Genomic characterization of thymic epithelial tumors in a real-world dataset.

BACKGROUND: Thymic epithelial tumors (TETs) are rare neoplasms arising in the mediastinum, including thymic carcinomas and thymomas. Due to their rarity, little is known about the genomic profiles of TETs. Herein, we investigated the genomic characteristics of TETs evaluated in a large comprehensive genomic profiling database in a real-world setting. METHODS: We included data from two different cohorts: Foundation Medicine Inc. (FMI) in the United States and the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) in Japan. Samples profiled were examined for all classes of alterations in 253 genes targeted across all assays. Tumor mutational burden (TMB) and microsatellite instability (MSI) were also evaluated. RESULTS: A total of 794 patients were collected in our study, including 722 cases from FMI and 72 cases from C-CAT. In the FMI data, CDKN2A (39.9%), TP53 (30.2%) and CDKN2B (24.6%) were frequently altered in thymic carcinoma, versus TP53 (7.8%), DNMT3A (6.8%), and CDKN2A (5.8%) in thymoma. TMB-high (≥10 mutations/Mb) and MSI were present in 7.0% and 2.3% of thymic carcinomas, and 1.6% and 0.3% of thymomas, respectively. Within C-CAT data, CDKN2A (38.5%), TP53 (36.5%) and CDKN2B (30.8%) were also frequently altered in thymic carcinoma, while alterations of TSC1, SETD2 and LTK (20.0% each) were found in thymoma. CONCLUSIONS: To the best of our knowledge, this is the largest cohort in which genomic alterations, TMB and MSI status of TETs were investigated. Potential targets for treatment previously unbeknownst in TETs are identified in this study, entailing newfound opportunities to advance therapeutic development.

Giant valley-Zeeman coupling in the surface layer of an intercalated transition metal dichalcogenide.

Spin-valley locking is ubiquitous among transition metal dichalcogenides with local or global inversion asymmetry, in turn stabilizing properties such as Ising superconductivity, and opening routes towards 'valleytronics'. The underlying valley-spin splitting is set by spin-orbit coupling but can be tuned via the application of external magnetic fields or through proximity coupling. However, only modest changes have been realized to date. Here, we investigate the electronic structure of the V-intercalated transition metal dichalcogenide V1/3NbS2 using microscopic-area spatially resolved and angle-resolved photoemission spectroscopy. Our measurements and corresponding density functional theory calculations reveal that the bulk magnetic order induces a giant valley-selective Ising coupling exceeding 50 meV in the surface NbS2 layer, equivalent to application of a ~250 T magnetic field. This energy scale is of comparable magnitude to the intrinsic spin-orbit splittings, and indicates how coupling of local magnetic moments to itinerant states of a transition metal dichalcogenide monolayer provides a powerful route to controlling their valley-spin splittings.

Impact of angiotensin II receptor antagonism on the sex-selective dysregulation of cardiovascular function induced by in utero dexamethasone exposure.

In utero exposure to glucocorticoids in late gestation programs changes in cardiovascular function. The objective of this study was to determine the degree to which angiotensin II mediates sex-biased changes in autonomic function as well as basal and stress-responsive cardiovascular function following in utero glucocorticoid exposure. Pregnant rats were administered the synthetic glucocorticoid dexamethasone (Dex; 0.4 mg/kg/day sc) or vehicle on gestation days 18-21. Mean arterial pressure, heart rate, and heart rate variability (HRV) were measured via radiotelemetry in freely moving, conscious adult rats. To evaluate the impact of stress, rats were placed in a restraint tube for 20 min. In a separate cohort of rats, restraint stress was performed before and after chronic treatment with the angiotensin type 1 receptor antagonist, losartan (30 mg/kg/day ip). Frequency domain analysis of HRV was evaluated, and data were integrated into low-frequency (LF, 0.20-0.75 Hz) and high-frequency (HF, 0.75-2.00 Hz) bands. Prenatal Dex resulted in an exaggerated pressor and heart rate response to restraint in female offspring that was attenuated by prior losartan treatment. HF power was higher in vehicle-exposed female rats compared with Dex females. Following losartan, HF power was equivalent between female vehicle and Dex-exposed rats. In utero exposure to Dex produced female-biased alterations in stress-responsive cardiovascular function, which may be indicative of a reduction in parasympathetic activity. Moreover, these findings suggest this autonomic dysregulation may be mediated, in part, by long-term changes in renin-angiotensin signaling.NEW & NOTEWORTHY Our findings reveal the involvement of angiotensin II on sex-selective cardiovascular function and autonomic changes in adult offspring exposed to dexamethasone during the last 4 days of gestation. We show that angiotensin II receptor blockade reverses the exaggerated pressor and heart rate response to acute restraint stress and the autonomic dysregulation observed in female, but not male, offspring exposed to dexamethasone in utero.

Development and Practical Implementation of a Deep Learning-Based Pipeline for Automated Pre- and Postoperative Glioma Segmentation.

BACKGROUND AND PURPOSE: Quantitative volumetric segmentation of gliomas has important implications for diagnosis, treatment, and prognosis. We present a deep-learning model that accommodates automated preoperative and postoperative glioma segmentation with a pipeline for clinical implementation. Developed and engineered in concert, the work seeks to accelerate clinical realization of such tools. MATERIALS AND METHODS: A deep learning model, autoencoder regularization-cascaded anisotropic, was developed, trained, and tested fusing key elements of autoencoder regularization with a cascaded anisotropic convolutional neural network. We constructed a dataset consisting of 437 cases with 40 cases reserved as a held-out test and the remainder split 80:20 for training and validation. We performed data augmentation and hyperparameter optimization and used a mean Dice score to evaluate against baseline models. To facilitate clinical adoption, we developed the model with an end-to-end pipeline including routing, preprocessing, and end-user interaction. RESULTS: The autoencoder regularization-cascaded anisotropic model achieved median and mean Dice scores of 0.88/0.83 (SD, 0.09), 0.89/0.84 (SD, 0.08), and 0.81/0.72 (SD, 0.1) for whole-tumor, tumor core/resection cavity, and enhancing tumor subregions, respectively, including both preoperative and postoperative follow-up cases. The overall total processing time per case was ∼10 minutes, including data routing (∼1 minute), preprocessing (∼6 minute), segmentation (∼1-2 minute), and postprocessing (∼1 minute). Implementation challenges were discussed. CONCLUSIONS: We show the feasibility and advantages of building a coordinated model with a clinical pipeline for the rapid and accurate deep learning segmentation of both preoperative and postoperative gliomas. The ability of the model to accommodate cases of postoperative glioma is clinically important for follow-up. An end-to-end approach, such as used here, may lead us toward successful clinical translation of tools for quantitative volume measures for glioma.

First-line nivolumab plus ipilimumab with two cycles of chemotherapy versus chemotherapy alone (four cycles) in advanced non-small-cell lung cancer: CheckMate 9LA 2-year update.

BACKGROUND: To further characterize survival benefit with first-line nivolumab plus ipilimumab with two cycles of chemotherapy versus chemotherapy alone, we report updated data from the phase III CheckMate 9LA trial with a 2-year minimum follow-up. PATIENTS AND METHODS: Adult patients were treatment naïve, with stage IV/recurrent non-small-cell lung cancer, no known sensitizing EGFR/ALK alterations, and an Eastern Cooperative Oncology Group performance status ≤1. Patients were randomized 1 : 1 to nivolumab 360 mg every 3 weeks plus ipilimumab 1 mg/kg every 6 weeks with two cycles of chemotherapy, or four cycles of chemotherapy. Updated efficacy and safety outcomes are reported, along with progression-free survival (PFS) after next line of treatment (PFS2), treatment-related adverse events (TRAEs) by treatment cycle, and efficacy outcomes in patients who discontinued all treatment components in the experimental arm due to TRAEs. RESULTS: With a median follow-up of 30.7 months, nivolumab plus ipilimumab with chemotherapy continued to prolong overall survival (OS) versus chemotherapy. Median OS was 15.8 versus 11.0 months [hazard ratio 0.72 (95% confidence interval 0.61-0.86)]; 2-year OS rate was 38% versus 26%. Two-year PFS rate was 20% versus 8%. ORR was 38% versus 25%, respectively; 34% versus 12% of all responses were ongoing at 2 years. Median PFS2 was 13.9 versus 8.7 months. Improved efficacy outcomes in the experimental versus control arm were observed across most subgroups, including by programmed death-ligand 1 and histology. No new safety signals were observed; onset of grade 3/4 TRAEs was mostly observed during the first two treatment cycles in the experimental arm. In patients who discontinued all components of nivolumab plus ipilimumab with chemotherapy treatment due to TRAEs (n = 61) median OS was 27.5 months; 56% of responders had an ongoing response ≥1 year after discontinuation. CONCLUSIONS: With a 2-year minimum follow-up, nivolumab plus ipilimumab with two cycles of chemotherapy provided durable efficacy benefits over chemotherapy with a manageable safety profile and remains an efficacious first-line treatment of advanced non-small-cell lung cancer.

Targeting KRAS in non-small-cell lung cancer: recent progress and new approaches.

Rat sarcoma (RAS) is the most frequently mutated oncogene in human cancer, with Kirsten rat sarcoma (KRAS) being the most commonly mutated RAS isoform. Overall, KRAS accounts for 85% of RAS mutations observed in human cancers and is present in 35% of lung adenocarcinomas (LUADs). While the use of targeted therapies and immune checkpoint inhibitors (CPIs) has drastically changed the treatment landscape of advanced non-small-cell lung cancer (NSCLC) in recent years, historic attempts to target KRAS (both direct and indirect approaches) have had little success, and no KRAS-specific targeted therapies have been approved to date for patients in this molecular subset of NSCLC. With the discovery by Ostrem, Shokat, and colleagues of the switch II pocket on the surface of the active and inactive forms of KRAS, we now have an improved understanding of the complex interactions involved in the RAS family of signaling proteins which has led to the development of a number of promising direct KRASG12C inhibitors, such as sotorasib and adagrasib. In previously treated patients with KRASG12C-mutant NSCLC, clinical activity has been shown for both sotorasib and adagrasib monotherapy; these data suggest promising new treatment options are on the horizon. With the stage now set for a new era in the treatment of KRASG12C-mutated NSCLC, many questions remain to be answered in order to further elucidate the mechanisms of resistance, how best to use combination strategies, and if KRASG12C inhibitors will have suitable activity in earlier lines of therapy for patients with advanced/metastatic NSCLC.

Newly diagnosed patients with advanced non-small cell lung cancer: A clinical description of those with moderate to severe depressive symptoms.

OBJECTIVES: The aims of this observational study were to 1) accrue newly diagnosed patients with advanced-stage non-small cell lung cancer (NSCLC) awaiting the start of first-line treatment and identify those with moderate to severe depressive symptoms and, 2) provide a clinical description of the multiple, co-occurring psychological and behavioral difficulties and physical symptoms that potentially exacerbate and maintain depressive symptoms. MATERIALS AND METHODS: Patients with stage IV NSCLC (N = 186) were enrolled in an observational study (ClinicalTrials.gov Identifier: NCT03199651) and completed the American Society of Clinical Oncology-recommended screening measure for depression (Patient Health Questionnaire-9 [PHQ-9]). Individuals with none/mild (n = 119; 64 %), moderate (n = 52; 28 %), and severe (n = 15; 8 %) depressive symptoms were identified. Patients also completed measures of hopelessness, generalized anxiety disorder (GAD) symptoms, stress, illness perceptions, functional status, and symptoms. RESULTS: Patients with severe depressive symptoms reported concomitant feelings of hopelessness (elevating risk for suicidal behavior), anxiety symptoms suggestive of GAD, and traumatic, cancer-specific stress. They perceived lung cancer as consequential for their lives and not controllable with treatment. Pain and multiple severe symptoms were present along with substantial functional impairment. Patients with moderate depressive symptoms had generally lower levels of disturbance, though still substantial. The most salient differences were low GAD symptom severity and fewer functional impairments for those with moderate symptoms. CONCLUSIONS: Depressive symptoms of moderate to severe levels co-occur in a matrix of clinical levels of anxiety symptoms, traumatic stress, impaired functional status, and pain and other physical symptoms. All of the latter factors have been shown, individually and collectively, to contribute to the maintenance or exacerbation of depressive symptoms. As life-extending targeted and immunotherapy use expands, prompt identification of patients with moderate to severe depressive symptoms, referral for evaluation, and psychological/behavioral treatment are key to maximizing treatment outcomes and quality of life for individuals with advanced NSCLC.

Shallow bore-hole three-axial fiber Bragg grating strain sensor for Etna volcano monitoring.

We present the realization, installation, and first results of a three-axial Fiber Bragg Grating (FBG) strain sensor prototype. This sensor has been developed in the framework of the Mediterranean supersite volcanoes (http://www.med-suv.eu, 2013) project and, in particular, with the aim at contributing to the study and monitoring of Etna volcano. The FBG sensor was installed in the facilities of the Serra La Nave Astrophysical Observatory (Catania, Italy) about 7 km south-west from the summit craters, at an elevation of about 1740 m. The three-axial device showed a dynamic range of some hundreds of microstrains with microstrain resolution (submicrostrain concerning the vertical component). That is a good trade-off among performances, cost, and power consumption. The sensor structure and its read-out system are innovative in their assembly and offers practical advantages in comparison with traditional strain meters. As a demonstration of the performances of our device, the data of about 28 months of operation are presented together with the records of some local, regional, and teleseismic events. The sensor along the vertical axis showed to be the best performing one, having a power spectral density of about -90 dB re. 1ε2/Hz around one day period.

Heavy-ion induced two-neutron transfer reactions and the role of pairing / Reacciones de transferencia de dos neutrones inducidas por iones pesados y el papel del apareamiento

Abstract Heavy-ion induced two-neutron transfer reactions (18O,16O) at 84 MeV were studied on several targets up to high excitation energy of the residual nucleus thanks to the use of the MAGNEX magnetic spectrometer to detect the ejectiles. The obtained results indicate of the important role played by the nuclear paring.

Resumen Se estudiaron reacciones de transferencia de dos neutrones inducidas por iones pesados (18O, 16O) a 84 MeV en varios blancos hasta una alta energía de excitación del núcleo residual gracias al uso del espectrómetro magnético MAGNEX para detectar los residuos eyectados. Los resultados obtenidos indican el importante papel desempeñado por el apareamiento nuclear.

The NUMEN project: Heavy-Ion Double Charge Exchange reactions towards 0νββ NME determination / El proyecto NUMEN: reacciones de intercambio de cargas dobles de iones pesados hacia la determinación de 0νββ NME

Abstract NUMEN proposes cross sections measurements of Heavy-Ion double charge exchange reactions as an innovative tool to access the nuclear matrix elements, entering the expression of the life time of Neutrinoless double beta decay (0νββ). A key aspect of the projectis the use at INFN-Laboratori Nazionali del Sud (LNS) of the Superconducting Cyclotron (CS) for the acceleration of the required high resolution and low emittance heavy-ion beams and of MAGNEX large acceptance magnetic spectrometer for the detection of the ejectiles. The experimental measurements of double charge exchange reactions induced by heavy ions present a number of challenging aspects, since such reactions are characterized by very low cross sections. First experimental results give encouraging indication on the capability to access quantitative information towards the determination of the Nuclear Matrix Elements for 0νββ decay.

Resumen NUMEN propone mediciones de secciones eficaces de reacciones de intercambio de carga doble de iones pesados como una herramienta innovadora para acceder a los elementos de la matriz nuclear, entrando en la expresión del tiempo de vida de la desintegración beta doble sin neutrino (0νββ). Un aspecto clave del proyecto es el uso en INFN-Laboratori Nazionali del Sud (LNS) del ciclotrón superconductor (CS) para la aceleración de los haces de iones pesados de alta resolución y baja emitancia requeridos y del espectrómetro magnético de gran aceptación MAGNEX para la detección de los residuos eyectados. Las mediciones experimentales de reacciones de intercambio de carga doble inducidas por iones pesados presentan una serie de aspectos desafiantes, ya que tales reacciones se caracterizan por secciones eficaces muy bajas. Los primeros resultados experimentales dan una indicación alentadora sobre la capacidad de acceder a información cuantitativa para la determinación de los Elementos de la Matriz Nuclear para la descomposición de 0νββ.

Detection of endocarditis bacteria in tonsillar mucosa of Afghan population.

Endocarditis is a cardiovascular disease caused by the inflammation of the inner tissues of the heart, the endocardium, usually of the valves. Bacteraemia is essential in the development of endocarditis, and there are some findings that the main pathogens of endocarditis are viridans group streptococci: Streptococcus oralis, Streptococcus sanguinis, and Enterococcus faecalis. There is strong evidence that endocarditis bacteria are present in the tonsillar microbiota, so that tonsillar infection is associated with an increased risk of endocarditis. The aim of this manuscript is to investigate the presence of the main pathogens of endocarditis in tonsillar microbiota of an Afghan population group. A sample of 80 tonsil swabs were analyzed by quantitative real time PCR to detect endocarditis pathogens and an estimation of the total bacterial load. The median bacterial load in PCR reaction was 1.4x106 (interquartile range 4,7x105 - 2,9x106). Three species, S. Oralis, S. Sanguinis, and E. Faecalis were found in large amounts in all specimens. On the other hand, S. Mitis was never detected. The S. Aureus was found in 3 samples with a prevalence of 0.04 (C.I. 0.01-0.10). The S. Mutans was found in 33 samples with a prevalence of 0.41 (C.I. 0.31-0.52). Endocarditis bacteria has been found into the tonsillar microbiota, so there is sufficient evidence to justify that the oral cavity is a reservoir of endocarditis bacteria that can have a significant impact on the cardiovascular function.

Human polyomavirus in tonsillar microbiota of an Afghan population group.

Some studies have evidenced the role of human polyomaviruses in head and neck squamous cell carcinoma. BK, JC and SV40 human polyoma viruses are widely recognized as etiological agents associated with malignancies. The aim of this study was to analyse the prevalence of BK, IC and SV40 in tonsillar microbiota in a group of Afghan volunteers. A sample of the tonsillar microbiota was taken from a single site using a sterile oral swab paper stick. A fixed volume of purified DNA from each sample was tested by quantitative real-time polymerase chain reactions to evaluate the number of human cells and the number of viral genomes in each sample. The cell number was evaluated via the quantification of a single copy genomic sequence, which is located in the HMBS locus. The median analyzed cell number in each reaction was 4343 (interquartile range 2074-8470). SV40 was never detected, while prevalence rate was 0.11 (C.I. 0.06-0.20) for BK and 0.10 (C.I. 0.05-0.19) for JC. Further studies are necessary to clarify whether polyomaviruses can be considered a risk factor of oral, oropharyngeal and laryngeal malignancies.

Human papilloma virus in the tonsillar microbiota of an Afghan population group.

Cancer of the oral cavity is known to have a diverse aetiology that includes infectious agents. Human papilloma virus has been found to be associated with several types of human cancer, inclusive of cervical, vulvar, vaginal, penile, anal, and cancer of tonsil. The aim of this manuscript is to investigate the presence of human papilloma virus in tonsillar microbiota of an Afghan population group. A sample of the tonsillar microbiota was collected by oral swab paper stick from 80 healthy donors. The sample was investigated for the presence of high-risk human papillomavirus types 16, 18, 31 and 45 by real time PCR. Eight samples produced some positive endpoint signals for human papillomaviruses. The human papillomavirus 31 was the unique papillomavirus detected; its calculated prevalence rate was 0.10 (C.I. 0.05-0.19). However, the viral load was always very low, in the order of 10-3 viral genomes per cell. The high prevalence of high-risk human papillomavirus in healthy population suggest a need for further investigation on virus spreading and supports the development of vaccination strategies.

Investigation of the

This Letter reports a study of the highly debated ^{10}Li structure through the d(^{9}Li,p)^{10}Li one-neutron transfer reaction at 100 MeV. The ^{10}Li energy spectrum is measured up to 4.6 MeV and angular distributions corresponding to different excitation energy regions are reported for the first time. The comparison between data and theoretical predictions, including pairing correlation effects, shows the existence of a p_{1/2} resonance at 0.45±0.03 MeV excitation energy, while no evidence for a significant s-wave contribution close to the threshold energy is observed. Moreover, two high-lying structures are populated at 1.5 and 2.9 MeV. The corresponding angular distributions suggest a significant s_{1/2} partial-wave contribution for the 1.5 MeV structure and a mixing of configurations at higher energy, with the d_{5/2} partial-wave contributing the most to the cross section.

High-Precision Probe of the Fully Sequential Decay Width of the Hoyle State in

The decay path of the Hoyle state in ^{12}C (E_{x}=7.654 MeV) has been studied with the ^{14}N(d,α_{2})^{12}C(7.654) reaction induced at 10.5 MeV. High resolution invariant mass spectroscopy techniques have allowed us to unambiguously disentangle direct and sequential decays of the state passing through the ground state of ^{8}Be. Thanks to the almost total absence of background and the attained resolution, a fully sequential decay contribution to the width of the state has been observed. The direct decay width is negligible, with an upper limit of 0.043% (95% C.L.). The precision of this result is about a factor 5 higher than previous studies. This has significant implications on nuclear structure, as it provides constraints to 3α cluster model calculations, where higher precision limits are needed.

Low-radio-frequency eclipses of the redback pulsar J2215+5135 observed in the image plane with LOFAR.

The eclipses of certain types of binary millisecond pulsars (i.e. 'black widows' and 'redbacks') are often studied using high-time-resolution, 'beamformed' radio observations. However, they may also be detected in images generated from interferometric data. As part of a larger imaging project to characterize the variable and transient sky at radio frequencies <200 MHz, we have blindly detected the redback system PSR J2215+5135 as a variable source of interest with the Low-Frequency Array (LOFAR). Using observations with cadences of two weeks - six months, we find preliminary evidence that the eclipse duration is frequency dependent (∝ν-0.4), such that the pulsar is eclipsed for longer at lower frequencies, in broad agreement with beamformed studies of other similar sources. Furthermore, the detection of the eclipses in imaging data suggests an eclipsing medium that absorbs the pulsed emission, rather than scattering it. Our study is also a demonstration of the prospects of finding pulsars in wide-field imaging surveys with the current generation of low-frequency radio telescopes.

New methods to constrain the radio transient rate: results from a survey of four fields with LOFAR.

We report on the results of a search for radio transients between 115 and 190 MHz with the LOw-Frequency ARray (LOFAR). Four fields have been monitored with cadences between 15 min and several months. A total of 151 images were obtained, giving a total survey area of 2275 deg2. We analysed our data using standard LOFAR tools and searched for radio transients using the LOFAR Transients Pipeline. No credible radio transient candidate has been detected; however, we are able to set upper limits on the surface density of radio transient sources at low radio frequencies. We also show that low-frequency radio surveys are more sensitive to steep-spectrum coherent transient sources than GHz radio surveys. We used two new statistical methods to determine the upper limits on the transient surface density. One is free of assumptions on the flux distribution of the sources, while the other assumes a power-law distribution in flux and sets more stringent constraints on the transient surface density. Both of these methods provide better constraints than the approach used in previous works. The best value for the upper limit we can set for the transient surface density, using the method assuming a power-law flux distribution, is 1.3 × 10-3 deg-2 for transients brighter than 0.3 Jy with a time-scale of 15 min, at a frequency of 150 MHz. We also calculated for the first time upper limits for the transient surface density for transients of different time-scales. We find that the results can differ by orders of magnitude from previously reported, simplified estimates.