Summary Background Chimeric antigen receptor (CAR) modified T cells targeting CD19 have shown activity in case series of patients with acute and chronic lymphocytic leukaemia and B-cell lymphomas, ...but feasibility, toxicity, and response rates of consecutively enrolled patients treated with a consistent regimen and assessed on an intention-to-treat basis have not been reported. We aimed to define feasibility, toxicity, maximum tolerated dose, response rate, and biological correlates of response in children and young adults with refractory B-cell malignancies treated with CD19-CAR T cells. Methods This phase 1, dose-escalation trial consecutively enrolled children and young adults (aged 1–30 years) with relapsed or refractory acute lymphoblastic leukaemia or non-Hodgkin lymphoma. Autologous T cells were engineered via an 11-day manufacturing process to express a CD19-CAR incorporating an anti-CD19 single-chain variable fragment plus TCR zeta and CD28 signalling domains. All patients received fludarabine and cyclophosphamide before a single infusion of CD19-CAR T cells. Using a standard 3 + 3 design to establish the maximum tolerated dose, patients received either 1 × 106 CAR-transduced T cells per kg (dose 1), 3 × 106 CAR-transduced T cells per kg (dose 2), or the entire CAR T-cell product if sufficient numbers of cells to meet the assigned dose were not generated. After the dose-escalation phase, an expansion cohort was treated at the maximum tolerated dose. The trial is registered with ClinicalTrials.gov , number NCT01593696. Findings Between July 2, 2012, and June 20, 2014, 21 patients (including eight who had previously undergone allogeneic haematopoietic stem-cell transplantation) were enrolled and infused with CD19-CAR T cells. 19 received the prescribed dose of CD19-CAR T cells, whereas the assigned dose concentration could not be generated for two patients (90% feasible). All patients enrolled were assessed for response. The maximum tolerated dose was defined as 1 × 106 CD19-CAR T cells per kg. All toxicities were fully reversible, with the most severe being grade 4 cytokine release syndrome that occurred in three (14%) of 21 patients (95% CI 3·0–36·3). The most common non-haematological grade 3 adverse events were fever (nine 43% of 21 patients), hypokalaemia (nine 43% of 21 patients), fever and neutropenia (eight 38% of 21 patients), and cytokine release syndrome (three 14%) of 21 patients). Interpretation CD19-CAR T cell therapy is feasible, safe, and mediates potent anti-leukaemic activity in children and young adults with chemotherapy-resistant B-precursor acute lymphoblastic leukaemia. All toxicities were reversible and prolonged B-cell aplasia did not occur. Funding National Institutes of Health Intramural funds and St Baldrick's Foundation.
Full-color, catalyst-free InGaN/GaN dot-in-a-wire light-emitting diodes (LEDs) were monolithically grown on Si(111) by molecular beam epitaxy, with the emission characteristics controlled by the dot ...properties in a single epitaxial growth step. With the use of p-type modulation doping in the dot-in-a-wire heterostructures, we have demonstrated the most efficient phosphor-free white LEDs ever reported, which exhibit an internal quantum efficiency of ∼56.8%, nearly unaltered CIE chromaticity coordinates with increasing injection current, and virtually zero efficiency droop at current densities up to ∼640 A/cm2. The remarkable performance is attributed to the superior three-dimensional carrier confinement provided by the electronically coupled dot-in-a-wire heterostructures, the nearly defect- and strain-free GaN nanowires, and the significantly enhanced hole transport due to the p-type modulation doping.
Close white dwarf binaries consisting of a white dwarf and an A-, F-, G-, or K-type main-sequence star, henceforth close WD+AFGK binaries, are ideal systems to understand the nature of type Ia ...supernovae progenitors and to test binary evolution models. In this work we identify 775 WD+AFGK candidates from TGAS (The Tycho-Gaia Astrometric Solution) and Gaia Data Release 2 (DR2), a well-defined sample of stars with available parallaxes, and we measure radial velocities (RVs) for 275 of them with the aim of identifying close binaries. The RVs have been measured from high-resolution spectra obtained at the Xinglong 2.16 m Telescope and the San Pedro Mártir 2.12 m Telescope and/or from available LAMOST DR6 (low-resolution) and RAVE DR5 (medium-resolution) spectra. We identify 23 WD+AFGK systems displaying more than 3 RV variation among 151 systems for which the measured values are obtained from different nights. Our WD+AFGK binary sample contains both AFGK dwarfs and giants, with a giant fraction ∼43%. The close binary fractions we determine for the WD+AFGK dwarf and giant samples are 24% and 15%, respectively. We also determine the stellar parameters (i.e., effective temperature, surface gravity, metallicity, mass, and radius) of the AFGK companions with available high-resolution spectra. The stellar parameter distributions of the AFGK companions that are members of close and wide binary candidates do not show statistically significant differences.
The digestive tract development in goat kids around weaning is vital to the establishment of digestion and absorption function, growth, and health of adults. The objective was to explore the effects ...of age and solid feed on the anatomical and morphological development of the gastrointestinal tract of Laiwu Black goat kids. Forty-eight female Laiwu Black goats at 8 ages (1, 7, 14, 28, 42, 56, 70, and 84 d; 6 goats per group) were selected and killed for anatomical and morphological analysis. The goats experienced the following 4 diet phases: maternal colostrum (MC; d 1, d 7), maternal milk (MM; d 14, d 28), maternal milk plus solid diet (MMSD; d 42, d 56) and only solid diet (OSD; d 70, d 84). The body and carcass weights were not significantly changed during MC and MM phases but changed during the MMSD phase. The absolute growth of body and carcass weights were higher in the MMSD phase than in MM phase. In addition, the dressing percentage was the highest in the MMSD phase. The body size indices evolved progressively and increased over time. The percentage of internal and external organs to body weight decreased over time, whereas the percentage to complex stomach percentage increased. The rumen and omasum weight experienced synchronous absolute growth over time, especially in the OSD phase. In contrast, the absolute growth of the reticulum and abomasum was the highest in MMSD and MC phases, respectively. After weaning, the goats showed the highest papillae height, lamina propria, muscle layer thickness, and epithelial thickness. The OSD phase showed the highest colonic mucosa thickness, ileal villus height, and ileal muscle layer thickness. The crypt depth was higher in the MMSD phase than in the MM phase. Moreover, the crypt depth and muscle layer thickness of jejunum increased over time. Furthermore, duodenal crypt depth, muscle layer thickness, and epithelial thickness increased in the OSD phase compared with other stages. In conclusion, the histological investigation supports the improvement of the morphological development of the digestive tract and the growth performance in the solid feed phase. It is recommended to add solid food as early as 4 wk old.
The predicted 2–4°C increment in temperature by the end of the 21st Century poses a threat to rice production. The impact of high temperatures at night is more devastating than day-time or mean daily ...temperatures. Booting and flowering are the stages most sensitive to high temperature, which may sometimes lead to complete sterility. Humidity also plays a vital role in increasing the spikelet sterility at increased temperature. Significant variation exists among rice germplasms in response to temperature stress. Flowering at cooler times of day, more pollen viability, larger anthers, longer basal dehiscence and presence of long basal pores are some of the phenotypic markers for high-temperature tolerance. Protection of structural proteins, enzymes and membranes and expression of heat shock proteins (HSPs) are some of the biochemical processes that can impart thermo-tolerance. All these traits should be actively exploited in future breeding programmes for developing heat-resistant cultivars. Replacement of heat-sensitive cultivars with heat-tolerant ones, adjustment of sowing time, choice of varieties with a growth duration allowing avoidance of peak stress periods, and exogenous application of plant hormones are some of the adaptive measures that will help in the mitigation of forecast yield reduction due to global warming.
Freezing of gait (FOG) is a common and challenging clinical symptom in Parkinson’s disease. In this review, we summarise the recent insights into freezing of gait and highlight the strategies that ...should be considered to improve future treatment. There is a need to develop individualised and on-demand therapies, through improved detection and wearable technologies. Whilst there already exist a number of pharmacological (e.g., dopaminergic and beyond dopamine), non-pharmacological (physiotherapy and cueing, cognitive training, and non-invasive brain stimulation) and surgical approaches to freezing (i.e., dual-site deep brain stimulation, closed-loop programming), an integrated collaborative approach to future research in this complex area will be necessary to systematically investigate new therapeutic avenues. A review of the literature suggests standardising how gait freezing is measured, enriching patient cohorts for preventative studies, and harnessing the power of existing data, could help lead to more effective treatments for freezing of gait and offer relief to many patients.
Amauroderma
s.lat. has been defined mainly by the morphological features of non-truncate and double-walled basidiospores with a distinctly ornamented endospore wall. In this work, taxonomic and ...phylogenetic studies on species of
Amauroderma
s.lat. are carried out by morphological examination together with ultrastructural observations, and molecular phylogenetic analyses of multiple loci including the internal transcribed spacer regions (ITS), the large subunit of nuclear ribosomal RNA gene (nLSU), the largest subunit of RNA polymerase II (
RPB1
) and the second largest subunit of RNA polymerase II (
RPB2
), the translation elongation factor 1-α gene (
TEF
) and the β-tubulin gene (
TUB
). The results demonstrate that species of
Ganodermataceae
formed ten clades. Species previously placed in
Amauroderma
s.lat. are divided into four clades:
Amauroderma
s.str.,
Foraminispora
,
Furtadoa
and a new genus
Sanguinoderma
. The classification of
Amauroderma
s.lat. is thus revised, six new species are described and illustrated, and eight new combinations are proposed. SEM micrographs of basidiospores of
Foraminispora
and
Sanguinoderma
are provided, and the importance of SEM in delimitation of taxa in this study is briefly discussed. Keys to species of
Amauroderma
s.str.,
Foraminispora
,
Furtadoa
, and
Sanguinoderma
are also provided.
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Although wetting agents have been developed to limit tear film dewetting over contact lenses, systematic analyses correlating wetting agent properties to mechanisms of the tear film ...destabilization are not readily available. Clarifying destabilization characteristics across key physio-chemical variables will provide a rational basis for identifying optimal wetting agents.
We employ an in-house, in vitro platform to comprehensively evaluate drainage and dewetting dynamics of five wetting agents across seventeen different formulations and two model tear film solutions. We consider the film thickness evolution, film thickness at breakup, dewetted front propagation, and develop correlations to contact angle to compare the samples.
Zwitterionic wetting agents effectively stabilize the tear film by reducing the film thickness at the onset of dewetting, and delaying the propagation of dewetted regions across the lens. Furthermore, tuning wetting agent surface concentrations and utilizing binary mixtures of wetting agents can enhance wetting characteristics. Finally, despite disparities in wetting agent molecular properties, the time to dewet 50% of the lens scales linearly with the product of the receding contact angle and contact angle hysteresis. Hence, we fundamentally establish the importance of minimizing the absolute contact angle and contact angle hysteresis for effective wetting performance.
The widespread existence of nonylphenol in the environmental rendered from wastewater discharge has become a growing concern for its endocrine disrupting effects on microorganisms. In this study, the ...performance of nitrifying and denitrifying microbial community in a sequencing batch reactor (SBR) was investigated under different nonylphenol concentrations. The SBR was shown to be less effective in nitrogen removal at higher concentration of nonylphenol. Proteobacteria, Bacteroidetes, and Actinobacteria were characterized by 454 pyrosequencing as the dominant bacteria, nitrogen removal functional bacteria in these three phyla were inhibited by nonylphenol, and Proteobacteria and Actinobacteria were more sensitive to nonylphenol. With the accumulation of nonylphenol, the population of the most abundant denitrifying bacteria (
Thauera
spp.) and nitrifying bacteria (
Nitrosomonas
spp.) significantly reduced. Microbial diversity increased due to nonylphenol perturbation, which is indicated by the changes in microbial alpha diversity. Principal component analysis showed high similarity between microbial community in low and high concentration of nonylphenol, and the core genera involved in nitrogen removal had a low correlation with other genera shown in co-occurrence network. Moreover, linear discriminant analysis effect size analysis revealed intergroup differences in microorganisms. The mechanism of accumulated NP on the diversity and metabolism of the microbial community was examined. This paper established a theoretical foundation for the treatment of NP-containing wastewater and provided hints for further research about NP impact on biological nitrogen removal.
Graphical abstract
The purposes of this survey were to show the current situation of oncology critical care medicine in China by questionnaire, to understand the resource distribution of oncology critical care ...medicine, and to analyze and evaluate the existing resources and reserve capacity of oncology critical care medicine in China.
We conducted the survey mainly in the form of an online questionnaire. The Committee of Cancer Critical Care Medicine of the Chinese Anticancer Association (CACA) initiated the survey on November 1st, 2017, and 36 member hospitals nationwide participated in the survey. The questionnaire included ten items: investigator information, hospital information, general information of oncology critical care department, staffing of oncology critical care department, management in oncology critical care department, technical skills in oncology critical care department, patient source in oncology critical care department, equipment configuration in oncology critical care department, special skills in oncology critical care department and summary of the information.
The survey results included information from 28 member units, all of which were tertiary hospitals, distributed in 20 provinces and 4 direct-controlled municipalities. The results are as follows. (1) The total ratio of beds in the oncology critical care department to hospital beds was 1.06%, and the average number of beds in the oncology critical care department was 16.36. (2) The ratio of physicians in the oncology critical care department to beds was approximately 0.62:1, and the ratio of nurses to beds was approximately 1.98:1. (3) According to the census of the population and gross domestic product (GDP) of different regions conducted by the State Statistics Bureau in 2017, the ratio of beds in the oncology critical care department for tumor patients to population was 4.55 beds per 10 million people, and the ratio of beds in the oncology critical care department to GDP was 8.00 beds per RMB 100 billion, on average. (4) According to the requirements of the guidelines for the development and management of critical care medicine in China, the facilities in departments of oncology critical care medicine meet the requirements, and the technical skills of medical staff are competent.
The development of oncology critical care in China is becoming better, but there is still a certain gap compared with the intensive care unit (ICU) standards in China and the average level of the nationwide. The development of oncology critical care medicine is urgent.
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