tbuckley/cabot-search huggingface dataset:
Response to: ‘Gut-derived CD8+ tissue-resident memory T cells are expanded in the peripheral blood and synovia of SpA patients’ by Guggino <i>et al</i>
Authors: Zoya Qaiyum, Eric Gracey, YuChen Yao, Robert D Inman
Journal: Annals of the Rheumatic Diseases (2019)

Paradox of circulating TRMs.Response to: 'Gutderived CD8+ tissue-resident memory T cells are expanded in the peripheral blood and synovia of SpA patients' by Guggino et al We were pleased to receive the correspondence of Guggino et al 1 commenting on our recent publication. 2Their studies confirm our findings of an expansion of cells with an expression profile consistent with tissue-resident memory cells (TRMs) in synovial fluid of spondyloarthritis (SpA).They have added the valuable insight that these cells are also expanded in gut tissues of patients with SpA.The CD8+ T cell in question reported by Guggino and colleagues, and the InEx cells in our paper, may well be TRMs.But at present, the field is wrestling with nomenclature.First, resident memory cells, by definition, do not leave the tissues in which they reside. 3This tissue retention is best characterised by the expression of CD69, which blocks S1PR activity, hence limiting TRMs egress from tissue to the blood where S1P levels are high. 4Second, as Guggino et al point out, many of the CD8+ T cells present in the gut are closely associated with the epithelia.CD8+ T cells in the gut epithelia are the prototypic intestinal epithelial lymphocyte (IEL), hence labelling the cells under discussion exclusively as TRMs should also acknowledge a large body of research on IEL.For example, CD8+ IEL were recently found to be depleted in gut biopsies from patients with HLA-B27+ axial SpA. 5 The interplay of gut and joint inflammation has been supported by the clinical overlap between SpA and inflammatory bowel disease (IBD) 6 and between gut infection and reactive arthritis 7 as well as shared genetic susceptibility between IBD and ankylosing spondylitis. 6Cells that posses a gutresident phenotype that are expanded in the SpA joint include TRM and mucosa-associated invariant T cells, 8 the latter contributing to the interleukin 17-mediated inflammation in axial spondyloarthritis.Therapeutic modulation of gut-joint trafficking holds the potential for novel treatment approaches to SpA.
Emerging roles of F-box proteins in cancer drug resistance
Authors: Linzhi Yan, Min Lin, Shuya Pan, Yehuda G. Assaraf, Zhi-wei Wang, Xueqiong Zhu
Journal: Drug Resistance Updates (2019)

Chemotherapy continues to be a major treatment strategy for various human malignancies. However, the frequent emergence of chemoresistance compromises chemotherapy efficacy leading to poor prognosis. Thus, overcoming drug resistance is pivotal to achieve enhanced therapy efficacy in various cancers. Although increased evidence has revealed that reduced drug uptake, increased drug efflux, drug target protein alterations, drug sequestration in organelles, enhanced drug metabolism, impaired DNA repair systems, and anti-apoptotic mechanisms, are critically involved in drug resistance, the detailed resistance mechanisms have not been fully elucidated in distinct cancers. Recently, F-box protein (FBPs), key subunits in Skp1-Cullin1-F-box protein (SCF) E3 ligase complexes, have been found to play critical roles in carcinogenesis, tumor progression, and drug resistance through degradation of their downstream substrates. Therefore, in this review, we describe the functions of FBPs that are involved in drug resistance and discuss how FBPs contribute to the development of cancer drug resistance. Furthermore, we propose that targeting FBPs might be a promising strategy to overcome drug resistance and achieve better treatment outcome in cancer patients. Lastly, we state the limitations and challenges of using FBPs to overcome chemotherapeutic drug resistance in various cancers.
NK012, a polymeric micelle formulation containing SN-38, markedly enhanced the antitumor activity of SN-38 against orthotopic glioblastoma multiforme tumors in a mouse model
Authors: Jun-ichiro Kuroda, Masahiro Yasunaga, Jun-ichi Kuratsu, Yasuhiro Matsumura
Journal: Cancer Research (2008)

5616  Background: The present standard therapy for glioblastoma multiforme (GBM) consists of surgery, radiotherapy and chemotherapy with nitrosoureas. However, tumors recur in almost all patients receiving the standard therapy, and the one-year survival rate is only 26%. In addition, combination chemotherapy with ifosfamide, carboplatin, and etoposide is toxic and not very effective. Thus, new modalities that will maximize the potential of cytotoxic drugs and reasonably prolong the overall survival of patients with GBM are urgently needed. NK012 is a drug formulation composed of polymeric micelles containing SN-38; about 80% of the SN-38 inside the micelles is gradually released within 48 hours under physiological conditions. The purpose of this study was to determine whether NK012 is an appropriate formulation for the treatment of GBM. Methods; We used human GBM cell lines to measure the cytotoxicity of NK012, CPT-11 and ACNU in vitro. A human GBM line, U87MG, transfected with the luciferase gene was inoculated into the brains of nude mice to analyze the pharmacokinetic character and in vivo antitumor activity of the drugs. Assays for SN-38 and CPT-11 were performed using high-performance liquid chromatography (HPLC). Fluorescence microscopy was used to examine the distribution of NK012 and CPT-11 in vivo. All statistical tests were two-sided. Results; NK012 inhibited the cell growth of human GM lines in vitro with an IC50 range of 0.01 - 0.1 nM. The growth-inhibitory effects of NK012 were 100-fold more potent than those of CPT-11, whereas the IC50 values of NK012 were almost the same as those of SN-38. Compared with CPT-11, NK012 had a significantly more potent antitumor activity against orthotopic GBM xenografts. Enhanced and prolonged distributions of free SN-38 were observed in the tumors after the injection of NK012. Conclusion: NK012 may be a promising SN-38-based formulation that enhances the antitumor activity of SN-38 in orthotopicU87MG tumors.
CDK4/6 inhibitor treatment for patients with hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer: a US Food and Drug Administration pooled analysis
Authors: Jennifer J Gao, Joyce Cheng, Erik Bloomquist, Jacquelyn Sanchez, Suparna B Wedam, Harpreet Singh, Laleh Amiri-Kordestani, Amna Ibrahim, Rajeshwari Sridhara, Kirsten B Goldberg, Marc R Theoret, Paul G Kluetz, Gideon M Blumenthal, Richard Pazdur, Julia A Beaver, Tatiana M Prowell
Journal: The Lancet Oncology (2019)
Temporal representation and reasoning in non-human animals
Authors: Angelica Kaufmann, Arnon Cahen
Journal: Behavioral and Brain Sciences (2019)

Abstract Hoerl &amp; McCormack argue that comparative and developmental psychology teaches us that “neither animals nor infants can think and reason about time.” We argue that the authors neglect to take into account pivotal evidence from ethology that suggests that non-human animals do possess a capacity to represent and reason about time, namely, work done on Sumatran orangutans’ long travel calls.
Integration of immunogenic activation and immunosuppressive reversion using mitochondrial-respiration-inhibited platelet-mimicking nanoparticles
Authors: Xiaoli Mai, Yewei Zhang, Haijian Fan, Weitong Song, Ying Chang, Bo Chen, Jiong Shi, Xiaoyan Xin, Zhaogang Teng, Jianfei Sun, Gaojun Teng
Journal: Biomaterials (2019)
Multispectral immunofluorescence and computational imaging analysis define the prognostic role of T-cell infiltrates in gastric cancer
Authors: B.R. Challoner, K. von Loga, A. Woolston, B. Griffiths, L. Hewitt, Y. Saito, N. Sivamanoharan, D. Mansfield, A.A. Melcher, H. Grabsch, M. Gerlinger
Journal: Annals of Oncology (2019)
Preventing inpatient falls with injuries using integrative machine learning prediction: a cohort study
Authors: Lin Wang, Zhong Xue, Chika F. Ezeana, Mamta Puppala, Shenyi Chen, Rebecca L. Danforth, Xiaohui Yu, Tiancheng He, Mark L. Vassallo, Stephen T. C. Wong
Journal: npj Digital Medicine (2019)

Abstract Patient falls during hospitalization can lead to severe injuries and remain one of the most vexing patient-safety problems facing hospitals. They lead to increased medical care costs, lengthened hospital stays, more litigation, and even death. Existing methods and technology to address this problem mostly focus on stratifying inpatients at risk, without predicting fall severity or injuries. Here, a retrospective cohort study was designed and performed to predict the severity of inpatient falls, based on a machine learning classifier integrating multi-view ensemble learning and model-based missing data imputation method. As input, over two thousand inpatient fall patients’ demographic characteristics, diagnoses, procedural data, and bone density measurements were retrieved from the HMH clinical data warehouse from two separate time periods. The predictive classifier developed based on multi-view ensemble learning with missing values (MELMV) outperformed other three baseline models; achieved a cross-validated AUC of 0.713 (95% CI, 0.701–0.725), an AUC of 0.808 (95% CI, 0.740–0.876) on the separate testing set. Our studies show the efficacy of integrative machine-learning based classifier model in dealing with multi-source patient data, which in this case delivers robust predictive performance on the severity of patient falls. The severe fall index provided by the MELMV classifier is calculated to identify inpatients who are at risk of having severe injuries if they fall, thus triggering additional steps of intervention to prevent a harmful fall, beyond the standard-of-care procedure for all high-risk fall patients.
Association of PARP inhibitors and docetaxel resistance through suppressing a tumor microenvironment-associated secretory program.
Authors: Song Zhao, Ilsa Coleman, Roger Coleman, Peter Nelson
Journal: Journal of Clinical Oncology (2013)

e22212 Background: Acquired resistance to therapeutics accounts for the majority of treatment failures in metastatic cancer. In response to genotoxic stress induced by therapeutics such as radiation and chemotherapy, tumor microenvironment (TME) undergoes marked molecular alterations manifested by increased secretion of cytokines and growth factors, which in turn promote tumor growth, facilitate epithelial-mesenchymal transition, and ultimately result in resistance to chemotherapy. Fibroblasts are a major component of TME and a primary source of cytokines and growth factor secretion following damage. Preliminary results from our lab indicated PARP1 may be involved in regulating this secretory program. We hypothesized that PARP inhibition would suppress the TME-associated secretory program and thereby overcome chemotherapy resistance. Methods: Transcript profiles of cytokines and growth factors were analyzed with quantitative real-time PCR and cDNA microarrays in prostate fibroblasts after treatment with radiation or docetaxel, in combination with one of three PARP inhibitors (PARPi). We evaluated the effects of the docetaxel-induced fibroblast secretory program, in the absence or presence of PARPi, on the proliferation and drug sensitivity of prostate cancer cell lines. Results: Similar to radiation, docetaxel induced the secretion of cytokines and growth factors in prostate fibroblasts. PARP1 was activated by docetaxel treatment. Exposure to PARPi suppressed the docetaxel-induced secretory program. Further analysis suggested that PARPi abrogates activation of p38MAPK pathway. While conditioned medium from docetaxel-treated prostate fibroblasts stimulated growth and chemotherapy resistance, the addition of PARPi attenuated these effects. Conclusions: Docetaxel induces extracellular secretion of pro-tumorigenic cytokines and growth factors by components of the TME. PARP inhibitors attenuated docetaxel resistance through suppression of this secretory program, supporting a new mechanism of action for this class of drugs. Combinatorial use of cytotoxic agents and microenvironment-directed therapies may reduce treatment resistance.
PIRCh-seq: functional classification of non-coding RNAs associated with distinct histone modifications
Authors: Jingwen Fang, Qing Ma, Ci Chu, Beibei Huang, Lingjie Li, Pengfei Cai, Pedro J. Batista, Karen Erisse Martin Tolentino, Jin Xu, Rui Li, Pengcheng Du, Kun Qu, Howard Y. Chang
Journal: Genome biology (2019)

We develop PIRCh-seq, a method which enables a comprehensive survey of chromatin-associated RNAs in a histone modification-specific manner. We identify hundreds of chromatin-associated RNAs in several cell types with substantially less contamination by nascent transcripts. Non-coding RNAs are found enriched on chromatin and are classified into functional groups based on the patterns of their association with specific histone modifications. We find single-stranded RNA bases are more chromatin-associated, and we discover hundreds of allele-specific RNA-chromatin interactions. These results provide a unique resource to globally study the functions of chromatin-associated lncRNAs and elucidate the basic mechanisms of chromatin-RNA interactions.
Enhancing the R‐ISS classification of newly diagnosed multiple myeloma by quantifying circulating clonal plasma cells
Authors: Wilson I. Gonsalves, Dragan Jevremovic, Bharat Nandakumar, Angela Dispenzieri, Francis K. Buadi, David Dingli, Martha Q. Lacy, Suzanne R. Hayman, Prashant Kapoor, Nelson Leung, Amie Fonder, Miriam Hobbs, Yi Lisa Hwa, Eli Muchtar, Rahma Warsame, Taxiarchis V. Kourelis, Stephen Russell, John A. Lust, Yi Lin, Ronald S. Go, Mustaqeem A. Siddiqui, Robert A. Kyle, Morie A. Gertz, S. Vincent Rajkumar, Shaji K. Kumar
Journal: American Journal of Hematology (2019)

Abstract Our prior studies identified the prognostic significance of quantifying cPCs by multiparametric flow cytometry (MFC) in newly diagnosed multiple myeloma (NDMM) patients. We evaluated if a similar quantification of cPCs could add prognostic value to the current R‐ISS classification of 556 consecutive NDMM patients seen at the Mayo Clinic, Rochester from 2009 to 2017. Those patients that had ≥5 cPCs/μL and either R‐ISS stage I or stage II disease were re‐classified as R‐ISS IIB stage for the purposes of this study. The median time to next therapy (TTNT) and overall survival (OS) for patients with ≥5 cPCs/μL at diagnosis was as follows: R‐ISS I (N = 110) ‐ 40 months and not reached; R‐ISS II (N = 69) ‐ 30 and 72 months; R‐ISS IIB (N = 96) ‐ 21 and 45 months and R‐ISS III (N = 281) ‐ 20 and 47 months respectively. Finally, ≥ 5 cPCs/μL retained its adverse prognostic significance in a multivariable model for TTNT and OS. Hence, quantifying cPCs by MFC can potentially enhance the R‐ISS classification of a subset of NDMM patients with stage I and II disease by identifying those patients with a worse than expected survival outcome.
Antibiotics: two fifths of US outpatient prescriptions may be inappropriate, study finds
Authors: Elisabeth Mahase
Journal: BMJ (2019)

As many as two in five antibiotic prescriptions (43%) provided in outpatient settings in the US could be inappropriate, a study published by The BMJ has found.1

Researchers from Oregon, USA, looked at prescriptions in ambulatory settings such as primary care and found that a quarter (25%) were deemed to be inappropriate, while a further 18% did not have an indication.

However, primary care providers (general practice, paediatrics, and internal medicine) performed the best, giving a considerably lower percentage of antibiotic prescriptions without a documented indication (12%) than other specialists such as gynaecologists and urologists, who commonly prescribed antibiotics (24%), as well as those in all other specialties (29%).

The research team …
m6A mRNA methylation regulates CTNNB1 to promote the proliferation of hepatoblastoma
Authors: Li Liu, Jing Wang, Guifeng Sun, Qiong Wu, Ji Ma, Xin Zhang, Nan Huang, Zhixuan Bian, Song Gu, Min Xu, Minzhi Yin, Fenyong Sun, Qiuhui Pan
Journal: Molecular Cancer (2019)

Abstract Background N 6 -Methyladenosine (m 6 A) modification has been implicated in many biological processes. It is important for the regulation of messenger RNA (mRNA) stability, splicing, and translation. However, its role in cancer has not been studied in detail. Here we investigated the biological role and underlying mechanism of m 6 A modification in hepatoblastoma (HB). Methods We used Reverse transcription quantitative real-time PCR (RT-qPCR) and Western blotting to determine the expression of m 6 A related factors. And we clarified the effects of these factors on HB cells using cell proliferation assay, colony formation, apoptotic assay. Then we investigated of methyltransferase-like 13 (METTL3) and its correlation with clinicopathological features and used xenograft experiment to check METTL3 effect in vivo. m 6 A-Seq was used to profiled m 6 A transcriptome-wide in hepatoblastoma tumor tissue and normal tissue. Finally, methylated RNA immunoprecipitation (MeRIP) assay, RNA remaining assay to perform the regulator mechanism of MEETL3 on the target CTNNB1 in HB. Results In this research, we discovered that m 6 A modifications are increased in hepatoblastoma, and METTL3 is the main factor involved with aberrant m 6 A modification. We also profiled m 6 A across the whole transcriptome in hepatoblastoma tumor tissues and normal tissues. Our findings suggest that m 6 A is highly expressed in hepatoblastoma tumors. Also, m 6 A is enriched not only around the stop codon, but also around the coding sequence (CDS) region. Gene ontology analysis indicates that m 6 A mRNA methylation contributes significantly to regulate the Wnt/β-catenin pathway. Reduced m 6 A methylation can lead to a decrease in expression and stability of the CTNNB1. Conclusion Overall our findings suggest enhanced m 6 A mRNA methylation as an oncogenic mechanism in hepatoblastoma, METTL3 is significantly up-regulated in HB and promotes HB development. And identify CTNNB1 as a regulator of METTL3 guided m 6 A modification in HB.
Complete colonic closure with an over-the-scope clip placed for a colorectal anastomotic fistula: a big mistake
Authors: Benedetto Mangiavillano, Francesco Auriemma, Mario Bianchetti, Alessandro Repici
Journal: Endoscopy (2019)

Colorectal postsurgical leaks and fistulas are severe complications that increase morbidity and mortality. The recent development of the over-the-scope clip (OTSC) has dramatically decreased the number of surgical reinterventions required [1].
Identification of a Novel Promiscuous Anti-NY-ESO-1 Immunogenic CD4+ Peptide Containing a CD8+ T-Cell Epitope Highly Present in Metastatic Gastric Cancer Responding to Combined Radiotherapy/Anti-PD-1 Immunotherapy
Authors: M. Merhi, A. Raza, V. Inchakalody, S. Sivaraman, F. Panayampilly, S. Mestiri, S. Hydrose, N. Allahverdi, M. Jalis, A. Relecom, L. Al Zaidan, J. Feilchenfeldt, M.S. Elkhatim Hamid, M. Mostafa, A.R. Zar Gul, S.U. Khan, S. Dermime
Journal: Annals of Oncology (2019)
Abstract I27: Pancreatic cancer immunotherapy: Moving forward
Authors: Dung T. Le
Journal: Cancer Research (2019)

Abstract As immunotherapy becomes a pillar of therapy for some of our patients with solid tumors, the role in pancreatic cancer remains limited despite a multitude of studies testing combinations of novel agents. The landscape of effective systemic therapies to date is limited to combination chemotherapy and PARP inhibitors in a small subset of patients with germline BRCA mutations. We also currently await the phase 3 data testing PEGPH20, a recombinant hyaluronidase, in combination with gemcitabine and nab-paclitaxel. These more recent studies were developed from studying and targeting the unique characteristics of pancreatic cancer based on the genomics, chemotherapy sensitivity, and tumor microenvironment characterization. Research in combination strategies that include immunotherapy agents is continuing to build on what we are actively learning about the genomics, epigenetics, RNA expression, and tumor microenvironment characterization specific to pancreatic cancer biology. Historically, studies involving single-agent immunotherapy approaches to pancreatic cancer have yielded responses in 0 or 1 patient. More recent studies with combination immunotherapy approaches with and without chemotherapy have increased the number of responders, but responses still occur in only a handful of patients except in studies where the agents are combined with chemotherapy, which may be the driver of the responses. Further characterization of the responders may help us to identify predictive biomarkers, and further understanding of the nonresponders can help drive future directions. This lecture will review the current strategies that have made it into clinical trials or strategies being proposed for further study and preliminary data that are available to support continued development. Advances in increasing T-cell delivery such as cell-based or neoantigen vaccines, modified T cells, viral and bacterial vectors, or bispecific antibodies may increase immune cell infiltration into tumors while new agonist agents promoting immune cell activation or antagonist targeting negative checkpoints or immune cell populations can increase the probability of success. The combination of increasing the number of responders and better understanding those subsets will eventually lead to additional treatment options for our patients. Citation Format: Dung T. Le. Pancreatic cancer immunotherapy: Moving forward [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr I27.
Liver‐on‐a‐Chip: In Vitro Human Liver Model of Nonalcoholic Steatohepatitis by Coculturing Hepatocytes, Endothelial Cells, and Kupffer Cells (Adv. Healthcare Mater. 24/2019)
Authors: Ceri‐Anne E. Suurmond, Soufian Lasli, Floor W. van den Dolder, Aly Ung, Han‐Jun Kim, Praveen Bandaru, KangJu Lee, Hyun‐Jong Cho, Samad Ahadian, Nureddin Ashammakhi, Mehmet R. Dokmeci, Junmin Lee, Ali Khademhosseini
Journal: Advanced Healthcare Materials (2019)

In article number 1901379, Junmin Lee, Ali Khademhosseini, and co-workers, develop an in vitro human liver model of non-alcoholic fatty liver disease (NAFLD) by co-culturing human hepatocytes, umbilical vein endothelial cells (HUVECs), and Kupffer cells (KCs) into spheroids. The proposed system is an appropriate model to mimic and monitor the progression of NAFLD from steatosis into steatohepatitis.
Association between hidradenitis suppurativa, depression, anxiety, and suicidality: A systematic review and meta-analysis
Authors: Kevin R. Patel, Harrison H. Lee, Supriya Rastogi, Paras P. Vakharia, Tammy Hua, Krishan Chhiba, Vivek Singam, Jonathan I. Silverberg
Journal: Journal of the American Academy of Dermatology (2019)
Abstract 15029: Impaired Hyperemic Myocardial Blood Flow is Associated With Subclinical Systolic Dysfunction and Myocardial Injury in Aortic Stenosis
Authors: Wunan Zhou, Yee-Ping Sun, Sanjay Divakaran, Alvin Chandra, Navkaranbir S Bajaj, Leanne Barrett, Laurel Campbell, Bibbo Courtney, Jon Hainer, Eldrin F Lewis, Viviany Taqueti, Sharmila Dorbala, Ron Blankstein, Pinak B Shah, Tsuyoshi Kaneko, Dale Adler, Patrick O’Gara, Marcelo F Di Carli
Journal: Circulation (2019)

Introduction: Impairment of hyperemic myocardial blood flow (MBF), an integrated measure of ventricular-aortic impedance and coronary microvascular dysfunction, has been observed in aortic stenosis...
Pre-therapeutic Evaluation of Patient-Specific Responses to Immune-Checkpoint Inhibition in Colorectal Cancer
Authors: T. Sturmheit, L. Konczalla, T. Sutus Temovski, A. Günther, F. Brauneck, J. Li, D. Perez, M. Jücker, J. Thastrup, W. Fiedler, J. Wellbrock, J. Kupper, A. Block
Journal: Annals of Oncology (2019)