Podophyllotoxin is an important and much sought after antimitotic natural lead compound, since it paved the way for three hemisynthetic derivatives of podophyllotoxin, e.g., etoposide, teniposide and ...etopophos, which are widely used as anticancer drugs and show good clinical effects against several types of neoplasms. Although the publication of the recent reviews by Gordaliza in 2004 and You in 2005, which covered the literatures concerning podophyllotoxin until the early part of 2003, there have been significant number of works carried out on podophyllotoxin recently. Therefore, this review presents up-to-date coverage of podophyllotoxin in regard to hemisynthesis, biosynthesis, biological activities, mode of action and structure-activity relationship.
Background:
Despite the acknowledged benefits of immune checkpoint inhibitor (ICI)-based combination therapy (either with other checkpoint inhibitors, chemotherapy, targeted therapy, or ...radiotherapy), little is known about the impact of age on the efficacy of ICI -based combination therapy in non-small-cell lung cancer (NSCLC) patients. We conducted a systematic review and meta-analysis to investigate the differences in the benefits of ICI-based combination therapy for NSCLC by age (cut-off age, 65 years).
Methods:
We systematically searched randomized controlled trials (RCTs) of ICI plus other therapies including other ICIs, chemotherapies, targeted therapies, or radiotherapies, in the PubMed, Embase, and Cochrane databases with available hazard ratios (HRs) and 95% confidence intervals (CIs) for death and disease progression according to patient age. The search deadline was May 25, 2020. First, we calculated the pooled HRs of younger and older patients based on the HRs from each trial. Second, we assessed the pooled ratio of HRs reported in older patients to the HRs reported in younger patients for progression or death by the random-effects model. An estimated pooled HR ratio was lower than 1 indicating a better effect in older patients and higher than 1 indicating a better effect in younger patients.
Results:
A total of 10 eligible RCTs were included in our meta-analysis. The pooled HR for overall survival (OS) comparing ICI combined with other therapies to non-ICI regimens was 0.67 (95%CI 0.58–0.78) for younger patients and 0.79 (95%CI 0.70–0.90) for older patients. The pooled HRs ratio for OS reported in older patients compared to younger patients was 1.16 (95%CI 0.99–1.34), indicating no statistically significant difference between younger and older patients. Consistent with the findings related to OS, the analysis also demonstrated that ICI-based immunotherapy could significantly prolong progression-free survival (PFS) in younger and older patients (HR = 0.55; 95% CI 0.47–0.66, and HR = 0.64; 95% CI 0.57–0.71). The same results could also be observed in the pooled HRs ratio for PFS (HR = 1.15, 95%CI 0.91–1.46) indicating comparable efficacy of ICI-based combination therapy in younger and older patients with NSCLC.
Conclusion:
ICI-based combination therapy vs. non-ICI treatment had comparable efficacy in younger and older NSCLC patients with a cut-off age of 65 years.
Herein, a novel fluorescence nanosensor using intrinsic fluorescent polydopamine nanoparticles (PDA NPs) as an effective signal reporter has been constructed for the simple, rapid and sequential ...detection of mercury ions (Hg
) and l-ascorbic acid (AA) based on a coordination effect and redox reaction. The fluorescence of the PDA NPs could be specifically quenched by Hg
through intense coordination effects between the Hg
and the groups (catechol, amine, ketone and imine) on the surface of the PDA NPs. However, when AA and Hg
coexisted in solution, the fluorescence of the PDA NPs pronouncedly recovered
the redox reaction of Hg
, with it being reduced to Hg
by AA. The fluorescence quenching mechanism of Hg
towards the PDA NPs and the redox reaction between Hg
and AA were also fully investigated. The nanosensor exhibited high sensitivity and desirable selectivity for Hg
and AA detection. Moreover, the strategy was successfully explored in real samples (tap water, lake water and human serum samples) with satisfactory recoveries. The developed nanosensor provides new sights and good inspiration for Hg
and AA detection under real conditions.
Steatotic livers tolerate ischemia-reperfusion injury (IRI) poorly, increasing the risk of organ dysfunction. Ferroptosis is considered the initiating factor of organ IRI. Heme oxygenase oxygen-1 ...(HO-1)-modified bone marrow mesenchymal stem cells (BMMSCs) (HO-1/BMMSCs) can reduce hepatic IRI; however, the role of ferroptosis in IRI of steatotic grafts and the effect of HO-1/BMMSCs-derived exosomes (HM-exos) on ferroptosis remain unknown.
A model of rat liver transplantation (LT) with a severe steatotic donor liver and a model of hypoxia and reoxygenation (H/R) of steatotic hepatocytes were established. Exosomes were obtained by differential centrifugation, and the differentially expressed genes (DEGs) in liver after HM-exo treatment were detected using RNA sequencing. The expression of ferroptosis markers was analyzed. microRNA (miRNA) sequencing was used to analyze the miRNA profiles in HM-exos.
We verified the effect of a candidate miRNA on ferroptosis of H/R treated hepatocytes, and observed the effect of exosomes knockout of the candidate miRNA on hepatocytes ferroptosis. In vitro, HM-exo treatment reduced the IRI in steatotic grafts, and enrichment analysis of DEGs suggested that HM-exos were involved in the regulation of the ferroptosis pathway. In vitro, inhibition of ferroptosis by HM-exos reduced hepatocyte injury. HM-exos contained more abundant miR-124-3p, which reduced ferroptosis of H/R-treated cells by inhibiting prostate six transmembrane epithelial antigen 3 (STEAP3), while overexpression of Steap3 reversed the effect of mir-124-3p. In addition, HM-exos from cell knocked out for miR-124-3p showed a weakened inhibitory effect on ferroptosis. Similarly, HM-exo treatment increased the content of miR-124-3p in grafts, while decreasing the level of STEAP3 and reducing the degree of hepatic ferroptosis.
Ferroptosis is involved in the IRI during LT with a severe steatotic donor liver. miR-124-3p in HM-exos downregulates Steap3 expression to inhibit ferroptosis, thereby attenuating graft IRI, which might be a promising strategy to treat IRI in steatotic grafts.
This paper examines the causes and consequences of venture capital (VC) stage financing. Using information about the physical location of an entrepreneurial firm and the geographic distance between ...the VC investor and the firm, I show that VC investors located farther away from an entrepreneurial firm tend to finance the firm using a larger number of financing rounds, shorter durations between successive rounds, and investing a smaller amount in each round. However, VC investors' propensity to stage is independent of whether the firm is located in a close-knit community. I also find that VC staging positively affects the entrepreneurial firm's propensity to go public, operating performance in the initial public offering (IPO) year, and post-IPO survival rate, but only if the firm is located far away from the VC investor. However, the effect of VC staging on entrepreneurial firm's performance is independent of whether it is located in a close-knit community. The findings are robust to a variety of alternative proximity measures, instrumental variables, and econometric approaches for dealing with endogeneity problems.
Objective Winter-over expeditioners in Antarctica are challenged by various environmental and psycho-social stress factors, which may induce psychophysiological changes. The autonomic nervous system ...(ANS) plays a crucial role in the adaptation process under stress. However, the relationship between ANS activity and the mood states of expeditioners remains largely unexplored. This study aims to uncover the pattern of ANS adjustment under extreme Antarctic environments and provide new insights into the correlations between ANS activity and mood state changes, which may provide scientific data for medical interventions. Methods Fourteen expeditioners at Zhongshan Station participated in this study. The study was conducted during four representative periods: pre-Antarctica, Antarctica-1 (pre-winter), Antarctica-2 (winter), and Antarctica-3 (summer). The heart rate variability (HRV) of the expeditioners was continuously measured for 24 hours to evaluate ANS activity. Plasma levels of catecholamines were tested by ELISA. Mood states were assessed by the Profile of Mood States (POMS) scale. Results HRV analysis showed a disturbance of ANS during winter and summer periods. For frequency domain parameters, very low frequency (VLF), low frequency (LF), high frequency (HF), and total power (TP) significantly increased during the second half of the mission. Especially, LF/HF ratio decreased during summer, indicating the predominance of vagal tone. Results of the time domain analysis showed increased heart rate variability during the austral winter and summer. Plasma epinephrine (E) significantly increased during residence in Antarctica. Compared with pre-Antarctica, the vigor, depression, and anger scores of the expeditioners decreased significantly during the austral summer. Notably, the depression score showed a moderate positive correlation with LF/HF, while weak negative correlations with other HRV indicators, including TP, VLF, and LF. Anger score showed a moderate positive correlation with LF/HF and weak negative correlations with the average normal-to-normal (NN) interval, and the root mean square of differences between adjacent RR intervals (RMSSD). Plasma E level weakly correlated with the average NN interval. Conclusion Prolonged residence in Antarctica increased the ANS activities and shifted the cardiac autonomic modulation towards vagal predominance. The alteration of HRV correlated with mood states and plasma epinephrine levels.
Abstract Background Traumatic proximal tibiofibular fracture and dislocation (PTFD) have been rarely studied and are easily missed in clinical practice. PTFD is considered a marker of severely ...traumatized knees. The purpose of this study was to retrospectively analyze the incidence and impact of PTFD in traumatized knees with vascular injury. Methods Patients with knee trauma and vascular injury were included from January 2022 to October 2023. X-rays and CT scans of included patients were retrospectively analyzed to determine the presence of PTFD. Patients were further divided into PTFD group and non-PTFD group for further comparative analysis. Results A total of 27 patients (28 limbs) were included. Incidence of PTFD was 39.3% (11/28) in traumatic knee with vascular injury, including 8 anterolateral dislocations and 3 posteromedial dislocations. PTFD group had significantly more limbs with open injuries compared with non-PTFD group (10/11 VS 7/17, p <0.05). Amputation rate of PTFD group was as high as 40% (4/10), compared to 23.5% (4/17) in non-PTFD group. However, the difference between two groups was not statistically significant ( p >0.05). Conclusions PTFD was easily overlooked or missed. In traumatized knees with vascular injury, incidence of PTFD was high. The presence of PTFD might indicate severe knee trauma and the possibility of open injury. Although there was no significant difference compared with non-PTFD group, PTFD group had a relatively high amputation rate of 40%.
Recommendation systems are designed to recommend personalized content to improve user experience. At present, the recommendation systems still face some challenges such as poor interpretability, cold ...start problem and serialized recommendation modeling. Recently, the knowledge graph (KG) containing a large amount of semantic and structural information has been widely used in a variety of different recommendation tasks to alleviate the above problems. This paper systematically reviews the innovative applications of knowledge graph embedding (KGE) in different recommendation tasks. It first summarizes three common recommendation tasks and four applying goals of knowledge graph embedding. Then, it generalizes four types of knowledge graph embedding methods according to specific technologies, including traditional embedding method, embedding propagation method, heterogeneous graph embedding method and graph neural network based method. It further elaborates on the applying characteristics and strategies of the ab
The invasion of
in Taiwan was first recorded in 2017. The deformed wing virus (DWV) has been identified as a common bee virus in apiculture around the world. Ectoparasitic mites are the main DWV ...vector for horizontal transmission. However, there are few studies about the ectoparasitic mite of
, which has been found in
. In this study, the prevalence of DWV among four hosts, including
,
,
, and
, was determined. The results showed that a high DWV-A prevalence rate in A. florea, ranging from 69.2% to 94.4%, was detected. Additionally, the genome of DWV isolates was sequenced and subjected to phylogenetic analysis based on the complete polyprotein sequence. Furthermore, isolates from
and
both formed a monophyletic group for the DWV-A lineage, and the sequence identity was 88% between the isolates and DWV-A reference strains. As noted above, two isolates could be the novel DWV strain. It cannot be excluded that novel DWV strains could pose an indirect threat to sympatric species, such as
and
.
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