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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  [2351 journals]
  • Correction to: Critical role of interleukin-23 in development of asthma
           promoted by cigarette smoke
    • Abstract: The original publication of this paper contains a mistake.
      PubDate: 2019-07-01
  • Pathological cardiac hypertrophy: the synergy of adenylyl cyclases
           inhibition in cardiac and immune cells during chronic catecholamine stress
    • Abstract: Response to stressors in our environment and daily lives is an adaptation conserved through evolution as it is beneficial in enhancing the survival and continuity of humans. Although stressors have evolved, the drastic physiological response they elicit still remains unchanged. The chronic secretion and circulation of catecholamines to produce physical responses when they are not required may result in pathological consequences which affect cardiac function drastically. This review seeks to point out the probable implication of chronic stress in inducing an inflammation disorder in the heart. We discussed the likely synergy of a G protein-independent stimuli signaling via β2-adrenergic receptors in both cardiomyocytes and immune cells during chronic catecholamine stress. To explain this synergy, we hypothesized the possibility of adenylyl cyclases having a regulatory effect on G protein-coupled receptor kinases. This was based on the negative correlations they exhibit during normal cardiac function and heart failures. As such, the downregulation of adenylyl cyclases in cardiomyocytes and immune cells during chronic catecholamine stress enhances the expressions of G protein-coupled receptor kinases. In addition, we explain the maladaptive roles played by G protein-coupled receptor kinase and extracellular signal-regulated kinase in the synergistic cascade that pathologically remodels the heart. Finally, we highlighted the therapeutic potentials of an adenylyl cyclases stimulator to attenuate pathological cardiac hypertrophy (PCH) and improve cardiac function in patients developing cardiac disorders due to chronic catecholamine stress.
      PubDate: 2019-07-01
  • Bone marrow chimeras—a vital tool in basic and translational
    • Abstract: Bone marrow chimeras are used routinely in immunology research as well as in other fields of biology. Here, we provide a concise state-of-the-art review about the types of chimerisms that can be achieved and the type of information that each model generates. We include separate sections for caveats and future developments. We provide examples from the literature in which different types of chimerism were employed to answer specific questions. While simple bone marrow chimeras allow to dissect the role of genes in distinct cell populations such as the hematopoietic cells versus non-hematopoietic cells, mixed bone marrow chimeras can provide detailed information about hematopoietic cell types and the intrinsic and extrinsic roles of individual genes. The advantages and caveats of bone marrow chimerism for the study of microglia are addressed, as well as alternatives to irradiation that minimize blood-brain-barrier disruption. Elementary principles are introduced and their potential is exemplified through summarizing recent studies.
      PubDate: 2019-07-01
  • A rapid, safe, and quantitative in vitro assay for measurement of
           uracil-DNA glycosylase activity
    • Abstract: Base excision repair (BER) is a frontline repair mechanism that operates through the G1 phase of the cell cycle, which ensures the genome integrity by repairing thousands of DNA lesions due to endogenous and exogenous agents. Its correct functioning is fundamental for cell viability and the health of the organism. Uracil is one of the most prevalent lesions that appears in DNA arising by spontaneous or enzymatic deamination of cytosine or misincorporation of the deoxyuridine 5′-triphosphate nucleotide (dUTP) in place of deoxythymidine 5′-triphosphate (dTTP) during DNA replication. In the first pathway, the uracil will preferentially pair with adenine, leading to C:G → T:A transition. When uracil in DNA arises from misincorporation of dUTP instead of dTTP, this process will result in A:U pairs. Organisms counteract the mutagenic effects of uracil in DNA using the BER repair system, which is mediated by a member of the uracil-DNA glycosylase (UDG) superfamily. Several assays evaluating the in vitro BER enzyme activity have been described so far. Some of these measure the BER activity by an oligonucleotide incision assay using radiolabeled duplex oligo. Others use circular double-stranded DNA substrates containing a defined lesion. The novelty of our method resides in its rapidity and safety (radioactive free detection) as well as in the possibility of having a reliable quantitative determination of UDG activity in both cell and tissue extracts. We also demonstrated the effectiveness of our method in assessing UDG activity in cell lines with a reduced DNA repair capacity and in different kinds of tissues. Key messages • Base excision repair is a fundamental repair mechanism ensuring the genome integrity. • Uracil is one of the most prevalent lesions that appears in DNA. • The mutagenic effects of uracil in DNA are mitigated by the uracil-DNA glycosylase. • Several assays evaluating the in vitro BER activity have been described so far. • A safe and quantitative assay evaluating the in vitro UDG activity is required.
      PubDate: 2019-07-01
  • The protean world of non-coding RNAs in glioblastoma
    • Abstract: Non-coding ribonucleic acids (ncRNAs) are a diverse group of RNA molecules that are mostly not translated into proteins following transcription. We review the role of ncRNAs in the pathobiology of glioblastoma (GBM), and their potential applications for GBM therapy. Significant advances in our understanding of the protean manifestations of ncRNAs have been made, allowing us to better decipher the molecular complexity of GBM. A large number of regulatory ncRNAs appear to have a greater influence on the molecular pathology of GBM than thought previously. Importantly, also, a range of therapeutic approaches are emerging whereby ncRNA-based systems may be used to molecularly target GBM. The most successful of these is RNA interference, and some of these strategies are being evaluated in ongoing clinical trials. However, a number of limitations exist in the clinical translation of ncRNA-based therapeutic systems, such as delivery mechanisms and cytotoxicity; concerted research endeavors are currently underway in an attempt to overcome these. Ongoing and future studies will determine the potential practical role for ncRNA-based therapeutic systems in the clinical management of GBM. These applications may be especially promising, given that current treatment options are limited and prognosis remains poor for this challenging malignancy.
      PubDate: 2019-07-01
  • Mevalonate promotes differentiation of regulatory T cells
    • Abstract: Mevalonate is a precursor in a biosynthetic pathway that is important for the coordination of regulatory T cell (Treg) proliferation and upregulation of the suppressive function that establishes the functional competency of Tregs. The extensive role of mevalonate and its underlying effect on Treg differentiation are still unclear. We found that mevalonate increases in vitro differentiation of induced Tregs (iTregs) without broadly affecting Th1 and Th17 cell differentiation. Furthermore, an adoptive transfer study showed that mevalonate enhanced peripherally induced Treg cells (pTregs) in mesenteric lymphocytes in vivo. Mevalonate-treated iTregs exhibited greater suppressive activity against effector cells than untreated Tregs. Mechanistically, mevalonate enhanced transforming growth factor (TGF)-β signaling by increasing the phosphorylation of Smad3, but not Smad2, and by promoting Foxp3 expression. Furthermore, we demonstrated that mevalonate treatment ameliorated dextran sulfate sodium (DSS)-induced colitis and resulted in an increased percentage of Tregs in vivo. Our results suggest that mevalonate enhanced Treg differentiation and ameliorated DSS colitis, indicating its potential for treatment of inflammatory diseases.
      PubDate: 2019-07-01
  • RPSAP52 lncRNA is overexpressed in pituitary tumors and promotes cell
           proliferation by acting as miRNA sponge for HMGA proteins
    • Abstract: Long non-coding RNAs (lncRNAs) are emerging as fundamental players in cancer biology. Indeed, they are deregulated in several neoplasias and have been associated with cancer progression, tumor recurrence, and resistance to treatment, thus representing potential biomarkers for cancer diagnosis, prognosis, and therapy. In this study, we aimed to identify lncRNAs associated with pituitary tumorigenesis. We have analyzed the lncRNA expression profile of a panel of gonadotroph pituitary adenomas in comparison with normal pituitaries. Then, we focused on RPSAP52, a novel lncRNA antisense for the HMGA2 gene, whose overexpression plays a critical role in the development of pituitary adenomas. We report that RPSAP52 expression is highly upregulated in gonadotroph and prolactin-secreting pituitary adenomas, where it correlates with that of HMGA2, compared with normal pituitary tissues. Conversely, its expression showed a variable behavior in somatotroph adenomas. We also demonstrate that RPSAP52 enhances HMGA2 protein expression in a ceRNA-dependent way acting as sponge for miR-15a, miR-15b, and miR-16, which have been already described to be able to target HMGA2. Interestingly, RPSAP52 also positively modulates HMGA1, the other member of the High-Mobility Group A family. Moreover, functional studies indicate that RPSAP52 promotes cell growth by enhancing the G1-S transition of the cell cycle. The results reported here reveal a novel mechanism, based on the overexpression of the lncRNA RPSAP52, which contributes to pituitary tumorigenesis, and propose this lncRNA as a novel player in the development of these tumors. Key Messages RPSAP52 is overexpressed in pituitary adenomas. RPSAP52 increases HMGA protein levels. A ceRNA mechanism is proposed for the increased HMGA1/2 expression.
      PubDate: 2019-07-01
  • Therapeutic potential of AAV9-S15D-RLC gene delivery in humanized MYL2
           mouse model of HCM
    • Abstract: Familial hypertrophic cardiomyopathy (HCM) is an autosomal dominant disorder characterized by ventricular hypertrophy, myofibrillar disarray, and fibrosis, and is primarily caused by mutations in sarcomeric genes. With no definitive cure for HCM, there is an urgent need for the development of novel preventive and reparative therapies. This study is focused on aspartic acid-to-valine (D166V) mutation in the myosin regulatory light chain, RLC (MYL2 gene), associated with a malignant form of HCM. Since myosin RLC phosphorylation is critical for normal cardiac function, we aimed to exploit this post-translational modification via phosphomimetic-RLC gene therapy. We hypothesized that mimicking/modulating cardiac RLC phosphorylation in non-phosphorylatable D166V myocardium would improve heart function of HCM-D166V mice. Adeno-associated virus, serotype-9 (AAV9) was used to deliver phosphomimetic human RLC variant with serine-to-aspartic acid substitution at Ser15-RLC phosphorylation site (S15D-RLC) into the hearts of humanized HCM-D166V mice. Improvement of heart function was monitored by echocardiography, invasive hemodynamics (PV-loops) and muscle contractile mechanics. A significant increase in cardiac output and stroke work and a decrease in relaxation constant, Tau, shown to be prolonged in HCM mice, were observed in AAV- vs. PBS-injected HCM mice. Strain analysis showed enhanced myocardial longitudinal shortening in AAV-treated vs. control mice. In addition, increased maximal contractile force was observed in skinned papillary muscles from AAV-injected HCM hearts. Our data suggest that myosin RLC phosphorylation may have important translational implications for the treatment of RLC mutations-induced HCM and possibly play a role in other disease settings accompanied by depressed Ser15-RLC phosphorylation. Key messages HCM-D166V mice show decreased RLC phosphorylation and decompensated function. AAV9-S15D-RLC gene therapy in HCM-D166V mice, but not in WT-RLC, results in improved heart performance. Global longitudinal strain analysis shows enhanced contractility in AAV vs controls. Increased systolic and diastolic function is paralleled by higher contractile force. Phosphomimic S15D-RLC has a therapeutic potential for HCM.
      PubDate: 2019-07-01
  • Targeted inhibition of histone deacetylase leads to suppression of Ewing
           sarcoma tumor growth through an unappreciated EWS-FLI1/HDAC3/HSP90
           signaling axis
    • Abstract: Ewing sarcoma (ES) are aggressive pediatric bone and soft tissue tumors driven by EWS-ETS fusion oncogenes, most commonly EWS-FLI1. Treatment of ES patients consists of up to 9 months of alternating courses of 2 chemotherapeutic regimens. Furthermore, EWS-ETS-targeted therapies have yet to demonstrate clinical benefit, thereby emphasizing a clinical responsibility to search for new therapeutic approaches. Our previous in silico drug screening identified entinostat as a drug hit that was predicted to reverse the ES disease signatures and EWS-FLI1-mediated gene signatures. Here, we establish preclinical proof of principle by investigating the in vitro and in vivo efficacy of entinostat in preclinical ES models, as well as characterizing the mechanisms of action and in vivo pharmacokinetics of entinostat. ES cells are preferentially sensitive to entinostat in an EWS-FLI1 or EWS-ERG-dependent manner. Entinostat induces apoptosis of ES cells through G0/G1 cell cycle arrest, intracellular reactive oxygen species (ROS) elevation, DNA damage, homologous recombination (HR) repair impairment, and caspase activation. Mechanistically, we demonstrate for the first time that HDAC3 is a transcriptional target of EWS-FLI1 and that entinostat inhibits growth of ES cells through suppressing a previously unexplored EWS-FLI1/HDAC3/HSP90 signaling axis. Importantly, entinostat significantly reduces tumor burden by 97.4% (89.5 vs. 3397.3 mm3 of vehicle, p < 0.001) and prolongs the median survival of mice (15.5 vs. 8.5 days of vehicle, p < 0.001), in two independent ES xenograft mouse models, respectively. Overall, our studies demonstrate promising activity of entinostat against ES, and support the clinical development of the entinostat-based therapies for children and young adults with metastatic/relapsed ES. Key messages • Entinostat potently inhibits ES both in vitro and in vivo. • EWS-FLI1 and EWS-ERG confer sensitivity to entinostat treatment. • Entinostat suppresses the EWS-FLI1/HDAC3/HSP90 signaling. • HDAC3 is a transcriptional target of EWS-FLI1. • HDAC3 is essential for ES cell viability and genomic stability maintenance.
      PubDate: 2019-07-01
  • Critical role of interleukin-23 in development of asthma promoted by
           cigarette smoke
    • Abstract: It has been recently reported that cigarette smoke exposure during allergen sensitization facilitates the development of allergic asthma; however, the underlying mechanisms remain elusive. We evaluated the role of interleukin (IL-23) in a cigarette smoke extract (CSE)-induced Dermatophagoides pteronyssinus (Dp)-allergic asthma mouse model. BALB/c mice were exposed to CSE during allergen sensitization period. Anti-IL-23p19 or IL-23R antibody was administered during the sensitization period. And we evaluated several immunological responses. The expression of IL-23 and IL-23 receptor (IL-23R) was examined in lung tissue. IL-23 and IL-23R expression was increased in the airway epithelium of Dp/CSE co-administered mice. CSE administration during the sensitization promoted Dp-allergic sensitization and the development of asthma phenotypes. Additionally, the proportion of innate lymphoid type 2 cells (ILC2) was also increased by CSE and Dp co-instillation. Anti-IL-23 or IL-23R antibody treatment during allergen sensitization significantly diminished phenotypes of allergic asthma and the ILC2 population. The levels of IL-33 and thymic stromal lymphopoietin (TSLP) were also significantly reduced by anti-IL-23 or IL-23R antibody treatment. IL-23 may thus play a significant role in cigarette smoke-induced allergic sensitization and asthma development. Clinically, the increase in allergen sensitization due to cigarette exposure causes onset of asthma, and IL-23 may be important in this mechanism. Key messages IL-23 and IL-23R expression was increased in the lung epithelium of Dp and CSE co-exposed mice during sensitization period. The population of ILC2s was increased in Dp and CSE co-exposed mice during sensitization period. Anti-IL23 or IL-23R antibody treatment with co-administration of CSE and HDM during sensitization period significantly suppresses ILC2. In vitro, IL-23 blockade in Dp and CSE-stimulated epithelial cells suppressed IL-13 expression in ILC2.
      PubDate: 2019-07-01
  • Regulation and role of the ER stress transcription factor CHOP in alveolar
           epithelial type-II cells
    • Abstract: Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by type-II alveolar epithelial cell (AECII) injury and fibroblast hyperproliferation. Severe AECII endoplasmic reticulum (ER) stress is thought to underlie IPF, but is yet incompletely understood. We studied the regulation of C/EBP homologous protein (CHOP), a proapoptotic ER-stress-related transcription factor (TF) in AECII-like cells. Interestingly, single or combined overexpression of the active ER stress transducers activating transcription factor-4 (Atf4) and activating transcription factor-6 (p50Atf6) or spliced x-box-binding protein-1 (sXbp1) in MLE12 cells did not result in a substantial Chop induction, as compared to the ER stress inducer thapsigargin. Employing reporter gene assays of distinct CHOP promoter fragments, we could identify that, next to the conventional amino acid (AARE) and ER stress response elements (ERSE) within the CHOP promoter, activator protein-1 (AP-1) and c-Ets-1 TF binding sites are necessary for CHOP induction. Serial deletion and mutation analyses revealed that both AP-1 and c-Ets-1 motifs act in concert to induce CHOP expression. In agreement, CHOP promoter activity was greatly enhanced upon combined versus single overexpression of AP-1 and c-Ets-1. Moreover, combined overexpression of AP-1 and c-Ets-1 in MLE12 cells alone in the absence of any other ER stress inducer was sufficient to induce Chop protein expression. Further, AP-1 and c-Ets-1 were upregulated in AECII under ER stress conditions and in human IPF. Finally, Chop overexpression in vitro resulted in AECII apoptosis, lung fibroblast proliferation, and collagen-I production. We propose that CHOP activation by AP-1 and c-Ets-1 plays a key role in AECII maladaptive ER stress responses and consecutive fibrosis, offering new therapeutic prospects in IPF. Key messages Overexpression of active ER stress sensors Atf4, Atf6, and Xbp1 does not induce Chop. AP-1 and c-Ets-1 TFs are necessary for induction of the ER stress factor Chop. AP-1 and c-Ets-1 alone induce Chop expression in the absence of any ER stress inducers. AP-1 and c-Ets-1 are induced in AECII under ER stress conditions and in human IPF. Chop expression alone triggers AECII apoptosis and consecutive profibrotic responses.
      PubDate: 2019-07-01
  • Regulation of osteoblast behaviors via cross-talk between Hippo/YAP and
           MAPK signaling pathway under fluoride exposure
    • Abstract: Titanium is widely used in implant materials, while excessive fluoride may have negative effects on the osseointegration between the titanium and osteoblasts. Although the underlying mechanisms are still not clear, the mitogen-activated protein kinase (MAPK) or Yes-associated protein (YAP) signaling pathways are thought to be involved. This study evaluated the role of Hippo/YAP and MAPK signaling pathway in osteoblast behaviors under excessive fluoride exposure in vitro and in vivo. Commercially pure Ti (cp-Ti) samples were exposed to fluoride (0, 0.1, and 1.0 mM NaF) for 7 days. Cell adhesion was observed using a laser scanning confocal microscope. Cell viability and apoptosis were evaluated by CCK-8 assay and flow cytometry, respectively. The expressions of osteoblast markers and key molecules in MAPK and YAP pathway were detected by Western blot. In vivo studies were evaluated by histology methods in C57/BL6 mice model. Our results showed that 1.0 mM NaF destroyed the passivation film on cp-Ti surface, which further inhibited the osteoblast adhesion and spreading. Meanwhile, compared to other groups, 1.0 mM NaF led to a remarkable reduction in cell viability (P < 0.05), as well as increased apoptosis (P < 0.05) and downregulation of osteogenesis protein expression (P < 0.05). MAPK and YAP signaling pathways were also activated under 1.0 mM NaF exposure, and JNK seemed to regulate YAP phosphorylation in response to NaF impacts on osteoblasts. In vivo fluorosis mouse model further indicated that 100 ppm NaF group (high fluoride group) increased bone resorption and inhibited the nuclear translocation of YAP. The osteoblast behaviors were negatively altered under excessive fluoride, and MAPK/JNK axis contributed to YAP signaling activation in regulating NaF-induced osteoblast behaviors. Key messages • Excessive fluoride inhibited osteoblast behaviors and bone formation. • YAP and MAPK signaling pathways were activated in osteoblasts under fluoride exposure. • Fluoride regulated osteoblast behaviors via the cross-talk between YAP and MAPK.
      PubDate: 2019-07-01
  • Preclinical studies of a death receptor 5 fusion protein that ameliorates
           acute liver failure
    • Abstract: Acute liver failure (ALF) is a life-threatening disease with a high mortality rate. There is an urgent need to develop new drugs with high efficacy and low toxicity. In this study, we produced a pharmaceutical-grade soluble death receptor 5 (sDR5)-Fc fusion protein for treating ALF and evaluated the pharmacology, safety, pharmacokinetics, efficacy, and mechanisms of sDR5-Fc in mice, rats, and cynomolgus monkeys. sDR5-Fc bound with high affinity to both human and monkey tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) effectively blocked TRAIL-induced apoptosis in vitro and significantly ameliorated ALF induced by concanavalin A (Con A) in mice. Mechanistically, sDR5-Fc inhibited hepatocyte death and reduced inflammation in vivo. Furthermore, sDR5-Fc attenuated the production of inflammatory cytokines by splenocytes activated with Con A or an anti-CD3 antibody in vitro. Consistent with these results, splenocytes from TRAIL−/− mice produced much lower levels of inflammatory cytokines than those from TRAIL+/+ mice. In cynomolgus monkeys, sDR5-Fc was safe and well tolerated when intravenously administered as a single dose of up to 1200 mg/kg or multiple doses of 100 mg/kg. After treatment with a single dose, linear pharmacokinetics with a mean half-life of > 1.9 days were observed. After 12 weekly doses, sDR5-Fc exposure increased in an approximately dose-proportional manner, and the mean accumulation ratio ranged from 1.82- to 2.11-fold. These results support further clinical development of our sDR5-Fc protein as the first TRAIL-targeting drug for ALF treatment. Key messages sDR5-Fc binds with high affinity to TRAIL to effectively block TRAIL-induced apoptosis. sDR5-Fc ameliorates Con A-induced acute liver failure in mice by inhibiting hepatocyte death and inflammation. sDR5-Fc or TRAIL knockout attenuates the production of inflammatory cytokines by activated splenocytes in vitro. sDR5-Fc is safe and well tolerated in acute or long-term toxicity study.
      PubDate: 2019-06-22
  • Sphingosine-coating of plastic surfaces prevents ventilator-associated
    • Abstract: Ventilator-associated pneumonia (VAP) is a major cause of morbidity and mortality in critically ill patients. Here, we employed the broad antibacterial effects of sphingosine to prevent VAP by developing a novel method of coating surfaces of endotracheal tubes with sphingosine and sphingosine analogs. Sphingosine and phytosphingosine coatings of endotracheal tubes prevent adherence and mediate killing of Pseudomonas aeruginosa, Acinetobacter baumannii, and Staphylococcus aureus, even in biofilms. Most importantly, sphingosine-coating of endotracheal tubes also prevented P. aeruginosa and S. aureus pneumonia in vivo. Coating of the tubes with sphingosine was stable, without obvious side effects on tracheal epithelial cells and did not induce inflammation. In summary, we describe a novel method to coat plastic surfaces and provide evidence for the application of sphingosine and phytosphingosine as novel antimicrobial coatings to prevent bacterial adherence and induce killing of pathogens on the surface of endotracheal tubes with potential to prevent biofilm formation and VAP. Key messages Novel dip-coating method to coat plastic surfaces with lipids. Sphingosine and phytosphingosine as novel antimicrobial coatings on plastic surface. Sphingosine coatings of endotracheal tubes prevent bacterial adherence and biofilms. Sphingosine coatings of endotracheal tubes induce killing of pathogens. Sphingosine coatings of endotracheal tubes ventilator-associated pneumonia.
      PubDate: 2019-06-20
  • Correction to: Elevated expression of CST1 promotes breast cancer
           progression and predicts a poor prognosis
    • Abstract: In Figure 7f the panel for c-myc of MDA-MB-468 was erroneously duplicated. The corrected version of the figure is shown in this paper. This correction does not influence the conclusion of the study and we sincerely apologize for this oversight.
      PubDate: 2019-06-15
  • Combination of PARP inhibitor and temozolomide to suppress chordoma
    • Abstract: Chordoma, a malignant bone cancer, is highly resistant to conventional therapeutic approaches; this greatly limits radio- and chemotherapeutic options and disease management. In the present study, we investigated three patient-derived chordoma cell lines to elucidate the molecular mechanism of resistance to therapeutics. An in vitro high-throughput chemical screening assay and an in vivo xenograft model were used to identify novel chemosensitizers for chordoma. We found that patient-derived chordoma cell lines recapitulated disease phenotypes, which were highlighted by robust resistance to medical therapy manifested as lack of DNA damage accumulation. Mechanistically, the PARP DNA repair pathway was found to play a central role in this resistance. Chemical screening confirmed that PARP inhibitors could strikingly enhance temozolomide (TMZ) therapy in chordoma cells. Combining the FDA-approved PARP inhibitor, olaparib, with chemotherapeutics not only potentiated DNA damage accumulation, cell cycle arrest, and apoptosis in vitro but also suppressed chordoma xenograft expansion in vivo. We conclude that combining PARP inhibition with TMZ could be an effective therapeutic approach for the clinical management of chordoma. Key messages The PARP DNA repair pathway enhances chemoresistance in chordoma cells. Combining PARP inhibitors with genotoxic agents induces chordoma cell cytotoxicity. PARP inhibitor combining with temozolomide suppresses growth of chordoma in vivo.
      PubDate: 2019-06-14
  • Improvement of mesenchymal stromal cells and their derivatives for
           treating acute liver failure
    • Abstract: After the death of large numbers of cells in liver tissue is triggered by various hepatotoxic factors, intimidating and life-threatening acute liver failure (ALF) can develop with high mortality and expensive costs. Although liver transplantation and hepatocyte transplantation have become substitutes for improving liver regeneration, their applications are inhibited by scarce tissue and cell resources. Therefore, the transplantation of mesenchymal stromal cells (MSCs) and their derivatives including hepatocyte-like cells (HLCs), conditioned medium (CM), and exosomes (Ex) can help alleviate liver injury in ALF individuals or animal models via engraftment into liver tissue, hepatogenic differentiation, the promotion of host hepatocyte proliferation, the secretion of anti-inflammatory factors and antioxidants, and the enhancement of liver regeneration in vivo. In addition, biomaterial scaffolds protect MSCs against a harsh microenvironment in vitro and in vivo, in addition to providing physical and directional support for liver regeneration. In this review, we aimed to discuss the underlying mechanisms and therapeutic effects of MSCs and their derivatives on rescuing ALF animal models according to current studies. Further breakthroughs are required to establish safer, more stable, and more effective stem cell–based therapy in regenerative medicine for repairing liver injury, thus reducing the morbidity and mortality of ALF in the near future.
      PubDate: 2019-06-13
  • Radiation-induced glucocorticoid receptor promotes CD44+ prostate cancer
           stem cell growth through activation of SGK1-Wnt/β-catenin signaling
    • Abstract: We observed cancer stem cell (CSC) population increase in radioresistant LNCaP (LNCaPR18) and C4-2 (C4-2R26) prostate cancer (PCa) cells compared with respective parental cells. Since the CD44 level increase was most significant in radioresistant PCa cells compared with parental cells among CSC markers tested, we isolated the CD44+ population from LNCaP/LNCaPR18 and C4-2/C4-2R26 cell sets via the immunomagnetic separation method and used them as CSC sources. We detected lower AR level, but higher glucocorticoid receptor (GR) level in CD44+ CSCs than CD44- non-CSCs. Higher GR level in CD44+ CSCs than CD44- cells was also detected when cells were isolated from mouse tumor tissues of LNCaPR18 cell and C4-2R26 cell–derived human xenografts and grown in culture. We then found blocking the GR signaling by adding the anti-GR agent mifepristone into the cell culture inhibited the CD44+ CSC growth while the addition of the anti-AR agent enzalutamide enhanced the CSC growth. In xenograft mouse studies in which tumors were developed from the injection of CD44+ CSCs of LNCaPR18 or C4-2R26 cell lines, retarded tumor growth in mifepristone-injected mice was observed compared with vehicle-treated mice. We next discovered the GR regulation of Wnt/β-catenin signaling pathway. We further found that the serum/glucocorticoid regulated kinase 1 (SGK1) is the GR downstream molecule that mediates Wnt/β-catenin signaling activation. Therefore, inhibition of either SGK1 or Wnt/β-catenin signaling impaired the in vitro CD44+ CSC growth. From these results, we suggest that blocking GR signaling or its downstream SGK1-Wnt/β-catenin signaling axis may suppress the radiation-induced CSC increase in PCa. Key Messages Higher CSC population exists in radioresistant PCa cells than parental cells. Higher GR levels (and lower AR level) in CD44+ CSCs than CD44- non-CSCs. Use of anti-GR agent blocked the growth of CD44+ CSCs in in vitro/in vivo tests. GR downstream SGK1-Wnt/β-catenin signaling axis mediates the CSC increase. Targeting this signaling axis may enhance the radiotherapy efficacy in treating PCa.
      PubDate: 2019-06-11
  • Heterogeneous intracellular TRAIL-receptor distribution predicts poor
           outcome in breast cancer patients
    • Abstract: Upon ligand binding, plasma membrane–located TNF-related apoptosis-inducing ligand (TRAIL)–receptors 1 and 2 induce apoptosis as well as cancer-promoting signaling in cancer cells. TRAIL-R3 and TRAIL-R4 are believed to negatively regulate TRAIL-mediated apoptosis. Intracellular localization of TRAIL-receptors, as observed in many tumor cells, has been associated with oncogenic features, which are distinct from membrane-associated TRAIL-R signaling. Here, analyzing a panel of 354 breast cancer specimens, we found that an unfavorable outcome correlating with cancer-promoting properties of TRAIL-R1, TRAIL-R2, and TRAIL-R4 was most significantly defined by their intracellular distribution and mutual co-expression. A nuclear or cytoplasmic heterogeneous expression pattern correlated with markedly decreased overall survival and discriminated high-risk breast cancer patients from low-risk patients with a homogeneous distribution of expression, i.e., nuclear and cytoplasmic expression. The homogeneous TRAIL-R expression was associated with favorable breast cancer surrogate markers corresponding with excellent survival prognoses at 5 years after diagnosis (hazard ratio, 0.043) and over the complete course of follow-up (hazard ratio, 0.098; both p < 0.001). No associations with specific intrinsic breast cancer subtypes were found. Our data suggest that the determination of intracellular co-expression patterns of TRAIL-R1, TRAIL-R2, and TRAIL-R4 provides an innovative and robust method for risk stratification in breast cancer patients beyond conventional prognostic markers. Key messages A total of 70% of breast cancer specimens show comparably high levels of intracellular TRAIL-Rs. Nuclear or cytoplasmic TRAIL-R co-expression occurs in the majority of tumors. A total of 25% of tumors show a heterogeneous expression of cytoplasmic or nuclear TRAIL-Rs. Patients with a heterogeneous TRAIL-R expression present with poor prognoses. Additive TRAIL-R-based risk stratification comprises different breast cancer subtypes.
      PubDate: 2019-06-10
  • Tumor cells endowed with professional antigen-presenting cell functions
           prime PBLs to generate antitumor CTLs
    • Abstract: Intrinsic genetic instability of tumor cells leads to continuous production of mutated proteins referred to as tumor-specific neoantigens. Generally, they are recognized as nonself products by the host immune system. However, an effective adaptive response clearing neoantigen-expressing cells is lost in tumor diseases. Most advanced therapeutic strategies aim at inducing neoantigen-specific immune activation through personalized approaches. They include tumor cell exome sequencing, human leukocyte antigen (HLA) typing, synthesis, and injection of peptides/RNA with adjuvants. Here, we propose an innovative method to induce a CD8+ T cytotoxic lymphocyte (CTL) immune response against tumor neoantigens bypassing the steps needed in current therapeutic strategies of personalized vaccination. We assumed that tumor cells can be the most efficient and precise factory of major histocompatibility complex (MHC) class I-associated, tumor neoantigen-derived peptides. Hence, endowing tumor cells with professional antigen-presenting functions would prime CD8+ T lymphocytes towards a response against nonself tumor antigens. To explore this possibility, both adenocarcinoma and melanoma human cells were engineered to express both CD80 and CD86 costimulatory molecules. HLA-matched lymphocytes were then primed through cocultivation with the engineered tumor cells. The generation of tumor-specific CD8+ T lymphocytes was tested through the combined analysis of cell activation markers, formation of immunologic synapses, generation of tumor antigen-specific CD8+ T lymphocytes, and cytotoxic activity. Our data consistently indicate that tumor cells endowed with professional antigen-presenting functions can generate an effective tumor-specific CTL immune response. This finding may open avenues towards the development of innovative antitumor immunotherapies. Key messages We established a novel method to induce antitumor CTLs without a need to identify TAAs and/or tumor neoantigens. This strategy relies on transducing tumor cells with a retroviral vector expressing both CD80 and CD86. In this way, tumor cells prime naïve CD8+ T lymphocytes in a way that CTLs killing the same tumor cells are generated. These findings open the way towards preclinical assays in the perspective to introduce this antitumor immunotherapy strategy in clinic.
      PubDate: 2019-06-03
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