Inflammation and activation of the neuroendocrine systems comprise important aspects of stroke pathophysiology. The present study investigated whether baseline plasma brain natriuretic peptide (BNP), ...N‐terminal pro‐brain natriuretic peptide (NT‐proBNP), cortisol and copeptin levels on admission can predict short‐term outcomes and mortality after acute ischaemic stroke. The study group consisted of 189 patients who had their first acute ischaemic stroke. Plasma levels of BNP, NT‐proBNP, cortisol and copeptin were evaluated to determine their value with respect to predicting functional outcome and mortality within 3 months. As a result of cardiovascular and neurological investigations (including imaging techniques), lesion size, stroke subtype classification and clinical outcome after 3 months were determined. Plasma levels of BNP, NT‐proBNP, cortisol and copeptin were associated with stroke severity, as well as short‐term functional outcomes. After adjusting for all other significant outcome predictors, NT‐proBNP, cortisol and copeptin remained as independent outcome predictors. In the receiver operating characteristic curve analysis, the biomarker panel (including BNP, NT‐proBNP, cortisol and copeptin) predicted functional outcome and death within 90 days significantly more efficiently than the National Institute of Health Stroke Scale (NIHSS) or the biomarker alone. Copeptin showed a significantly greater discriminatory ability as a single biomarker compared to BNP, NT‐proBNP, cortisol and NIHSS score. These results suggest that a biomarker panel may add valuable and time‐sensitive prognostic information in the early evaluation of acute ischaemic stroke. This may provide a channel for interventional therapy in acute stroke.
The mechanism of superconductivity in cuprates remains one of the big challenges of condensed matter physics. High-Tc
cuprates crystallize into a layered perovskite structure featuring copper oxygen ...octahedral coordination. Due to the Jahn Teller effect in combination with the strong static Coulomb interaction, the octahedra in high-Tc
cuprates are elongated along the c axis, leading to a 3dx²-y² orbital at the top of the band structure wherein the doped holes reside. This scenario gives rise to 2D characteristics in high-Tc
cuprates that favor d-wave pairing symmetry. Here, we report superconductivity in a cuprate Ba₂CuO4-y, wherein the local octahedron is in a very exceptional compressed version. The Ba₂CuO4-y compound was synthesized at high pressure at high temperatures and shows bulk superconductivity with critical temperature (Tc
) above 70 K at ambient conditions. This superconducting transition temperature is more than 30 K higher than the Tc
for the isostructural counterparts based on classical La₂CuO₄. X-ray absorption measurements indicate the heavily doped nature of the Ba₂CuO4-y superconductor. In compressed octahedron, the 3d3z²-r² orbital will be lifted above the 3dx²-y² orbital, leading to significant 3D nature in addition to the conventional 3dx²-y² orbital. This work sheds important light on advancing our comprehensive understanding of the superconducting mechanism of high Tc
in cuprate materials.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent for coronavirus 2019 (COVID-19) pneumonia. Little is known about the kinetics, tissue distribution, ...cross-reactivity, and neutralization antibody response in patients with COVID-19. Two groups of patients with RT-PCR-confirmed COVID-19 were enrolled in this study: 12 severely ill patients in intensive care units who needed mechanical ventilation and 11 mildly ill patients in isolation wards. Serial clinical samples were collected for laboratory detection. Results showed that most of the severely ill patients had viral shedding in a variety of tissues for 20-40 days after onset of disease (8/12, 66.7%), while the majority of mildly ill patients had viral shedding restricted to the respiratory tract and had no detectable virus RNA 10 days after onset (9/11, 81.8%). Mildly ill patients showed significantly lower IgM response compared with that of the severe group. IgG responses were detected in most patients in both the severe and mild groups at 9 days after onset, and remained at a high level throughout the study. Antibodies cross-reactive to SARS-CoV and SARS-CoV-2 were detected in patients with COVID-19 but not in patients with MERS. High levels of neutralizing antibodies were induced after about 10 days after onset in both severely and mildly ill patients which were higher in the severe group. SARS-CoV-2 pseudotype neutralization test and focus reduction neutralization test with authentic virus showed consistent results. Sera from patients with COVID-19 inhibited SARS-CoV-2 entry. Sera from convalescent patients with SARS or Middle East respiratory syndrome (MERS) did not. Anti-SARS-CoV-2 S and N IgG levels exhibited a moderate correlation with neutralization titers in patients' plasma. This study improves our understanding of immune response in humans after SARS-CoV-2 infection.
Tumor mutational burden (TMB) measurements aid in identifying patients who are likely to benefit from immunotherapy; however, there is empirical variability across panel assays and factors ...contributing to this variability have not been comprehensively investigated. Identifying sources of variability can help facilitate comparability across different panel assays, which may aid in broader adoption of panel assays and development of clinical applications.
Twenty-nine tumor samples and 10 human-derived cell lines were processed and distributed to 16 laboratories; each used their own bioinformatics pipelines to calculate TMB and compare to whole exome results. Additionally, theoretical positive percent agreement (PPA) and negative percent agreement (NPA) of TMB were estimated. The impact of filtering pathogenic and germline variants on TMB estimates was assessed. Calibration curves specific to each panel assay were developed to facilitate translation of panel TMB values to whole exome sequencing (WES) TMB values.
Panel sizes >667 Kb are necessary to maintain adequate PPA and NPA for calling TMB high versus TMB low across the range of cut-offs used in practice. Failure to filter out pathogenic variants when estimating panel TMB resulted in overestimating TMB relative to WES for all assays. Filtering out potential germline variants at >0% population minor allele frequency resulted in the strongest correlation to WES TMB. Application of a calibration approach derived from The Cancer Genome Atlas data, tailored to each panel assay, reduced the spread of panel TMB values around the WES TMB as reflected in lower root mean squared error (RMSE) for 26/29 (90%) of the clinical samples.
Estimation of TMB varies across different panels, with panel size, gene content, and bioinformatics pipelines contributing to empirical variability. Statistical calibration can achieve more consistent results across panels and allows for comparison of TMB values across various panel assays. To promote reproducibility and comparability across assays, a software tool was developed and made publicly available.
•Estimation of TMB varies across different panels, with panel size, gene content and bioinformatics pipelines contributing to empirical variability.•Panel sizes greater than 667Kb are necessary to maintain adequate PPA and NPA for calling TMB high versus TMB low across the range of cutoffs used in practice.•Statistical calibration can achieve more consistent results across panels and allows for comparison of TMB values across various panel assays.
Abstract This study is to explore and compare the features of the cells and cancer stem-like cells (CSCs) isolated from both glioblastoma and astrocytoma on expression of anti-apoptotic and multidrug ...resistance–associated protein (MRP) genes. As a result, the mRNA expression of livin, livinα and MRP1 was up-regulated in human CSCs from 2 times to 85 times, but the gene expression of MRP3 was down-regulated from 0.09 times to 0.5 times. After just differentiation the mRNA expression of livin, livinα and MRP3 was up-regulated from9 times to 64 times, but the mRNA expression of MRP1 was down-regulated from 0.01 times to 0.03 times. It is a rare report that glioma stem-like cells can be induced successfully from a grade 2–3 astrocytoma tissue. The properties of glioblastoma and astrocytoma stem-like cells on anti-apoptotic and MRP genes are: anti-apoptotic gene livin and survivin are elevated in CSCs but are the most increased in just differentiated CSCs; MRP1 gene is significantly increased and MRP3 is decreased in CSCs, but when differentiating the MRP3 gene starts a remarkable increase in CSCs; the expression of anti-apoptotic and MRP genes shows no differences between the CSCs isolated from glioblastoma and astrocytoma tissues.
Abstract
Cancer cell metabolism leads to a uniquely acidic microenvironment in solid tumors, but exploiting the labile extracellular pH differences between cancer and normal tissues for clinical use ...has been challenging. Here we describe the clinical translation of ONM-100, a nanoparticle-based fluorescent imaging agent. This is comprised of an ultra-pH sensitive amphiphilic polymer, conjugated with indocyanine green, which rapidly and irreversibly dissociates to fluoresce in the acidic extracellular tumor microenvironment due to the mechanism of nanoscale macromolecular cooperativity. Primary outcomes were safety, pharmacokinetics and imaging feasilibity of ONM-100. Secondary outcomes were to determine a range of safe doses of ONM-100 for intra-operative imaging using commonly used fluorescence camera systems. In this study (Netherlands National Trial Register #7085), we report that ONM-100 was well tolerated, and four solid tumor types could be visualized both in- and ex vivo in thirty subjects. ONM-100 enables detection of tumor-positive resection margins in 9/9 subjects and four additional otherwise missed occult lesions. Consequently, this pH-activatable optical imaging agent may be clinically beneficial in differentiating previously unexploitable narrow physiologic differences.
We aimed to investigate the efficacy and tolerability of sorafenib combined with cisplatin and 5-fluorouracil (5-FU) in patients with recurrent or metastatic nasopharyngeal carcinoma (NPC).
It was a ...Simon two-stage designed trial. Chemotherapy-naive patients with recurrent or metastatic disease were enrolled. The regimen was sorafenib 400 mg orally b.i.d., cisplatin 80 mg/m2 i.v. day 1, and 5-FU 1000 mg/m2/day CIV for 4 days, repeated every 21 days. After a maximum of six cycles of chemotherapy, patients received maintenance of sorafenib.
In total, 54 patients were enrolled. The objective response rate reached 77.8%, including 1 complete response and 41 partial responses. The median progression-free survival was 7.2 months (95% CI 6.8–8.4 months), and the median overall survival was 11.8 months (95% CI 10.6–18.7 months). Major toxic effects included hand–foot skin reaction, myelosuppression, and gastrointestinal (GI) reaction. The incidence of hemorrhage was 22.2%, and one patient with liver metastases died of GI bleeding. Contrast-enhanced ultrasonography was carried out in a subset of patients with liver metastases.
Combination of sorafenib, cisplatin (80 mg/m2) and 5-FU (3000 mg/m2) was tolerable and feasible in recurrent or metastatic NPC. Further randomized trials to compare sorafenib plus cisplatin and 5-FU with standard dose of cisplatin plus 5-FU in NPC are warranted.
Data from clinical trials of human papillomavirus (HPV) vaccines showed that women naïve (negative for both type-specific antibodies and DNA) to vaccine types would derive benefit from vaccination; ...therefore, an understanding of the proportion of naïve women in different age groups is important for developing HPV vaccination strategies.
From November 2012 to April 2013, a total of 7372 healthy women aged 18–45 years were recruited in five provinces in China. Cervical specimens and serum samples were collected for each woman at entry. Cervical specimens were first tested by the HPV DNA enzyme immunoassay method; if positive, the specimens were then tested by reverse hybridization line probe assay and HPV-16 and HPV-18 specific polymerase chain reactions. Neutralizing antibodies against HPV-16 or HPV-18 were tested with a pseudovirion-based neutralization assay.
The overall prevalence of high-risk HPV DNA was 14.8% (1088/7367, 95% CI 14.0–15.6), and the seroprevalence of neutralizing antibodies against HPV-16 and HPV-18 was 12.6% (925/7367) and 4.9% (364/7367), respectively. In younger women (18–26 years) and middle-aged women (27–45 years), 83.8% (3116/3719) and 81.4% (2968/3648) were naïve to both HPV-16 and HPV-18 (both neutralizing antibodies and DNA were negative), respectively. In addition, 98.5% (3664/3719) and 98.0% (3575/3648) of the younger or middle-aged women were naïve to at least one HPV type (HPV-16 or HPV-18).
This study revealed that the majority of Chinese women aged 18–26 years and 27–45 years were naïve to both HPV-16 and HPV-18 and would thus derive full benefit from bivalent HPV vaccination.
Knowledge of the in-situ stress field in the rock mass at depth is important to provide stress boundary conditions for underground excavation design, stability evaluation, and the optimization of ...ground support systems. In the present study, in-situ stress measurement using hydraulic fracturing method is conducted in the Beishan area in Gansu Province, China, a preferred candidate site for China's high-level radioactive waste repository. Information on the stress magnitudes and orientations in three sub-areas is obtained from 136 measurement points in nine sub-vertical boreholes at depths ranging from 30 to 700m, and the distribution characteristics of the in-situ stress field is analyzed. The pressure–time records obtained from the test intervals with pre-existing fractures are discussed according to the acoustic borehole televiewer (BHTV) images. The measurement results indicate that the regional stress field is dominated by horizontal stress within most of the measurement depth ranges. A piecewise distribution of the principal stresses reveals approximately three stress domains with increasing depth. At shallow and medium depths, the stress fields are characterized by σH>σh>σv and σH>σv>σh, respectively, where σH, σh, and σv are maximum horizontal, minimum horizontal, and vertical stresses, respectively. With further increase of depth, the maximum principal stress changes from horizontal to vertical (i.e. σv>σH>σh). Fracture impression results reveal that the maximum horizontal stress is dominantly oriented in the NNE–NEE direction, which is in agreement with the orientation of regional tectonic stress field generated from movement of the Earth's tectonic plates. In addition, it is found that the orientations of σH are affected by the geological structures significantly.
•Geological features of the Beishan area are described.•The results of the hydro-fracturing in-situ stress measurements are presented.•The distribution characteristics of the in-situ stress filed are analyzed.•The regional stress field associated with the geological evolution is discussed.
Using a conjunction of Cluster in the mid‐altitude dayside magnetosphere and Swarm in the low‐altitude ionosphere, we show, by employing multi‐spacecraft analysis, that matched, strong magnetic ...perturbations and the corresponding mesoscale field‐aligned current (FAC) structures are measured in the high latitude polar cusp region during the 7 October 2015 storm. Two pairs of opposite (positive/negative) FACs are observed by both Cluster and Swarm, which may relate to pulsed magnetic reconnection at the dayside magnetopause. Furthermore, the current intensity of these matched FACs decreases from high to low latitude, consistent with the time elapsed since reconnection. Corresponding geomagnetic disturbances are also observed by ground stations. Our observations provide direct evidence for the coupling of mesoscale FACs between the magnetosphere, ionosphere and ground in the polar cusp region, where the signatures are driven in this case by conditions suitable for inducing reconnection.
Plain Language Summary
Field‐aligned currents (FACs) are the key medium for the interaction between the distant space magnetosphere (a region filled with Earth's magnetic field) and the near‐Earth space ionosphere. Magnetic reconnection is the most important process to transfer solar wind energy from dayside magnetosphere to nightside, which is accompanied by the generation of FACs extending from the high latitude region of the ionosphere to the magnetosphere. For such structures, extending across different space regions, joint observations by multiple spacecraft are necessary. Using simultaneous measurements of Cluster in the magnetosphere, Swarm in the ionosphere and geomagnetic stations on the ground, coordinated mesoscale FAC structures could show matched signatures in the magnetosphere and the ionosphere and the corresponding geomagnetic disturbances on the ground. Our observations provide direct evidence for the magnetosphere‐ionosphere‐ground coupling during the pulsed magnetic reconnection process.
Key Points
Multi‐spacecraft Cluster and Swarm reveal matched magnetic perturbation and corresponding mesoscale field‐aligned currents (FACs) at different altitudes in the cusp region
Multiple pairs of opposite FACs associated with pulsed magnetic reconnection are dominant currents system at the dayside during storm time
Direct evidence for detailed dayside mesoscale FACs coupling between magnetosphere, ionosphere and ground is provided
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