Glioblastomas (GBMs) are among the most malignant of all human tumors and have poor prognosis. The current standard of care (SOC) includes maximal surgical tumor resection followed by adjuvant ...temozolomide (TMZ) and concomitant radiotherapy (RT). However, even with this treatment, the 5-year survival rate is less than 10%, and thus, follow-up treatment is required to improve efficacy. In GBMs as well as many other solid cancers, PI3K/mTOR signaling is overactivated. Therefore, multiple tumor-based PI3K inhibitors have been studied in various cancers. In the current study, we investigated the effect of the dual PI3K/mTOR inhibitor dactolisib on TMZ+RT treatment in three human GBM cell lines and a orthotopic xenograft model. Dactolisib alone induced cytotoxicity and pro-apoptotic effects, which act as antitumor factors. Combined with SOC treatment, dactolisib inhibited cell viability, induced enhanced pro-apoptotic effect, and attenuated migration/invasion in all three cell lines, thereby enhancing the SOC therapeutic effect. Protein microarray analysis showed that A172 cells treated with TMZ+RT+dactolisib had higher p27 and lower Bcl-2 expression than other groups. Moreover, in the xenograft model, oral dactolisib combined with TMZ+RT inhibited tumor growth and prolonged survival. Thus, SOC combined with dactolisib shows potent anti-tumor activity and has promising potential for solid tumor treatment.
Abstract
Climate change has led to an increasing trend in the intensity of global extreme weather events, including chilling. Breeding cultivars with high cold tolerance could be an important pathway ...to mitigate the negative effects of climate change. For rice, few studies have been focusing on the responses of different cold‐tolerance cultivars on chilling stress. In this study, we selected four japonica rice cultivars and conducted a chilling treatment experiment (with three chilling temperatures and three chilling durations) at the booting and flowering stages in 2020 and 2021 in Northeast China. The results showed that chilling treatment at the booting stage affected the biomass allocation and yield traits more than the chilling treatment at the flowering stage did. Overall, the chilling treatment affected the cold‐sensitive cultivars more than the cold‐tolerant cultivars. Among all the study yield traits, chilling treatment affected spikelet fertility the most, followed by the number of grains per panicle. For every 10°C day increase in CDD at the booting (flowering) stage, the grain yield per plant and spikelet fertility decreased by 4.8–12.8% and 3.6–10.8% (2.1–5.3% and 2.2–4.9%), respectively. Even with the intense chilling treatment, the cold‐tolerant cultivars had relatively high number of effective spikes per plant, grain weight, and stable spikelet fertility, hence they maintained relatively high grain yield. Therefore, it is important to factor in the cold tolerance of the cultivars when assessing the chilling effects on biomass allocation and yield traits for rice. In order to combat the negative effects of extremely low temperature at the reproductive stage on rice grain yield, the future breeding technology could focus on improving the spikelet fertility, grain filling size, and number of spikes per plant.
High-flow nasal cannula oxygen therapy (HFNC) is recommended for patients with COVID-19. However, the increasing use of HFNC brings a risk of delayed intubation. The optimal timing of switching from ...HFNC to invasive mechanical ventilation (IMV) remains unclear. An effective predictor is needed to assist in deciding on the timing of intubation. Respiratory rate and oxygenation (ROX) index, defined as (SpO2/FiO2) / respiratory rate, has already shown good diagnostic accuracy. Modified ROX (mROX) index, defined as (PaO2 /FiO2) / respiratory rate, might be better than the ROX index in predicting HFNC failure.
The aim was to evaluate the predictive value of mROX for HFNC failure in patients with COVID-19.
Severe or critical patients with COVID-19 treated with HFNC were enrolled in two clinical centers. Laboratory indicators, respiratory parameters, and mROX index at 0 h and 2 h after initial HFNC were collected. Based on the need for IMV after HFNC initiation, the patients were divided into an HFNC failure group and an HFNC success group. The predictive value of mROX index for IMV was evaluated by the area under the receiver operating characteristic curve (AUROC) and logistic regression analysis. We performed Kaplan–Meier survival analysis using the log-rank test.
Sixty patients with COVID-19 (mean ± SD age, 62.8 ± 14.1 years; 42 patients were male) receiving HFNC were evaluated, including 18 critical and 42 severe cases. A total of 33 patients had hypertension; 14 had diabetes; 17 had chronic cardiac disease; 11 had chronic lung disease; 13 had chronic kidney disease; and 17 had a history of stroke. The AUROC of mROX index at 2 h was superior to that of other respiratory parameters to predict the need for IMV (0.959; p < 0.001). At the mROX index cutoff point of 4.45, predicting HFNC failure reached the optimal threshold, with specificity of 94% and sensitivity of 92%. Logistic regression analysis showed that 2-h mROX index < 4.45 was a protective factor for IMV (odd radio 0.18; 95% CI 0.05–0.64; p = 0.008). In the HFNC failure group, the median time from HFNC to IMV was 22.5 h. The 28-day mortality of the late intubation patients (≥ 22.5 h) was higher than that of the early intubation patients (< 22.5 h) (53.8% vs. 8.3%; p = 0.023).
mROX at 2 h is a good early warning index of the need for IMV in patients with COVID-19 after HFNC initiation. Early intubation may lead to better survival in patients with 2-h mROX index < 4.45.
Finding stable and bioavailable calcium supplements is crucial for addressing calcium deficiency. In this study, glycated peptide-calcium chelates (WMPHs-COS-Ca) were prepared from walnut meal ...protein hydrolysates (WMPHs) and chitosan oligosaccharides (COSs) through the Maillard reaction, and the structural properties and stability of the WMPHs-COS-Ca were characterized. The results showed that WMPHs and COSs exhibited high binding affinities, with a glycation degree of 64.82%. After glycation, Asp, Lys, and Arg decreased by 2.07%, 0.46%, and 1.06%, respectively, which indicated that these three amino acids are involved in the Maillard reaction. In addition, compared with the WMPHs, the emulsifying ability and emulsion stability of the WMPHs-COS increased by 10.16 mg
/g and 52.73 min, respectively, suggesting that WMPHs-COS have better processing characteristics. After chelation with calcium ions, the calcium chelation rate of peptides with molecular weights less than 1 kDa was the highest (64.88%), and the optimized preparation conditions were 5:1
/
for WMPH-COS/CaCl
s, with a temperature of 50 °C, a chelation time of 50 min, and a pH of 7.0. Scanning electron microscopy showed that the "bridging role" of WMPHs-COS changed to a loose structure. UV-vis spectroscopy and Fourier transform infrared spectrometry results indicated that the amino nitrogen atoms, carboxyl oxygen atoms, and carbon oxygen atoms in WMPHs-COS chelated with calcium ions, forming WMPHs-COS-Ca. Moreover, WMPHs-COS-Ca was relatively stable at high temperatures and under acidic and alkaline environmental and digestion conditions in the gastrointestinal tract, indicating that WMPHs-COS-Ca have a greater degree of bioavailability.
In biological systems, molecular assembly primarily relies on the assistance of molecular chaperones. Inspired by nature, strategies like ‘chaperone‐assisted assembly’ and ‘catalyzed assembly’ have ...been proposed for the sophisticated control of molecular assembly. Nonetheless, significant challenges remain in the rational design of such systems, calling for a deep understanding of underlying principles. Herein, we demonstrate an artificial chaperone serves a dual role, that is catalyst in low dosages and inhibitor in high dosages, in regulating the supramolecular polymerization of peptides. Low dosages of carboxymethyl cellulose, as the chaperones, catalyze the assembly of Aβ16‐22 peptides into fibrils through multi‐step phase separation, while high dosages trap the peptides into coacervate intermediates and therefore inhibit the fibrillation. Consequently, the quantity of chaperones does not follow the intuition that ‘more is better’ for catalyzing assembly but instead has an optimal molar ratio. Investigation reveals that the interplay and evolution of electrostatic and hydrophobic interactions are the keys to achieving these processes. This study provides insights into the multifaceted roles artificial chaperones may play in a dosage‐dependent manner and enriches the toolkit for efficient and controllable construction of complex assembly systems.
An artificial chaperone can serve opposite roles, a catalyst at low dosage while an inhibitor at high dosage, in regulating the supramolecular polymerization of peptides. This system undergoes a cascading phase separation process, and the interplay and evolution of electrostatic and hydrophobic interactions between chaperones and peptides are the keys to achieving these processes.
Distinct vascular patterns, including microvascular invasion (MVI) and vessels encapsulating tumour clusters (VETC), are associated with poor outcomes of hepatocellular carcinoma (HCC). Imaging ...surrogates of these vascular patterns potentially help to predict post-resection recurrence. Herein, a prognostic model integrating imaging-based surrogates of these distinct vascular patterns was developed to predict postoperative recurrence-free survival (RFS) in patients with HCC.
Clinico-radiological data of 1,285 patients with HCC from China undergoing surgical resection were retrospectively enrolled from seven medical centres between 2014 and 2020. A prognostic model using clinical data and imaging-based surrogates of MVI and VETC patterns was developed (n = 297) and externally validated (n = 373) to predict RFS. The surrogates (i.e. MVI and VETC scores) were individually built from preoperative computed tomography using two independent cohorts (n = 360 and 255). Whether the model's stratification was associated with postoperative recurrence following anatomic resection was also evaluated.
The MVI and VETC scores demonstrated effective performance in their respective training and validation cohorts (AUC: 0.851–0.883 for MVI and 0.834–0.844 for VETC). The prognostic model incorporating serum alpha-foetoprotein, tumour multiplicity, MVI score, and VETC score achieved a C-index of 0.748–0.764 for the developing and external validation cohorts and generated three prognostically distinct strata. For patients at model-predicted medium risk, anatomic resection was associated with improved RFS (p <0.05). By contrast, anatomic resection had no impact on RFS in patients at model-predicted low or high risk (both p >0.05).
The proposed model integrating imaging-based surrogates of distinct vascular patterns enabled accurate prediction for RFS. It can potentially be used to identify HCC surgical candidates who may benefit from anatomic resection.
MVI and VETC are distinct vascular patterns of HCC associated with aggressive biological behaviour and poor outcomes. Our multicentre study provided a model incorporating imaging-based surrogates of these patterns for preoperatively predicting RFS. The proposed model, which uses imaging detection to estimate the risk of MVI and VETC, offers an opportunity to help shed light on the association between tumour aggressiveness and prognosis and to support the selection of the appropriate type of surgical resection.
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•CT features were effective at estimating microvascular invasion and vessels encapsulating tumour clusters (VETC) patterns.•Nomogram incorporating both imaging surrogates showed informative recurrence prediction.•The nomogram may facilitate allocation of surgical candidates with hepatocellular carcinoma to the optimal type of resection.
APSES (Asm1p, Phd1p, Sok2p, Efg1p, and StuAp) family transcription factors play crucial roles in various biological processes of fungi, however, their functional characterization in phytopathogenic ...fungi is limited. In this study, we explored the role of SsStuA, a typical APSES transcription factor, in the regulation of cell wall integrity (CWI), sclerotia formation and pathogenicity of
, which is a globally important plant pathogenic fungus. A deficiency of
led to abnormal phosphorylation level of SsSmk3, the key gene
for UDP-GlcNAc synthesis was unable to respond to cell wall stress, and decreased tolerance to tebuconazole. In addition, Δ
was unable to form sclerotia but produced more compound appressoria. Nevertheless, the virulence of Δ
was significantly reduced due to the deficiency of the invasive hyphal growth and increased susceptibility to hydrogen peroxide. We also revealed that SsStuA could bind to the promoter of catalase family genes which regulate the expression of catalase genes. Furthermore, the level of reactive oxygen species (ROS) accumulation was found to be increased in Δ
. In summary, SsStuA, as a core transcription factor involved in the CWI pathway and ROS response, is required for vegetative growth, sclerotia formation, fungicide tolerance and the full virulence of
.
With the rapid development of smart cities in the world, research relating to smart city evaluation has become a new research hotspot in academia. However, there are general problems of cognitive ...deprivation, lack of planning experience, and low level of coordination in smart cities construction. It is necessary for us to develop a set of scientific, reasonable, and effective evaluation index systems and evaluation models to analyze the development degree of urban wisdom. Based on the theory of the urban system, we established a comprehensive evaluation index system for urban intelligent development based on the people-oriented, city-system, and resources-flow (PSF) evaluation model. According to the characteristics of the comprehensive evaluation index system of urban intelligent development, the analytic hierarchy process (AHP) combined with the experts’ opinions determine the index weight of this system. We adopted the neural network model to construct the corresponding comprehensive evaluation model to characterize the non-linear characteristics of the comprehensive evaluation indexes system, thus to quantitatively quantify the comprehensive evaluation indexes of urban intelligent development. Finally, we used the AHP, AHP-BP (Back Propagation), and AHP-ELM (Extreme Learning Machine) models to evaluate the intelligent development level of 151 cities in China, and compared them from the perspective of model accuracy and time cost. The final simulation results show that the AHP-ELM model is the best evaluation model.
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