Bone Marrow Mesenchymal Stem Cells Support Acute Myeloid Leukemia Bioenergetics and Enhance Antioxidant Defense and Escape from Chemotherapy.

Like normal hematopoietic stem cells, leukemic stem cells depend on their bone marrow (BM) microenvironment for survival, but the underlying mechanisms remain largely unknown. We have studied the contribution of nestin+ BM mesenchymal stem cells (BMSCs) to MLL-AF9-driven acute myeloid leukemia (AML) development and chemoresistance in vivo. Unlike bulk stroma, nestin+ BMSC numbers are not reduced in AML, but their function changes to support AML cells, at the expense of non-mutated hematopoietic stem cells (HSCs). Nestin+ cell depletion delays leukemogenesis in primary AML mice and selectively decreases AML, but not normal, cells in chimeric mice. Nestin+ BMSCs support survival and chemotherapy relapse of AML through increased oxidative phosphorylation, tricarboxylic acid (TCA) cycle activity, and glutathione (GSH)-mediated antioxidant defense. Therefore, AML cells co-opt energy sources and antioxidant defense mechanisms from BMSCs to survive chemotherapy.D.F. was supported by Associazione Italiana Ricerca sul Cancro (AIRCFellowship 20930 for Abroad) and scholarships from Società Italiana di Ematologia (SIE) and Associazione "Amici di Beat Leukemia Dr. Alessandro Cevenini ONLUS" and AIL Bologna ODV. A.S.-A. was supported by a European Hematology Association Research Fellowship and C.L.F-C. by a fellowship from Boehringer Foundation. This work was supported by core support grants from the Wellcome Trust (203151/Z/16/Z) and the MRC to the Cambridge Stem Cell Institute, and the Instituto de Salud Carlos III (ISCIII), Ministerio de Ciencia, Innovación y Universidades (MCNU) and Pro CNIC Foundation to CNIC, which is a Severo Ochoa Center of Excellence (SEV-2015-0505). This work was supported by MCNU (Plan Nacional grant SAF-2011-30308 to S.M.-F.; Ramón y Cajal Program grants RYC-2011-09726 to A.S.-A. and RYC-2009-04703 to S.M.-F.); Marie Curie Career Integration Program grants (FP7-PEOPLE-2011-RG-294262/294096) to A.S.-A. and S.M.-F.; Spanish Ministry of Science, Innovation and Universities (BIO2015-67580-P and PGC2018- 097019-B-I00), Carlos III Institute of Health-Fondo de Investigación Sanitaria grant PRB3(IPT17/0019 - ISCIII-SGEFI / ERDF, ProteoRed), Fundació MaratóTV3 (grant 122/C/2015) and “la Caixa” Banking Foundation (project code HR17-00247) to J.V.; the Medical Research Council grant MRC_MC_UU_12022/6 to C.F; an ERC award (COMAL: 647685) and a CRUK Programme Award to B.J.H; the Swiss National Science Foundation (SNF, 31003A_173224/1 & 31003A_173224/1) and the Gertrude von Meissner Foundation (Basel, Switzerland) to J.S.; ISCIII Spanish Cell Therapy Network TerCel, ConSEPOC-Comunidad de Madrid grant (S2010/BMD-2542), National Health Service Blood and Transplant (United Kingdom), European Union’s Horizon 2020 research (ERC- 2014-CoG-648765) and a Programme Foundation Award (C61367/A26670) from Cancer Research UK to S.M.-F., who was also supported in part by an International Early Career Scientist grant of the Howard Hughes Medical Institute

Influence of clinical and neurocognitive factors in psychosocial functioning after a first episode non-affective psychosis : Differences between males and females

Deficits in psychosocial functioning are present in the early stages of psychosis. Several factors, such as premorbid adjustment, neurocognitive performance, and cognitive reserve (CR), potentially influence functionality. Sex differences are observed in individuals with psychosis in multiple domains. Nonetheless, few studies have explored the predictive factors of poor functioning according to sex in first-episode psychosis (FEP). This study aimed to explore sex differences, examine changes, and identify predictors of functioning according to sex after onset. The initial sample comprised 588 individuals. However, only adults with non-affective FEP (n = 247, 161 males and 86 females) and healthy controls (n = 224, 142 males and 82 females) were included. A comprehensive assessment including functional, neuropsychological, and clinical scales was performed at baseline and at 2-year follow-up. A linear regression model was used to determine the predictors of functioning at 2-year follow-up. FEP improved their functionality at follow-up (67.4% of both males and females). In males, longer duration of untreated psychosis (β = 0.328, p = 0.003) and worse premorbid adjustment (β = 0.256, p = 0.023) were associated with impaired functioning at 2-year follow-up, while in females processing speed (β = 0.403, p = 0.003), executive function (β = 0.299, p = 0.020) and CR (β = −0.307, p = 0.012) were significantly associated with functioning. Our data indicate that predictors of functioning at 2-year follow-up in the FEP group differ according to sex. Therefore, treatment and preventative efforts may be adjusted taking sex into account. Males may benefit from functional remediation at early stages. Conversely, in females, early interventions centered on CR enhancement and cognitive rehabilitation may be recommended

Use of Mesenchymal Stem Cells in Pre-Clinical Models of Spinal Cord Injury

Spinal Cord Injury (SCI) is a devastating disease that causes disruption of sensorimotor function below the site of injury. Current management is based on surgical decompression of the neural tissue and pharmacotherapy; however, there is no gold standard treatment readily available for patients in the clinic. This indicates that novel therapeutic strategies for the treatment are still needed in the clinical setting. There are several alternatives that are currently under investigation for the treatment of this disease, with increasing focus in regenerative medicine treatments. Mesenchymal stem cells (MSCs) are one of the most promising candidates for stem cell therapy in SCI, as they are easily obtained, have high safety profiles, and help with neural regeneration in SCI mainly via release of trophic factors, neovascularization, and immunomodulation. In this work, authors provide an insight of the available MSC for neural regeneration, their therapeutic role, and the potential MSC-based therapies for SCI

Influence of clinical and neurocognitive factors in psychosocial functioning after a first episode non-affective psychosis: Differences between males and females

Background: Deficits in psychosocial functioning are present in the early stages of psychosis. Several factors, such as premorbid adjustment, neurocognitive performance, and cognitive reserve (CR), potentially influence functionality. Sex differences are observed in individuals with psychosis in multiple domains. Nonetheless, few studies have explored the predictive factors of poor functioning according to sex in first-episode psychosis (FEP). This study aimed to explore sex differences, examine changes, and identify predictors of functioning according to sex after onset. Materials and methods: The initial sample comprised 588 individuals. However, only adults with non-affective FEP (n = 247, 161 males and 86 females) and healthy controls (n = 224, 142 males and 82 females) were included. A comprehensive assessment including functional, neuropsychological, and clinical scales was performed at baseline and at 2-year follow-up. A linear regression model was used to determine the predictors of functioning at 2-year follow-up. Results: FEP improved their functionality at follow-up (67.4% of both males and females). In males, longer duration of untreated psychosis (β = 0.328, p = 0.003) and worse premorbid adjustment (β = 0.256, p = 0.023) were associated with impaired functioning at 2-year follow-up, while in females processing speed (β = 0.403, p = 0.003), executive function (β = 0.299, p = 0.020) and CR (β = -0.307, p = 0.012) were significantly associated with functioning. Conclusion: Our data indicate that predictors of functioning at 2-year follow-up in the FEP group differ according to sex. Therefore, treatment and preventative efforts may be adjusted taking sex into account. Males may benefit from functional remediation at early stages. Conversely, in females, early interventions centered on CR enhancement and cognitive rehabilitation may be recommended

The role of cognitive reserve and clinical symptoms in the association between genetic liability for educational attainment and functioning in first-episode psychosis: a mediation analysis

Background: Polygenic risk scores for educational attainment (PRSEA), cognitive reserve (CR), and clinical symptoms are associated with psychosocial functioning in first-episode psychosis (FEP). Nevertheless, the mechanisms underlying their complex interaction is yet to be explored. This study aimed to assess the mediating role of CR and clinical symptoms, both negative (NS) and positive (PS), on the interrelationship between PRSEA and functionality, one year after a FEP.Methods: A total of 162 FEP patients underwent clinical, functional, and genetic assessments. Using genome-wide association study (GWAS) summary results, PRSEA were constructed for each individual. Two mediation models were explored. The parallel mediation model explored the relationship of PRSEA with functionality through CR and clinical symptoms, NS, and PS. The serial mediation model tested a causal chain of the three mediators: CR, NS and PS. Mediation analysis was performed using the PROCESS function V.4.1 in SPSS V.22.Results: A serial mediation model revealed a causal chain for PRSEA > CR > NS > Functionality (β=-0.35, 95%CI [-0.85, -0.04], pConclusions: Both CR and NS mediate the relationship between PRSEA and functionality at one-year follow-up, using serial mediation analysis. This may be relevant for prevention and personalized early intervention to reduce illness impact and improve functional outcomes in FEP patients.</p

Epigenetic Silencing of Peroxisome Proliferator-Activated Receptor γ Is a Biomarker for Colorectal Cancer Progression and Adverse Patients' Outcome

The relationship between peroxisome proliferator-activated receptor γ (PPARG) expression and epigenetic changes occurring in colorectal-cancer pathogenesis is largely unknown. We investigated whether PPARG is epigenetically regulated in colorectal cancer (CRC) progression. PPARG expression was assessed in CRC tissues and paired normal mucosa by western blot and immunohistochemistry and related to patients' clinicopathological parameters and survival. PPARG promoter methylation was analyzed by methylation-specific-PCR and bisulphite sequencing. PPARG expression and promoter methylation were similarly examined also in CRC derived cell lines. Chromatin immunoprecipitation in basal conditions and after epigenetic treatment was performed along with knocking-down experiments of putative regulatory factors. Gene expression was monitored by immunoblotting and functional assays of cell proliferation and invasiveness. Methylation on a specific region of the promoter is strongly correlated with PPARG lack of expression in 30% of primary CRCs and with patients' poor prognosis. Remarkably, the same methylation pattern is found in PPARG-negative CRC cell lines. Epigenetic treatment with 5′-aza-2′-deoxycytidine can revert this condition and, in combination with trichostatin A, dramatically re-activates gene transcription and receptor activity. Transcriptional silencing is due to the recruitment of MeCP2, HDAC1 and EZH2 that impart repressive chromatin signatures determining an increased cell proliferative and invasive potential, features that can experimentally be reverted. Our findings provide a novel mechanistic insight into epigenetic silencing of PPARG in CRC that may be relevant as a prognostic marker of tumor progression