bluuebunny/crossref_metadata_2025_split huggingface dataset:
An ARC-Regulated IL1β/Cox-2/PGE2/β-Catenin/ARC Circuit Controls Leukemia–Microenvironment Interactions and Confers Drug Resistance in AML
Authors: Carter Bing Z. , Mak Po Yee , Wang Xiangmeng , Tao Wenjing , Ruvolo Vivian , Mak Duncan , Mu Hong , Burks Jared K. , Andreeff Michael 
Published: January 2019

Abstract

The apoptosis repressor with caspase recruitment domain (ARC) protein is a strong independent adverse prognostic marker in acute myeloid leukemia (AML). We previously reported that ARC regulates leukemia–microenvironment interactions through the NFκB/IL1β signaling network. Malignant cells have been reported to release IL1β, which induces PGE2 synthesis in mesenchymal stromal cells (MSC), in turn activating β-catenin signaling and inducing the cancer stem cell phenotype. Although Cox-2 and its enzymatic product PGE2 play major roles in inflammation and cancer, the regulation and role of PGE2 in AML are largely unknown. Here, we report that AML–MSC cocultures greatly increase Cox-2 expression in MSC and PGE2 production in an ARC/IL1β–dependent manner. PGE2 induced the expression of β-catenin, which regulated ARC and augmented chemoresistance in AML cells; inhibition of β-catenin decreased ARC and sensitized AML cells to chemotherapy. NOD/SCIDIL2RγNull-3/GM/SF mice transplanted with ARC-knockdown AML cells had significantly lower leukemia burden, lower serum levels of IL1β/PGE2, and lower tissue human ARC and β-catenin levels, prolonged survival, and increased sensitivity to chemotherapy than controls. Collectively, we present a new mechanism of action of antiapoptotic ARC by which ARC regulates PGE2 production in the tumor microenvironment and microenvironment-mediated chemoresistance in AML.

Significance: The antiapoptotic protein ARC promotes AML aggressiveness by enabling detrimental cross-talk with bone marrow mesenchymal stromal cells.
Loss of E-Cadherin Inhibits CD103 Antitumor Activity and Reduces Checkpoint Blockade Responsiveness in Melanoma
Authors: Shields Bradley D. , Koss Brian , Taylor Erin M. , Storey Aaron J. , West Kirk L. , Byrum Stephanie D. , Mackintosh Samuel G. , Edmondson Rick , Mahmoud Fade , Shalin Sara C. , Tackett Alan J. 
Published: January 2019

AbstractIdentifying controlling features of responsiveness to checkpoint blockade therapies is an urgent goal in oncology research. Our group and others have previously shown melanoma tumors resistant to checkpoint blockade display features of mesenchymal transition, including E-cadherin loss. Here, we present the first in vivo evidence that E-cadherin from tumor cells facilitate immune attack, using a B16F10 melanoma mouse model in which E-cadherin is exogenously expressed (B16.Ecad). We find, compared with vector control, B16.Ecad exhibits delayed tumor growth, reduced metastatic potential, and increased overall survival in vivo. Transplantation of B16.Ecad into Rag1−/− and CD103−/− mice abrogated the tumor growth delay. This indicates the anti-melanoma response against B16.Ecad is both immune and CD103+ mediated. Moreover, B16.Ecad showed increased responsiveness to combination immune checkpoint blockade (ICB) compared with vector control. This work establishes a rationale for ICB responses observed in high E-cadherin–expressing tumors and suggests therapeutic advancement through amplifying CD103+ immune cell subsets.Significance: These findings identify the mechanism behind checkpoint blockade resistance observed in melanoma that has undergone mesenchymal transition and suggest activation of CD103+ immune cells as a therapeutic strategy against other E-cadherin–expressing malignancies.
BET Inhibitors Potentiate Chemotherapy and Killing of SPOP-Mutant Colon Cancer Cells via Induction of DR5
Authors: Tan Xiao , Tong Jingshan , Wang Yi-Jun , Fletcher Rochelle , Schoen Robert E. , Yu Jian , Shen Liangfang , Zhang Lin 
Published: January 2019

Abstract

Bromodomain and extraterminal domain (BET) family proteins such as BRD4 are epigenetic readers that control expression of a number of oncogenic proteins. Targeting this family of proteins has recently emerged as a promising anticancer approach. BET inhibitors (BETi), either alone or in combination with other anticancer agents, have exhibited efficacy in a variety of tumors. However, the molecular mechanisms underlying differential response to BETi are not well understood. In this study, we report that death receptor 5 (DR5), a key component of the extrinsic apoptotic pathway, is markedly induced in response to BRD4 depletion and BETi treatment in colorectal cancer cells. Induction of DR5, following BET inhibition, was mediated by endoplasmic reticulum stress and CHOP-dependent transcriptional activation. Enhanced DR5 induction was necessary for the chemosensitization and apoptotic effects of BETi and was responsible for increased BETi sensitivity in colorectal cancer cells containing a mutation in speckle-type POZ protein (SPOP), a subunit of BRD4 E3 ubiquitin ligase. In a colorectal cancer xenograft model, BETi combined with chemotherapy suppressed the tumor growth in a DR5-dependent manner and potently inhibited patient-derived xenograft tumor growth with enhanced DR5 induction and apoptosis. These findings suggest that BETi alone or in combination with chemotherapy is effective against colorectal cancer due to enhanced DR5 induction and apoptosis. DR5 induction may also serve as a useful marker for designing personalized treatment and improved colorectal cancer combination therapies.

Significance: These findings reveal how BET inhibition sensitizes chemotherapy and kills a subset of colon cancer cells with specific genetic alterations and may provide a new molecular marker for improving colon cancer therapies.
Capmatinib (INC280) Is Active Against Models of Non–Small Cell Lung Cancer and Other Cancer Types with Defined Mechanisms of MET Activation
Authors: Baltschukat Sabrina , Engstler Barbara Schacher , Huang Alan , Hao Huai-Xiang , Tam Angela , Wang Hui Qin , Liang Jinsheng , DiMare Matthew T. , Bhang Hyo-Eun Carrie , Wang Youzhen , Furet Pascal , Sellers William R. , Hofmann Francesco , Schoepfer Joseph , Tiedt Ralph 
Published: January 2019

Abstract

Purpose:
The selective MET inhibitor capmatinib is being investigated in multiple clinical trials, both as a single agent and in combination. Here, we describe the preclinical data of capmatinib, which supported the clinical biomarker strategy for rational patient selection.

Experimental Design:
The selectivity and cellular activity of capmatinib were assessed in large cellular screening panels. Antitumor efficacy was quantified in a large set of cell line– or patient-derived xenograft models, testing single-agent or combination treatment depending on the genomic profile of the respective models.

Results:
Capmatinib was found to be highly selective for MET over other kinases. It was active against cancer models that are characterized by MET amplification, marked MET overexpression, MET exon 14 skipping mutations, or MET activation via expression of the ligand hepatocyte growth factor (HGF). In cancer models where MET is the dominant oncogenic driver, anticancer activity could be further enhanced by combination treatments, for example, by the addition of apoptosis-inducing BH3 mimetics. The combinations of capmatinib and other kinase inhibitors resulted in enhanced anticancer activity against models where MET activation co-occurred with other oncogenic drivers, for example EGFR activating mutations.

Conclusions:
Activity of capmatinib in preclinical models is associated with a small number of plausible genomic features. The low fraction of cancer models that respond to capmatinib as a single agent suggests that the implementation of patient selection strategies based on these biomarkers is critical for clinical development. Capmatinib is also a rational combination partner for other kinase inhibitors to combat MET-driven resistance.
Agnostic-Histology Approval of New Drugs in Oncology: Are We Already There?
Authors: Hierro Cinta , Matos Ignacio , Martin-Liberal Juan , Ochoa de Olza Maria , Garralda Elena 
Published: January 2019

AbstractOver the last several years, several molecular aberrations have been unevenly described across cancers, although the distinct functional relevance in each biological context is not yet fully understood. Novel discoveries have led to the development of drugs tailored to the molecular profile of patients, thus increasing the likelihood of response among biomarker-selected patients. In this context, there has been a progressive redefinition of a precision medicine framework where evidence-based development and earlier approvals might now be driven by this molecular information. Innovative trial designs have greatly facilitated the evaluation and approval of new drugs in small cohorts of orphan cancers in which histology-dependent molecularly defined trials might be logistically difficult. However, accelerated approvals based on this agnostic-histology development model have brought new clinical, regulatory, and reimbursement challenges. In this article, we will highlight many of the biologic issues and clinical trial design challenges characterizing the development of tissue-agnostic compounds. Also, we will review some of the key factors involved in the development of pembrolizumab and larotrectinib, the first two drugs that have been approved by the U.S. Food and Drug Administration in an histology-agnostic manner. Because we anticipate that agnostic-histology approvals will continue to grow, we aim to provide insight into the current panorama of targeted drugs that are following this strategy and some premises to take into consideration. Clinicians and regulators should be prepared to overcome the associated potential hurdles, ensuring that uncertainties are dealt with properly and allowing new, promising agents to arrive faster to the market.
Methylation Biomarker Panel Performance in EsophaCap Cytology Samples for Diagnosing Barrett's Esophagus: A Prospective Validation Study
Authors: Wang Zhixiong , Kambhampati Thiruvengadam Swetha , Cheng Yulan , Ma Ke , Simsek Cem , Tieu Alan H. , Abraham John M. , Liu Xi , Prasath Vishnu , Duncan Mark , Stark Alejandro , Trick Alexander , Tsai Hua-Ling , Wang Hao , He Yulong , Khashab Mouen A. , Ngamruengphong Saowanee , Shin Eun J. , Wang Tza-Huei , Meltzer Stephen J. 
Published: January 2019

Abstract

Purpose:
Barrett's esophagus is the only known precursor of esophageal adenocarcinoma (EAC). Although endoscopy and biopsy are standard methods for Barrett's esophagus diagnosis, their high cost and risk limit their use as a screening modality. Here, we sought to develop a Barrett's esophagus detection method based on methylation status in cytology samples captured by EsophaCap using a streamlined sensitive technique, methylation on beads (MOB).

Experimental Design:
We conducted a prospective cohort study on 80 patients (52 in the training set; 28 in the test set). We used MOB to extract and bisulfite-convert DNA, followed by quantitative methylation-specific PCR to assess methylation levels of 8 previously selected candidate markers. Lasso regression was applied to establish a prediction model in the training set, which was then tested on the independent test set.

Results:
In the training set, five of eight candidate methylation biomarkers (p16, HPP1, NELL1, TAC1, and AKAP12) were significantly higher in Barrett's esophagus patients than in controls. We built a four-biomarker-plus-age lasso regression model for Barrett's esophagus diagnosis. The AUC was 0.894, with sensitivity 94.4% [95% confidence interval (CI), 71%–99%] and specificity 62.2% (95% CI, 44.6%–77.3%) in the training set. This model also performed with high accuracy for Barrett's esophagus diagnosis in an independent test set: AUC = 0.929 (P &lt; 0.001; 95% CI, 0.810%–1%), with sensitivity=78.6% (95% CI, 48.8%–94.3%) and specificity = 92.8% (95% CI, 64.1%–99.6%).

Conclusions:
EsophaCap, in combination with an epigenetic biomarker panel and the MOB method, is a promising, well-tolerated, low-cost esophageal sampling strategy for Barrett's esophagus diagnosis. This approach merits further prospective studies in larger populations.
Low Body Mass Index and Myeloablative Conditioning Regimen Prolong the Duration of Parenteral Nutrition During Hematopoietic Stem Cell Transplantation
Authors: Kamiya Takaki , Hira Daiki , Hoshino Nobuo , Kurihara Mika , Nakagawa Mayumi , Sasaki Masaya , Terada Tomohiro 
Published: January 2019

<b><i>Background/Aims:</i></b> Patients undergoing hematopoietic stem cell transplantation (HSCT) often receive total parenteral nutrition (TPN) due to poor oral intake. In clinical practice, it is difficult to predict adequate nutritional management, especially the duration of parenteral nutrition (PN), because of inter-individual variability in the conditions and types of treatment regimens. This study investigated the relationship between patient factors and the duration of TPN and the duration of PN. <b><i>Methods:</i></b> Data on clinical features, patient characteristics, and the duration of TPN and PN were collected from medical records of 61 of 73 patients who underwent HSCT between April 2010 and December 2014 and were analyzed by multiple linear regression analysis. <b><i>Results:</i></b> Forty-nine patients (80.3%) received TPN and 53 (86.9%) received PN. Sixty patients were affected by poor oral intake soon after pretreatment. Body mass index (BMI) was significantly correlated with the duration of TPN (β = –2.733; 95% CI –4.679 to –0.787). BMI (β = –2.260; 95% CI –4.304 to –0.213) and conditioning regimen (β = 12.726; 95% CI 0.692–24.76) were significantly correlated with the duration of PN. <b><i>Conclusions:</i></b> BMI at admission and the type of conditioning regimen should be considered in choosing the nutritional management plan in patients with HSCT with poor oral intake.
BIOCHEMICAL CHARACTERISTICS OF THIONIC FLUVISOL LINKED TO LAND USE TYPES IN SOUTHERN VIETNAM
Authors: Chung Nguyen Tan , Chung Sy Danh , Thoi Hoang Van 
Published: January 2019

Thionic Fluvisols soil in Southern Vietnam is like typical acid sulfate soil in the tropics and is severely polluted due to human activities. Salinity intrusion and industrial wastewater contamination are the main cause of environmental degradation in soil ecosystem. This research was aimed to determine a link between biochemical soil properties and land use types to provide suitable solutions for afforestation and soil restoration. Soil sampling was conducted in five different land use types at four soil layers (O, AB, Bj and Cp). The five land use types were sugarcane crop; Melaleuca plantation; 2-year Acacia plantation; 5-year Acacia plantation; and control (grass-covered land). The results showed that soil in those five land use types were very acidic (pH â‰¤ 4) having poor-nutrient condition with Â range of Â orthophosphate Â contentÂ of 378 - 640 mg/kg, N-NH4 Â of 586 - 999 mg/kg and N-NO3 of 830 - 1,112 mg/kg. Concentration of toxic ions was very high with large variation among land use types and soil depths i.e. 1,799 â€“ 12,403 mg SO42-/kg; 22 - 1,645 mg exchangeable Fe/kg and 34 - 88 mg Al3+/kg soil. The lowest concentration of exchangeable Fe3+ and SO42- ions were found in sugarcane and Melaleuca plantations, respectively. Twenty-three sulfur-oxidizing bacteria and two iron-oxidizing bacteria were identified. All these bacteria were initially identified as Thiobacillus sp. Sugarcane and Melaleuca plantations exhibited the most diverse Thiobacillus species which linked to reduction of exchangeable Fe and SO42- concentrations in these two land use types. This study indicated that Thiobacillus sp. could grow well in the Thionic Fluvisols. It is proposed that Melaleuca and sugarcane species could reduce iron and sulfur contents in Thionic Fluvisols in the tropics.
JABON (Anthocephalus cadamba Roxb) POTENCY FOR REMEDIATING LEAD (Pb) TOXICITY UNDER NUTRIENT CULTURE CONDITION
Authors: Setyaningsih Luluk , Setiadi Yadi , Budi Sri Wilarso , Hamim Hamim , Sopandie Didy 
Published: January 2019

Information on metal adaptation of plants is necessary to understand the mechanism of heavy metal, including lead (Pb), remediation mediated by forest plants in contaminated land. This study aimed to find out the adaptation mechanism of jabon (Anthocephalus cadamba Roxb) seedlings to excessive lead level based on the tolerance index of growth performance and lead transport to plant tissue.Â The seedlings were exposed to lead (Pb(NO3)2) with the concentrations of 0, 0.5, 1, 1.5, 5 and 10 mM in nutrient culture for 15 days. The result showed that the tolerance index (TI) of the seedlings was significantly decreased by Pb exposure up to 1.5 mM, but the TI values were more than 75%.Â All seedlings died at Pb concentration of 5 mM and up.Â Pb accumulated in all parts of the seedlings, with the highest concentration found in the leaves (735.9 ppm) under Pb concentration of 0.5 mM.Â Â The Pb was found to be transported to the top portion of the seedlings indicated by Transport Factor (TF) that was more than 1. The results suggest that jabon can adapt to excessive Pb exposure up to 1.5 mM and has the potential as a remediator plant.
GROWTH AND MEAT QUALITY ENHANCEMENT OF STRIPED CATFISH (Pangasianodon hypophthalmus) USING RECOMBINANT GROWTH HORMONE
Authors: Lubis Reni Agustina , Alimuddin Alimuddin , Utomo Nur Bambang Priyo 
Published: January 2019

The application of fish recombinant growth hormone (rGH) has been known as one of the methods to improve the growth performance of cultured fishes, one of which is the striped catfish Pangasianodon hypophthalmus, a species that is becoming commercially attractive in Indonesia. Hence, this study was aimed to evaluate the effects of rGH supplementation in commercial diet on the growth, feed utilization and flesh quality in P. hypophthalmus grow out. The rGH was mixed with chicken egg yolk and sprayed on the commercial feeds with different protein levels (32, 28 and 23%). In the control, the feeds were also sprayed with chicken egg yolk but without rGH.Â Striped catfish with body weights of 110.66 Â± 1.32 g ind-1 were fed on rGH-supplemented diets two times a week during the first and third months, and during the rest of the months they were fed on diet without rGH supplementation. The fishes were reared for 120 days in 18 hapa (2Ã—1Ã—1.5 m3) with initial density of 20 fishes per hapa. The result showed that the highest weight gain, specific growth rate (SGR), and lowest feed conversion ratio (FCR) were obtained by fishes fed on 32% protein content with rGH-supplemented diet. No significant difference was observed in the weight gain, SGR and FCR in rGH treated group with 28% protein content with rGH supplemented diet and non-rGH control group receiving 32% protein diet. Similar moisture content of meat, protein content of meat, belly fat and edible portion were observed in rGH-supplemented diet and their control. Except in the treatment 23% protein content rGH supplemented diet that has lower lipid content in fish body and meat. The highest SGR was obtained when the fishes were fed on the 32% protein feed combined with rGH. Enrichment with rGH depleted the fat content in the meat of fish fed on all levels of protein in which the lowest fat was found in the 23% protein feed.
Entraining CAPE for Better Assessment of Tornado Outbreak Potential in the Warm Sector of Extratropical Cyclones
Authors: Tochimoto Eigo , Sueki Kenta , Niino Hiroshi 
Published: January 2019

Abstract
Convective available potential energy (CAPE) is known to lack skill in discussing the environments of tornadic and nontornadic storms, or those of tornado outbreaks and nonoutbreaks. In this paper, a composite analysis of extratropical cyclones that caused 15 or more tornadoes [outbreak cyclones (OCs)] and 5 or fewer tornadoes [nonoutbreak cyclones (NOCs)] in the United States in April and May between 1995 and 2012 shows that entraining-CAPE (E-CAPE), which considers the effects of the entrainment of environmental air, is useful in the analysis of the environments of OCs and NOCs. E-CAPE in the warm sector of OCs is larger than that in the warm sector of NOCs (statistically significant at the 95%–99% level). Moreover, the regions with large E-CAPE for both OCs and NOCs are more closely correlated with the locations of tornadoes than those with large CAPE. The larger E-CAPE near the center in the warm sector of OCs is due to greater moisture at low and midlevels that results from advection by strong southerly winds and synoptic-scale ascent, respectively. The composite analysis also shows that E-EHI, E-SCP, and E-STP, for which traditional CAPE used in the energy helicity index (EHI), supercell composite parameter (SCP), and significant tornado parameter (STP) is substituted by E-CAPE, are more strongly correlated with tornado locations than are the original EHI, SCP, and STP, respectively.
Strengthen governability rather than deepen democracy: why local governments introduce participatory governance
Authors: Kübler Daniel , Rochat Philippe E. , Woo Su Yun , van der Heiden Nico 
Published: January 2019

Innovations in participatory governance have been widely discussed but their introduction as such is rarely examined. This article seeks to understand why, in a context of established democracy, local authorities engage in participatory governance. Using a data set on the implementation of mini-publics in 1505 Swiss municipalities in the period 2000 to 2012, we test five hypotheses about the introduction of participatory governance. We find that mini-publics in Swiss municipalities are policy-oriented procedures that involve only a small proportion of the citizenry. Municipalities who implement mini-publics are those that do not have a municipal assembly tradition, whose public services are under growth pressure, who feature many different political groups as well as strong party and community ties, and who have a strongly professionalized public administration. We conclude that the expansion of participatory governance is driven by an agenda to increase governability in an adversarial context with strong and fragmented group interests. Points for practitioners This study explores the introduction of mini-publics in Swiss municipalities. Mini-publics are participatory designs in which small groups of citizens deliberate on a topic related to municipal policymaking. Most mini-public exercises found in this study were related to spatial planning, but sustainability and youth were recurrent fields as well. Mini-publics have become part of public administration practice and are set up in the hope that they will help find solutions to conflicts and foster the acceptance of policy decisions.
Principle and Practice in Commonwealth Industrial Arbitration after Sixty Years
Authors: McGarvie R. E. 
Published: January 2019

In its joint judgment in the Standard Hours Inquiry, 1947 the Full Court of the Commonwealth Court of Conciliation and Arbitration observed:The issue, as the history of the case indicates, comes to this Court as a number of industrial disputes (over 100 applications are before the Court) between many registered organizations of workers and their employers who are respondents. Some of these disputes are of long standing; others of them were created when it was known that the Court proposed to make a general investigation into standard hours. It is a commonplace of Australian industrial law that the limit of the constitutional power of the Court is to settle these disputes each within its ambit, and the ultimate judgment will in fact settle these particular disputes, and do no more. But we know, as a matter of practical fact, that it will in the long run lead to uniform standard hours throughout Australia. The responsibility of this onerous task does not properly belong to this Court. It is bound only to settle the dispute. It is something additional that State legislatures and State industrial tribunals make its decisions in these disputes the bases of industrial determinations.