Cell therapy approaches hold great potential for treating retinopathies, which are currently incurable. This study addresses the problem of inadequate migration and integration of transplanted cells ...into the host retina. To this end, we have identified the chemokines that were most upregulated during retinal degeneration and that could chemoattract mesenchymal stem cells (MSCs). The results were observed using a pharmacological model of ganglion/amacrine cell degeneration and a genetic model of retinitis pigmentosa, from both mice and human retinae. Remarkably, MSCs overexpressing Ccr5 and Cxcr6, which are receptors bound by a subset of the identified chemokines, displayed improved migration after transplantation in the degenerating retina. They also led to enhanced rescue of cell death and to preservation of electrophysiological function. Overall, we show that chemokines released from the degenerating retinae can drive migration of transplanted stem cells, and that overexpression of chemokine receptors can improve cell therapy-based regenerative approaches.
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Inadequate migration and integration of transplanted cells into the retina limit the efficacy of cell therapy approaches. Pesaresi et al. found that chemokines released from the degenerating retina can drive migration of transplanted stem cells overexpressing Ccr5 and Cxcr6 receptors, thereby resulting in rescue of retinal degeneration.
The past few years have witnessed an exponential increase of interest in the reprogramming process. This has been motivated by the enthusiasm of unravelling key aspects not only of cell identity and ...dedifferentiation, but also of the endogenous regenerative capacities of mammalian organs.
Here, we present the most recent advances in the field of reprogramming, stressing how they are re-defining the rules of cell fate and plasticity in vivo. Specifically, we focus on the emerging role of the tissue microenvironment, with particular emphasis on tissue damage, inflammation and senescence that can facilitate in vivo reprogramming and regeneration through cell-extrinsic mechanisms.
This work deals with the molecular design, synthesis and biological activity of a series of tetrahydro1,4dioxanisoquinolines and dimethoxyisoquinoline analogues. This study describes the synthesis ...strategy of these potential antitumor compounds, their multi-step synthesis and their optimization. A series of tetrahydroisoquinolines was synthesized and their cytotoxicity evaluated. Some of these tetrahydroisoquinolines showed promising KRas inhibition, antiangiogenesis activity and antiosteoporosis properties. Molecular modeling studies showed that compound 12 bind in the p1 pocket of the KRas protein making interactions with the hydrophobic residues Leu56, Tyr64, Tyr71 and Thr74 and hydrogen bonds with residues Glu37 and Asp38.
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•18 Dioxigenated tetradydroisoquinoline compounds were synthesized from the corresponding aldehyde.•Compounds 12, 13, 14, 15, 16, 18, 20 and 21 exhibited significant cytotoxic activity.•Isoquinoline 14 presents the best KRas activity profile on RKO KRasSL.•Molecular modeling studies showed that the tetrahydroisoquinoline 12 binds directly to the p1 pocket of the KRas protein.
The Italian patient association for Multiple Osteochondromas, Ollier Disease, and Maffucci Syndrome, Associazione Conto Alla Rovescia-ACAR Aps, conducted a mixed-methods study at its 2023 annual ...conference. The study included the Open Dialogue Approach and a feedback survey to identify the main priorities in the transitioning process from paediatric to adult healthcare for patients with Multiple Osteochondromas, Ollier Disease, and Maffucci Syndrome.
The common needs identified by patients, families, caregivers, and healthcare professionals were coordination and continuity of care, patient empowerment and communication, social and practical support, and transition planning and support.
This experience fostered a sense of collaboration and cooperation among stakeholders, helping to build trust and create a shared vision for improving the quality of care for these patients. Furthermore, it could be considered a starting point for other patient associations interested in using different approaches to identify the needs of their members and actively involve all stakeholders.
Müller glial cells (MGCs) represent the most plastic cell type found in the retina. Following injury, zebrafish and avian MGCs can efficiently re-enter the cell cycle, proliferate and generate new ...functional neurons. The regenerative potential of mammalian MGCs, however, is very limited. Here, we showed that N-methyl-d-aspartate (NMDA) damage stimulates murine MGCs to re-enter the cell cycle and de-differentiate back to a progenitor-like stage. These events are dependent on the recruitment of endogenous bone marrow cells (BMCs), which, in turn, is regulated by the stromal cell-derived factor 1 (SDF1)-C-X-C motif chemokine receptor type 4 (CXCR4) pathway. BMCs mobilized into the damaged retina can fuse with resident MGCs, and the resulting hybrids undergo reprogramming followed by re-differentiation into cells expressing markers of ganglion and amacrine neurons. Our findings constitute an important proof-of-principle that mammalian MGCs retain their regenerative potential, and that such potential can be activated via cell fusion with recruited BMCs. In this perspective, our study could contribute to the development of therapeutic strategies based on the enhancement of mammalian endogenous repair capabilities.
•Endogenous bone marrow cells migrate into NMDA-damaged murine retinae and fuse with retinal Müller glial cells (MGCs).•MGCs can be reprogrammed to retinal progenitors to then differentiate into ganglion and amacrine neurons.•Modulation of the SDF1/CXCR4 pathway regulates BMC migration, BMC-MGC fusion, and MGC reprogramming.
Retinal degeneration is present in a large and heterogeneous group of debilitating diseases, often not curable. Cell therapy represents an interesting approach to regenerate injured retinal tissue. However, it comes with some hurdles in terms of engraftment and differentiation of the transplanted cells. Here, we reported that murine Müller glia cells can be converted into retinal neurons after fusion with endogenous bone marrow cells. The efficiency of this mechanism can be enhanced by perturbation of the SDF1/CXCR4 signaling pathway. Our study provides an important proof-of-principle that the limited endogenous regeneration capability of mammals can be enhanced by modulation of specific signaling pathways.
The NA62 experiment at CERN, aimed to measure K + rarr pi + nunumacr branching fraction (O(10 -11 )) , relies on a gas based RICH detector for pi/mu separation and level 0 trigger. The experiment ...requirements for this detector are mainly a time resolution better than 100 ps and a muon rejection better than 5 times 10 -3 in the momentum range 15-35 GeV/c. A first prototype of such a detector has been built and tested in 2007; it is a full length (18 m) Ne filled vessel equipped with a spherical mirror and 96 PMs on its focal plane, ap17 m upstream of the mirror. This prototype has been tested at CERN SPS on a 200 GeV/c pion beam mainly as a first check of its time resolution and of the light collection technique; the time resolution has been found to be about 65 ps, and the light collection, i.e. the number of hit PMs per ring, fairly as expected.
This book features technical portrayals of today's constantly developing banking issues; including stock market contagion, the impact of internet technology (IT) and financial innovation on stock ...markets, and a perspective on the loan puzzle in emerging markets.
The detection of homologous recombination deficiency (HRD) can identify patients who are more responsive to platinum and poly ADP ribose polymerase inhibitors (PARPi). MyChoice CDx (Myriad) is the ...most used HRD test in ovarian cancer (OC). However, some limitations of commercial tests exist, because of the high rate of inconclusive results, costs, and the impossibility of evaluating functional resistance mechanisms.
Two academic genomic tests and a functional assay, the RAD51 foci, were evaluated to detect HRD. One hundred patients with high-grade OC enrolled in the MITO16A/MaNGO-OV2 trial and treated with first-line therapy with carboplatin, paclitaxel, and bevacizumab were analyzed.
The failure rate of the two genomic assays was 2%. The sensitivity in detecting HRD when compared with Myriad was 98.1% and 90.6%, respectively. The agreement rate with Myriad was 0.92 and 0.87, with a Cohen’s κ coefficient corresponding to 0.84 and 0.74, respectively. For the RAD51 foci assay, the failure rate was 30%. When the test was successful, discordant results for deficient and proficient tumors were observed, and additional HRD patients were identified compared to Myriad; sensitivity was 82.9%, agreement rate was 0.65, and Cohen’s κ coefficient was 0.18. The HRD detected by genomic assays and residual tumor at primary surgery and stage was correlated with progression-free survival at multivariate analysis.
Results suggest the feasibility of academic tests for assessing HRD status that show robust concordance with Myriad and correlation with clinical outcome. The contribution of the functional information related to the RAD51 foci test to the genomic data needs further investigation.
•Deficiency in homologous recombination repair of DNA generates genomic instability and permanent genomic changes.•HRD status is fundamental for identifying OC patients suitable for platinum and PARPi treatment.•HRD testing is considered a topic with urgent need for improvement, going beyond those available commercially.•Within this study, two academic genomic tests and a functional assay, the RAD51 foci, were evaluated to detect HRD.•Our tests compare favorably with the reference Myriad assay and correlate with the outcome of high-grade OC patients.
The phosphatase of regenerating liver (PRL) family, a unique class of oncogenic phosphatases, consists of three members: PRL-1, PRL-2, and PRL-3. Aberrant overexpression of PRL-3 has been found in ...multiple solid tumor types. Ectopic expression of PRLs in cells induces transformation, increases mobility and invasiveness, and forms experimental metastases in mice. We have now shown that small interfering RNA-mediated depletion of PRL expression in cancer cells results in the down-regulation of p130Cas phosphorylation and expression and prevents tumor cell anchorage-independent growth in soft agar. We have also identified a small molecule, 7-amino-2-phenyl-5H-thieno3,2-cpyridin-4-one (thienopyridone), which potently and selectively inhibits all three PRLs but not other phosphatases in vitro. The thienopyridone showed significant inhibition of tumor cell anchorage-independent growth in soft agar, induction of the p130Cas cleavage, and anoikis, a type of apoptosis that can be induced by anticancer agents via disruption of cell-matrix interaction. Unlike etoposide, thienopyridone-induced p130Cas cleavage and apoptosis were not associated with increased levels of p53 and phospho-p53 (Ser(15)), a hallmark of genotoxic drug-induced p53 pathway activation. This is the first report of a potent selective PRL inhibitor that suppresses tumor cell three-dimensional growth by a novel mechanism involving p130Cas cleavage. This study reveals a new insight into the role of PRL-3 in priming tumor progression and shows that PRL may represent an attractive target for therapeutic intervention in cancer.
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