Enhancing allocentric spatial recall in pre-schoolers through navigational training programme

Unlike for other abilities, children do not receive systematic spatial orientation training at school, even though navigational training during adulthood improves spatial skills. We investigated whether navigational training programme (NTP) improved spatial orientation skills in pre-schoolers. We administered 12-week NTP to seventeen 4- to 5-year-old children (training group, TG). The TG children and 17 age-matched children (control group, CG) who underwent standard didactics were tested twice before (T0) and after (T1) the NTP using tasks that tap into landmark, route and survey representations. We determined that the TG participants significantly improved their performances in the most demanding navigational task, which is the task that taps into survey representation. This improvement was significantly higher than that observed in the CG, suggesting that NTP fostered the acquisition of survey representation. Such representation is typically achieved by age seven. This finding suggests that NTP improves performance on higher-level navigational tasks in pre-schooler

Genome-Wide Multiple Sclerosis Association Data and Coagulation

The emerging concept of a crosstalk between hemostasis, inflammation, and immune system prompt recent works on coagulation cascade in multiple sclerosis (MS). Studies on MS pathology identified several coagulation factors since the beginning of the disease pathophysiology: fibrin deposition with breakdown of blood brain barrier, and coagulation factors within active plaques may exert pathogenic role, especially through the innate immune system. Studies on circulating coagulation factors showed complex imbalance involving several components of hemostasis cascade (thrombin, factor X, factor XII). To analyze the role of the coagulation process in connection with other pathogenic pathways, we implemented a systematic matching of genome-wide association studies (GWAS) data with an informative and unbiased network of coagulation pathways. Using MetaCore (version 6.35 build 69300, 2018) we analyzed the connectivity (i.e., direct and indirect interactions among two networks) between the network of the coagulation process and the network resulting from feeding into MetaCore the MS GWAS data. The two networks presented a remarkable over-connectivity: 958 connections vs. 561 expected by chance; z-score = 17.39; p-value < 0.00001. Moreover, genes coding for cluster of differentiation 40 (CD40) and plasminogen activator, urokinase (PLAU) shared both networks, pointed to an integral interplay between coagulation cascade and main pathogenic immune effectors. In fact, CD40 pathways is especially operative in B cells, that are currently a major therapeutic target in MS field. The potential interaction of PLAU with a signal of paramount importance for B cell pathogenicity, such as CD40, suggest new lines of research and pave the way to implement new therapeutic targets

Correlation between NK function and response to trastuzumab in metastatic breast cancer patients

<p>Abstract</p> <p>Background</p> <p>Trastuzumab is a monoclonal antibody selectively directed against Her2 and approved for the treatment of Her2 overexpressing breast cancer patients. Its proposed mechanisms of action include mediation of antibody-dependent cellular cytotoxicity (ADCC) by triggering FcγRIII on natural killer (NK) cells. This study addresses the correlation between overall NK function and trastuzumab's clinical activity.</p> <p>Subjects and methods</p> <p>Clinical and immunological responses were assessed in 26 patients receiving trastuzumab monotherapy as maintenance management after chemotherapy (8 mg/kg load and then standard doses of 6 mg/kg every 3 weeks). Cytotoxic activity against the MHC class I-negative standard NK target K562 cell line and HER2-specific ADCC against a trastuzumab-coated Her2-positive SKBR3 cell line were assessed in peripheral blood mononuclear cells (PBMC) harvested after the first standard dose. After six months, seventeen patients were scored as responders and nine as non-responders according to the RECIST criteria, while Progression-Free Survival (PFS) was calculated during a 12 months follow-up.</p> <p>Results</p> <p>The responders had significantly higher levels of both NK and ADCC activities (p < 0.05) that were not different from those of eleven normal controls. The NK activity of the non-responders was significantly (p < 0.05) lower than that of the normal controls. At twelve months, there was a marked correlation between PFS and NK activity only. PFS was significantly longer in patients with high levels of NK activity, whereas its pattern was unrelated to high or low ADCC activity.</p> <p>Conclusion</p> <p>One of the mechanisms of action of trastuzumab is NK cell-mediated ADCC lysis of the Her2-positve target cell. We show here that its potency is correlated with the short-term response to treatment, whereas longer protection against tumor expansion seems to be mediated by pure NK activity.</p

Immune-Complexome Analysis Identifies Immunoglobulin-Bound Biomarkers That Predict the Response to Chemotherapy of Pancreatic Cancer Patients

Pancreatic Ductal Adenocarcinoma (PDA) is an aggressive malignancy with a very poor outcome. Although chemotherapy (CT) treatment has poor efficacy, it can enhance tumor immunogenicity. Tumor-Associated Antigens (TAA) are self-proteins that are overexpressed in tumors that may induce antibody production and can be PDA theranostic targets. However, the prognostic value of TAA-antibody association as Circulating Immune Complexes (CIC) has not yet been elucidated, mainly due to the lack of techniques that lead to their identification. In this study, we show a novel method to separate IgG, IgM, and IgA CIC from sera to use them as prognostic biomarkers of CT response. The PDA Immune-Complexome (IC) was identified using a LTQ-Orbitrap mass spectrometer followed by computational analysis. The analysis of the IC of 37 PDA patients before and after CT revealed differential associated antigens (DAA) for each immunoglobulin class. Our method identified different PDA-specific CIC in patients that were associated with poor prognosis patients. Finally, CIC levels were significantly modified by CT suggesting that they can be used as effective prognostic biomarkers to follow CT response in PDA patients

Integrative Analysis of Novel Metabolic Subtypes in Pancreatic Cancer Fosters New Prognostic Biomarkers

Background: Most of the patients with Pancreatic Ductal Adenocarcinoma (PDA) are not eligible for a curative surgical resection. For this reason there is an urgent need for personalized therapies. PDA is the result of complex interactions between tumor molecular profile and metabolites produced by its microenvironment. Despite recent studies identified PDA molecular subtypes, its metabolic classification is still lacking.Methods: We applied an integrative analysis on transcriptomic and genomic data of glycolytic genes in PDA. Data were collected from public datasets and molecular glycolytic subtypes were defined using hierarchical clustering. The grade of purity of the cancer samples was assessed estimating the different amount of stromal and immunological infiltrate among the identified PDA subtypes. Analyses of metabolomic data from a subset of PDA cell lines allowed us to identify the different metabolites produced by the metabolic subtypes. Sera of a cohort of 31 PDA patients were analyzed using Q-TOF mass spectrometer to measure the amount of metabolic circulating proteins present before and after chemotherapy.Results: Our integrative analysis of glycolytic genes identified two glycolytic and two non-glycolytic metabolic PDA subtypes. Glycolytic patients develop disease earlier, have poor prognosis, low immune-infiltrated tumors, and are characterized by a gain in chr12p13 genomic region. This gain results in the over-expression of GAPDH, TPI1, and FOXM1. PDA cell lines with the gain of chr12p13 are characterized by an higher lipid uptake and sensitivity to drug targeting the fatty acid metabolism. Our sera proteomic analysis confirms that TPI1 serum levels increase in poor prognosis gemcitabine-treated patients.Conclusions: We identify four metabolic PDA subtypes with different prognosis outcomes which may have pivotal role in setting personalized treatments. Moreover, our data suggest TPI1 as putative prognostic PDA biomarker

Topographical working memory: differences in pointing versus performing a pathway in 4-5 year old children

Recently, several studies have highlighted the importance of topographical working memory in navigation. This was also supported by clinical evidence showing the presence of specific topographical working memory deficits in different types of pathologies that disrupt navigational skills (i.e., individuals affected by developmental topographical disorientation; patients treated surgically for a drug-resistant temporal lobe epilepsy; stroke patients; patients affected by Alzheimer Dementia). In the present study, we take into account the contribution of motor action to spatial representation during navigation by comparing two tasks (WalCT: Piccardi et al., 2008; 2014 and Laser-WalCT: De Nigris et al., 2013) of topographical working memory, one in which the child has to perform by walking the path previously demonstrated by the examiner and another one, in which the child has to manually point the path previously observed. A total of 51 (19 females) typically developing children aged 4–5 years performed WalCT, Laser-WalCT and Corsi Block-Tapping Test (CBT; Corsi, 1972), the latter a well-known visuo-spatial memory test. Cognitive non-verbal test (Raven’s Coloured Progressive Matrices, CPM; Raven, 1986) was performed to assess cognitive development. WalCT, Laser-WalCT and CBT were performed in randomized order and analyzed according to the longest list of items that the children were be able to repeat. Our results showed no gender differences supporting previous findings, suggesting that sex differences on spatial tasks emerge in adolescence. We also found that a greater effort was needed to reproduce a sequence of steps in a large-scale context than to reproduce a sequence of reaching movements in a small-scale context. In general, working memory measured on large-scale context, with or without motor activity, develops later than working memory measured on small-scale context. Specifically, 4 years old children demonstrated more difficulty in performing Laser-WalCT than WalCT with respect to 5 years children. The difference between WalCT and Laser-WalCT in 4 years old children is an interesting finding, since older children as well as young adults and adults did not differ in their performance when they had to act on a pathway or to point it. This data suggests the presence of a specific time period in which motor action has to be integrated with navigational information