Failure to undergo activation-induced cell death due to global dysregulation of apoptosis is the pathogenic hallmark of large granular lymphocyte (LGL) leukemia. Consequently, immunosuppressive ...agents are rational choices for treatment. This first prospective trial in LGL leukemia was a multicenter, phase 2 clinical trial evaluating methotrexate (MTX) at 10 mg/m(2) orally weekly as initial therapy (step 1). Patients failing MTX were eligible for treatment with cyclophosphamide at 100 mg orally daily (step 2). The overall response in step 1 was 38% with 95% confidence interval (CI): 26 and 53%. The overall response in step 2 was 64% with 95% CI: 35 and 87%. The median overall survival for patients with anemia was 69 months with a 95% CI lower bound of 46 months and an upper bound not yet reached. The median overall survival for patients with neutropenia has not been reached 13 years from study activation. Serum biomarker studies confirmed the inflammatory milieu of LGL but were not a priori predictive of response. We identify a gene expression signature that correlates with response and may be STAT3 mutation driven. Immunosuppressive therapies have efficacy in LGL leukemia. Gene signature and mutational profiling may be an effective tool in determining whether MTX is an appropriate therapy.
The cross section of the e+e−→Λc+Λ¯c− process is measured with unprecedented precision using data collected with the BESIII detector at /¯s=4574.5, 4580.0, 4590.0 and 4599.5 MeV. The nonzero cross ...section near the Λc+Λ¯c− production threshold is cleared. At center-of-mass energies /¯s=4574.5 and 4599.5 MeV, the higher statistics data enable us to measure the Λc polar angle distributions. From these, the Λc electric over magnetic form-factor ratios (|GE/GM|) are measured for the first time. They are found to be 1.14±0.14±0.07 and 1.23±0.05±0.03, respectively, where the first uncertainties are statistical and the second are systematic.
Cell-free DNA (cf-DNA)-based liquid biopsy is emerging as a revolutionary new method in individualized cancer treatment and prognosis monitoring, although detecting early-stage cancers using cf-DNA ...remains challenging, partially because of the undefined biological background of cf-DNA.
We investigated somatic mutations in the cf-DNA of 259 cancer-free individuals with a median age of 47 years using an endogenous barcoding duplex method with an ultralow base error rate (2 × 10−7) and compared the variant allele frequencies (VAFs) of these mutations between the cf-DNA and the corresponding blood cell DNA.
Sixty percent (155/259) of the samples showed at least one nonsynonymous mutation on either of two similar target panels covering 508 and 559 cancer-related genes. For individuals older than 50 years of age, the positive rate increased to 76%. Most cf-DNA mutations were also present at similar VAFs in the paired blood cell DNA. The most frequently mutated genes were driver genes of hematologic malignancies, including DNMT3A, TET2, AXSL1, and JAK2. However, the other 58.4% (192/329) of the mutations were likely ‘passenger mutations’ of clonal hematopoiesis, including mutations in NOTCH2, FAT3, EXT2, ERBB4, and ARID2, which are driver genes of solid tumors.
Hematopoietic clone-derived mutations, including ‘driver mutations’ and ‘passenger mutations’, are prevalent in the cf-DNA of both healthy individuals and cancer patients and may be a potential source of false positives in the liquid biopsy. Our results also suggest the ineffectiveness for distinguishing clonal hematopoietic mutations of low VAF (≤0.1%) from tumor-derived mutations using conventional next-generation sequencing of blood cell DNA. However, an error correction model with an ultralow error rate and high coverage depth is required for blood cell DNA sequencing, which is difficult and costly to achieve with current technologies.
We report a successful observation of pressure-induced superconductivity in a topological compound Bi 2 Te 3 with T c of ∼3 K between 3 to 6 GPa. The combined high-pressure structure investigations ...with synchrotron radiation indicated that the superconductivity occurred at the ambient phase without crystal structure phase transition. The Hall effects measurements indicated the hole-type carrier in the pressure-induced superconducting Bi 2 Te 3 single crystal. Consequently, the first-principles calculations based on the structural data obtained by the Rietveld refinement of X-ray diffraction patterns at high pressure showed that the electronic structure under pressure remained topologically nontrivial. The results suggested that topological superconductivity can be realized in Bi 2 Te 3 due to the proximity effect between superconducting bulk states and Dirac-type surface states. We also discuss the possibility that the bulk state could be a topological superconductor.
Objectives
Sarcopenia, an age-related decrease in muscle mass and function, is associated with several potential adverse health outcomes. Its association with another age-related syndrome, dysphagia ...remains unclear. This systematic review and meta-analysis aims to explore the association between sarcopenia and dysphagia.
Methods
PubMed, Embase, Scopus and CINAHL were searched for cross-sectional, case-control and cohort studies that investigated the association between sarcopenia and dysphagia. First author, publication year, study type, sample size, inclusion and exclusion criteria, participant demographics, definition and measurement for evaluation of sarcopenia and dysphagia, main outcomes were retrieved. The association between sarcopenia and dysphagia were expressed by odds ratio (OR) and 95% confidence interval (CI).
Results
9 studies are eligible in the systematic review, and 5 cross-sectional studies comprising 913 participants which showed dichotomous classification of sarcopenia and dysphagia were included in the meta-analysis. The crude odds ratios (ORs) were extracted from 5 studies, and 4 of them also provide adjusted ORs. The crude ORs between sarcopenia and dysphagia is 6.17 (95% CI, 3.81-10.00), after adjusting for some confounders, such as age, sex, Barthel Index score, nutritional status, sarcopenia is also have an association with dysphagia (adjusted ORs, 4.06; 95% CI, 2.27-7.29). The subgroup analysis showed that there was no significant difference between different sarcopenia diagnostic criteria, assessment tools of skeletal muscle mass and dysphagia.
Conclusion
Sarcopenia was positively associated with dysphagia. Prevention and screening of dysphagia is essential among sarcopenic old patients. The causal relationship requires more prospective cohort study for confirmation.
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.
Surface soil (0–10
cm) samples from 53 sampling sites including rural and urban areas of Hong Kong were collected and analyzed for 16 EPA priority polycyclic aromatic hydrocarbons (PAHs). Total PAH ...concentrations were in the range of 7.0–410
μg
kg
−1 (dry wt), with higher concentrations in urban soils than that in rural soils. The three predominant PAHs were Fluoranthene, Naphthalene and Pyrene in rural soils, while Fluoranthene, Naphthalene and Benzo(b + k)fluoranthene dominated the PAHs of urban soils. The values of PAHs isomer indicated that biomass burning might be the major origin of PAHs in rural soils, but vehicular emission around the heavy traffic roads might contribute to the soil PAHs in urban areas. A cluster analysis was performed and grouped the detectable PAHs under 4 clusters, which could be indicative of the PAHs with different origins and PAHs affected by soil organic carbon contents respectively.
Baseline information is provided on levels, distributions and possible sources of PAHs in Hong Kong soils.
Two-dimensional crystals with angstrom-scale pores are widely considered as candidates for a next generation of molecular separation technologies aiming to provide extreme, exponentially large ...selectivity combined with high flow rates. No such pores have been demonstrated experimentally. Here we study gas transport through individual graphene pores created by low intensity exposure to low kV electrons. Helium and hydrogen permeate easily through these pores whereas larger species such as xenon and methane are practically blocked. Permeating gases experience activation barriers that increase quadratically with molecules' kinetic diameter, and the effective diameter of the created pores is estimated as ∼2 angstroms, about one missing carbon ring. Our work reveals stringent conditions for achieving the long sought-after exponential selectivity using porous two-dimensional membranes and suggests limits on their possible performance.
Inactivation of the tumor suppressor p53 and/or overexpression of the oncogene MDM2 frequently occur in human cancers, and are associated with poor prognosis, advanced forms of the disease, and ...chemoresistance. MDM2, the major negative regulator of p53, induces p53 degradation and inactivates its tumor suppressing activity. In turn, p53 regulates MDM2 expression. This MDM2-p53 negative feedback loop has been widely studied and presents an attractive target for cancer therapy, with a few of the inhibitors of this interaction already having advanced into clinical trials. Additionally, there is an increasing interest in understanding MDM2's p53-independent activities in carcinogenesis and cancer progression, which may also have implications for cancer therapy. This review aims to highlight the various roles that the MDM2-p53 interaction plays in cancer, the p53 independent oncogenic activities of MDM2 and the various strategies that may be used to target MDM2 and the MDM2-p53 interaction. We will summarize the major preclinical and clinical evidences of MDM2 inhibitors for human cancer treatment and make suggestions to further improve efficacy and safety of this interesting class of cancer therapeutics.
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