BackgroundAbout 10–15% of adult, and most pediatric, gastrointestinal stromal tumors (GIST) lack mutations in KIT, PDGFRA, SDHx, or RAS pathway components (KRAS, BRAF, NF1). The identification of additional mutated genes in this rare subset of tumors can have important clinical benefit to identify altered biological pathways and select targeted therapies.MethodsWe performed comprehensive genomic profiling (CGP) for coding regions in more than 300 cancer-related genes of 186 GISTs to assess for their somatic alterations.ResultsWe identified 24 GIST lacking alterations in the canonical KIT/PDGFRA/RAS pathways, including 12 without SDHx alterations. These 24 patients were mostly adults (96%). The tumors had a 46% rate of nodal metastases. These 24 GIST were more commonly mutated at 7 genes: ARID1B, ATR, FGFR1, LTK, SUFU, PARK2 and ZNF217. Two tumors harbored FGFR1 gene fusions (FGFR1–HOOK3, FGFR1–TACC1) and one harbored an ETV6–NTRK3 fusion that responded to TRK inhibition. In an independent sample set, we identified 5 GIST cases lacking alterations in the KIT/PDGFRA/SDHx/RAS pathways, including two additional cases with FGFR1–TACC1 and ETV6–NTRK3 fusions.ConclusionsUsing patient demographics, tumor characteristics, and CGP, we show that GIST lacking alterations in canonical genes occur in younger patients, frequently metastasize to lymph nodes, and most contain deleterious genomic alterations, including gene fusions involving FGFR1 and NTRK3. If confirmed in larger series, routine testing for these translocations may be indicated for this subset of GIST. Moreover, these findings can be used to guide personalized treatments for patients with GIST. Trial registration NCT 02576431. Registered October 12, 2015Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-1075-6) contains supplementary material, which is available to authorized users.

Objective: We aimed at evaluating whether the addition of low-dose metformin to dietary treatment could be an effective approach in nondiabetic patients with nonalcoholic fatty liver disease (NAFLD). Methods: We carried out a 6-month prospective study in a series of overweight or obese patients with ultrasonographic diagnosis of hepatic steatosis. In total, 50 patients were enrolled and randomized into two groups: the first group (n ¼ 25) was given metformin (1 g per day) plus dietary treatment and the second group (n ¼ 25) was given dietary treatment alone. Results: At the end of the study, the proportion of patients with echographic evidence of fatty liver was reduced in both the metformin (Po0.0001) and the diet group (P ¼ 0.029). Moreover, patient body mass index and waist circumference significantly decreased in both groups (Po0.001). Fasting glucose, insulin resistance (evaluated as homeostasis model assessment of insulin resistance (HOMA-IR)) and serum adiponectin decreased in both groups, although these changes reached statistical significance only in the metformin group. In this group, HOMA-IR decreased from 3.3±1.6 to 2.4±1.2 (P ¼ 0.003), whereas it decreased from 3.2 ± 1.6 to 2.8 ± 1.1 (not significant, NS) in the diet group. Similarly, the proportion of patients with impaired fasting glucose declined from 35 to 5% (P ¼ 0.04) in the metformin and from 32 to 12% (NS) in the diet group. At baseline, B40% of patients in both groups met the diagnostic criteria of metabolic syndrome. This proportion decreased to 20% in the metformin group (P ¼ 0.008) and to 32% in the diet group (NS). Conclusions: In our 6-month prospective study, both low-dose metformin and dietary treatment alone ameliorated liver steatosis and metabolic derangements in patients with NAFLD. However, metformin was more effective than dietary treatment alone in normalizing several metabolic parameters in these patients.

We perform a set of detailed numerical simulations of single-phase, fully saturated flow in stochastically generated, three-dimensional pore structures with diverse porosities (ϕ) and degrees of connectivity, and analyze the probability density functions (PDFs) of the pore sizes, S, and vertical velocity components, w, which are aligned with the mean flow direction. Both of the PDFs are markedly skewed with pronounced positive tails. This feature of the velocity PDF is dictated by the pore structure and determines the shortest travel times, one of the key transport attributes that underpins the success or the failure of environmental remediation techniques. Using a maximum likelihood approach, we determine that the PDFs of S and w decay according to an exponential and a stretched exponential model, respectively. A strong correlation between the key parameters governing the decay of the upper tails of the two PDFs is found, which provides a quantitative result for this analogy that so far has been stated only qualitatively. The parameter governing the concavity of the tail of the velocity PDF varies linearly with porosity over the entire range of tested values (0.2≤ϕ≤0.6). The parameters controlling the spread of the upper tails of the PDFs of S and w appear to be linked by a power-law relationship.

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Background and purpose: The objective of this study was to assess the neurological manifestations in a series of consecutive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-positive patients, comparing their frequency with a population hospitalized in the same period for flu/respiratory symptoms, finally not related to SARS-CoV-2. Methods: Patients with flu/respiratory symptoms admitted to Fondazione Policlinico Gemelli hospital from 14 March 2020 to 20 April 2020 were retrospectively enrolled. The frequency of neurological manifestations of patients with SARS-CoV-2 infection was compared with a control group. Results: In all, 213 patients were found to be positive for SARS-CoV-2, after reverse transcriptase polymerase chain reaction on nasal or throat swabs, whilst 218 patients were found to be negative and were used as a control group. Regarding central nervous system manifestations, in SARS-CoV-2-positive patients a higher frequency of headache, hyposmia and encephalopathy always related to systemic conditions (fever or hypoxia) was observed. Furthermore, muscular involvement was more frequent in SARS-CoV-2 infection. Conclusions: Patients with COVID-19 commonly have neurological manifestations but only hyposmia and muscle involvement seem more frequent compared with other flu diseases.

Abstract. We use three methods to identify power-law scaling of multi-scale log air permeability data collected by Tidwell and Wilson on the faces of a laboratory-scale block of Topopah Spring tuff: method of moments (M), Extended Self-Similarity (ESS) and a generalized version thereof (G-ESS). All three methods focus on q-th-order sample structure functions of absolute increments. Most such functions exhibit power-law scaling at best over a limited midrange of experimental separation scales, or lags, which are sometimes difficult to identify unambiguously by means of M. ESS and G-ESS extend this range in a way that renders power-law scaling easier to characterize. Our analysis confirms the superiority of ESS and G-ESS over M in identifying the scaling exponents, ξ(q), of corresponding structure functions of orders q, suggesting further that ESS is more reliable than G-ESS. The exponents vary in a nonlinear fashion with q as is typical of real or apparent multifractals. Our estimates of the Hurst scaling coefficient increase with support scale, implying a reduction in roughness (anti-persistence) of the log permeability field with measurement volume. The finding by Tidwell and Wilson that log permeabilities associated with all tip sizes can be characterized by stationary variogram models, coupled with our findings that log permeability increments associated with the smallest tip size are approximately Gaussian and those associated with all tip sizes scale show nonlinear variations in ξ(q) with q, are consistent with a view of these data as a sample from a truncated version (tfBm) of self-affine fractional Brownian motion (fBm). Since in theory the scaling exponents, ξ(q), of tfBm vary linearly with q we conclude that nonlinear scaling in our case is not an indication of multifractality but an artifact of sampling from tfBm. This allows us to explain theoretically how power-law scaling of our data, as well as of non-Gaussian heavy-tailed signals subordinated to tfBm, are extended by ESS. It further allows us to identify the functional form and estimate all parameters of the corresponding tfBm based on sample structure functions of first and second orders.

Gastrointestinal stromal tumors (GIST) arise within the interstitial cell of Cajal (ICC) lineage due to activating KIT/PDGFRA mutations. Both ICC and GIST possess primary cilia (PC), which coordinate PDGFRA and Hedgehog signaling, regulators of gastrointestinal mesenchymal development. Therefore, we hypothesized that Hedgehog signaling may be altered in human GIST and controls KIT expression. Quantitative RT-PCR, microarrays, and next generation sequencing were used to describe Hedgehog/PC-related genes in purified human ICC and GIST. Genetic and pharmacologic approaches were employed to investigate the effects of GLI manipulation on KIT expression and GIST cell viability. We report that Hedgehog pathway and PC components are expressed in ICC and GIST and subject to dysregulation during GIST oncogenesis, irrespective of KIT/PDGFRA mutation status. Using genomic profiling, 10.2% of 186 GIST studied had potentially deleterious genomic alterations in 5 Hedgehog-related genes analyzed, including in the PTCH1 tumor suppressor (1.6%). Expression of the predominantly repressive GLI isoform, GLI3, was inversely correlated with KIT mRNA levels in GIST cells and non-KIT/non-PDGFRA mutant GIST. Overexpression of the 83-kDa repressive form of GLI3 or small interfering RNA-mediated knockdown of the activating isoforms GLI1/2 reduced KIT mRNA. Treatment with GLI1/2 inhibitors, including arsenic trioxide, significantly increased GLI3 binding to the KIT promoter, decreased KIT expression, and reduced viability in imatinib-sensitive and imatinib-resistant GIST cells. These data offer new evidence that genes necessary for Hedgehog signaling and PC function in ICC are dysregulated in GIST. Hedgehog signaling activates KIT expression irrespective of mutation status, offering a novel approach to treat imatinib-resistant GIST.

We analyze directional dependence and scaling of air log permeability statistics characterizing minipermeameter measurements by Tidwell and Wilson on the faces of a 30 by 30 by 30 cm(3) size unsaturated block of Berea sandstone. We find distinct differences between the statistics and scaling behaviors of data measured on faces parallel and normal to bedding, and of incremental measurements in three orthogonal directions along these faces. Whereas the distribution on of data and their increments parallel to bedding are heavy tailed, those of increments normal to bedding are Gaussian. Order q sample structure functions of increments parallel to bedding scale as powers xi(q) of directional lag, s(d), over limited ranges of s(d). Using moment and extended self-similarity methods of analysis we find xi(q) to be generally nonlinear in q, tending to be concave in q on faces normal to bedding and convex on faces parallel to bedding. Whereas the literature attributes nonlinear scaling of xi(q) with q to multifractals or fractional Laplace motions, we find the data to be consistent with sub-Gaussian random fields subordinated to truncated (monofractal, self-affine) fractional Gaussian noise. The increments exhibit negative statistical dependence (antipersistence) that varies with direction parallel to bedding and is more pronounced on faces parallel than normal to bedding