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  Subjects -> MEDICAL SCIENCES (Total: 8036 journals)
    - ALLERGOLOGY AND IMMUNOLOGY (205 journals)
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    - CARDIOVASCULAR DISEASES (322 journals)
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    - INTERNAL MEDICINE (158 journals)
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    - MEDICAL GENETICS (59 journals)
    - MEDICAL SCIENCES (2127 journals)
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    - SURGERY (380 journals)
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MEDICAL SCIENCES (2127 journals)                  1 2 3 4 5 6 7 8 | Last

Showing 1 - 200 of 3562 Journals sorted alphabetically
16 de Abril     Open Access  
3D Printing in Medicine     Open Access   (Followers: 2)
AADE in Practice     Hybrid Journal   (Followers: 5)
ABCS Health Sciences     Open Access   (Followers: 4)
Abia State University Medical Students' Association Journal     Full-text available via subscription  
ACIMED     Open Access   (Followers: 1)
ACS Medicinal Chemistry Letters     Hybrid Journal   (Followers: 44)
Acta Bio Medica     Full-text available via subscription   (Followers: 2)
Acta Bioethica     Open Access  
Acta Bioquimica Clinica Latinoamericana     Open Access   (Followers: 1)
Acta Científica Estudiantil     Open Access  
Acta Facultatis Medicae Naissensis     Open Access  
Acta Informatica Medica     Open Access   (Followers: 1)
Acta Medica (Hradec Králové)     Open Access  
Acta Medica Bulgarica     Open Access  
Acta Medica Colombiana     Open Access   (Followers: 1)
Acta Médica Costarricense     Open Access   (Followers: 2)
Acta Medica Indonesiana     Open Access  
Acta Medica International     Open Access  
Acta medica Lituanica     Open Access  
Acta Medica Marisiensis     Open Access  
Acta Medica Martiniana     Open Access  
Acta Medica Nagasakiensia     Open Access   (Followers: 1)
Acta Medica Peruana     Open Access   (Followers: 2)
Acta Médica Portuguesa     Open Access  
Acta Medica Saliniana     Open Access  
Acta Scientiarum. Health Sciences     Open Access   (Followers: 1)
Acupuncture & Electro-Therapeutics Research     Full-text available via subscription   (Followers: 6)
Acupuncture and Natural Medicine     Open Access  
Addiction Science & Clinical Practice     Open Access   (Followers: 8)
Addictive Behaviors Reports     Open Access   (Followers: 9)
Adıyaman Üniversitesi Sağlık Bilimleri Dergisi / Health Sciences Journal of Adıyaman University     Open Access  
Adnan Menderes Üniversitesi Sağlık Bilimleri Fakültesi Dergisi     Open Access  
Advanced Biomedical Research     Open Access  
Advanced Health Care Technologies     Open Access   (Followers: 4)
Advanced Science, Engineering and Medicine     Partially Free   (Followers: 8)
Advances in Bioscience and Clinical Medicine     Open Access   (Followers: 6)
Advances in Clinical Chemistry     Full-text available via subscription   (Followers: 26)
Advances in Life Course Research     Hybrid Journal   (Followers: 8)
Advances in Lipobiology     Full-text available via subscription   (Followers: 1)
Advances in Medical Education and Practice     Open Access   (Followers: 29)
Advances in Medical Ethics     Open Access  
Advances in Medical Research     Open Access  
Advances in Medical Sciences     Hybrid Journal   (Followers: 7)
Advances in Medicinal Chemistry     Full-text available via subscription   (Followers: 5)
Advances in Medicine     Open Access   (Followers: 3)
Advances in Microbial Physiology     Full-text available via subscription   (Followers: 4)
Advances in Molecular Oncology     Open Access   (Followers: 2)
Advances in Molecular Toxicology     Full-text available via subscription   (Followers: 7)
Advances in Parkinson's Disease     Open Access  
Advances in Phytomedicine     Full-text available via subscription  
Advances in Preventive Medicine     Open Access   (Followers: 6)
Advances in Protein Chemistry and Structural Biology     Full-text available via subscription   (Followers: 20)
Advances in Regenerative Medicine     Open Access   (Followers: 3)
Advances in Skeletal Muscle Function Assessment     Open Access  
Advances in Therapy     Hybrid Journal   (Followers: 5)
Advances in Veterinary Science and Comparative Medicine     Full-text available via subscription   (Followers: 15)
Advances in Virus Research     Full-text available via subscription   (Followers: 5)
Advances in Wound Care     Hybrid Journal   (Followers: 11)
Aerospace Medicine and Human Performance     Full-text available via subscription   (Followers: 12)
African Health Sciences     Open Access   (Followers: 3)
African Journal of Biomedical Research     Open Access   (Followers: 1)
African Journal of Clinical and Experimental Microbiology     Open Access   (Followers: 2)
African Journal of Laboratory Medicine     Open Access   (Followers: 2)
African Journal of Medical and Health Sciences     Open Access   (Followers: 2)
African Journal of Trauma     Open Access   (Followers: 1)
Afrimedic Journal     Open Access   (Followers: 2)
Aggiornamenti CIO     Hybrid Journal   (Followers: 1)
AIDS Research and Human Retroviruses     Hybrid Journal   (Followers: 9)
AJOB Primary Research     Partially Free   (Followers: 3)
AJSP: Reviews & Reports     Hybrid Journal  
Aktuelle Ernährungsmedizin     Hybrid Journal   (Followers: 4)
Al-Azhar Assiut Medical Journal     Open Access  
Alexandria Journal of Medicine     Open Access   (Followers: 1)
Allgemeine Homöopathische Zeitung     Hybrid Journal   (Followers: 3)
Alpha Omegan     Full-text available via subscription  
ALTEX : Alternatives to Animal Experimentation     Open Access   (Followers: 3)
Althea Medical Journal     Open Access  
American Journal of Biomedical Engineering     Open Access   (Followers: 13)
American Journal of Biomedical Research     Open Access   (Followers: 2)
American Journal of Biomedicine     Full-text available via subscription   (Followers: 7)
American Journal of Chinese Medicine, The     Hybrid Journal   (Followers: 4)
American Journal of Clinical Medicine Research     Open Access   (Followers: 7)
American Journal of Family Therapy     Hybrid Journal   (Followers: 11)
American Journal of Law & Medicine     Full-text available via subscription   (Followers: 11)
American Journal of Lifestyle Medicine     Hybrid Journal   (Followers: 5)
American Journal of Managed Care     Full-text available via subscription   (Followers: 11)
American Journal of Medical Case Reports     Open Access   (Followers: 1)
American Journal of Medical Sciences and Medicine     Open Access   (Followers: 4)
American Journal of Medicine     Hybrid Journal   (Followers: 48)
American Journal of Medicine and Medical Sciences     Open Access   (Followers: 1)
American Journal of Medicine Studies     Open Access   (Followers: 1)
American Journal of Medicine Supplements     Full-text available via subscription   (Followers: 3)
American Journal of the Medical Sciences     Hybrid Journal   (Followers: 12)
American Journal on Addictions     Hybrid Journal   (Followers: 9)
American medical news     Free   (Followers: 3)
American Medical Writers Association Journal     Full-text available via subscription   (Followers: 5)
Amyloid: The Journal of Protein Folding Disorders     Hybrid Journal   (Followers: 5)
Anales de la Facultad de Medicina     Open Access  
Anales de la Facultad de Medicina, Universidad de la República, Uruguay     Open Access  
Anales del Sistema Sanitario de Navarra     Open Access   (Followers: 1)
Analgesia & Resuscitation : Current Research     Hybrid Journal   (Followers: 6)
Anatolian Clinic the Journal of Medical Sciences     Open Access  
Anatomica Medical Journal     Open Access  
Anatomical Science International     Hybrid Journal   (Followers: 3)
Anatomical Sciences Education     Hybrid Journal   (Followers: 1)
Anatomy     Open Access   (Followers: 1)
Anatomy Research International     Open Access   (Followers: 2)
Angewandte Schmerztherapie und Palliativmedizin     Hybrid Journal  
Angiogenesis     Hybrid Journal   (Followers: 3)
Ankara Medical Journal     Open Access   (Followers: 2)
Ankara Üniversitesi Tıp Fakültesi Mecmuası     Open Access  
Annales de Pathologie     Full-text available via subscription  
Annales françaises d'Oto-rhino-laryngologie et de Pathologie Cervico-faciale     Full-text available via subscription   (Followers: 3)
Annals of African Medicine     Open Access   (Followers: 2)
Annals of Anatomy - Anatomischer Anzeiger     Hybrid Journal   (Followers: 2)
Annals of Bioanthropology     Open Access   (Followers: 4)
Annals of Biomedical Engineering     Hybrid Journal   (Followers: 17)
Annals of Biomedical Sciences     Full-text available via subscription   (Followers: 3)
Annals of Clinical Hypertension     Open Access  
Annals of Clinical Microbiology and Antimicrobials     Open Access   (Followers: 12)
Annals of Family Medicine     Open Access   (Followers: 14)
Annals of Health Research     Open Access  
Annals of Ibadan Postgraduate Medicine     Open Access  
Annals of Medical and Health Sciences Research     Open Access   (Followers: 7)
Annals of Medicine     Hybrid Journal   (Followers: 12)
Annals of Medicine and Surgery     Open Access   (Followers: 7)
Annals of Microbiology     Hybrid Journal   (Followers: 11)
Annals of Nigerian Medicine     Open Access   (Followers: 1)
Annals of Rehabilitation Medicine     Open Access  
Annals of Saudi Medicine     Open Access  
Annals of the New York Academy of Sciences     Hybrid Journal   (Followers: 5)
Annals of The Royal College of Surgeons of England     Full-text available via subscription   (Followers: 3)
Annual Reports in Medicinal Chemistry     Full-text available via subscription   (Followers: 7)
Annual Reports on NMR Spectroscopy     Full-text available via subscription   (Followers: 5)
Annual Review of Medicine     Full-text available via subscription   (Followers: 16)
Anthropological Review     Open Access   (Followers: 23)
Anthropologie et santé     Open Access   (Followers: 5)
Antibiotics     Open Access   (Followers: 9)
Antibodies     Open Access   (Followers: 2)
Antibody Technology Journal     Open Access   (Followers: 1)
Antibody Therapeutics     Open Access  
Anuradhapura Medical Journal     Open Access  
Anwer Khan Modern Medical College Journal     Open Access   (Followers: 2)
Apmis     Hybrid Journal   (Followers: 1)
Apparence(s)     Open Access   (Followers: 1)
Applied Clinical Informatics     Hybrid Journal   (Followers: 3)
Applied Clinical Research, Clinical Trials and Regulatory Affairs     Hybrid Journal  
Applied Medical Informatics     Open Access   (Followers: 12)
Arab Journal of Nephrology and Transplantation     Open Access   (Followers: 1)
Archive of Clinical Medicine     Open Access   (Followers: 1)
Archive of Community Health     Open Access   (Followers: 1)
Archives Medical Review Journal / Arşiv Kaynak Tarama Dergisi     Open Access  
Archives of Asthma, Allergy and Immunology     Open Access  
Archives of Medical and Biomedical Research     Open Access   (Followers: 3)
Archives of Medical Laboratory Sciences     Open Access   (Followers: 1)
Archives of Medicine and Health Sciences     Open Access   (Followers: 3)
Archives of Medicine and Surgery     Open Access  
Archives of Trauma Research     Open Access   (Followers: 3)
Archivos de Medicina (Manizales)     Open Access  
ArgoSpine News & Journal     Hybrid Journal  
Arquivos Brasileiros de Oftalmologia     Open Access   (Followers: 1)
Arquivos de Ciências da Saúde     Open Access  
Arquivos de Medicina     Open Access  
Ars Medica : Revista de Ciencias Médicas     Open Access  
ARS Medica Tomitana     Open Access   (Followers: 1)
Art Therapy: Journal of the American Art Therapy Association     Full-text available via subscription   (Followers: 15)
Arterial Hypertension     Open Access   (Followers: 1)
Artificial Intelligence in Medicine     Hybrid Journal   (Followers: 14)
Artificial Organs     Hybrid Journal   (Followers: 1)
ASHA Leader     Open Access  
Asia Pacific Family Medicine     Open Access   (Followers: 1)
Asia Pacific Journal of Clinical Nutrition     Full-text available via subscription   (Followers: 11)
Asia Pacific Journal of Clinical Trials : Nervous System Diseases     Open Access  
Asian Bioethics Review     Full-text available via subscription   (Followers: 3)
Asian Biomedicine     Open Access   (Followers: 2)
Asian Journal of Cell Biology     Open Access   (Followers: 5)
Asian Journal of Health     Open Access   (Followers: 3)
Asian Journal of Medical and Biological Research     Open Access   (Followers: 4)
Asian Journal of Medical and Pharmaceutical Researches     Open Access   (Followers: 1)
Asian Journal of Medical Sciences     Open Access   (Followers: 2)
Asian Journal of Scientific Research     Open Access   (Followers: 3)
Asian Journal of Transfusion Science     Open Access   (Followers: 1)
Asian Medicine     Hybrid Journal   (Followers: 5)
Asian Pacific Journal of Cancer Prevention     Open Access  
ASPIRATOR : Journal of Vector-borne Disease Studies     Open Access  
Astrocyte     Open Access  
Atención Familiar     Open Access  
Atención Primaria     Open Access   (Followers: 1)
Atti della Accademia Peloritana dei Pericolanti - Classe di Scienze Medico-Biologiche     Open Access  
Audiology - Communication Research     Open Access   (Followers: 10)
Auris Nasus Larynx     Full-text available via subscription  
Australian Coeliac     Full-text available via subscription   (Followers: 1)
Australian Family Physician     Full-text available via subscription   (Followers: 3)
Australian Journal of Medical Science     Full-text available via subscription   (Followers: 1)
Autopsy and Case Reports     Open Access  
Avicenna     Open Access   (Followers: 3)
Avicenna Journal of Clinical Medicine     Open Access  
Avicenna Journal of Medicine     Open Access   (Followers: 1)
Bangabandhu Sheikh Mujib Medical University Journal     Open Access   (Followers: 1)

        1 2 3 4 5 6 7 8 | Last

Similar Journals
Journal Cover
Angiogenesis
Journal Prestige (SJR): 2.177
Citation Impact (citeScore): 5
Number of Followers: 3  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Print) 1573-7209 - ISSN (Online) 0969-6970
Published by Springer-Verlag Homepage  [2351 journals]
  • Platelets: the holy grail in cancer blood biomarker research'
    • Authors: Siamack Sabrkhany; Marijke J. E. Kuijpers; Arjan W. Griffioen; Mirjam G. A. oude Egbrink
      Pages: 1 - 2
      Abstract: We would like to promote the fact that platelets are increasingly emerging as a rich source of potential biomarkers for cancer. Blood platelets contain vast amounts of bioactive proteins, such as growth factors, chemokines, and cytokines. These proteins are either synthesized by the megakaryocytes that produce the platelets or are sequestered by the circulating platelets from the blood, in which case these proteins may originate from the tumor. Recent studies in patients have demonstrated that the presence of cancer influences multiple platelet characteristics (e.g., platelet count, volume, activation status, proteins, and RNA content). Interestingly, these changes happened already in early stages of the disease before metastasis had occurred. Additionally, exploiting these platelet alterations enabled discrimination of patients with early-stage cancer from healthy sex- and age-matched individuals. Therefore, we challenge clinicians and researchers to look beyond traditional fluid sources such as plasma or serum, and to take platelets and their content into account as they may become the holy grail in cancer blood biomarker research.
      PubDate: 2019-02-01
      DOI: 10.1007/s10456-018-9651-4
      Issue No: Vol. 22, No. 1 (2019)
       
  • The therapeutic potential of targeting the endothelial-to-mesenchymal
           transition
    • Authors: Shirley Man; Gonzalo Sanchez Duffhues; Peter ten Dijke; David Baker
      Pages: 3 - 13
      Abstract: Endothelial cells (ECs) have been found to be capable of acquiring a mesenchymal phenotype through a process known as endothelial-to-mesenchymal transition (EndMT). First seen in the developing embryo, EndMT can be triggered postnatally under certain pathological conditions. During this process, ECs dedifferentiate into mesenchymal stem-like cells (MSCs) and subsequently give rise to cell types belonging to the mesoderm lineage. As EndMT contributes to a multitude of diseases, pharmacological modulation of the signaling pathways underlying EndMT may prove to be effective as a therapeutic treatment. Additionally, EndMT in ECs could also be exploited to acquire multipotent MSCs, which can be readily re-differentiated into various distinct cell types. In this review, we will consider current models of EndMT, how manipulation of this process might improve treatment of clinically important pathologies and how it could be harnessed to advance regenerative medicine and tissue engineering.
      PubDate: 2019-02-01
      DOI: 10.1007/s10456-018-9639-0
      Issue No: Vol. 22, No. 1 (2019)
       
  • Excess vascular endothelial growth factor-A disrupts pericyte recruitment
           during blood vessel formation
    • Authors: Jordan Darden; Laura Beth Payne; Huaning Zhao; John C. Chappell
      Pages: 167 - 183
      Abstract: Pericyte investment into new blood vessels is essential for vascular development such that mis-regulation within this phase of vessel formation can contribute to numerous pathologies including arteriovenous and cerebrovascular malformations. It is critical therefore to illuminate how angiogenic signaling pathways intersect to regulate pericyte migration and investment. Here, we disrupted vascular endothelial growth factor-A (VEGF-A) signaling in ex vivo and in vitro models of sprouting angiogenesis, and found pericyte coverage to be compromised during VEGF-A perturbations. Pericytes had little to no expression of VEGF receptors, suggesting VEGF-A signaling defects affect endothelial cells directly but pericytes indirectly. Live imaging of ex vivo angiogenesis in mouse embryonic skin revealed limited pericyte migration during exposure to exogenous VEGF-A. During VEGF-A gain-of-function conditions, pericytes and endothelial cells displayed abnormal transcriptional changes within the platelet-derived growth factor-B (PDGF-B) and Notch pathways. To further test potential crosstalk between these pathways in pericytes, we stimulated embryonic pericytes with Notch ligands Delta-like 4 (Dll4) and Jagged-1 (Jag1) and found induction of Notch pathway activity but no changes in PDGF Receptor-β (Pdgfrβ) expression. In contrast, PDGFRβ protein levels decreased with mis-regulated VEGF-A activity, observed in the effects on full-length PDGFRβ and a truncated PDGFRβ isoform generated by proteolytic cleavage or potentially by mRNA splicing. Overall, these observations support a model in which, during the initial stages of vascular development, pericyte distribution and coverage are indirectly affected by endothelial cell VEGF-A signaling and the downstream regulation of PDGF-B-PDGFRβ dynamics, without substantial involvement of pericyte Notch signaling during these early stages.
      PubDate: 2019-02-01
      DOI: 10.1007/s10456-018-9648-z
      Issue No: Vol. 22, No. 1 (2019)
       
  • Staphylococcus aureus alpha toxin activates Notch in vascular cells
    • Authors: Sonia L. Hernandez; Mildred Nelson; Georgia R. Sampedro; Naina Bagrodia; Ann M. Defnet; Bianca Lec; Jared Emolo; Rebecca Kirschner; Lydia Wu; Henry Biermann; Stephanie Shen; Juliane Bubeck Wardenburg; Jessica J. Kandel
      Pages: 197 - 209
      Abstract: Staphylococcus aureus infection is one of the leading causes of morbidity in hospitalized patients in the United States, an effect compounded by increasing antibiotic resistance. The secreted agent hemolysin alpha toxin (Hla) requires the receptor A Disintegrin And Metalloproteinase domain-containing protein 10 (ADAM10) to mediate its toxic effects. We hypothesized that these effects are in part regulated by Notch signaling, for which ADAM10 activation is essential. Notch proteins function in developmental and pathological angiogenesis via the modulation of key pathways in endothelial and perivascular cells. Thus, we hypothesized that Hla would activate Notch in vascular cells. Human umbilical vein endothelial cells were treated with recombinant Hla (rHla), Hla-H35L (genetically inactivated Hla), or Hank’s solution (HBSS), and probed by different methods. Luciferase assays showed that Hla (0.01 µg/mL) increased Notch activation by 1.75 ± 0.5-fold as compared to HBSS controls (p < 0.05), whereas Hla-H35L had no effect. Immunocytochemistry and Western blotting confirmed these findings and revealed that ADAM10 and γ-secretase are required for Notch activation after inhibitor and siRNA assays. Retinal EC in mice engineered to express yellow fluorescent protein (YFP) upon Notch activation demonstrated significantly greater YFP intensity after Hla injection than controls. Aortic rings from Notch reporter mice embedded in matrix and incubated with rHla or Hla-H35L demonstrate increased Notch activation occurs at tip cells during sprouting. These mice also had higher skin YFP intensity and area of expression after subcutaneous inoculation of S. aureus expressing Hla than a strain lacking Hla in both EC and pericytes assessed by microscopy. Human liver displayed strikingly higher Notch expression in EC and pericytes during S. aureus infection by immunohistochemistry than tissues from uninfected patients. In sum, our results demonstrate that the S. aureus toxin Hla can potently activate Notch in vascular cells, an effect which may contribute to the pathobiology of infection with this microorganism.
      PubDate: 2019-02-01
      DOI: 10.1007/s10456-018-9650-5
      Issue No: Vol. 22, No. 1 (2019)
       
  • Interleukin-8 release by endothelial colony-forming cells isolated from
           idiopathic pulmonary fibrosis patients might contribute to their
           pathogenicity
    • Abstract: Introduction Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by obliteration of alveolar architecture, resulting in declining lung function and ultimately death. Pathogenic mechanisms involve a concomitant accumulation of scar tissue together with myofibroblasts activation and a strong abnormal vascular remodeling. Endothelial progenitor cells (ECFC subtype) have been investigated in several human lung diseases as a potential actor in IPF. We previously demonstrated that ECFCs are down-regulated in IPF in contrast to healthy controls. We postulated here that ECFCs might behave as a liquid biopsy in IPF patients and that they exert modified vasculogenic properties. Methods and results ECFCs isolated from controls and IPF patients expressed markers of the endothelial lineage and did not differ concerning adhesion, migration, and differentiation in vitro and in vivo. However, senescent and apoptotic states were increased in ECFCs from IPF patients as shown by galactosidase staining, p16 expression, and annexin-V staining. Furthermore, conditioned medium of IPF-ECFCs had increased level of interleukin-8 that induced migration of neutrophils in vitro and in vivo. In addition, an infiltration by neutrophils was shown in IPF lung biopsies and we found in a prospective clinical study that a high level of neutrophils in peripheral blood of IPF patients was associated to a poor prognosis. Conclusion To conclude, our study shows that IPF patients have a senescent ECFC phenotype associated with an increased IL-8 secretion potential that might contribute to lung neutrophils invasion during IPF.
      PubDate: 2019-05-01
       
  • ADAM10 controls the differentiation of the coronary arterial endothelium
    • Abstract: The coronary vasculature is crucial for normal heart function, yet much remains to be learned about its development, especially the maturation of coronary arterial endothelium. Here, we show that endothelial inactivation of ADAM10, a key regulator of Notch signaling, leads to defects in coronary arterial differentiation, as evidenced by dysregulated genes related to Notch signaling and arterial identity. Moreover, transcriptome analysis indicated reduced EGFR signaling in A10ΔEC coronary endothelium. Further analysis revealed that A10ΔEC mice have enlarged dysfunctional hearts with abnormal myocardial compaction, and increased expression of venous and immature endothelium markers. These findings provide the first evidence for a potential role for endothelial ADAM10 in cardioprotective homeostatic EGFR signaling and implicate ADAM10/Notch signaling in coronary arterial cell specification, which is vital for normal heart development and function. The ADAM10/Notch signaling pathway thus emerges as a potential therapeutic target for improving the regenerative capacity and maturation of the coronary vasculature.
      PubDate: 2019-05-01
       
  • Interleukin-22 promotes tumor angiogenesis
    • Abstract: TH17 cells play important yet complex roles in cancer development and progression. We previously reported that TH17 cells and IL-17 mediate resistance to anti-VEGF therapy by inducing recruitment of immunosuppressive and proangiogenic myeloid cells to the tumor microenvironment. Here, we demonstrate that IL-22, a key effector cytokine expressed by TH17 cells, directly acts on endothelial cells to promote tumor angiogenesis. IL-22 induces endothelial cell proliferation, survival, and chemotaxis in vitro and neovascularization in an ex vivo mouse choroid explant model. Blockade of IL-22, with a neutralizing antibody, significantly inhibits tumor growth associated with reduced microvascular density. No synergistic effect of IL-22 with VEGF was observed. These results identify IL-22 as a potential therapeutic target for blocking tumor angiogenesis.
      PubDate: 2019-05-01
       
  • TSPYL5-mediated inhibition of p53 promotes human endothelial cell function
    • Abstract: Testis-specific protein, Y-encoded like (TSPYL) family proteins (TSPYL1-6), which are members of the nucleosome assembly protein superfamily, have been determined to be involved in the regulation of various cellular functions. However, the potential role of TSPYL family proteins in endothelial cells (ECs) has not been determined. Here, we demonstrated that the expression of TSPYL5 is highly enriched in human ECs such as human umbilical vein endothelial cells (HUVECs) and human pluripotent stem cell-differentiated ECs (hPSC-ECs). Importantly, TSPYL5 overexpression was shown to promote EC proliferation and functions, such as migration and tube formation, by downregulating p53 expression. Adriamycin-induced senescence was markedly blocked by TSPYL5 overexpression. In addition, the TSPYL5 depletion-mediated loss of EC functions was blocked by p53 inhibition. Significantly, TSPYL5 overexpression promoted angiogenesis in Matrigel plug and wound repair in a mouse skin wound healing model in vivo. Our results suggest that TSPYL5, a novel angiogenic regulator, plays a key role in maintaining endothelial integrity and function. These findings extend the understanding of TSPYL5-dependent mechanisms underlying the regulation of p53-related functions in ECs.
      PubDate: 2019-05-01
       
  • The regulatory network of miR-141 in the inhibition of angiogenesis
    • Abstract: The miR-200 family, consisting of miR-200a/b/c, miR-141, and miR-429, is well known to inhibit epithelial-to-mesenchymal transition (EMT) in cancer invasion and metastasis. Among the miR-200 family members, miR-200a/b/c and miR-429 have been reported to inhibit angiogenesis. However, the role of miR-141 in angiogenesis remains elusive, as contradicting results have been found in different cancer types and tumor models. Particularly, the effect of miR-141 in vascular endothelial cells has not been defined. In this study, we used several in vitro and in vivo models to demonstrate that miR-141 in endothelial cells inhibits angiogenesis. Additional mechanistic studies showed that miR-141 suppresses angiogenesis through multiple targets, including NRP1, GAB1, CXCL12β, TGFβ2, and GATA6, and bioinformatics analysis indicated that miR-141 and its targets comprise a powerful and precise regulatory network to modulate angiogenesis. Taken together, these data not only demonstrate an anti-angiogenic effect of miR-141, further strengthening the critical role of miR-200 family in the process of angiogenesis, but also provides a valuable cancer therapeutic target to control both angiogenesis and EMT, two essential steps in tumor growth and metastasis.
      PubDate: 2019-05-01
       
  • A ribosomal DNA-hosted microRNA regulates zebrafish embryonic angiogenesis
    • Abstract: MicroRNAs (miRNAs) are single-stranded small non-coding RNAs, generally 18–25 nucleotides in length, that act as repressors of gene expression. miRNAs are encoded by independent genes or processed from a variety of different RNA species. So far, there is no evidence showing that the ribosomal DNA-hosted microRNA is implicated in vertebrate development. Currently, we found a highly expressed small RNA hosted in ribosomal DNA was predicted as a novel miRNA, named miR-ntu1, in zebrafish endothelial cells by deep sequencing analysis. The miRNA was validated by custom-designed Taqman PCR, Northern Blot, and in silico analysis. Furthermore, we demonstrated that miR-ntu1 played a crucial role in zebrafish angiogenesis via modulation of Notch signaling. Our findings provide a notable case that a miRNA hosted in ribosomal DNA is involved in vertebrate development.
      PubDate: 2019-05-01
       
  • Live imaging of angiogenesis during cutaneous wound healing in adult
           zebrafish
    • Abstract: Angiogenesis, the growth of new blood vessels from pre-existing vessels, is critical for cutaneous wound healing. However, it remains elusive how endothelial cells (ECs) and pericytes (PCs) establish new blood vessels during cutaneous angiogenesis. We set up a live-imaging system to analyze cutaneous angiogenesis in adult zebrafish. First, we characterized basic structures of cutaneous vasculature. In normal skin tissues, ECs and PCs remained dormant to maintain quiescent blood vessels, whereas cutaneous injury immediately induced angiogenesis through the vascular endothelial growth factor signaling pathway. Tortuous and disorganized vessel networks formed within a few weeks after the injury and subsequently normalized through vessel regression in a few months. Analyses of the repair process of injured single blood vessels revealed that severed vessels elongated upon injury and anastomosed with each other. Thereafter, repaired vessels and adjacent uninjured vessels became tortuous by increasing the number of ECs. In parallel, PCs divided and migrated to cover the tortuous blood vessels. ECs sprouted from the PC-covered tortuous vessels, suggesting that EC sprouting does not require PC detachment from the vessel wall. Thus, live imaging of cutaneous angiogenesis in adult zebrafish enables us to clarify how ECs and PCs develop new blood vessels during cutaneous angiogenesis.
      PubDate: 2019-05-01
       
  • AutoTube: a novel software for the automated morphometric analysis of
           vascular networks in tissues
    • Abstract: Due to their involvement in many physiologic and pathologic processes, there is a great interest in identifying new molecular pathways that mediate the formation and function of blood and lymphatic vessels. Vascular research increasingly involves the image-based analysis and quantification of vessel networks in tissue whole-mounts or of tube-like structures formed by cultured endothelial cells in vitro. While both types of experiments deliver important mechanistic insights into (lymph)angiogenic processes, the manual analysis and quantification of such experiments are typically labour-intensive and affected by inter-experimenter variability. To bypass these problems, we developed AutoTube, a new software that quantifies parameters like the area covered by vessels, vessel width, skeleton length and branching or crossing points of vascular networks in tissues and in in vitro assays. AutoTube is freely downloadable, comprises an intuitive graphical user interface and helps to perform otherwise highly time-consuming image analyses in a rapid, automated and reproducible manner. By analysing lymphatic and blood vascular networks in whole-mounts prepared from different tissues or from gene-targeted mice with known vascular abnormalities, we demonstrate the ability of AutoTube to determine vascular parameters in close agreement to the manual analyses and to identify statistically significant differences in vascular morphology in tissues and in vascular networks formed in in vitro assays.
      PubDate: 2019-05-01
       
  • Kruppel-like factor 4 regulates developmental angiogenesis through
           disruption of the RBP-J–NICD–MAML complex in intron 3 of Dll4
    • Abstract: Angiogenesis is a multistep process that requires highly regulated endothelial cell (EC) behavior. The transcription factor Krüppel-like factor 4 (KLF4) is a critical regulator of several basic EC functions; we have recently shown that KLF4 disturbs pathological (tumor) angiogenesis by mediating the expression of members of VEGF and Notch signaling pathways. Notch signaling is central to orchestration of sprouting angiogenesis but little is known about the upstream regulation of Notch itself. To determine the role of KLF4 in normal (developmental) angiogenesis, we used a mouse retinal angiogenesis model. We found that endothelial-specific overexpression of KLF4 in transgenic mice (EC-K4 Tg) leads to increased vessel density, branching and number of tip cell filopodia as assessed on postnatal day 6 (P6). The hypertrophic vasculature seen with sustained KLF4 overexpression is not stable and undergoes prominent remodeling during P7–P12 resulting in a normal appearing retinal vasculature in adult EC-K4 Tg mice. We find that KLF4 inhibits Delta-like 4 (DLL4) expression in the angiogenic front during retinal vascular development. Furthermore, in an oxygen-induced retinopathy model, overexpression of KLF4 results in decreased vaso-obliteration and neovascular tuft formation that is similar to genetic or pharmacologic DLL4 inhibition. Mechanistically, we show that KLF4 disables the activity of the essential Notch transcriptional activator RBP-J by interfering with binding of co-activators NICD and MAML at intron 3 of the Notch ligand DLL4. In summary, our experimental results demonstrate a regulatory role of KLF4 in developmental angiogenesis through regulation of DLL4 transcription.
      PubDate: 2019-05-01
       
  • Mouse models of Alzheimer’s disease cause rarefaction of pial
           collaterals and increased severity of ischemic stroke
    • Abstract: Vascular dysfunction contributes to the progression and severity of Alzheimer’s disease (AD). Patients with AD also sustain larger infarctions after ischemic stroke; however, the responsible mechanisms are unknown. Pial collaterals are the primary source of protection in stroke. Unfortunately, natural aging and other vascular risk factors cause a decline in collateral number and diameter (rarefaction) and an increase in stroke severity. Herein, we tested the hypothesis that AD accelerates age-induced collateral rarefaction and examined potential underlying mechanisms. Triple and double transgenic mouse models of AD both sustained collateral rarefaction by 8 months of age, well before the onset of rarefaction caused by aging alone (16 months of age). Rarefaction, which did not progress further at 18 months of age, was accompanied by a twofold increase in infarct volume after MCA occlusion. AD did not induce rarefaction of similarly sized pial arterioles or penetrating arterioles. Rarefaction was minimal and occurred only at 18 months of age in a parenchymal vascular amyloid-beta model of AD. Rarefaction was not associated with amyloid-beta deposition on collaterals or pial arteries, nor was plaque burden or CD11b+ cell density greater in brain underlying the collateral zones versus elsewhere. However, rarefaction was accompanied by increased markers of oxidative stress, inflammation, and aging of collateral endothelial and mural cells. Moreover, rarefaction was lessened by deletion of CX3CR1 and prevented by overexpression of eNOS. These findings demonstrate that mouse models of AD promote rarefaction of pial collaterals and implicate inflammation-induced accelerated aging of collateral wall cells. Strategies that reduce vascular inflammation and/or increase nitric oxide may preserve collateral function.
      PubDate: 2019-05-01
       
  • Angiogenic desmoplastic histopathological growth pattern as a prognostic
           marker of good outcome in patients with colorectal liver metastases
    • Abstract: Background In patients with resectable colorectal liver metastases (CRLM), distinct histopathological growth patterns (HGPs) develop at the interface between the tumour and surrounding tissue. The desmoplastic (d) HGP is characterised by angiogenesis and a peripheral fibrotic rim, whereas non-angiogenic HGPs co-opt endogenous sinusoidal hepatic vasculature. Evidence from previous studies has suggested that patients with dHGP in their CRLM have improved prognosis as compared to patients with non-desmoplastic HGPs. However, these studies were relatively small and applied arbitrary cut-off values for the determination of the predominant HGP. We have now investigated the prognostic effect of dHGP in a large cohort of patients with CRLM resected either with or without neoadjuvant chemotherapy. Methods All consecutive patients undergoing a first partial hepatectomy for CRLM between 2000 and 2015 at a tertiary referral centre were considered for inclusion. HGPs were assessed in archival H&E stained slides according to recently published international consensus guidelines. The dHGP was defined as desmoplastic growth being present in 100% of the interface between the tumour and surrounding liver. Results In total, HGPs in CRLMs from 732 patients were assessed. In the chemo-naive patient cohort (n = 367), the dHGP was present in 19% (n = 68) and the non-dHGP was present in 81% (n = 299) of patients. This dHGP subgroup was independently associated with good overall survival (OS) (HR: 0.39, p < 0.001) and progression-free survival (PFS) (HR: 0.54, p = 0.001). All patients with any CRLM with a non-dHGP had significantly reduced OS compared to those patients with 100% dHGP, regardless of the proportion of non-dHGP (all p values ≤ 0.001). In the neoadjuvantly treated patient cohort (n = 365), more patients were found to express dHGP (n = 109, 30%) (adjusted odds ratio: 2.71, p < 0.001). On univariable analysis, dHGP was associated with better OS (HR 0.66, p = 0.009) and PFS (HR 0.67, p = 0.002). However, after correction for confounding by means of multivariable analysis no significant association of dHGP with OS (HR 0.92, p = 0.623) or PFS (HR 0.76, p = 0.065) was seen. Conclusions The current study demonstrates that the angiogenic dHGP in CRLM resected from chemo-naive patients acts as a strong, positive prognostic marker, unmatched by any other prognosticator. This observation warrants the evaluation of the clinical utility of HGPs in prospective clinical trials.
      PubDate: 2019-05-01
       
  • Cancer-derived exosomal miR-221-3p promotes angiogenesis by targeting
           THBS2 in cervical squamous cell carcinoma
    • Abstract: Aims Recently, cancer-derived exosomes were shown to have pro-metastasis function in cancer, but the mechanism remains unclear. Angiogenesis is essential for tumor progression and is a great promising therapeutic target for advanced cervical cancer. Here, we investigated the role of cervical cancer cell-secreted exosomal miR-221-3p in tumor angiogenesis. Methods and results miR-221-3p was found to be closely correlated with microvascular density in cervical squamous cell carcinoma (CSCC) by evaluating the microvascular density with immunohistochemistry and miR-221-3p expression with in situ hybridization in clinical specimens. Using the groups of CSCC cell lines (SiHa and C33A) with miR-221-3p overexpression and silencing, the CSCC exosomes were characterized by electron microscopy, western blotting, and fluorescence microscopy. The enrichment of miR-221-3p in CSCC exosomes and its transfer into human umbilical vein endothelial cells (HUVECs) were confirmed by qRT-PCR. CSCC exosomal miR-221-3p promoted angiogenesis in vitro in Matrigel tube formation assay, spheroid sprouting assay, migration assay, and wound healing assay. Then, exosome intratumoral injection indicated that CSCC exosomal miR-221-3p promoted tumor growth in vivo. Thrombospondin-2 (THBS2) was bioinformatically predicted to be a direct target of miR-221-3p, and this was verified by using the in vitro and in vivo experiments described above. Additionally, overexpression of THBS2 in HUVECs rescued the angiogenic function of miR-221-3p. Conclusions Our results suggest that CSCC exosomes transport miR-221-3p from cancer cells to vessel endothelial cells and promote angiogenesis by downregulating THBS2. Therefore, CSCC-derived exosomal miR-221-3p could be a possible novel diagnostic biomarker and therapeutic target for CSCC progression.
      PubDate: 2019-04-15
       
  • Prognostic effect of VEGF gene variants in metastatic non-small-cell lung
           cancer patients
    • Abstract: Introduction Clinical and pathological characteristics are still considered prognostic markers in metastatic non-small-cell lung cancer (NSCLC) patients but they cannot explain all interindividual variability. Tumoral angiogenesis mediated by the vascular endothelial growth factor (VEGF) is critical for the progression and metastasis of the disease. We aimed to investigate the prognostic role of genetic variants within the VEGF pathway in patients with metastatic NSCLC. Materials and methods We prospectively included 170 patients with metastatic NSCLC treated with first-line platinum-based chemotherapy. A comprehensive panel of single-nucleotide polymorphisms (SNPs) in genes belonging to the VEGF pathway (VEGFA, VEGFR1/FLT1, VEGFR2/KDR, GRB2, ITGAV, KISS1, KRAS, PRKCE, HIF1α, MAP2K4, MAP2K6, and MAPK11) were genotyped in blood DNA samples. SNPs were evaluated for association with overall survival (OS) and progression-free survival (PFS). Results In multivariate analyses adjusted for patient characteristics, we found that VEGFA rs2010963 and VEGFR2 rs2071559 were significantly associated with OS [Hazard Ratio (HR) 0.7 (0.5–0.9); p = 0.026 and HR 1.5 (1.1–2.3); p = 0.025, respectively]. Additionally, ITGAV rs35251833 and MAPK11 rs2076139 were significantly associated with PFS [HR 2.5 (1.4–4.3; p = 0.002 and HR 0.6 (0.5–0.9); p = 0.013, respectively]. Conclusion Our findings reinforce the potential clinical value of germline variants in VEGFA and VEGFR2 and show for the first time variants in ITGAV and MAPK11 as promising prognostic markers in metastatic NSCLC patients receiving platinum-based chemotherapy.
      PubDate: 2019-04-11
       
  • The plaque-aortic ring assay: a new method to study human
           atherosclerosis-induced angiogenesis
    • Abstract: Progression of atherosclerotic plaques into life-threatening lesions is associated with angiogenesis which contributes to intraplaque hemorrhages and plaque instability. The lack of adequate models for the study of human plaque-induced angiogenesis has limited progress in this field. We describe here a novel ex vivo model which fills this gap. Plaques obtained from 15 patients who underwent endarterectomy procedures were co-cultured in collagen gels with rat aorta rings which served as read-out of human plaque angiogenic activity. The majority of plaque fragments markedly stimulated angiogenic sprouting from the aortic rings while concurrently promoting the outgrowth of resident macrophages from the aortic adventitia. This stimulatory activity correlated with the presence of intraplaque macrophages. Proteomic analysis of plaque secretomes revealed heterogeneity of macrophage-stimulatory cytokine and angiogenic factor production by different plaques. VEGF was identified in some of the plaque secretomes. Antibody-mediated blockade of VEGF had significant but transient inhibitory effect on angiogenesis, which suggested redundancy of plaque-derived angiogenic stimuli. Pharmacologic ablation of adventitial macrophages permanently impaired the angiogenic response of aortic rings to plaque stimuli. Our results show that human plaque-induced angiogenesis can be reproduced ex vivo using rat aortic rings as read-out of plaque angiogenic activity. This model can be used to identify key cellular and molecular mechanisms responsible for the neovascularization of human plaques.
      PubDate: 2019-04-09
       
  • Exhaustion of the bone marrow progenitor cell reserve is associated with
           major events in severe limb ischemia
    • Abstract: Lower numbers of progenitor cells (PCs) in peripheral blood (PB) have been associated with cardiovascular events in high-risk populations. Therapies aiming to increase the numbers of PCs in circulation have been developed, but clinical trials did not result in better outcomes. It is currently unknown what causes the reduction in PB PC numbers: whether it is primary depletion of the progenitor cell reserve, or a reduced mobilization of PCs from the bone marrow (BM). In this study, we examine if PB and BM PC numbers predict Amputation-Free Survival (AFS) in patients with Severe Limb Ischemia (SLI). We obtained PB and BM from 160 patients enrolled in a clinical trial investigating BM cell therapy for SLI. Samples were incubated with antibodies against CD34, KDR, CD133, CD184, CD14, CD105, CD140b, and CD31; PC populations were enumerated by flow cytometry. Higher PB CD34+ and CD133+ PC numbers were related to AFS (Both Hazard Ratio [HRevent] = 0.56, p = 0.003 and p = 0.0007, respectively). AFS was not associated with the other cell populations in PB. BM PC numbers correlated with PB PC numbers and showed similar HRs for AFS. A further subdivision based on relative BM and PB PC numbers showed that BM PC numbers, rather than mobilization, associated with AFS. Both PB and BM PC numbers are associated with AFS independently from traditional risk factor and show very similar risk profiles. Our data suggest that depletion of the progenitor cell reserve, rather than decreased PC mobilization, underlies the association between PB PC numbers and cardiovascular risk.
      PubDate: 2019-03-30
       
  • A new prognostic model for survival in second line for metastatic renal
           cell carcinoma: development and external validation
    • Authors: Lisa Derosa; Mohamed Amine Bayar; Laurence Albiges; Gwénaël Le Teuff; Bernard Escudier
      Abstract: Background In patients with metastatic renal cell carcinoma (mRCC), the oncologic benefit of second-line treatment for high volume tumors or presence of more than five risk factors remain to be defined. Our aim was to develop and externally validate a new model most likely to correctly predict overall survival (OS) categories in second line. Method mRCC patients treated within clinical trials at Gustave Roussy Cancer Campus (GRCC) formed the discovery set. Patients from two phase III trials from Pfizer database (PFIZERDB), AXIS (NCT00678392), and INTORSECT (NCT00474786), formed the external validation set. New prognostic factors were analyzed using a multivariable Cox model with a backward selection procedure. Performance of the GRCC model and the prognostic classification scheme derived from it, measuring by R2, c-index, and calibration, was evaluated on the validation set and compared to MSKCC and IMDC models. Results Two hundred and twenty-one patients were included in the GRCC cohort and 855 patients in the PFIZERDB. Median OS was similar in the discovery and validation cohorts (16.8 [95% CI 12.9–21.7] and 15.3 [13.6–17.2] months, respectively). Backward selection procedure identified time from first to second-line treatment and tumor burden as new independent prognostic factors significantly associated to OS after adjusting for IMDC prognostic factors (HR 1.68 [1.23–2.31] and 1.43 [1.03–1.99], respectively). Dividing patients into four risk groups, based on the number of factors selected in GRCC model, median OS from the start of second line in the validation cohort was not reached (NE) [95% CI 24.9–NE] in the favorable risk group (n = 20), 21.8 months [18.6–28.2] in the intermediate-risk group (n = 367), 12.7 months [11.0–15.8] in the low poor-risk group (n = 347), and 5.5 months [4.7–6.4] in the high poor-risk group (n = 121). Finally, this model and its prognostic classification scheme provided the better fit, with higher R2 and higher c-index compared to other possible classification schemes. Conclusion A new prognostic model was developed and validated to estimate overall survival of patients with previously treated mRCC. This model is an easy-to-use tool that allows accurate estimation of patient survival to inform decision making and follow-up after first line for mRCC.
      PubDate: 2019-02-09
      DOI: 10.1007/s10456-019-09664-2
       
 
 
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