Purpose The aim of the present study was to investigate the prognostic value of tumor-infiltrated lymphocytes (TILs), especially the prognostic value of Foxp3+ regulatory T cells (Tregs), CD8+ CTLs ...and Tregs/CD8+ ratios in gastric cancer patients after R0 resection. Patients and methods From 133 patients, CD4+, CD8+ and Foxp3+ TILs were assessed by immunohistochemistry in tissue microarrays and N1 regional lymph nodes sections containing gastric cancer. The prognostic effects of low- or high-density TIL subsets were evaluated by Cox regression and Kaplan-Meier analysis using median values as cutoff, while the effects of Foxp3+/CD8+ ratios were evaluated using the value determined by ROC cure analysis as cutoff. Results It was found that CD4+ and CD8+ TILs were not associated with overall survival (OS). In the tumor sites, higher Foxp3+ Tregs/CD8+ ratio was an independent factor for worse OS (multivariate analysis HR = 2.827, P = 0.037). The 1-year, 2-year and 3-year OS rates were 90, 77.5 and 70% for the group with intratumoral high Tregs/CD8+ ratio, compared with 100, 94.3 and 90.5% for the group with intratumoral low ratio. At the same time, the presence of intratumoral high Foxp3+ Tregs was also associated with worse OS (log rank test, P = 0.025); however, it was not an independent predictor and correlated with intratumoral Foxp3+ Tregs/CD8+ ratio (χ ² test, P < 0.001). Although the infiltration of Foxp3+ Tregs in N1 regional lymph nodes was associated with lymph node metastasis (P = 0.028), it was not associated with prognosis (P = 0.458). Conclusions Intratumoral high Foxp3+ Tregs/CD8+ ratio was an independent predictor for the prognosis of gastric cancer. It can be inferred that a combination of deletion of Tregs and stimulation of CD8+ effector T cells may be an effective immunotherapy to prolong survival after surgery.
Secondary lymphoid tissue chemokine (SLC) is strongly expressed in secondary lymphoid organs. Its ability to facilitate chemotaxis of both dendritic cells (DC) and T cells makes it a promising ...candidate for cancer therapy. In this study, we modified a BMDC vaccine by incorporating the SLC mature peptide gene. The efficacy of this vaccine was evaluated using a mouse hepatocellular carcinoma (HCC) model, with rAAV2 as the gene delivery vector. The rAAV2 encoding SLC (rAAV2-SLC) transfected immature BMDCs at high efficiency and the anti-tumor effects of SLC gene modified BMDCs (rAAV2-SLC/BMDC) were evaluated. In addition, rAAV2-SLC/BMDC vaccine injected directly into tumors attracted more CD4
+ and CD8
+ T lymphocytes into tumors and showed stronger anti-tumor effects than footpad delivery. Moreover, we found that the phenotypic expression of MHC II, the secretion of IL-12 and IFN-γ, and T cell stimulation were increased in vitro following treatment with rAAV2-SLC/BMDC vaccine and these responses were inhibited by PTX. In vivo, PTX also inhibited the anti-tumor effects of the vaccine. The results suggest that the expression of SLC by rAAV2-SLC/BMDC plays more than a chemotactic role in anti-tumor responses, thus these studies further demonstrate that SLC has potential to be valuable in cancer therapy.
Metabolic syndrome (MS) comprises a set of conditions that are risk factors for cardiovascular diseases and diabetes. Numerous epidemiological studies on MS have been conducted, but there has not ...been a systematic analysis of the prevalence of MS in the Chinese population. Therefore, the aim of this study was to estimate the pooled prevalence of MS among subjects in Mainland China.
We performed a systematic review by searching both English and Chinese literature databases. Random or fixed effects models were used to summarize the prevalence of MS according to statistical tests for heterogeneity. Subgroup, sensitivity, and meta-regression analyses were performed to address heterogeneity. Publication bias was evaluated using Egger's test.
Thirty-five papers were included in the meta-analysis, with a total population of 226,653 Chinese subjects. Among subjects aged 15 years and older, the pooled prevalence was 24.5% (95% CI: 22.0-26.9%). By sex, the prevalences were 19.2% (95% CI: 16.9-21.6%) in males and 27.0% (95% CI: 23.5-30.5%) in females. The pooled prevalence of MS increased with age (15-39 years: 13.9%; 40-59 years: 26.4%; and 60 years: 32.4%). Individuals living in urban areas (24.9%, 95% CI: 18.5-31.3%) were more likely to suffer from MS than those living in rural areas (19.2%, 95% CI: 14.8-23.7%). Hypertension was the most prevalent component of MS in males (52.8%), while the most prevalent component of MS for females was central obesity (46.1%).
Our systematic review suggested a high prevalence of MS among subjects in Mainland China, indicating that MS is a serious public health problem. Therefore, more attention should be paid to the prevention and control of MS.
We previously reported that the intronic tagSNP +357G/C in the metastasis suppressor HTPAP is associated with metastasis and prognosis of hepatocellular carcinoma (HCC). The aim of this study was to ...investigate whether SNPs in the HTPAP promoter modulate HTPAP expression and prognosis of HCC. Genomic DNA from 572 microdissected HCCs were genotyped by pyrosequencing and verified by direct sequencing. Haplotype blocks were analyzed. Reporter plasmids were constructed and transfected into HCC cell lines. Transcriptional activities of plasmids were analyzed by dual-luciferase reporter systems. HTPAP expression was measured by real-time quantitative PCR, western blots, and tissue microarrays. Invasion was assessed by Matrigel assays. The prognostic values of HTPAP promoter SNPs in HCC were evaluated by Kaplan-Meier and Cox regression analyses. We identified six SNPs, including -1053A/G and +64G/C, in the HTPAP promoter. The SNPs were in complete linkage disequilibrium, resulting in three promoter haplotypes (promoter I:-1053AA/+64GG, promoter II: -1053AG/+64GC, and promoter III: -1053GG/+64CC). Promoter I manifested the highest luciferase index (p<0.005). However, no significant difference was observed between promoters II and III. We consistently found that HTPAP mRNA and protein levels were significantly higher in promoter I than that of promoter II+III (p<0.001). Invasion was increased in HCC cells transfected with promoters II+III compared to those transfected with promoter I (p<0.05). The HTPAP promoter II+III haplotype was associated with significantly increased metastasis compared to that of promoter I (p = 0.023). The postoperative five-year overall survival of patients with promoters II+III was lower than that of patients with promoter I (p = 0.006). Multivariate analysis showed that the promoter II+III haplotype was an adverse prognostic marker in HCC. The genetic variants at loci -1053 and +64 of the HTPAP promoter affect the expression of HTPAP, which might be a novel determinant and target for HCC prognosis.
Abstract
In the eighth data release (DR8) of the Large Sky Area Multi-Object Fiber Spectroscopic Telescope, more than 318,740 low-resolution stellar spectra with types from B to early F and ...signal-to-noise ratios >50 were released. With this large volume of the early-type stars, we tried machine-learning algorithms to search for class-one and class-two chemical peculiars (CP1 and CP2), and to detect spectral features to distinguish the two classes in low-resolution spectra. We selected the XGBoost algorithm after comparing the classification efficiency of three machine-learning ensemble algorithms. Using XGBoost followed by the visual investigation, we presented a catalog of 20,694 sources, including 17,986 CP1 and 2708 CP2, in which 6917 CP1 and 1652 CP2 are newly discovered. We also list the spectral features to separate CP1 from CP2 discovered through XGBoost. The stellar parameters (including effective temperature (
T
eff
), surface gravity (log
g
), metallicity Fe/H), the spatial distribution in Galactic coordinates, and the color magnitude were provided for all of the entries of the catalog. The
T
eff
for CP1 distributes from ∼6000 to ∼8500 K, while for CP2 it distributes from ∼7000 to ∼13,700 K. The log
g
of CP1 ranges from 2.8 to 4.8 dex, peaking at 4.5 dex, and of CP2 it ranges from 2.0 to 5.0 dex, peaking at 3.6 dex, respectively. The Fe/H of CP1 and CP2 are from −1.4 to 0.4 dex, and the Fe/H of CP1 are on average higher than that of CP2. Almost all of the targets in our sample locate around the Galactic plane.
A new numerical procedure is proposed to analyse solid particle erosion caused by slurry. The procedure works involves two mechanisms. First, high-concentration particles are considered as a ...continuous granular phase and tracked through the Eulerian–Eulerian two-fluid method. Second, the continuous granular phase near the pipe wall is converted into discrete incident and rebound particles by a particle separation method. The procedure is validated through comparison with experimental data available in the literature. Additionally, the performance and efficiency of the new method are compared with those of the dense discrete phase method and the discrete element method.
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•The new method involves the analysis of solid particle erosion caused by high-concentration particles.•High-concentration particles are treated as a continuous granular phase.•A particle separation method is employed to convert the continuous phase into discrete particles.•Incident particles are distinguished from rebound particles in the near-wall region.•The new method significantly reduces the required computational resources compared with DEM and DDPM.
In randomized studies, the strategy of pulmonary vein antral isolation (PVI) plus linear ablation has failed to increase success rates for persistent atrial fibrillation (PeAF) ablation when compared ...with PVI alone. Peri-mitral reentry related atrial tachycardia due to incomplete linear block is an important cause of clinical failures of a first ablation procedure. Ethanol infusion (EI) into the vein of Marshall (EI-VOM) has been demonstrated to facilitate a durable mitral isthmus linear lesion.
This trial is designed to compare arrhythmia-free survival between PVI and an ablation strategy termed upgraded ‘2C3L’ for the ablation of PeAF.
The PROMPT-AF study (clinicaltrials.gov 04497376) is a prospective, multicenter, open-label, randomized trial using a 1:1 parallel-control approach. Patients (n = 498) undergoing their first catheter ablation of PeAF will be randomized to either the upgraded ‘2C3L’ arm or PVI arm in a 1:1 fashion. The upgraded ‘2C3L’ technique is a fixed ablation approach consisting of EI-VOM, bilateral circumferential PVI, and 3 linear ablation lesion sets across the mitral isthmus, left atrial roof, and cavotricuspid isthmus. The follow-up duration is 12 months. The primary end point is freedom from atrial arrhythmias of >30 seconds, without antiarrhythmic drugs, in 12 months after the index ablation procedure (excluding a blanking period of 3 months).
The PROMPT-AF study will evaluate the efficacy of the fixed ‘2C3L’ approach in conjunction with EI-VOM, compared with PVI alone, in patients with PeAF undergoing de novo ablation.
Le-Cao-Shi (LCS) has long been used as a folk traditional Chinese medicine formula against liver injuries, whereas its pharmacological mechanisms remain elusive. Our study aims to investigate the ...underlying mechanism of LCS in treating liver injuries
integrated network pharmacology, metabonomics, and experimental validation. By network pharmacology, 57 compounds were screened as candidate compounds based on ADME parameters from the LCS compound bank (213 compounds collected from the literature of three single herbs). According to online compound-target databases, the aforementioned candidate compounds were predicted to target 87 potential targets related to liver injuries. More than 15 pathways connected with these potential targets were considered vital pathways in collectively modulating liver injuries, which were found to be relevant to cancer, xenobiotic metabolism by cytochrome P450 enzymes, bile secretion, inflammation, and antioxidation. Metabonomics analysis by using the supernatant of the rat liver homogenate with UPLC-Q-TOF/MS demonstrated that 18 potential biomarkers could be regulated by LCS, which was closely related to linoleic acid metabolism, glutathione metabolism, cysteine and methionine metabolism, and glycerophospholipid metabolism pathways. Linoleic acid metabolism and glutathione metabolism pathways were two key common pathways in both network pharmacology and metabonomics analysis. In ELISA experiments with the CCl
-induced rat liver injury model, LCS was found to significantly reduce the levels of inflammatory parameters, decrease liver malondialdehyde (MDA) levels, and enhance the activities of hepatic antioxidant enzymes, which validated that LCS could inhibit liver injuries through anti-inflammatory property and by suppressing lipid peroxidation and improving the antioxidant defense system. Our work could provide new insights into the underlying pharmacological mechanisms of LCS against liver injuries, which is beneficial for its further investigation and modernization.
Objective:
To evaluate the effectiveness and safety of using off-the-shelf “Octopus” technique to treat ruptured or symptomatic thoracoabdominal aortic aneurysm (TAAA) and pararenal abdominal aortic ...aneurysm (PRAAA).
Methods and Results:
All cases who underwent “Octopus” technique from May 2016 to May 2019 at our center were retrospectively analyzed. A total of 10 cases (8 males) were included. The mean age was 54.5±14.2 years (range: 31–80 years). Eight cases presented as aneurysm rupture or impending rupture accepted emergency repair. Technical success, defined by placement of all endografts as planned, was achieved in all cases. A total of 30 target visceral branches were successfully cannulated, 9 celiac arteries were covered intentionally. Intraoperative endoleak was observed in 6 patients, all of them were gutter leak. During hospital stay, there was no death, no side branch occlusion or spinal cord ischemia. Median follow-up was 30 months (range: 12–50 months). One patient died of lung cancer at 14-month follow-up. There was no secondary endoleak. The primary endoleak were found spontaneously resolved in 3 cases at 7 days, 3-month, and 1-year imaging. One persistent endoleak totally resolved after sealing of gutter spaces at 4-month follow-up. The other 2 persistent endoleak decreased during follow-up, which are still under observation. The branch patency rate was 90.3% (28/31). All the 3 occluded branches were renal arteries. Branch occlusion occurred in 2 cases at 1-month follow-up and 1 case at 2-year follow-up, but renal insufficiency was not observed in these cases. Obvious aneurysm sac shrinkage (≥5 mm) was observed in all cases. The aneurysm size shrunk from 7.6±1.9 to 5.5±1.4 cm. No spinal cord ischemia occurred during follow-up.
Conclusion:
Treatment of ruptured TAAA and PRAAA with “Octopus” technique is feasible and safe for high surgical risk patients in the absence of fenestrated and branched devices. The long-term clinical outcomes needed to be investigated.
Chloroquine, a lysosomal inhibitor, is used for malaria, rheumatoid arthritis, and lupus erythematosus therapy. In our previous study, FIP-gts, an immunomodulatory protein from Ganoderma tsugae, ...inhibited cell viability in lung cancer cells and urothelial cancer cells. Urothelial carcinoma is the most common type of bladder cancer. Cisplatin resistance is an important issue in urothelial carcinoma therapy.
The aim of this study is to investigate the effect of combination treatment with FIP-gts and chloroquine on cytotoxicity to resensitize the cisplatin-resistant cells.
FIP-gts and chloroquine cytotoxicity were determined by evaluating CCK-8 assay. Cell death pathways, ROS and cell cycle arrested were analysed through flow cytometry and Western blot. ShRNA targeting to autophagy-related genes were tested to evaluate their autophagic cell death for resistant urothelial cells.
Using CCK-8 assay, chloroquine increased FIP-gts-induced cytotoxicity in parental and cisplatin-resistant urothelial cancer cell lines. On flow cytometry, chloroquine enhanced FIP-gts-mediated sub-G1 accumulation, annexin V positive signal and mitochondrial membrane potential loss. Caspase-3/PARP cascade and z-VAD-fmk were performed to prove that FIP-gts and chloroquine induced caspase-independent cell death. Using H2DCFDA staining and flow cytometry, FIP-gts and chloroquine did not induce ROS production. N-acetyl cysteine, a ROS scavenger, inhibited the cytotoxicity and LC3-II accumulation in FIP-gts and chloroquine-treated N/P cells. To elucidate the role of autophagy in caspase-independent cell death by FIP-gts and chloroquine, LC3 shRNA were used to inhibit autophagy in N/P cells. The capabilities of FIP-gts and chloroquine to induce cytotoxicity and sub-G1 phase accumulation were abolished in autophagy-defective cells. This is the first study to reveal the novel function of FIP-gts in triggering caspase-independent cell death in cisplatin-resistant urothelial cancer cells.
Chloroquine enhanced FIP-gts-induced autophagy dependent caspase-independent cell death via abundant autophagosome accumulation. Combination treatment with FIP-gts and chloroquine may provide a new strategy for urothelial cancer therapy.
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