Bedaquiline treatment significantly improves multidrug-resistant tuberculosis (MDR-TB) patient treatment outcomes. However, safety and efficacy data are lacking for bedaquiline used with background ...regimens to treat Chinese TB patients. Here, we describe our initial clinical experience for bedaquiline treatment of a large multicentre cohort of MDR-TB and extensively drug-resistant tuberculosis (XDR-TB) patients in China.
Patients (177) received 24-week bedaquiline treatment combined with personalized anti-TB drug background regimens. As primary efficacy endpoints, times to initial sputum culture conversion were measured.
Of 177 MDR-TB patients completing the 24-week treatment course, sputum culture conversion occurred for 151/177 (85.3%), while 26 had unfavourable outcomes, including 3/177 (1.7%) deaths and 23/177 (13.0%) non-responders at treatment completion. The median time to sputum culture conversion was 4 (interquartile range 2–8) weeks. Conversion rates were 33/39 (84.6%, 95% confidence interval (CI) 73.3–95.9) for MDR-TB patients, 47/56 (83.9%, 95% CI 74.3–93.6) for pre-XDR-TB patients and 71/82 (86.6%, 95% CI 79.2–94.0) for XDR-TB patients. Multivariate analysis demonstrated that patients with low body mass index (odds ratio 7.356; 95% CI 2.652–20.401) were at significantly high risk of unfavourable outcomes, with serious adverse events noted in 15 (8.5%) patients, including six with corrected QT interval (QTc) prolongation times (>500 ms).
Bedaquiline, when included in background regimens for treatment of MDR-TB and XDR-TB patients in China, was safe and associated with a high rate of culture conversion.
Two-dimensional (2D) materials have been studied extensively as monolayers, vertical or lateral heterostructures. To achieve functionalization, monolayers are often patterned using soft lithography ...and selectively decorated with molecules. Here we demonstrate the growth of a family of 2D materials that are intrinsically patterned. We demonstrate that a monolayer of PtSe
can be grown on a Pt substrate in the form of a triangular pattern of alternating 1T and 1H phases. Moreover, we show that, in a monolayer of CuSe grown on a Cu substrate, strain relaxation leads to periodic patterns of triangular nanopores with uniform size. Adsorption of different species at preferred pattern sites is also achieved, demonstrating that these materials can serve as templates for selective self-assembly of molecules or nanoclusters, as well as for the functionalization of the same substrate with two different species.
The processes X(3872) ... , and γD+D− are searched for in a 9.0 fb−1 data sample collected at center-of-mass energies between 4.178 and 4.278 GeV with the BESIII detector. We observe X(3872) ... . ...and find evidence for X (3872)→γJ/ψ with statistical significances of 7.4 σ and 3.5σ, respectively. No evident signals for X(3872)→γψ(2S) and γD+D− are found, and the upper limit on the relative branching ratio Rγψ ≡ {BX(3872)→γψ(2S)}/{BX(3872)→γJ/ψ} <0.59 is set at 90% confidence level. Measurements of branching ratios relative to decay X(3872)→π+π−J/ψ are also reported for decays ... .,γψ(2S), γJ/ψ, and γD+D−, as well as the non-... three-body decays ... .(ProQuest: ... denotes formulae omitted.)
Galectin-1 (Gal-1) is involved in several pathological activities associated with tumor progression and chemoresistance, however, the role and molecular mechanism of Gal-1 activity in hepatocellular ...carcinoma (HCC) epithelial-mesenchymal transition (EMT) and sorafenib resistance remain enigmatic. In the present study, forced Gal-1 expression promoted HCC progression and sorafenib resistance. Gal-1 elevated αvβ3-integrin expression, leading to AKT activation. Moreover, Gal-1 overexpression induced HCC cell EMT via PI3K/AKT cascade activation. Clinically, our data revealed that Gal-1 overexpression is correlated with poor HCC survival outcomes and sorafenib response. These data suggest that Gal-1 may be a potential therapeutic target for HCC and a biomarker for predicting response to sorafenib treatment.
D-type cyclins (D1, D2 and D3) and their associated cyclin-dependent kinases (CDK4 and CDK6) are components of the core cell cycle machinery that drives cell proliferation. Inhibitors of CDK4 and ...CDK6 are currently being tested in clinical trials for patients with several cancer types, with promising results. Here, using human cancer cells and patient-derived xenografts in mice, we show that the cyclin D3-CDK6 kinase phosphorylates and inhibits the catalytic activity of two key enzymes in the glycolytic pathway, 6-phosphofructokinase and pyruvate kinase M2. This re-directs the glycolytic intermediates into the pentose phosphate (PPP) and serine pathways. Inhibition of cyclin D3-CDK6 in tumour cells reduces flow through the PPP and serine pathways, thereby depleting the antioxidants NADPH and glutathione. This, in turn, increases the levels of reactive oxygen species and causes apoptosis of tumour cells. The pro-survival function of cyclin D-associated kinase operates in tumours expressing high levels of cyclin D3-CDK6 complexes. We propose that measuring the levels of cyclin D3-CDK6 in human cancers might help to identify tumour subsets that undergo cell death and tumour regression upon inhibition of CDK4 and CDK6. Cyclin D3-CDK6, through its ability to link cell cycle and cell metabolism, represents a particularly powerful oncoprotein that affects cancer cells at several levels, and this property can be exploited for anti-cancer therapy.
A multi-cancer early detection (MCED) test used to complement existing screening could increase the number of cancers detected through population screening, potentially improving clinical outcomes. ...The Circulating Cell-free Genome Atlas study (CCGA; NCT02889978) was a prospective, case-controlled, observational study and demonstrated that a blood-based MCED test utilizing cell-free DNA (cfDNA) sequencing in combination with machine learning could detect cancer signals across multiple cancer types and predict cancer signal origin (CSO) with high accuracy. The objective of this third and final CCGA substudy was to validate an MCED test version further refined for use as a screening tool.
This pre-specified substudy included 4077 participants in an independent validation set (cancer: n = 2823; non-cancer: n = 1254, non-cancer status confirmed at year-one follow-up). Specificity, sensitivity, and CSO prediction accuracy were measured.
Specificity for cancer signal detection was 99.5% 95% confidence interval (CI): 99.0% to 99.8%. Overall sensitivity for cancer signal detection was 51.5% (49.6% to 53.3%); sensitivity increased with stage stage I: 16.8% (14.5% to 19.5%), stage II: 40.4% (36.8% to 44.1%), stage III: 77.0% (73.4% to 80.3%), stage IV: 90.1% (87.5% to 92.2%). Stage I-III sensitivity was 67.6% (64.4% to 70.6%) in 12 pre-specified cancers that account for approximately two-thirds of annual USA cancer deaths and was 40.7% (38.7% to 42.9%) in all cancers. Cancer signals were detected across >50 cancer types. Overall accuracy of CSO prediction in true positives was 88.7% (87.0% to 90.2%).
In this pre-specified, large-scale, clinical validation substudy, the MCED test demonstrated high specificity and accuracy of CSO prediction and detected cancer signals across a wide diversity of cancers. These results support the feasibility of this blood-based MCED test as a complement to existing single-cancer screening tests.
NCT02889978.
•In a validation study, an MCED test identified a diversity of cancer signals with high specificity.•The MCED test predicted the origin of the cancer signal with high accuracy across multiple cancer types.•Results support the use of this MCED test on a population scale as a complement to existing single-cancer screening tests.
Ti
C
T
and other types of MXene nanosheets are an exciting new class of 2D materials. However, little has been reported on manipulating the shape of MXene nanosheets. Here, we demonstrate that flat ...Ti
C
T
nanosheets encapsulated within spray-dried droplets can be scrolled, bent, and folded into 3D crumpled structures. This morphological change was observed to be reversible upon rehydration.
The complicated structure of the neutron cannot be calculated using first-principles calculations due to the large colour charge of quarks and the self-interaction of gluons. Its simplest structure ...observables are the electromagnetic form factors1, which probe our understanding of the strong interaction. Until now, a small amount of data has been available for the determination of the neutron structure from the time-like kinematical range. Here we present measurements of the Born cross section of electron–positron annihilation reactions into a neutron and anti-neutron pair, and determine the neutron’s effective form factor. The data were recorded with the BESIII experiment at centre-of-mass energies between 2.00 and 3.08 GeV using an integrated luminosity of 647.9 pb−1. Our results improve the statistics on the neutron form factor by more than a factor of 60 over previous measurements, demonstrating that the neutron form factor data from annihilation in the time-like regime is on par with that from electron scattering experiments. The effective form factor of the neutron shows a periodic behaviour, similar to earlier observations of the proton form factor. Future works—both theoretical and experimental—will help illuminate the origin of this oscillation of the electromagnetic structure observables of the nucleon.Form factors encode the structure of nucleons. Measurements from electron–positron annihilation at BESIII reveal an oscillating behaviour of the neutron electromagnetic form factor, and clarify a long-standing photon–nucleon interaction puzzle.
We studied the phylogeography of Chinese yew (Taxus wallichiana), a tree species distributed over most of southern China and adjacent regions. A total of 1235 individuals from 50 populations from ...China and North Vietnam were analysed for chloroplast DNA variation using polymerase chain reaction-restriction fragment length polymorphism of the trnL-F intron-spacer region. A total of 19 different haplotypes were distinguished. We found a very high level of population differentiation and a strong phylogeographic pattern, suggesting low levels of recurrent gene flow among populations. Haplotype differentiation was most marked along the boundary between the Sino-Himalayan and Sino-Japanese Forest floristic subkingdoms, with only one haplotype being shared among these two subkingdoms. The Malesian and Sino-Himalayan Forest subkingdoms had five and 10 haplotypes, respectively, while the relatively large Sino-Japanese Forest subkingdom had only eight. The strong geography-haplotype correlation persisted at the regional floristic level, with most regions possessing a unique set of haplotypes, except for the central China region. Strong landscape effects were observed in the Hengduan and Dabashan mountains, where steep mountains and valleys might have been natural dispersal barriers. The molecular phylogenetic data, together with the geographic distribution of the haplotypes, suggest the existence of several localized refugia during the last glaciation from which the present-day distribution may be derived. The pattern of haplotype distribution across China and North Vietnam corresponded well with the current taxonomic delineation of the three intraspecific varieties of T. wallichiana.
ABSTRACT The Andromeda Galaxy recurrent nova M31N 2008-12a had been observed in eruption 10 times, including yearly eruptions from 2008 to 2014. With a measured recurrence period of days (we believe ...the true value to be half of this) and a white dwarf very close to the Chandrasekhar limit, M31N 2008-12a has become the leading pre-explosion supernova type Ia progenitor candidate. Following multi-wavelength follow-up observations of the 2013 and 2014 eruptions, we initiated a campaign to ensure early detection of the predicted 2015 eruption, which triggered ambitious ground- and space-based follow-up programs. In this paper we present the 2015 detection, visible to near-infrared photometry and visible spectroscopy, and ultraviolet and X-ray observations from the Swift observatory. The LCOGT 2 m (Hawaii) discovered the 2015 eruption, estimated to have commenced at August 28.28 0.12 UT. The 2013-2015 eruptions are remarkably similar at all wavelengths. New early spectroscopic observations reveal short-lived emission from material with velocities ∼13,000 km s−1, possibly collimated outflows. Photometric and spectroscopic observations of the eruption provide strong evidence supporting a red giant donor. An apparently stochastic variability during the early supersoft X-ray phase was comparable in amplitude and duration to past eruptions, but the 2013 and 2015 eruptions show evidence of a brief flux dip during this phase. The multi-eruption Swift/XRT spectra show tentative evidence of high-ionization emission lines above a high-temperature continuum. Following Henze et al. (2015a), the updated recurrence period based on all known eruptions is days, and we expect the next eruption of M31N 2008-12a to occur around 2016 mid-September.
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