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Patient-derived tumour organoids (PDOs) have revolutionised our understanding of cancer biology and the applications of personalised therapies. These advancements are principally ascribed to the ability of PDOs to consistently recapitulate and maintain the genomic, proteomic and morphological characteristics of parental tumours. Given these characteristics, PDOs (and their extended biobanks) are a representative preclinical model eminently suited to translate relevant scientific findings into personalized therapies rapidly. Here, we summarise recent advancements in PDOs from the perspective of cancer biology and clinical applications, focusing on the current challenges and opportunities of reconstructing and standardising more sophisticated PDO models. STATEMENT OF SIGNIFICANCE: Patient-derived tumour organoids (PDOs), three-dimensional (3D) self-assembled organotypic structures, have revolutionised our understanding of cancer biology and the applications of personalised therapies. These advancements are principally ascribed to the ability of PDOs to consistently recapitulate and maintain the genomic, proteomic and morphological characteristics of parental tumours. Given these characteristics, PDOs (and their extended biobanks) are a representative preclinical model eminently suited to translate relevant scientific findings into personalized therapies rapidly.

To retrospectively evaluate the clinical efficacy and safety of percutaneous kyphoplasty (PKP) for the management of osteoblastic-related metastatic vertebral lesions.A total of 31 patients with 58 osteoblastic-related metastatic vertebral lesions underwent PKP were reviewed. The clinical efficacy was assessed based on parameters including visual analogue scale, Oswestry Disability Index, vertebral body height variation and quality of life. Major and minor complications were systematically evaluated to assess the safety of the procedure.Average follow-up period was 22.5 ± 11.1 months(range, 3 to 46 months). The procedure duration time ranged from 50 to 180 minutes (average 96.8 ± 36.9 minutes). Mean visual analogue scale scores decreased significantly from 6.1 ± 1.8 pre-operatively to 2.7 ± 1.5 at 3 days after PKP (p0.001), and remained largely immutable at 1 month (2.0 ± 0.7; 31 patients; p0.001), 3 months (2.4 ± 1.2; 30 patients; p0.001) and 1 year (3.0 ± 1.0; 27 patients; p0.001). Oswestry Disability Index scores and vertebral body height variation also changed after the procedure, with significant differences between pre-operative scores and at each follow-up examination (p0.001). Mean quality of life scores were 90.8 ± 12.9 pre-operatively and improved to 99.5 ± 12.1(27 patients, p0.001) at 1 year after PKP. The only minor encountered complication was bone cement leakage, which was seen in 6.5%(2 of 31) of patients. None of the patients experienced major complications.PKP is a safe and effective treatment strategy for osteoblastic-related metastatic vertebral lesions from a variety of tumor etiologies.

A highly efficient and environmentally benign 1,3-dipolar cycloaddition of C, N - cyclic azomethine imines with 5-alkenyl thiazolones and 2-arylidenindane-1,3-diones is developed for the construction of congested quaternary spiro-carbon centers. All these transformations can be smoothly performed in ethanol at room temperature, providing a catalyst-free and atom-economical access to diversely substituted novel isoquinoline-fused spirocycles in almost quantitative yields with high diastereoselectivities. The promising anti-tumor activity of these structurally novel spirocyclic compounds is reported as well.

Background Few studies examining the impact of metabolic syndrome and depressive symptoms on subsequent functional disability are available. Objectives To determine the impact of baseline metabolic syndrome and depressive symptoms on subsequent functional disability. Methods This study used data from the 2011 baseline and 2013, 2015 and 2018 follow-up waves of the China Health and Retirement Longitudinal Study (CHARLS). Functional status was assessed by activities of daily living (ADLs) and instrumental ADLs (IADLs). Analyses were restricted to middle-aged and older adults (≥50 years) free of functional disability at baseline. Metabolic syndrome, depressive symptoms, and covariates were measured at baseline. New-onset ADL and IADL disability were obtained in follow-up measurements. Competitive risks based on survival analysis were conducted to examine the impact of baseline metabolic syndrome and depressive symptoms on subsequent functional disability after covariates were controlled. Results Baseline depressive symptoms significantly predicted functional disability over a 7-year follow-up after adjusting for covariates (Hazard ratio [HR] = 1.54, 95% confidence intervals [CI] = 1.40–1.70 for ADL disability; HR=1.36, 95% CI=1.25–1.48 for IADL disability). Metabolic syndrome significantly predicted ADL disability (HR=1.25, 95% CI=1.14–1.38) but not IADL disability (HR=1.02, 95% CI=0.94–1.10). No significant additive interaction between metabolic syndrome and depressive symptoms on functional disability was found. Conclusion The current study found that baseline depressive symptoms were significantly associated with both ADL and IADL disabilities, while metabolic syndrome significantly predicted ADL disability. In addition, some indications showed that the effect in those with both conditions was greater than the sum of the effects separately.

Inclusion is often considered a crux of diversity management. However, little is known about how board diversity affects corporate performance through organizational inclusive behavior. Using the inventor-level patenting data, we find that firms with more ethnic minority directors attract more productive ethnic minority inventors and promote greater collaboration among inventors, leading to more patents and patents with greater market value. Our findings are robust to a battery of sensitivity tests. Overall, our study offers new evidence that racially diverse boards cultivate inclusive environment for inventors to succeed.

To compare the clinical and radiographic results of bipedicular and unipedicular approaches(UPK and BPK) in the management of metastatic vertebral lesions MATERIALS AND METHODS: Eighty-two patients with 159 metastatic vertebral lesions who underwent UPK(25 cases, 69 lesions) or BPK(57 cases, 90 lesions) were retrospectively evaluated. Clinical results were assessed mainly depending on the Visual Analogue Scale(VAS) score, Oswestry Disability Index(ODI) and Quality of Life(QoL). Radiographic outcomes were evaluated primarily on the basis of bone cement distribution and changes in vertebral body height(VBH). Major and minor complications were systematically evaluated and compared to assess the safety of the 2 procedures.No statistically significant differences were observed in age, sex, types of lesions, location of lesions, posterior vertebral body and/or pedicle involvement, percentage of vertebra invasion between the groups(p=0.17-0.83). The radiographic parameter VBH was similarly improved in both groups(p=0.26-0.93). There was a significant improvement in the clinical parameters VAS score, ODI, and QoL at each follow-up examination compared with the preoperative results(p0.001). Significant improvement was observed in the VBH at each follow-up point(p0.05) compared to pre-procedure. UPK was superior to BPK in terms of the operative duration(p0.001), cement volume(p=0.004), and surgical complications(p=0.04).Both UPK and BPK resulted in similar clinical and radiographic outcomes in patients with metastatic vertebral lesions. The UPK had advantages including a shorter operation and lower cement volume than the BPK, which may have played an important role in reducing the incidence of complications. UPK can replace BPK in the treatment of metastatic vertebral lesions.

Methylmercury (MeHg) is a potential neurotoxin that is highly toxic to the human central nervous system. Although MeHg neurotoxicity has been widely studied, the mechanism of MeHg neurotoxicity has not yet been fully elucidated. Some research evidence suggests that oxidative stress and autophagy are important molecular mechanisms of MeHg-induced neurotoxicity. Researchers have widely accepted that oxidative stress regulates the autophagy pathway. The current study reviews the activation of Nuclear factor-erythroid-2-related factor (Nrf2)-related oxidative stress pathways and autophagy signaling pathways in the case of MeHg neurotoxicity. In addition, autophagy mainly plays a role in the neurotoxicity of MeHg through mTOR-dependent and mTOR-independent autophagy signaling pathways. Finally, the regulation of autophagy by reactive oxygen species (ROS) and Nrf2 in MeHg neurotoxicity was explored in this review, providing a new concept for the study of the neurotoxicity mechanism of MeHg.

Methylmercury (MeHg) is a long-lasting organic environmental pollutant that poses a great threat to human health. Ingestion of seafood containing MeHg is the most important way by which it comes into contact with human body, where the central nervous system (CNS) is the primary target of MeHg toxicity. During periods of pre-plus postnatal, in particular, the brain of offspring is vulnerable to specific developmental insults that result in abnormal neurobehavioral development, even without symptoms in mothers. While many studies on neurotoxic effects of MeHg on the developing brain have been conducted, the mechanisms of oxidative stress in MeHg-induced neurodevelopmental toxicity is less clear. Hitherto, no single process can explain the many effects observed in MeHg-induced neurodevelopmental toxicity. This review summarizes the possible mechanisms of oxidative stress in MeHg-induced neurodevelopmental toxicity, highlighting modulation of Nrf2/Keap1/Notch1, PI3K/AKT, and PKC/MAPK molecular pathways as well as some preventive drugs, and thus contributes to the discovery of endogenous and exogenous molecules that can counteract MeHg-induced neurodevelopmental toxicity.

Limited and censored time-to-failure data are common in practical life testing, which may lead to a lack of knowledge, i.e., epistemic uncertainties, and makes it difficult to evaluate product reliability accurately. Under this situation, the large-sample based probability theory is not appropriate anymore. To deal with such problem, in this paper, the uncertainty theory based reliability evaluation is proposed to cope with the limited and censored time-to-failure data, where two types of life testing censoring (type-I and type-II censoring) and two types of time-to-failure data (precise and interval data) are considered. Firstly, the lifetime model and reliability evaluations based on uncertainty theory are presented. Then, the uncertain statistics method is presented for each combination of censoring types and data types in life testing, which includes four steps: order statistics construction, belief degree construction according to the Laplace principle of indifference, parameter estimation based on the uncertain principle of least squares, and uncertain hypothesis testing. Two simulation studies and two practical cases with comprehensive and in-depth discussion are conducted to illustrate the practicability and effectiveness of the proposed method. The results show that the proposed method can quantify epistemic uncertainties properly and provide more stable and accurate mean time to failure results under limited and censored time-to-failure data compared with probability and Bayesian probability methods.

Introduction High altitude polycythemia (HAPC) is a common chronic disease at high altitudes. It is characterized by excessive erythrocytosis (≥190 g·L-1 in females or ≥210 g·L-1 in males). HAPC severely jeopardizes the health status of plateau dwellers. The Qinghai-Tibet plateau, with an elevation above 4000 m, is the highest plateau in the world. Both Han and Tibetan populations residing there face the threat of HAPC. Therapeutic erythrocytapheresis (TE) was introduced to Tibet as an alternative to phlebotomy in 2015. Methods In this study, we retrospectively analyzed 155 patients with HAPC treated with TE in Tibet. Routine blood testing values before and after TE were compared to evaluate treatment efficacy. The efficiency rate, defined as the rate of increase in red blood cell depletion attained by TE compared with 450 mL whole blood phlebotomy, was calculated using whole blood volume and hematocrit before and after treatment and used to identify patients who maintained a normal hemoglobin level in the year after the TE procedure. Results On average, TE reduced red blood cell levels by 1.5×1012·L-1, hemoglobin concentration by 52 g·L-1, and hematocrit by 14% (P Conclusions TE is a feasible therapeutic method to treat HAPC on the Qinghai-Tibet plateau. The efficiency rate is a useful tool to predict the expected interval between TE procedures.

Hypothesis G-quadruplex structure has raised increasing attention in supramolecular chemistry as an effective template for ordered functional materials. Thus, it is of practical significance to advance our understanding regarding G-quadruplex structures. Typically, G-quadruplex structures are formed in the presence of suitable metal ions. New methods to construct such structures need to be explored. Experiments The supramolecular assembly between CTAB and a guanosine derivative at different molar ratios was systematically studied, including assembly mechanisms, morphology, and macroscopic properties. Cationic surfactants with different alkyl chains were studied as control experiments. Findings A novel strategy to construct G-quadruplex with the promotion of the cationic surfactant CTAB is presented in this work. The structure-property relationships of G-quadruplex gels are characterized by rheology and shrinkage ratio experiments. MacKintosh’s theory was used to rationalize the relationship between gel elasticity and water content. The transition of G-quadruplex structures could be easily enabled by modulating CTAB concentration, which promotes the phase transition from gel/sol biphase to homogeneous sol phase. This work will provide a new viewpoint for the construction and modulation of G-quadruplex structures.

How post-burial terrestrial in situ cosmogenic nuclides (TCN) production is build-up in slow burial condition remains uncertain. In this study, we dated high fluvial terrace sediments that overlain by loess with a slow deposition rate that is based on the assumption of steady accumulation rate via 26Al/10Be burial dating method. For sample in deep and rapid buried condition prior to slow overlying, post-burial production shows low component (4–6%) in measured concentration. However, post-burial production occupied 39–79% of measured 26Al and 10Be concentrations, which suggests approximately 0.2–0.3 Ma underestimation in simple burial dating mode if post-burial production is neglected. Corrected by post-burial production, we yielded burial ages of two top terraces (ca. 1.7–2.5 Ma and 1.5 Ma, respectively) below the Tangxian planation surface along the Jinshan Gorge of the Yellow River, implying that the Jinshan Gorge initially incised at ca. 1.7–2.5 Ma, corresponding well to regional tectonic activities, such as extension in the Fenwei Graben, accelerative uplift of the Tangxian planation surface, vigorous dissection of North China, and significant tectonic deformation in northeastern Tibetan Plateau. The slow burial mode is probably a potential method for plateau paleo-elevation estimation taking advantage of height sensitivity of TCN production rate if overlying loess magnetostratigraphic age is known.

At present, a variety of lubricating oils are available for R290 room air conditioners (RACs). R290 is highly miscible with mineral oils (MOs), while it is partially miscible with some alkylene oils (PAGs). In this paper, the oil retention behavior of a 1.5 HP R290 RAC with two miscible MOs and two partially miscible PAGs was studied. Firstly, the OCR of a R290 rotary compressor with PAG VG60 or MO VG100 was measured in compressor performance test platform, and it was 0.66–0.88%. Then the oil retention and its mass distribution within the RAC using PAG VG60 or MO VG100 were measured by Remove and Weight Technique (RWT) and Mix and Sample Technique (MST). And then, the oil retention when using PAG VG40 or MO VG56 was measured by RWT for further comparison. Results showed that the oil retention was 1.9–8.2 g, only 0.79%–3.9% of the total oil quantity. The oil mass in heat exchangers was nearly proportional to the local refrigerant mass, while that in gas line was greatly affected by the viscosity grade of oil. It was verified that the miscibility effect of the R290/PAG mixture was mild on this R290 RAC, and the viscosity grade of oil was the most critical parameter for the oil retention in the gas line.

Application of heterogeneous advanced oxidation processes (AOPs) for wastewater treatment suffers from the low oxidant utilization efficiency, slow catalytic cycling and severe matrix interference. Herein, we report that amorphous zirconium dioxide (aZrO

We aimed to investigate the clinical outcomes of percutaneous kyphoplasty (PKP) for spinal metastases in older adult patients with comorbidities.Ninety-two older adults (age ≥ 60 years) with spinal metastases who underwent 148 PKP procedures were retrospectively analyzed. Tokuhashi scores, Tomita scores, age-adjusted Charlson Comorbidity Index (aCCI) scores, and American Society of Anesthesiologists (ASA) scores were evaluated before the procedure. The visual analog scale (VAS), Oswestry Disability Index (ODI), vertebral body height (VBH), and quality of life (QoL) were used to assess the efficacy of the procedure. Clinical safety was evaluated based on periprocedural complications.Tokuhashi scores and Tomita scores were 7.3 ± 4.0 and 5.8 ± 2.1, respectively. Excluding cancer-related factors, twelve patients (13.0%) had aCCI scores ≥4. Forty-three patients (46.7%) had ASA status ≥ III. Compared to preoperative status, average VAS scores, ODI scores, VBH variation, and QoL scores significantly improved at each follow-up examination point after PKP (p 0.001). No major complications occurred, nor was there decompensation of comorbidities in the perioperative period. Seventeen segments (11.5%) of twelve patients (13.0%) suffered bone cement leakage. Among them, one patient suffered intercostal neuralgia cured by steroid injection, and the other patient suffered hyperesthesia, which disappeared after taking gabapentin (0.3 g, bid) for five weeks. Another minor complication of local hematoma occurred in one patient, which spontaneously resolved without surgical intervention.PKP serves as a safe approach to provide significant pain relief, vertebral body height restoration, and QoL improvements for spinal metastases in older adults, independent of underlying disease.

The New Delhi β-Lactamase 1 (NDM-1), one of the most prevalent types of metallo-β-lactamases, has attracted extensive attention since its discovery. Extensive efforts have been made to develop inhibitor of NDM-1, however, no inhibitor is available clinically so far. It is reported that Benzo[d][1,2]selenazol-3(2H)-one derivatives as covalent NDM-1 inhibitors can restore the efficacy of meropenem against NDM-1producing strains. In this study, 38 novel benzo or pyrido[d][1,2]selenazol-3(2H)-one derivatives were designed based on NDM-1 protein structure and structure-activity relationships study. Representative compound 15l exhibits significant synergistic antibacterial activity with meropenem against NDM-1 producing carbapenem-resistant Enterobacteriaceae (CRE) isolates, especially clinical CRE isolates (FIC indices ranging from 0.0625 to 0.25). ESI-MS analysis demonstrats that 15l covalently binds to NDM-1 enzyme, and the IC

Nineteen TH03 analogues were designed and synthesized as tubulin colchicine-binding site inhibitors with potent antiproliferative activities. Among these compounds, 3,5-dimethoxyphenylpyridines 8j bearing a 4-methoxybenzyl aniline side-chain displayed the best antiproliferative activities against glioma (U87MG and U251). In addition, the trimethoxyphenylpyridine 8o bearing a 4-methyl-N-methyl aniline side-chain showed the best antiproliferative activities against colon carcinoma and lung cancer with the lowest IC

Using auto-planning, the dosimetric and biological differences between PET- and CT-based target delineation in LA-NSCLC were studied. Twenty-three patients with IIIA-IIIB NSCLC were included in this retrospective study. For each patient, two AP plans (Plan_PET, Plan_CT) were generated based on PET- and CT-based gross tumor volume (GTVPET, GTVCT). The volume, boundary and center of mass (COM) of GTVPET and GTVCT were compared. Dosimetric indicators such as mean lung dose (MLD) and so on were evaluated. Tumor control probability (TCP) of GTVPET and GTVCT and normal tissue complication probability (NTCP) of total lung and heart were calculated. A paired-samples t-test was used to check for significant differences (p

Apigenin (API) is a plant flavone that is known to exert a protective effect in rheumatoid arthritis (RA), which is a chronic autoimmune disease. However, the molecular mechanism for API's protective effect against RA is still unclear. Here, a collagen-induced arthritis (CIA) mouse model was used to assess the protective effect of API on RA. Histomorphological studies, immunohistochemistry, RT-PCR, and western blot were conducted to elucidate the roles of synovial hyperplasia, angiogenesis, and osteoclastogenesis in the protective effect of API on RA. Fibroblast-like synoviocytes (FLSs) were isolated to measure the effect of API on FLS proliferation and apoptosis. API exhibited a significant protective effect in CIA mice in a dose- and time-dependent manner. An increase in apoptosis and decrease in proliferation were observed after the API treatment in FLSs, suggesting that API might inhibit synovial hyperplasia. Moreover, CIA angiogenesis was repressed by API via down-regulation of VEGF and VEGFR. Furthermore, API regulated the osteoclastogenesis-associated RANKL/RANK/OPG system in CIA mice. Therefore, API inhibits CIA by repressing synovial hyperplasia, angiogenesis, and osteoclastogenesis. This suggested that API might be a putative low toxicity candidate drug for RA treatment.

Landscape pattern evolution leads to changes of landscape spatial structure, which are intuitively reflected in the changes of ecosystem structure and composition and finally affect ecological security. In this paper, we assessed the spatiotemporal variation of the ecological security and landscape pattern of the middle and lower reaches of Shule River Basin in 1987–2015. Further, we analyzed the correlation between the ecological security and landscape pattern of the study region and correlation coefficients were calculated. On this basis, the key landscape pattern indices influencing the ecological security of the study region were identified. This may provide useful information for ecological regulation and design. The results show that: (1) From 1987 to 2015, the ecological security in the middle and lower reaches of the Shule River Basin was of medium or low level, showing periodic “U” shaped fluctuations, and the fluctuation period was gradually shortened. In addition, there was an overall spatial pattern of “high ecological security in the west, middle and south and low ecological security in the east”. (2) The landscape pattern showed clear stage characteristics. The complexity of landscape pattern increased from 1987 to 1996 and decreased after 1996. (3) Landscape size, shape, quantity, type and spatial configuration had important impacts on ecological security and showed significant temporal variation. In a period when the influence of human activities was weak, ecological security was mainly related to landscape area indices. With increase in human activities, landscape shape, fragmentation and connectivity changed greatly, which led to changes in the structure and composition of ecosystem, thus finally affecting ecological security.

China started to establish export processing zones (EPZs) in 2000 to better manage foreign processing business. The cluster of export processing business inside the EPZs provides an opportunity for neighboring Chinese firms to observe. Chinese firms quickly imitate foreign exporters in both export and import patterns. Exports of the exact products shipped from EPZs immediately increase throughout the province, with the largest gains in the city containing the EPZ, and the next largest in the cities adjacent to the EPZ. Chinese firms also import the same equipment imported by firms in EPZs, suggesting that they imitate foreign technology. Furthermore, we find that Chinese firms who imitate experience modest gains in profitability and productivity. We conclude that a key ingredient of China’s success in trade has been its ability to attract foreign capital and subsequently imitate them.

Struvite crystallization is one of the most promising routes for phosphorus recovery from phosphorus-rich sludge. However, the adsorption of alginic acid, a surrogate of extracellular polymeric substances in phosphorus-rich sludge, on struvite crystals has been proved to significantly inhibit struvite crystallization. To comprehensively understand the inhibitory mechanism, the adsorption behavior was evaluated at various adsorption time, the concentration of alginic acid, pH and ionic strength in the present study. Subsequently, adsorption equilibrium isotherm, kinetic and thermodynamics models were employed to fit the adsorption data. Interestingly, the adsorption mechanism was explored by X-ray photoelectron spectra (XPS) and Fourier transform infrared spectroscopy analysis (FTIR), which was further elucidated by triple-layer model (TLM). The results indicated that the adsorption capacity of struvite crystals almost reached a plateau value within the first 30 min. Meanwhile, the adsorption capacity was significantly reduced with increasing pH, but slightly increased with increasing ionic strength. Moreover, the adsorption process obeyed pseudo-second order kinetic model and Langmuir adsorption isotherm model, whereas intra-particle diffusion was a main rate-limited step. Furthermore, hydrogen bonding and surface complexation between alginic acid and struvite crystals dominated the adsorption mechanism. Additionally, alginic acid underwent surface reactions by virtue of two outer-sphere surface complexes and one inner-sphere surface complex. The findings presented herein will facilitate understanding of the inhibitory mechanism of organic matters on struvite crystallization from phosphorus-rich sludge.