Application of exosomes in tumor immunity: recent progresses.

Exosomes are small extracellular vesicles secreted by cells, ranging in size from 30 to 150 nm. They contain proteins, nucleic acids, lipids, and other bioactive molecules, which play a crucial role in intercellular communication and material transfer. In tumor immunity, exosomes present various functions while the following two are of great importance: regulating the immune response and serving as delivery carriers. This review starts with the introduction of the formation, compositions, functions, isolation, characterization, and applications of exosomes, and subsequently discusses the current status of exosomes in tumor immunotherapy, and the recent applications of exosome-based tumor immunity regulation and antitumor drug delivery. Finally, current challenge and future prospects are proposed and hope to demonstrate inspiration for targeted readers in the field.

Genetically predicted serum testosterone and risk of gynecological disorders: a Mendelian randomization study.

Background: Testosterone plays a key role in women, but the associations of serum testosterone level with gynecological disorders risk are inconclusive in observational studies. Methods: We leveraged public genome-wide association studies to analyze the effects of four testosterone related exposure factors on nine gynecological diseases. Causal estimates were calculated by inverse variance-weighted (IVW), MR-Egger and weighted median methods. The heterogeneity test was performed on the obtained data through Cochrane's Q value, and the horizontal pleiotropy test was performed on the data through MR-Egger intercept and MR-PRESSO methods. "mRnd" online analysis tool was used to evaluate the statistical power of MR estimates. Results: The results showed that total testosterone and bioavailable testosterone were protective factors for ovarian cancer (odds ratio (OR) = 0.885, P = 0.012; OR = 0.871, P = 0.005) and endometriosis (OR = 0.805, P = 0.020; OR = 0.842, P = 0.028) but were risk factors for endometrial cancer (OR = 1.549, P < 0.001; OR = 1.499, P < 0.001) and polycystic ovary syndrome (PCOS) (OR = 1.606, P = 0.019; OR = 1.637, P = 0.017). dehydroepiandrosterone sulfate (DHEAS) is a protective factor against endometriosis (OR = 0.840, P = 0.016) and premature ovarian failure (POF) (OR = 0.461, P = 0.046) and a risk factor for endometrial cancer (OR= 1.788, P < 0.001) and PCOS (OR= 1.970, P = 0.014). sex hormone-binding globulin (SHBG) is a protective factor against endometrial cancer (OR = 0.823, P < 0.001) and PCOS (OR = 0.715, P = 0.031). Conclusion: Our analysis suggested causal associations between serum testosterone level and ovarian cancer, endometrial cancer, endometriosis, PCOS, POF.

Identification of metabolic biomarkers for diagnosis of epithelial ovarian cancer using internal extraction electrospray ionization mass spectrometry (iEESI-MS).

BACKGROUND: Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancies. The poor prognosis of EOC is mainly due to its asymptomatic early stage, lack of effective screening methods, and a late diagnosis in the advanced stages of the disease. OBJECTIVE: This study investigated metabolomic abnormalities in epithelial ovarian cancers. METHODS: Our study developed a novel strategy to rapidly identify the metabolic biomarkers in the plasma of the EOC patients using Internal Extraction Electrospray Ionization Mass Spectrometry (IEESI-MS) and Liquid Chromatography-mass Spectrometry (HPLC-MS), which could distinguish the differential metabolites in between plasma samples collected from 98 patients with epithelial ovarian cancer, including 78 cases with original (P), and 20 cases with self-configuration (ZP), as well as 60 healthy subjects, including 30 cases in the original sample (H), 30 cases in self-configuration (ZH), and 6 cases in a blind sample (B). RESULTS: Our study detected 880 metabolites based on criteria variable importance in projection (VIP) > 1, among which 26 metabolites were selected for further identification. They are mainly metabolism-related lipids, amino acids, nucleic acids, and others. The metabolic pathways associated with the differential metabolites were explored by the KEGG analysis, a comprehensive database that integrates genome, chemistry, and system function information. The abnormal metabolites of EOC patients identified by IEESI-MS and HPLC-MS included Lysophosphatidylcholine (16:0) [Lyso PC (16:0)], L-Phenylalanine, L-Leucine, Phenylpyruvic acid, L-Tryptophan, and L-Histidine. CONCLUSIONS: Identifying the abnormal metabolites of EOC patients through metabolomics analyses could provide a new strategy to identify valuable potential biomarkers for the screening and early diagnosis of EOC.

Profiling of Urine Carbonyl Metabolic Fingerprints in Bladder Cancer Based on Ambient Ionization Mass Spectrometry.

The diagnosis of bladder cancer (BC) is currently based on cystoscopy, which is invasive and expensive. Here, we describe a noninvasive profiling method for carbonyl metabolic fingerprints in BC, which is based on a desorption, separation, and ionization mass spectrometry (DSI-MS) platform with N,N-dimethylethylenediamine (DMED) as a differential labeling reagent. The DSI-MS platform avoids the interferences from intra- and/or intersamples. Additionally, the DMED derivatization increases detection sensitivity and distinguishes carboxyl, aldehyde, and ketone groups in untreated urine samples. Carbonyl metabolic fingerprints of urine from 41 BC patients and 41 controls were portrayed and 9 potential biomarkers were identified. The mechanisms of the regulations of these biomarkers have been tentatively discussed. A logistic regression (LR) machine learning algorithm was applied to discriminate BC from controls, and an accuracy of 85% was achieved. We believe that the method proposed here may pave the way toward the point-of-care diagnosis of BC in a patient-friendly manner.

[Perlman syndrome research progress].

Perlman syndrome is a rare autosomal recessive congenital overgrowth syndrome caused by pathogenic variants of the DIS3L2 gene at 2q37 region. Clinically this syndrome is characterized by polyhydramnios, macrosomia, distinctive facial appearance, and renal dysplasia. Prognosis of the disease is poor, and survivors usually have mental delay and a high risk of developing Wilms tumor. At present, the pathogenesis of this disease is still poorly understood. This article intends to provide a review for this disease.

Distribution of perfluorooctane sulfonate in mice and its effect on liver lipidomic.

Perfluorooctane sulfonate (PFOS) is an emerging persistent organic pollutant (POP), and the harm caused by the enrichment of PFOS in living organism has attracted more and more attention. In this work, animal exposure model to PFOS was established. Mass spectrometry (MS), mass spectrometry imaging (MSI), hematoxylin and eosin (H&E) staining and lipidomics were combined for the study of the organ targeting of PFOS, the toxicity and possible mechanism caused by PFOS. PFOS most accumulated in the liver, followed by the lungs, kidneys, spleen, heart and brain. Combined with H&E staining and matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI MSI) results, it was found that the accumulation of PFOS indeed caused damage in particular areas of specific organ, like in the liver and in the marginal area of the heart. This work found that PFOS could cross the blood-brain barrier, entered the brain and caused the neurotoxicity, which was surprising and might be the reason that high dose of PFOS could cause convulsions. From the liver lipidomic analysis, we found that PFOS exposure mainly affected glycerophospholipid metabolism and sphingolipid metabolism. The up-regulated ceramide and lysophosphatidylcholine (LPC) might lead to liver cell apoptosis, and the decrease in liver triglyceride (TG) content might result in insufficient energy in mice and cause liver morphological damage. Phosphatidylcholine (PC) synthesis via phosphatidylethanolamine N-methyltransferase (PEMT) pathway might be a mechanism of self-protection in animals against PFOS induced inflammation. This study might provide new insight into underlying toxicity mechanism after exposure to PFOS.

MicroRNA-155 is upregulated in the placentas of patients with preeclampsia and affects trophoblast apoptosis by targeting SHH/GLi1/BCL2.

The pathogenesis of preeclampsia (PE) is complicated and multiple risk factors have been associated with its occurrence. Still, the underlying molecular mechanisms involved in PE remain elusive. Aberrant apoptosis and insufficient invasion of trophoblasts have been observed and are considered vital pathological features in PE. Herein, we found that miR-155 can specifically degrade the mRNA of the Hedgehog ligand sonic hedgehog (SHH), using dual luciferase reporter assays. Quantitative real-time PCR found that administering miR-155 mimics or inhibitors could significantly decrease or increase the expression of SHH in the trophoblasts, respectively. The transcription levels of miR-155 in the placenta were higher in patients with PE compared to the levels in healthy pregnant women, as shown by quantitative real-time PCR. Serum levels of miR-155 could predict the diagnosis of PE by receiver operating characteristic curve analysis and diagnosis evaluation tests. A significant increase in apoptosis was observed after administering miR-155 in HTR8/SVneo cells cultured ex vivo, accompanied by reduced proliferation. Mechanistically, transcriptional activity and expression of GLi1 were also inhibited under treatment of miR-155, and could be recovered after supplying additional recombinant human SHH to primary trophoblasts from patients, as determined by luciferase activity assays and western blotting. We further found that inhibiting miR-155 increased the production of SHH and improved the phenotype in primary trophoblasts from patients with PE. Our data show that miR-155 regulates apoptosis of trophoblasts in PE, which has potential value for predicting PE risk and might be deemed as a therapeutic target for treating PE.

STAT3-Induced lncRNA SNHG17 Exerts Oncogenic Effects on Ovarian Cancer through Regulating CDK6.

Emerging studies indicate that long noncoding RNAs (lncRNAs) play crucial roles in ovarian cancer (OC). By analyzing high-throughput data, we found that SNHG17 was highly expressed in multiple OC cohorts. However, its functions in OC were not explored. In this study, lncRNA expression in OC was analyzed by a series of microarray data. The functions of SNHG17 were investigated by various in vitro and in vivo assays. Fluorescence in situ hybridization (FISH), RNA pull-down, chromatin immunoprecipitation (ChIP), RNA immunoprecipitation (RIP), and luciferase reporter assays were used to reveal the potential mechanisms involved in the effects of SNHG17. We found that SNHG17 was overexpressed in OC and that the oncogenic transcription factor STAT3 was involved in promoting its expression. In addition, high SNHG17 expression was associated with a poor prognosis in OC. Functional analysis revealed that SNHG17 could promote OC cell growth. Mechanistically, SNHG17 was found to be located predominantly in the cytoplasm. It could regulate expression of CDK6, an important cell-cycle regulator, by acting as a molecular sponge for miR-214-3p. In summary, our study suggested that SNHG17 acted as an oncogene in OC, which might serve as a novel target for OC diagnosis and therapy.

Successful management of a pregnant woman with Kasabach-Merritt syndrome and preeclampsia: A case report.

INTRODUCTION: Kasabach-Merritt Syndrome (KMS) is an extremely rare disease in adults, which lead to consumptive coagulopathy characterized by severe hypofibrinogenemia and thrombocytopenia. PATIENT CONCERNS:: a 25-year-old Chinese pregnant women complicated by preeclampsia and KMS presented with refractory postpartum hemorrhage and incision bleeding after cesarean section. DIAGNOSIS: The diagnosis of KMS was made based on clinical manifestation of Kaposiform Hemangioendothelioma, severe hypofibrinogenemia and thrombocytopenia. INTERVENTIONS: After a poor response to massive blood products transfusion for 1 week, corticosteroid treatment was initiated for 3 days. OUTCOMES: The patient reached a normal platelet count and a mild anemia within 4 weeks. Two months later, all laboratory values had returned to normal, and the incision was healing well. CONCLUSION: Pregnancy complicated by preeclampsia and surgery may have contributions for the development of Kasabach-Merritt syndrome. Corticosteroid is indicated in the episode of acute Kasabach-Merritt syndrome after the failure of massive blood transfusion.

Stimulus-responsive tea polyphenols as nanocarrier for selective intracellular drug delivery.

Nanodrug delivery systems have been widely researched to achieve efficient antitumor drug delivery. However, the controlled drug delivery at tumor cells remains the main challenge for antitumor therapy. Herein, a pH and reduction-responsive nanocarrier based on green tea polyphenols was employed as a smart excipient for chemotherapy drug delivery. Paclitaxel, as a chemotherapy drug, was loaded in the nanocarrier, noted as green tea polyphenol/paclitaxel. The green tea polyphenol/paclitaxel kept constant diameter at physiological condition (i.e. pH 7.4), while gradually enlarged at acid environment (pH = 5.5) and the reductive environment. The in vitro paclitaxel release results indicated that the release of paclitaxel from the green tea polyphenol/paclitaxel at pH 7.4 was slow, whereas obviously accelerated at the acid environment (pH = 5.5) and the reductive environment. The in vitro antitumor assay showed more efficient tumor cells inhibition of green tea polyphenol/paclitaxel than free paclitaxel. Meanwhile, due to the proper size (∼100 nm), green tea polyphenol/paclitaxel could effectively accumulate at tumor sites. In the in vivo mice bearing A549 xenograft mouse models, green tea polyphenol/paclitaxel exhibited satisfactory antitumor effect and depressed system toxicity when compared with free paclitaxel, owing to the enhanced paclitaxel accumulation and controlled paclitaxel release in the tumor cells. With simple compositions and satisfactory antitumor effects, this green tea polyphenol-based nanocarrier can be a promising nanodrug delivery system for the therapy of cancers.

The Prognostic and Clinical Value of CD44 in Colorectal Cancer: A Meta-Analysis.

Background: CD44 is widely used as a putative cancer stem cells (CSCs) marker for colorectal cancer (CRC). However, the prognostic role of CD44 in CRC remains controversial. Methods: We performed a systematic review and meta-analysis to evaluate the association of various CD44 isoforms and overall survival (OS) and clinicopathological features of CRC patients. Results: A total of 48 studies were included in the meta-analysis. Total CD44 isoforms overexpression was significantly correlated with worse OS of patients with CRC (HR = 1.32, 95% CI = 1.08-1.61, P = 0.007). In a stratified analysis, a higher level of either CD44v6 or CD44v2 had an unfavorable impact on OS (HRCD44v6 = 1.50, 95% CI = 1.10-2.14, P = 0.010; HRCD44v2 = 2.93, 95% CI = 1.49-5.77, P = 0.002). Additionally, CD44 was shown to be associated with some clinicopathological features, such as lymph node metastasis (ORCD44 = 1.56, 95% CI = 1.01-2.41, P = 0.044; ORCD44v6 = 1.97, 95% CI = 1.19-3.26, P = 0.008; ORTotal CD44 isoforms = 1.57, 95% CI = 1.15-2.14, P = 0.004), distant metastasis (ORCD44 = 2.90, 95% CI = 1.08-7.83, P = 0.035; ORTotal CD44 isoforms = 1.89, 95% CI = 1.02-3.53, P = 0.044). Moreover, a high level of CD44 showed a possible correlation with poor differentiation (ORTotal CD44 isoforms = 1.44, 95% CI = 1.00-2.08, P = 0.051), elevated level of CD44v6 tend to be correlated with tumor size (OR = 1.71, 95% CI = 0.99-2.96, P = 0.056). Conclusions: This meta-analysis demonstrated that CD44 overexpression might be an unfavorable prognostic factor for CRC patients and could be used to predict poor differentiation, lymph node metastasis and distant metastasis.

Metal-organic frameworks as affinity agents to enhance the microdialysis sampling efficiency of fatty acids.

Microdialysis (MD) has been extensively used for in vivo sampling of hydrophilic analytes such as neurotransmitters and drug metabolites. In contrast, there have been few reports on sampling of lipophilic analytes by MD. Lipophilic analytes are easily adsorbed on the surfaces of the dialysis membrane and the inner wall of tubing, which leads to a very low relative recovery (RR). In this work, a strategy to develop an enhanced MD sampling of fatty acids (FAs) by using metal-organic frameworks (MOFs) as affinity agents in the perfusion fluid was investigated. Two MOFs, MIL-101 and ZIF-8, were synthesized and tested for the first time. A 2 times higher RR, about 70% RR, was obtained. The FT-IR experiment showed that the unsaturated metal sites in MOFs could coordinate with FAs, therefore the FAs were encapsulated into MOFs, avoiding FAs to be absorbed on the surfaces of the dialysis membrane and the inner wall of tubing. Moreover, incorporation of FAs into MOFs led to a decrease of free concentration of FAs inside the MD membrane and an increase of concentration gradient, allowing more FAs to diffuse across the membrane. Consequentially, an enhanced RR was obtained. The approach was successfully used to monitor the time profile of targeted FAs in cell culture media after lipopolysaccharide (LPS)-induced inflammation.

A uniform 2,5-dihydroxybenzoic acid layer as a matrix for MALDI-FTICR MS-based lipidomics.

A very uniform 2,5-dihydroxybenzoic acid (DHB) layer was for the first time constructed and used as a matrix for matrix-assisted laser desorption ionization Fourier transform ion cyclotron resonance mass spectrometry (MALDI-FTICR MS) for quickly exploring the changes in lipids within biological systems. Lipid extracts from biological samples were dissolved in chloroform and deposited onto the DHB layer. Benefiting from the insolubility of DHB in chloroform, the uniform matrix crystals were still maintained, and more importantly, the lipid analytes were distributed homogeneously on the layer, which significantly increased the reproducibility of analysis using MALDI-FTICR MS. Taking advantage of the benefit of high resolution of FTICR MS and the fragment ions obtained by MS/MS, lots of lipids were identified. This method was used for exploring the changes of lipids in drug-resistant tumor cells compared with paired drug-sensitive tumor cells. The principal component analysis (PCA) and partial least-squares discriminant analysis (PLS-DA) were employed for discovery of the changed lipids. This method, characterized by the simplicity and the speediness, demonstrated a new and promising approach for lipidomics study.

Bilateral cadaveric Achilles tendon graft in reconstruction after Achilles tendon tumor resection.

The standard approach to reconstruction after resection of a diffuse-type tenosynovial giant cell tumor is a local patch with free flaps. However, in cases in which the Achilles tendon involvement is extensive, and the entire tendon must be removed, an autologous flap graft might not be adequate to allow a return to function. We report a case of a 52-year-old female patient who developed bilateral tumors of the Achilles tendon, with a 10-year duration. By the time, she sought medical help, both Achilles tendons required removal. We chose to use Achilles tendon allografts to replace the Achilles tendons. Postoperatively, the patient did well. The allograft shortened the recovery time, and the patient regained full ankle range of motion.