Outcome of brain metastases from adrenocortical carcinoma: a pooled analysis.

PURPOSE: Brain metastases rarely complicate the natural history of patients with adrenocortical carcinoma (ACC). No information is available regarding the life expectancy and efficacy of treatments in ACC patients with brain involvement. METHODS: A pooled analysis was performed by searching on PubMed and using the keywords: "brain metastases in adrenocortical carcinoma", and "leptomeningeal metastases in adrenocortical carcinoma". Four patients diagnosed at Spedali Civili Hospital in Brescia were added to the analysis. Data concerning demographic, disease characteristics, adopted treatments and patient prognosis were collected. RESULTS: A total of 27 patients (18 adults and 9 children) were included in this study, 22 of them had an adequate follow-up. Brain metastases occurred late in the natural history of adult patients but not in that of children. Surgery plus/minus radiation therapy was the treatment of choice. Adult patients with brain metastases had a poor prognosis with a median progression-free survival (PFS) and overall survival (OS) of 2 and 7 months, respectively. Median PFS and OS were not attained in children. CONCLUSION: Brain metastases in ACC patients are rare and are associated with poor prognosis, particularly in adults. Surgery plus/minus radiotherapy is the only therapeutic approach that can offer patients a chance to obtain durable local disease control.

Sources and space-time distribution of the electromagnetic pulses in experiments on inertial confinement fusion and laser-plasma acceleration.

When high-energy and high-power lasers interact with matter, a significant part of the incoming laser energy is transformed into transient electromagnetic pulses (EMPs) in the range of radiofrequencies and microwaves. These fields can reach high intensities and can potentially represent a significative danger for the electronic devices placed near the interaction point. Thus, the comprehension of the origin of these electromagnetic fields and of their distribution is of primary importance for the safe operation of high-power and high-energy laser facilities, but also for the possible use of these high fields in several promising applications. A recognized main source of EMPs is the target positive charging caused by the fast-electron emission due to laser-plasma interactions. The fast charging induces high neutralization currents from the conductive walls of the vacuum chamber through the target holder. However, other mechanisms related to the laser-target interaction are also capable of generating intense electromagnetic fields. Several possible sources of EMPs are discussed here and compared for high-energy and high-intensity laser-matter interactions, typical for inertial confinement fusion and laser-plasma acceleration. The possible effects on the electromagnetic field distribution within the experimental chamber, due to particle beams and plasma emitted from the target, are also described. This article is part of a discussion meeting issue 'Prospects for high gain inertial fusion energy (part 2)'.

Ultrafast electron and proton bunches correlation in laser-solid matter experiments.

The interaction of an ultra-intense laser with a solid state target allows the production of multi-MeV proton and ion beams. This process is explained by the target normal sheath acceleration (TNSA) model, predicting the creation of an electric field on the target rear side, due to an unbalanced positive charge. This process is related to the emission of relativistic ultrafast electrons, occurring at an earlier time. In this work, we highlight the correlations between the ultrafast electron component and the protons by their simultaneous detection by means of an electro-optical sampling and a time-of-flight diagnostics, respectively, supported by numerical simulations showing an excellent agreement.

Seminoma in an adult striped dolphin Stenella coeruleoalba: tomographic, macroscopical, histological and immunohistochemical study.

Testicular neoplasms have been extensively described and characterized in domestic animals, but reports in wildlife species, including marine mammals, are scarce. This case report describes a testicular seminoma in an adult striped dolphin Stenella coeruleoalba stranded along the coasts of the Canary Islands. Post-mortem computerized tomography (CT) showed a prominent enlargement of the cranial pole of the right testicle, displacing the intestinal loops. Necropsy gross findings confirmed the presence of a testicular mass, bulging at the cut surface, with multiple well-delimitated whitish nodular lesions. Histologically, intratubular and diffuse neoplastic germinative cell proliferation was described. Complementary immunohistochemical assessments for vimentin and CD117 antibodies were negative. To the authors' knowledge, this is the first seminoma described in a S. coeruleoalba. We suggest that post-mortem (PM) pre-necropsy CT in dolphins is a useful tool for anatomic-guided pathology in such cases.

Biallelic mutations in DYNC2LI1 are a rare cause of Ellis-van Creveld syndrome.

Ellis-van Creveld syndrome (EvC) is a chondral and ectodermal dysplasia caused by biallelic mutations in the EVC, EVC2 and WDR35 genes. A proportion of cases with clinical diagnosis of EvC, however, do not carry mutations in these genes. To identify the genetic cause of EvC in a cohort of mutation-negative patients, exome sequencing was undertaken in a family with 3 affected members, and mutation scanning of a panel of clinically and functionally relevant genes was performed in 24 additional subjects with features fitting/overlapping EvC. Compound heterozygosity for the c.2T>C (p.Met1?) and c.662C>T (p.Thr221Ile) variants in DYNC2LI1, which encodes a component of the intraflagellar transport-related dynein-2 complex previously found mutated in other short-rib thoracic dysplasias, was identified in the 3 affected members of the first family. Targeted resequencing detected compound heterozygosity for the same missense variant and a truncating change (p.Val141*) in 2 siblings with EvC from a second family, while a newborn with a more severe phenotype carried 2 DYNC2LI1 truncating variants. Our findings indicate that DYNC2LI1 mutations are associated with a wider clinical spectrum than previously appreciated, including EvC, with the severity of the phenotype likely depending on the extent of defective DYNC2LI1 function.

Measurement of the plasma astrophysical S factor for the 3He(d,p)4He reaction in exploding molecular clusters.

The plasma astrophysical S factor for the 3He(d,p)4He fusion reaction was measured for the first time at temperatures of few keV, using the interaction of intense ultrafast laser pulses with molecular deuterium clusters mixed with 3He atoms. Different proportions of D2 and 3He or CD4 and 3He were mixed in the gas target in order to allow the measurement of the cross section for the 3He(d,p)4He reaction. The yield of 14.7 MeV protons from the 3He(d,p)4He reaction was measured in order to extract the astrophysical S factor at low energies. Our result is in agreement with other S factor parametrizations found in the literature.

Temperature measurements of fusion plasmas produced by Petawatt-Laser-Irradiated D2 - (3)He or CD4 - (3)He clustering gases.

Two different methods have been employed to determine the plasma temperature in a laser-cluster fusion experiment on the Texas Petawatt laser. In the first, the temperature was derived from time-of-flight data of deuterium ions ejected from exploding D(2) or CD(4) clusters. In the second, the temperature was measured from the ratio of the rates of two different nuclear fusion reactions occurring in the plasma at the same time: D(d,(3)He)n and (3)He(d,p)(4)He. The temperatures determined by these two methods agree well, which indicates that (i) the ion energy distribution is not significantly distorted when ions travel in the disassembling plasma; (ii) the kinetic energy of deuterium ions, especially the "hottest part" responsible for nuclear fusion, is well described by a near-Maxwellian distribution.

Molecular characterization of Wolbachia strains associated with the invasive Asian citrus psyllid Diaphorina citri in Brazil.

Wolbachia is a symbiont intensively studied due to its ability to interfere with their host's reproduction, and it has been recently proposed as an alternative tool to control insect pests or vectors of diseases. The Asian citrus psyllid Diaphorina citri is an important pest of citrus since it vectors the bacterium that causes the "Huanglongbing" disease in citrus. The frequency and diversity of Wolbachia associated with D. citri is unknown, limiting the utilization of Wolbachia as an alternative strategy for insect management. Thus, we aimed to determine the natural rate of infection, to characterize the Wolbachia strains associated with this psyllid by "multilocus sequencing typing" (MLST) and wsp analysis, and to verify the association of the symbiont to particular genotypes of the host. Analysis indicated Wolbachia infects 100 % of all specimens tested from all 15 sampled populations. MLST revealed the occurrence of five new sequence types (STs) of Wolbachia, while analysis based on the wsp sequences indicated only four different types of Wolbachia. ST-173 was predominant, while the remaining STs were population specific. Analysis of the host-symbiont relationship did not reveal any particular association of Wolbachia and haplotypes or a decrease in nucleotide diversity of D. citri in populations in which more than one ST was recorded. The consequences of the diversity of STs reported are still unknown, but the fact that Wolbachia infection is fixed and that there is one ST with a broad distribution highlights the use of this symbiont as an alternative strategy to control D. citri.

Using population genetic methods to identify the origin of an invasive population and to diagnose cryptic subspecies of Telchin licus (Lepidoptera: Castniidae).

Telchin licus, the giant sugarcane borer, is an important pest species of sugarcane in northeast Brazil. Four subspecies of Telchin licus are recognized in Brazil based on their geographic distribution and subtle differences in wing colour pattern. Some taxa are morphologically indistinguishable, and their accurate identification is key to their efficient control. Mitochondrial genes sequences (cytochrome oxidase I and subunit 6 of the nicotinamide adenine dinucleotide dehydrogenase) were applied to delimit taxonomic entities of T. licus, and to infer the origin of a newly established population in the state of São Paulo. The molecular data indicated that specimens sampled at different regions in Brazil are morphologically cryptic but genetically isolated entities, and at least three subspecies were assigned to the sampled localities. These data also suggested that the population collected from the state of São Paulo must have a common origin with populations from northeast Brazil, which corroborate the hypothesis that ornamental plants infested with larvae of T. licus might have been transported from the northeast to the southeast regions.

Measuring the principal Hugoniot of inertial-confinement-fusion-relevant TMPTA plastic foams.

Wetted-foam layers are of significant interest for inertial-confinement-fusion capsules, due to the control they provide over the convergence ratio of the implosion and the opportunity this affords to minimize hydrodynamic instability growth. However, the equation of state for fusion-relevant foams are not well characterized, and many simulations rely on modeling such foams as a homogeneous medium with the foam average density. To address this issue, an experiment was performed using the VULCAN Nd:glass laser at the Central Laser Facility. The aim was to measure the principal Hugoniot of TMPTA plastic foams at 260mg/cm^{3}, corresponding to the density of liquid DT-wetted-foam layers, and their "hydrodynamic equivalent" capsules. A VISAR was used to obtain the shock velocity of both the foam and an α-quartz reference layer, while streaked optical pyrometry provided the temperature of the shocked material. The measurements confirm that, for the 20-120 GPa pressure range accessed, this material can indeed be well described using the equation of state of the homogeneous medium at the foam density.

Genetic variability and demographic history of Heliothis virescens (Lepidoptera: Noctuidae) populations from Brazil inferred by mtDNA sequences.

Intra- and inter-population genetic variability and the demographic history of Heliothis virescens (F.) populations were evaluated by using mtDNA markers (coxI, coxII and nad6) with samples from the major cotton- and soybean-producing regions in Brazil in the growing seasons 2007/08, 2008/09 and 2009/10. AMOVA indicated low and non-significant genetic structure, regardless of geographical scale, growing season or crop, with most of genetic variation occurring within populations. Clustering analyzes also indicated low genetic differentiation. The haplotype network obtained with combined datasets resulted in 35 haplotypes, with 28 exclusive occurrences, four of them sampled only from soybean fields. The minimum spanning network showed star-shaped structures typical of populations that underwent a recent demographic expansion. The recent expansion was supported by other demographic analyzes, such as the Bayesian skyline plot, the unimodal distribution of paired differences among mitochondrial sequences, and negative and significant values of neutrality tests for the Tajima's D and Fu's F(S) parameters. In addition, high values of haplotype diversity (H) and low values of nucleotide diversity (π), combined with a high number of low frequency haplotypes and values of θ(π)<θ(W), suggested a recent demographic expansion of H. virescens populations in Brazil. This demographic event could be responsible for the low genetic structure currently found; however, haplotypes present uniquely at the same geographic regions and from one specific host plant suggest an initial differentiation among H. virescens populations within Brazil.

New mutations in ZFPM2/FOG2 gene in tetralogy of Fallot and double outlet right ventricle.

Conotruncal defects (CTDs) represent 15-20% of all congenital heart defects. Mutations in a number of genes have been associated with CTD in humans and animal models. We investigated the occurrence and the prevalence of GATA4, NKX2.5, ZFPM2/FOG2, GDF1, and ISLET1 gene mutations in a large cohort of individuals with CTD, including tetralogy of Fallot with or without pulmonary atresia (TOF, 178 patients), double outlet right ventricle (DORV, 13 patients), and truncus arteriosus (11 patients). Denaturing high-performance liquid chromatography (DHPLC) analysis followed by bidirectional sequencing disclosed no putative pathogenic mutation in GATA4, ISLET1, and GDF1 genes. Two novel (Ile227Val, Met544Ile) and one previously reported (Glu30Gly) possibly pathogenic missense variants were identified in the ZFPM2/FOG2 gene in 3 sporadic patients of 202 (1.5%) with CTD, including 1 of 178 (0.6%) with TOF and 2 of 13 (15.4%) with DORV. Mutation analysis also detected one known missense change (Arg25Cys) in NKX2.5 gene in two (1.1%) sporadic patients with TOF. These sequence alterations were found to be absent in 500 population-matched controls. In conclusion, the present results (i) indicate and confirm that mutations in the GATA4, GDF1, and ISLET1 genes are not major determinants in the pathogenesis of TOF, (ii) provide supportive evidence of an association between ZFPM2/FOG2 gene and TOF/DORV, and (iii) provide additional examples of the possible contribution of the Arg25Cys change in the NKX2.5 to a small number of TOF cases.

Enhanced laser-driven proton acceleration using nanowire targets.

Laser-driven proton acceleration is a growing field of interest in the high-power laser community. One of the big challenges related to the most routinely used laser-driven ion acceleration mechanism, Target-Normal Sheath Acceleration (TNSA), is to enhance the laser-to-proton energy transfer such as to maximize the proton kinetic energy and number. A way to achieve this is using nanostructured target surfaces in the laser-matter interaction. In this paper, we show that nanowire structures can increase the maximum proton energy by a factor of two, triple the proton temperature and boost the proton numbers, in a campaign performed on the ultra-high contrast 10 TW laser at the Lund Laser Center (LLC). The optimal nanowire length, generating maximum proton energies around 6 MeV, is around 1-2 [Formula: see text]m. This nanowire length is sufficient to form well-defined highly-absorptive NW forests and short enough to minimize the energy loss of hot electrons going through the target bulk. Results are further supported by Particle-In-Cell simulations. Systematically analyzing nanowire length, diameter and gap size, we examine the underlying physical mechanisms that are provoking the enhancement of the longitudinal accelerating electric field. The parameter scan analysis shows that optimizing the spatial gap between the nanowires leads to larger enhancement than by the nanowire diameter and length, through increased electron heating.

Accurate spectra for high energy ions by advanced time-of-flight diamond-detector schemes in experiments with high energy and intensity lasers.

Time-Of-Flight (TOF) methods are very effective to detect particles accelerated in laser-plasma interactions, but they show significant limitations when used in experiments with high energy and intensity lasers, where both high-energy ions and remarkable levels of ElectroMagnetic Pulses (EMPs) in the radiofrequency-microwave range are generated. Here we describe a novel advanced diagnostic method for the characterization of protons accelerated by intense matter interactions with high-energy and high-intensity ultra-short laser pulses up to the femtosecond and even future attosecond range. The method employs a stacked diamond detector structure and the TOF technique, featuring high sensitivity, high resolution, high radiation hardness and high signal-to-noise ratio in environments heavily affected by remarkable EMP fields. A detailed study on the use, the optimization and the properties of a single module of the stack is here described for an experiment where a fast diamond detector is employed in an highly EMP-polluted environment. Accurate calibrated spectra of accelerated protons are presented from an experiment with the femtosecond Flame laser (beyond 100 TW power and ~ 1019 W/cm2 intensity) interacting with thin foil targets. The results can be readily applied to the case of complex stack configurations and to more general experimental conditions.

No fitness costs are induced by Spiroplasma infections of Aphis citricidus reared on two different host plants.

Aphids can harbor several secondary symbionts that alter important aphid-related ecological traits, such as defense against natural enemies, heat tolerance and host plant utilization. One of these secondary symbionts, Spiroplasma, is well known in Drosophila as a sex modulator and by interacting with the host immune system. However, little is known on the effects of Spiroplasma on aphids, such as its influence on the host immune defense against fungi and on host plant utilization. Aphid infections by Spiroplasma are known to be low and few aphid species were reported to be infected with this secondary symbiont, however aphids belonging to the genus Aphis in neotropical regions show high infection rates by Spiroplasma. Thus, we investigated the association of Spiroplasma with the tropical aphid Aphis citricidus through comparative biology experiments on two host plants with different nutritional value to the aphid. We demonstrate Spiroplasma induced no significant fitness costs to A. citricidus on either host plant as no changes in the fitness traits we assessed were observed. Spiroplasma infection only induced sutle changes on host longevity and fecundity. Therefore, we concluded Spiroplasma established a neutral interaction with A. citricidus under the selection pressure we tested, and argue on stress conditions that could better demonstrate the role of Spiroplasma in A. citricidus bioecology and associated costs involved.

Network indirect comparison of 3 BRAF + MEK inhibitors for the treatment of advanced BRAF mutated melanoma.

BACKGROUD: Synergistic combinations between BRAF and MEK inhibitors, such as dabrafenib plus trametinib, vemurafenib plus cobimetinib or encorafenib plus binimetinib, represent the current standard of care in metastatic or locally advanced BRAF V600 mutated malignant melanomas (MM). However, no studies explored the direct head-to-head comparison between the three different combinations. In this paper, we performed a network meta-analysis to evaluate their efficacy in terms of overall survival (OS), progression-free survival (PFS), overall response rate (ORR) and safety profile. METHOD: We performed a systematic review of the literature about published first line trials of BRAF and MEK inhibitors doublets in advanced mutated malignant melanoma. We compared then the results with an adjusted indirect analysis of randomized-controlled trials. Our primary survival outcome was OS. Secondary endpoints were PFS, ORR, G3-4 toxicities described in at least 5% of patients in experimental arms. RESULTS: We identified three phase-3 trials: coBRIM (vemurafenib and cobimetinib), COMBI-v (dabrafenib and trametinib) and Columbus study (encorafenib and binimetinib) for a total of 1230 included patients. The control arm was vemurafenib in all studies. The indirect comparison revealed no statistically differences for OS, PFS and ORR across trials, while safety profile differed between the three couples of agents. CONCLUSION: This indirect adjusted meta-analysis suggests a similar efficacy and a slightly different safety profile, related to specific molecular properties of the three different BRAF and MEK inhibitors currently approved in the management of advanced MM.

New models of care and multidimensional solutions for oncological patients in the post-acute SARS-COV-2 period: a "Second Phase" also for cancer patients.

In Italy, SARS-CoV-2 outbreak registered a high transmission and disease rates. During the acute phase, oncologists provided to re-organize services and prioritize treatments, in order to limit viral spread and to protect cancer patients. The progressive reduction of the number of infections has prompted Italian government to gradually loosen the national confinement measures and to start the "Second phase" of measures to contain the pandemic. The issue on how to organize cancer care during this post-acute SARS-CoV-2 phase appears crucial and a reassessment of healthcare services is needed requiring new models of care for oncological patients. In order to address major challenges in cancer setting during post-acute SARS-CoV-2 phase, this work offers multidimensional solutions aimed to provide a new way to take care of cancer patients.

Thomson parabola and time-of-flight detector cross-calibration methodology on the ALLS 100 TW laser-driven ion acceleration beamline.

We report on the cross-calibration of Thomson Parabola (TP) and Time-of-Flight (TOF) detectors as particle diagnostics, implemented on the most recent setup of the ALLS 100 TW laser-driven ion acceleration beamline. The Microchannel Plate (MCP) used for particle detection in the TP spectrometer has been calibrated in intensity on the tandem linear accelerator at the Université de Montréal. The experimental data points of the scaling factor were obtained by performing a pixel cluster analysis of single proton impacts on the MCP. A semi-empirical model was extrapolated and fitted to the data to apply the calibration also to higher kinetic energies and to extend it to other ion species. Two TOF lines using diamond detectors, placed at +6° and -9° with respect to the target-normal axis, were benchmarked against the TP spectrometer measurements to determine the field integrals related to its electric and magnetic dispersions. The mean integral proton numbers obtained on the beamline were about 4.1 × 1011 protons/sr with a standard deviation of 15% in the central section of the spectrum around 3 MeV, hence witnessing the high repeatability of the proton bunch generation. The mean maximum energy was of 7.3 ± 0.5 MeV, well in agreement with similar other 100 TW-scale laser facilities, with the best shots reaching 9 MeV and nearly 1012 protons/sr. The used particle diagnostics are compatible with the development of a high-repetition rate targetry due to their fast online readout and are therefore a crucial step in the automation of any beamline.

Generation of intense quasi-electrostatic fields due to deposition of particles accelerated by petawatt-range laser-matter interactions.

We demonstrate here for the first time that charge emitted by laser-target interactions at petawatt peak-powers can be efficiently deposited on a capacitor-collector structure far away from the target and lead to the rapid (tens of nanoseconds) generation of large quasi-static electric fields over wide (tens-of-centimeters scale-length) regions, with intensities much higher than common ElectroMagnetic Pulses (EMPs) generated by the same experiment in the same position. A good agreement was obtained between measurements from a classical field-probe and calculations based on particle-flux measurements from a Thomson spectrometer. Proof-of-principle particle-in-cell simulations reproduced the measurements of field evolution in time, giving a useful insight into the charging process, generation and distribution of fields. The understanding of this charging phenomenon and of the related intense fields, which can reach the MV/m order and in specific configurations might also exceed it, is very important for present and future facilities studying laser-plasma-acceleration and inertial-confinement-fusion, but also for application to the conditioning of accelerated charged-particles, the generation of intense electric and magnetic fields and many other multidisciplinary high-power laser-driven processes.

Microwave field distribution and electron cyclotron resonance heating process.

In an electron cyclotron resonance ion source, ions are produced from a plasma generated and sustained by microwaves with a proper frequency. Some experiments showed that the plasma formation, the consequent amount of particles extracted from the source, and the related beam shape strongly depend on the frequency of the electromagnetic wave feeding the cavity. In order to have a better understanding of these phenomena, in this work we deal with the description of the motion of a charged particle inside the plasma chamber model of the SERSE ion source operating at INFN-LNS in Catania, the analysis being applicable to any similar apparatus. The electromagnetic fields inside the vacuum filled chamber were determined theoretically and, together with proper simulations, their fundamental role on the particle motion, on their confinement, and on the energy transfer they are subjected to during their motion within the cavity is shown.