Summary
We performed a retrospective study analysing the effect of sorafenib, an oral fms‐Like Tyrosine Kinase 3 (FLT3)/multikinase inhibitor, as post‐transplant maintenance in adult patients with ...FLT3‐internal tandem duplication (ITD) acute myeloid leukaemia (AML). We identified consecutive patients with FLT3‐ITD AML diagnosed between 2008 and 2014 who received haematopoietic cell transplantation (HCT) in first complete remission (CR1). Post‐HCT initiation of sorafenib (yes/no) was evaluated as a time‐varying covariate in the overall survival/progression‐free survival (OS/PFS) analysis and we performed a landmark analysis of controls alive without relapse at the median date of sorafenib initiation. We identified 26 sorafenib patients and 55 controls. Median follow‐up was 27·2 months post‐HCT for sorafenib survivors, and 38·4 months for controls (P = 0·021). The median time to initiating sorafenib was 68 days post‐HCT; 43 controls were alive without relapse at this cut‐off. Sorafenib patients had improved 2‐year OS in the d+68 landmark analysis (81% vs. 62%, P = 0·029). Sorafenib was associated with improved 2‐year PFS (82% vs. 53%, P = 0·0081) and lower 2‐year cumulative incidence of relapse (8·2% vs. 37·7%, P = 0·0077). In multivariate analysis, sorafenib significantly improved OS Hazard ratio (HR) 0·26, P = 0·021 and PFS (HR 0·25, P = 0·016). There was no difference in 2‐year non‐relapse mortality (9·8% vs. 9·3%, P = 0·82) or 1‐year chronic graft‐versus‐host disease (55·5% vs. 37·2%, P = 0·28). These findings suggest potential benefit of post‐HCT sorafenib in FLT3‐ITD AML, and support further evaluation of post‐HCT FLT3 inhibition.
Mutations of genes encoding isocitrate dehydrogenase (IDH1 and IDH2) have been recently described in acute myeloid leukemia (AML). Serum and myeloblast samples from patients with IDH-mutant AML ...contain high levels of the metabolite 2-hydroxyglutarate (2-HG), a product of the altered IDH protein. In this prospective study, we sought to determine whether 2-HG can potentially serve as a noninvasive biomarker of disease burden through serial measurements in patients receiving conventional therapy for newly diagnosed AML. Our data demonstrate that serum, urine, marrow aspirate, and myeloblast 2-HG levels are significantly higher in IDH-mutant patients, with a correlation between baseline serum and urine 2-HG levels. Serum and urine 2-HG, along with IDH1/2-mutant allele burden in marrow, decreased with response to treatment. 2-HG decrease was more rapid with induction chemotherapy compared with DNA-methyltransferase inhibitor therapy. Our data suggest that serum or urine 2-HG may serve as noninvasive biomarkers of disease activity for IDH-mutant AML.
The ever-increasing growth of user demand, the limitations of the third generation of wireless mobile communication systems, and the emergence of new mobile broadband technologies on the market have ...brought researchers and industries to a thorough reflection on the fourth generation. Many prophetic visions have appeared in the literature presenting 4G as the ultimate boundary of wireless mobile communication without any limit to its potential, but in practical terms not giving any design rules and thus any definition of it. In this article we give a pragmatic definition of 4G derived from a new user-centric methodology that considers the user as the "cornerstone" of the design. In this way, we devise fundamental user scenarios that implicitly reveal the key features of 4G, which are then expressed explicitly in a new framework - the "user-centric" system - that describes the various level of interdependency among them. This approach consequently contributes to the identification of the real technical step-up of 4G with respect to 3G. Finally, an example of a potential 4G application is also given in order to demonstrate the validity of the overall methodology
We apply the complex de Broglie–Bohm formulation of quantum mechanics in Chou and Wyatt (Phys Rev A 76: 012115,
2007
), Gozzi (Phys Lett B 165: 351,
1985
), Bhalla et al. (Am J Phys 65: 1187,
1997
) ...to a spatially closed homogeneous and isotropic early universe whose matter contents are radiation and dust perfect fluids. We then show that an expanding classical universe can emerge from an oscillating (with complex scale factor) quantum universe without singularity. Furthermore, the universe obtained in this process has no horizon or flatness problems.
Lung cancer screening (LCS) has the potential to reduce the risk of lung cancer death in healthy individuals, but the impact of coexisting chronic illnesses on LCS outcomes has not been well defined. ...Consideration of the complex relationship between baseline risk of lung cancer, treatment-related harms, and risk of death from competing causes is crucial in determining the balance of benefits and harms of LCS.
To summarize evidence, identify knowledge and research gaps, prioritize topics, and propose methods for future research on how best to incorporate comorbidities in making decisions regarding LCS.
A multidisciplinary group of international clinicians and researchers reviewed available data on the effects of comorbidities on LCS outcomes, focusing on the juxtaposition of lung cancer risk and competing risks of death, consideration of benefits and risks in patients with chronic obstructive pulmonary disease, communication of risk, and treatment of screen-detected lung cancer.
This statement identifies gaps in knowledge regarding how comorbidities and competing causes of death impact outcomes in LCS, and we have developed questions to help guide future research efforts to better inform patient selection, education, and implementation of LCS.
There is an urgent need for further research that can help guide clinical decision-making with patients who may not benefit from LCS owing to coexisting chronic illness. This statement establishes a research framework to address essential questions regarding how to incorporate and communicate risks of comorbidities into patient selection and decisions regarding LCS.
Context. The nearby Sy 1 galaxy NGC 1097 represents an ideal laboratory for exploring the molecular chemistry in the surroundings of an active galactic nucleus (AGN). Aims. Exploring the distribution ...of different molecular species allows us to understand the physical processes affecting the interstellar medium both in the AGN vicinity and in the outer star forming molecular ring. Methods. We carried out 3 mm ALMA observations that include seven different molecular species, namely HCN, HCO+, CCH, CS, HNCO, SiO, HC3N, and SO, as well as the 13C isotopologues of the first two. Spectra were extracted from selected positions and all species were imaged over the central 2 kpc (~30′′) of the galaxy at a resolution of ~2.2′′ × 1.5′′ (150 pc × 100 pc). Results. HCO+ and CS appear to be slightly enhanced in the star forming ring. CCH shows the largest variations across NGC 1097 and is suggested to be a good tracer of both obscured and early stage star formation. HNCO, SiO, and HC3N are significantly enhanced in the inner circumnuclear disk surrounding the AGN. Conclusions. Differences in the molecular abundances are observed between the star forming ring and the inner circumnuclear disk. We conclude that the HCN/HCO+ and HCN/CS differences observed between AGN-dominated and starburst (SB) galaxies are not due to a HCN enhancement due to X-rays, but rather this enhancement is produced by shocked material at distances of 200 pc from the AGN. Additionally, we claim that lower HCN/CS is a combination of a small underabundance of CS in AGNs, together with excitation effects, where a high density gas component (~106 cm-3) may be more prominent in SB galaxies. However, the most promising are the differences found among the dense gas tracers that, at our modest spatial resolution, seem to outline the physical structure of the molecular disk around the AGN. In this picture, HNCO probes the well-shielded gas in the disk, surrounding the dense material moderately exposed to the X-ray radiation traced by HC3N. Finally SiO might be the innermost molecule in the disk structure.
Abstract
BACKGROUND
Although World Health Organization (WHO) grade I meningiomas are considered “benign” tumors, an elevated Ki-67 is one crucial factor that has been shown to influence tumor ...behavior and clinical outcomes. The ability to preoperatively discern Ki-67 would confer the ability to guide surgical strategy.
OBJECTIVE
In this study, we develop a machine learning (ML) algorithm using radiomic feature analysis to predict Ki-67 in WHO grade I meningiomas.
METHODS
A retrospective analysis was performed for a cohort of 306 patients who underwent surgical resection of WHO grade I meningiomas. Preoperative magnetic resonance imaging was used to perform radiomic feature extraction followed by ML modeling using least absolute shrinkage and selection operator wrapped with support vector machine through nested cross-validation on a discovery cohort (n = 230), to stratify tumors based on Ki-67 <5% and ≥5%. The final model was independently tested on a replication cohort (n = 76).
RESULTS
An area under the receiver operating curve (AUC) of 0.84 (95% CI: 0.78-0.90) with a sensitivity of 84.1% and specificity of 73.3% was achieved in the discovery cohort. When this model was applied to the replication cohort, a similar high performance was achieved, with an AUC of 0.83 (95% CI: 0.73-0.94), sensitivity and specificity of 82.6% and 85.5%, respectively. The model demonstrated similar efficacy when applied to skull base and nonskull base tumors.
CONCLUSION
Our proposed radiomic feature analysis can be used to stratify WHO grade I meningiomas based on Ki-67 with excellent accuracy and can be applied to skull base and nonskull base tumors with similar performance achieved.
Solid Lipid Nanoparticles (SLN) and Nanostructured Lipid Carriers (NLC) are receiving increasing interest as an approach to encapsulate natural extracts to increase the physicochemical stability of ...bioactives. Cannabis extract-derived cannabidiol (CBD) has potent therapeutic properties, including anti-inflammatory, antioxidant, and neuroprotective properties. In this work, physicochemical characterization was carried out after producing Compritol-based nanoparticles (cSLN or cNLC) loaded with CBD. Then, the determination of the encapsulation efficiency (EE), loading capacity (LC), particle size (Z-Ave), polydispersity index (PDI), and zeta potential were performed. Additionally, the viscoelastic profiles and differential scanning calorimetry (DSC) patterns were recorded. As a result, CBD-loaded SLN showed a mean particle size of 217.2 ± 6.5 nm, PDI of 0.273 ± 0.023, and EE of about 74%, while CBD-loaded NLC showed Z-Ave of 158.3 ± 6.6 nm, PDI of 0.325 ± 0.016, and EE of about 70%. The rheological analysis showed that the loss modulus for both lipid nanoparticle formulations was higher than the storage modulus over the applied frequency range of 10 Hz, demonstrating that they are more elastic than viscous. The crystallinity profiles of both CBD-cSLN (90.41%) and CBD-cNLC (40.18%) were determined. It may justify the obtained encapsulation parameters while corroborating the liquid-like character demonstrated in the rheological analysis. Scanning electron microscopy (SEM) study confirmed the morphology and shape of the developed nanoparticles. The work has proven that the solid nature and morphology of cSLN/cNLC strengthen these particles' potential to modify the CBD delivery profile for several biomedical applications.
Current genetic data are equivocal as to whether goat domestication occurred multiple times or was a singular process. We generated genomic data from 83 ancient goats (51 with genome-wide coverage) ...from Paleolithic to Medieval contexts throughout the Near East. Our findings demonstrate that multiple divergent ancient wild goat sources were domesticated in a dispersed process that resulted in genetically and geographically distinct Neolithic goat populations, echoing contemporaneous human divergence across the region. These early goat populations contributed differently to modern goats in Asia, Africa, and Europe. We also detect early selection for pigmentation, stature, reproduction, milking, and response to dietary change, providing 8000-year-old evidence for human agency in molding genome variation within a partner species.
In this study, hydroxyapatite (HA), bredigite (BR) and hydroxyapatite/bredigite (HABR) (50/50) nanoparticles were synthesized using sol–gel method and characterized by X-ray diffractometer (XRD) and ...Transmission electron microscopy (TEM). Poly(3-hydroxybutyrate-co-3-hydroxyvalerate) or PHBV nanofibers containing different concentrations (0, 5, 10 and 15%) of HA or BR or HABR nanoparticles were prepared by electrospinning process. Physiochemical properties of the prepared nanofibers were evaluated by scanning electron microscopy (SEM), Fourier transform infrared (FT-IR) and differential scanning calorimetry (DSC). Evaluation of their mechanical properties showed that the addition of 10% of any one of the above mentioned nanoparticles to PHBV produced composite nanofibers with regard to their tensile strength and Young's modulus. PHBV containing either 10% HA or 10% HABR showed higher mechanical strength and Young's modulus than the PHBV fibers incorporated with 10% BR. At the same time, studies on the ability of bone formation of the nanofibers in simulated body fluid (SBF) confirmed higher bone-like apatite formation on PHBV fibers containing either 10% HABR or BR compared to the HA composite. We concluded that the 10% HABR incorporated PHBV nanofibers possess optimized mechanical properties with high ability for apatite formation, thus potentially suitable as a novel substrate for bone regeneration application compared to the most commonly studied HA composite fibers.
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