Subjects -> MEDICAL SCIENCES (Total: 8529 journals)
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    - INTERNAL MEDICINE (167 journals)
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    - MEDICAL SCIENCES (2342 journals)
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    - SURGERY (401 journals)
    - UROLOGY, NEPHROLOGY AND ANDROLOGY (153 journals)

MEDICAL SCIENCES (2342 journals)            First | 3 4 5 6 7 8 9 10 | Last

Showing 1201 - 1400 of 3562 Journals sorted alphabetically
Journal of health sciences     Open Access  
Journal of Health Sciences / Sağlık Bilimleri Dergisi     Open Access  
Journal of Health Sciences and Medicine     Open Access  
Journal of Health Sciences and Surveillance System     Open Access  
Journal of Health Sciences Scholarship     Open Access  
Journal of Health Specialties     Open Access  
Journal of Health Studies     Open Access  
Journal of Healthcare Informatics Research     Hybrid Journal   (Followers: 1)
Journal of Heavy Metal Toxicity and Diseases     Open Access  
Journal of Helminthology     Hybrid Journal   (Followers: 2)
Journal of Herbs Spices & Medicinal Plants     Hybrid Journal  
Journal of HIV for Clinical and Scientific Research     Open Access   (Followers: 1)
Journal of Hospital Medicine     Hybrid Journal   (Followers: 10)
Journal of Huazhong University of Science and Technology [Medical Sciences]     Hybrid Journal  
Journal of Human Hypertension     Hybrid Journal   (Followers: 3)
Journal of Human Rhythm     Open Access  
Journal of Human Transcriptome     Open Access  
Journal of Ideas in Health     Open Access  
Journal of Inflammation     Open Access   (Followers: 2)
Journal of Inflammation Research     Open Access  
Journal of Injury and Violence Research     Open Access   (Followers: 7)
Journal of Innovation in Health Informatics     Open Access   (Followers: 17)
Journal of Institute of Medicine     Open Access  
Journal of Insulin Resistance     Open Access   (Followers: 1)
Journal of Interactional Research in Communication Disorders     Hybrid Journal   (Followers: 5)
Journal of Interferon & Cytokine Research     Hybrid Journal   (Followers: 3)
Journal of International Medical Research     Open Access   (Followers: 4)
Journal of Interventional Medicine     Open Access   (Followers: 1)
Journal of Investigative Medicine     Hybrid Journal   (Followers: 3)
Journal of Islamabad Medical & Dental College     Open Access  
Journal of Istanbul Faculty of Medicine     Open Access  
Journal of Karnali Academy of Health Sciences     Open Access   (Followers: 1)
Journal of Kathmandu Medical College     Open Access   (Followers: 1)
Journal of King Abdulaziz University : Medical Sciences     Open Access   (Followers: 2)
Journal of Laboratory Medicine     Hybrid Journal   (Followers: 27)
Journal of Laryngology and Voice     Open Access   (Followers: 11)
Journal of Lasers in Medical Sciences     Open Access  
Journal of Law, Medicine & Ethics     Hybrid Journal   (Followers: 24)
Journal of Legal Medicine     Hybrid Journal   (Followers: 7)
Journal of Limb Lengthening & Reconstruction     Open Access  
Journal of Lumbini Medical College     Open Access   (Followers: 1)
Journal of Mahatma Gandhi Institute of Medical Sciences     Open Access  
Journal of Manipulative and Physiological Therapeutics     Hybrid Journal   (Followers: 6)
Journal of Manmohan Memorial Institute of Health Sciences     Open Access   (Followers: 1)
Journal of Marine Medical Society     Open Access  
Journal of Materials Science : Materials in Medicine     Hybrid Journal   (Followers: 4)
Journal of Maternal and Child Health     Open Access  
Journal of Mechanics in Medicine and Biology     Hybrid Journal  
Journal of Medical and Biological Engineering     Hybrid Journal   (Followers: 4)
Journal of Medical and Biomedical Sciences     Open Access   (Followers: 2)
Journal of Medical Case Reports     Open Access   (Followers: 1)
Journal of Medical Cases     Open Access   (Followers: 6)
Journal of Medical Colleges of PLA     Full-text available via subscription  
Journal of Medical Disorders     Open Access  
Journal of Medical Economics     Hybrid Journal   (Followers: 8)
Journal of Medical Education and Curricular Development     Open Access   (Followers: 6)
Journal of Medical Ethics     Partially Free   (Followers: 25)
Journal of Medical Ethics and History of Medicine     Open Access   (Followers: 15)
Journal of Medical Humanities     Hybrid Journal   (Followers: 21)
Journal of Medical Hypotheses and Ideas     Open Access  
Journal of Medical Imaging and Health Informatics     Full-text available via subscription   (Followers: 1)
Journal of Medical Investigation and Practice     Open Access  
Journal of Medical Laboratory and Diagnosis     Open Access  
Journal of Medical Law and Ethics     Full-text available via subscription   (Followers: 15)
Journal of Medical Microbiology     Full-text available via subscription   (Followers: 6)
Journal of Medical Sciences     Open Access  
Journal of Medical Sciences     Open Access  
Journal of Medical Screening     Hybrid Journal   (Followers: 6)
Journal of Medical Signals and Sensors     Open Access   (Followers: 3)
Journal of Medical Society     Open Access  
Journal of Medical Systems     Hybrid Journal  
Journal of Medical Toxicology     Hybrid Journal   (Followers: 6)
Journal of Medical Ultrasound     Open Access   (Followers: 2)
Journal of Medicinal Botany     Open Access  
Journal of Medicinal Chemistry     Hybrid Journal   (Followers: 197)
Journal of Medicine     Open Access   (Followers: 1)
Journal of Medicine and Biomedical Research     Open Access   (Followers: 1)
Journal of Medicine and Philosophy     Hybrid Journal   (Followers: 8)
Journal of Medicine and the Person     Hybrid Journal  
Journal of Medicine in Scientific Research     Open Access  
Journal of Medicine in the Tropics     Open Access  
Journal of Medicine Research and Development     Open Access   (Followers: 3)
Journal of Medicine, Physiology and Biophysics     Open Access   (Followers: 5)
Journal of Medicines Development Sciences     Open Access   (Followers: 1)
Journal of Metabolomics & Systems Biology     Open Access  
Journal of Mind and Medical Sciences     Open Access   (Followers: 1)
Journal of Molecular Medicine     Hybrid Journal   (Followers: 11)
Journal of Movement Disorders     Open Access   (Followers: 2)
Journal of Muscle Research and Cell Motility     Hybrid Journal   (Followers: 1)
Journal of Nanotechnology in Engineering and Medicine     Full-text available via subscription   (Followers: 6)
Journal of Natural Medicines     Hybrid Journal  
Journal of Natural Science, Biology and Medicine     Open Access   (Followers: 3)
Journal of Nature and Science of Medicine     Open Access   (Followers: 4)
Journal of Negative and No Positive Results     Open Access  
Journal of Nepalgunj Medical College     Open Access  
Journal of Neurocritical Care     Open Access  
Journal of Neurodegenerative Diseases     Open Access   (Followers: 2)
Journal of Neurorestoratology     Open Access  
Journal of Neuroscience and Neurological Disorders     Open Access  
Journal of Nobel Medical College     Open Access  
Journal of Obesity and Bariatrics     Open Access  
Journal of Occupational Health     Open Access  
Journal of Occupational Therapy Education     Open Access   (Followers: 9)
Journal of Ocular Biology, Diseases, and Informatics     Hybrid Journal  
Journal of Oral Biology and Craniofacial Research     Full-text available via subscription  
Journal of Oral Health and Craniofacial Science     Open Access  
Journal of Orofacial Sciences     Open Access  
Journal of Otorhinolaryngology, Hearing and Balance Medicine     Open Access   (Followers: 1)
Journal of Ovarian Research     Open Access  
Journal of Ozone Therapy     Open Access  
Journal of Palliative Medicine     Hybrid Journal   (Followers: 47)
Journal of Paramedical Sciences & Rehabilitation     Open Access  
Journal of Parkinsonism and Restless Legs Syndrome     Open Access   (Followers: 2)
Journal of Parkinson’s Disease and Alzheimer’s Disease     Open Access  
Journal of Participatory Medicine     Open Access  
Journal of Patan Academy of Health Sciences     Open Access  
Journal of Pathogens     Open Access   (Followers: 1)
Journal of Patient Experience     Open Access  
Journal of Patient Safety and Risk Management     Hybrid Journal   (Followers: 1)
Journal of Patient-Centered Research and Reviews     Open Access  
Journal of Patient-Reported Outcomes     Open Access  
Journal of Periodontal Research     Hybrid Journal  
Journal of Personalized Medicine     Open Access   (Followers: 3)
Journal of Pest Science     Hybrid Journal   (Followers: 1)
Journal of Pharmaceutical Policy and Practice     Open Access   (Followers: 4)
Journal of Physiobiochemical Metabolism     Hybrid Journal   (Followers: 2)
Journal of Physiology-Paris     Hybrid Journal   (Followers: 2)
Journal of Pioneering Medical Sciences     Open Access  
Journal of Postgraduate Medicine     Open Access  
Journal of Pregnancy     Open Access   (Followers: 4)
Journal of Prevention & Intervention Community     Hybrid Journal   (Followers: 6)
Journal of Preventive Medicine and Public Health     Open Access  
Journal of Primary Prevention     Hybrid Journal   (Followers: 7)
Journal of Prosthodontic Research     Full-text available via subscription   (Followers: 1)
Journal of Prosthodontics     Hybrid Journal   (Followers: 2)
Journal of Receptor, Ligand and Channel Research     Open Access  
Journal of Regenerative Medicine     Partially Free   (Followers: 3)
Journal of Research in Medical Sciences     Open Access   (Followers: 2)
Journal of Science and Applications : Biomedicine     Open Access   (Followers: 1)
Journal of Science and Technology (Ghana)     Open Access   (Followers: 3)
Journal of Scientific Innovation in Medicine     Open Access  
Journal of Scientific Perspectives     Open Access   (Followers: 1)
Journal of Sensory Studies     Hybrid Journal   (Followers: 4)
Journal of Shaheed Suhrawardy Medical College     Open Access  
Journal of Shoulder and Elbow Arthroplasty     Open Access  
Journal of Sleep Disorders : Treatment & Care     Hybrid Journal   (Followers: 10)
Journal of South American Earth Sciences     Hybrid Journal   (Followers: 5)
Journal of Spinal Cord Medicine     Hybrid Journal   (Followers: 4)
Journal of Spinal Disorders & Techniques     Hybrid Journal   (Followers: 2)
Journal of Sports Medicine and Allied Health Sciences : Official Journal of the Ohio Athletic Trainers Association     Open Access   (Followers: 1)
Journal of Stem Cell Therapy and Transplantation     Open Access   (Followers: 1)
Journal of Stomal Therapy Australia     Full-text available via subscription  
Journal of Strength and Conditioning Research     Hybrid Journal   (Followers: 73)
Journal of Substance Use     Hybrid Journal   (Followers: 14)
Journal of Surgical Academia     Open Access   (Followers: 1)
Journal of Surgical and Clinical Research     Open Access  
Journal of Surgical Case Reports     Open Access  
Journal of Surgical Education     Full-text available via subscription   (Followers: 3)
Journal of Surgical Technique and Case Report     Open Access  
Journal of Systemic Therapies     Full-text available via subscription   (Followers: 3)
Journal of Taibah University Medical Sciences     Open Access  
Journal of Telemedicine and Telecare     Hybrid Journal   (Followers: 12)
Journal of The Academy of Clinical Microbiologists     Open Access  
Journal of the American Association for Laboratory Animal Science     Full-text available via subscription   (Followers: 7)
Journal of the American College of Certified Wound Specialists     Hybrid Journal   (Followers: 2)
Journal of the American College of Clinical Wound Specialists     Hybrid Journal   (Followers: 2)
Journal of the American Medical Directors Association     Hybrid Journal   (Followers: 6)
Journal of the American Medical Informatics Association : JAMIA     Hybrid Journal   (Followers: 35)
Journal of the American Podiatric Medical Association     Full-text available via subscription   (Followers: 7)
Journal of the Anatomical Society of India     Full-text available via subscription  
Journal of the Anus, Rectum and Colon     Open Access  
Journal of The Arab Society for Medical Research     Open Access  
Journal of the Australasian College of Nutritional and Environmental Medicine     Full-text available via subscription  
Journal of the Australasian Society of Aerospace Medicine     Open Access   (Followers: 1)
Journal of the Ceylon College of Physicians     Open Access  
Journal of the Chinese Medical Association     Open Access   (Followers: 2)
Journal of the College of Community Physicians of Sri Lanka     Open Access  
Journal of The Egyptian Public Health Association     Open Access   (Followers: 1)
Journal of the Formosan Medical Association     Open Access   (Followers: 2)
Journal of the Ghana Science Association     Full-text available via subscription   (Followers: 3)
Journal of the Grodno State Medical University     Open Access   (Followers: 1)
Journal of the History of Medicine and Allied Sciences     Hybrid Journal   (Followers: 17)
Journal of the International Society for Telemedicine and eHealth     Open Access   (Followers: 3)
Journal of the Learning Sciences     Hybrid Journal   (Followers: 17)
Journal of the Medical Library Association     Open Access   (Followers: 283)
Journal of the Medical Sciences (Berkala ilmu Kedokteran)     Open Access   (Followers: 1)
Journal of the National Medical Association     Full-text available via subscription  
Journal of the Peripheral Nervous System     Hybrid Journal   (Followers: 3)
Journal of the Postgraduate Institute of Medicine     Open Access  
Journal of the Renin-Angiotensin-Aldosterone System     Open Access   (Followers: 1)
Journal of the Royal Society of Medicine     Hybrid Journal   (Followers: 2)
Journal of the Ruhunu Clinical Society     Open Access  
Journal of the Scientific Society     Open Access   (Followers: 1)
Journal of the Siena Academy of Sciences     Open Access   (Followers: 1)
Journal of Therapeutic Ultrasound     Open Access  
Journal of Thyroid Research     Open Access   (Followers: 1)
Journal of Tissue Engineering     Open Access   (Followers: 6)
Journal of Tissue Viability     Full-text available via subscription   (Followers: 3)
Journal of Topology     Hybrid Journal   (Followers: 1)
Journal of Toxicology     Open Access   (Followers: 11)

  First | 3 4 5 6 7 8 9 10 | Last

Similar Journals
Journal Cover
Journal of Molecular Medicine
Journal Prestige (SJR): 2.177
Citation Impact (citeScore): 5
Number of Followers: 11  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 1432-1440 - ISSN (Online) 0946-2716
Published by Springer-Verlag Homepage  [2626 journals]
  • Liquid biopsies for multiple myeloma in a time of precision medicine
    • Abstract: Multiple myeloma (MM) is a challenging, progressive, and highly heterogeneous hematological malignancy. MM is characterized by multifocal proliferation of neoplastic plasma cells in the bone marrow (BM) and sometimes in extramedullary organs. Despite the availability of novel drugs and the longer median overall survival, some patients survive more than 10 years while others die rapidly. This heterogeneity is mainly driven by biological characteristics of MM cells, including genetic abnormalities. Disease progressions are mainly due to the inability of drugs to overcome refractory disease and inevitable drug-resistant relapse. In clinical practice, a bone marrow biopsy, mostly performed in one site, is still used to access the genetics of MM. However, BM biopsy use is limited by its invasive nature and by often not accurately reflecting the mutational profile of MM. Recent insights into the genetic landscape of MM provide a valuable opportunity to implement precision medicine approaches aiming to enable better patient profiling and selection of targeted therapies. In this review, we explore the use of the emerging field of liquid biopsies in myeloma patients considering current unmet medical needs, such as assessing the dynamic mutational landscape of myeloma, early predictors of treatment response, and a less invasive response monitoring.
      PubDate: 2020-04-04
       
  • Expression of long pentraxin 3 in human nasal mucosa fibroblasts, tissues,
           and secretions of chronic rhinosinusitis without nasal polyps
    • Abstract: Numerous studies have shown that microbiomes play an important role in the pathogenesis of chronic rhinosinusitis (CRS). In addition to a known short pentraxin, C-reactive protein, long pentraxin 3 (PTX3) belongs to pentraxin family which detects conserved microbial pentraxin motifs and mobilizes early defense against foreign invaders, but its participation in CRS remains unclear. In the present study, through an intensive screening, peptidoglycan (PGN) was selected as a main material to investigate the action mechanism of a cell wall component on CRS without nasal polyps (CRSsNP) nasal mucosa-derived fibroblasts and the PTX3 expression in human nasal mucosa tissue and discharge. The PGN not only enhanced PTX3 mRNA and protein production in cells but also caused marked PTX3 secretion into extracellular space. The pharmacological interventions indicated that the PTX3 induction was mediated mainly through toll-like receptor 2 (TLR2), phosphoinositide-phospholipase C (PI-PLC), protein kinase C (PKC), NF-κB, and cAMP response element binding protein (CREB), which was further confirmed by the observations that a direct PKC activator (phorbol ester) had a similar inductory effect on PTX3 expression/production and the siRNA interference knockdown of PKCμ/δ, NF-κB, and CREB compromised PTX3 production. Meanwhile, PTX3 was found to be overexpressed/produced in nasal mucosa and discharge/secretion of the CRSsNP patients. Collectively, we first demonstrated here that PGN enhances PTX3 expression and release in nasal fibroblasts through TLR2, PI-PLC, PKCμ/δ, NF-κB, and CREB signaling pathways. The PTX3 is overexpressed in nasal mucosa and discharge/secretion of CRSsNP patients, revealing its possible importance in CRSsNP development and progression. Key messages Long pentraxin 3 (PTX3) is highly expressed in nasal mucosa and discharge/secretion of patients of chronic rhinosinusitis without nasal polyps (CRSsNP). The bacteria cell wall component-peptidoglycan (PGN) causes PTX3 expression in CRSsNP nasal mucosa-derived fibroblasts, contributing to the PTX3 increase in tissues. PGN induces PTX3 expression through a previously known IκB/NF-κB and a novel PKCμ/δ and CREB signaling pathway. The PTX3 may be used as a biomarker for CRS.
      PubDate: 2020-04-02
       
  • Correction to: AVE0991, a nonpeptide angiotensin-(1–7) mimic, inhibits
           angiotensin II–induced abdominal aortic aneurysm formation in
           apolipoprotein E knockout mice
    • Abstract: The corrected Figure 7 image is presented in this paper.
      PubDate: 2020-03-30
       
  • Retraction Note: Role of the NF-κB signaling cascade and NF-κB-targeted
           genes in failing human hearts
    • Abstract: The Editor-in-Chief has retracted this article [1] because a number of lanes in Figs. 3, 4 and 6 of this article are duplicated.
      PubDate: 2020-03-27
       
  • The therapeutic potential of Aurora kinases targeting in glioblastoma:
           from preclinical research to translational oncology
    • Abstract: Glioblastoma is the most common aggressive primary brain tumor. Standard care includes maximal safe surgical resection, radiation, and chemotherapy with temozolomide. However, the impact of this therapeutic approach on patient survival is disappointing and poor outcomes are frequently observed. Therefore, new therapeutic targets are needed to treat this potentially deadly tumor. Aurora kinases are one of today’s most sought-after classes of therapeutic targets to glioblastoma therapy. They are a family of proteins composed of three members: Aurora-A, Aurora-B, and Aurora-C that play different roles in the cell division through regulation of chromosome segregation. Deregulation of these genes has been reported in glioblastoma and a progressive number of studies have shown that inhibition of these proteins could be a promising strategy for the treatment of this tumor. This review discusses the preclinical and early clinical findings on the potential use of the Aurora kinases as new targets for the treatment of glioblastoma. Key messages GBM is a very aggressive tumor with limited therapeutic options. Aurora kinases are a family of serine/threonine kinases implicated in GBM pathology. Aurora kinases are critical for glioblastoma cell growth, apoptosis, and chemoresistance. Inhibition of Aurora kinases has a synergistic or sensitizing effect with chemotherapy drugs, radiotherapy, or with other targeted molecules in GBM. Several Aurora kinase inhibitors are currently in clinical trials.
      PubDate: 2020-03-26
       
  • Mitigating off-target effects in CRISPR/Cas9-mediated in vivo gene editing
    • Abstract: The rapid advancement of genome editing technologies has opened up new possibilities in the field of medicine. Nuclease-based techniques such as the CRISPR/Cas9 system are now used to target genetically linked disorders that were previously hard-to-treat. The CRISPR/Cas9 gene editing approach wields several advantages over its contemporary editing systems, notably in the ease of component design, implementation and the option of multiplex genome editing. While results from the early phase clinical trials have been encouraging, the small patient population recruited into these trials hinders a conclusive assessment on the safety aspects of the CRISPR/Cas9 therapy. Potential safety concerns include the lack of fidelity in the CRISPR/Cas9 system which may lead to unintended DNA modifications at non-targeted gene loci. This review focuses modifications to the CRISPR/Cas9 components that can mitigate off-target effects in in vitro and preclinical models and its translatability to gene therapy in patient populations.
      PubDate: 2020-03-20
       
  • TMEM16A drives renal cyst growth by augmenting Ca 2+ signaling in M1 cells
    • Abstract: Polycystic kidney disease (PKD) leads to continuous decline of renal function by growth of renal cysts. Enhanced proliferation and transepithelial chloride secretion through cystic fibrosis transmembrane conductance regulator (CFTR) and Ca2+-activated TMEM16A Cl− channels is thought to cause an increase in cyst volume. Recent work shows the pro-proliferative role of the Ca2+ activated Cl− channel TMEM16A (anoctamin 1), and demonstrates the essential contribution of TMEM16A to CFTR-dependent Cl− secretion. The present data demonstrate an increase in intracellular Ca2+ ([Ca2+]i) signals and Cl− secretion by TMEM16A, in renal collecting duct principle cells from dog (MDCK) and mouse (M1) as well as primary tubular epithelial cells from PKD1−/− knockout mice. M1 organoids proliferated, increased expression of TMEM16A, and secreted Cl− upon knockdown of endogenous polycystin 1 or 2 (PKD1,2), by retroviral transfection with shPKD1 and shPKD2, respectively. Knockdown of PKD1 or PKD2 increased basal intracellular Ca2+ levels and enhanced purinergic Ca2+ release from endoplasmic reticulum. In contrast, ryanodine receptors were found not to be expressed in mouse renal epithelial cells and caffeine had no effects on [Ca2+]i. Ca2+ signals, proliferation, and Cl− secretion were largely reduced by knockdown or blockade of TMEM16A. TMEM16A may be therefore important for enhanced Ca2+ release from IP3-sensitive Ca2+ stores in polycystic kidney disease. Key messages • ADPKD leads to continuous decline of renal function by growth of renal cysts. • Knockdown of PKD1 or PKD2 increases TMEM16A expression. • TMEM16A enhanced intracellular Ca2+ signals, Cl− secretion, and proliferation. • TMEM16A contributes to cyst growth in ADPKD.
      PubDate: 2020-03-18
       
  • Sex differences on adipose tissue remodeling: from molecular mechanisms to
           therapeutic interventions
    • Abstract: Sexual dimorphism greatly influences adipose tissue remodeling, which is characterized by changes in the activity, number, and/or size of adipocytes in response to distinct stimuli, including lifestyle and anti-obesity drugs. This sex dependence seems to be due to the anatomical and endocrine disparities between men and women. At the molecular level, sex hormones are believed to mediate such differences and involve estrogen and androgen receptor-induced gene expression. The signaling pathways that regulate adipose tissue metabolism and function include peroxisome proliferator-activated receptor gamma, uncoupling protein 1 (UCP1), 5’ adenosine monophosphate-activated protein kinase (AMPK), and mitochondrial oxidative phosphorylation (OXPHOS), among other molecular players. Sex hormone-related pathways also interplay with adrenergic signaling, probably the most well-characterized molecular mechanism implicated in the remodeling of white adipose tissue. This review overviews and integrates the signaling pathways behind sexual dimorphism in adipose tissue remodeling, hoping to increase the knowledge on the pathogenesis of diseases, such as obesity and related comorbidities, and consequently, to drive future studies to investigate the regulation of this tissue homeostasis, either in men or women.
      PubDate: 2020-03-10
       
  • Enhancers and MYC interplay in hematopoiesis
    • Abstract: Transcription requires the fine interplay between enhancers and transcription factors. Enhancers are able to activate transcription of genes involved in normal cell biology, whereas aberrant enhancer activity leads to oncogenesis. MYC is a well-established proto-oncogene involved in half of human cancers amplifying the output of its targets. The crosstalk between MYC and enhancers is known for many years since the discovery of IgH enhancer juxtaposition with MYC in high-grade lymphomas. Here, we focus mainly in the enhancers surrounding MYC in the 8q24 locus. That region comprises several enhancers that associate with other transcription factors, transmembrane receptors, and fusion genes composing complex regulatory networks aberrantly expressed in almost all types of hematological malignancies. Understanding the nature of these interactions in normal blood cells and in leukemias/lymphomas will expand MYC targeting options in the armamentarium against hematological cancers.
      PubDate: 2020-03-06
       
  • P38 MAPK and glucocorticoid receptor crosstalk in bronchial epithelial
           cells
    • Abstract: p38 MAPK inhibition may have additive and synergistic anti-inflammatory effects when used with corticosteroids. We investigated crosstalk between p38 MAPK inhibitors and corticosteroids in bronchial epithelial cells to investigate synergistic effects on cytokine production and the molecular mechanisms involved. Effects of the p38 MAPK inhibitor BIRB-796 and dexamethasone alone and in combination on LPS, polyI:C or TNFα -induced IL-6, CXCL8 and RANTES were assessed in 16HBEs (human epithelial cell line) and on TNFα-induced IL-6 and CXCL8 in primary human epithelial cells from asthma patients and healthy controls. 16HBEs were used to assess effects of BIRB-796 alone and in combination with dexamethasone on glucocorticoid receptor (GR) activity by reporter gene assay, expression of GR target genes and nuclear localisation using Western blot. The effects of BIRB-796 on TNFα stimulated phosphorylation of p38 MAPK and GR at serine (S) 226 by Western blot. Epithelial levels of phosphorylated p38 MAPK and GR S226 were determined by immunohistochemistry in bronchial biopsies from asthma patients and healthy controls. BIRB-796 in combination with dexamethasone increased inhibition of cytokine production in a synergistic manner. Combination treatment significantly increased GR nuclear localisation compared to dexamethasone alone. BIRB-796 inhibited TNFα-induced p38 MAPK and GR S226 phosphorylation. Phosphorylated GR S226 and p38 MAPK levels were increased in bronchial epithelium of more severe asthma patients. Molecular crosstalk exists between p38 MAPK activation and GR function in human bronchial epithelial cells, which alters GR activity. Combining a p38 MAPK inhibitor and a corticosteroid may demonstrate therapeutic potential in severe asthma. Key messages • Combination of corticosteroid and p38 inhibitor in human bronchial epithelial cells • Combination increased cytokine inhibition synergistically and nuclear GR • p38 MAPK inhibition reduced TNFα-induced phosphorylation of GR at S226 but not S211 • Phosphorylated GRS226 and p38 is increased in bronchial epithelium in severe asthma • Combining a p38 inhibitor and a corticosteroid may be effective in asthma treatment
      PubDate: 2020-03-01
       
  • Intravascular adhesion and recruitment of neutrophils in response to CXCL1
           depends on their TRPC6 channels
    • Abstract: Here we report a novel role for TRPC6, a member of the transient receptor potential (TRPC) channel family, in the CXCL1-dependent recruitment of murine neutrophil granulocytes. Representing a central element of the innate immune system, neutrophils are recruited from the blood stream to a site of inflammation. The recruitment process follows a well-defined sequence of events including adhesion to the blood vessel walls, migration, and chemotaxis to reach the inflammatory focus. A common feature of the underlying signaling pathways is the utilization of Ca2+ ions as intracellular second messengers. However, the required Ca2+ influx channels are not yet fully characterized. We used WT and TRPC6−/− neutrophils for in vitro and TRPC6−/− chimeric mice (WT mice with WT or TRPC6−/− bone marrow cells) for in vivo studies. After renal ischemia and reperfusion injury, TRPC6−/− chimeric mice had an attenuated TRPC6−/− neutrophil recruitment and a better outcome as judged from the reduced increase in the plasma creatinine concentration. In the cremaster model CXCL1-induced neutrophil adhesion, arrest and transmigration were also decreased in chimeric mice with TRPC6−/− neutrophils. Using atomic force microscopy and microfluidics, we could attribute the recruitment defect of TRPC6−/− neutrophils to the impact of the channel on adhesion to endothelial cells. Mechanistically, TRPC6−/− neutrophils exhibited lower Ca2+ transients during the initial adhesion leading to diminished Rap1 and β2 integrin activation and thereby reduced ICAM-1 binding. In summary, our study reveals that TRPC6 channels in neutrophils are crucial signaling modules in their recruitment from the blood stream in response to CXCL1. Key point Neutrophil TRPC6 channels are crucial for CXCL1-triggered activation of integrins during the initial steps of neutrophil recruitment.
      PubDate: 2020-03-01
       
  • Altered molecular signatures during kidney development after intrauterine
           growth restriction of different origins
    • Abstract: This study was performed to identify transcriptional alterations in male intrauterine growth restricted (IUGR) rats during and at the end of nephrogenesis in order to generate hypotheses which molecular mechanisms contribute to adverse kidney programming. IUGR was induced by low protein (LP) diet throughout pregnancy, bilateral uterine vessel ligation (LIG), or intrauterine stress (IUS) by sham operation. Offspring of unimpaired dams served as controls. Significant acute kidney damage was ruled out by negative results for proteins indicative of ER-stress, autophagy, apoptosis, or infiltration with macrophages. Renal gene expression was examined by transcriptome microarrays, demonstrating 53 (LP, n = 12; LIG, n = 32; IUS, n = 9) and 134 (LP, n = 10; LIG, n = 41; IUS, n = 83) differentially expressed transcripts on postnatal days (PND) 1 and 7, respectively. Reduced Pilra (all IUGR groups, PND 7), Nupr1 (LP and LIG, PND 7), and Kap (LIG, PND 1) as well as increased Ccl20, S100a8/a9 (LIG, PND 1), Ifna4, and Ltb4r2 (IUS, PND 7) indicated that inflammation-related molecular dysregulation could be a “common” feature after IUGR of different origins. Network analyses of transcripts and predicted upstream regulators hinted at proinflammatory adaptions mainly in LIG (arachidonic acid-binding, neutrophil aggregation, toll-like-receptor, NF-kappa B, and TNF signaling) and dysregulation of AMPK and PPAR signaling in LP pups. The latter may increase susceptibility towards obesity-associated kidney damage. Western blots of the most prominent predicted upstream regulators confirmed significant dysregulation of RICTOR in LP (PND 7) and LIG pups (PND 1), suggesting that mTOR-related processes could further modulate kidney programming in these groups of IUGR pups. Key messages Inflammation-related transcripts are dysregulated in neonatal IUGR rat kidneys. Upstream analyses indicate renal metabolic dysregulation after low protein diet. RICTOR is dysregulated after low protein diet and uterine vessel ligation.
      PubDate: 2020-03-01
       
  • A new immunotherapy schedule in addition to first-line hormone therapy for
           metastatic breast cancer patients in a state of clinical benefit during
           hormone therapy
    • Abstract: Acquired resistance occurs in metastatic hormone receptor–positive breast cancer patients. The addition of interferon beta/interleukin-2 immunotherapy to first-line salvage hormone therapy (HT) prolonged progression-free (PFS) and overall survivals (OS) in 26 patients, as compared with 30 historical controls and literature data. This was a 2 : 1 ratio case–control retrospective observational study. The cases were from an open pilot study, started in 1992, and controls were recruited in 2006. The planned mean follow-up time was the time at which more than 80% of controls progressed. The median PFS was significantly longer in the cases than that in controls, 33.1 (95% CI 24.5–41.8) vs 18 (95% CI 12.1–23.8) months (p < 0.0001). Also, median OS was significantly longer in the cases, 81 vs 62 (95% CI 48.1–75.9) months (p < 0.0029). When analysis of the 2 groups was adjusted for the disease-free interval (DFI), hormone receptor status, HER2, site of metastases and molecular-targeted therapies, the hazard ratio for PFS and for OS in the cases increased from 2.347 to 3.090 and from 1.874 to 2.147, respectively. This occurred in spite of the higher proportion of controls (82% vs 7.1%) treated with aromatase inhibitors (AIs), while selective oestrogen receptor modulators (SERMs) were given to 92.9% of the cases and to 18% of the control group (p < 0.0001). Immunotherapy significantly prolonged PFS and OS during conventional first-line HT. A multi-centre randomised clinical trial is advised to enter this immunotherapy into clinical practice. Key messages • Acquired resistance occurs in metastatic endocrine-dependent breast cancer patients. • Interferon beta-interleukin-2 immunotherapy added to first-line salvage hormone therapy prolonged progression-free (PFS) and overall (OS) survivals in 26 patients of a pilot study as compared with 30 historical controls. • In this 2:1 ratio case–control prospective observational study, the PFS median time was significantly longer in the study group than that in controls, 33.1 (95% CI 24.5–41.8) vs 18 (95% CI 12.1–23.8) months (p < 0.0001). • Also, the OS median time was significantly longer in the study group, 81 vs 62 (95% CI 48.1–75.9) months (p < 0.0029).
      PubDate: 2020-03-01
       
  • Novel anti-invasive properties of a Fascin1 inhibitor on colorectal cancer
           cells
    • Abstract: Tumor invasion and metastasis involve processes in which actin cytoskeleton rearrangement induced by Fascin1 plays a crucial role. Indeed, Fascin1 has been found overexpressed in tumors with worse prognosis. Migrastatin and its analogues target Fascin1 and inhibit its activity. However, there is need for novel and smaller Fascin1 inhibitors. The aim of this study was to assess the effect of compound G2 in colorectal cancer cell lines and compare it to migrastatin in in vitro and in vivo assays. Molecular modeling, actin-bundling, cell viability, inmunofluorescence, migration, and invasion assays were carried out in order to test anti-migratory and anti-invasive properties of compound G2. In addition, the in vivo effect of compound G2 was evaluated in a zebrafish model of invasion. HCT-116 cells exhibited the highest Fascin1 expression from eight tested colorectal cancer cell lines. Compound G2 showed important inhibitory effects on actin bundling, filopodia formation, migration, and invasion in different cell lines. Moreover, compound G2 treatment resulted in significant reduction of invasion of DLD-1 overexpressing Fascin1 and HCT-116 in zebrafish larvae xenografts; this effect being less evident in Fascin1 known-down HCT-116 cells. This study proves, for the first time, the in vitro and in vivo anti-tumoral activity of compound G2 on colorectal cancer cells and guides to design improved compound G2-based Fascin1 inhibitors. Key messages • Fascin is crucial for tumor invasion and metastasis and is overexpressed in bad prognostic tumors. • Several adverse tumors overexpress Fascin1 and lack targeted therapy. • Anti-fascin G2 is for the first time evaluated in colorectal carcinoma and compared with migrastatin. • Filopodia formation, migration activity, and invasion in vitro and in vivo assays were performed. • G2 blocks actin structures, migration, and invasion of colorectal cancer cells as fascin-dependent.
      PubDate: 2020-03-01
       
  • Identification and preclinical development of an anti-proteolytic uPA
           antibody for rheumatoid arthritis
    • Abstract: Blocking the proteolytic capacity of urokinase-type plasminogen activator (uPA) with a monoclonal antibody (mAb) reduces arthritis progression in the collagen-induced mouse arthritis model to an extent that is on par with the effect of blocking tumor necrosis factor-alpha by etanercept. Seeking to develop a novel therapy for rheumatoid arthritis, a humanized mAb, NNC0266-0043, was selected for its dual inhibition of both the zymogen activation and the proteolytic capacity of human uPA. The antibody revealed nonlinear elimination kinetics in cynomolgus monkeys consistent with binding to and turnover of endogenous uPA. At a dose level of 20.6 mg kg−1, the antibody had a plasma half-life of 210 h. Plasma uPA activity, a pharmacodynamic marker of anti-uPA therapy, was reduced to below the detection limit during treatment, indicating that an efficacious plasma concentration was reached. Pharmacokinetic modeling predicted that sufficient antibody levels can be sustained in arthritis patients dosed subcutaneously once weekly. The anti-uPA mAb was also well tolerated in cynomolgus monkeys at weekly doses up to 200 mg kg−1 over 4 weeks. The data from cynomolgus monkeys and from human material presented here indicates that anti-uPA mAb NNC0266-0043 is suitable for clinical testing as a novel therapeutic for rheumatic diseases. Key messages Background: Anti-uPA therapy is on par with etanercept in a mouse arthritis model. A new humanized antibody blocks activation and proteolytic activity of human uPA. The antibody represents a radically novel mode-of-action in anti-rheumatic therapy. The antibody has PK/PD properties in primates consistent with QW clinical dosing.
      PubDate: 2020-02-27
       
  • Synovial fibroblast-derived exosomal microRNA-106b suppresses chondrocyte
           proliferation and migration in rheumatoid arthritis via down-regulation of
           PDK4
    • Abstract: Fibroblast-derived exosomes have been reported to transfer microRNAs to recipient cells, where they regulate target gene expression, which is of interest for understanding the basic biology of inflammation, tissue homeostasis, and development of therapeutic approaches. Initial microarray-based analysis carried out in this study identified the rheumatoid arthritis (RA)–related differentially expressed gene pyruvate dehydrogenase kinase 4 (PDK4). Subsequently, the upstream regulatory microRNA-106b (miR-106b) of PDK4 was predicted with bioinformatic analyses. A collagen-induced arthritis (CIA)-induced mouse model was established, and exosomes were isolated from synovial fibroblasts (SFs) and transferred into chondrocytes to identify the role of exosomes in rheumatoid arthritis (RA). We found that PDK4 was poorly expressed in RA cartilage tissues and chondrocytes, while miR-106b was highly expressed in RA SFs and SF-derived exosomes. Notably, PDK4 was confirmed as a target gene of miR-106b. Over-expression of PDK4 promoted the proliferation and migration abilities of chondrocytes and inhibited their apoptosis as well as affected the receptor activator of nuclear factor kappa B ligand (RANKL)/RANK/osteoprotegerin (OPG) system. Meanwhile, miR-106b was delivered from SFs to chondrocytes through exosomes, which suppressed chondrocyte proliferation and migration and accelerated apoptosis as well as affected the RANKL/RANK/OPG system via down-regulation of PDK4. Furthermore, in vivo results validated that miR-106b inhibition could relieve CIA-induced RA. Taken together, SF-derived exosomal miR-106b stimulates RA initiation by targeting PDK4, indicating a physiologically validated potential approach for the prevention and treatment of RA. Key messages PDK4 is decreased in chondrocytes of RA, while miR-106b is increased in SFBs. PDK4 promotes proliferation and migration of chondrocytes. miR-106b could target 3′UTR of PDK4 gene. SFB-exosomal miR-106b inhibits proliferation and migration of chondrocytes. Inhibition of miR-106b attenuates RA progression in a CIA mouse model.
      PubDate: 2020-02-20
       
  • ASK1 inhibition: a therapeutic strategy with multi-system benefits
    • Abstract: p38 mitogen-activated protein kinases (P38α and β) and c-Jun N-terminal kinases (JNK1, 2, and 3) are key mediators of the cellular stress response. However, prolonged P38 and JNK signalling is associated with damaging inflammatory responses, reactive oxygen species–induced cell death, and fibrosis in multiple tissues, such as the kidney, liver, central nervous system, and cardiopulmonary systems. These responses are associated with many human diseases, including arthritis, dementia, and multiple organ dysfunctions. Attempts to prevent P38- and JNK-mediated disease using small molecule inhibitors of P38 or JNK have generally been unsuccessful. However, apoptosis signal-regulating kinase 1 (ASK1), an upstream regulator of P38 and JNK, has emerged as an alternative drug target for limiting P38- and JNK-mediated disease. Within this review, we compile the evidence that ASK1 mediates damaging cellular responses via prolonged P38 or JNK activation. We discuss the potential benefits of ASK1 inhibition as a therapeutic and summarise the studies that have tested the effects of ASK1 inhibition in cell and animal disease models, in addition to human clinical trials for a variety of disorders.
      PubDate: 2020-02-14
       
  • Exploring the role of high-mobility group box 1 (HMGB1) protein in the
           pathogenesis of Huntington’s disease
    • Abstract: Huntington’s disease (HD) is an autosomal-dominant neurodegenerative disorder caused by an increased and unstable CAG DNA expansion in the Huntingtin (HTT) gene, resulting in an elongated polyglutamine tract in huntingtin protein. Despite its monogenic cause, HD pathogenesis remains elusive and without any approved disease-modifying therapy as yet. A growing body of evidence highlights the emerging role of high-mobility group box 1 (HMGB1) protein in HD pathology. HMGB1, being a nuclear protein, is primarily implicated in DNA repair, but it can also translocate to the cytoplasm and participate into numerous cellular functions. Cytoplasmic HMGB1 was shown to directly interact with huntingtin under oxidative stress conditions and induce its nuclear translocation, a key process in the HD pathogenic cascade. Nuclear HMGB1 acting as a co-factor of ataxia telangiectasia mutated and base excision repair (BER) complexes can exert dual roles in CAG repeat instability and affect the final DNA repair outcome. HMGB1 can inhibit mutant huntingtin aggregation, protecting against polyglutamine-induced neurotoxicity and acting as a chaperon-like molecule, possibly via autophagy regulation. In addition, HMGB1 being a RAGE and TLR-2, TLR-3, and TLR-4 ligand may further contribute to HD pathogenesis by triggering neuroinflammation and apoptosis. Furthermore, HMGB1 participates at the unfolded protein response (UPR) system and can induce protein degradation and apoptosis associated with HD. In this review, we discuss the multiple role of HMGB1 in HD pathology, providing mechanistic insights that could direct future studies towards the development of targeted therapeutic approaches.
      PubDate: 2020-02-08
       
  • Spatial localization of endothelial cells in heterotypic spheroids
           influences Notch signaling
    • Abstract: Cell-based therapeutic approaches are an exciting strategy to replenish compromised endothelial cell (EC) populations that contribute to impaired vasculogenesis. Co-cultures of ECs and mesenchymal stromal cells (MSCs) can enhance neovascularization over ECs alone, but the efficacy of cells is limited by rapid cell death upon implantation. Co-culture spheroids exhibit improved survival compared with monodisperse cells, yet little is known about the influence of spatial regulation of ECs within co-culture spheroids. We hypothesized that EC sprouting from co-culture spheroids is a function of EC spatial localization. We formed co-culture spheroids containing ECs and MSCs in two formats: ECs uniformly distributed throughout the spheroid (i.e., mixed) or seeded on the perimeter of the MSC core (i.e., shell). Qualitative observations suggested increased vasculogenesis for mixed co-culture spheroids compared with shell conformations as early as day 3, yet quantitative metrics did not reveal significant differences in network formation between these 3D structures. Notch3 expression demonstrated significant increases in cell-cell communication in mixed conformations compared with shell counterparts. Furthermore, knockdown of Notch3 in MSCs abrogated the vasculogenic potential of mixed spheroids, supporting its role in promoting EC-MSC contacts. This study highlights the direct impact of EC-MSC contacts on sprouting and provides insight to improve the quality of network formation. Key messages • Endothelial cell (EC) localization can be controlled in co-culture EC-MSC spheroids. • Mixed spheroids exhibit consistent networks compared to shell counterparts. • Differences in NOTCH3 were observed between mixed and shell spheroids. • NOTCH3 may be a necessary target for improved vasculogenic potential.
      PubDate: 2020-02-04
       
  • p53 regulates its own expression by an intrinsic exoribonuclease activity
           through AU-rich elements
    • Abstract: The onco-suppressor p53 protein plays also an important role in the control of various aspects of health and disease. p53 levels are low in normal cells and elevated under stress conditions. While low levels of p53 promote tumor formation, overactive p53 leads to premature aging and cell death. RNA degradation is a critical level of regulation contributing to the control of gene expression. p53, as an RNA-binding protein, exerts 3′ → 5′ exoribonuclease activity, mediating degradation of adenylate/uridylate-rich elements (ARE)–containing ssRNAs. The 3′-UTR of p53-mRNA, which is a target of p53 itself, harbors cis-acting AREs. Our results suggest that p53 controls its own expression through murine double-minute 2 (mdm2)–independent “RNA decay” function in cytoplasm. We demonstrate that p53 expresses an exoribonuclease activity through the binding to ARE sequences of p53-mRNA via translation-independent and translation-dependent polysome-associated pathways. Antagonistic interplay was detected between p53 levels and execution of its exoribonuclease function mirrored in low p53 levels in normal cells, due to the efficient exoribonuclease activity, and in the accumulation of p53 in cells exposed to p53-activating drugs in accordance with the reduced exoribonuclease activity. Apparently, p53, via control of its own mRNA stability and/or translation in cytoplasm, might act as a negative regulator of p53-mRNA levels. The observed connection between exoribonuclease activity and p53 abundance highlights the importance of this function affecting p53 expression, imperative for multiple functions, with implications for the steady-state levels of protein and for the p53 stress response. The modulation in expression of exoribonuclease activity would be translated into the alterations in p53 level. Key messages p53 controls its own expression through mdm2-independent “RNA decay” function in cytoplasm. p53 expresses an exoribonuclease activity through the binding to ARE sequences of p53-mRNA. Antagonistic interplay exists between stress-induced p53 and execution of its exoribonuclease function.
      PubDate: 2020-02-04
       
 
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