Familial aggregation of MATRICS Consensus Cognitive Battery scores in a large sample of outpatients with schizophrenia and their unaffected relatives

Background The increased use of the MATRICS Consensus Cognitive Battery (MCCB) to investigate cognitive dysfunctions in schizophrenia fostered interest in its sensitivity in the context of family studies. As various measures of the same cognitive domains may have different power to distinguish between unaffected relatives of patients and controls, the relative sensitivity of MCCB tests for relative-control differences has to be established. We compared MCCB scores of 852 outpatients with schizophrenia (SCZ) with those of 342 unaffected relatives (REL) and a normative Italian sample of 774 healthy subjects (HCS). We examined familial aggregation of cognitive impairment by investigating within-family prediction of MCCB scores based on probands' scores.Methods Multivariate analysis of variance was used to analyze group differences in adjusted MCCB scores. Weighted least-squares analysis was used to investigate whether probands' MCCB scores predicted REL neurocognitive performance.Results SCZ were significantly impaired on all MCCB domains. REL had intermediate scores between SCZ and HCS, showing a similar pattern of impairment, except for social cognition. Proband's scores significantly predicted REL MCCB scores on all domains except for visual learning.Conclusions In a large sample of stable patients with schizophrenia, living in the community, and in their unaffected relatives, MCCB demonstrated sensitivity to cognitive deficits in both groups. Our findings of significant within-family prediction of MCCB scores might reflect disease-related genetic or environmental factors

New insight into the catalytic -dependent and -independent roles of METTL3 in sustaining aberrant translation in chronic myeloid leukemia

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm caused by the presence of tyrosine kinase BCR-ABL1 fusion protein, which deregulate transcription and mRNA translation. Tyrosine kinase inhibitors (TKIs) are the first-choice treatment. However, resistance to TKIs remains a challenge to cure CML patients. Here, we reveal that the m(6)A methyltransferase complex METTL3/METTL14 is upregulated in CML patients and that is required for proliferation of primary CML cells and CML cell lines sensitive and resistant to the TKI imatinib. We demonstrate that depletion of METTL3 strongly impairs global translation efficiency. In particular, our data show that METTL3 is crucial for the expression of genes involved in ribosome biogenesis and translation. Specifically, we found that METTL3 directly regulates the level of PES1 protein identified as an oncogene in several tumors. We propose a model in which nuclear METTL3/METTL14 methyltransferase complex modified nascent transcripts whose translation is enhanced by cytoplasmic localization of METTL3, independently from its catalytic activity. In conclusion, our results point to METTL3 as a novel relevant oncogene in CML and as a promising therapeutic target for TKI resistant CML

Genetic variation is associated with RTN4R expression and working memory processing in healthy humans

The Nogo receptor (NgR) is implicated in neurodevelopmental processes and it participates in inhibiting axonal growth. Consistent with its high levels of expression in the prefrontal cortex, animal studies indicate that NgR is relevant for prefrontal-related cognitive processing. Given that genetic variation may alter mechanisms of gene expression impacting molecular and systems-level phenotypes, we investigated the association of genetic variation with the expression of the NgR coding gene (RTN4R), as well as with prefrontal correlates at progressively greater biological distance from gene effects. First, we studied the association of single nucleotide polymorphisms (SNPs) with RTN4R mRNA expression in postmortem prefrontal cortex of humans without psychiatric illnesses. Then, we probed in peripheral blood mononuclear cells (PBMCs) the association that we found in prefrontal tissue. Thus, we investigated whether functional genetic variation affecting RTN4R expression is also associated with prefrontal activity during working memory. We found that rs696884 (A/G) predicted these phenotypes. Specifically, the AA genotype was associated with lower RTN4R mRNA expression levels in the prefrontal cortex and PBMCs and inefficient prefrontal activity during working memory compared to the GG genotype. These results suggest that genetic variation associated with RTN4R mRNA expression influences prefrontal physiology in healthy individuals. Furthermore, they highlight the need for further investigations of the role of NgR in the pathophysiology of brain disorders associated with prefrontal dysfunction

Combined effect of genetic variants in the GluN2B coding gene (GRIN2B) on prefrontal function during working memory performance

Background The GluN2B subunit of N-methyl-d-aspartate receptors is crucially involved in the physiology of the prefrontal cortex during working memory (WM). Consistently, genetic variants in the GluN2B coding gene (GRIN2B) have been associated with cognitive phenotypes. However, it is unclear how GRIN2B genetic variation affects gene expression and prefrontal cognitive processing. Using a composite score, we tested the combined effect of GRIN2B variants on prefrontal activity during WM performance in healthy subjects. Method We computed a composite score to combine the effects of single nucleotide polymorphisms on post-mortem prefrontal GRIN2B mRNA expression. We then computed the composite score in independent samples of healthy participants in a peripheral blood expression study (n = 46), in a WM behavioural study (n = 116) and in a WM functional magnetic resonance imaging study (n = 122). Results Five polymorphisms were associated with GRIN2B expression: rs2160517, rs219931, rs11055792, rs17833967 and rs12814951 (all corrected p < 0.05). The score computed to account for their combined effect reliably indexed gene expression. GRIN2B composite score correlated negatively with intelligence quotient, WM behavioural efficiency and dorsolateral prefrontal cortex activity. Moreover, there was a non-linear association between GRIN2B genetic score and prefrontal activity, i.e. both high and low putative genetic score levels were associated with high blood oxygen level-dependent signals in the prefrontal cortex. Conclusions Multiple genetic variants in GRIN2B are jointly associated with gene expression, prefrontal function and behaviour during WM. These results support the role of GRIN2B genetic variants in WM prefrontal activity in human adults

Central Nervous System Involvement in Adult Acute Lymphoblastic Leukemia: Diagnostic Tools, Prophylaxis, and Therapy.

Abstract In adult patients with acute lymphoblastic leukemia (ALL), Central Nervous System (CNS) involvement is associated with a very poor prognosis. The diagnostic assessment of this condition relies on the use of neuroradiology, conventional cytology (CC) and flow cytometry (FCM). Among these approaches, which is the gold standard it is still a matter of debate. Neuroradiology and CC have a limited sensitivity with a higher rate of false negative results. FCM demonstrated a superior sensitivity over CC, particularly when low levels of CNS infiltrating cells are present. Although prospective studies of a large series of patients are still awaited, a positive finding by FCM appears to anticipate an adverse outcome even if CC shows no infiltration. Current strategies for adult ALL CNS-directed prophylaxis or therapy involve systemic and intrathecal chemotherapy and radiation therapy. An early and frequent intrathecal injection of cytostatic combined with systemic chemotherapy is the most effective strategy to reduce the frequency of CNS involvement. In patients with CNS overt ALL, at diagnosis or upon relapse, allogeneic hematopoietic stem cell transplantation might be considered. This review discusses risk factors, diagnostic techniques for identification of CNS infiltration and modalities of prophylaxis and therapy to manage it

Central Nervous System Involvement in Adult Acute Lymphoblastic Leukemia: Diagnostic Tools, Prophylaxis, and Therapy.

Abstract In adult patients with acute lymphoblastic leukemia (ALL), Central Nervous System (CNS) involvement is associated with a very poor prognosis. The diagnostic assessment of this condition relies on the use of neuroradiology, conventional cytology (CC) and flow cytometry (FCM). Among these approaches, which is the gold standard it is still a matter of debate. Neuroradiology and CC have a limited sensitivity with a higher rate of false negative results. FCM demonstrated a superior sensitivity over CC, particularly when low levels of CNS infiltrating cells are present. Although prospective studies of a large series of patients are still awaited, a positive finding by FCM appears to anticipate an adverse outcome even if CC shows no infiltration. Current strategies for adult ALL CNS-directed prophylaxis or therapy involve systemic and intrathecal chemotherapy and radiation therapy. An early and frequent intrathecal injection of cytostatic combined with systemic chemotherapy is the most effective strategy to reduce the frequency of CNS involvement. In patients with CNS overt ALL, at diagnosis or upon relapse, allogeneic hematopoietic stem cell transplantation might be considered. This review discusses risk factors, diagnostic techniques for identification of CNS infiltration and modalities of prophylaxis and therapy to manage it

Minimal residual disease negativity in elderly patients with acute myeloid leukemia may indicate different postremission strategies than in younger patients.

In the present analysis, we evaluated whether in elderly acute myeloid leukemia (AML) patients (>60 years), minimal residual disease (MRD) assessed by flow cytometry may have a role in guiding choice of postremission strategies. We analyzed 149 young and 61 elderly adults who achieved morphological CR after induction course of EORTC/GIMEMA protocols. Elderly patients reached a postconsolidation MRD negative status less frequently than younger ones (11 vs 28 %, p = 0.009). MRD negativity resulted in a longer 5-year disease-free survival (DFS) both in elderly (57 vs 13 %, p = 0.0197) and in younger patients (56 vs 31 %, p = 0.0017). Accordingly, 5-year cumulative incidence of relapse (CIR) of both elderly (83 vs 42 %, p = 0.045) and younger patients (59 vs 24 % p = NS) who were MRD positive doubled that of MRD negative ones. Nevertheless, CIR of MRD negative elderly patients was twofold higher than that of younger MRD negative ones (42 vs 24 %, p = NS). In conclusion, elderly patients in whom chemotherapy yields a MRD negative CR have duration of DFS and rate of CIR significantly better than those who remain MRD positive. Nonetheless, the high CIR rate observed in the elderly suggests that MRD negativity might have different therapeutic implications in this population than in the younger counterpart

DRD2 Co-expression Network and a related Polygenic Index predict Imaging, Behavioral, and Clinical Phenotypes linked to Schizophrenia

Genetic risk for schizophrenia (SCZ) is determined by many genetic loci whose compound biological effects are difficult to determine. We hypothesized that co-expression pathways of SCZ risk genes are associated with system-level brain function and clinical phenotypes of SCZ. We examined genetic variants related to the dopamine D2 receptor gene DRD2 co-expression pathway and associated them with working memory (WM) behavior, the related brain activity and treatment response. Using two independent post-mortem prefrontal messenger RNA (mRNA) data sets (total N = 249), we identified a DRD2 co-expression pathway enriched for SCZ risk genes. Next, we identified non-coding single-nucleotide polymorphisms (SNPs) associated with co-expression of this pathway. These SNPs were associated with regulatory genetic loci in the dorsolateral prefrontal cortex (Po0.05). We summarized their compound effect on co-expression into a Polygenic Co-expression Index (PCI), which predicted DRD2 pathway co-expression in both mRNA data sets (all Po0.05). We associated the PCI with brain activity during WM performance in two independent samples of healthy individuals (total N = 368) and 29 patients with SCZ who performed the n-back task. Greater predicted DRD2 pathway prefrontal co-expression was associated with greater prefrontal activity and longer WM reaction times (all corrected Po0.05), thus indicating inefficient WM processing. Blind prediction of treatment response to antipsychotics in two independent samples of patients with SCZ suggested better clinical course of patientswith greater PCI (total N = 87; Po0.05). The findings on this DRD2 co-expression pathway are a proof of concept that gene co-expression can parse SCZ risk genes into biological pathways associated with intermediate phenotypes as well as with clinically meaningful information