Fanconi anemia (FA) is a rare genomic instability disorder characterized by progressive bone marrow failure and predisposition to cancer. FA-associated gene products are involved in the repair of DNA ...interstrand crosslinks (ICLs). Fifteen FA-associated genes have been identified, but the genetic basis in some individuals still remains unresolved. Here, we used whole-exome and Sanger sequencing on DNA of unclassified FA individuals and discovered biallelic germline mutations in ERCC4 (XPF), a structure-specific nuclease-encoding gene previously connected to xeroderma pigmentosum and segmental XFE progeroid syndrome. Genetic reversion and wild-type ERCC4 cDNA complemented the phenotype of the FA cell lines, providing genetic evidence that mutations in ERCC4 cause this FA subtype. Further biochemical and functional analysis demonstrated that the identified FA-causing ERCC4 mutations strongly disrupt the function of XPF in DNA ICL repair without severely compromising nucleotide excision repair. Our data show that depending on the type of ERCC4 mutation and the resulting balance between both DNA repair activities, individuals present with one of the three clinically distinct disorders, highlighting the multifunctional nature of the XPF endonuclease in genome stability and human disease.
In this work we assess the role played by the dynamical adaptation of the interactions network, among agents playing Coordination Games, in reaching global coordination and in the equilibrium ...selection. Specifically, we analyze a coevolution model that couples the changes in agents' actions with the network dynamics, so that while agents play the game, they are able to sever some of their current connections and connect with others. We focus on two action update rules: Replicator Dynamics (RD) and Unconditional Imitation (UI), and we define a coevolution rule in which, apart from action updates, with a certain rewiring probability p, agents unsatisfied with their current connections are able to eliminate a link and connect with a randomly chosen neighbor. We call this probability to rewire links the 'network plasticity'. We investigate a Pure Coordination Game (PCG), in which choices are equivalent, and on a General Coordination Game (GCG), for which there is a risk-dominant action and a payoff-dominant one. Changing the plasticity parameter, there is a transition from a regime in which the system fully coordinates on a single connected component to a regime in which the system fragments in two connected components, each one coordinated on a different action (either if both actions are equivalent or not). The nature of this fragmentation transition is different for different update rules. Second, we find that both for RD and UI in a GCG, there is a regime of intermediate values of plasticity, before the fragmentation transition, for which the system is able to fully coordinate on a single component network on the payoff-dominant action, i.e., coevolution enhances payoff-dominant equilibrium selection for both update rules.
Women with advanced endometrial cancer that progressed during platinum-containing therapy were randomly assigned to lenvatinib plus pembrolizumab or physician’s choice of chemotherapy (doxorubicin or ...paclitaxel). The median progression-free survival was 7.2 months with lenvatinib plus pembrolizumab and 3.8 months with chemotherapy; the median overall survival was 18.3 months and 11.4 months, respectively.
The consensus statements regarding first-line therapies in women with ovarian cancer, reached at the Fifth Ovarian Cancer Consensus Conference held in Tokyo, Japan, in November 2015 are reported. ...Three topics were reviewed and the following statements are recommended: (i) Surgery: the subgroups that should be considered in first-line ovarian cancer clinical trials should be (a) patients undergoing primary debulking surgery and (b) patients receiving neo-adjuvant chemotherapy. The amount of residual disease following surgery should further stratify patients into those with absent gross residual disease and others. (ii) Control arms for chemotherapy: for advanced stage ovarian cancer the standard is intravenous 3-weekly carboplatin and paclitaxel. Acceptable alternatives, which should be stratified variables in trials when more than one regimen is offered, include weekly paclitaxel plus 3-weekly carboplatin, the addition of bevacizumab to 3-weekly carboplatin and paclitaxel, and intraperitoneal therapy. (iii) Trial Endpoints: overall survival is the preferred primary endpoint for first-line clinical trials with or without a maintenance component. Progression-free survival (PFS) is an alternative primary endpoint, but if PFS is chosen overall survival must be measured as a secondary endpoint and PFS must be supported by additional endpoints, including predefined patient reported outcomes and time to first or second subsequent therapy. For neoadjuvant therapy, additional ‘window of opportunity’ endpoints should be included.
Bladder cancer is lethal in its advanced, muscle-invasive phase with very limited therapeutic advances
. Recent molecular characterization has defined new (epi)genetic drivers and potential targets ...for bladder cancer
. The immune checkpoint inhibitors have shown remarkable efficacy but only in a limited fraction of bladder cancer patients
. Here, we show that high G9a (EHMT2) expression is associated with poor clinical outcome in bladder cancer and that targeting G9a/DNMT methyltransferase activity with a novel inhibitor (CM-272) induces apoptosis and immunogenic cell death. Using an immunocompetent quadruple-knockout (Pten
; Trp53
; Rb1
; Rbl1
) transgenic mouse model of aggressive metastatic, muscle-invasive bladder cancer, we demonstrate that CM-272 + cisplatin treatment results in statistically significant regression of established tumors and metastases. The antitumor effect is significantly improved when CM-272 is combined with anti-programmed cell death ligand 1, even in the absence of cisplatin. These effects are associated with an endogenous antitumor immune response and immunogenic cell death with the conversion of a cold immune tumor into a hot tumor. Finally, increased G9a expression was associated with resistance to programmed cell death protein 1 inhibition in a cohort of patients with bladder cancer. In summary, these findings support new and promising opportunities for the treatment of bladder cancer using a combination of epigenetic inhibitors and immune checkpoint blockade.
Fanconi Anemia (FA) is the most prevalent inherited bone marrow failure (BMF) syndrome. Nevertheless, the pathophysiological mechanisms of BMF in FA have not been fully elucidated. Since FA cells are ...defective in DNA repair, we hypothesized that FA hematopoietic stem and progenitor cells (HSPCs) might express DNA damage-associated stress molecules such as Natural Killer group 2 member D ligands (NKG2D-Ls). These ligands could then interact with the activating NKG2D receptor expressed in cytotoxic NK or CD8+ T cells which may result in progressive HSPCs depletion. Our results indeed demonstrated upregulated levels of NKG2D-Ls in cultured FA fibroblasts and T cells, which were further exacerbated by mitomycin C or formaldehyde. Notably, a high proportion of BM CD34+ HSPCs from FA patients also expressed increased levels of NKG2D-Ls, which correlated inversely with the percentage of CD34+ cells in BM. Remarkably, the reduced clonogenic potential characteristic of FA HSPCs was improved by blocking NKG2D/NKG2D-L interactions. Moreover, the in vivo blockage of these interactions in a BMF FA mouse model ameliorated the anemia in these animals. Our study demonstrates the involvement of NKG2D/NKG2D-L interactions in FA HSPC functionality, suggesting an unexpected role of the immune system in the progressive BMF characteristic of FA.
Summary
Arachidonic fatty acid (AA) induces adipogenesis in human mesenchymal stem cells cultures, and high concentrations inhibit osteoblastogenesis; whereas eicosapentaenoic and docosahexaenoic ...fatty acids do not induce adipogenesis and do not inhibit osteoblastogenesis. In mesenchymal stem cells, omega-6 arachidonic polyunsaturated fatty acid promotes the differentiation of adipocytes and inhibits the osteoblast differentiation. While omega-3 fatty acids do not affect the adipogenic differentiation their effects on osteoblastogenesis are less relevant. An increased ratio of omega-3/omega-6 fatty acid consumption can prevent bone mass loss.
Introduction
Consumption of omega-3 may protect against osteoporosis since they may inhibit osteoclastogenesis. However, with aging, MSC in bone marrow are increasingly differentiated into adipocytes, reducing the number of osteoblasts. Products derived from omega-6 and omega-3 metabolism may affect MSC differentiation into osteoblasts and adipocytes.
Methods
Human MSC have been differentiated into osteoblasts or adipocytes in the presence of omega-6 (AA), or omega-3 (DHA and EPA), and osteoblastic and adipocytic markers have been analyzed.
Results
AA decreases the expression of osteogenic markers and the osteoprotegerin/receptor activator of nuclear factor kappa β ligand gene expression ratio (
opg/rankl
). High concentrations of AA inhibit the mineralization and cause the appearance of adipocytes in MSC differentiating into osteoblasts to a higher extent than DHA or EPA. In MSC differentiated into adipocytes, AA increases adipogenesis, while DHA and EPA do not affect it. AA caused the appearance of adipocytes in undifferentiated MSC. The lipoxygenase gene (
alox15b
) is induced by omega-3 in MSC induced to osteoblasts, and by omega-6 in MSC induced to adipocytes.
Conclusions
An increase in the intake of omega-3 respect to omega-6 may provide protection against the loss of bone mass, since omega-6 favors the osteoclastic activity by diminishing the
opg/rankl
gene expression in osteoblasts and promotes MSC differentiation into adipocytes, thus diminishing the production of osteoblasts.
The analysis of triacylglycerols by high-temperature gas chromatography, along the last 10 years has been reviewed in this paper. The interest in this topic has grown along the last years due to the ...triacylglycerols are the main components of oils and fats and they are being used for the characterization and authentication of foods products. The most commonly used procedures, including the official methodologies, applying high-temperature gas chromatographic techniques are shown. Their importance in the characterization of different kind of samples, vegetable oils, seeds, dairy products, etc., is considered. This review is not intended to be a comprehensive dissertation on the field of triacylglycerols analysis since that would require sufficient space to occupy a book in its own right. Rather, it will outline selected considerations and developments, where the technique has been applied.
Fanconi anemia (FA) is a DNA repair syndrome generated by mutations in any of the 22 FA genes discovered to date
. Mutations in FANCA account for more than 60% of FA cases worldwide
. Clinically, FA ...is associated with congenital abnormalities and cancer predisposition. However, bone marrow failure is the primary pathological feature of FA that becomes evident in 70-80% of patients with FA during the first decade of life
. In this clinical study (ClinicalTrials.gov, NCT03157804 ; European Clinical Trials Database, 2011-006100-12), we demonstrate that lentiviral-mediated hematopoietic gene therapy reproducibly confers engraftment and proliferation advantages of gene-corrected hematopoietic stem cells (HSCs) in non-conditioned patients with FA subtype A. Insertion-site analyses revealed the multipotent nature of corrected HSCs and showed that the repopulation advantage of these cells was not due to genotoxic integrations of the therapeutic provirus. Phenotypic correction of blood and bone marrow cells was shown by the acquired resistance of hematopoietic progenitors and T lymphocytes to DNA cross-linking agents. Additionally, an arrest of bone marrow failure progression was observed in patients with the highest levels of gene marking. The progressive engraftment of corrected HSCs in non-conditioned patients with FA supports that gene therapy should constitute an innovative low-toxicity therapeutic option for this life-threatening disorder.
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