Microenvironment in neuroblastoma: Isolation and characterization of tumor-derived mesenchymal stromal cells

Background: It has been proposed that mesenchymal stromal cells (MSCs) promote tumor progression by interacting with tumor cells and other stroma cells in the complex network of the tumor microenvironment. We characterized MSCs isolated and expanded from tumor tissues of pediatric patients diagnosed with neuroblastomas (NB-MSCs) to define interactions with the tumor microenvironment. Methods: Specimens were obtained from 7 pediatric patients diagnosed with neuroblastoma (NB). Morphology, immunophenotype, differentiation capacity, proliferative growth, expression of stemness and neural differentiation markers were evaluated. Moreover, the ability of cells to modulate the immune response, i.e. inhibition of phytohemagglutinin (PHA) activated peripheral blood mononuclear cells (PBMCs) and natural killer (NK) cytotoxic function, was examined. Gene expression profiles, known to be related to tumor cell stemness, Wnt pathway activation, epithelial-mesenchymal transition (EMT) and tumor metastasis were also evaluated. Healthy donor bone marrow-derived MSCs (BM-MSC) were employed as controls. Results: NB-MSCs presented the typical MSC morphology and phenotype. They showed a proliferative capacity superimposable to BM-MSCs. Stemness marker expression (Sox2, Nanog, Oct3/4) was comparable to BM-MSCs. NB-MSC in vitro osteogenic and chondrogenic differentiation was similar to BM-MSCs, but NB-MSCs lacked adipogenic differentiation capacity. NB-MSCs reached senescence phases at a median passage of P7 (range, P5-P13). NB-MSCs exhibited greater immunosuppressive capacity on activated T lymphocytes at a 1:2 (MSC: PBMC) ratio compared with BM-MSCs (p = 0.018). NK cytotoxic activity was not influenced by co-culture, either with BM-MSCs or NB-MSCs. Flow-cytometry cell cycle analysis showed that NB-MSCs had an increased number of cells in the G0-G1 phase compared to BM-MSCs. Transcriptomic profiling results indicated that NB-MSCs were enriched with EMT genes compared to BM-MSCs. Conclusions: We characterized the biological features, the immunomodulatory capacity and the gene expression profile of NB-MSCs. The NB-MSC gene expression profile and their functional properties suggest a potential role in promoting tumor escape, invasiveness and metastatic traits of NB cancer cells. A better understanding of the complex mechanisms underlying the interactions between NB cells and NB-derived MSCs should shed new light on potential novel therapeutic approaches

On gauge/string correspondence and mirror symmetry

We consider a mirror dual of the Berkovits-Vafa A-model for the BPS superstring on $AdS_5\times S^5$ in the form of a deformed superconifold. Via geometric transition, the theory has a dual description as the hermitian gaussian one-matrix model. We show that the A-model amplitudes of generic $AdS_2\times S^4$ branes, breaking the superconformal symmetry as $U(2,2|4)\to OSp(4^*|4)$, are evaluated in terms of observables in the matrix model. As such, upon the usual identification $g_{YM}^2=g_s$, these can be expanded as Drukker-Gross circular 1/2-BPS Wilson loops in the perturbative regime of ${\cal N}=4$ SYM.Comment: 1+13 pages, minor changes, added refrences, version to appear in JHE

Ultrarelativistic circular orbits of spinning particles in a Schwarzschild field

Ultrarelativistic circular orbits of spinning particles in a Schwarzschild field described by the Mathisson-Papapetrou equations are considered. The preliminary estimates of the possible synchrotron electromagnetic radiation of highly relativistic protons and electrons on these orbits in the gravitational field of a black hole are presentedComment: 9 page

General approach to the study of vacuum space-times with an isometry

In vacuum space-times the exterior derivative of a Killing vector field is a 2-form (named here as the Papapetrou field) that satisfies Maxwell's equations without electromagnetic sources. In this paper, using the algebraic structure of the Papapetrou field, we will set up a new formalism for the study of vacuum space-times with an isometry, which is suitable to investigate the connections between the isometry and the Petrov type of the space-time. This approach has some advantages, among them, it leads to a new classification of these space-times and the integrability conditions provide expressions that determine completely the Weyl curvature. These facts make the formalism useful for application to any problem or situation with an isometry and requiring the knowledge of the curvature.Comment: 24 pages, LaTeX2e, IOP style. To appear in Classical and Quantum Gravit

Efficacy and Safety of Trifluridine/Tipiracil Treatment in Patients With Metastatic Gastric Cancer Who Had Undergone Gastrectomy: Subgroup Analyses of a Randomized Clinical Trial

Importance Trifluridine/tipiracil (FTD/TPI) treatment has shown clinical benefit in patients with pretreated metastatic gastric cancer or gastroesophageal junction cancer (mGC/GEJC). Patients who have undergone gastrectomy constitute a significant proportion of patients with mGC/GEJC. Objective To assess the efficacy and safety of FTD/TPI among patients with previously treated mGC/GEJC who had or had not undergone gastrectomy. Design, Setting, and Participants This preplanned subgroup analysis of TAGS (TAS-102 Gastric Study), a phase 3, randomized, placebo-controlled, clinical trial included patients with mGC/GEJC who had received at least 2 previous chemotherapy regimens, and was conducted at 110 academic hospitals in 17 countries in Europe, Asia, and North America, with enrollment between February 24, 2016, and January 5, 2018; the data cutoff was March 31, 2018. Interventions Patients were randomized 2:1 to receive oral FTD/TPI 35 mg/m2 twice daily or placebo twice daily with best supportive care on days 1 through 5 and days 8 through 12 of each 28-day treatment cycle. Main Outcomes and Measures The primary end point was overall survival. This subgroup analysis was conducted to examine potential trends and was not powered for statistical significance. Efficacy and safety end points were evaluated in the subgroups. Results Of 507 randomized patients (369 [72.8%] male; mean [SD] age, 62.5 [10.5] years), 221 (43.6%) had undergone gastrectomy (147 randomized to FTD/TPI and 74 to placebo) and 286 (56.4%) had not undergone gastrectomy (190 randomized to FTD/TPI and 96 to placebo). In the gastrectomy subgroup, the overall survival hazard ratio (HR) in the FTD/TPI group vs placebo group was 0.57 (95% CI, 0.41-0.79), and the progression-free survival HR was 0.48 (95% CI, 0.35-0.65). In the no gastrectomy subgroup, the overall survival HR in the FTD/TPI group vs placebo group was 0.80 (95% CI, 0.60-1.06), and the progression-free survival HR was 0.65 (95% CI, 0.49-0.85). Among FTD/TPI-treated patients, grade 3 or higher adverse events of any cause occurred in 122 of 145 patients (84.1%) in the gastrectomy subgroup and 145 of 190 (76.3%) in the no gastrectomy subgroup: 64 (44.1%) in the gastrectomy subgroup and 50 (26.3%) in the no gastrectomy subgroup had grade 3 or higher neutropenia, 31 (21.4%) in the gastrectomy subgroup and 33 (17.4%) in the no gastrectomy subgroup had grade 3 or higher anemia, and 21 (14.5%) in the gastrectomy subgroup and 10 (5.3%) in the no gastrectomy subgroup hD grade 3 or higher leukopenia. In the gastrectomy subgroup, 94 (64.8%) had dosing modifications because of adverse events vs 101 (53.2%) in the no gastrectomy subgroup; 15 (10.3%) in the gastrectomy group and 28 (14.7%) in the no gastrectomy group discontinued treatment because of adverse events. Treatment exposure was similar between groups. Conclusions and Relevance The FTD/TPI treatment was tolerable and provided efficacy benefits among patients with pretreated mGC/GEJC regardless of previous gastrectomy

Motivational profiles and change in physical activity during a weight loss intervention: a secondary data analysis

Background High levels of moderate-to-vigorous intensity physical activity (MVPA) are strongly associated with sustained weight loss, however the majority of adults are unsuccessful in maintaining high levels of MVPA long-term. Our goal was to identify profiles based on exercise motives, and examine the association between motivational profile and longitudinal changes in MVPA during a weight loss intervention. Methods Adults with overweight or obesity (n&thinsp;=&thinsp;169, mean&thinsp;&plusmn;&thinsp;SE; age 39&thinsp;&plusmn;&thinsp;0.7&thinsp;years, BMI 34.4&thinsp;&plusmn;&thinsp;0.3&thinsp;kg/m2, 83% female) underwent an 18-month behavioral weight loss program, including 6&thinsp;months of supervised exercise, followed by 6&thinsp;months of unsupervised exercise. Participants self-reported behavioral regulations for exercise at baseline (BREQ-2). Latent profile analysis identified subgroups from external, introjected, identified, and intrinsic regulations measured at baseline. Mean differences in device-measured total MVPA were compared across motivational profiles at baseline, after 6&thinsp;months of supervised exercise and after a subsequent 6&thinsp;months of unsupervised exercise. Results Three motivational profiles emerged: high autonomous (high identified and intrinsic, low external regulations; n&thinsp;=&thinsp;52), high combined (high scores on all exercise regulations; n&thinsp;=&thinsp;25), and moderate combined (moderate scores on all exercise regulations; n&thinsp;=&thinsp;92). Motivational profile was not associated with baseline level of MVPA or the increase in MVPA over the 6-month supervised exercise intervention (high autonomous: 21&thinsp;&plusmn;&thinsp;6&thinsp;min/d; high combined: 20&thinsp;&plusmn;&thinsp;9&thinsp;min/d; moderate combined: 33&thinsp;&plusmn;&thinsp;5&thinsp;min/d; overall P&thinsp;&gt;&thinsp;0.05). However, during the transition from supervised to unsupervised exercise, MVPA decreased, on average, within all three profiles, but the high autonomous profile demonstrated the least attenuation in MVPA (&minus;&thinsp;3&thinsp;&plusmn;&thinsp;6&thinsp;min/d) compared to the moderate combined profile (&minus;&thinsp;20&thinsp;&plusmn;&thinsp;5&thinsp;min/d; P&thinsp;=&thinsp;0.043). Conclusions Results were in alignment with the Self-Determination Theory. Adults motivated by autonomous reasons (value benefits of exercise, intrinsic enjoyment) may be more likely to sustain increases in MVPA once support is removed, whereas participants with moderate-to-high scores on all types of exercise regulations may need additional long-term support in order to sustain initial increases in MVPA.</p

Hedgehog pathway mutations drive oncogenic transformation in high-risk T-cell acute lymphoblastic leukemia.

The role of Hedgehog signaling in normal and malignant T-cell development is controversial. Recently, Hedgehog pathway mutations have been described in T-ALL, but whether mutational activation of Hedgehog signaling drives T-cell transformation is unknown, hindering the rationale for therapeutic intervention. Here, we show that Hedgehog pathway mutations predict chemotherapy resistance in human T-ALL, and drive oncogenic transformation in a zebrafish model of the disease. We found Hedgehog pathway mutations in 16% of 109 childhood T-ALL cases, most commonly affecting its negative regulator PTCH1. Hedgehog mutations were associated with resistance to induction chemotherapy (P = 0.009). Transduction of wild-type PTCH1 into PTCH1-mutant T-ALL cells induced apoptosis (P = 0.005), a phenotype that was reversed by downstream Hedgehog pathway activation (P = 0.007). Transduction of most mutant PTCH1, SUFU, and GLI alleles into mammalian cells induced aberrant regulation of Hedgehog signaling, indicating that these mutations are pathogenic. Using a CRISPR/Cas9 system for lineage-restricted gene disruption in transgenic zebrafish, we found that ptch1 mutations accelerated the onset of notch1-induced T-ALL (P = 0.0001), and pharmacologic Hedgehog pathway inhibition had therapeutic activity. Thus, Hedgehog-activating mutations are driver oncogenic alterations in high-risk T-ALL, providing a molecular rationale for targeted therapy in this disease