tbuckley/cabot-search huggingface dataset:
Monoacylglycerol Lipase Inhibition Protects From Liver Injury in Mouse Models of Sclerosing Cholangitis
Authors: Matteo Tardelli, Francesca V. Bruschi, Claudia D. Fuchs, Thierry Claudel, Nicole Auer, Victoria Kunczer, Maximilian Baumgartner, Onne A.H.O. Ronda, Henk Jan Verkade, Tatjana Stojakovic, Hubert Scharnagl, Aida Habib, Robert Zimmermann, Sophie Lotersztajn, Michael Trauner
Journal: Hepatology (2019)

Background and Aims Monoacylglycerol lipase (MGL) is the last enzymatic step in triglyceride degradation, hydrolyzing monoglycerides into glycerol and fatty acids (FAs) and converting 2‐arachidonoylglycerol into arachidonic acid, thus providing ligands for nuclear receptors as key regulators of hepatic bile acid (BA)/lipid metabolism and inflammation. We aimed to explore the role of MGL in the development of cholestatic liver and bile duct injury in mouse models of sclerosing cholangitis, a disease so far lacking effective pharmacological therapy. Approach and Results To this aim we analyzed the effects of 3,5‐diethoxycarbonyl‐1,4‐dihydrocollidine (DDC) feeding to induce sclerosing cholangitis in wild‐type (WT) and knockout (MGL −/− ) mice and tested pharmacological inhibition with JZL184 in the multidrug resistance protein 2 knockout ( Mdr2−/− ) mouse model of sclerosing cholangitis. Cholestatic liver injury and fibrosis were assessed by serum biochemistry, liver histology, gene expression, and western blot characterization of BA and FA synthesis/transport. Moreover, intestinal FAs and fecal microbiome were analyzed. Transfection and silencing were performed in Caco2 cells. MGL −/− mice were protected from DDC‐induced biliary fibrosis and inflammation with reduced serum liver enzymes and increased FA/BA metabolism and β‐oxidation. Notably, pharmacological (JZL184) inhibition of MGL ameliorated cholestatic injury in DDC‐fed WT mice and protected Mdr2−/− mice from spontaneous liver injury, with improved liver enzymes, inflammation, and biliary fibrosis. In vitro experiments confirmed that silencing of MGL decreases prostaglandin E 2 accumulation in the intestine and up‐regulates peroxisome proliferator–activated receptors alpha and gamma activity, thus reducing inflammation. Conclusions Collectively, our study unravels MGL as a metabolic target, demonstrating that MGL inhibition may be considered as potential therapy for sclerosing cholangitis.
Reduced Dose of Post-Transplant Cyclophosphamide for HLA Haploidentical Peripheral Blood Stem Cell Transplantation
Authors: Satoshi Morishige, Yoshitaka Yamasaki, Shuki Oya, Takayuki Nakamura, Maki Ymaguchi, Kazutoshi Aoyama, Ritsuko Seki, Fumihiko Mouri, Koichi Osaki, Koji Nagafuji
Journal: Blood (2018)
Incidence and death in 29 cancer groups in 2017 and trend analysis from 1990 to 2017 from the Global Burden of Disease Study
Authors: Longfei Lin, Lei Yan, Yuling Liu, Fang Yuan, Hui Li, Jian Ni
Journal: Journal of Hematology & Oncology (2019)

Cancer has become the second most serious disease threatening human health, followed by cardiovascular diseases. This study aimed to quantitatively estimate the mortality, morbidity, and analyze the trends of 29 cancer groups in 195 countries/regions between 1990 and 2017.Detailed information of 29 cancer groups were collected from the Global Burden of Disease (GBD) study in 2017 and age-standardized incidence rates (ASIR) and age-standardized death rates (ASDR) of 29 cancer groups were calculated based on gender, age, region, and country. Trend analyses were conducted for major cancer types.In 2017, the global death population caused by cancer reached 9 million, which was nearly twice the number in 1990. The ASDR and ASIR of cancer in males were about 1.5 times those of females. Breast cancer showed the highest mortality rate in females in 2017. Individuals aged over 50 are at high risk of developing cancer and the number of cases and deaths in this age group accounted for more than 80% of all cancers in all age groups. Asia has the heaviest cancer burden due to its large population density. Different cancers in varied countries globally have their own characteristics. The ASDR and ASIR of some major cancers demonstrated changes from 1990 to 2017.Analyses of these data provided basis for future investigations to the common etiological factors, leading to the occurrence of different cancers, the development of prevention strategies based on local characteristics, socioeconomic and other conditions, and the formulation of more targeted interventions.
Genetic Risk of Arrhythmic Phenotypes in Patients With Dilated Cardiomyopathy
Authors: Marta Gigli, Marco Merlo, Sharon L. Graw, Giulia Barbati, Teisha J. Rowland, Dobromir B. Slavov, Davide Stolfo, Mary E. Haywood, Matteo Dal Ferro, Alessandro Altinier, Federica Ramani, Francesca Brun, Andrea Cocciolo, Ilaria Puggia, Gaetano Morea, William J. McKenna, Francisco G. La Rosa, Matthew R.G. Taylor, Gianfranco Sinagra, Luisa Mestroni
Journal: Journal of the American College of Cardiology (2019)
Serum MicroRNA-371a-3p Levels Predict Viable Germ Cell Tumor in Chemotherapy-naïve Patients Undergoing Retroperitoneal Lymph Node Dissection
Authors: John T. Lafin, Nirmish Singla, Solomon L. Woldu, Yair Lotan, Cheryl M. Lewis, Kuntal Majmudar, Anna Savelyeva, Payal Kapur, Vitaly Margulis, Douglas W. Strand, Matthew J. Murray, James F. Amatruda, Aditya Bagrodia
Journal: European Urology (2019)
Mesenchymal stem cell-derived exosomes as a nanotherapeutic agent for amelioration of inflammation-induced astrocyte alterations in mice
Authors: Panpan Xian, Yue Hei, Rui Wang, Tian Wang, Junle Yang, Jianying Li, Zhengli Di, Zhiqin Liu, Andrius Baskys, Weiping Liu, Shengxi Wu, Qianfa Long
Journal: Theranostics (2019)

Mesenchymal stem cell-derived exosomes (MSC-Exo) have robust anti-inflammatory effects in the treatment of neurological diseases such as epilepsy, stroke, or traumatic brain injury. While astrocytes are thought to be mediators of these effects, their precise role remains poorly understood. To address this issue, we investigated the putative therapeutic effects and mechanism of MSC-Exo on inflammation-induced alterations in astrocytes. Methods: Lipopolysaccharide (LPS)-stimulated hippocampal astrocytes in primary culture were treated with MSC-Exo, which were also administered in pilocarpine-induced status epilepticus (SE) mice. Exosomal integration, reactive astrogliosis, inflammatory responses, calcium signaling, and mitochondrial membrane potentials (MMP) were monitored. To experimentally probe the molecular mechanism of MSC-Exo actions on the inflammation-induced astrocytic activation, we inhibited the nuclear factor erythroid-derived 2, like 2 (Nrf2, a key mediator in neuroinflammation and oxidative stress) by sgRNA (in vitro) or ML385 (Nrf2 inhibitor) in vivo. Results: MSC-Exo were incorporated into hippocampal astrocytes as well as attenuated reactive astrogliosis and inflammatory responses in vitro and in vivo. Also, MSC-Exo ameliorated LPS-induced aberrant calcium signaling and mitochondrial dysfunction in culture, and SE-induced learning and memory impairments in mice. Furthermore, the putative therapeutic effects of MSC-Exo on inflammation-induced astrocytic activation (e.g., reduced reactive astrogliosis, NF-κB deactivation) were weakened by Nrf2 inhibition. Conclusions: Our results show that MSC-Exo ameliorate inflammation-induced astrocyte alterations and that the Nrf2-NF-κB signaling pathway is involved in regulating astrocyte activation in mice. These data suggest the promising potential of MSC-Exo as a nanotherapeutic agent for the treatment of neurological diseases with hippocampal astrocyte alterations.
When the levee breaks: a practical guide to sketching algorithms for processing the flood of genomic data
Authors: Will P. M. Rowe
Journal: Genome biology (2019)

Abstract Considerable advances in genomics over the past decade have resulted in vast amounts of data being generated and deposited in global archives. The growth of these archives exceeds our ability to process their content, leading to significant analysis bottlenecks. Sketching algorithms produce small, approximate summaries of data and have shown great utility in tackling this flood of genomic data, while using minimal compute resources. This article reviews the current state of the field, focusing on how the algorithms work and how genomicists can utilize them effectively. References to interactive workbooks for explaining concepts and demonstrating workflows are included at https://github.com/will-rowe/genome-sketching .
Abstract 15075: Genomic Risk Stratification Predicts All-Cause Mortality After Cardiac Catheterization
Authors: Michael Levin, Rachel Kember, Renae Judy, David Birtwell, Heather Williams, Jay Giri, Tom Cappola, Daniel Rader, Scott Damrauer
Journal: Circulation (2018)

Introduction: Coronary artery disease (CAD) is influenced by traditional risk factors, including diabetes, hypertension, hyperlipidemia, BMI, and smoking. More than 75 genetic loci have also been a...
Efficacy and Long-term Peripheral Sensory Neuropathy of 3 vs 6 Months of Oxaliplatin-Based Adjuvant Chemotherapy for Colon Cancer
Authors: Takayuki Yoshino, Takeharu Yamanaka, Eiji Oki, Masahito Kotaka, Dai Manaka, Tetsuya Eto, Junichi Hasegawa, Akinori Takagane, Masato Nakamura, Takeshi Kato, Yoshinori Munemoto, Shintaro Takeuchi, Hiroyuki Bando, Hiroki Taniguchi, Makio Gamoh, Manabu Shiozawa, Tsunekazu Mizushima, Shigetoyo Saji, Yoshihiko Maehara, Atsushi Ohtsu, Masaki Mori
Journal: JAMA Oncology (2019)

Oxaliplatin-based chemotherapy is associated with debilitating peripheral sensory neuropathy (PSN) for patients with stage III colon cancer.To assess disease-free survival (DFS) and long-lasting PSN in patients treated with 3 vs 6 months of adjuvant oxaliplatin-based chemotherapy.An open-label, multicenter, phase 3 randomized clinical trial of 1313 Asian patients with stage III colon cancer was conducted investigating the noninferiority of 3 vs 6 months of adjuvant oxaliplatin-based chemotherapy. From August 1, 2012, to June 30, 2014, participants were randomized to the 2 treatment groups. Data were analyzed from July 2017 to June 2018.Patients were randomized to receive 3 or 6 months of adjuvant chemotherapy. The choice of chemotherapy regimen, with the drugs modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or capecitabine plus oxaliplatin (CAPOX), was at the discretion of the treating physician.The primary outcome was DFS. Secondary end points included the evaluation of PSN for up to 3 years and overall survival.Of the 1313 patients (651 were women and mean age was 66 [range, 28-85] years) enrolled and randomized, 22 were not treated because 10 were unable to begin treatment within 2 weeks of enrollment, 7 withdrew their consent, and 5 were not treated for various other reasons. Of 1291 patients treated (650 in the 3-month arm and 641 in the 6-month arm), 969 (75%) received the chemotherapy drug CAPOX. The hazard ratio (HR) for DFS of the 3-month arm compared with the 6-month arm was 0.95 (95% CI, 0.76-1.20). Hazard ratios were 1.07 (95% CI, 0.71-1.60) and 0.90 (95% CI, 0.68-1.20) for the drugs mFOLFOX6 and CAPOX, and 0.81 (95% CI, 0.53-1.24) and 1.07 (95% CI, 0.81-1.40) for patients with low-risk disease (TNM classification stages T1-3 and N1) and high-risk disease (stages T4 or N2), respectively. The rates of any grade of PSN lasting for 3 years in the 3-month vs 6-month treatment arms were 9.7% vs 24.3% (P < .001). Incidence of PSN lasting for 3 years was significantly lower for patients treated with CAPOX than for patients treated with mFOLFOX6 in both the 3-month (7.9% vs 15.7%; P = .04) and 6-month arms (21.0% vs 34.1%; P = .02).The incidence of long-lasting PSN was significantly lower for 3 months than for 6 months of therapy, and significantly lower for treatment with the drug CAPOX than with mFOLFOX6. Since the shortened therapy duration did not compromise outcomes, a 3-month course of CAPOX may be the most appropriate treatment option, particularly for patients with low-risk disease.UMIN Clinical Trials Registry: UMIN000008543.
Outcomes Based on CNS Disease Status in Pediatric Acute Myeloid Leukemia and the Role of Peripheral Blood Contamination in Diagnostic Lumbar Punctures; A Report from the Children's Oncology Group Studies AAML0531 and AAML1031
Authors: Matthew A. Kutny, Todd A Alonzo, Robert B Gerbing, Yi-Cheng Wang, Richard Aplenc, Alan S Gamis, James Feusner, William G. Woods, Soheil Meshinchi, Donna Johnston
Journal: Blood (2017)
Unsuspected Protumorigenic Signaling Role for the Oncometabolite GABA in Advanced Prostate Cancer
Authors: Renea A. Taylor, Matthew J. Watt
Journal: Cancer Research (2019)

Abstract Elucidating the events that underpin the transition from androgen-dependent to castrate-resistant prostate cancer (CRPC) remains a clinical challenge. In this issue of Cancer Research, Gao and colleagues identify that the γ-aminobutyric acid (GABA) shunt is upregulated with the onset of CRPC, via phosphorylation and activation of glutamate decarboxylase (GAD) 65. Overproduction of GABA, an oncometabolite, can directly regulate nuclear androgen receptor signaling to drive tumorigenesis, thereby providing a link between aberrant metabolism and protumorigenic signaling in advanced prostate cancer. The findings from this study support exploring the GABA shunt, GAD65 in particular, as a molecular target in the treatment of CRPC. See related article by Gao et al., p. 4638
Improving Response to FLT3 Inhibitors–BCL2 the Rescue?
Authors: Alexander E. Perl
Journal: Clinical Cancer Research (2019)

As single agents, FLT3 inhibitors are active in FLT3-mutated acute myeloid leukemia (AML) therapy but not curative. The BCL2 inhibitor, venetoclax, enhances responses to low intensity AML chemotherapy but its activity is limited by MCL1 upregulation. FLT3 inhibitors downregulate MCL1 and synergize with venetoclax in preclinical AML models.See related article by Ma et al., p. 6815.
Targeted inhibition of STAT3 as a potential treatment strategy for atherosclerosis
Authors: Qi Chen, Jianjun Lv, Wenwen Yang, Baoping Xu, Zheng Wang, Zihao Yu, Jiawei Wu, Yang Yang, Yuehu Han
Journal: Theranostics (2019)

Atherosclerosis is the main pathological basis of ischemic cardiovascular and cerebrovascular diseases and has attracted more attention in recent years.Multiple studies have demonstrated that the signal transducer and activator of transcription 3 (STAT3) plays essential roles in the process of atherosclerosis.Moreover, aberrant STAT3 activation has been shown to contribute to the occurrence and development of atherosclerosis.Therefore, the study of STAT3 inhibitors has gradually become a focal research topic.In this review, we describe the crucial roles of STAT3 in endothelial cell dysfunction, macrophage polarization, inflammation, and immunity during atherosclerosis.STAT3 in mitochondria is mentioned as well.Then, we present a summary and classification of STAT3 inhibitors, which could offer potential treatment strategies for atherosclerosis.Furthermore, we enumerate some of the problems that have interfered with the development of mature therapies utilizing STAT3 inhibitors to treat atherosclerosis.Finally, we propose ideas that may help to solve these problems to some extent.Collectively, this review may be useful for developing future STAT3 inhibitor therapies for atherosclerosis.
A hMTR4‐PDIA3P1‐miR‐125/124‐TRAF6 Regulatory Axis and Its Function in NF kappa B Signaling and Chemoresistance
Authors: Chen Xie, Li‐Zhen Zhang, Zhan‐Li Chen, Wang‐Jing Zhong, Jian‐Hong Fang, Ying Zhu, Man‐Huan Xiao, Zhi‐Wei Guo, Na Zhao, Xionglei He, Shi‐Mei Zhuang
Journal: Hepatology (2019)

Background and Aims DNA damage‐induced NF‐κB activation is a major obstacle to effective antitumour chemotherapy. Long noncoding RNAs (lncRNAs) that regulate chemoresistance of cancer cells remain largely unknown. This study aimed to characterize the lncRNAs that may affect chemotherapy sensitivity. Approach and Results We found that lncRNA PDIA3P1 (protein disulfide isomerase family A member 3 pseudogene 1) was up‐regulated in multiple cancer types and following treatment with DNA‐damaging chemotherapeutic agents, like doxorubicin (Dox). Higher PDIA3P1 level was associated with poorer recurrence‐free survival of human hepatocellular carcinoma (HCC). Both gain‐of‐function and loss‐of‐function studies revealed that PDIA3P1 protected cancer cells from Dox‐induced apoptosis and allowed tumor xenografts to grow faster and to be more resistant to Dox treatment. Mechanistically, miR‐125a/b and miR‐124 suppressed the expression of tumor necrosis factor receptor‐associated factor 6 (TRAF6), but PDIA3P1 bound to miR‐125a/b/miR‐124 and relieved their repression on TRAF6, leading to activation of the nuclear factor kappa B (NF‐κB) pathway. Consistently, the effect of PDIA3P1 inhibition in promoting Dox‐triggered apoptosis was antagonized by silencing the inhibitor of κBα (IκBα) or overexpressing TRAF6. Administration of BAY 11‐7085, an NF‐κB inhibitor attenuated PDIA3P1‐induced resistance to Dox treatment in mouse xenografts. Moreover, up‐regulation of PDIA3P1 was significantly correlated with elevation of TRAF6, phosphorylated p65, or NF‐κB downstream anti‐apoptosis genes in human HCC tissues. These data indicate that enhanced PDIA3P1 expression may confer chemoresistance by acting as a microRNA sponge to increase TRAF6 expression and augment NF‐κB signaling. Subsequent investigations into the mechanisms of PDIA3P1 up‐regulation revealed that human homologue of mRNA transport mutant 4 (hMTR4), which promotes RNA degradation, could bind to PDIA3P1, and this interaction was disrupted by Dox treatment. Overexpression of hMTR4 attenuated Dox‐induced elevation of PDIA3P1, whereas silencing hMTR4 increased PDIA3P1 level, suggesting that Dox may up‐regulate PDIA3P1 by abrogating the hMTR4‐mediated PDIA3P1 degradation. Conclusion There exists a hMTR4‐PDIA3P1‐miR‐125/124‐TRAF6 regulatory axis that regulates NF‐κB signaling and chemoresistance, which may be exploited for anticancer therapy.
Suppression of monosodium urate crystal-induced inflammation by inhibiting TGF-β-activated kinase 1-dependent signaling: role of the ubiquitin proteasome system
Authors: Anil K. Singh, Mahamudul Haque, Kayla O’Sullivan, Mukesh Chourasia, Madhu M. Ouseph, Salahuddin Ahmed
Journal: Cellular and Molecular Immunology (2019)
Point‐of‐care biomarkers in asthma management: Time to move forward
Authors: Kjell Alving, Zuzana Diamant, Sarah Lucas, Helgo Magnussen, Ian D. Pavord, Giorgio Piacentini, David Price, Nicolas Roche, Joaquin Sastre, Mike Thomas, Omar Usmani, Leif Bjermer
Journal: Allergy (2019)
Histone H3 modifying genes may serve as a predictive marker for metastasis in synovial sarcoma.
Authors: Achal Awasthi, Nathan David Seligson, Sherri Z. Millis, John L. Hays, James Lin Chen
Journal: Journal of Clinical Oncology (2019)

11058 Background: Synovial sarcomas (SS) are rare, mesenchymal tumors that exhibit heterogeneous clinical behavior. SS is characterized molecularly by a fusion of the SS18 and one of three SSX genes. While fusion type has been shown to play a role in prognosis, little is known regarding the role of secondary genomic variants in SS. We hypothesized that frequently mutated secondary mutations corresponded to altered molecular pathways associated with accelerated disease progression. Here we present further analysis of the largest study of secondary SS genomic alterations and their potential clinical implications particularly in regard to Histone H3 modifying genes. Methods: Comprehensive Genomic Profiling (CGP) from 203 SS18-SSX fusion positive SS subjects were obtained from Foundation Medicine (FMI). Correlation between gene expression and survival endpoints were assessed in two independent datasets (GSE40018, n = 34; GSE40021, n = 58). A histone H3 score (HH3 Score ) was calculated through summation of expression values of MLL2, MLL3, SETD2. Altered expression was assessed for genes mutated in &gt; 5% of SS in the FMI dataset. Datasets were also combined with appropriate adjustments for multivariate analysis. Cox proportional hazard, and Chi-squared test were used as appropriate. Results: In CGP profiling of SS, only 4 genes were seen in &gt; 5% of subjects ( MLL3 9%, SETD2 7%, MYO18A 6%, MLL2 6%). 3 of these variants are known to regulate histone H3 activity and are collectively altered in 22% (44 of 203) of the FMI SS subjects. Notably, these H3 targeted gene alterations were found to be mutually exclusive of one another (p &lt; 0.001). In 2 independent SS datasets, subjects with high histone H3 modifying gene RNA expression levels (HH3 Score ) demonstrated worsened outcomes with earlier tumor metastasis (GSE40018: HR = 0.41, 95%CI 0.15-1.07, p = 0.07; GSE40021: HR = 0.22, 95%CI 0.09-0.52, p &lt; 0.001). Multivariate analysis demonstrated that HH3 Score remained significantly correlated to metastasis-free survival (HR = 0.41, 95%CI 0.22-0.77, p &lt; 0.01) when subjects’ age (p &lt; 0.001) and fusion type (p = 0.60) were taken into consideration. Conclusions: Altered expression of histone H3 modifying genes may serve as a key driver for SS progression. Further prospective research is necessary to confirm its prognostic importance.
More positive attitude and less symptom burden for male smokers with lung cancer.
Authors: Zhimin Niu, Yongsheng Wang
Journal: Journal of Clinical Oncology (2013)

e20692 Background: Cigarette smoking causes many kinds of cancer, and it is more closely related with lung cancer, rather than other cancers. Smoking is the leading cause of lung cancer and ninety percent of the smokers are male in China, but there is little published data concerning the psychological responses in the male smokers with lung cancer and its influence on the symptom burden. The aim of the study is to verify the hypothesis that male smokers with lung cancer have more positive attitude and less symptom burden, comparing to male non-smokers. Methods: 194 men with cancer in West China Hospital, Sichuan, China, were assessed by self-administered questionnaire. Psychological response was measured by the Chinese version of Mini-Mental Adjustment to Cancer scale (Mini-MAC), and symptom burden was measured by the physical symptom distress scale from the Rotterdam Symptom Checklist (RSCL). Results: We found that smokers with lung cancer got higher scores in Positive Attitude and less symptom burden than non-smokers. Patients with degrees lower than high school got higher scores of positive attitude comparing to college graduate patients (p=0.038). Smokers with lung cancer who knew the potential carcinogenicity of cigarette showed less negative emotion (p=0.011). The psychological response was not affected by age, clinical stage, cell type, smoking duration and amount. Conclusions: Our study suggests that smokers with lung cancer have more positive attitude and less symptom burden, and prone to accept subsequent treatment.