Targeting the phosphatidylinositol 3-kinase/Akt/mechanistic target of rapamycin signaling pathway in B-lineage acute lymphoblastic leukemia: An update

Despite considerable progress in treatment protocols, B-lineage acute lymphoblastic leukemia (B-ALL) displays a poor prognosis in about 15–20% of pediatric cases and about 60% of adult patients. In addition, life-long irreversible late effects from chemo- and radiation therapy, including secondary malignancies, are a growing problem for leukemia survivors. Targeted therapy holds promising perspectives for cancer treatment as it may be more effective and have fewer side effects than conventional therapies. The phosphatidylinositol 3-phosphate kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) signaling pathway is a key regulatory cascade which controls proliferation, survival and drug-resistance of cancer cells, and it is frequently upregulated in the different subtypes of B-ALL, where it plays important roles in the pathophysiology, maintenance and progression of the disease. Moreover, activation of this signaling cascade portends a poorer prognosis in both pediatric and adult B-ALL patients. Promising preclinical data on PI3K/Akt/mTOR inhibitors have documented their anticancer activity in B-ALL and some of these novel drugs have entered clinical trials as they could lead to a longer event-free survival and reduce therapy-associated toxicity for patients with B-ALL. This review highlights the current status of PI3K/Akt/mTOR inhibitors in B-ALL, with an emphasis on emerging evidence of the superior efficacy of synergistic combinations involving the use of traditional chemotherapeutics or other novel, targeted agents

miRNAs as Influencers of Cell-Cell Communication in Tumor Microenvironment

microRNAs (miRNAs) are small noncoding RNAs that regulate gene expression at the posttranscriptional level, inducing the degradation of the target mRNA or translational repression. MiRNAs are involved in the control of a multiplicity of biological processes, and their absence or altered expression has been associated with a variety of human diseases, including cancer. Recently, extracellular miRNAs (ECmiRNAs) have been described as mediators of intercellular communication in multiple contexts, including tumor microenvironment. Cancer cells cooperate with stromal cells and elements of the extracellular matrix (ECM) to establish a comfortable niche to grow, to evade the immune system, and to expand. Within the tumor microenvironment, cells release ECmiRNAs and other factors in order to influence and hijack the physiological processes of surrounding cells, fostering tumor progression. Here, we discuss the role of miRNAs in the pathogenesis of multicomplex diseases, such as Alzheimer's disease, obesity, and cancer, focusing on the contribution of both intracellular miRNAs, and of released ECmiRNAs in the establishment and development of cancer niche. We also review growing evidence suggesting the use of miRNAs as novel targets or potential tools for therapeutic applications

Propositions for public policies and dissemination of organic farming based upon spatial analyses / Réflexion à partir d’une analyse spatialesur les politiques de soutien et la diffusion de l’agriculture biologique

Building on three studies conducted on the spatial diffusion of organic farming (OF) in France, the objective of this article is to provide analysis on incentives and obstacles for the development of OF. What restrains the OF adoption is represented by three types of risks (agronomic, economic and moral) which reduce the propensity to convert to organic farming. Our work is based on national data bases on certified farms in 2010 and beneficiaries of aid for conversion to organic farming between 1993 and 2010. If these data do not make it possible to analyse the motivations at the individual level, they provide original findings by their completeness and the mobilization of different spatial and temporal scales, and a set of tools for exploratory and econometric spatial analysis. The main results are commented: characterization of the spatial heterogeneity of OF, relationship between OF and markets access, territories characteristics (agronomic, socioeconomic, institutional) that increase or decrease their propensity to host organic farms. They provide a basis to discuss the implications of public policies aiming to remove the bottlenecks and stimulate the development of OF in all territories, according to the national objectives

Preserved decision making ability in early multiple sclerosis

Background : The purpose of this study was to assess decision making in patients with multiple sclerosis (MS) at the earliest clinically detectable time point of the disease. Methods : Patients with definite MS (n = 109) or with clinically isolated syndrome (CIS, n = 56), a disease duration of 3 months to 5 years, and no or only minor neurological impairment (Expanded Disability Status Scale [EDSS] score 0-2.5) were compared to 50 healthy controls using the Iowa Gambling Task (IGT). Results : The performance of definite MS, CIS patients, and controls was comparable for the two main outcomes of the IGT (learning index: p = 0.7; total score: p = 0.6). The IGT learning index was influenced by the educational level and the co-occurrence of minor depression. CIS and MS patients developing a relapse during an observation period of 15 months dated from IGT testing demonstrated a lower learning index in the IGT than patients who had no exacerbation (p = 0.02). When controlling for age, gender and education, the difference between relapsing and non-relapsing patients was at the limit of significance (p = 0.06). Conclusion : Decision making in a task mimicking real life decisions is generally preserved in early MS patients as compared to controls. A possible consequence of MS relapsing activity in the impairment of decision making ability is also suspected in the early phase of M

Aging Reduces The Primary Humoral Response And The In Vitro Cytokine Production In Mice.

Aging is accompanied by a decrease in several physiological functions that make older individuals less responsive to environmental challenges. In the present study, we analyzed the immune response of female BALB/c mice (N = 6) of different ages (from 2 to 96 weeks) and identified significant age-related alterations. Immunization with hapten-protein (trinitrophenyl-bovine serum albumin) conjugates resulted in lower antibody levels in the primary and secondary responses of old mice (72 weeks old). Moreover, young mice (2, 16, and 32 weeks old) maintained specific antibodies in their sera for longer periods after primary immunization than did old mice. However, a secondary challenge efficiently induced memory in old mice, as shown by the increased antibody levels in their sera. The number of CD4+ and CD8+ T cells in the spleen increased until 8 weeks of age but there was no change in the CD4+/CD8+ ratio with aging. Splenic T cells from old mice that had or had not been immunized were less responsive to concanavalin-A and showed reduced cytokine production compared to young mice (IL-2: 57-127 vs 367-1104 pg/mL, IFN-gamma: 2344-12,836 vs 752-23,106 pg/mL and IL-10: 393-2172 vs 105-2869 pg/mL in old and young mice, respectively). These data suggest that there are significant changes in the organization of the immune system throughout life. However, the relevance of these alterations for the functioning of the immune system is unknown.401111-2

Functioning and disability in multiple sclerosis from the patient perspective

Multiple sclerosis (MS) has a great impact on functioning and disability. The perspective of those who experience the health problem has to be taken into account to obtain an in-depth understanding of functioning and disability. The objective was to describe the areas of functioning and disability and relevant contextual factors in MS from the patient perspective. A qualitative study using focus group methodology was performed. The sample size was determined by saturation. The focus groups were digitally recorded and transcribed verbatim. The meaning condensation procedure was used for data analysis. Identified concepts were linked to International Classification of Functioning, Disability and Health (ICF) categories according to established linking rules. Six focus groups with a total of 27 participants were performed. In total, 1327 concepts were identified and linked to 106 ICF categories of the ICF components Body Functions, Activities and Participation and Environmental Factors. This qualitative study reports on the impact of MS on functioning and disability from the patient perspective. The participants in this study provided information about all physical aspects and areas of daily life affected by the disease, as well as the environmental factors influencing their lives

The Hubble Space Telescope UV Legacy Survey of Galactic Globular Clusters. XIII. ACS/WFC Parallel-Field Catalogues

As part of the Hubble Space Telescope UV Legacy Survey of Galactic Globular Clusters, 110 parallel fields were observed with the Wide Field Channel of the Advanced Camera for Surveys, in the outskirts of 48 globular clusters, plus the open cluster NGC 6791. Totalling about $0.3$ square degrees of observed sky, this is the largest homogeneous Hubble Space Telescope photometric survey of Galalctic globular clusters outskirts to date. In particular, two distinct pointings have been obtained for each target on average, all centred at about $6.5$ arcmin from the cluster centre, thus covering a mean area of about $23\,{\rm arcmin^{2}}$ for each globular cluster. For each field, at least one exposure in both F475W and F814W filters was collected. In this work, we publicly release the astrometric and photometric catalogues and the astrometrised atlases for each of these fields.Comment: 30 pages, 23 figures. Accepted by MNRA

Association between non-O blood group and spontaneous abortion in women with inherited thrombophilia

Abstract Background Spontaneous abortion is reported to be one of the most frequent pregnancy complications reaching a prevalence up to 15%. The association between congenital thrombophilia and pregnancy loss has been debated in several studies with conflicting results. We aimed to retrospectively evaluate the prevalence of inherited thrombophilia (i.e antithrombin, protein S and C deficiencies, factor V Leiden and prothrombin variant) in a group of women with a personal history of miscarriage. The prevalence non-O blood group, considered the most common thrombophilic condition, was concomitantly considered. Materials and methods A group of n. 566 women with a personal history of spontaneous abortion recruited among caregivers of patients admitted to the Medical Department of our University Hospital between December 2011 and December 2019 were enrolled. Women under 18 yrs, those with a personal history of venous and/or arterial thrombosis and with an acquired thrombophilic condition were excluded. An equally number of healthy women without a personal history of pregnancy loss acted as controls. The Odds Ratios (ORs) and 95% confidence intervals (CIs) were calculated as an estimate of pregnancy loss developing. Results Out of n. 566 enrolled women, n. 127 (22.4%) had an inherited thrombophilic condition. The prevalence of congenital thrombophilia was significantly higher in women with miscarriage than controls (OR 2.12; CI 95% 1.51–2.92). Non-O blood type was observed in n. 325 (57.4%) women. The prevalence of non-O blood group was significantly higher in women with pregnancy loss (p 0.01) and the association of thrombophilia and non-O blood type further increased the risk of pregnancy loss (OR 3.28; CI 95% 2.01–5.36). Conclusions Both inherited thrombophilia and non-O blood type should be considered risk factors for pregnancy loss. The knowledge of this information may help the clinician to better manage women with pregnancy loss. Further studies are required to confirm our findings. Funding Acknowledgement Type of funding sources: None