Recent (1975-2003) changes in the Miage debris covere glacier tongue (Mont Blanc, Italy) from analysis of aerial photos and maps

The present study aims at identifying any changes in volume and thickness of the Miage Glacier tongue (Mont Blanc Massif, Italy) during the period 1975-2003. The Miage glacier developed the largest part of its debris cover over the last century, now found mostly between the glacier terminus (about 1850 m a.s.l.) and the upper ablation tongue (c. 2400 m a.s.l.) on a surface area of c. 4 km 2 The period examined (1975-2003) addresses climate conditions which were glacier-favourable (around the . 1980s), as well as glacier-unfavourable (since the early to mid-1990s), thus contributing to an understanding of the behaviour of debris covered glaciers under a changing climate. The analysis was based on the comparison between digital elevation models (DEMs), derived from historical records, specifically maps (1975; scale 1:10,000) and photogrammetric surveys (1991 and 2003, scale 1:15,000). The results show a general glacier volume loss (\u201316.640 x 10 6 m 3 ( from 1975 to 2003; nevertheless if we focus on the two time sub-windows (i.e.: 1975-1991 and 1991-2003) opposite trends are found: in the period 1975-1991 the volume variation of the Miage Glacier was about +19.25 710 6 m 3 , in the period 1991-2003, on the other hand, a volume decrease of about \u201336.2 710 6 m 3 occurred. Analysis shows that volume changes were strongly influenced by the supraglacial debris coverage which on Miage glacier tongue modulates the magnitude and rates of buried ice ablation

Severe growth hormone deficiency and pituitary malformation in a patient with chromosome 2p25 duplication and 2q37 deletion.

We report on a male child ascertained at 4.8 years of age with severe growth failure, growth hormone (GH) deficiency, psychomotor delay with prevalent speech impairment, and a distinct phenotype. An evaluation of his hypothalamic-pituitary region by Magnetic Resonance Imaging (MRI) revealed pituitary hypoplasia with pituitary stalk interruption and ectopic posterior pituitary lobe, which are considered prognostic markers of permanent GH deficiency. Prenatal chromosome analysis because of increased nuchal translucency revealed a normal male karyotype, whereas postnatal high resolution banding raised the suspicion of a 2q abnormality. Subsequently, array Comparative Genomic Hybridization (array-CGH) revealed a de novo complex genomic rearrangement consisting of a 2p25 duplication and a 2q37 deletion: arr[hg19] 2p25.3p25.1(30,341-9,588,369)x3,2q37.2q37.3(235,744,424-243,041,305)x1. FISH analysis showed that the abnormal chromosome 2 mimicked the derivative of an inversion with the duplicated 2p region located distally at 2q. This is, to the best of our knowledge, the first case with distal 2p25 duplication and 2q37 deletion and pituitary malformation leading to GH deficiency

Salvage rates and prognostic factors after relapse in children and adolescents with initially localised synovial sarcoma

Background: Previous studies have reported a poor outcome for synovial sarcoma patients whose tumours relapse. Methods: This study analysed 44 relapsing cases in a series of 118 consecutive patients<21 yr of age with non-metastatic synovial sarcoma prospectively enrolled in Italian paediatric protocols between 1979 and 2006. In an effort to identify a possible risk-adapted stratification enabling a better planning of second-line treatment, the relapsing patients' outcome was analysed vis-à-vis their clinical picture at onset, first-line treatments, clinical findings at the time of first relapse and second-line treatment modalities. Results: The first event was a local recurrence in only 15 cases, and metastatic in 29 (associated with local relapse too in 7 cases). The time to relapse ranged from 4 to 108 months (median 20 months). Overall survival was 29.7% and 21.0% five and ten years after relapsing, respectively. The variables influencing survival were the timing and type of relapse (combined) and the chances of a secondary remission, which correlated strongly with the feasibility of complete surgery. Conclusions: Our study confirmed a largely unsatisfactory prognosis after recurrences in children and adolescents with synovial sarcoma: the chances of survival can be estimated on the basis of several variables for the purposes of planning risk-adapted salvage protocols. An aggressive surgical approach should be recommended. New effective systemic agents are warranted, and experimental therapies can be offered to patients with little chance of salvage. © 2012 Elsevier Ltd. All rights reserved

Inhibitory 2B4 contributes to NK cell education and immunological derangements in XLP1 patients

X-linked lymphoproliferative disease 1 (XLP1) is an inherited immunodeficiency, caused by mutations in SH2D1A encoding Signaling Lymphocyte Activation Molecule (SLAM)-associated protein (SAP). In XLP1, 2B4, upon engagement with CD48, has inhibitory instead of activating function. This causes a selective inability of cytotoxic effectors to kill EBV-infected cells, with dramatic clinical sequelae. Here, we investigated the NK cell education in XLP1, upon characterization of killer Ig-like receptor (KIR)/KIR-L genotype and phenotypic repertoire of self-HLA class I specific inhibitory NK receptors (self-iNKRs). We also analyzed NK-cell cytotoxicity against CD48+ or CD48− KIR-ligand matched or autologous hematopoietic cells in XLP1 patients and healthy controls. XLP1 NK cells may show a defective phenotypic repertoire with substantial proportion of cells lacking self-iNKR. These NK cells are cytotoxic and the inhibitory 2B4/CD48 pathway plays a major role to prevent killing of CD48+ EBV-transformed B cells and M1 macrophages. Importantly, self-iNKR defective NK cells kill CD48− targets, such as mature DCs. Self-iNKR− NK cells in XLP1 patients are functional even in resting conditions, suggesting a role of the inhibitory 2B4/CD48 pathway in the education process during NK-cell maturation. Killing of autologous mature DC by self-iNKR defective XLP1 NK cells may impair adaptive responses, further exacerbating the patients’ immune defect

Proton pump inhibitor chemosensitization in human osteosarcoma: from the bench to the patients' bed.

BACKGROUND: Major goals in translational oncology are to reduce systemic toxicity of current anticancer strategies and improve effectiveness. An extremely efficient cancer cell mechanism to avoid and/or reduce the effects of highly cytotoxic drugs is the establishment of an acidic microenvironment, an hallmark of all malignant tumors. The H\u2009+-rich milieu that anticancer drugs meet once they get inside the tumor leads to their protonation and neutralization, therefore hindering their access into tumor cells. We have previously shown that proton pump inhibitors (PPI) may efficiently counterattack this tumor advantage leading to a consistent chemosensitization of tumors. In this study, we investigated the effects of PPI in chemosensitizing osteosarcoma. METHOD: MG-63 and Saos-2 cell lines were used as human osteosarcoma models. Cell proliferation after pretreatment with PPI and subsequent treatment with cisplatin was evaluated by using erythrosin B dye vital staining. Tumour growth was evaluated in xenograft treated with cisplatin after PPI pretreatment. Subsequently, a multi-centre historically controlled trial, was performed to evaluate the activity of a pre-treatment administration of PPIs as chemosensitizers during neoadjuvant chemotherapy based on methotrexate, cisplatin, and adriamycin. RESULTS: Preclinical experiments showed that PPI sensitize both human osteosarcoma cell lines and xenografts to cisplatin. A clinical study subsequently showed that pretreatment with PPI drug esomeprazole leads to an increase in the local effect of chemotherapy, as expressed by percentage of tumor necrosis. This was particularly evident in chondroblastic osteosarcoma, an histological subtype that normally shows a poor histological response. Notably, no significant increase in toxicity was recorded in PPI treated patients. CONCLUSION: This study provides the first evidence that PPI may be beneficially added to standard regimens in combination to conventional chemotherapy

Cell-laden hydrogel as a clinical-relevant 3D model for analyzing neuroblastoma growth, immunophenotype, and susceptibility to therapies

High risk Neuroblastoma (NB) includes aggressive, metastatic solid tumors of childhood. The survival rate improved only modestly, despite the use of combination therapies including novel immunotherapies based on the antibody mediated targeting of tumor-associated surface ligands. Treatment failures may be due to the lack of adequate in vitro models for studying, in a given patient, the efficacy of potential therapeutics, including those aimed to enhance anti-tumor immune responses. We here propose a 3D alginate-based hydrogel as extracellular microenvironment to evaluate the effects of the three-dimensionality on biological and immunological properties of NB cells. NB cell lines grown within the 3D alginate spheres presented spheroid morphology, optimal survival, and proliferation capabilities, and a reduced sensitivity to the cytotoxic effect of imatinib mesylate. 3D cultured NB cells were also evaluated for the constitutive and IFN-y-induced expression of surface molecules capable of tuning the anti-tumor activity of NK cells including immune checkpoint ligands. In particular, IFN-y induced de novo expression of high amounts of HLA-I molecules, which protected NB cells from the attack mediated by KIR/KIR-L matched NK cells. Moreover, in the 3D alginate spheres, the cytokine increased the expression of the immune checkpoint ligands PD-Ls and B7-H3 while virtually abrogating that of PVR, a ligand of DNAM-1 activating receptor, whose expression correlates with high susceptibility to NK-mediated killing. Our 3D model highlighted molecular features that more closely resemble the immunophenotypic variants occurring in vivo and not fully appreciated in classical 2D culture conditions.Thus, based on our results, 3D alginate-based hydrogels might represent a clinical-relevant cell culture platform where to test the efficacy of personalized therapeutic approaches aimed to optimize the current and innovative immune based therapies in a very systematic and reliable way

Cardiogenic hypertension in maturing dogs

The purpose of this study was to evaluate whether the heart can induce high blood pressure by maintaining an inappropriately elevated cardiac output/body weight ratio during growth. Direct (femoral artery) mean arterial pressure (MAP), heart rate, cardiac output/body weight ratio (as defined by M-mode echocardiography), and total peripheral vascular resistance were measured and calculated every 2 months in nine conscious dogs during development from 2 to 10 months of age. In four dogs a J-shaped catheter for atrial pacing was chronically implanted at the age of 3 months, and their hearts were permanently paced at 130 beats/min until maturity. The aim of atrial pacing was to prevent the natural slowing of the heart rate and, consequently, to maintain a cardiac output/body weight ratio that was inappropriately high in relation to age during growth. Five dogs were studied as controls. No hemodynamic differences were observed until the age of 4 months. From the age of 5 to 10 months heart rate was kept at 130 beats/min by atrial pacing in the atrially paced group, and the mean cardiac output/body weight ratio did not decrease (196 +/- 24 vs 191 +/- 34 [SE] ml/min/kg). MAP rose from 62 +/- 4 to 116 +/- 8 mm Hg, and total peripheral resistance increased from 0.34 +/- 0.07 to to 0.61 +/- 0.09 mm Hg/ml/min/kg.(ABSTRACT TRUNCATED AT 250 WORDS

Gemcitabine and docetaxel in relapsed and unresectable high-grade osteosarcoma and spindle cell sarcoma of bone

BACKGROUND: Few new compounds are available for relapsed osteosarcoma. We retrospectively evaluated the activity of gemcitabine (G) plus docetaxel (D) in patients with relapsed high-grade osteosarcoma and high-grade spindle cell sarcoma of bone (HGS). METHODS: Patients receiving G 900 mg/m(2) d 1, 8; D 75 mg/m(2) d 8, every 21 days were eligible. Primary end-point: progression-free survival (PFS) at 4 months; secondary end-point: overall survival (OS) and response rate. RESULTS: Fifty-one patients were included, with a median age of 17 years (8–71), 26 (51 %) were pediatric patients. GD line of treatment: 2nd in 14 patients, ≥3rd in 37. 25 (49 %) patients had metastases limited to lungs, 26 (51 %) multiple sites. Histology: 40 (78 %) osteosarcoma, 11 (22 %) HGS. Eight (16 %) patients achieved surgical complete response (sCR2) after GD. Four-month PFS rate was 46 %, and significantly better for patients with ECOG 0 (ECOG 0: 54 % vs ECOG 1: 43 % vs ECOG 2: 0 %; p = 0.003), for patients undergoing metastasectomy after GD (sCR2 75 % vs no-sCR2 40 %, p = 0.02) and for osteosarcoma (osteosarcoma 56 % vs HGS 18 %; p = 0.05), with no differences according to age, line of treatment, and pattern of metastases. Forty-six cases had RECIST measurable disease: 6 (13 %) patients had a partial response (PR), 20 (43 %) had stable disease (SD) and 20 (43 %) had progressive disease (PD). The 1-year OS was 30 %: 67 % for PR, 54 % for SD and 20 % for PD (p = 0.005). CONCLUSIONS: GD is an active treatment for relapsed high-grade osteosarcoma, especially for ECOG 0 patients, and should be included in the therapeutic armamentarium of metastatic osteosarcoma

Solid-state synthesis of mixed trihalides via reversible absorption of dihalogens by non porous onium salts

1,6-Bis(trimethylammonium) hexane bis(trihalides) and mixed bis(trihalides) have been synthesized by treating the corresponding dihydrated halides with molecular dihalogens under gas-solid and solution conditions. Despite the starting halides being non-porous, the trihalide syntheses occur homogeneously, in quantitative yields, and reversibly. In all cases halogen bond prevails over hydrogen bond, dihalogens substitute for the hydration water of starting halide anions and trihalides are formed. The stability of the obtained trihalides is mainly due to cooperative halogen bond and cation templation effect. Hexamethonium halides are proven effective solids for the clathration and storage of molecular dihalogens. While the starting salts are not isostructural, all the formed trihalides and mixed trihalides are isostructural