tbuckley/cabot-search huggingface dataset:
The therapeutic potential of second and third generation CB1R antagonists
Authors: Resat Cinar, Malliga R. Iyer, George Kunos
Journal: Pharmacology & Therapeutics (2020)

Endocannabinoids acting via CB1 receptors (CB1R) play a critical role in regulating energy homeostasis, which was the rationale for the pharmaceutical development of CB1R antagonists for the treatment of obesity. Although the first-in-class CB1R antagonist rimonabant proved to be effective in mitigating obesity and its multiple cardiometabolic complications, it was withdrawn from clinical use due to CNS-mediated neuropsychiatric side effects, which halted the further therapeutic development of the whole class of these compounds. Compared to the brain, CB1Rs are expressed at low yet functional levels in peripheral organs involved in regulating energy homeostasis, including liver, skeletal muscle, adipose tissue and endocrine pancreas. In recent preclinical studies, selective targeting of these receptors by 'second generation' peripherally restricted CB1R antagonists replicated the metabolic benefits of rimonabant in rodent models of obesity and diabetes without causing CNS-mediated side effects. Increased CB1R activity also contributes to complex, multifactorial disorders such as various forms of tissue fibrosis, treatment of which may benefit from simultaneous engagement of more than one therapeutic target. Accordingly, novel 'third generation' hybrid inhibitors of peripheral CB1R and inducible NO synthase were tested in mouse models of liver and pulmonary fibrosis where their antifibrotic efficacy was found to exceed the efficacy of drugs that inhibit only one of these targets. In this review, we will discuss the challenges and opportunities offered by second and third generation CB1R antagonists and their potential therapeutic uses.
An Intraocular Pressure Polygenic Risk Score Stratifies Multiple Primary Open-Angle Glaucoma Parameters Including Treatment Intensity
Authors: Ayub Qassim, Emmanuelle Souzeau, Owen M. Siggs, Mark M. Hassall, Xikun Han, Helen L. Griffiths, N. Andrew Frost, Neeru A. Vallabh, James F. Kirwan, Geeta Menon, Angela J. Cree, Anna Galanopoulos, Ashish Agar, Paul R. Healey, Stuart L. Graham, John Landers, Robert J. Casson, Puya Gharahkhani, Colin E. Willoughby, Alex W. Hewitt, Andrew J. Lotery, Stuart MacGregor, Jamie E. Craig
Journal: Ophthalmology (2020)
H‐Ras Transformation of Mammary Epithelial Cells Induces ERK‐Mediated Spreading on Low Stiffness Matrix
Authors: Christopher Plunkett, Aditya Kumar, Jaime Yrastorza, Yang‐Hsun Hou, Jesse K. Placone, Gillian Grennan, Adam J. Engler
Journal: Advanced Healthcare Materials (2020)

Abstract Oncogenic transformation of mammary epithelial cells (MECs) is a critical step in epithelial‐to‐mesenchymal transition (EMT), but evidence also shows that MECs undergo EMT with increasing matrix stiffness; the interplay of genetic and environmental effects on EMT is not clear. To understand their combinatorial effects on EMT, premalignant MCF10A and isogenic Ras‐transformed MCF10AT are cultured on polyacrylamide gels ranging from normal mammary stiffness, ≈150 Pa, to tumor stiffness, ≈5700 Pa. Though cells spread on stiff hydrogels independent of transformation, only 10AT cells exhibit heterogeneous spreading behavior on soft hydrogels. Within this mixed population, spread cells exhibit an elongated, mesenchymal‐like morphology, disrupted localization of the basement membrane, and nuclear localization of the EMT transcription factor TWIST1. MCF10AT spreading is not driven by typical mechanosensitive pathways including YAP and TGF‐β or by myosin contraction. Rather, ERK activation induces spreading of MCF10AT cells on soft hydrogels and requires dynamic microtubules. These findings indicate the importance of oncogenic signals, and their hierarchy with substrate mechanics, in regulating MEC EMT.
Lux-Lung 3: Afatinib Versus Cisplatin and Pemetrexed in Japanese Patients with Adenocarcinoma of the Lung Harboring an EGFR Mutation
Authors: N. Yamamoto, M. Schuler, K. O'Byrne, V. Hirsh, T. Mok, T. Kato, H. Yoshioka, I. Okamoto, A Yokoyama, D. Massey, H. Jones, V. Zazulina, M. Shahidi, L. Sequist, J.C.-H. Yang
Journal: Annals of Oncology (2012)
Pain Palliation of Bone Metastases Using Magnetic Resonance Guided Focused Ultrasound - Multi-Center Multi-trial Results
Authors: R. Catane, D. Gianfelice, M. Kawasaki, D. Iozeffi, S. Kanyev, A. Napoli, P. Ghanouni, G. Lo, Y. Inbar, L. Shay Levi
Journal: Annals of Oncology (2012)
Fyn Kinase Is Involved in EPO Receptor Signaling and Is Required to Harmonize the Response to Oxidation
Authors: Elisabetta Beneduce, Alessandro Mattè, Luigia De Falco, Serge Cedrick, Emanuela Tolosano, Deborah Chiabrando, Angela Siciliano, Achille Iolascon, Mohandas Narla, Lucia De Franceschi
Journal: Blood (2017)
MCM As A Useful Biomarker For Graded Differentiation In Urothelial Cancer
Authors: N. Narine, D.N. Rana, G. Stewart, B.M. Thottakam, A. Donnini, A. Wilson, B. Turner, W. Burrill, K. Saeb-Parsy, D. Harrison
Journal: Annals of Oncology (2012)
Detection in two hospitals of transferable ceftazidime-avibactam resistance in Klebsiella pneumoniae due to a novel VEB β-lactamase variant with a Lys234Arg substitution, Greece, 2019
Authors: E. Voulgari, S.D. Kotsakis, P. Giannopoulou, E. Perivolioti, L.S. Tzouvelekis, V. Miriagou
Journal: Eurosurveillance (2020)

Two ceftazidime-avibactam (CAZ-AVI)-resistant Klebsiella pneumoniae carbapenemase (KPC)-positive K. pneumoniae strains, including one pandrug resistant, were isolated in 2019 from two Greek hospitals. The strains were sequence types (ST)s 258 and 147 and both harboured similar self-transmissible IncA/C2 plasmids encoding a novel Lys234Arg variant of the Vietnamese extended-spectrum β-lactamase (VEB)-1, not inhibited by AVI (VEB-25). Conjugal transfer of VEB-25-encoding plasmids to Escherichia coli yielded CAZ-AVI-resistant clones, supporting that VEB-25 is directly linked to the derived phenotype.
Bronchoscopic Intervention for Airway Stenosis Caused by Thyroid Tumor
Authors: C. Kitagawa, M. Oki, Y. Murakami, K. Hori, Y. Funahashi, S. Oka, R. Tsuboi, M. Ryuge, Y. Kogure, H. Saka
Journal: Annals of Oncology (2012)
Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels as Drug Targets for Neurological Disorders
Authors: Bina Santoro, Mala M. Shah
Journal: The Annual Review of Pharmacology and Toxicology (2020)

The hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are voltage-gated ion channels that critically modulate neuronal activity. Four HCN subunits ( HCN1–4) have been cloned, each having a unique expression profile and distinctive effects on neuronal excitability within the brain. Consistent with this, the expression and function of these subunits are altered in diverse ways in neurological disorders. Here, we review current knowledge on the structure and distribution of the individual HCN channel isoforms, their effects on neuronal activity under physiological conditions, and how their expression and function are altered in neurological disorders, particularly epilepsy, neuropathic pain, and affective disorders. We discuss the suitability of HCN channels as therapeutic targets and how drugs might be strategically designed to specifically act on particular isoforms. We conclude that medicines that target individual HCN isoforms and/or their auxiliary subunit, TRIP8b, may provide valuable means of treating distinct neurological conditions.
Bevacizumab (BEV) + Low-Dose Interferon-α2A (IFN) for First-Line Treatment of Metastatic Renal Cell Carcinoma (MRCC): Final Safety and Efficacy Data from the Prospective Bevlin Study
Authors: B. Melichar, S. Bracarda, V. Matveev, A. Kaprin, B. Alekseev, R. Janciauskiene, B. Lutiger, M.E. Gore, G. Mickisch, J. Bellmunt
Journal: Annals of Oncology (2012)
Efficacy and Safety of Bevacizumab in Metastatic Colorectal Cancer (MCRC): First-Line Analysis of Pooled Data From Randomized Controlled Trials (RCTS)
Authors: F.F. Kabbinavar, H.I. Hurwitz, N.C. Tebbutt, B.J. Giantonio, Z. Guan, L. Mitchell, D. Waterkamp, J. Tabernero
Journal: Annals of Oncology (2012)
A New Era of Assessment of Entrustable Professional Activities Applied to General Pediatrics
Authors: Patricia A. Carney
Journal: JAMA Network Open (2020)

Daniel J. Schumacher, MD, MEd; Daniel C. West, MD; Alan Schwartz, PhD; Su-Ting Li, MD, MPH; Leah Millstein, MD; Elena C. Griego, MD; Teri Turner, MD, MEd, MPH; Bruce E. Herman, MD; Robert Englander, MD, MPH; Joni Hemond, MD; Valera Hudson, MD, MS; Lauren Newhall, DO; Kenya McNeal Trice, MD; Julie Baughn, MD; Erin Giudice, MD; Hannah Famiglietti, MD; Jonathan Tolentino, MD; Kimberly Gifford, MD; Carol Carraccio, MD, MA; for the Association of Pediatric Program Directors Longitudinal Educational Assessment Research Network General Pediatrics Entrustable Professional Activities Study Group
Effects of Electronic Cigarettes on Indoor Air Quality and Health
Authors: Liqiao Li, Yan Lin, Tian Xia, Yifang Zhu
Journal: Annual Review of Public Health (2020)

With the rapid increase in electronic cigarette (e-cig) users worldwide, secondhand exposure to e-cig aerosols has become a serious public health concern. We summarize the evidence on the effects of e-cigs on indoor air quality, chemical compositions of mainstream and secondhand e-cig aerosols, and associated respiratory and cardiovascular effects. The use of e-cigs in indoor environments leads to high levels of fine and ultrafine particles similar to tobacco cigarettes (t-cigs). Concentrations of chemical compounds in e-cig aerosols are generally lower than those in t-cig smoke, but a substantial amount of vaporized propylene glycol, vegetable glycerin, nicotine, and toxic substances, such as aldehydes and heavy metals, has been reported. Exposures to mainstream e-cig aerosols have biologic effects but only limited evidence shows adverse respiratory and cardiovascular effects in humans. Long-term studies are needed to better understand the dosimetry and health effects of exposures to secondhand e-cig aerosols.
Association of the Polymorphism rs13259960 in <i><scp>SLEAR</scp></i> With Predisposition to Systemic Lupus Erythematosus
Authors: Zhen Fan, Xiaowei Chen, Lu Liu, Caihong Zhu, Jinhua Xu, Xianyong Yin, Yujun Sheng, Zhengwei Zhu, Leilei Wen, Xianbo Zuo, Xiaodong Zheng, Yaohua Zhang, Jingkai Xu, He Huang, Fusheng Zhou, Liangdan Sun, Jianjun Luo, Dongdong Zhang, Xiaomin Chen, Ya Cui, Yajing Hao, Yong Cui, Xuejun Zhang, Runsheng Chen
Journal: Arthritis & Rheumatology (2020)

Objective Genome‐wide association studies have identified many susceptibility loci for systemic lupus erythematosus ( SLE ). However, most of these loci are located in noncoding regions of the genome. Long noncoding RNA s (lnc RNA s) are pervasively expressed and have been reported to be involved in various diseases. This study aimed to explore the genetic significance of lnc RNA s in SLE . Methods A genome‐wide survey of SLE risk variants in lnc RNA gene loci was performed in Han Chinese subjects (4,556 with SLE and 9,451 healthy controls). The functional relevance of an SLE risk variant in one of the lnc RNA genes was explored using biochemical and molecular cell biology analyses. In vitro loss‐of‐function and gain‐of‐function strategies were used to clarify the functional and phenotypic relevance of this SLE susceptibility lnc RNA . Moreover, correlation of this lnc RNA with the degree of apoptosis in the peripheral blood of SLE patients was evaluated. Results A novel SLE susceptibility locus in a lnc RNA gene, designated SLEAR (for SLE ‐associated RNA ), was identified at the single‐nucleotide polymorphism rs13259960 (odds ratio 1.35, P combined = 1.03 × 10 −11 ). The A&gt;G variation at rs13259960, located in an intronic enhancer, was found to impair STAT 1 recruitment to the enhancer that loops to the SLEAR promoter, resulting in decreased SLEAR production in peripheral blood mononuclear cells from patients with SLE (3 with the G/G genotype, 22 with A/G, and 103 with A/A at rs13259960; P = 0.0241). Moreover, SLEAR interacted with the RNA binding proteins interleukin enhancer binding factor 2, heterogeneous nuclear RNP F, and TATA ‐binding protein–associated factor 15, to form a complex for transcriptional activation of the downstream antiapoptotic genes. In addition, SLEAR regulated apoptosis of Jurkat cells in vitro, and its expression level was correlated with the degree of cell death in the peripheral blood of patients with SLE (r = 0.824, P = 2.15 × 10 −8 ; n = 30). Conclusion These findings suggest a mechanism by which the risk variant at rs13259960 modulates SLEAR expression and confers a predisposition to SLE . Taken together, these results may give insights into the etiology of SLE .
Prospective study reveals a microbiome signature that predicts the occurrence of post-operative enterocolitis in Hirschsprung disease (HSCR) patients
Authors: Weibing Tang, Yang Su, Chen Yuan, Yuqing Zhang, Lingling Zhou, Lei Peng, Pin Wang, Guanglin Chen, Yang Li, Hongxing Li, Zhengke Zhi, Hang Chang, Bo Hang, Jian-Hua Mao, Antoine M. Snijders, Yankai Xia
Journal: Gut Microbes (2020)

Hirschsprung disease (HSCR) is a birth defect with an approximate incidence of 1/5,000 live births, and up to one-third of HSCR patients develop Hirschsprung-associated enterocolitis (HAEC), the leading cause of HSCR-related death. Very little is known about the pathogenesis, prevention, and early diagnosis of HAEC. Here, we used a prospective study to investigate the enteric microbiome composition at the time of surgery as a predictor for developing postoperative HAEC. We identified a microbiome signature containing 21 operational taxonomic units (OTUs) that can potentially predict postoperative HAEC with ~85% accuracy. Furthermore, we identified exclusive breastfeeding as a novel protective factor for total HAEC (i.e., preoperative and postoperative HAEC combined). In addition, we discovered that breastfeeding was associated with a lowered risk for HAEC potentially mediated by modulating the gut microbiome composition characterized by a lower abundance of Gram-negative bacteria and lower LPS concentrations. In conclusion, modulating the gut microbiome by encouraging breastfeeding might prevent HAEC progression in HSCR patients.
Response to: ‘Polyfunctional TEM cells in psoriatic arthritis synovium skewed towards Th17 cells’ by Raychaudhuri <i>et al</i>
Authors: Mary Canavan, Sarah M Wade, Douglas J Veale, Ursula Fearon
Journal: Annals of the Rheumatic Diseases (2020)

We read with interest the research letter by Raychaudhuri et al , which examines the frequencies of cytokine producing CD4+ memory T cells in psoriatic arthritis (PsA) and rheumatoid arthritis (RA) synovial fluid mononuclear cells (SFMC) compared with peripheral blood mononuclear cells (PBMC).1 The authors examined the frequencies of single cytokine-producing T cells, specifically interleukin (IL)-17A+, IL-22+, tumour necrosis factor (TNF)+, interferon gamma (IFNγ)+ or IL-23R+ and report that Th17 cells are enriched in PsA SFMC, while RA is skewed to a Th1-like profile. In our previous publication, Wade et al ,2 we reported the frequencies of both single cytokine-producing and multiple cytokine (polyfunctional)-producing T cells, in addition to the frequencies of Th1, Th17 and exTh17 cells by using the Th17 lineage marker CD161. In our study, however, we reported these findings in synovial tissue biopsies from PsA patients, as opposed to …
Inactivation of the nuclear receptor TR3 as an important new drug target for treating RCC.
Authors: Maen Abdelrahim, Stephen Safe, Ala Abudayyeh
Journal: Journal of Clinical Oncology (2013)

e15618 Background: The high mortality of patients with RCC is due to poor performance of most chemotherapy. There is a critical need for development of new mechanism-based drugs.The nuclear orphan receptor NR4A1 (TR3, Nur77) are immediate early genes activated by various stressors. NR4A is highly expressed in multiple tumors. TR3 knockdown studies show that TR3 plays an important role in cancer cell growth and angiogenesis. The pro-oncogenic activity of this receptor is an excellent example of “non-oncogene addiction” which is essential for maintaining the cancer cell/tumor phenotype. Methods: Multiple RCC cell lines have been used. Several different classes of C-substituted DIMs summarized in Fig1 has been screened for TR3 deactivation in RCC cell lines using GAL4-TR3/UAS-luc constructs (Fig1). Effects of the C-DIM compounds on cancer cell growth and expression of Sp-regulated genes has been determined by cell counting, the MTT assay, western blot and activation of caspases 3 and 9 and directly compared to knockdown of TR3 by RNAi. Results: Knockdown of TR3 by RNAi has confirmed that TR3 is pro-oncogenic and we have focused on structure-activity relations (SARs) of C-DIM analogs to identify compounds that inactivate TR3. Renal cancer cells were treated with c-DIM TR3 inactivators and this significantly inhibited cell proliferation (Figs 2 and 3). Expression of TR3 in RCC cell lines has not previously been reported. Fig. 4 presents a western blot of cell lysates showing that TR3 is expressed in these cell lines. TR3 inactivators decreased expression of survivin and bcl-2 and this was accompanied by several apoptotic markers. These results show that RCC cells not only express TR3 but TR3 inactivators decrease the pro-survival genes and induce apoptosis which confirm that TR3 is also a target for renal cancer therapy. TR3 pro-oncogenic activity is due, in part, to the role of TR3 in constitutive expression of survivin and other Sp-regulated genes (VEGF, c-MET..). TR3 also involves in formation of a complex with p53 which inactivates the tumor suppressor gene. Thus inactivation of TR3 activates p53 pathway (Fig 5). Conclusions: TR3 is overexpressed in RCC. We have shown for the first time that TR3 is an important new drug target for treating RCC.
<i>Fusobacterium nucleatum</i> promotes colorectal cancer metastasis by modulating <i>KRT7-AS</i>/KRT7
Authors: Shujie Chen, Tingting Su, Ying Zhang, Allen Lee, Jiamin He, Qiwei Ge, Lan Wang, Jianmin Si, Wei Zhuo, Liangjing Wang
Journal: Gut Microbes (2020)

The enrichment of Fusobacterium nucleatum (Fn) has been identified in CRC patients and associated with worse outcomes. However, whether Fn was involved in the metastasis of CRC was not well determined. Here, we found that the abundance of Fn was significantly increased in CRC patients with lymph nodes metastasis. To further clarify the role of Fn in CRC metastasis, we performed transwell and wound healing assays after incubating CRC cell lines with or without Fn and injected Fn-treated or untreated CRC cells into nude mice via tail vein. The results indicated that Fn infection promoted CRC cells migration in vitro, as well as lung metastasis in vivo. Interestingly, colonization of Fn was detected in metastatic lung lesions of nude mice by fluorescence in situ hybridization. Mechanistically, RNA sequencing and validation study revealed that Fn significantly upregulated the expression of long non-coding RNA Keratin7-antisense (KRT7-AS) and Keratin7 (KRT7) in CRC cells. Importantly, Fn-induced CRC lung metastasis was attenuated by the depletion of KRT7-AS. In addition, KRT7-AS facilitated CRC cells migration by upregulating KRT7. Subsequently, we found that NF-κB signaling pathway was involved in the upregulation of KRT7-AS upon Fn infection. In conclusion, Fn infection upregulated KRT7-AS/KRT7 by activating NF-κB pathway, which promoted CRC cell migration in vitro and metastasis in vivo.
Turkish National Pediatric Cancer Registry 2002-2008 (Turkish Pediatric Oncology Group and Turkish Pediatric Hematology Society).
Authors: M. Tezer Kutluk, Akif Yesilipek
Journal: Journal of Clinical Oncology (2013)

10067 Background: In childhood cancers cure rates increased up to 80% in the developed countries. On the other hand cure rates goes down 10-20% percent in countries with low resource settings. Reliable pediatric cancer data is essential for all countries. We established a nationwide pediatric cancer registry. Methods: Turkish Pediatric Oncology &amp; Pediatric Hematology Society established a web-based database for the registry of all pediatric cancers. 11898 cases were registered between 2002-2008 from 65 centers. Various demographic data &amp; survival endpoints were recorded &amp; analyzed. Diseases were grouped according to the International Classification of Childhood Cancer. Results: In all 11898 cases, median age was 6 years (M/F= 6786/5112=1.32). Distribution in age groups were: 0-4 years, 42.5%; 5-9 years, 27.2%; 10-14 years, 23.4%; 15-19 years, 6.8%; &gt;19 years, 0.1%. Only 3.8% of cases were diagnosed with clinical+radiological, the rest with histopathological data Distribution of cases in disease groups were [median age in yrs, M/F]: Leukemias (n=3777) 31.7% [5.5, 2137/1640=.31]; Lymphomas (n=2040) 17.1% [8.3, 1405/635=2.21]; CNS tumors (n=1588) 13.3% [6.9, 913/675=1.3 ]; Sympathetic tumors (n=889) 7.5% [2.1, 453/436=1.03]; Retinoblastoma (n=371) 3.1% [2, 181/190=0.95]; Renal tumors (n=655) 5.5% [3, 333/322=1.03]; Hepatic (n=166) 1.4% [1.8, 101/65=1.5]; Bone tumors (n=717) 6% [12.2, 407/310=1.3]; Soft tissue tumors (n=773) 6.5% [6.5, 442/331=1.3]; Germ cell tumors (n=531) 4.5% [5, 210/321=0.6 ]; Carcinomas and other malignant epithelial tumors (n=323) 2.7% [12, 164/159=1.03]; Others/unspecified malignant tumors (n=68) 0.6% [4.5, 40/28=1.4]. Five-year overall survival in all cases was 65%. Conclusions: This registry provides a critical information about the distribution of childhood cancer since this is the only nationwide pediatric cancer registry in Turkey. With the recent trends in non-communicable diseases at global level, registry data will be very helpful for national cancer control plans, which will also be used to compare at national and international level. This will also be a good example for many other countries with similar resources to do such projects.
Limited Predictive Value of Scoring Systems for Metastatic Spinal Cord Compression (MSCC): Restrospective Monocentric Study
Authors: E. Tabouret, C. Cauvin, S. Fuentes, B. Esterni, T. Adetchessi, N. Salem, A. Madroszyk, A. Gonçalves, P. Viens, G. Gravis-Mescam
Journal: Annals of Oncology (2012)
Bifractionated CPT-11 with LV5FU2 Infusion (FOLFIRI-3) In Combination with Bevacizumab Followed by a Capecitabine and Bevacizumab Maintenance Therapy: A Phase II Study in First-Line Metastatic Colorectal Cancers
Authors: C.H.S. Kim, E. Curti, T. Nguyen, T. Maurina, Z. Lakkis, B. Heyd, E. Dobi, S. Fratte, B. Winkfield, C. Borg
Journal: Annals of Oncology (2012)
Phase III Trial of Treatment Duration for Oral Uracil and Tegaful/Leukovorin Adjuvant Chemotherapy for Patients (PTS) with Stage IIB/III Colon Cancer: Result of JFMC33-0502
Authors: K. Kondo, S. Sadahiro, T. Tsuchiya, K. Sasaki, K. Katsumata, G. Nishimura, Y. Kakeji, H. Baba, S. Kodaira, S. Saji
Journal: Annals of Oncology (2012)
Results of a Randomised Phase III Trial (EORTC 62012) of Single Agent Doxorubicin Versus Doxorubicin Plus Ifosfamide as First Line Chemotherapy for Patients with Advanced or Metastatic Soft Tissue Sarcoma: A Survival Study by the Eortc Soft Tissue and Bone Sarcoma Group
Authors: I. Judson, J. Verweij, H. Gelderblom, J.T. Hartmann, P. Schöffski, J. Blay, A.P.I. De Tos, S. Marreaud, S. Litiere, W.T.A. van der Graaf
Journal: Annals of Oncology (2012)