Neural stem cell transplantation in patients with progressive multiple sclerosis: an open-label, phase 1 study

Innovative pro-regenerative treatment strategies for progressive multiple sclerosis (PMS), combining neuroprotection and immunomodulation, represent an unmet need. Neural precursor cells (NPCs) transplanted in animal models of multiple sclerosis have shown preclinical efficacy by promoting neuroprotection and remyelination by releasing molecules sustaining trophic support and neural plasticity. Here we present the results of STEMS, a prospective, therapeutic exploratory, non-randomized, open-label, single-dose-finding phase 1 clinical trial (NCT03269071, EudraCT 2016-002020-86), performed at San Raffaele Hospital in Milan, Italy, evaluating the feasibility, safety and tolerability of intrathecally transplanted human fetal NPCs (hfNPCs) in 12 patients with PMS (with evidence of disease progression, Expanded Disability Status Scale >= 6.5, age 18-55 years, disease duration 2-20 years, without any alternative approved therapy). The safety primary outcome was reached, with no severe adverse reactions related to hfNPCs at 2-year follow-up, clearly demonstrating that hfNPC therapy in PMS is feasible, safe and tolerable. Exploratory secondary analyses showed a lower rate of brain atrophy in patients receiving the highest dosage of hfNPCs and increased cerebrospinal fluid levels of anti-inflammatory and neuroprotective molecules. Although preliminary, these results support the rationale and value of future clinical studies with the highest dose of hfNPCs in a larger cohort of patients

Differentiated neuroprogenitor cells incubated with human or canine adenovirus, or lentiviral vectors have distinct transcriptome profiles

Several studies have demonstrated the potential for vector-mediated gene transfer to the brain. Helper-dependent (HD) human (HAd) and canine (CAV-2) adenovirus, and VSV-G-pseudotyped self-inactivating HIV-1 vectors (LV) effectively transduce human brain cells and their toxicity has been partly analysed. However, their effect on the brain homeostasis is far from fully defined, especially because of the complexity of the central nervous system (CNS). With the goal of dissecting the toxicogenomic signatures of the three vectors for human neurons, we transduced a bona fide human neuronal system with HD-HAd, HD-CAV-2 and LV. We analysed the transcriptional response of more than 47,000 transcripts using gene chips. Chip data showed that HD-CAV-2 and LV vectors activated the innate arm of the immune response, including Toll-like receptors and hyaluronan circuits. LV vector also induced an IFN response. Moreover, HD-CAV-2 and LV vectors affected DNA damage pathways - but in opposite directions - suggesting a differential response of the p53 and ATM pathways to the vector genomes. As a general response to the vectors, human neurons activated pro-survival genes and neuron morphogenesis, presumably with the goal of re-establishing homeostasis. These data are complementary to in vivo studies on brain vector toxicity and allow a better understanding of the impact of viral vectors on human neurons, and mechanistic approaches to improve the therapeutic impact of brain-directed gene transfer

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Expressive Suppression Within Task-Oriented Dyads: The Moderating Role of Power

Although research has so far consistently revealed that using suppression to regulate emotions has adverse personal and social effects, it has been argued that suppression may be less detrimental within non-close relationships. In the present work, we examined the effects of experimentally induced suppression on expressive behavior, emotional experience, and social outcomes within task-oriented interactions between individuals randomly assigned to high/low vs. equal power positions. Eighty-eight participants were randomly paired with a partner of the same gender (forty-four dyads). After being randomly assigned to one of four experimental conditions created to manipulate suppression use and power, each dyad was asked to complete two problem-solving tasks. The results showed that the participants who were assigned to the subordinate (low-power) role and who used suppression to regulate their emotions reported more negative emotional experience than did individuals assigned to equal-power roles, as well as more inauthenticity and diminished feelings of rapport compared to subordinates who freely expressed their feelings. Moreover, we found that the use of suppression also influenced participants assigned to the manager (high-power) role, as they exhibited less positive behavior, reported less positive experience and lower feelings of rapport when interacting with a partner asked to suppress. When individuals were assigned to equal power roles, the participants instructed to use suppression reported lower levels of positive emotions than did their partners as well as higher feelings of inauthenticity compared to uninstructed participants. Overall, these findings seem to suggest that suppression may impair task-oriented interactions between high/low power individuals more than interactions between individuals sharing equal power

Whole transcriptome characterization of aberrant splicing events induced by lentiviral vector integrations

Gamma-retroviral/lentiviral vectors (γRV/LV) with self-inactivating (SIN) long terminal repeats (LTRs) and internal moderate cellular promoters pose a reduced risk of insertional mutagenesis when compared with vectors with active LTRs. Yet, in a recent LV-based clinical trial for β-thalassemia, vector integration within the HMGA2 gene induced the formation of an aberrantly spliced mRNA form that appeared to cause clonal dominance. Using a method that we developed, cDNA linear amplification-mediated PCR, in combination with high-throughput sequencing, we conducted a whole transcriptome analysis of chimeric LV-cellular fusion transcripts in transduced human lymphoblastoid cells and primary hematopoietic stem/progenitor cells. We observed a surprising abundance of read-through transcription originating outside and inside the provirus and identified the vector sequences contributing to the aberrant splicing process. We found that SIN LV has a sharply reduced propensity to engage in aberrant splicing compared with that of vectors carrying active LTRs. Moreover, by recoding the identified vector splice sites, we reduced residual read-through transcription and demonstrated an effective strategy for improving vectors. Characterization of the mechanisms and genetic features underlying vector-induced aberrant splicing will enable the generation of safer vectors, with low impact on the cellular transcriptome

Over-Under Triage nell’attivazione del Trauma Team: un’analisi retrospettiva nella ASST Monza

Introduction: Meeting the literature standards during the triage process of trauma victims, allows to make optimal use of the resources available in Trauma Centers and defines their level of quality and efficiency. Otherwise, it may occur over or under-triage. Up to now, in the reality under study and in the national literature, there wasn’t any available data about efficiency and effectiveness in the triage of traumatic patients, therefore the primary objective of this study is to evaluate the over and under-triage rate in activating Trauma Team (TT) in the ASST of Monza-San Gerardo Hospital. Method: The study design is retrospective monocentric observational. Results: During the analysis, the TT-activation in ASST of Monza-San Gerardo Hospital produced an over-triage of 62,9% and an under-triage of 1,7% for the same year. Discussion: The use of TT-activation algorithm is the first step of the entire care process of the trauma victim. This tool should guarantee the right balance between high sensitivity (under-triage → 0, accepting the risk of high over-triage rate) and high specificity (minimum over-triage rate with the possibility of higher under-triage). However, there is no sharing of these algorithms as they are inhomogeneous in the different realities; for example, the definition of major trauma, of TT and of its composition is still uneven. Conclusion: This study measured the over and under-triage rate related to the TT activation in the ASST of Monza. It is therefore advisable to monitor those rates periodically, as possible indicators of quality of assistance and to pursue the mission of increasing efficiency as well as effectiveness.Introduzione: Il rispetto degli standard presenti in letteratura durante il triage di persone vittima di trauma, permette di sfruttare in modo ottimale le risorse di cui dispongono i Trauma Center e ne definisce il livello di qualità ed efficienza. In caso contrario si può assistere ad over o under-triage. Fino a questo momento, nella realtà oggetto di studio e nella letteratura nazionale, non era disponibile alcuna misurazione di efficienza ed efficacia circa il relativo triage del paziente traumatico; pertanto l’obiettivo primario è ottenere dati relativi alle percentuali di over-triage e under-triage circa l’attivazione del Trauma Team (TT) nell’ASST di Monza-Ospedale San Gerardo. Metodo: Il disegno di studio è osservazionale retrospettivo monocentrico. Risultati: Nell’Ospedale San Gerardo, nel periodo esaminato, si è prodotto un over-triage del 62,9% ed un under-triage, relativo al medesimo anno, dell’1,7%. Discussione: Utilizzare un algoritmo decisionale di attivazione del TT è alla base dell’intero processo assistenziale della persona vittima di trauma. Questo strumento dovrebbe riportare il giusto compromesso tra sensibilità elevata (under-triage → 0, accettando il rischio di avere un over-triage elevato) e specificità elevata (over-triage minimo ma con possibilità di creare un più elevato under-triage). Non vi è tuttavia condivisione di tali algoritmi che risultano disomogenei nelle diverse realtà come è ancora disomogenea la definizione di trauma maggiore, del TT e della sua composizione. Conclusioni: Abbiamo misurato le percentuali di over e under triage relative all’attivazione del TT dell’ASST di Monza. Ci si aspetta di poterle monitorarle periodicamente, quali possibili indicatori di qualità d’assistenza al cittadino, ponendosi come mission, al pari dell’efficacia, di incrementare l’efficienza.&nbsp