Purpose This phase III study evaluated ribociclib plus fulvestrant in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer who were ...treatment naïve or had received up to one line of prior endocrine therapy in the advanced setting. Patients and Methods Patients were randomly assigned at a two-to-one ratio to ribociclib plus fulvestrant or placebo plus fulvestrant. The primary end point was locally assessed progression-free survival. Secondary end points included overall survival, overall response rate, and safety. Results A total of 484 postmenopausal women were randomly assigned to ribociclib plus fulvestrant, and 242 were assigned to placebo plus fulvestrant. Median progression-free survival was significantly improved with ribociclib plus fulvestrant versus placebo plus fulvestrant: 20.5 months (95% CI, 18.5 to 23.5 months) versus 12.8 months (95% CI, 10.9 to 16.3 months), respectively (hazard ratio, 0.593; 95% CI, 0.480 to 0.732; P < .001). Consistent treatment effects were observed in patients who were treatment naïve in the advanced setting (hazard ratio, 0.577; 95% CI, 0.415 to 0.802), as well as in patients who had received up to one line of prior endocrine therapy for advanced disease (hazard ratio, 0.565; 95% CI, 0.428 to 0.744). Among patients with measurable disease, the overall response rate was 40.9% for the ribociclib plus fulvestrant arm and 28.7% for placebo plus fulvestrant. Grade 3 adverse events reported in ≥ 10% of patients in either arm (ribociclib plus fulvestrant v placebo plus fulvestrant) were neutropenia (46.6% v 0%) and leukopenia (13.5% v 0%); the only grade 4 event reported in ≥ 5% of patients was neutropenia (6.8% v 0%). Conclusion Ribociclib plus fulvestrant might represent a new first- or second-line treatment option in hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer.
Although bioinert titanium has been widely applied in orthopedics and related fields, its usage is limited by its unsatisfying osteoinductivity, anti-infection capability, and wear-resistance. ...Osteoinductive apatite coating can be fabricated on a titanium surface by electrochemical methods, but this causes bacterial adhesion and poor wear-resistance. On the basis of pulse electrochemical technology, a wear-resistance and antibacterial osteoinductive coating was fabricated through codeposition of hydroxyapatite (HA) and nano-Ag effectuated by the cohybridization ofchitosan (CS) with Ag+ and Ca2+. A composite coating formed with uniformly dispersed spherical nanoparticles was obtained at optimized deposition potential, Ag concentration, and apatite concentration. The nanocomposite coating shows excellent bioinductive activity; it promotes preferential growth on the (002) face, and needle-like ordered arrangement of apatite. Due to the mediation of CS hybridization, a compact structure is achieved in the HA/Ag composite coating which significantly enhances the wear-resistance of the coating and reduces the release of Ca2+ and Ag+. The antibacterial rate of the coating on Escherichia coli and Staphylococcus aureus is up to 99% according to the antibacterial test. In conclusion, a wear-resistant and long-term antibacterial bioactive nanocomposite coating is successfully fabricated on titanium surface through the strategy established in this study.
Abstract
Flat bands in Van der Waals heterostructure provide an ideal platform for unveiling emergent quantum electronic phases. One celebrated example is twisted monolayer-bilayer graphene, in which ...the effects of electronic correlation have been observed. Here, we report the observation via scanning tunnelling microscopy and spectroscopy of correlated insulating states in twisted monolayer-bilayer graphene, leading to the formation of an electron crystal phase. At integer fillings, the strong Coulomb interaction redistributes flat-band electrons within one moiré unit cell, producing an insulating state with vanishing density of states at the Fermi level. Moreover, our approach enables the direct visualization of an ordered lattice of topological torus-shaped states, generated by the interaction between the electron crystal and the non-trivial band topology of twisted monolayer-bilayer graphene. Our results illustrate an efficient strategy for entwining topological physics with strong electron correlation in twisted van der Waals structures.
Canine distemper virus (CDV) is the causative agent of canine distemper (CD) that is a highly contagious, lethal, multisystemic viral disease of receptive carnivores. The prevalence of CDV is a major ...concern in susceptible animals. Presently, it is unclear whether intragenic recombination can contribute to gene mutations and segment reassortment in the virus. In this study, 25 full-length CDV genome sequences were subjected to phylogenetic and recombinational analyses. The results of phylogenetic analysis, intragenic recombination, and nucleotide selection pressure indicated that mutation and recombination occurred in the six individual genes segment (H, F, P, N, L, M) of the CDV genome. The analysis also revealed pronounced genetic diversity in the CDV genome according to the geographically distinct lineages (genotypes), namely Asia-1, Asia-2, Asia-3, Europe, America-1, and America-2. The six recombination events were detected using SimPlot and RDP programs. The analysis of selection pressure demonstrated that a majority of the nucleotides in the CDV individual gene were under negative selection. Collectively, these data suggested that homologous recombination acts as a key force driving the genetic diversity and evolution of canine distemper virus.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Antenatal corticosteroid therapy (ACT) is used clinically to prepare the fetal lung for impending preterm birth, but animal and human studies link corticosteroids to smaller birth size. Whether ACT ...is associated with birth size is debated; therefore, we assessed differences in birth size in treated versus untreated pregnancies.
This observational register-based study used data from the Finnish Medical Birth Register (FMBR) covering all births in Finland (January 1, 2006-December 31, 2010). We used unadjusted and adjusted regression analyses as well as propensity score matching (PSM) to analyze whether birth size differed by ACT exposure. PSM provides a stringent comparison, as subsamples were created matched on baseline and medical characteristics between treated and untreated women. All analyses were stratified by timing of birth. The primary study outcome was birth size: birth weight (BWT), birth length (BL), ponderal index (PI), and head circumference (HC) measured immediately after birth and recorded in the FMBR. Additional analyses explored indicators of neonatal health in relation to ACT exposure and birth size. A total of 278,508 live-born singleton births with ≥24 gestational completed weeks were registered in the FMBR during the 5-year study period. Over 4% of infants were born preterm, and 4,887 women were treated with ACT (1.75%). More than 44% of the exposed infants (n = 2,173) were born at term. First, results of unadjusted regression analyses using the entire sample showed the greatest reductions in BWT as compared to the other analytic methods: very preterm -61.26 g (±SE 24.12, P < 0.01), preterm -232.90 g (±SE 17.24, P < .001), near term -171.50 g (±SE 17.52, P < .001), and at term -101.95 g (±SE 10.89, P < .001). Second, using the entire sample, regression analyses adjusted for baseline and medical conditions showed significant differences in BWT between exposed and unexposed infants: very preterm -61.54 g (±SE 28.62, P < .03), preterm -222.78 g (±SE 19.64, P < .001), near term -159.25 g (±SE 19.14, P < .001), and at term -91.62 g (±SE 11.86, P < .03). Third, using the stringent PSM analyses based on matched subsamples, infants exposed to ACT weighed less at birth: -220.18 g (±SE 21.43, P < .001), -140.68 g (±SE 23.09, P < .001), and -89.38 g (±SE 14.16, P < .001), born preterm, near term, and at term, respectively. Similarly, significant reductions in BL and HC were also observed using the three analytic methods. There were no differences among postterm infants regardless of analytic method. Likewise, we observed no differences with respect to PI. Additional analyses showed that exposed and unexposed infants had generally similar Apgar scores at birth, yet the ACT-treated infants received greater medical care during the first 7 days of life and beyond. Our study is mainly limited by lack of data in FMBR specifying the interval between treatment and birth as well as other potential confounders that could not be tested.
In this study, ACT was consistently associated with reduction in birth size for infants born preterm, near term, or at term. Further investigation is warranted alongside reevaluation of guidelines. Efforts need to be made to correctly identify and target patients who will deliver preterm. Reduced growth should be considered when deliberating early care decisions.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A major goal of biomimetics is the development of chemical compositions and structures that simulate the extracellular matrix. In this study, gelatin-based electrospun composite fibrous membranes ...were prepared by electrospinning to generate bone scaffold materials. The gelatin-based multicomponent composite fibers were fabricated using co-electrospinning, and the composite fibers of chitosan (CS), gelatin (Gel), hydroxyapatite (HA), and graphene oxide (GO) were successfully fabricated for multi-function characteristics of biomimetic scaffolds. The effect of component concentration on composite fiber morphology, antibacterial properties, and protein adsorption were investigated. Composite fibers exhibited effective antibacterial activity against
and
. The study observed that the composite fibers have higher adsorption capacities of bovine serum albumin (BSA) at pH 5.32-6.00 than at pH 3.90-4.50 or 7.35. The protein adsorption on the surface of the composite fiber increased as the initial BSA concentration increased. The surface of the composite reached adsorption equilibrium at 20 min. These results have specific applications for the development of bone scaffold materials, and broad implications in the field of tissue engineering.
Osteoinductive and persistent antibacterial PLLA/HA/PDA/PPy/Ag composite fiber was successfully synthesized through the self-polymerization of Dopamine on the surface of PLLA/HA and electrochemical ...deposition of PPy-controlled Ag-NPs.
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•Stable silver-nanoparticles coating layer using electrochemical method.•Dopamine self-polymerized on the surface of electrospun fibers.•Steady and slow release of Ag for long-term antibacterial property.•Calcium phosphate surface for bioactivity and osteoinductivity.
Bone implant materials cause the most common complication of bone infections in orthopedic surgery, resulting in implant failure. Antibiotic treatment of bone infections leads to problems such as bacterial resistance and reduced osteogenic capacity. In this study, dopamine (DA) was self-polymerized on the surface of Polylactic acid (PLLA)/Hydroxyapatite (HA) nanowire composite fibers to form an adhesive polydopamine (PDA) membrane, and a stable silver-nanoparticles (Ag-NPs) coating layer was constructed on it by electrochemically driven Ag+ coordination and chelation through Polypyrrole (PPy) mediation, achieving steady and slow release of Ag-NPs. With optimized DA soaking time of 24 h and soaking concentration of 0.5 g·L−1, nanoparticles were uniformly distributed on PLLA/HA/PDA/PPy/Ag composite fibers and the hydrophilicity of the composite fibers was well-behaved. Besides, the composite fibers possessed good physiological stability and 100% antibacterial rate against Escherichia coli (E. coli) as well as Staphylococcus aureus (S. aureus). In addition, the composite fibers had promoted apatite nucleation and growth on surface and good cytocompatibility with osteoblasts, indicating ability of inducing osteogenic differentiation. In summary, a multi-functional PLLA/HA/PDA/PPy/Ag composite fiber with long-term antibacterial property, bioactivity and osteoinductivity was successfully constructed by electrospinning and electrochemical deposition.
Potent antibacterial fibers with the functional “triad” of photothermal, silver, and Dex were prepared by electrospinning, which can simultaneously kill multidrug-resistant bacteria and accelerate ...bone tissue healing due to the photothermal effect and release of Dex, which is good for photothermal therapy and bone regeneration of infectious bone defects.
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•Potent antibacterial electrospun fibers with the functional “triad” of photothermal, silver, and Dex.•Multidrug-resistant bacteria and accelerate bone tissue healing due to photothermal effect and release of Dex.•Induce differentiation of BMSCs into osteoblasts via local drug release.•Excellent osteogenic and angiogenic properties via functional electrospun fibers.
Bacteria-induced bone infections disrupt the healing and repair ability of bone tissue, posing a serious challenge to the treatment of clinical bone defects. In this study, novel composite fibers (PLLA/Dex/Ag fibers) with light-responsive rapid antibiosis and osteogenesis were obtained by mixing the photothermal agent silver nanoparticles (Ag-NPs) and the osteogenic drug dexamethasone (Dex) in polylactic acid (PLLA) using electrospinning, which can simultaneously kill multidrug-resistant bacteria and accelerate bone tissue healing due to the photothermal effect and release of Dex. Ag-NPs can act as antimicrobial agents released from the fibers and as photothermal agents to generate local high temperature and singlet state oxygen (1O2) under 808 nm light radiation, thereby killing the bacteria. The antimicrobial tests in vitro showed that PLLA/Dex/Ag fibers had an excellent antimicrobial effect on Escherichia coli and Staphylococcus aureus under NIR light radiation, shortening the effective antimicrobial time from 24 h to 6 h and achieving light-responsive antibiosis rapidly. Meanwhile, the released Dex could induce the differentiation of bone marrow mesenchymal stem cells into osteoblasts, thus promoting the healing of bone defects. In conclusion, this study provided a simple and effective strategy for the clinical treatment of bone infections.
Flame kernel generation is essential to the stability and efficiency of combustion in a spark engine. In this study, the initial process of flame kernel generation was studied in an optical spark ...engine. The engine was operated with the λ adjusted from 1.0 to 1.5, respectively. Meanwhile, the continuous arc motion was inventively quantified. First, the impact of single-coil and multi-coil discharge on the stability of the combustion and knocking tendency are examined. Secondly, the differences in arc development between single-coil and multi-coil discharge and the effect of the shortening phenomenon on the generation of the flame kernels are compared by optical images. Finally, arc shortening feathers (including timing, extent, and spatial location) are statistically analyzed over multiple cycles in conjunction with combustion phase. The results show that multi-coil discharge can make the flame kernels larger, which could keep the flame kernels from quenching. They also show that variations in arc shortening are linked to cycle-to-cycle fluctuations. Furthermore, a principal component analysis is done on the features of the first two arc shortenings and the CA05 phases. Precision control of the arc shortening features can greatly enhance the spark engine’s initial flame kernel stability and lower cycle-to-cycle fluctuations.
This article proposes a progressive frequency domain-guided depth model with adaptive preprocessing to solve the problem of defect detection with weak features based on X-ray images. In distinct ...intuitive surface defect detection tasks, non-destructive testing of castings using X-rays presents more complex and weak defect features, leading to lower accuracy and insufficient robustness on the part of current casting defect detection methods. To address these challenges, the proposed method establishes four specialized mechanisms to improve model accuracy. First, an adaptive image contrast enhancement method is proposed to enhance the features of defects in casting images to promote subsequent feature extraction and prediction. Second, a subtle clue mining module based on frequency domain attention is proposed to fully extract the discriminative features of casting defects. Third, a feature refinement module based on progressive learning is proposed to achieve a balance between feature resolution and semantic information. Finally, a refined deep regression supervision mechanism is designed to improve defect detection accuracy under strict intersection-to-union ratio standards. We established extensive ablation studies using casting defect images in GDXray, conducted detailed comparative experiments with other methods, and performed experiments to analyze the robustness of the resulting models. Compared with other X-ray defect detection methods, our framework achieves an average +4.6 AP. Compared to the baseline, our proposed refined deep regression supervision mechanism results in an improvement of 5.3 AP.
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