantly higher in the acute kidney injury group (P<0.015) and, at the same time, we did not find any significant difference in the serum creatinine levels between the two groups. Conclusion. Although serum creatinine is still the gold standard for diagnosis of acute kidney injury searching for other new markers is mandatory. Urinary kidney injury molecule 1 can be used as simple noninvasive and specific biomarker for early diagnosis of acute kidney injury.
Safety Message Verification Using History-Based Relative-Time Zone Priority Scheme
Authors: Banani Sam , Kittipiyakul Somsak , Thiemjarus Surapa , Gordon Steven
Published: March 2019

Safety message verification plays an important role in securing vehicular ad hoc networks (VANETs). As safety messages are broadcasted several times per second in a highly dense network, message arrival rate can easily exceed the verification rate of safety messages at a vehicle. As a result, an algorithm is needed for selecting and prioritizing relevant messages from received messages to increase the awareness of vehicles in the vicinity. This paper presents the history-based relative-time zone (HRTZ) priority scheme for selecting and verifying relevant received safety messages. HRTZ is an enhanced version of our previously proposed relative-time zone (RTZ) priority scheme. HRTZ achieves higher awareness of nearby vehicles and works in different road configurations. To increase awareness of neighboring vehicles, the average velocity of neighboring vehicles in the range of communication is used to determine the range of the danger zone and other zones. The messages are ranked based on the zone of transmitting vehicles, road configuration (with/without a barrier) and transmitting vehicle location and direction, and relative time between transmitting and receiving vehicles. Only the most up-to-date message from each vehicle is kept in the receiver’s buffer. As a result, each neighboring vehicle has only the most recent safety message in the buffer at any time. The simulation results show that HRTZ achieves a higher rate of verified messages with low delay for nearby vehicles and achieves higher awareness for vehicles in the vicinity, when compared to RTZ and other existing schemes.
Bayesian Analysis of Three-Parameter Frechet Distribution with Medical Applications
Authors: Abbas Kamran , Abbasi Nosheen Yousaf , Ali Amjad , Khan Sajjad Ahmad , Manzoor Sadaf , Khalil Alamgir , Khalil Umair , Khan Dost Muhammad , Hussain Zamir , Altaf Muhammad
Published: March 2019

The medical data are often filed for each patient in clinical studies in order to inform decision-making. Usually, medical data are generally skewed to the right, and skewed distributions can be the appropriate candidates in making inferences using Bayesian framework. Furthermore, the Bayesian estimators of skewed distribution can be used to tackle the problem of decision-making in medicine and health management under uncertainty. For medical diagnosis, physician can use the Bayesian estimators to quantify the effects of the evidence in increasing the probability that the patient has the particular disease considering the prior information. The present study focuses the development of Bayesian estimators for three-parameter Frechet distribution using noninformative prior and gamma prior under LINEX (linear exponential) and general entropy (GE) loss functions. Since the Bayesian estimators cannot be expressed in closed forms, approximate Bayesian estimates are discussed via Lindley’s approximation. These results are compared with their maximum likelihood counterpart using Monte Carlo simulations. Our results indicate that Bayesian estimators under general entropy loss function with noninformative prior (BGENP) provide the smallest mean square error for all sample sizes and different values of parameters. Furthermore, a data set about the survival times of a group of patients suffering from head and neck cancer is analyzed for illustration purposes.
Bcl-2 Is a Therapeutic Target for Hypodiploid B-Lineage Acute Lymphoblastic Leukemia
Authors: Diaz-Flores Ernesto , Comeaux Evan Q. , Kim Kailyn L. , Melnik Ella , Beckman Kyle , Davis Kara L. , Wu Kevin , Akutagawa Jon , Bridges Olga , Marino Roberta , Wohlfeil Margo , Braun Benjamin S. , Mullighan Charles G. , Loh Mignon L.
Published: March 2019

Acute lymphoblastic leukemia (ALL) is the most common cancer in children. The highest rates of treatment failure occur in specific genetic subsets of ALL, including hypodiploid B-cell ALL (B-ALL), for which effective alternative therapies to current intensive chemotherapy treatments have yet to be developed. Here, we integrated biochemical and genomic profiling with functional drug assays to select effective agents with therapeutic potential against hypodiploid B-ALL. ABT-199, a selective Bcl-2 inhibitor, was effective in reducing leukemic burden in vitro and in vivo in patient-derived xenograft models of hypodiploid B-ALL. Daily oral treatment with ABT-199 significantly increased survival in xenografted mice. The unexpected efficacy of ABT-199 observed in hypodiploid leukemias lacking BIM expression (the major reported mediator of ABT-199–induced apoptosis) led us to investigate the mechanism of action of ABT-199 in the absence of BIM. Treatment with ABT-199 elicited responses in a dose-dependent manner, from cell-cycle arrest at low nanomolar concentrations to cell death at concentrations above 100 nmol/L. Collectively, these results demonstrate the efficacy of Bcl-2 inhibition and potential therapeutic strategy in hypodiploid B-ALL.

Significance:

These results demonstrate the efficacy of ABT-199 in vivo and provide encouraging preclinical data of Bcl-2 as a potential target for the treatment of hypodiploid B-ALL.
MYC Drives Group 3 Medulloblastoma through Transformation of Sox2+ Astrocyte Progenitor Cells
Authors: Tao Ran , Murad Najiba , Xu Zhenhua , Zhang Peng , Okonechnikov Konstantin , Kool Marcel , Rivero-Hinojosa Samuel , Lazarski Christopher , Zheng Pan , Liu Yang , Eberhart Charles G. , Rood Brian R. , Packer Roger , Pei Yanxin
Published: March 2019

A subset of group 3 medulloblastoma frequently harbors amplification or overexpression of MYC lacking additional focal aberrations, yet it remains unclear whether MYC overexpression alone can induce tumorigenesis and which cells give rise to these tumors. Here, we showed that astrocyte progenitors in the early postnatal cerebellum were susceptible to transformation by MYC. The resulting tumors specifically resembled human group 3 medulloblastoma based on histology and gene-expression profiling. Gene-expression analysis of MYC-driven medulloblastoma cells revealed altered glucose metabolic pathways with marked overexpression of lactate dehydrogenase A (LDHA). LDHA abundance correlated positively with MYC expression and was associated with poor prognosis in human group 3 medulloblastoma. Inhibition of LDHA significantly reduced growth of both mouse and human MYC-driven tumors but had little effect on normal cerebellar cells or SHH-associated medulloblastoma. By generating a new mouse model, we demonstrated for the first time that astrocyte progenitors can be transformed by MYC and serve as the cells of origin for group 3 medulloblastoma. Moreover, we identified LDHA as a novel, specific therapeutic target for this devastating disease.

Significance:

Insights from a new model identified LDHA as a novel target for group 3 medulloblastoma, paving the way for the development of effective therapies against this disease.
Enhanced Fatty Acid Scavenging and Glycerophospholipid Metabolism Accompany Melanocyte Neoplasia Progression in Zebrafish
Authors: Henderson Fiona , Johnston Hannah R. , Badrock Andrew P. , Jones Emrys A. , Forster Duncan , Nagaraju Raghavendar T. , Evangelou Christos , Kamarashev Jivko , Green Michael , Fairclough Michael , Ramirez Irene Barinaga-Rementeria , He Shuning , Snaar-Jagalska B. Ewa , Hollywood Katherine , Dunn Warwick B. , Spaink Herman P. , Smith Michael P. , Lorigan Paul , Claude Emmanuelle , Williams Kaye J. , McMahon Adam W. , Hurlstone Adam
Published: March 2019

Alterations in lipid metabolism in cancer cells impact cell structure, signaling, and energy metabolism, making lipid metabolism a potential diagnostic marker and therapeutic target. In this study, we combined PET, desorption electrospray ionization-mass spectrometry (DESI-MS), nonimaging MS, and transcriptomic analyses to interrogate changes in lipid metabolism in a transgenic zebrafish model of oncogenic RAS-driven melanocyte neoplasia progression. Exogenous fatty acid uptake was detected in melanoma tumor nodules by PET using the palmitic acid surrogate tracer 14(R,S)-18F-fluoro-6-thia-heptadecanoic acid ([18F]-FTHA), consistent with upregulation of genes associated with fatty acid uptake found through microarray analysis. DESI-MS imaging revealed that FTHA uptake in tumors was heterogeneous. Transcriptome and lipidome analyses further highlighted dysregulation of glycerophospholipid pathways in melanoma tumor nodules, including increased abundance of phosphatidyl ethanolamine and phosphatidyl choline species, corroborated by DESI-MS, which again revealed heterogeneous phospholipid composition in tumors. Overexpression of the gene encoding lipoprotein lipase (LPL), which was upregulated in zebrafish melanocyte tumor nodules and expressed in the majority of human melanomas, accelerated progression of oncogenic RAS-driven melanocyte neoplasia in zebrafish. Depletion or antagonism of LPL suppressed human melanoma cell growth; this required simultaneous fatty acid synthase (FASN) inhibition when FASN expression was also elevated. Collectively, our findings implicate fatty acid acquisition as a possible therapeutic target in melanoma, and the methods we developed for monitoring fatty acid uptake have potential for diagnosis, patient stratification, and monitoring pharmacologic response.

Significance:

These findings demonstrate the translational potential of monitoring fatty acid uptake and identify lipoprotein lipase as a potential therapeutic target in melanoma.
Spindle Assembly Checkpoint Inhibition Can Resensitize p53-Null Stem Cells to Cancer Chemotherapy
Authors: Liu Changlong , Banister Carolyn E. , Buckhaults Phillip J.
Published: March 2019

TP53 mutations are common in most human cancers, but few therapeutic options for TP53-mutant tumors exist. To identify potential therapeutic options for cancer patients with TP53 mutations, we profiled 127 FDA-approved chemotherapy drugs against human embryonic stem cells (hESC) in which we engineered TP53 deletion by genome editing. We identified 27 cancer therapeutic drugs for which TP53 mutations conferred resistance; most of these drugs target DNA synthesis or topoisomerase and cause DNA damage. We then performed a genome-wide CRISPR/Cas9 knockout screen in the TP53-null hESC in the presence and absence of sublethal concentrations of cisplatin and identified 137 genes whose loss selectively resensitized the p53-null cells to this chemotherapeutic agent. Gene ontology classification of the resensitizing loci revealed significant overrepresentation of spindle checkpoint pathway genes. Moreover, we confirmed that targeting ZNF207/BuGZ sensitizes p53-null hESC to cisplatin. These data indicate that targeted inhibition of spindle assembly checkpoints (SAC) and chromosomal organizing centers may provide a way to treat p53-deficient cancer cells with standard chemotherapy drugs. Development of small-molecule inhibitors of SAC proteins may be a useful strategy for rescuing DNA-damaging chemotherapeutics in TP53-mutant cancers.

Significance:

These findings show that inhibition of spindle assembly checkpoints and chromosomal organizing centers may provide a new way to treat p53-deficient cancer cells with standard chemotherapy drugs.
EBF1-Mediated Upregulation of Ribosome Assembly Factor PNO1 Contributes to Cancer Progression by Negatively Regulating the p53 Signaling Pathway
Authors: Shen Aling , Chen Youqin , Liu Liya , Huang Yue , Chen Hongwei , Qi Fei , Lin Jiumao , Shen Zhiqing , Wu Xiangyan , Wu Meizhu , Li Qiongyu , Qiu Liman , Yu Na , Sferra Thomas J. , Peng Jun
Published: March 2019

The RNA-binding protein PNO1 is critical for ribosome biogenesis, but its potential role in cancer remains unknown. In this study, online data mining, cDNA, and tissue microarrays indicated that PNO1 expression was higher in colorectal cancer tissue than in noncancerous tissue, and its overexpression was associated with worse patient survival. Gain-of-function and loss-of-function studies demonstrated that PNO1 knockdown suppressed growth of colorectal cancer cells in vitro and in vivo, while PNO1 overexpression promoted colorectal cancer cell proliferation in vitro. In colorectal cancer cells expressing wild-type p53, PNO1 knockdown enhanced expression of p53 and its downstream gene p21, and reduced cell viability; these effects were prevented by p53 knockout and attenuated by the p53 inhibitor PFT-α. Moreover, PNO1 knockdown in HCT116 cells decreased levels of 18S rRNA, of 40S and 60S ribosomal subunits, and of the 80S ribosome. It also reduced global protein synthesis, increasing nuclear stress and inhibiting MDM2-mediated ubiquitination and p53 degradation. Overexpressing EBF1 suppressed PNO1 promoter activity and decreased PNO1 mRNA and protein, inhibiting cell proliferation and inducing cell apoptosis through the p53/p21 pathway. In colorectal cancer tissues, the expression of EBF1 correlated inversely with PNO1. Data mining of online breast and lung cancer databases showed increased PNO1 expression and association with poor patient survival; PNO1 knockdown reduced cell viability of cultured breast and lung cancer cells. Taken together, these findings indicate that PNO1 is overexpressed in colorectal cancer and correlates with poor patient survival, and that PNO1 exerts oncogenic effects, at least, in part, by altering ribosome biogenesis.

Significance:

This study identifies the ribosome assembly factor PNO1 as a potential oncogene involved in tumor growth and progression of colorectal cancer.
Circulating Tumor DNA in HER2-Amplified Breast Cancer: A Translational Research Substudy of the NeoALTTO Phase III Trial
Authors: Rothé Françoise , Silva Maria Joao , Venet David , Campbell Christine , Bradburry Ian , Rouas Ghizlane , de Azambuja Evandro , Maetens Marion , Fumagalli Debora , Rodrik-Outmezguine Vanessa , Di Cosimo Serena , Rosa Daniela , Chia Stephen , Wardley Andrew , Ueno Takayuki , Janni Wolfgang , Huober Jens , Baselga Jose , Piccart Martine , Loi Sherene , Sotiriou Christos , Dawson Sarah-Jane , Ignatiadis Michail
Published: March 2019

Purpose:

In the neoadjuvant treatment (NAT) setting, dual HER2-targeted therapy is associated with increased pathologic complete response (pCR) rates compared with each therapy alone. Biomarkers allowing to predict treatment response during NAT are needed. We aim to evaluate whether circulating tumor DNA (ctDNA) is associated with response to anti-HER2–targeted therapy.

Experimental Design:

Plasma DNA collected before NAT, at week 2, and before surgery from patients enrolled in the NeoALTTO trial was assessed using digital PCR for PIK3CA and TP53 mutation detection.

Results:

A total of 69 of 455 (15.2%) patients had a PIK3CA and/or TP53 mutation detected in the baseline tumor sample and evaluable ctDNA results from baseline samples. CtDNA was detected in 41%, 20%, and 5% patients before NAT, at week 2, and before surgery, respectively. ctDNA detection before NAT was significantly associated with older age and ER-negative status. ctDNA detection before NAT was associated with decreased odds of achieving pCR (OR = 0.15; 95% CI, 0.034–0.7; P = 0.0089), but not with event-free survival (EFS). Analyses for EFS were underpowered. Interestingly, the patients with HER2-enriched subtype tumors and undetectable ctDNA at baseline had the highest pCR rates. In contrast, patients with persistent ctDNA detection at baseline and week 2 had the lowest rate of pCR.

Conclusions:

ctDNA detection before neoadjuvant anti-HER2 therapies is associated with decreased pCR rates. Interestingly, patients with HER2-enriched tumors and undetectable ctDNA at baseline had the highest pCR rates, therefore appearing as the best candidates for treatment deescalation strategies.
PAK Kinase Inhibition Has Therapeutic Activity in Novel Preclinical Models of Adult T-Cell Leukemia/Lymphoma
Authors: Chung Elaine Y. , Mai Yun , Shah Urvi A. , Wei Yongqiang , Ishida Elise , Kataoka Keisuke , Ren Xiaoxin , Pradhan Kith , Bartholdy Boris , Wei Xiaolei , Zou Yiyu , Zhang Jinghang , Ogawa Seishi , Steidl Ulrich , Zang Xingxing , Verma Amit , Janakiram Murali , Ye B. Hilda
Published: March 2019

Purpose:

To evaluate therapeutic activity of PAK inhibition in ATLL and to characterize the role of PAK isoforms in cell proliferation, survival, and adhesion of ATLL cells in preclinical models.

Experimental Design:

Frequency and prognostic impact of PAK2 amplification were evaluated in an ATLL cohort of 370 cases. Novel long-term cultures and in vivo xenograft models were developed using primary ATLL cells from North American patients. Two PAK inhibitors were used to block PAK kinase activity pharmacologically. siRNA-based gene silencing approach was used to genetically knockdown (KD) PAK1 and PAK2 in ATLL cell lines.

Results:

PAK1/2/4 are the three most abundantly expressed PAK family members in ATLL. PAK2 amplifications are seen in 24% of ATLLs and are associated with worse prognosis in a large patient cohort. The pan-PAK inhibitor PF-3758309 (PF) has strong in vitro and in vivo activity in a variety of ATLL preclinical models. These activities of PF are likely attributed to its ability to target several PAK isoforms simultaneously because genetic silencing of either PAK1 or PAK2 produced more modest effects. PAK2 plays a major role in CADM1-mediated stromal interaction, which is an important step in systemic dissemination of the disease. This finding is consistent with the observation that PAK2 amplification is more frequent in aggressive ATLLs and correlates with inferior outcome.

Conclusions:

PAK2, a gene frequently amplified in ATLL, facilitates CADM1-mediated stromal interaction and promotes survival of ATLL cells. Taken together, PAK inhibition may hold significant promise as a targeted therapy for aggressive ATLLs.
Metabolic Detection of Bruton's Tyrosine Kinase Inhibition in Mantle Cell Lymphoma Cells
Authors: Lee Seung-Cheol , Shestov Alexander A. , Guo Lili , Zhang Qian , Roman Jeffrey C. , Liu Xiaobin , Wang Hong Y. , Pickup Stephen , Nath Kavindra , Lu Pin , Hofbauer Samuel , Mesaros Clementina , Wang Y. Lynn , Nelson David S. , Schuster Stephen J. , Blair Ian A. , Glickson Jerry D. , Wasik Mariusz A.
Published: March 2019

Current methods to evaluate effects of kinase inhibitors in cancer are suboptimal. Analysis of changes in cancer metabolism in response to the inhibitors creates an opportunity for better understanding of the interplay between cell signaling and metabolism and, from the translational perspective, potential early evaluation of response to the inhibitors as well as treatment optimization. We performed genomic, metabolomic, and fluxomic analyses to evaluate the mechanism of action of the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib (IBR) in mantle cell lymphoma (MCL) cells. Our comprehensive analysis of the data generated by these diverse technologies revealed that IBR profoundly affected key metabolic pathways in IBR-sensitive cells including glycolysis, pentose phosphate pathway, TCA cycle, and glutaminolysis while having much less effects on IBR-poorly responsive cells. Changes in 1H magnetic resonance spectroscopy (MRS)-detectable lactate and alanine concentrations emerged as promising biomarkers of response and resistance to IBR as demonstrated from experiments on various MCL cell lines. The metabolic network analysis on the 13C MRS and 13C LC/MS experimental data provided quantitative estimates of various intracellular fluxes and energy contributions. Glutaminolysis contributed over 50% of mitochondrial ATP production. Administration of the glutaminase inhibitor CB-839 induced growth suppression of the IBR-poorly responsive cells.

Implications:

Our study demonstrates application of the advanced metabolomic/fluxomic techniques for comprehensive, precise, and prompt evaluations of the effects of kinase inhibition in MCL cells and has strong translational implications by potentially permitting early evaluation of cancer patient response versus resistance to kinase inhibitors and on design of novel therapies for overcoming the resistance.
E-Cadherin Represses Anchorage-Independent Growth in Sarcomas through Both Signaling and Mechanical Mechanisms
Authors: Jolly Mohit Kumar , Ware Kathryn E. , Xu Shengnan , Gilja Shivee , Shetler Samantha , Yang Yanjun , Wang Xueyang , Austin R. Garland , Runyambo Daniella , Hish Alexander J. , Bartholf DeWitt Suzanne , George Jason T. , Kreulen R. Timothy , Boss Mary-Keara , Lazarides Alexander L. , Kerr David L. , Gerber Drew G. , Sivaraj Dharshan , Armstrong Andrew J. , Dewhirst Mark W. , Eward William C. , Levine Herbert , Somarelli Jason A.
Published: March 2019

CDH1 (also known as E-cadherin), an epithelial-specific cell–cell adhesion molecule, plays multiple roles in maintaining adherens junctions, regulating migration and invasion, and mediating intracellular signaling. Downregulation of E-cadherin is a hallmark of epithelial-to-mesenchymal transition (EMT) and correlates with poor prognosis in multiple carcinomas. Conversely, upregulation of E-cadherin is prognostic for improved survival in sarcomas. Yet, despite the prognostic benefit of E-cadherin expression in sarcoma, the mechanistic significance of E-cadherin in sarcomas remains poorly understood. Here, by combining mathematical models with wet-bench experiments, we identify the core regulatory networks mediated by E-cadherin in sarcomas, and decipher their functional consequences. Unlike carcinomas, E-cadherin overexpression in sarcomas does not induce a mesenchymal-to-epithelial transition (MET). However, E-cadherin acts to reduce both anchorage-independent growth and spheroid formation of sarcoma cells. Ectopic E-cadherin expression acts to downregulate phosphorylated CREB1 (p-CREB) and the transcription factor, TBX2, to inhibit anchorage-independent growth. RNAi-mediated knockdown of TBX2 phenocopies the effect of E-cadherin on CREB levels and restores sensitivity to anchorage-independent growth in sarcoma cells. Beyond its signaling role, E-cadherin expression in sarcoma cells can also strengthen cell–cell adhesion and restricts spheroid growth through mechanical action. Together, our results demonstrate that E-cadherin inhibits sarcoma aggressiveness by preventing anchorage-independent growth.

Implications:

We highlight how E-cadherin can restrict aggressive behavior in sarcomas through both biochemical signaling and biomechanical effects.
Feasibility of Remote Assessment of Human Prion Diseases for Research and Surveillance
Authors: Appleby Brian S. , Glisic Kathleen , Rhoads Daniel D. , Bizzi Alberto , Cohen Mark L. , Mahajan Supriya
Published: March 2019

Background: Prion disease research and surveillance can be challenging due to the disease’s difficulty to diagnose, rapid progression, and geographic dispersion. Improving accessibility through teleneurology could improve the ability to conduct these activities. Objectives: The aim of this study was to determine the feasibility of conducting teleneurology assessments for research and surveillance of prion diseases. Method: Participants were offered in-person visit, medical record review, or teleneurology assessment. Standardized histories and assessments evaluating cognition, functional ability, and neuropsychiatric symptoms were collected. Data regarding participants’ satisfaction with teleneurology were collected. Results: From April 2017 to July 2018, the study received 114 referrals. 45 and 5 participants consented for the teleneurology and medical record review arms of the study, respectively. 29 subjects participated in at least one teleneurology visit. Participants expressed satisfaction with teleneurology and found it easy to participate. Some aspects of the examination were hindered or interrupted due to technological reasons. Conclusions: We demonstrate the feasibility and preference of teleneurology as a modality in which subjects with prion disease can partake in clinical research. Technological aspects sometimes interfered with research assessments.
Pluralidade cristã e algumas questões do cenário religioso brasileiro
Authors: Souza André Ricardo de
Published: March 2019

Em meados do século passado, o panorama religioso brasileiro começou a ser caracterizado por uma pluralidade muito notadamente cristã e um mercado competitivo entre igrejas, algo que veio a se consolidar na última década mediante a explosão neopentecostal. Desde então e até o censo de 2010, o declínio católico acompanha a acelerada expansão evangélica, tendo havido também grande aumento dos sem religião. No presente decênio, verifica-se com mais nitidez outros fatores responsáveis pelo crescimento pentecostal, bem como dois dados novos e expressivos: considerável refreamento na proliferação dos irreligiosos e grande crescimento do espiritismo. Além disso, nota-se o acirramento da intolerância em relação aos adeptos dos cultos afro-brasileiros e algumas significativas manifestações contrárias, com caráter ecumênico.
First photographic record of the Rusty-spotted Cat Prionailurus rubiginosus (I. Geoffroy Saint-Hilaire, 1831) (Mammalia: Carnivora: Felidae) in Horton Plains National Park, Sri Lanka
Authors: Nimalrathna Thilina Sudarshana , Choo Yan Ru , Kudavidanage Enoka P. , Amarasinghe Thakshila Ravindra , Bandara Udamulle Gedara Sumith Indika , Wanninayaka Wanninayaka Aarahchilage Charitha Lakmal , Ravindrakumar Piyal , Chua Marcus Aik Hwee , Webb Edward L
Published: March 2019

The Rusty-spotted Cat Prionailurus rubiginosus is thought to be present in most forested areas of Sri Lanka.  Though it was suggested that the species may occur in montane regions, there was no photographic evidence to date.  Here we present the first photographic record of the Rusty-spotted Cat in Horton Plains National Park.  Individuals including cubs were photo-captured on 15 separate occasions during a 5,538 camera trap days study.  These photo-captures were made both during the day and night, and indicate the presence of a breeding population in this protected area.
Abstract 002: Resolvin D1 Limits Senescent Cells in Atherosclerosis
Authors: Sadhu Sudeshna , Rymut Nicholas , Heinz Justin , Fredman Gabrielle
Published: March 2019

Non-resolving inflammation is the underpinning of several prevalent diseases including atherosclerosis. Understanding new mechanisms to promote the resolution of inflammation in atherosclerosis are of interest. Resolution is mediated by resolvins, including Resolvin D1 (RvD1). We recently showed that RvD1 prevents lesional necrosis in

Ldlr
-/-

mice. However, the mechanisms underlying RvD1’s protective actions remain unknown. In this regard, the accumulation of senescent cells (SCs) was recently shown to promote necrotic core formation in

Ldlr
-/-

mice. SCs are harmful because they possess a pro-inflammatory and proteolytic phenotype called the senescence associated secretory phenotype (SASP). Because RvD1 decreased lesional necrosis, we questioned whether RvD1’s actions were through limiting SCs in plaques. First, we found that human symptomatic plaques had significantly less RvD1 and significantly more SCs (quantified by positive p16
INK4A
immunofluorescence staining) compared with asymptomatic plaques. To prove causation, we administered RvD1 to

Ldlr
-/-

mice during advanced atherosclerosis and observed a significant decrease in lesional SCs and necrosis compared with vehicle controls. Mechanistically, we found that RvD1 significantly decreased the SASP as well as beta-galactosidase and p16
INK4A
in WI-38 senescent cells. Importantly, a major component of the SASP is ADAM17, which is an enzyme that cleaves (and thus inactivates) a critical efferocytosis receptor on macrophages called MerTK. Because SCs are not cleared in plaques we questioned whether the SASP deranges efferocytosis mechanisms via their ability to cleave MerTK on macrophages. To investigate whether MerTK cleavage deranges SC clearance in plaques, we transplanted bone marrow from wild type (WT) or MerTK cleavage resistant (Mertk
CR
) mice into Ldlr
-/-
mice, and quantified the levels of lesional p16
INK4A
after 12 weeks of Western Diet feeding. Mertk
CR
mice had significantly less p16
INK4A
levels and smaller necrotic cores compared with WT controls. Overall, we identified new functions for RvD1 and uncovered, for the first time, an endogenous mechanism for SC clearance. Our findings may provide new therapeutic strategies to treat atherosclerosis.