BACKGROUNDPembrolizumab demonstrated durable antitumor activity in 233 patients with previously treated advanced microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) advanced ...solid tumors in the phase II multicohort KEYNOTE-158 (NCT02628067) study. Herein, we report safety and efficacy outcomes with longer follow-up for more patients with previously treated advanced MSI-H/dMMR noncolorectal cancers who were included in cohort K of the KEYNOTE-158 (NCT02628067) study. PATIENTS AND METHODSEligible patients with previously treated advanced noncolorectal MSI-H/dMMR solid tumors, measurable disease as per RECIST v1.1, and Eastern Cooperative Oncology Group performance status of 0 or 1 received pembrolizumab 200 mg Q3W for 35 cycles or until disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) as per RECIST v1.1 by independent central radiologic review. RESULTSThree hundred and fifty-one patients with various tumor types were enrolled in KEYNOTE-158 cohort K. The most common tumor types were endometrial (22.5%), gastric (14.5%), and small intestine (7.4%). Median time from first dose to database cut-off (5 October 2020) was 37.5 months (range, 0.2-55.6 months). ORR among 321 patients in the efficacy population (patients who received ≥1 dose of pembrolizumab enrolled ≥6 months before the data cut-off date) was 30.8% 95% confidence interval (CI) 25.8% to 36.2%. Median duration of response was 47.5 months (range, 2.1+ to 51.1+ months; '+' indicates no progressive disease by the time of last disease assessment). Median progression-free survival was 3.5 months (95% CI 2.3-4.2 months) and median overall survival was 20.1 months (95% CI 14.1-27.1 months). Treatment-related adverse events (AEs) occurred in 227 patients (64.7%). Grade 3-4 treatment-related AEs occurred in 39 patients (11.1%); 3 (0.9%) had grade 5 treatment-related AEs (myocarditis, pneumonia, and Guillain-Barre syndrome, n = 1 each). CONCLUSIONSPembrolizumab demonstrated clinically meaningful and durable benefit, with a high ORR of 30.8%, long median duration of response of 47.5 months, and manageable safety across a range of heavily pretreated, advanced MSI-H/dMMR noncolorectal cancers, providing support for use of pembrolizumab in this setting.
It is well established that the epidermal growth factor (EGF) receptor, receptor tyrosine-protein kinase erbB-2 (ERBB2)/human EGF receptor 2 (HER2), and, to a lesser extent, ERBB4/HER4, promote the ...pathogenesis of many types of human cancers. In contrast, the role that ERBB3/HER3, the fourth member of the ERBB family of receptor tyrosine kinases, plays in these diseases is poorly understood and, until recently, underappreciated. In large part, this was because early structural and functional studies suggested that ERBB3 had little, if any, intrinsic tyrosine kinase activity and, thus, was unlikely to be an important therapeutic target. Since then, however, numerous publications have demonstrated an important role for ERBB3 in carcinogenesis, metastasis, and acquired drug resistance. Furthermore, somatic ERBB3 mutations are frequently encountered in many types of human cancers. Dysregulation of ERBB3 trafficking as well as cooperation with other receptor tyrosine kinases further enhance ERBB3's role in tumorigenesis and drug resistance. As a result of these advances in our understanding of the structure and biochemistry of ERBB3, and a growing focus on the development of precision and combinatorial therapeutic regimens, ERBB3 is increasingly considered to be an important therapeutic target in human cancers. In this review, we discuss the unique structural and functional features of ERBB3 and how this information is being used to develop effective new therapeutic agents that target ERBB3 in human cancers.
Mean glandular dose (MGD) is the main dosimetric quantity in mammography. MGD evaluation is obtained by multiplying the entrance skin air kerma (ESAK) by normalized glandular dose (DgN) coefficients. ...While ESAK is an empirical quantity, DgN coefficients can only be estimated with Monte Carlo (MC) methods. Thus, a MC parameters benchmark is needed for effectively evaluating DgN coefficients. GEANT4 is a MC toolkit suitable for medical purposes that offers to the users several computational choices. In this work we investigate the GEANT4 performances testing the main PhysicsLists for medical applications. Four electromagnetic PhysicsLists were implemented: the linear attenuation coefficients were calculated for breast glandularity 0%, 50%, 100% in the energetic range 8-50 keV and DgN coefficients were evaluated. The results were compared with published data. Fit equations for the estimation of the G-factor parameter, introduced by the literature for converting the dose delivered in the heterogeneous medium to that in the glandular tissue, are proposed and the application of this parameter interaction-by-interaction or retrospectively is discussed. G4EmLivermorePhysicsList shows the best agreement for the linear attenuation coefficients both with theoretical values and published data. Moreover, excellent correlation factor (r2>0.99) is found for the DgN coefficients with the literature. The final goal of this study is to identify, for the first time, a benchmark of parameters that could be useful for future breast dosimetry studies with GEANT4.
We investigate linear, spin-field perturbations of Kerr black holes in the extremal limit throughout the complex-frequency domain. We calculate quasinormal modes of extremal Kerr as well as of ...near-extremal Kerr, via a novel approach: using the method of Mano, Suzuki, and Takasugi. We also show how, in the extremal limit, a branch cut is formed at the superradiant-bound frequency, ωSR, via a simultaneous accumulation of quasinormal modes and totally reflected modes. For real frequencies, we calculate the superradiant amplification factor, which yields the amount of rotational energy that can be extracted from a black hole. In the extremal limit, this factor is the largest, and it displays a discontinuity at ωSR for some modes. Finally, we find no exponentially growing modes nor branch points on the upper-frequency plane in extremal Kerr after a numerical investigation, thus providing evidence of the mode stability of this space-time away from the horizon.
Abstract
The Large Area Telescope (LAT) on board the Fermi Gamma-ray Space Telescope (Fermi) shows long-lasting high-energy emission in many gamma-ray bursts (GRBs), similar to X-ray afterglows ...observed by the Neil Gehrels Swift Observatory (Swift). Some LAT light curves (LCs) show a late-time flattening reminiscent of X-ray plateaus. We explore the presence of plateaus in LAT temporally extended emission analyzing GRBs from the second Fermi-LAT GRB Catalog from 2008 to 2016 May with known redshifts, and check whether they follow closure relations corresponding to four distinct astrophysical environments predicted by the external forward shock model. We find that three LCs can be fit by the same phenomenological model used to fit X-ray plateaus and show tentative evidence for the existence of plateaus in their high-energy extended emission. The most favorable scenario is a slow-cooling regime, whereas the preferred density profile for each GRBs varies from a constant-density interstellar medium to an
r
−2
wind environment. We also compare the end time of the plateaus in
γ
-rays and X-rays using a statistical comparison with 222 Swift GRBs with plateaus and known redshifts from 2005 January to 2019 August. Within this comparison, the case of GRB 090510 shows an indication of chromaticity at the end time of the plateau. Finally, we update the 3D fundamental plane relation among the rest-frame end time of the plateau, its correspondent luminosity, and the peak prompt luminosity for 222 GRBs observed by Swift. We find that these three LAT GRBs follow this relation.
Monozygotic (MZ) twins are partially concordant for most complex diseases, including autoimmune disorders. Whereas phenotypic concordance can be used to study heritability, discordance suggests the ...role of non-genetic factors. In autoimmune diseases, environmentally driven epigenetic changes are thought to contribute to their etiology. Here we report the first high-throughput and candidate sequence analyses of DNA methylation to investigate discordance for autoimmune disease in twins. We used a cohort of MZ twins discordant for three diseases whose clinical signs often overlap: systemic lupus erythematosus (SLE), rheumatoid arthritis, and dermatomyositis. Only MZ twins discordant for SLE featured widespread changes in the DNA methylation status of a significant number of genes. Gene ontology analysis revealed enrichment in categories associated with immune function. Individual analysis confirmed the existence of DNA methylation and expression changes in genes relevant to SLE pathogenesis. These changes occurred in parallel with a global decrease in the 5-methylcytosine content that was concomitantly accompanied with changes in DNA methylation and expression levels of ribosomal RNA genes, although no changes in repetitive sequences were found. Our findings not only identify potentially relevant DNA methylation markers for the clinical characterization of SLE patients but also support the notion that epigenetic changes may be critical in the clinical manifestations of autoimmune disease.
Infections caused by parasitic flatworms impose a considerable worldwide health burden. Recently, World Health Organization launched its roadmap for neglected diseases for the period 2021 to 2030 and ...oral treatment with praziquantel (PZQ) in tablet form is the main drug therapy for combating these diseases, but its use is limited by many drawbacks, including the high therapeutic dose due to the drug's low solubility and bioavailability. Among the strategies to improve PZQ performance, the use of drug nanocarriers has been cited as an interesting approach to overcome these pharmacological issues.
This review focuses on the various types of nanomaterials (polymeric, lipidic, inorganic nanoparticles, and nanocrystals) which have been recently used to improve PZQ therapy. In addition, recent advances in PZQ nanoformulations, developed to overcome the barriers of the conventional drug are described.
Considering the poor rate of discovery in the anthelmintic segment observed in recent decades, the effective management of existing drugs has become essential. The application of new strategies based on nanotechnology can extend the useful life of PZQ in new and more effective formulations. Pharmaceutical nanotechnology can solve the pharmacokinetic challenges characteristic of PZQ and improve its solubility and bioavailability.
ABSTRACT We report the Fermi Large Area Telescope (LAT) detections of high-energy (>100 MeV) γ-ray emission from two recent optically bright classical novae, V1369 Centauri 2013 and V5668 Sagittarii ...2015. At early times, Fermi target-of-opportunity observations prompted by their optical discoveries provided enhanced LAT exposure that enabled the detections of γ-ray onsets beginning ∼2 days after their first optical peaks. Significant γ-ray emission was found extending to 39-55 days after their initial LAT detections, with systematically fainter and longer-duration emission compared to previous γ-ray-detected classical novae. These novae were distinguished by multiple bright optical peaks that encompassed the time spans of the observed γ-rays. The γ-ray light curves and spectra of the two novae are presented along with representative hadronic and leptonic models, and comparisons with other novae detected by the LAT are discussed.
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