Highlights • The use of intelligent gelatinases-stimuli nanoparticles to deliver 5-aza-2′-deoxycytidine and 5-fluorouridine to gastric cancer cells. • The intelligent gelatinases-stimuli ...nanoparticles enhanced the stability of 5-aza-2′-deoxycytidine. • Incorporating 5-aza-2′-deoxycytidine into NPs significantly enhanced the sensitivity of gastric cancer cells to 5-fluorouridine.
Objective
To assess the association of baseline anti‐Müllerian hormone (AMH) levels with ovulation, time to ovulation and fertility outcomes in women with polycystic ovary syndrome (PCOS) receiving ...clomiphene citrate (CC) and compare this with placebo.
Design
Secondary analysis of the PCOSAct trial (NCT01573858).
Setting
27 trial centres in mainland China.
Population or sample
1000 infertile women with PCOS receiving either CC or placebo.
Methods
Baseline serum AMH was measured and analysed as a continuous and as a categorical variable. Interaction between AMH and CC was tested. Predictive values of AMH for ovulation, time to ovulation and fertility outcomes were assessed.
Main outcome measures
Ovulation and time to ovulation.
Results
900 baseline AMH data were available for analysis. There were no significant interactions with ovulation or conception for AMH and CC treatment (P = 0.782 and 0.419, respectively). Women in the upper quartile of AMH >15.88 ng/ml had significant lower ovulation (odds ratio OR 0.34, 95% CI 0.20–0.58) and conception rates (OR 0.65, 95% CI 0.42–1.00) compared with women in the lower quartile. Associations of AMH with clinical pregnancy (OR 0.98, 95% CI 0.95–1.01) and live birth (OR 0.98, 95% CI 0.96–1.01) were not significant. Ovulation rate increased until baseline AMH levels ≥7.0 ng/ml in women treated with CC but decreased when AMH increased in women with placebo. When AMH <7.0 ng/ml, an AMH threshold at 4.11 ng/ml predicted ovulation in women receiving CC (area under the curve AUC 0.64, 95% CI 0.42–0.86), with a sensitivity of 64% and a specificity of 62%, whereas prediction was poor for AMH ≥7.0 ng/ml (AUC 0.38, 95% CI 0.28–0.47). Median time to ovulation was 35 days in the lower quartile for women with placebo but this was significantly prolonged up to 98 days in the upper quartile. CC significantly shortened the time to ovulation up to 56 days.
Conclusions
Among women with PCOS, high baseline AMH levels were associated with a 20.1% lower chance of ovulation with a 63‐day longer time to ovulation. AMH can predict ovulation only when the baseline AMH level was <7.0 ng/ml in women with PCOS undergoing ovulation induction with CC.
Tweetable
Ovulation rate increased until baseline AMH levels ≥7.0 ng/ml in women treated with CC; a successful ovulation and time to ovulation was highly associated with baseline AMH level in these women.
Tweetable
Ovulation rate increased until baseline AMH levels ≥7.0 ng/ml in women treated with CC; a successful ovulation and time to ovulation was highly associated with baseline AMH level in these women.
Pancreatic adenosquamous carcinoma (ASPC) is a rare subtype of pancreatic cancer with lethal malignancy, and few studies have focused on the heterogeneity of ASPC. Here, we performed a single-cell ...sequencing procedure on pancreatic tumor tissue from an ASPC patient and a patient with high-grade intraductal papillary mucinous neoplasm (IPMN). Through the combined analysis of single-cell sequencing data from five pancreatic ductal adenocarcinoma (PDAC) patients, one IPMN patient, and one ASPC patient in a public database, we identified 11 main types of cells, including macrophages, B cells, cancer stem cells, ductal cells, fibroblasts, endo/stellate cells, neutrophils, acinar cells, T cells, natural killer (NK) cells, dendritic cells, and mast cells. Then, the different characteristics and differentiation paths of the immune microenvironment among IPMN, ASPC, and PDAC in macrophages, T cells, and cancer-associated fibroblasts (CAFs) were identified through multiple bioinformatics analyses. Two novel special cancer-associated fibroblasts were identified as nCAFs and imCAFs. Then, cancer cells in duct cells were identified using the infercnv software. Two ASPC-specific subgroups of cancer cells with squamous cell features were identified. Finally, the identified specific CAFs and cancer cells were mapped to TCGA-PAAD cohort through the cibersoftx software. All of these identified subgroups were calculated to have a significant prognostic value in pancreatic cancer patients. These findings will promote the clinical application of single-cell sequencing data of pancreatic cancer and deepen our understanding of ASPC.
S100A9 protein, which is recently classified as a novel damage associated molecular pattern, is released from stressed cells undergoing necrosis or secreted by living cells undergoing a stress that ...act as endogenous danger signal associated with infection, tissue damage and cancer. Here, we evaluated the relationship of serum S100A9 with viral replication and liver necroinflammation in patients with chronic hepatitis B (CHB) infection.
A total of one hundred and eighty-three recruited patients with CHB infection underwent liver biopsy for grading of necroinflammation (G) and staging of fibrosis (S). Forty-nine healthy individuals were included as healthy controls (HCs). Serum S100A9 levels were determined by enzyme-linked immunosorbent assay. Correlations of serum S100A9 with viral replication and liver necroinflammation were analyzed. The receiver operating characteristic curve was used to assess the discriminating power of serum S100A9 to grade liver necroinflammation (G). Liver normal L02 cells were transfected with a HBV plasmid, and S100A9 levels were determined.
Serum S100A9 levels were increased in CHB patients compared to HCs. Intrahepatic immunoreactivity for S100A9 was enhanced in liver sample from CHB patients. Infection of HBV also resulted in an elevated S100A9 expression in L02 cells. Serum S100A9 was correlated with the serum HBV DNA levels. CHB patients with moderate-to-severe liver necroinflammation (G ≥ 2) showed significantly higher serum S100A9 levels than those without or with mild necroinflammation (G < 2). In patients with normal ALT levels, the area under the curve (AUC) of S100A9 for discriminating patients with moderate-to-severe necroinflammation (G ≥ 2) was 0.791 95% confidence interval (CI), 0.670-0.913 with 91.7% sensitivity, 65.0% specificity and 78.3% accuracy. In patients with an alanine aminotransferase (ALT) < 2 upper limit of normal, the AUC of S100A9 for discriminating patients with moderate-to-severe necroinflammation (G ≥ 2) was 0.826 (95% CI, 0.729-0.923) with 87.9% sensitivity, 72.5% specificity and 80.2% accuracy.
HBV infection may enhance S100A9 expression. Serum S100A9 levels are correlated with viral load. Serum S100A9 has potential to discriminate the grades of liver necroinflammation, particularly in CHB patients with normal or mildly increased ALT levels.
After reviewing the diagnosis and treatment process of a patient with active cancer who experienced wake-up stroke, we have summarized the clinical manifestations, laboratory examination results, ...imaging features, pathological results, and treatment in this report. Patients with active cancer who experience wake-up stroke often have mild neurological deficits at the time of onset. For the patient in this study, laboratory test results were mainly characterized by abnormal coagulation function and elevated tumor markers. The brain magnetic resonance imaging (MRI) images were characterized by involvement of both the arterial and venous systems. Thrombolytic therapy during the window period can improve the symptoms of neurological deficits. Overall, anticoagulation therapy was safe and effective in our patient.
Abstract Docetaxel (DOC) is widely used as radiosensitizer in various tumors, including gastric cancer (GC), but its therapeutic effect remains to be improved. In this study, using docetaxel-loaded ...nanoparticles (DOC-NPs) based on gelatinase-stimuli strategy, we compared their radioenhancement efficacy with docetaxel in GC. Compared with DOC, radiosensitization of DOC-NPs was improved significantly (sensitization enhancement ratio increased 1.09-fold to 1.24-fold, P < 0.01) in all three gelatinase overexpressing GC cells, while increased slightly (1.02-fold, P = 0.38) in gelatinase deficient normal gastric mucosa cells. The improved radiosensitization efficacy was associated with enhanced G2/M arrest, increased reactive oxygen species (ROS), more effective DSBs and promoted apoptosis. More importantly, the radiosensitization efficacy of DOC-NPs (estimated as ‘‘very active’’) was more prominent than DOC (estimated as ‘‘moderately active’’) by intravenous injection in xenograft. In conclusion, DOC-NPs are highly selective radiosensitizers in gelatinase over-expressing tumors, and more effective than DOC. By manipulating the common microenvironment difference between tumor and normal tissue, gelatinase-mediated nanoscale delivery system serves as a potential strategy possessing both universality and selectivity for radiosensitizers.
The original specimens of both
Prunus zappeyana
and P. zappeyana var. subsimplex were found to belong to more than one taxon. In addition, P. zappeyana var. subsimplex was found to be invalid ...because, when the name was published, two separate descriptions were given to two cited collections, but not to the taxon, making the name unaccompanied with a description or diagnosis of this taxon (Art. 38.1 (a)). Therefore, a lectotype of
P. zappeyana
was designated under Art. 9.11 of ICN, by which
P. zappeyana
was placed in the synonymy of
P. veitchii
.
Efforts to precisely assess tumor-specific T-cell immune responses still face major challenges, and the potential molecular mechanisms mediating hepatocellular carcinoma (HCC) microenvironment ...imbalance after incomplete radiofrequency ablation (iRFA) are unclear. This study aimed to provide further insight into the integrated transcriptomic and proteogenomic landscape and identify a new target involved in HCC progression following iRFA.
Peripheral blood and matched tissue samples were collected from 10 RFA-treated HCC patients. Multiplex immunostaining and flow cytometry were used to assess local and systemic immune responses. Differentially expressed genes (DEGs) and differentially expressed proteins (DEPs) were explored via transcriptomic and proteogenomic analyses. Proteinase-3 (PRTN3) was identified in these analyses. And then, the ability of PRTN3 to predict overall survival (OS) was assessed in 70 HCC patients with early recurrence after RFA. In vitro CCK-8, wound healing and transwell assays were conducted to observe interactions between Kupffer cells (KCs) and HCC cells induced by PRTN3. The protein levels of multiple oncogenic factors and signaling pathway components were detected by western blotting. A xenograft mouse model was built to observe the tumorigenic effect of PRTN3 overexpression on HCC.
Multiplex immunostaining revealed no immediate significant change in local immune cell counts in periablational tumor tissues after 30 min of iRFA. Flow cytometry showed significantly increased levels of CD4
T cells, CD4
CD8
T cells, and CD4
CD25
CD127
Tregs and significantly decreased the levels of CD16
CD56
natural killer cells on day 5 after cRFA (p < 0.05). Transcriptomics and proteomics revealed 389 DEGs and 20 DEPs. Pathway analysis showed that the DEP-DEGs were mainly enriched in the immunoinflammatory response, cancer progression and metabolic processes. Among the DEP-DEGs, PRTN3 was persistently upregulated and closely associated with the OS of patients with early recurrent HCC following RFA. PRTN3 expressed in KCs may affect the migration and invasion of heat stress-treated HCC cells. PRTN3 promotes tumor growth via multiple oncogenic factors and the PI3K/AKT and P38/ERK signaling pathways.
This study provides a comprehensive overview of the immune response and transcriptomic and proteogenomic landscapes of the HCC milieu induced by iRFA, revealing that PRTN3 promotes HCC progression after iRFA.
ChiCTR2200055606, http://www.chictr.org.cn/showproj.aspx?proj=32588 .
MiR-21 is an oncogenic miR frequently elevated in gastric cancer. Overexpression of miR-21 decreases the sensitivity of gastric cancer cells to trastuzumab, which is a humanized monoclonal antibody ...targeting human epidermal growth factor receptor 2. However, optimization of miRNA or its anti-miRNA oligonucleotides (AMOs) for delivery is a challenge. Receptor-mediated endocytosis plays a crucial role in the delivery of biotherapeutics including AMOs. This study is a continuation of our earlier findings involving poly(ε-caprolactone) (PCL)-poly (ethylene glycol) (PEG) nanoparticles (PEG-PCL NPs), which were coated with trastuzumab to target gastric cancer cells with HER2 receptor over-expression using anti-miRNA-21 antisense oligonucleotides (AMO-21). The antibody conjugates (HER-PEG-PCL NPs) act against target cells via antibody-dependent mechanisms and also based on encapsutalated AMO-21. X-ray photoelectron spectroscopy validated the presence of trastuzumab on NP surface. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) revealed a stable antibody expression. The cell line specificity, cellular uptake, AMO-21 delivery, and cytotoxicity of the HER-PEG-PCL NPs were investigated. We found that the antibody conjugates significantly enhanced the cellular uptake of NPs. The HER-PEG-PCL NPs effectively suppressed the target miRNA expression in gastric cancer cells, which further up-regulated phosphatase and tensin homolog (PTEN). As a result, the sensitivity of HER2-expressing gastric cancer cells to trastuzumab was enhanced. The approach enhances the targeting by trastuzumab as well as antibody-dependent cellular cytotoxicity of immune effector cells. The antitumor effects of AMO-21-HER-PEG-PCL NPs were compared with trastuzumab in xenograft gastric cancer mice. The results provide insight into the biological and clinical potential of targeted AMO-21 delivery using modified trastuzumab for gastric cancer treatment.
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