Co-delivery of polyphyllin II and IR780 PLGA nanoparticles induced pyroptosis combined with photothermal to enhance hepatocellular carcinoma immunotherapy.

The clinical efficacy of immunotherapy for hepatocellular carcinoma (HCC) is significantly limited by the low immunogenicity of the tumor. Recent studies have revealed that both pyroptosis and photothermal therapy can effectively induce tumor immunogenic cell death (ICD) in liver cancer cells. Polyphyllin II (PPII), the major active component of Rhizoma Paridis, has been demonstrated for the first time to induce pyroptosis in tumor cells, while IR780 is activated by 808 nm laser to transform light energy into heat energy, effectively eliminating tumor cells. However, both PPII and IR780 are afflicted with challenges such as low solubility and poor targeting, significantly limiting their utilization. To address these problems, the pyroptosis inducer PPII and photosensitizer IR780 were co-loaded in PLGA nanoparticles by precipitation method, and the aptamer AS1411 was modified on the surface of nanoparticles to construct the targeting nanoparticles (Apt/PPII/IR780-NPs). The nanoparticles exhibit a pH/NIR dual-response intelligent release feature, which realizes the targeted and controlled release of drugs in tumor site. Furthermore, it can rapidly release PPII to induce cell pyroptosis under laser irradiation, combining with IR780-based photothermal therapy exert a significant synergistic anti-tumor effect in vitro and in vivo. This process not only promotes maturation of DCs and activates effector T cells, thereby initiating adaptive immunity, but also generates enduring and effective immune memory. In addition, Apt/PPII/IR780-NPs significantly improved the Anti-PD-1 efficacy. In summary, chemo-photothermal therapy based on Apt/PPII/IR780-NPs can significantly enhance tumor ICD, which provides a promising new strategy for HCC immunotherapy.

Barriers and facilitators for accepting health education of Chinese rural older adults in Henan Province: a qualitative study.

BACKGROUND: As global aging continues to intensify, the health status of the older people requires urgent attention, and health education provides a pathway for active aging. However, the current outlook on health education for older people in rural areas of China is not optimistic. This study used Social Ecosystems Theory and explored the deep-rooted influencing factors on the acceptance of health education from the perspective of the rural older people. METHODS: In this study, a purposive sampling method was adopted, and eligible rural older individuals were selected from Hebi city, Henan Province, China, from March to May 2023 as the research participants. A semistructured interview method was used to explore the factors affecting the acceptance of health education by older people. The interview data were analyzed using the qualitative content analysis method to obtain relevant themes and subthemes. RESULTS: A total of 14 participants were recruited for the interviews; 8 were male, 6 were female, most had an elementary school education, and most were farmers. The results of the thematic analysis revealed a total of nine facilitators and nine barriers in micro, meso and macro levels. Among the findings, our important and unique finding is that inadequate intergenerational support somewhat hinders older adults' exposure to health education. CONCLUSION: There are numerous and complex facilitators of and barriers to accessing health education for rural older adults; of these, a lack of intergenerational support is particularly important. In the future, health education needs to be centered on the families of older people with the assistance of village committees so that older people and their children can learn and communicate together.

[Anti-tumor mechanism of total saponins of Paridis Rhizoma on inducing ferroptosis of breast cancer MCF-7 cells].

This study aims to investigate the mechanism of total saponins of Paridis Rhizoma in inducing the ferroptosis of MCF-7 cells and provide a theoretical basis for the clinical treatment of breast cancer with total saponins of Paridis Rhizoma. The methyl thiazolyl tetrazolium(MTT) assay was employed to examine the effects of different concentrations of total saponins of Paridis Rhizoma on the proliferation of MCF-7 cells. A phase contrast inverted microscope was used to observe the morphological changes of MCF-7 cells. The colony formation assay was employed to test the colony formation of MCF-7 cells. The lactate dehydrogenase(LDH) release test was conducted to determine the cell membrane integrity of MCF-7 cells. The cell scratch assay was employed to examine the migration of MCF-7 cells. After that, the level of reactive oxygen species(ROS) in MCF-7 cells was observed by an inverted fluorescence microscope, and the content of Fe~(2+) in MCF-7 cells was detected by the corresponding kit. Transmission electron microscopy was employed to observe the mitochondrial ultrastructure of MCF-7 cells. Western blot was employed to determine the expression of ferroptosis-related proteins, such as p53, solute carrier family 7 member 11(SLC7A11), glutathione peroxidase 4(GPX4), acyl-CoA synthetase long-chain family member 4(ACSL4), and transferrin receptor protein 1(TFR1) in MCF-7 cells. The results showed that 1.5, 3, 4.5, 6, 7.5, and 9 µg·mL~(-1) total saponins of Paridis Rhizoma significantly inhibited the proliferation of MCF-7 cells, with the IC_(50) of 4.12 µg·mL~(-1). Total saponins of Paridis Rhizoma significantly damaged the morphology of MCF-7 cells, leading to the formation of vacuoles and the gradual shrinkage and detachment of cells. Meanwhile, total saponins of Paridis Rhizoma inhibited the colony formation of MCF-7 cells, destroyed the cell membrane(leading to the release of LDH), and shortened the migration distance of MCF-7 cells. Total saponins of Paridis Rhizoma treatment significantly increased the content of ROS, induced oxidative damage, and led to the accumulation of Fe~(2+) in MCF-7 cells. Furthermore, total saponins of Paridis Rhizoma changed the mitochondrial structure, increased the mitochondrial membrane density, led to the decrease or even disappear of ridges, promoted the expression of p53 protein, down-regulated the expression of SLC7A11 and GPX4, and up-regulated the expression of ACSL4 and TFR1. In summary, total saponins of Paridis Rhizoma can significantly inhibit the proliferation and migration of MCF-7 cells and destroy the cell structure by inducing ferroptosis.

Neoadjuvant Camrelizumab for Non-Small Cell Lung Cancer: A Retrospective Multicenter, Real-World Study (CTONG2004).

BACKGROUND: Camrelizumab has shown encouraging efficacy in advanced non-small cell lung cancer (NSCLC), either as monotherapy or combined with chemotherapy. However, evidence of neoadjuvant camrelizumab for NSCLC remains lacking. METHODS: Patients with NSCLC treated with neoadjuvant camrelizumab-based therapy followed by surgery between December 2020 and September 2021 were retrospectively reviewed. Demographic and clinical data, details of neoadjuvant therapy and surgical information were retrieved. RESULTS: In this multicenter retrospective real-world study, 96 patients were included. Ninety-five patients (99.0%) received neoadjuvant camrelizumab combined with platinum-based chemotherapy, with a median of 2 cycles (range 1-6). The median interval from the last dose to surgery was 33 days (range 13-102 days). Seventy patients (72.9%) underwent minimally invasive surgery. Lobectomy was the most frequent surgical procedure (94 [97.9%]). The median estimated intraoperative blood loss was 100 mL (range 5-1200 mL), and the median operative time was 3.0 h (range 1.5-6.5 h). The R0 resection rate was 93.8%. Twenty-one patients (21.9%) experienced postoperative complications, with the most common being cough and pain (both 6 [6.3%]). The overall response rate was 77.1% (95% CI 67.4-85.0%), and the disease control rate was 93.8% (95% CI 86.9-97.7%). Twenty-six patients (27.1%, 95% CI 18.5-37.1%) had pathological complete response. Neoadjuvant treatment-related adverse events of grade ≥ 3 were reported in seven patients (7.3%), with the most frequent being abnormal liver enzymes (two [2.1%]). No treatment-related deaths were reported. CONCLUSION: The real-world data indicated that camrelizumab-based therapy had promising efficacy for NSCLC in the neoadjuvant setting, with manageable toxicities. Prospective studies investigating neoadjuvant camrelizumab are warranted.

CD5L aggravates rheumatoid arthritis progression via promoting synovial fibroblasts proliferation and activity.

Rheumatoid arthritis (RA) is a chronic inflammatory disease with progressive cartilage erosion and joint destruction. Synovial fibroblasts (SFs) play a crucial role in the pathogenesis of RA. This study aims to explore the function and mechanism of CD5L during RA progression. We examined the levels of CD5L in synovial tissues and SFs. The collagen-induced arthritis (CIA) rat models were used to investigate the effect of CD5L on RA progression. We also investigated the effects of exogenous CD5L on the behavior and activity of RA synovial fibroblasts (RASFs). Our results showed that CD5L expression was significantly upregulated in synovium of RA patients and CIA-rats. Histology and Micro-CT analysis showed that synovial inflammation and bone destruction were more severe in CD5L-treated CIA rats compared with control rats. Correspondingly, CD5L blockade alleviated bone damage and synovial inflammation in CIA-rats. The exogenous CD5L treatment promoted RASFs proliferation invasion and proinflammatory cytokine production. Knockdown of CD5L receptor by siRNA significantly reversed the effect of CD5L treatment on RASFs. Moreover, we observed that CD5L treatment potentiated PI3K/Akt signaling in the RASFs. The promoted effects of CD5L on IL-6 and IL-8 expression were significantly reversed by PI3K/Akt signaling inhibitor. In conclusion, CD5L promote RA disease progression via activating RASFs. CD5L blocking is a potential therapeutic approach for RA patients.

Phosphorylation of androgen receptor by mTORC1 promotes liver steatosis and tumorigenesis.

BACKGROUND AND AIMS: Androgen receptor (AR) has been reported to play an important role in the development and progression of man's prostate cancer. Hepatocellular carcinoma (HCC) is also male-dominant, but the role of AR in HCC remains poorly understood. Mechanistic target of rapamycin complex 1 (mTORC1) also has been reported to be highly activated in HCC. In this study, we aimed to explore the role of AR phosphorylation and its relationship with mTORC1 in hepatocarcinogenesis. APPROACH AND RESULTS: In vitro experiment, we observed that mTORC1 interacts with hepatic AR and phosphorylates it at S96 in response to nutrient and mitogenic stimuli in HCC cells. S96 phosphorylation promotes the stability, nuclear localization, and transcriptional activity of AR, which enhances de novo lipogenesis and proliferation in hepatocytes and induces liver steatosis and hepatocarcinogenesis in mice independently and cooperatively with androgen. Furthermore, high ARS96 phosphorylation is observed in human liver steatotic and HCC tissues and is associated with overall survival and disease-free survival, which has been proven as an independent survival predictor for patients with HCC. CONCLUSIONS: AR S96 phosphorylation by mTORC1 drives liver steatosis and HCC development and progression independently and cooperatively with androgen, which not only explains why HCC is man-biased but also provides a target molecule for prevention and treatment of HCC and a potential survival predictor in patients with HCC.

Biomechanical mechanism driving typical postural shifts of lower limbs during sleeping in an aircraft seat.

The purpose of this study was to determine the biomechanical mechanisms driving passengers' lower-limb postural shifts during seated sleep on a flight to prevent negative effects on passengers' physical health. Twenty subjects participated in an observational study and a subsequent experiment on fatigue development and tissue oxygenation changes during seated sleep in an economy-class aircraft seat. Three of the most frequently used postures, which involved four targeted muscles of the legs and the thigh-buttock region, were selected and examined in the experiment with the following measures: muscle electromyogram, tissue oxygenation, and body contact pressure distribution. The results showed that the fatigue of the tibialis anterior and gastrocnemius and the compression of the region under the medial tuberosities were relieved by alternations among the three positions-position 1 (placing the shanks forwards), position 2 (placing the shanks neutrally), and position 3 (placing the shanks backwards). This research reveals the mechanical properties of the biomechanical factors functioning in lower-limb postural shifts during seated sleep and provides design optimization strategies for economy-class aircraft seats to reduce the negative effects on passenger health.

AI-based soundscape analysis: Jointly identifying sound sources and predicting annoyancea).

Soundscape studies typically attempt to capture the perception and understanding of sonic environments by surveying users. However, for long-term monitoring or assessing interventions, sound-signal-based approaches are required. To this end, most previous research focused on psycho-acoustic quantities or automatic sound recognition. Few attempts were made to include appraisal (e.g., in circumplex frameworks). This paper proposes an artificial intelligence (AI)-based dual-branch convolutional neural network with cross-attention-based fusion (DCNN-CaF) to analyze automatic soundscape characterization, including sound recognition and appraisal. Using the DeLTA dataset containing human-annotated sound source labels and perceived annoyance, the DCNN-CaF is proposed to perform sound source classification (SSC) and human-perceived annoyance rating prediction (ARP). Experimental findings indicate that (1) the proposed DCNN-CaF using loudness and Mel features outperforms the DCNN-CaF using only one of them. (2) The proposed DCNN-CaF with cross-attention fusion outperforms other typical AI-based models and soundscape-related traditional machine learning methods on the SSC and ARP tasks. (3) Correlation analysis reveals that the relationship between sound sources and annoyance is similar for humans and the proposed AI-based DCNN-CaF model. (4) Generalization tests show that the proposed model's ARP in the presence of model-unknown sound sources is consistent with expert expectations and can explain previous findings from the literature on soundscape augmentation.

Analysis of the information ability of nurses in county hospitals in northern Henan province: a survey.

OBJECTIVE: To investigate the status quo of nursing information ability of nurses in county-level hospitals and analyze its influencing factors. METHODS: In June 2022, a total of 303 on-the-job clinical nurses from 3 county-level hospitals in Hebi City, Henan Province were selected as subjects by convenience sampling method. General data questionnaire and self-rating nursing information ability scale were used to investigate them. RESULTS: The total score of nursing information ability of 303 nurses in county hospitals of Hebi City, Henan Province was (77.72 ± 18.76). There were statistically significant differences in the scores of nursing information ability among different ages, working years, positions, education, marriage, monthly income, whether they had learned computer-related knowledge and skills, and whether they had participated in the learning or training of nursing information system (all p < 0.05).Multiple linear regression analysis showed that age, years, position, monthly income and whether they had learned computer-related knowledge and skills were the main influencing factors of nursing information ability of county-level nurses (all p < 0.05). CONCLUSIONS: The nursing information ability of nurses in county-level hospitals in northern Henan is at a medium level. The government or society should provide training and guidance on nursing information ability, so as to provide more opportunities for nurses in county-level hospitals to participate in and learn nursing information technology to improve their ability.

Long non-coding RNA ENST00000469812 promotes Enterovirus type 71 replication via targeting the miR-4443/NUPR1 axis in rhabdomyosarcoma cells.

Hand, foot, and mouth disease (HFMD) caused by Enterovirus type 71 (EV71) is a serious threat to children's health. However, the pathogenic mechanism of EV71 is still unclear. Long non-coding RNAs (lncRNAs), some of which bind to miRNA as competitive endogenous RNAs (ceRNA) and weaken the silencing effect on the mRNA of downstream target genes, play a key role in regulating the viral infection process. In this study, through experimental verification, we found miR-4443 to be downregulated in cells infected with EV71. Next, by predicting lncRNAs that potentially regulate miR-4443, we found that EV71 infection induced upregulation of lncRNA ENST00000469812 and then further downregulated miR-4443 expression by direct interaction. We also demonstrated that nuclear protein 1 (NUPR1) is one of the target genes of miR-4443 and is involved in the ENST00000469812/miR-4443/NUPR1 regulatory axis. Finally, the ENST00000469812/miR-4443/NUPR1 regulatory axis exhibited a positive effect on EV71 replication. Here, we lay a foundation for exploring the pathogenic mechanism of EV71 and identify potential targets for HFMD treatment.

Silencing of B7-H4 induces intracellular oxidative stress and inhibits cell viability of breast cancer cells via downregulating PRDX3.

Breast cancer (BC) is the most common malignancy in women worldwide, accounting for 15.5% of total cancer deaths. B7-H4 belongs to the B7 family members and plays an important role in the development of a variety of cancers, while Peroxiredoxin III (PRDX3) is an antioxidant protein found in mitochondria. Aberrant expression of B7-H4 or PRDX3 has been implicated in the tumorigenesis of various cancers. However, the functional roles of B7-H4 and PRDX3 in BC and the underlying mechanisms remain unclear. In this research, we found that silencing of B7-H4 by siRNA could lead to not only cell viability inhibition but also the downregulation of PRDX3 in MCF-7 and T47D cells. In order to reveal the roles of PRDX3 in the B7-H4 pathway, we firstly transfected siRNA specifically targeting PRDX3 into MCF-7 and T47D cells, and the results showed that silencing of PRDX3 also inhibited the viability of MCF-7 and T47D cells significantly, accompanied by the increase of reactive oxygen species (ROS) levels. Then we overexpressed the expression of PRDX3 by transfecting PRDX3 expression plasmids into B7-H4 knocking-down cells of MCF-7 and T47D. The results showed that compared with the control groups (MCF-7 or T47D/siNC+pcDNA3.1 vector), cell viabilities were significantly inhibited in RNAi groups (MCF-7 or T47D/siB7-H4+pcDNA3.1 vector), and mildly inhibited in revertant groups (MCF-7 or T47D/siB7-H4+pcDNA3.1 PRDX3), meanwhile, ROS levels significantly elevated in RNAi groups and had no significant changes in revertant groups. All these results indicate that silencing of B7-H4 increases intracellular ROS levels and affects cell viability by modulating the expression of PRDX3 in BC cells, which may provide a potential strategy and therapeutic target for the treatment of BC.

Prognostic Value of a Four-miRNA Signature in Patients With Lymph Node Positive Locoregional Esophageal Squamous Cell Carcinoma Undergoing Complete Surgical Resection.

OBJECTIVE: This study was intended to identify prognostic biomarkers for lymph node (LN)-positive locoregional esophageal squamous cell carcinoma (ESCC) patients. SUMMARY OF BACKGROUND DATA: Surgery is a major treatment for LN-positive locoregional ESCC patients in China. However, patient outcomes are poor and heterogeneous. METHODS: ESCC-associated miRNAs were identified by microarray and validated by quantitative real-time polymerase chain reaction analyses in ESCC and normal esophageal epithelial samples. A multi-miRNA based classifier was established using a least absolute shrinkage and selection operator model in a training set of 145 LN-positive locoregional ESCCs, and further assessed in internal testing and independent validation sets of 145 and 243 patients, respectively. RESULTS: Twenty ESCC-associated miRNAs were identified and validated. A 4-miRNA based classifier (miR-135b-5p, miR-139-5p, miR-29c-5p, and miR-338-3p) was generated to classify LN-positive locoregional ESCC patients into high and low-risk groups. Patients with high-risk scores in the training set had a lower 5-year overall survival rate [8.7%, 95% confidence interval (CI): 0-20.3] than those with low-risk scores (50.3%, 95% CI: 40.0-60.7; P < 0.0001). The prognostic accuracy of the classifier was validated in the internal testing (P < 0.0001) and independent validation sets (P = 0.00073). Multivariate survival analyses showed that the 4-miRNA based classifier was an independent prognostic factor, and the combination of the 4-miRNA based classifier and clinicopathological prognostic factors significantly improved the prognostic accuracy of clinicopathological prognostic factors alone. CONCLUSION: Our 4-miRNA based classifier is a reliable prognostic prediction tool for overall survival in LN-positive locoregional ESCC patients and might offer a novel probability of ESCC treatment individualization.

Adenovirus-mediated anti-AEG-1 ScFv expression driven by stathmin promoter inhibits tumor growth in cervical cancer.

BACKGROUND: Astrocyte-elevated gene-1 (AEG-1) is over-expressed in many cancer cells and has multiple key functions in tumor initiation and progression. Currently, targeted-AEG-1 siRNA is one of the most common techniques to down-regulate AEG-1 expression, but the lack of tumor specificity and available delivery system make it difficult to enter clinical trials. METHODS: In this study, we creatively developed an adenovirus-mediated anti-AEG-1 single-chain antibody fragment (ScFv) expression system driven by a tumor specific promoter, and experimented with it in human cervical carcinoma cells to investigate the effect on tumor's proliferation and apoptosis. RESULTS: The results showed that of HeLa and SiHa cells treated with this recombinant anti-AEG-1 ScFv adenovirus not only inhibited cell growth, but induced apoptosis both in vitro and in vivo. Furthermore, we also observed that the expressions of several apoptosis-related genes like Akt 1 and c-Myc decreased, while NF-κB (p65) and cleaved caspase 3 increased on protein levels in vivo. CONCLUSION: We concluded that stathmin promoter-driving anti-AEG-1 ScFv adenoviral system may be a breakthrough for its dual-specificity, and serve as an adjuvant tumor specific therapy method in the treatment for human cervical cancers.

Hyaluronan-mediated motility receptor confers resistance to chemotherapy via TGFß/Smad2-induced epithelial-mesenchymal transition in gastric cancer.

Chemotherapy is one of the vital treatments for gastric cancer (GC) patients, especially those suffering advanced stages. Chemoresistance results in tumor relapse, leading to poor prognosis in GC patients; thus, identifying key regulators in this process might provide novel clues for GC therapy. Herein, we identify hyaluronan-mediated motility receptor (HMMR) as a key regulator of chemoresistance in GC. HMMR was found to be substantially up-regulated in 5-fluorouracil (5-Fu)-resistant GC biopsies and cell lines. High expression of HMMR significantly correlates with tumor relapse and predicts poorer prognosis in GC patients. Moreover, we observed that HMMR induced epithelial-mesenchymal transition and increased the cancer stem cell properties of GC, thus rendering resistance to chemotherapy. Importantly, silencing of HMMR effectively increased the susceptibility to 5-Fu therapy both in vitro and in vivo. Furthermore, we demonstrated that HMMR activates the TGF-ß/Smad2 signaling pathway, which was required for the HMMR-mediated oncogenic effects and exhibited significant clinical relevance with HMMR expression. These findings reveal a critical role for HMMR in the chemoresistance of GC and suggest that HMMR might be a potential prognostic marker or therapeutic target against the disease.-Zhang, H., Ren, L., Ding, Y., Li, F., Chen, X., Ouyang, Y., Zhang, Y., Zhang, D. Hyaluronan-mediated motility receptor confers resistance to chemotherapy via TGFß/Smad2-induced epithelial-mesenchymal transition in gastric cancer.

Signet ring cell component in pretreatment biopsy predicts pathological response to preoperative chemoradiotherapy in rectal cancer.

PURPOSE: Neoadjuvant therapy is routinely used in the management of locally advanced rectal cancer. This study aimed to evaluate the predictive value of pathological parameters in tumor response after treatment. METHODS: We reviewed the hematoxylin-eosin slides from pretreatment biopsies of 150 rectal cancer patients who received preoperative chemoradiotherapy (PCRT) at Sun Yat-sen University Cancer Center between May 2013 and June 2016. Pathological and clinical parameters were both studied. The tumor response after chemoradiotherapy was evaluated using the tumor regression grade (TRG). Logistic regression was used to evaluate the relevance between these parameters and tumor response. RESULTS: Complete tumor response (TRG0 and pCR) to PCRT was identified in 40 (26.7%) patients. The pCR rate was 93.33% (14 of 15) in cases with signet ring cell component versus 19.26% (26 of 135) in those without signet ring cell component (p < 0.001). Four cases with signet ring cell component were evaluated as clinical complete response (cCR), all of whom also achieved pCR; in contrast, only 9 of 15 (60%) cCR cases without signet ring cell achieved pCR. CONCLUSION: Our data suggest that the signet ring cell component in pretreatment biopsies may be a potential predictor of tumor response to PCRT in rectal cancer. This suggests patients with clinical complete response are more suitable for a wait-and-watch approach.

Astragaloside IV Attenuates Lipopolysaccharides-Induced Pulmonary Epithelial Cell Injury through Inhibiting Autophagy.

BACKGROUND: Astragaloside IV has shown its promising effect on acute respiratory distress syndrome (ARDS). OBJECTIVES: We aim to explore whether astragaloside IV is effective for ARDS treatment in a lipopolysaccharides (LPS)-induced cell model and whether autophagy is involved in the therapeutic function of astragaloside IV. METHODS: MLE-12 cells were induced by LPS to construct an ARDS model in vitro. Cell viability was estimated by cell counting kit-8 and cell apoptosis by flow cytometry. Lactate dehydrogenase (LDH), malondialdehyde (MDA) and superoxide dismutase (SOD) levels were measured by enzyme-linked immunosorbent assay kit. The expression of tumour necrosis factor (TNF)-α, interleukin (IL)-6, zonula occludens (ZO)-1, Beclin-1 and autophagy-related (atg) 5 mRNA was evaluated by quantitative PCR, and the expression of ZO-1, microtubule-associated proteins 1A/1B light chain 3B (LC3B) I and, LC3B II protein by Western blot. RESULTS: LPS effectively inhibited cell viability and LC3B I expression and enhanced LC3B II, Beclin-1 and atg5 expressions in MLE-12 cells. In LPS-induced ARDS cell model, astragaloside IV up-regulated cell viability, SOD activity and ZO-1 and LC3B I expressions but down-regulated cell apoptosis, TNF-α, IL-6, LC3B II, Beclin-1 and atg5 expressions and LDH and MDA levels. 3-methyladenine promoted cell viability and ZO-1 expression, down-regulated Beclin-1 and atg5 expression, while Rapamycin (Rap) had an opposite effect. Astragaloside IV suppressed cell viability and ZO-1 expression after the Rap treatment. CONCLUSIONS: Astragaloside IV might suppress autophagy initiation directly or indirectly through suppressing the oxidative stress and inflammatory response, which further enhances the cell viability and tight junction and reduces apoptosis in LPS-stimulated pulmonary endothelial ARDS cell model, thus exerting its therapeutic function in ARDS.

Dickkopf-related protein 1, a new biomarker for local immune status and poor prognosis among patients with colorectal liver Oligometastases: a retrospective study.

BACKGROUND: It was reported that tumor-expressed dickkopf-related (DKK) proteins affect micro-environment. However, the influence of DKK1 on colorectal cancer (CRC) liver oligometastases (CRCLOM) remains unclear. METHODS: CRC cases after resection of liver oligometastases were enrolled in Sun Yat-Sen University Cancer Center with intact clinical data. Serum DKK1 was detected by ELISA assay. Immunofluorescent staining examination for CD3 and CD8 in slices were also conducted. RESULTS: Among 65 patients included, the recurrence-free survival (RFS) and overall survival (OS) were significantly better in the low serum DKK1 group (RFS: P = 0.021; OS: P = 0.043). DKK1 was overexpressed in stage IV CRC patients in TCGA data. The number of CD8+ tumor-infiltrating lymphocytes (TILs) in invasive margin of CRC liver oligometastases was significantly higher in low serum DKK1 group (P = 0.042). CONCLUSION: Elevated serum DKK1 level was associated with poorer RFS and OS, and less CD8+ TILs in invasive margin in CRC liver oligometastases. DKK1 might serve as a supplementalprognostic factor for clinical risk score and a potential target for immunotherapy.

Expression of Demethylase Genes, FTO and ALKBH1, Is Associated with Prognosis of Gastric Cancer.

BACKGROUND: Reversible N6-methyladenosine (m6A) modifications in messenger RNAs can be categorized under the field of "RNA epigenetics." However, the potential role of m6A-related genes in gastric cancer (GC) prognosis has not been systematically researched. AIMS: This study was aimed at providing insights into the prognostic role of m6A-related gene expression, at both mRNA and protein levels. METHODS: Kaplan-Meier (KM) plotter database and The Cancer Genome Atlas (TCGA) database were used to explore the prognostic significance of individual m6A-related genes in overall survival (OS) and progression-free survival at the mRNA level. For independent validation, the protein level of genes significantly associated with prognosis in both databases was further detected in 450 paired GC and corresponding adjacent non-tumor tissues using tissue microarray (TMA)-based immunohistochemistry (IHC). The relationship between the FTO and ALKBH1 expression and the clinicopathological characteristics was explored. RESULTS: Among nine m6A-related genes, aberrantly high mRNA expression of FTO and ALKBH1 was associated with poor OS in the KM and TCGA cohorts. However, the TMA-IHC indicated that protein expression of FTO and ALKBH1 was markedly downregulated in GC tissues. A lower protein level of ALKBH1 was closely correlated with larger tumor sizes (≥ 5 cm) and more advanced TNM stages, while lower FTO protein expression was associated with shorter OS in GC patients. CONCLUSIONS: Aberrant expression of demethylase genes, FTO and ALKBH1, has a distinct prognostic value in GC patients, indicating that FTO and ALKBH1 may play vital roles in GC progression and metastasis.

Genetic and clonal dissection of osteosarcoma progression and lung metastasis.

Osteosarcoma is a primary malignant bone tumor that has a high potential to metastasize to lungs. Little is known about the mechanisms underlying the dissemination of OS cancer cells to lungs. We performed whole exome sequencing of 13 OS primary tumors, with matched lung metastases and normal tissues. Phylogenetic analyses revealed that lung metastatic tumors often harbor clones that are nonexistent or rare in the matched primary OS tumors. Spatially and temporally separated lung metastases were from parallel seeding events with a polyphyletic pattern. Loss of TP53 or RB1 is among the early events during OS tumorigenesis, while loss of PTEN is involved at the later stages associated with lung metastases. Finally, KEAP1 was identified as a novel biomarker for increased metastatic risk. Patients whose primary tumors harbored KEAP1 amplification have significantly poorer lung-metastasis free survival. This finding was validated in two independent datasets. Further, in vitro experiments exhibited that KEAP1 depletion suppressed the invasion of OS cells. Our findings uncover the patterns of clonal evolution during OS progression and highlight KEAP1 as a novel candidate associated with the risk of lung metastasis in OS patients.

Solitary Pulmonary Lesion in Patients with History of Malignancy: Primary Lung Cancer or Metastatic Cancer?

BACKGROUND: Defining the status of solitary pulmonary lesion (SPL) in patients with history of malignancy is important because primary lung cancer (PLC) or intrapulmonary metastasis might indicate different surgical strategies. The aim of this study is to identify factors related to the status of these lesions and construct a clinical model to estimate the pretest probability of PLC. METHODS: From January 2005 to January 2016, 104 patients with previous malignancy and suitable for surgery were retrospectively studied. Univariate and multivariate analyses were performed to identify possible factors related to SPLs. A nomogram was constructed to differentiate PLC from intrapulmonary metastasis. RESULTS: Ninety-seven (93.3%) patients were diagnosed as malignant postoperatively, including 61 patients with intrapulmonary metastasis and 36 patients with PLC. Multivariate analysis showed that site of primary tumor [head and neck squamous cell cancer: odds ratio (OR) = 28.509, P = 0.006; genitourinary cancer: OR = 23.928, P = 0.012], negative lymph node status of primary tumor (OR = 3.154, P = 0.038), spiculation of SPL (OR = 3.972, P = 0.022), and central location of SPL (OR = 4.679, P = 0.026) were four independent factors differentiating PLC from intrapulmonary metastasis. All of these were included in the nomogram. The C-index of the nomogram for predicting probability was 0.82. CONCLUSIONS: Incidence of malignant SPLs was fairly high in patients with history of malignancy. A nomogram including site and lymph node status of primary tumor, and spiculation and location of SPL might be a good tool for differentiating PLC from intrapulmonary metastasis preoperatively and guiding treatment.