Extensive molecular characterization of human colorectal cancer (CRC) via Next Generation Sequencing (NGS) indicated that genetic or epigenetic dysregulation of a relevant, but limited, number of ...molecular pathways typically occurs in this tumor. The molecular picture of the disease is significantly complicated by the frequent occurrence of individually rare genetic aberrations, which expand tumor heterogeneity. Inter- and intratumor molecular heterogeneity is very likely responsible for the remarkable individual variability in the response to conventional and target-driven first-line therapies, in metastatic CRC (mCRC) patients, whose median overall survival remains unsatisfactory. Implementation of an extensive molecular characterization of mCRC in the clinical routine does not yet appear feasible on a large scale, while multigene panel sequencing of most commonly mutated oncogene/oncosuppressor hotspots is more easily achievable. Here, we report that clinical multigene panel sequencing performed for anti-EGFR therapy predictive purposes in 639 formalin-fixed paraffin-embedded (FFPE) mCRC specimens revealed previously unknown pairwise mutation associations and a high proportion of cases carrying actionable gene mutations. Most importantly, a simple principal component analysis directed the delineation of a new molecular stratification of mCRC patients in eight groups characterized by non-random, specific mutational association patterns (MAPs), aggregating samples with similar biology. These data were validated on a The Cancer Genome Atlas (TCGA) CRC dataset. The proposed stratification may provide great opportunities to direct more informed therapeutic decisions in the majority of mCRC cases.
To evaluate the prognostic stratification ability of 4C Mortality Score and COVID-19 Mortality Risk Score in different age groups. Retrospective study, including all patients, presented to the ...Emergency Department of the University Hospital Careggi, between February, 2020 and May, 2021, and admitted for SARS-CoV2. Patients were divided into four subgroups based on the quartiles of age distribution: patients < 57 years (G1, n = 546), 57-71 years (G2, n = 508), 72-81 years (G3, n = 552), and > 82 years (G4, n = 578). We calculated the 4C Mortality Score and COVID-19 Mortality Risk Score. The end-point was in-hospital mortality. In the whole population (age 68 ± 16 years), the mortality rate was 19% (n = 424), and increased with increasing age (G1: 4%, G2: 11%, G3: 22%, and G4: 39%, p < 0.001). Both scores were higher among non-survivors than survivors in all subgroups (4C-MS, G1: 6 3-7 vs 3 2-5; G2: 10 7-11 vs 7 5-8; G3: 11 10-14 vs 10 8-11; G4: 13 12-15 vs 11 10-13, all p < 0.001; COVID-19 MRS, G1: 8 7-9 vs 9 9-11, G2: 10 8-11 vs 11 10-12; G3: 11 10-12 vs 12 11-13; G4: 11 10-13 vs 13 12-14, all p < 0.01). The ability of both scores to identify patients at higher risk of in-hospital mortality, was similar in different age groups (4C-MS: G1 0.77, G2 0.76, G3 0.68, G4 0.72; COVID-19 MRS: G1 0.67, G2 0.69, G3 0.69, G4 0.72, all p for comparisons between subgroups = NS). Both scores confirmed their good performance in predicting in-hospital mortality in all age groups, despite their different mortality rate.
A complete ultrasound examination (cUS) of the liver was performed on 172 female sheep and compared to the performance of a fast-focused ultrasound technique to diagnose echinococcal cysts. The ...scanned area was divided in: HYP (right hypocondrium), zone (Z)1 from HYP to the 11th intercostal space (IS), Z2 (10th-8th IS) and Z3 (7th-5th IS). Contiguous scans were also examined (HYP + Z1, Z1 + Z2, Z2 + Z3). Furthermore, during the procedures, the sheep were divided into three groups according to the body weight: Group (G) 1 (lighter), G2 (medium), and G3 (heavier). Finally, diagnostic outcomes were compared with necropsy findings. cUS obtained the highest values of sensitivity (Se) (91%), Specificity (Sp) (80%), and positive-zones (124/138, 90%), as compared to the other scans. cUS was also characterized by high values of Se and Sp and was able to identify a great number of positive-zones, when sheep were divided by body-weight groups. Similar performances were obtained in G1 by HYP (Se: 91%-Sp: 82%; 18/20, 90% of positive-zones) and HYP + Z1 scans (Se: 91%-Sp: 82; 90% of positive-zones, 18/20). Thus, in lighter breeds, the examination of HYP and HYP + Z1 scan windows could be considered reliable techniques for identifying the infected animals, while in heavier sheep the cUS still represents the best option.
ABSTRACT The HARPS spectrograph is showing an extreme stability, close to the m s−1 level, over more than 10 years of data. However, the radial velocities of some stars are contaminated by a spurious ...one-year signal with an amplitude that can be as high as a few m s−1. This signal is in opposition of phase with the revolution of Earth around the Sun and can be explained by the deformation of spectral lines crossing block stitchings of the CCD when the spectrum of an observed star is alternatively blueshifted and redshifted due to the motion of Earth around the Sun. This annual perturbation can be suppressed by either removing those affected spectral lines from the correlation mask used by the cross-correlation technique to derive precise radial velocities, or by simply fitting a yearly sinusoid to the radial velocity data. This is mandatory if we want to detect long-period low-amplitude signals in the HARPS radial velocities of quiet solar-type stars.
Meningiomas are common brain tumors that arise from the meningeal membranes that envelope the brain and spinal cord. The World Health Organization classifies these tumors into three histopathological ...grades. Because of tumor recurrence, treating meningiomas may be challenging even in well-differentiated grade I (GI) neoplasms. Indeed, around 5% of completely resected GI meningiomas relapse within 5 years. Therefore, identifying driver mutations in GI meningiomas through next generation sequencing (NGS) assays is paramount. The aim of this study was to validate the use of the 50-gene AmpliSeq Hotspot Cancer Panel v2 to identify the mutational status of 23 GI meningioma, namely, 12 non recurrent and 11 recurrent. In 18 out of the 23 GI meningiomas analyzed, we identified at least one gene mutation (78.2%). The most frequently mutated genes were c-kit (39.1%), ATM (26.1%), TP53 (26.1%), EGFR (26.1%), STK11 (21.7%), NRAS (17.4%), SMAD4 (13%), FGFR3 (13%), and PTPN11 (13%); less frequent mutations were SMARCB1 (8.7%), FLT3 (8.7%), KRAS (8.7%), FBWX7 (8.7%), ABL1 (8.7%), ERBB2 (8.7%), IDH1 (8.7%), BRAF (8.7%), MET (8.7%), HRAS (4.3%), RB1 (4.3%), CTNNB1 (4.3%), PIK3CA (4.3%), VHL (4.3%), KDR (4.3%), APC (4.3%), NOTCH1 (4.3%), JAK3 (4.3%), and SRC (4.3%). To our knowledge, mutations in all of these genes, except for TP53, STK11, SMARCB1, PIK3CA, VHL, and BRAF, have never been described before in meningiomas. Hence, these findings demonstrate the viability of NGS to detect new genetic alterations in GI meningiomas. Equally important, this technology enabled us to detect possible novel actionable mutations not previously associated with GI and for which selective inhibitors already exist.
The differential outcomes across the age spectrum of transcatheter aortic valve implantation (TAVI) recipients are still debated. Aim of the study was to evaluate the clinical outcomes of oldest-old ...patients undergoing TAVI in the large “Registro Italiano GISE sull'impianto di Valvola Aortica Percutanea (RISPEVA)” registry. A total of 3,507 patients were stratified according to age: 1,381 were ≥85 years, 2,126 were <85 years. Primary endpoints were death at 30-days and complete follow-up (FU) (medium 368 days). Cerebrovascular events, myocardial infarction, bleedings, vascular complications at 30-days and complete FU were considered. In the unadjusted analysis, 30-days mortality in the oldest-old group was higher than in younger patients (4.2% vs 2.4%; p = 0.007); this difference kept true also at complete FU (19.6% vs 15.9%; p = 0.014). After propensity score (PS) matching, the oldest-old population showed a higher mortality solely at 30-days (4.7% vs 2.4%; p = 0.016), while the survival at complete FU was similar to that of younger patients (20.1% vs 18.0%; p = 0.286). The incidence of non-fatal outcomes resulted comparable between the 2 groups, also after propensity score matching. At the multivariate logistic regression analysis procedural major or disabling bleedings, cerebrovascular events, cardiogenic shock resulted predictors of 30-days death in the oldest-old cohort. In conclusion, patients ≥85 years can safely undergo TAVI being not more exposed to procedural complications than those <85 years; nevertheless they showed worse 30-days mortality, probably driven by reduced tolerance to complications. Passed the critical periprocedural phase, patients ≥85 years had a similar survival to those <85 years with comparable risk profile.
ABSTRACT
A dozen short-period detached binaries are known to host transiting circumbinary planets. In all circumbinary systems so far, the planetary and binary orbits are aligned within a couple of ...degrees. However, the obliquity of the primary star, which is an important tracer of their formation, evolution, and tidal history, has only been measured in one circumbinary system until now. EBLM J0608-59/TOI-1338 is a low-mass eclipsing binary system with a recently discovered circumbinary planet identified by TESS. Here, we perform high-resolution spectroscopy during primary eclipse to measure the projected stellar obliquity of the primary component. The obliquity is low, and thus the primary star is aligned with the binary and planetary orbits with a projected spin–orbit angle β = 2${_{.}^{\circ}}$8 ± 17${_{.}^{\circ}}$1. The rotation period of 18.1 ± 1.6 d implied by our measurement of vsin i⋆ suggests that the primary has not yet pseudo-synchronized with the binary orbit, but is consistent with gyrochronology and weak tidal interaction with the binary companion. Our result, combined with the known coplanarity of the binary and planet orbits, is suggestive of formation from a single disc. Finally, we considered whether the spectrum of the faint secondary star could affect our measurements. We show through simulations that the effect is negligible for our system, but can lead to strong biases in vsin i⋆ and β for higher flux ratios. We encourage future studies in eclipse spectroscopy test the assumption of a dark secondary for flux ratios ≳1 ppt.
Osimertinib showed great clinical efficacy for activated-EGFR NCLC patient treatment. The aim of this work was to test the efficacy of a complete EGFR-inhibition by osimertinib plus the monoclonal ...antibody cetuximab or the MEK1/2-inhibitor selumetinib in EGFR-mutated NCLC in vivo models.
We evaluated combinations of osimertinib plus selumetinib/cetuximab in HCC827 (E746-A759del/T790M-), H1975 (L858R/T790M+), and PC9-T790M (E746-A759del /T790M+) xenografts in second-line therapy after the development of resistance to osimertinib, and in first-line therapy, and we explored mechanisms of resistance to these treatments.
The addition of selumetinib or cetuximab to osimertinib in second-line therapy reverted the sensibility to osimertinib in the majority of mice, with a response rate (RR) of 50% to 80%, and a median progression-free survival (mPFS) of first- plus second-line of therapy of 28 weeks. The early use of combinations in first-line therapy increased the RR to 90%, with an mPFS not reached in all combination arms in the three xenografts models, with a statistically significant superiority (p < 0.005) as compared to osimertinib, achieving in first-line therapy an mPFS time of 17 to 18 weeks. Moreover, in ex vivo primary cell cultures obtained from osimertinib plus selumetinib-resistant tumors, we found Hedgehog pathway activation and we showed that therapy with an SMO inhibitor plus osimertinib and selumetinib inhibited proliferation and migratory and invasive properties of resistant cells.
We showed that a dual vertical EGFR blockade with osimertinib plus selumetinib/cetuximab is a novel effective therapeutic option in EGFR-mutated NCLC and that hedgehog pathway activation and its interplay with MAPK is involved in resistance to these combination treatments.
Despite its high content of flavonoids, bergamot (Citrus bergamia) juice, is considered a waste product of the essential oil industry. In the present contribution, the potential of bergamot juice ...against inflammation process is highlighted. After a fast and accurate characterization, by a novel UHPLC-IT-TOF platform, we evaluated the in vitro effect of bergamot juice against inflammatory response induced by Escherichia coli lipopolysaccharide (LPS) in J774A.1 murine macrophages. Bergamot juice reduced reactive oxygen species (ROS) release and other important pro-inflammatory mediators, such as nitric oxide (NO), inducible nitric oxide synthase (iNOS) and cycloxygenase-2 (COX-2) protein expression. Moreover, the cytoprotective haem-oxygenase-1 (OH-1) enzyme expression in LPS-stimulated J774A.1 macrophages was enhanced. Our results demonstrated that bergamot juice acts as antioxidant and anti-inflammatory agent in LPS-treated J774A.1 macrophages.
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