tbuckley/cabot-search huggingface dataset:
A combination treatment of HDAC inhibitors and PPARγ agonists increase E-cadherin expression and inhibit prostate cancer growth and invasion in mice
Authors: Jean-Sebastien Annicotte, Pierre Dubus, François Iborra, Thierry Maudelonde, Stephane Culine, Lluis Fajas
Journal: Cancer Research (2006)

1785   PPARγ is a member of the hormone nuclear receptor super family, which activity is regulated by ligands. Prostaglandin J2 and the anti-diabetic drugs thiazolidinediones (TZD) have been determined as natural and synthetic ligands of PPARγ respectively. Beside its established participation in adipocyte biology and glucose homeostasis, PPARγ activation was reported to inhibit the proliferation of prostate carcinoma cells. These observations suggest that induction of differentiation by activation of PPARγ may represent a promising novel therapeutic approach for cancer, as already demonstrated in xenograft models of prostate cancer. However, a recent randomized placebo controlled clinical trial showed no effect of the PPARγ agonist rosiglitazone on the PSA doubling time in prostate cancer patients compared to the placebo arm. This suggests that PPARγ might not be permissive to ligand activation in prostate cancer cells. Association of PPARγ with repressing factors or post-translational modifications in PPARγ protein could explain this lack of effect of PPARγ ligands in cancer cells. Supporting this hypothesis we demonstrate that PPARγ activity is stimulated by several histone deacetylase (HDAC) inhibitors. We previously showed that HDAC3 is complexed with PPARγ and that this association results in the repression of PPARγ target genes, in a ligand dependent manner. Consequently, HDAC inhibitors had a synergistic effect with TZDs in the activation of PPAR-target genes. Using prostate cancer xenograft mice models we demonstrate in this study that the combination therapy using the PPARγ agonist pioglitazone and the HDAC inhibitor valproic acid is more efficient in inhibiting prostate tumor growth than each individual therapy. We show that the combination treatment impairs bone-invasive potential of prostate cancer cells in mice. We demonstrate that expression of E-cadherin, which is a protein involved in the control of cell migration and invasion is highly up regulated in the presence of valproic acid and pioglitazone. Furthermore, we show that E-cadherin expression responds only to the combination treatment, and not to single PPARγ agonists. This defines a new class of PPARγ target genes. New clinical trials using a combination therapy with PPARγ agonists and HDAC inhibitors are guaranteed.
Macrophage Uptake of Necrotic Cell DNA Activates the AIM2 Inflammasome to Regulate a Proinflammatory Phenotype in CKD
Authors: Takanori Komada, Hyunjae Chung, Arthur Lau, Jaye M. Platnich, Paul L. Beck, Hallgrimur Benediktsson, Henry J. Duff, Craig N. Jenne, Daniel A. Muruve
Journal: Journal of the American Society of Nephrology (2018)

Nonmicrobial inflammation contributes to CKD progression and fibrosis. Absent in melanoma 2 (AIM2) is an inflammasome-forming receptor for double-stranded DNA. AIM2 is expressed in the kidney and activated mainly by macrophages. We investigated the potential pathogenic role of the AIM2 inflammasome in kidney disease. In kidneys from patients with diabetic or nondiabetic CKD, immunofluorescence showed AIM2 expression in glomeruli, tubules, and infiltrating leukocytes. In a mouse model of unilateral ureteral obstruction (UUO), Aim2 deficiency attenuated the renal injury, fibrosis, and inflammation observed in wild-type (WT) littermates. In bone marrow chimera studies, UUO induced substantially more tubular injury and IL-1β cleavage in Aim2-/- or WT mice that received WT bone marrow than in WT mice that received Aim2-/- bone marrow. Intravital microscopy of the kidney in LysM(gfp/gfp) mice 5-6 days after UUO demonstrated the significant recruitment of GFP+ proinflammatory macrophages that crawled along injured tubules, engulfed DNA from necrotic cells, and expressed active caspase-1. DNA uptake occurred in large vacuolar structures within recruited macrophages but not resident CX3CR1+ renal phagocytes. In vitro, macrophages that engulfed necrotic debris showed AIM2-dependent activation of caspase-1 and IL-1β, as well as the formation of AIM2+ ASC specks. ASC specks are a hallmark of inflammasome activation. Cotreatment with DNaseI attenuated the increase in IL-1β levels, confirming that DNA was the principal damage-associated molecular pattern in this process. Therefore, the activation of the AIM2 inflammasome by DNA from necrotic cells drives a proinflammatory phenotype that contributes to chronic injury in the kidney.
Injection de cyano-acrylate dans le traitement des varices gastriques et ectopiques
Authors: S Elmansouri, FZ Elrhaoussi, M Tahiri Joutei Hassani, F Haddad, W Hliwa, W Badre
Journal: Endoscopy (2018)

L'hémostase endoscopique par injection de N-2-Butyl Cyanoacryalte (N2BC) est actuellement la méthode de référence dans le traitement de l'hémorragie par rupture des varices gastriques et ectopiques.
Off-label drugs directly compete with licensed drugs for same use, rules European court
Authors: Deborah Cohen, Clare Dyer
Journal: BMJ (2018)

Drugs used off label for a particular condition can be considered to be in direct competition with those that have market authorisation for that use, the European Court of Justice (ECJ) has ruled.

The ruling confirms that an alleged agreement between Roche and Novartis to discourage doctors from prescribing the cheaper bevacizumab (Avastin) for eye conditions in favour of the pricier ranibizumab (Lucentis) is covered by European competition law, and the companies could face penalties if found to have acted anti-competitively.

Lincoln Tsang, a partner at the Arnold & Porter law firm in London, who advises drug makers and previously worked for the Medicines and Healthcare Products Regulatory Agency, told the news agency STAT,1 “This case has immense implications for the EU, given the increasing pressure imposed by governmental payers to …
Facteurs de risque et conséquences de la conversion de DSM colorectale en RME dans un centre de référence européen
Authors: E Perez-Cuadrado-Robles, C Snauwaert, TG Moreels, A Jouret-Mourin, P Deprez, H Piessevaux
Journal: Endoscopy (2018)

Il existe des données limitées concernant les facteurs de risque et les conséquences de la conversion de la dissection sous-muqueuse endoscopique (DSM) colorectale à la résection muqueuse (DSM hybride) en Europe.
Resultats d'une Enquete sur l'Endoscopie Digestive Interventionnelle en Afrique Subsaharienne
Authors: A Tshimpi, JR Makulo, H Situakibanza, R Matanda, JM Kayembe, S Mbendi
Journal: Endoscopy (2018)

L'endoscopie digestive est peu développée en Afrique subsaharienne (ASS). Dans la plupart des pays d'ASS, l'activité d'endoscopie digestive est limitée, et l'endoscopie digestive interventionnelle (EDI) l'est encore plus. L'objectif de ce travail était d'obtenir des données sur la pratique de l'EDI en ASS en 2017.
Pharmacokinetic (PK)-driven individualization of pazopanib therapy in patients with solid tumors: A phase 1 study (MC1112).
Authors: Keith Christopher Bible, Pamela Jo Harris, Jill K. Burton, Jun Yin, Rui Qin, Daniel Satele, Charles Erlichman, Paul Haluska, Ramesh K. Ramanathan
Journal: Journal of Clinical Oncology (2016)

2577 Background: Pazopanib (Pz) is a kinase inhibitor approved in renal cell carcinoma and soft tissue sarcoma (800 mg/day fasting) with activity also in other cancers. We found a strong correlation between attained Pz blood concentrations (CPz ) and RECIST PR in a prior study in thyroid cancer; no patients (pts) in the lowest CPz quintile attained PR (Lancet Oncol. 2010;11:962-72). Methods: We posited that the proportion of pts attaining target steady state CPz (T-CPzS , > 30 μg/mL), and perhaps the proportion with potential to respond to therapy, might be increased by PK-guided Pz dosage modification. CPzS was assessed day 14 of each 28 day cycle. To increase CPzS , dosing was modified from fasting to fed day 28 in sub-T-CPzS pts, with escalation to 1000, then 1200, mg/day fed in later cycles in response to persistently sub-T-CPzS , if tolerated. Sample size of 54 gave 90% power (1-sided, 5% significance level) to have at least 9 sub-T-CPzS pts; if > 3 of the 9 or 26.4% sub-T-CPzS pts convert to T-CPzS in later cycles, this strategy would be considered promising. Results: Accrual was completed, with 54 pts enrolled and 48 evaluable. Median age = 60 (range 28-84); median cycles = 2 (range 1-26). Of 48 evaluable pts, 15 (31.25%) attained sub-T-CPzS cycle 1; 4 (26.7%) of 15 attained T-CPzS upon dosing individualization in later cycles, meeting preset criteria to consider results promising. Eight pts with sub-T-CPzS altered dosing from fasting to fed, achieving 85.5% relative increase in CPzS . Failure to attain T-CPzS among the 15 initially sub-target pts was primarily due to cancer progression (7 pts, 46.7%). Of 48 evaluable pts, 6 attained PR (12.5%). CPzS was higher (mean 50.4 μg/mL [95% CI, 25.7 – 75.1] vs 41.7 μg/mL [95%CI, 11.1 – 72.2]) among those attaining PR. Of 54 enrolled, 3 (5.6%) had > 1 grade 4+ non-hematologic AE at least possibly related to study medication, including 1 death (pneumonitis, possibly related). Conclusions: Pz as conventionally administered results in sub-T-CPzS in > 30% of pts, with potential to be remediated by PK-guided dosage individualization. We next propose to assess the effects of this approach on response rates in kidney and thyroid cancers. Support: UM-1 CA186686-03 (NCT01552356). Clinical trial information: NCT01552356.
Use of brain diffusion tensor imaging for the prediction of long-term neurological outcomes in patients after cardiac arrest: a multicentre, international, prospective, observational, cohort study
Authors: Lionel Velly, Vincent Perlbarg, Thomas Boulier, Nicolas Adam, Sebastien Delphine, Charles-Edouard Luyt, Valentine Battisti, Gregory Torkomian, Charlotte Arbelot, Russell Chabanne, Betty Jean, Carol Di Perri, Steven Laureys, Giuseppe Citerio, Alessia Vargiolu, Benjamin Rohaut, Nicolas Bruder, Nadine Girard, Stein Silva, Vincent Cottenceau, Thomas Tourdias, Olivier Coulon, Bruno Riou, Lionel Naccache, Rajiv Gupta, Habib Benali, Damien Galanaud, Louis Puybasset, Jean-Michel Constantin, Jean Chastre, Julien Amour, Corine Vezinet, Jean-Jacques Rouby, Mathieu Raux, Olivier Langeron, Vincent Degos, Francis Bolgert, Nicolas Weiss, Thomas Similowski, Alexandre Demoule, Alexandre Duguet, Eleonore Tollard, Benoit Veber, Jean-Albert Lotterie, Paola SANCHEZ-PENA, Michèle Génestal, Mirko Patassini
Journal: The Lancet Neurology (2018)
Application of stem cells in tissue engineering for defense medicine
Authors: Chinedu Cletus Ude, Azizi Miskon, Ruszymah Bt Hj Idrus, Muhamad Bin Abu Bakar
Journal: Military Medical Research (2018)

The dynamic nature of modern warfare, including threats and injuries faced by soldiers, necessitates the development of countermeasures that address a wide variety of injuries. Tissue engineering has emerged as a field with the potential to provide contemporary solutions. In this review, discussions focus on the applications of stem cells in tissue engineering to address health risks frequently faced by combatants at war. Human development depends intimately on stem cells, the mysterious precursor to every kind of cell in the body that, with proper instruction, can grow and differentiate into any new tissue or organ. Recent reports have suggested the greater therapeutic effects of the anti-inflammatory, trophic, paracrine and immune-modulatory functions associated with these cells, which induce them to restore normal healing and tissue regeneration by modulating immune reactions, regulating inflammation, and suppressing fibrosis. Therefore, the use of stem cells holds significant promise for the treatment of many battlefield injuries and their complications. These applications include the treatment of injuries to the skin, sensory organs, nervous system tissues, the musculoskeletal system, circulatory/pulmonary tissues and genitals/testicles and of acute radiation syndrome and the development of novel biosensors. The new research developments in these areas suggest that solutions are being developed to reduce critical consequences of wounds and exposures suffered in warfare. Current military applications of stem cell-based therapies are already saving the lives of soldiers who would have died in previous conflicts. Injuries that would have resulted in deaths previously now result in wounds today; similarly, today's permanent wounds may be reduced to tomorrow's bad memories with further advances in stem cell-based therapies.
Phase I Study of Intrapleural Gene-Mediated Cytotoxic Immunotherapy in Patients with Malignant Pleural Effusion
Authors: Charu Aggarwal, Andrew R. Haas, Susan Metzger, Laura K. Aguilar, Estuardo Aguilar-Cordova, Andrea G. Manzanera, Gregoria Gómez-Hernández, Sharyn I. Katz, Evan W. Alley, Tracey L. Evans, Joshua M. Bauml, Roger B. Cohen, Corey J. Langer, Steven M. Albelda, Daniel H. Sterman
Journal: Molecular Therapy (2018)

Gene-mediated cytotoxic immunotherapy (GMCI) is an immune strategy implemented through local delivery of an adenovirus-based vector expressing the thymidine kinase gene (aglatimagene besadenovec, AdV-tk) followed by anti-herpetic prodrug valacyclovir. A phase I dose escalation trial of GMCI followed by chemotherapy was conducted in patients with malignant pleural effusion (MPE). AdV-tk was administered intrapleurally (IP) in three cohorts at a dose of 1 × 1012 to 1013 vector particles. Primary endpoint was safety; secondary endpoints included response rate, progression-free survival, and overall survival. Nineteen patients were enrolled: median age 67 years; 14 with malignant mesothelioma, 4 non-small-cell lung cancer (NSCLC), and 1 breast cancer. There were no dose limiting toxicities. All 3 patients in cohort 2 experienced transient cytokine release syndrome (CRS). Addition of celecoxib in cohort 3 reduced the incidence and severity of CRS (none > grade 2). Three patients are alive (23–33 months after GMCI), and 3 of 4 NSCLC patients had prolonged disease stabilization; one is alive 29 months after GMCI, 3.6 years after initial diagnosis. GMCI was safe and well tolerated in combination with chemotherapy in patients with MPE and showed encouraging response. Further studies are warranted to determine efficacy. Gene-mediated cytotoxic immunotherapy (GMCI) is an immune strategy implemented through local delivery of an adenovirus-based vector expressing the thymidine kinase gene (aglatimagene besadenovec, AdV-tk) followed by anti-herpetic prodrug valacyclovir. A phase I dose escalation trial of GMCI followed by chemotherapy was conducted in patients with malignant pleural effusion (MPE). AdV-tk was administered intrapleurally (IP) in three cohorts at a dose of 1 × 1012 to 1013 vector particles. Primary endpoint was safety; secondary endpoints included response rate, progression-free survival, and overall survival. Nineteen patients were enrolled: median age 67 years; 14 with malignant mesothelioma, 4 non-small-cell lung cancer (NSCLC), and 1 breast cancer. There were no dose limiting toxicities. All 3 patients in cohort 2 experienced transient cytokine release syndrome (CRS). Addition of celecoxib in cohort 3 reduced the incidence and severity of CRS (none > grade 2). Three patients are alive (23–33 months after GMCI), and 3 of 4 NSCLC patients had prolonged disease stabilization; one is alive 29 months after GMCI, 3.6 years after initial diagnosis. GMCI was safe and well tolerated in combination with chemotherapy in patients with MPE and showed encouraging response. Further studies are warranted to determine efficacy.
Conserved and Divergent Features of Mesenchymal Progenitor Cell Types within the Cortical Nephrogenic Niche of the Human and Mouse Kidney
Authors: Nils O. Lindström, Jinjin Guo, Albert D. Kim, Tracy Tran, Qiuyu Guo, Guilherme De Sena Brandine, Andrew Ransick, Riana K. Parvez, Matthew E. Thornton, Laurence Basking, Brendan Grubbs, Jill A. McMahon, Andrew D. Smith, Andrew P. McMahon
Journal: Journal of the American Society of Nephrology (2018)

Cellular interactions among nephron, interstitial, and collecting duct progenitors drive mammalian kidney development. In mice, Six2+ nephron progenitor cells (NPCs) and Foxd1+ interstitial progenitor cells (IPCs) form largely distinct lineage compartments at the onset of metanephric kidney development. Here, we used the method for analyzing RNA following intracellular sorting (MARIS) approach, single-cell transcriptional profiling, in situ hybridization, and immunolabeling to characterize the presumptive NPC and IPC compartments of the developing human kidney. As in mice, each progenitor population adopts a stereotypical arrangement in the human nephron-forming niche: NPCs capped outgrowing ureteric branch tips, whereas IPCs were sandwiched between the NPCs and the renal capsule. Unlike mouse NPCs, human NPCs displayed a transcriptional profile that overlapped substantially with the IPC transcriptional profile, and key IPC determinants, including FOXD1, were readily detected within SIX2+ NPCs. Comparative gene expression profiling in human and mouse Six2/SIX2+ NPCs showed broad agreement between the species but also identified species-biased expression of some genes. Notably, some human NPC-enriched genes, including DAPL1 and COL9A2, are linked to human renal disease. We further explored the cellular diversity of mesenchymal cell types in the human nephrogenic niche through single-cell transcriptional profiling. Data analysis stratified NPCs into two main subpopulations and identified a third group of differentiating cells. These findings were confirmed by section in situ hybridization with novel human NPC markers predicted through the single-cell studies. This study provides a benchmark for the mesenchymal progenitors in the human nephrogenic niche and highlights species-variability in kidney developmental programs.
Cancer vaccine formulation dictates synergy with CTLA-4 and PD-L1 checkpoint blockade therapy
Authors: Yared Hailemichael, Amber Woods, Tihui Fu, Qiuming He, Michael C. Nielsen, Farah Hasan, Jason Roszik, Zhilan Xiao, Christina Vianden, Hiep Khong, Manisha Singh, Meenu Sharma, Faisal Faak, Derek Moore, Zhimin Dai, Scott M. Anthony, Kimberly S. Schluns, Padmanee Sharma, Victor H. Engelhard, Willem W. Overwijk
Journal: Journal of Clinical Investigation (2018)

Anticancer vaccination is a promising approach to increase the efficacy of cytotoxic T lymphocyte–associated protein 4 (CTLA-4) and programmed death ligand 1 (PD-L1) checkpoint blockade therapies. However, the landmark FDA registration trial for anti–CTLA-4 therapy (ipilimumab) revealed a complete lack of benefit of adding vaccination with gp100 peptide formulated in incomplete Freund's adjuvant (IFA). Here, using a mouse model of melanoma, we found that gp100 vaccination induced gp100-specific effector T cells (Teffs), which dominantly forced trafficking of anti–CTLA-4–induced, non-gp100–specific Teffs away from the tumor, reducing tumor control. The inflamed vaccination site subsequently also sequestered and destroyed anti–CTLA-4–induced Teffs with specificities for tumor antigens other than gp100, reducing the antitumor efficacy of anti–CTLA-4 therapy. Mechanistically, Teffs at the vaccination site recruited inflammatory monocytes, which in turn attracted additional Teffs in a vicious cycle mediated by IFN-γ, CXCR3, ICAM-1, and CCL2, dependent on IFA formulation. In contrast, nonpersistent vaccine formulations based on dendritic cells, viral vectors, or water-soluble peptides potently synergized with checkpoint blockade of both CTLA-4 and PD-L1 and induced complete tumor regression, including in settings of primary resistance to dual checkpoint blockade. We conclude that cancer vaccine formulation can dominantly determine synergy, or lack thereof, with CTLA-4 and PD-L1 checkpoint blockade therapy for cancer.
Polymer-Mediated Inhibition of Pro-invasive Nucleic Acid DAMPs and Microvesicles Limits Pancreatic Cancer Metastasis
Authors: Ibtehaj Naqvi, Ruwan Gunaratne, Jessica E. McDade, Angelo Moreno, Rachel E. Rempel, Douglas C. Rouse, Silvia Gabriela Herrera, David S. Pisetsky, Jaewoo Lee, Rebekah R. White, Bruce A. Sullenger
Journal: Molecular Therapy (2018)

Nucleic acid binding polymers (NABPs) have been extensively used as vehicles for DNA and RNA delivery. More recently, we discovered that a subset of these NABPs can also serve as anti-inflammatory agents by capturing pro-inflammatory extracellular nucleic acids and associated protein complexes that promote activation of toll-like receptors (TLRs) in diseases such as lupus erythematosus. Nucleic-acid-mediated TLR signaling also facilitates tumor progression and metastasis in several cancers, including pancreatic cancer (PC). In addition, extracellular DNA and RNA circulate on or within lipid microvesicles, such as microparticles or exosomes, which also promote metastasis by inducing pro-tumorigenic signaling in cancer cells and pre-conditioning secondary sites for metastatic establishment. Here, we explore the use of an NABP, the 3rd generation polyamidoamine dendrimer (PAMAM-G3), as an anti-metastatic agent. We show that PAMAM-G3 not only inhibits nucleic-acid-mediated activation of TLRs and invasion of PC tumor cells in vitro, but can also directly bind extracellular microvesicles to neutralize their pro-invasive effects as well. Moreover, we demonstrate that PAMAM-G3 dramatically reduces liver metastases in a syngeneic murine model of PC. Our findings identify a promising therapeutic application of NABPs for combating metastatic disease in PC and potentially other malignancies. Nucleic acid binding polymers (NABPs) have been extensively used as vehicles for DNA and RNA delivery. More recently, we discovered that a subset of these NABPs can also serve as anti-inflammatory agents by capturing pro-inflammatory extracellular nucleic acids and associated protein complexes that promote activation of toll-like receptors (TLRs) in diseases such as lupus erythematosus. Nucleic-acid-mediated TLR signaling also facilitates tumor progression and metastasis in several cancers, including pancreatic cancer (PC). In addition, extracellular DNA and RNA circulate on or within lipid microvesicles, such as microparticles or exosomes, which also promote metastasis by inducing pro-tumorigenic signaling in cancer cells and pre-conditioning secondary sites for metastatic establishment. Here, we explore the use of an NABP, the 3rd generation polyamidoamine dendrimer (PAMAM-G3), as an anti-metastatic agent. We show that PAMAM-G3 not only inhibits nucleic-acid-mediated activation of TLRs and invasion of PC tumor cells in vitro, but can also directly bind extracellular microvesicles to neutralize their pro-invasive effects as well. Moreover, we demonstrate that PAMAM-G3 dramatically reduces liver metastases in a syngeneic murine model of PC. Our findings identify a promising therapeutic application of NABPs for combating metastatic disease in PC and potentially other malignancies.
DNA methylation modules in airway smooth muscle are associated with asthma severity
Authors: Mark M. Perry, Paul Lavender, Chih-hsi Scott Kuo, Francesca Galea, Charalambos Michaeloudes, James M. Flanagan, Kian Fan Chung, Ian M. Adcock
Journal: European Respiratory Journal (2018)

Asthma is a chronic airway inflammatory disorder characterised by airway hyperresponsiveness, inflammation and remodelling, including airway smooth muscle cell (ASMC) hyperplasia and subepithelial airway fibrosis [1, 2]. ASMCs from severe asthmatics are hyperproliferative, release more pro-inflammatory cytokines and are corticosteroid-insensitive compared with those from healthy individuals and non-severe asthma patients [3, 4]. Genetic and epigenetic processes such as miRNA expression and DNA methylation have been implicated in asthma pathogenesis [5]. Indeed, DNA methylation is altered in asthmatic blood cells [5] and may be a biomarker of atopy [6]. Abnormal DNA methylation patterns distinguish airway smooth muscle cell function in asthma and asthma severity <http://ow.ly/cTrK30iCwVK>