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Between 1958 and 1999, notable lithic localities recorded prehistoric activities in Xiqiao Town of Nanhai District, Foshan City, Guangdong Province, from which double-shouldered and microlith-stone artefacts were uncovered. Currently, the "Xiqiaoshan site" is recognized as a substantial Neolithic quarry and processing location, dating back to 4‒7 ka B P. Subsequently, from 2011 to 2022, we conducted multiple geological environmental surveys and analyses on Xiqiaoshan Mountain. A well-preserved Quaternary stratigraphic profile was discovered north of Fuxian village in the southeast foothills of Xiqiaoshan Mountain. The sedimentological, geochemical, and geochronological results indicate the presence of two primary sedimentary strata in the Fuxian locality. The upper unit comprises the Holocene swamp facies, with a calibrated AMS14C dating range from 5052‒5409 a B P; whereas, the lower unit comprises the late Pleistocene alluvial-diluvial strata, with a calibrated AMS14C dating range from 38420‒40502 a B P, and an optically stimulated luminescence (OSL) dating range of 41.977‒43.796 ka B P. Late Pleistocene strata yielded two sand-gravel layers containing Paleolithic artefacts, which are marked as layers A1 and A2. The predominant artefacts in lower layer A1 include larger scrapers, pointed tools, tongue-shaped edged tools, and small flake tools, such as various scrapers, denticulates, notches, knives, utilized flakes, and cores, including tanged axe-shaped knives. In the upper layer A2, backed or tanged knives appear more frequently. The other small flake tools from this layer (A2) were not significantly different from those in lower layer A1. One bifacially prepared core for producing small elongated flakes is of particular interest for this artefact. Based on the average deposition rate, the computational age of the A1 layer was 46.511‒47.325 ka B P, whereas that of the A2 layer was 41.977‒42.167 ka B P. Although the number of artefacts within the Holocene sediments (>5 ka B P) overlying the late Pleistocene strata is limited, the characteristics of inheritance and development are still evident in the types of artefacts. The discovery presented in this study has completely updated and extended the connotation of Xiqiaoshan National Geopark and "Xiqiaoshan culture,"breaking through the late Pleistocene Paleolithic remains records with exact dating in the Pearl River Delta region for the first time. Therefore, a ground-breaking discovery can accurately trace the footsteps of modern humans in the coastal areas of South China from 40‒50 ka. It also reveals the rich features of lithic industry and the developmental characteristics and evolution of its cultural connotations during this period. The present study shows that during the relatively warm and humid conditions of marine isotope stages 3 (MIS3) interglacial period and the subsequent cold and arid stage of MIS2, human population in the Fuxian locality encountered environmental challenges and adopted new subsistence strategy, which is of great significance for understanding modern human responses and adaptations to global and regional environmental and climate change.

Purpose: The incidence of hemodynamic instability associated with dexmedetomidine (DEX) sedation has been reported to exceed 50%, with substantial inter-individual variability in response. Genetic factors have been suggested to contribute significantly to such variation. The aim of this study was to identify the clinical, pharmacokinetic, and genetic factors associated with DEX-induced hemodynamic instability in pediatric anesthesia patients. Methods: A cohort of 270 pediatric patients scheduled for elective interventional surgery received an intranasal dose of 3 mcg·kg-1 of dexmedetomidine, and subsequent propofol induction was conducted when patients had a UMSS of 2–4. The primary endpoint was hemodynamic instability—defined as a composite of hypotension and/or bradycardia, which is characterized by a 20% reduction from age-specific baseline values. Plasma concentrations of dexmedetomidine were determined, and single-nucleotide polymorphisms (SNPs) were genotyped. A validated population pharmacokinetic model was used to estimate pharmacokinetic parameters. LASSO regression was used to identify significant factors, and a Cox's proportional hazards model-derived nomogram for hemodynamic instability was developed. Results: Hemodynamic instability was observed in 52 out of 270 patients (209 events), resulting in a cumulative incidence of 16.30% at 90 min, as estimated by Kaplan–Meier estimation, and it was associated with a median time to event of 35 min. The interval time between DEX initiation and propofol induction was 16 min (IQR: 12–22 min). The cumulative incidence was 8.2% within 22 min after DEX initiation. The identified significant risk factors for DEX-associated hemodynamic instability included weight, DEX clearance, concomitant propofol use, and the following gene variants UGT2B10 rs1841042 (hazard ratio (HR):1.41, 95% confidence interval (CI): 1.12–1.79), CYP2A6 rs8192733 (HR:0.28, 95%CI:0.09–0.88), ADRA2B rs3813662 (HR:1.39,95%CI:1.02–1.89), CACNA2D2 rs2236957 (HR:1.46, 95%CI:1.09–1.96), NR1I2 rs3814057 (HR:0.64, 95%CI:0.43–0.95), and CACNB2 rs10764319 (HR:1.40,95%CI:1.05–1.87). The areas under the curve for the training and test cohorts were 0.881 and 0.762, respectively. The calibration curve indicated excellent agreement. Conclusion: The predictive nomogram, which incorporates genetic variants (UGT2B10, CYP2A6, ADRA2B, CACNA2D2, NR1I2 , and CACNB2) along with clinical factors such as weight, DEX clearance, and propofol use, may help prevent DEX-associated hemodynamic instability. Delayed hemodynamic instability is likely to occur after 35-min DEX initiation in patients with lower DEX clearance after propofol induction. [ABSTRACT FROM AUTHOR]

Vancomycin has a narrow therapeutic window and a high inter‐individual pharmacokinetic variability, especially in neonates with fast maturational and pathophysiological changes, that needs individualized dosing. Physiologically based pharmacokinetic (PBPK) model and population pharmacokinetic (PopPK) model are both useful tools in model‐informed precision dosing, while the former is under research in application of vancomycin in neonates. This study aimed to develop a PBPK model of vancomycin in adult and pediatric population, and compared it with published PopPK model (priori or Bayesian method) in predicting vancomycin concentration in 230 neonatal patients (postmenstrual age, PMA, 25‐45 weeks). The developed PBPK model showed a good fit between predictions and observations. PBPK model and PopPK model are complementary in different clinical scenarios of vancomycin application. The physiological‐change description of PBPK model showed a superior advantage in initial dosing optimization. As for subsequent dose optimization, PopPK Bayesian forecasting performed better than the PBPK estimation in neonates. However, initial precision dosing tools for early neonates (with PMA < 36 weeks) still need further exploitation. [ABSTRACT FROM AUTHOR]

Anlotinib and osimertinib are a class of tyrosine kinase inhibitors for the treatment of malignant tumor. The combination of anlotinib and osimertinib is currently used for treating non-small cell lung cancer (NSCLC) patients. This study aimed to develop a simple and rapid isotope-labeled UHPLC–MS/MS method for the simultaneous determination of anlotinib and osimertinib in human plasma. The analytes were extracted by protein precipitation with acetonitrile and were then separated on a Shim-pack GIST C18 column. The detection was performed on Shimadzu 8050 triple quadruple mass spectrometer in the positive electrospray ionization mode with multiple reaction monitoring. The precursor-to-product ion transitions were m/z 408.10→ 339.75, 500.25→ 72.20 and 413.50 → 344.50 for anlotinib, osimertinib and D5-anlotinib, respectively. Validation is based on US Food and Drug Administration guidelines. The linearity ranges were 0.5–100 ng/mL for anlotinib and were 1–500 ng/mL for osimertinib with the correlation coefficients (r  2) ≥ 0.99. Accuracy and precision, matrix effect, extraction recovery and stability of anlotinib and osimertinib were acceptable after validation. The UHPLC–MS/MS method was successfully validated and was applied to monitor the concentration of anlotinib and osimertinib in NSCLC patients. [ABSTRACT FROM AUTHOR]

Previous exposure‐response analyses for rituximab suggest that higher rituximab concentrations were associated with an improvement in efficacy, however, clinical studies investigating a higher rituximab dose had mixed results. To further explore the exposure‐response relationship of rituximab, a prospective observational analysis was performed involving 121 newly diagnosed patients with diffuse large B‐cell lymphoma treated with triweekly rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R‐CHOP). The trough concentration in the first cycle (C1‐trough) was significantly higher in patients achieving complete response (CR) compared with patients that did not achieve CR (22.00 μg/ml vs. 16.62 μg/ml, p = 0.0016), however, this difference between the two groups disappeared in later cycles. The relationship between rituximab C1‐trough and achieving a CR was confirmed by matched‐pair logistic regression analysis (odds ratio, 0.79; p = 0.0020). In addition, a higher C1‐trough (≥18.40 μg/ml) was associated with longer progression‐free survival (p < 0.0001) and overall survival (p = 0.0038). The percentages of patients that did not achieve a CR and had recurrence after CR within 24 months were 35% and 22.50%, respectively, for patients with a C1‐trough less than or equal to 18.40 μg/ml, compared with 12.35% and 6.17% for patients with C1‐trough greater than 18.40 μg/ml. Disease stage was found to be the most significant influencing factor of C1‐trough, with 51.02% of patients at stage IV with an observed C1‐trough less than 18.40 μg/ml. For these advanced patients, population pharmacokinetic simulations using an established model suggest that a loading dose of 800 mg/m2 may help to improve clinical outcomes. [ABSTRACT FROM AUTHOR]

Human Atg4 homologs are cysteine proteases, which play key roles in the macroautophagy/autophagy process by cleaving Atg8 homologs for conjugation to lipid membranes and for deconjugation of Atg8 homologs from membranes. Expression of ATG4B is significantly increased in colorectal cancer cells compared to normal cells, suggesting that ATG4B may be important for cancer biology. Inhibition of ATG4B may reduce the autophagy activity, thereby sensitizing cancer cells to therapeutic agents. Thus, developing specific and potent ATG4B inhibitors for research as well as for potential therapeutic uses is highly needed. In this study, we integrated in silico screening and in vitro assays to discover a potent ATG4B inhibitor, named S130, from a noncommercial library. This chemical binds to ATG4B with strong affinity and specifically suppresses the activity of ATG4B but not other proteases. S130 did not cause the impairment of autophagosome fusion, nor did it result in the dysfunction of lysosomes. Instead, S130 might attenuate the delipidation of LC3-II on the autolysosomes to suppress the recycling of LC3-I, which normally occurs after LC3-II cleavage by ATG4B. Intriguingly, S130 induced cell death, which was accompanied with autophagy stress and could be further exacerbated by nutrient deprivation. Such cytotoxicity could be partially reversed by enhancing ATG4B activity. Finally, we found that S130 was distributed in tumor tissues in vivo and was also effective in arresting the growth of colorectal cancer cells. Thus, this study indicates that ATG4B is a potential anticancer target and S130 might be a novel small-molecule candidate for future cancer therapy. [ABSTRACT FROM AUTHOR]

BACKGROUND Coaxial electrospray is an emerging technology to produce multilayer micro- and nano-particles ( NPs) with well controlled shape and size. ALA-PDT is a fascinating technology used in the treatment for skin and other cancers. In this work, ALA-loaded poly(lactide-co-glycolide) ( PLGA) ( PLGA-ALA) NPs with high drug loading efficiency were produced via coaxial electrospray and used for the PDT treatment in HSC-3 cells. RESULTS Results showed that 200-1000 nm PLGA-ALA NPs with 60-75% ALA loading efficiency were successfully produced. ALA and PLGA were well integrated and no extra chemical reaction occurred during the electrospray. PLGA-ALA NPs displayed a delayed release of ALA in PBS solution up to 7 days. A massive accumulation of PpIX in HSC-3 cells happened after the incubation of PLGA-ALA NPs. With light irradiation, these PLGA-ALA NPs showed a remarkable cytotoxicity against HSC-3 cells, leading to 40-70% cell death depending on the incubation dose. CONCLUSIONS Coaxial electrospraying is a facile method to prepare PLGA-ALA NPs with high drug loading content and efficiency, and PLGA-ALA NPs turned out to be an effective vehicle for delivering ALA to tumor cells. © 2015 Society of Chemical Industry [ABSTRACT FROM AUTHOR]

Nano-solid-base catalyst K2O/ γ-Al2O3 was prepared and adopted for the synthesis of biodiesel by transesterification of rapeseed oil with methanol. The particle diameter of the catalyst was about 50 nm, which was measured by transmission electron microscopy (TEM). The variables affecting the yield of biodiesel during transesterification, such as mass ratio of KNO3 to γ-Al2O3, calcination temperature, calcination time, and catalyst content, molar ratio of methanol to oil, reaction temperature and reaction time were investigated. The catalyst obtained by calcining a mixture of KNO3 and γ-Al2O3 $$ ({{m_{KNO_3 } } \mathord{\left/ {\vphantom {{m_{KNO_3 } } {m_{\gamma - Al_2 O_3 } }}} \right. \kern-\nulldelimiterspace} {m_{\gamma - Al_2 O_3 } }} = 70\% ) $$ at 600 °C for 3 h, was found to be the optimum one, which gave the highest catalytic activity in reaction. With 3% ( m catalyst/ m oil) catalyst, when the transesterification carried out at a molar ratio of methanol to oil 12:1, a reaction temperature of 70 °C, and a reaction time of 3 h, yield of 94% was achieved. [ABSTRACT FROM AUTHOR]