Abstract
A more common and noninvasive predicting biomarker for programmed cell death 1 (PD-1) antibody remains to be explored. We assessed 46 patients with advanced gastric cancer who received PD-1 ...antibody immunotherapy and 425-genes next-generation sequencing (NGS) testing. Patients who had a > 25% decline in maximal somatic variant allelic frequency (maxVAF) had a longer progression free survival (PFS) and higher response rate than those who did not (7.3 months vs 3.6 months,
p
= 0.0011; 53.3% vs 13.3%,
p
= 0.06). The median PFS of patients with undetectable and detectable post-treatment circulating tumor DNA (ctDNA) was 7.4 months vs. 4.9 months (
p
= 0.025). Mutation status of TGFBR2, RHOA, and PREX2 in baseline ctDNA influenced the PFS of immunotherapy (
p
< 0.05). Patients with alterations in CEBPA, FGFR4, MET or KMT2B (
p
= 0.09) gene had greater likelihood of immune-related adverse events (irAEs). ctDNA can serve as a potential biomarker of the response to immunotherapy in advanced gastric cancers, and its potential role in predicting irAEs worth further exploration.
Androgen deprivation therapy (ADT), including enzalutamide, induces resistance in prostate cancer; ADT resistance is associated with neuroendocrine differentiation (NED) and tumor-associated ...macrophages (TAM). This study aimed to investigate the association between enzalutamide-induced NED and TAMs and its mechanism.
The association between enzalutamide-induced NED and TAMs was investigated by IHC using prostate cancer tissues, enzalutamide-resistant mouse xenografts, and a coculture system. The underlying mechanisms were assessed using
cytokine antibody arrays, ELISAs, chromatin immunoprecipitation, and other methods. An orthotopic prostate cancer mouse model was established to evaluate the
effects of combined IL6 receptor (IL6R) and high mobility group box 1 (HMGB1) inhibition on enzalutamide resistance.
High CD163 expression was observed in ADT-treated prostate cancer or castration-resistant prostate cancer (CRPC) tissues with high levels of neuron-specific enolase (NSE) and chromogranin A (CHGA) and in enzalutamide-resistant xenografts, indicating the crucial roles of NED and TAMs in enzalutamide resistance. Specifically, enzalutamide-induced HMGB1 expression facilitated TAM recruitment and polarization and drove NED via β-catenin stabilization. HMGB1-activated TAMs secreted IL6 to augment enzalutamide-induced NED and directly promote HMGB1 transcription via STAT3. Finally, inhibition of the IL6/STAT3 pathway by tocilizumab combined with HMGB1 knockdown inhibited enzalutamide-induced resistance in an orthotopic prostate cancer mouse model.
Enzalutamide elevates HMGB1 levels, which recruits and activates TAMs. Moreover, IL6 secreted by HMGB1-activated TAMs facilitates the enzalutamide-induced NED of prostate cancer, forming a positive feedback loop between NED in prostate cancer and TAMs. The combined inhibition of IL6R and HMGB1 may serve as a new treatment for enzalutamide resistance in patients with advanced or metastatic prostate cancer.
.
High fecundity is a common characteristic of insect pests which increases the difficulty of population control. Serine/threonine kinase Akt is an indispensable component of the insulin signaling ...pathway. Silencing of LsAkt severely hinders reproduction in Lasioderma serricorne, a stored product insect pest. However, the post‐transcriptional pathway of LsAkt in L. serricorne remains unknown. This study identified 2 binding sites of miR‐9c‐5p and novel‐mir50 in the coding sequences of LsAkt. The expression profiles of 2 microRNAs (miRNAs) and LsAkt displayed an opposite pattern during the adult stages. Luciferase reporter assay showed that novel‐mir50 and miR‐9c‐5p could downregulate the expression of LsAkt. Overexpression of miR‐9c‐5p and novel‐mir50 by injection of mimics inhibited the expression of LsAkt and reduced oviposition, decreased egg hatchability, and blocked ovarian development. It also decreased the expression of genes involved in ovarian development (LsVg and LsVgR) and the nutritional signaling pathway (LsTOR, LsS6K, and Ls4EBP), and reduced the phosphorylation of Akt. Conversely, injection of miR‐9c‐5p and novel‐mir50 inhibitors induced the expressions of LsAkt, LsVg, LsVgR, LsTOR, LsS6K, and Ls4EBP, enhanced Akt phosphorylation level, and accelerated ovarian development. Injection of bovine insulin downregulated the expression of miR‐9c‐5p and novel‐mir50 and upregulated the LsAkt expression. It also rescued the reproductive development defects associated with miR‐9c‐5p/novel‐mir50 overexpression, forming a positive regulatory loop of insulin signaling. These results indicate that miR‐9c‐5p/novel‐mir50 regulates the female reproduction of L. serricorne by targeting Akt in response to insulin signaling. The data also demonstrate the effects of the insulin/miRNA/Akt regulatory axis in insect reproduction.
We first revealed the important role of miR‐9c‐5p and novel‐mir50 in regulating the reproductive development by targeted Akt of Lasioderma serricorne, and verified the function of insulin/miRNA/Akt regulatory axis in reproductive development.
Coelomycete is a general term used for asexual fungi which produce conidia in fruiting bodies: pycnidial, acervular, cupulate, pycnothyria or stromatic conidiomata. The group contains numerous plant ...pathogenic, saprobic and endophytic species associated with a wide range of hosts. Traditionally, morphological characters and host associations have been used as criteria to identify and classify coelomycetes, and this has resulted in a poor understanding of their generic and species boundaries. DNA based taxonomic studies have provided a better outlook of the phylogenetic and evolutionary trends in coelomycetes. However, the present outcomes represent only a preliminary step towards the understanding of coelomycetes. Many genera have not been revisited since they were first described. The present study revises the classification of the hyaline-spored coelomycetes and provides a modern taxonomic framework based on both morphology and phylogeny. In total, 248 genera were investigated, of which less than 100 are known to have sequence data. Multi-locus sequence data analyses of 28S nrDNA, 18S nrDNA, ITS, RNA polymerase II second largest subunit (
rpb2
), and part of the translation elongation factor 1-alpha gene (
tef1
) and β-tubulin (
tub2
) gene regions were analysed. As a result, three new genera and 23 new species are introduced. In addition, three new links between sexual and asexual genera are provided. There are 138 genera that lack sequence data, and these are treated as Ascomycota, genera
incertae sedis
. Line drawings and descriptions are provided based on the examination of types and fresh collections and on the literature.
Porphyromonas gingivalis (P. gingivalis), a key pathogen in periodontitis, has been shown to accelerate the progression of atherosclerosis (AS). However, the definite mechanisms remain elusive. ...Emerging evidence supports an association between mitochondrial dysfunction and AS. In our study, the impact of P. gingivalis on mitochondrial dysfunction and the potential mechanism were investigated. The mitochondrial morphology of EA.hy926 cells infected with P. gingivalis was assessed by transmission electron microscopy, mitochondrial staining, and quantitative analysis of the mitochondrial network. Fluorescence staining and flow cytometry analysis were performed to determine mitochondrial reactive oxygen species (mtROS) and mitochondrial membrane potential (MMP) levels. Cellular ATP production was examined by a luminescence assay kit. The expression of key fusion and fission proteins was evaluated by western blot and immunofluorescence. Mdivi-1, a specific Drp1 inhibitor, was used to elucidate the role of Drp1 in mitochondrial dysfunction. Our findings showed that P. gingivalis infection induced mitochondrial fragmentation, increased the mtROS levels, and decreased the MMP and ATP concentration in vascular endothelial cells. We observed upregulation of Drp1 (Ser616) phosphorylation and translocation of Drp1 to mitochondria. Mdivi-1 blocked the mitochondrial fragmentation and dysfunction induced by P. gingivalis. Collectively, these results revealed that P. gingivalis infection promoted mitochondrial fragmentation and dysfunction, which was dependent on Drp1. Mitochondrial dysfunction may represent the mechanism by which P. gingivalis exacerbates atherosclerotic lesions.
Brain-derived neurotrophic factor (BDNF) with neuronic development and function is a promising therapeutic agent for treating depressive disorder, according to the neurotrophin hypothesis. However, ...the delivery of BDNF into the brain is not easy as these large protein molecules cannot efficiently cross the blood-brain barrier (BBB) and easily suffer oxidative damage in vivo. Therefore, the quercetin-based alginate nanogels (quercetin nanogels) loaded with BDNF have been developed, which could efficiently bypass the BBB via the nose-to-brain pathway and protect BDNF from oxidative damage, providing an effective route for the therapy of depressive disorders by intranasal delivery. Quercetin nanogels exhibited uniform size distribution, excellent biocompatibility, and potent antioxidant and anti-inflammatory activities. Quercetin nanogels in the thermosensitive gel achieved sustained and controlled release of BDNF with non-Fick's diffusion, exhibited rapid brain distribution, and achieved nearly 50-fold enhanced bioavailability compared to oral quercetin. Quercetin nanogels as a therapeutic drug delivery carrier exerted antidepressant effects on reserpine-induced rats, effectively delivered BDNF to reverse despair behavior in stress-induced mice, and exhibited antidepressant effects on chronic mild unpredictable stimulation (CUMS) rats. These antidepressant effects of BDNF-Quercetin nanogels for CUMS rats are associated with the regulation of the glutamatergic system, PI3K-Akt, and BDNF-TrkB signaling pathway. In this study, we provide a promising strategy for brain delivery of BDNF for treating depressive disorders, effectively achieved through combining quercetin nanogels and intranasal administration.
Electrospun nanofiber membranes having a hierarchical structure with multilevel roughness were generated
via
electrospinning of poly(vinylidene fluoride) (PVDF)-SiO
2
blend solutions. The composite ...PVDF-SiO
2
nanofiber membranes were then endowed with superhydrophobicity by the fluorosilanization of the surface with low surface energy fluoroalkylsilane (FAS). The results showed that when the SiO
2
content in the dope solutions increased from 0 wt% to 8 wt%, the water contact angles of the FAS modified nanofiber membranes increased significantly from 130.4° to 160.5°. The increment of the silica content in the dope solutions decreased the fiber diameters and pore sizes of the modified membranes, while the mechanical properties were enhanced with the silica addition. The liquid entry pressures of the membranes increased gradually from 84 kPa to 195 kPa with silica addition due to the increased contact angles and decreased pore size. Vacuum membrane distillation experiments were carried out for the modified nanofiber membranes to evaluate the anti-wetting properties. The optimal superhydrophobic nanofiber membrane maintained a stable flux of 31.5 kg m
−2
h
−1
with a permeate conductivity approximately 10 μs cm
−1
over the entire test, while the fluxes and conductivities of the nanofiber membranes without superhydrophobicity showed a significant decrease and increase, respectively. The results indicated that the superhydrophobic modification process rendered the nanofiber membrane anti-wetting properties without compromising its excellent permeability.
Superhydrophobic nanofiber membranes with high permeate fluxes and anti-wetting properties were prepared by hydrophobic modification of PVDF-SiO
2
nanofiber membranes.
Domain adaptation, as an important branch of transfer learning, can be applied to cope with data insufficiency and high subject variabilities in motor imagery electroencephalogram (MI-EEG) based ...brain-computer interfaces. The existing methods generally focus on aligning data and feature distribution; however, aligning each source domain with the informative samples of the target domain and seeking the most appropriate source domains to enhance the classification effect has not been considered. In this paper, we propose a dual alignment-based multi-source domain adaptation framework, denoted DAMSDAF. Based on continuous wavelet transform, all channels of MI-EEG signals are converted respectively and the generated time-frequency spectrum images are stitched to construct multi-source domains and target domain. Then, the informative samples close to the decision boundary are found in the target domain by using entropy, and they are employed to align and reassign each source domain with normalized mutual information. Furthermore, a multi-branch deep network (MBDN) is designed, and the maximum mean discrepancy is embedded in each branch to realign the specific feature distribution. Each branch is separately trained by an aligned source domain, and all the single branch transfer accuracies are arranged in descending order and utilized for weighted prediction of MBDN. Therefore, the most suitable number of source domains with top weights can be automatically determined. Extensive experiments are conducted based on 3 public MI-EEG datasets. DAMSDAF achieves the classification accuracies of 92.56%, 69.45% and 89.57%, and the statistical analysis is performed by the kappa value and
t-
test. Experimental results show that DAMSDAF significantly improves the transfer effects compared to the present methods, indicating that dual alignment can sufficiently use the different weighted samples and even source domains at different levels as well as realizing optimal selection of multi-source domains.
Background Nutritional status and inflammation are closely associated with poor outcome in malignant tumors. However, the prognostic impact of postoperative in these variables on breast cancer (BC) ...remains inconclusive. We aimed to determine whether prognostic nutritional index (PNI), systemic immune-inflammation index (SII), neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) affect two long-term outcomes among patients after curative resection of BC. Methods We retrospectively reviewed 508 patients with BC treated with curative surgery between February 5, 2013 and May 26, 2020. All patients were divided into 3 groups based on tertiles (T1-T3) of PNI, SII, NLR, and PLR. The effects of four indexes on disease-free survival (DFS) and overall survival (OS) have been evaluated using Cox proportional hazards models and Kaplan-Meier method. Results Compared with PNI-lowest cases, patients with highest PNI showed significantly longer DFS (multivariate adjusted hazard ratio HR = 0.37, 95% confident interval CI 0.19-0.70, P for trend = 0.002), whereas higher PLR seemed to be marginally associated with poorer DFS (P for trend = 0.086 and 0.074, respectively). Subgroup analyses indicate the potential modification effects of family history of BC and radiotherapy on the prognosis value of PNI to DFS in BC patients (P for interaction = 0.004 and 0.025, respectively). In addition, the levels of three inflammatory indices, namely SII, NLR, and PLR might be positively related with increased age at diagnosis (all P for trend < 0.001). Conclusions A high PNI was associated with better DFS, supporting its roles as prognostic parameters for patients with BC. The nutritional status and systemic immune may exert great effects on patient prognosis. Further studies are warrant to explore the prognosis value of PLR. Keywords: Breast cancer, Prognostic nutritional index, Systemic immune-inflammation index, Neutrophil-lymphocyte ratio, Platelet-lymphocyte ratio
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