Oral micronized progesterone versus vaginal progesterone for luteal phase support in fresh embryo transfer cycles: a multicenter, randomized, non-inferiority trial.

STUDY QUESTION: Does oral micronized progesterone result in a non-inferior ongoing pregnancy rate compared to vaginal progesterone gel as luteal phase support (LPS) in fresh embryo transfer cycles? SUMMARY ANSWER: The ongoing pregnancy rate in the group administered oral micronized progesterone 400 mg per day was non-inferior to that in the group administered vaginal progesterone gel 90 mg per day. WHAT IS KNOWN ALREADY: LPS is an integrated component of fresh IVF, for which an optimal treatment regimen is still lacking. The high cost and administration route of the commonly used vaginal progesterone make it less acceptable than oral micronized progesterone; however, the efficacy of oral micronized progesterone is unclear owing to concerns regarding its low bioavailability after the hepatic first pass. STUDY DESIGN, SIZE, DURATION: This non-inferiority randomized trial was conducted in eight academic fertility centers in China from November 2018 to November 2019. The follow-up was completed in April 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS: A total of 1310 infertile women who underwent their first or second IVF cycles were enrolled. On the day of hCG administration, the patients were randomly assigned to one of three groups for LPS: oral micronized progesterone 400 mg/day (n = 430), oral micronized progesterone 600 mg/day (n = 440) or vaginal progesterone 90 mg/day (n = 440). LPS was started on the day of oocyte retrieval and continued till 11-12 weeks of gestation. The primary outcome was the rate of ongoing pregnancy. MAIN RESULTS AND THE ROLE OF CHANCE: In the intention-to-treat analysis, the rate of ongoing pregnancy in the oral micronized progesterone 400 mg/day group was non-inferior to that of the vaginal progesterone gel group [35.3% versus 38.0%, absolute difference (AD): -2.6%; 95% CI: -9.0% to 3.8%, P-value for non-inferiority test: 0.010]. There was insufficient evidence to support the non-inferiority in the rate of ongoing pregnancy between the oral micronized progesterone 600 mg/day group and the vaginal progesterone gel group (31.6% versus 38.0%, AD: -6.4%; 95% CI: -12.6% to -0.1%, P-value for non-inferiority test: 0.130). In addition, we did not observe a statistically significant difference in the rate of live births between the groups. LIMITATIONS, REASONS FOR CAUTION: The primary outcome of our trial was the ongoing pregnancy rate; however, the live birth rate may be of greater clinical interest. Although the results did not show a difference in the rate of live births, they should be confirmed by further trials with larger sample sizes. In addition, in this study, final oocyte maturation was triggered by hCG, and the findings may not be extrapolatable to cycles with gonadotropin-releasing hormone agonist triggers. WIDER IMPLICATIONS OF THE FINDINGS: Oral micronized progesterone 400 mg/day may be an alternative to vaginal progesterone gel in patients reluctant to accept the vaginal route of administration. However, whether a higher dose of oral micronized progesterone is associated with a poorer pregnancy rate or a higher rate of preterm delivery warrants further investigation. STUDY FUNDING/COMPETING INTEREST(S): This research was supported by a grant from the National Natural Science Foundation of China (82071718). None of the authors have any conflicts of interest to declare. TRIAL REGISTRATION NUMBER: This trial was registered at the Chinese Clinical Trial Registry (http://www.chictr.org.cn/) with the number ChiCTR1800015958. TRIAL REGISTRATION DATE: May 2018. DATE OF FIRST PATIENT'S ENROLMENT: November 2018.

Exploring the influencing factors of unmet palliative care needs in Chinese patients with end-stage renal disease undergoing maintenance hemodialysis: a cross-sectional study.

BACKGROUND: The role of palliative care for end-stage renal disease (ESRD) patients have been proven in some developed countries, but it is still unclear in the mainland of China. In fact, patients with ESRD experience many unmet palliative care needs, such as physical, psychological, social and spiritual needs, but the factors influencing these needs have not investigated. METHODS: A cross-sectional study was conducted at two hemodialysis centers in the mainland of China from January to September 2022. Convenience sampling was used to collect data on the participants' socio-demographics, clinical characteristics, the Palliative Care Outcome Scale (POS), the Dialysis Symptom Index (DSI), the Karnofsky Performance Status Scale (KPS), the Patient Health Questionnaire-9 item (PHQ-9), and the Social Support Rate Scale (SSRS). Data were analyzed using latent profile analysis, Kruskal-Wallis test, one-way analysis of variance (ANOVA), the chi-square test and multinomial logistic regression analysis. RESULTS: Three hundred five participants were included in this study, and divided palliative care needs into three categories: Class 1, mild palliative care needs (n = 154, 50.5%); Class 2, moderate palliative care needs (n = 89, 29.2%); Class 3, severe palliative care needs (n = 62, 20.3%). Based on the analysis of three profiles, the influencing factors of unmet needs were further analyzed. Compared with Class 3, senior high school education, the household per capita monthly income < 2,000, low KPS scores, high PHQ-9 scores, and low SSRS scores were less likely to be in Class 1 (OR = 0.03, P = 0.012; OR = 0.003, P < 0.001; OR = 1.15, P < 0.001; OR = 0.55, P < 0.001; OR = 1.35, P = 0.002; respectively) and Class 2 (OR = 0.03, P = 0.007; OR = 0.05, P = 0.011; OR = 1.10, P = 0.001; OR = 0.60, P = 0.001; OR = 1.32, P = 0.003; respectively), and high symptom severity were less likely to be in Class 1 (OR = 0.82, P = 0.001). Moreover, compared with Class 1, the household per capita monthly income < 2,000 (OR = 16.41, P < 0.001), high symptom severity scores (OR = 1.12, P = 0.002) and low KPS scores (OR = 0.95, P = 0.002) were more likely to be in Class 2. CONCLUSIONS: This study showed that almost half of ESRD patients receiving MHD presented moderate to severe palliative care needs, and the unmet needs were mainly affected by education level, financial pressure, functional status, symptom burden and social support. In the future, it is important to identify the populations with the greatest need for palliative care and consider the influencing factors of unmet needs from a comprehensive perspective, so as to help them improve health-related quality of life.

Tumor Necrosis Factor Alpha Level in the Uterine Fluid of Patients with Polycystic Ovary Syndrome and Its Correlation with Clinical Parameters.

Objective: This study aimed to analyze tumor necrosis factor alpha (TNF-α) level in the uterine fluid of patients with polycystic ovary syndrome (PCOS) and its correlation with the clinical parameters of PCOS. Methods: A total of 162 patients treated in the Reproductive Medicine Center of the General Hospital of Ningxia Medical University between December 2019 and November 2021 were enrolled as research subjects, including 80 patients with PCOS and 82 patients with other gynecological disease, who were used as the controls. The patients' general data, along with blood glucose, blood lipid, insulin, and sex hormone levels and other data, were collected. The TNF-α levels in the patients' serum and uterine fluid were detected using enzyme-linked immunosorbent assay. Results: Compared with the patients in the control group, the body mass index (BMI), anti-Müllerian hormone, luteinizing hormone, testosterone (T), fasting insulin (FINS), homeostasis model assessment insulin resistance (HOMA-IR), triglyceride (TG), and low-density lipoprotein (LDL) of patients with PCOS were higher, and high-density lipoprotein was lower (P < 0.05). The TNF-α levels in the serum and uterine fluid of patients with PCOS were higher than those in the control group (P < 0.01), and the TNF-α levels in the uterine fluid of these patients was significantly correlated with BMI, T, FINS, HOMA-IR, serum TNF-α, TG, and LDL (P < 0.05). Conclusion: There is local inflammation in the uterine cavity of patients with PCOS, and the detection of cytokines in uterine secretions may be a simple and feasible method of understanding the uterine microenvironment of patients with PCOS.

Clinical Value of Contrast-Enhanced Ultrasound in Breast Cancer Diagnosis.

Breast cancer (BC) ranks first in morbidity and mortality among female malignant tumors worldwide. This study is aimed at clarifying clinical value of contrast-enhanced ultrasound (CEUS) in the diagnosis and differentiation of BC. A total of 108 BC patients admitted to our hospital from January 2019 to December 2021 were enrolled. All patients underwent conventional color Doppler ultrasound and CEUS imaging examination. All ultrasound images were analyzed by a senior (5+ years) sonographer. The lesion location, echo, size, and color Doppler flow imaging (CDFI) blood flow distribution of benign and malignant BC were assessed. The transverse and longitudinal diameters of malignant BC presented significant elevation compared with the control group (P < 0.05). CEUS is more reliable than conventional ultrasound in the differentiation of benign and malignant breast lesions, and CEUS has the best reliability. The comparison of CEUS observation indicators between benign and malignant groups demonstrated that CEUS enhancement patterns (time and intensity) and morphological features (lesion boundary, shape, range, homogeneity, and filling defect) presented statistical significance (P < 0.01). Irregular shape and range expansion were high-specificity indicators (all >90.00%); fast-forward, high enhancement, clear boundary, and range expansion were high-sensitivity (all >90.00%); and fast-forward, high enhancement, and clear boundary were low-specificity indicators (all <50.00%); moderate sensitivity is as follows: homogeneous enhancement and range expansion (all >80.00%). The area under curve of CEUS (0.735 ± 0.053) presented elevation relative to conventional ultrasound (0.901 ± 0.024), with statistical significance (Z1 = 2.462, P < 0.05). Relative to conventional ultrasound, the specificity and positive predictive value of CEUS presented elevation (P < 0.05). In conclusion, in the differentiation of benign and malignant breast lesions, CEUS has better diagnostic accuracy and reliability than conventional ultrasound. The diagnostic advantages of CEUS are to elevate the diagnostic specificity and positive predictive value and reduce the misdiagnosis rate.

Corrigendum: Artesunate Suppresses Choroidal Melanoma Vasculogenic Mimicry Formation and Angiogenesis via the Wnt/CaMKII Signaling Axis.

[This corrects the article DOI: 10.3389/fonc.2021.714646.].

Constructing a Novel Signature Based on Immune-Related lncRNA to Improve Prognosis Prediction of Cervical Squamous Cell Carcinoma Patients.

We downloaded gene expression data, clinical data, and somatic mutation data of cervical squamous cell carcinoma (CSCC) patients from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. Predictive lncRNAs were screened using univariate analysis and least absolute shrinkage and selection operator (LASSO) regression, and risk scores were calculated for each patient according to the expression levels of lncRNAs and regression coefficients to establish a risk model that could be a novel signature. We assessed the correlation between immune infiltration status, chemotherapeutics sensitivity, immune checkpoint proteins (ICP), and the signature. Therefore, we selected 11 immune-related lncRNAs (WWC2,AS2, STXBP5.AS1, ERICH6.AS1, USP30.AS1, LINC02073, RBAKDN, IL21R.AS1, LINC02078, DLEU1, LINC00426, BOLA3.AS1) to construct the risk model. Patients who were in the high-risk group had a shorter survival time than those in the low-risk group (p < 0.001). Risk scores in the signature were negatively correlated with macrophage M1, macrophage M2, and T cell CD8 + ; what's more, T cell CD8 + was higher in the low-risk group. The expression levels of ICP such as PD-L1, PD-1, CTLA-4, TIGIT, LAG-3, and TIM-3 were substantially higher in the low-risk group. For chemotherapeutic agents, high-risk scores were associated with higher half-inhibitory concentrations (IC50) of cisplatin. These findings suggested that the risk model can be a novel signature for predicting CSCC patients' prognosis, and it also can be used to formulate clinical treatment plans for CSCC patients.

Dual VEGF/PDGF knockdown suppresses vasculogenic mimicry formation in choroidal melanoma cells via the Wnt5a/ß-catenin/AKT signaling pathway.

OBJECTIVE: This study aimed to explore the effects of knocking down both vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF) on vasculogenic mimicry (VM) formation in choroidal melanoma (CM) cells. METHODS: Cell counting Kit (CCK)-8, monoclonal formation, wound healing, transwell and flow cytometry assays were used to observe the cell effects in CM cell line, ocular choroidal melanoma-1 cells (OCM-1) with respect to proliferation, migration, invasion and apoptosis. Three-dimensional (3D) cultures were also used to characterize VM tube structural effects in OCM-1 cells and western blotting was used to characterize protein expression changes in VM-related markers. RESULTS: Dual VEGF/PDGF knockdown suppressed cell proliferation, migration and invasion, but promoted cell apoptosis. It also reduced VM tube structures in OCM-1 cells. VM associated markers including, VE-cadherin, EphA2 and MT1-MMP were also down-regulated in OCM-1 cells. Similarly, Wnt5a, ß-catenin and phosphorylated-AKT levels were also down-regulated. Western blotting and 3D cultures further demonstrated that combined Wnt5a silencing with dual VEGF/PDGF knockdown significantly decreased VE-cadherin and EphA2 levels and reduced VM tube structures in OCM-1 cells. CONCLUSIONS: Dual VEGF/PDGF knockdown suppressed cell growth and metastasis in OCM-1 cells, and blocked the Wnt5a/ß-catenin/AKT signaling pathway thereby inhibiting VM formation.

Association of lncRNA H19 polymorphisms with cancer susceptibility: An updated meta-analysis based on 53 studies.

The association between polymorphisms in lncRNA H19 and cancer susceptibility remains to be inconsistent. This study aimed to provide a more precise estimation of the relationship between lncRNA H19 polymorphisms and the risk of cancer based on all available published studies. 53 studies encompassing 32,376 cases and 43,659 controls were included in our meta-analysis by searching the Pubmed, Embase, Web of Science, WanFang, and China National Knowledge Infrastructure databases. Pooled ORs and their 95% CIs were used to estimate the strength between the SNPs in H19 (rs217727, rs2839698, rs2107425, rs3024270, rs2735971, rs3741216, and rs3741219) and cancer susceptibility. The results showed that H19 rs2839698 polymorphism was associated with increased cancer risk in all participants under three genetic models. However, no significant association was identified between the other six SNPs as well as an overall cancer risk. Stratification by ethnicity showed that rs2839698 mutation indicated to be an important hazardous factor for the Asian population. While rs2107425 mutation had a protective effect on the Caucasian population. Stratification by cancer type identified that rs217727 mutation was linked to increased susceptibility to oral squamous cell carcinoma, lung cancer, and hepatocellular carcinoma; whereas rs2839698 mutation was associated with an elevated risk of hematological tumor and digestive system tumor (p < 0.05). Besides, the rs2735971 mutation was connected with the digestive system tumor. In summary, the rs217727, rs2839698, rs2107425 and rs2735971 polymorphisms in H19 have associations with cancer susceptibility.

Artesunate Suppresses Choroidal Melanoma Vasculogenic Mimicry Formation and Angiogenesis via the Wnt/CaMKII Signaling Axis.

Angiogenesis and vasculogenic mimicry (VM) are considered to be the main processes to ensure tumor blood supply during the proliferation and metastasis of choroidal melanoma (CM). The traditional antimalarial drug artesunate (ART) has some potential anti-CM effects; however, the underlying mechanisms remain unclarified. Recent studies have shown that the Wnt5a/calmodulin-dependent kinase II (CaMKII) signaling pathway has a close correlation with angiogenesis and VM formation. This study demonstrated that ART eliminated VM formation by inhibiting the aforementioned signaling pathway in CM cells. The microvessel sprouting of the mouse aortic rings and the microvessel density of chicken chorioallantoic membrane (CAM) decreased significantly after ART treatment. VM formation assay and periodic acid schiff (PAS) staining revealed that ART inhibited VM formation in CM. Moreover, ART downregulated the expression levels of the angiogenesis-related proteins vascular endothelial growth factor receptor (VEGFR) 2, platelet-derived growth factor receptor (PDGFR) and vascular endothelial growth factor (VEGF) A, and VM-related proteins ephrin type-A receptor (EphA) 2 and vascular endothelial (VE)-cadherin. The expression of hypoxia-inducible factor (HIF)-1α, Wnt5a, and phosphorylated CaMKII was also downregulated after ART treatment. In addition, we further demonstrated that ART inhibited the proliferation, migration, and invasion of OCM-1 and C918 cells. Collectively, our results suggested that ART inhibited angiogenesis and VM formation of choroidal melanoma likely by regulating the Wnt5a/CaMKII signaling pathway. These findings further supported the feasibility of ART for cancer therapy.

Integrated analysis of key microRNAs /TFs /mRNAs/ in HPV-positive cervical cancer based on microRNA sequencing and bioinformatics analysis.

BACKGROUND: Cervical squamous cell carcinoma (CESC) is one of the most common malignancies associated with mortality in females. Its onset and prognosis are primarily concerned with persistent infection with high-risk types of human papillomavirus (HPV). However, the molecular mechanisms of HPV-positive CESC remain unclear. METHODS: In this study, we conducted a high-throughput sequencing to identify differentially expressed miRNAs (DEMs). Besides, three series were selected from the Gene Expression Omnibus (GEO) database to identify differentially expressed genes (DEGs). Then the miRNA-TF-gene regulatory network was constructed using bioinformatic methods. Genes in the network were performed functional enrichment analysis and protein-protein interaction (PPI) network analysis. Ultimately, the expression levels of six key miRNAs, TFs, and mRNAs were validated by 20 HPV-positive CESC tissues and 15 normal cervical samples. RESULTS: A total of 52 DEMs and 300 DEGs differed between the HPV-positive CESC and normal cervical samples. Then the miRNA-TF-gene regulatory network was constructed consisting of 22 miRNAs, 6 TFs, and 76 corresponding genes, among which miR-149-5p, miRNA-1248 and E2F4 acted as key regulators. PPI network analysis showed that ten genes including TOP2A, AURKA, CHEK1, KIF11, MCM4, MKI67, DTL, FOXM1, SMC4, and FBXO5 were recognized as hub genes with the highest connectivity degrees. Besides, five key molecules miRNA-149-5p, E2F4, KIF11, DTL, and SMC4 were suggested to play crucial roles in the development of HPV-positive CESC. CONCLUSION: These results present a unique insight into the pathological mechanisms of HPV-positive CESC and possibly provides potential therapeutic targets.

The percentage of cells with 17p deletion and the size of 17p deletion subclones show prognostic significance in chronic lymphocytic leukemia.

TP53 disruption is considered to be the most important prognostic factor in chronic lymphocytic leukemia (CLL), but not all patients with TP53 disruption have similar dismal outcomes. We evaluated the prognostic value of TP53 disruption in CLL patients without treatment indications. Data of 305 CLL patients were analyzed. 41 of them (13%) had TP53 disruption. Patients with lower percentage of cells with del(17p) had significantly better survival. Patients with mutated IGHV, ß2-microglobulin ≤3.5 mg/L, wild-type TP53, age ≤65 years or without complex karyotype (CK) had relatively favorable outcomes in the del(17p) group. Furthermore, patients with del(17p) as a minor clone showed survival advantage compared with those with del(17p) as a major clone. These data suggest that the percentage of cells with del(17p), the size of the del(17p) subclone, CLL International Prognostic Index, and CK should be considered to build refined prognostication models for patients with TP53 disruption.

The possible association between the presence of an MPO -463 G > A (rs2333227) polymorphism and cervical cancer risk.

PURPOSE: The association between myeloperoxidase (MPO) polymorphism and the risk of cervical cancer is inconclusive. We performed a meta-analysis to clarify if a correlation exists between MPO polymorphism and the risk for developing cervical cancer. METHODS: All case-control research studies that determined a relationship between MPO and cervical cancer reported up until March 1, 2018 in PubMed, Web of Science, VIP, WanFang, and the CNKI Database were accessed and included. The strength of association was evaluated with pooled odds ratios (ORs) and their corresponding 95% confidence intervals (95% CIs). We used sensitivity analysis to detect the stability of our results, conducted Q-test to evaluate heterogeneity and applied Begg's funnel plot and Egger's test to investigate any publication bias among selected studies. RESULTS: In this meta-analysis, we included 5 eligible studies in the final evaluation, which included 1125 patients with cervical cancer and 1150 cancer-free control patients. A potential association between the MPO -463 G > A polymorphism and cervical cancer risk was observed (recessive model: OR = 0.65, 95%, CI: 0.43-0.98, P = 0.038; homozygous model: OR = 0.65, 95%, CI: 0.43-0.99, P = 0.045), which indicates that genotype AA reduces the risk of cervical cancer by 35% compared to GG/GA or GG genotypes in our results. A stratified analysis by ethnicity identified a significant correlation among Caucasian patients (recessive model: OR = 0.57, 95%, CI: 0.34-0.95, P = 0.029; homozygous model: OR = 0.60, 95%, CI: 0.36-0.99, P = 0.048) and a stratified analysis by source of control identified a significant correlation among population-based studies. CONCLUSIONS: Our results suggest that the presence of polymorphism, -463 G > A in patients might offer them protection against cervical cancer. By implementing randomized case-control or cohort studies with larger sample sizes, the clinical significance of our results can be further strengthened and verified.

ERCC1 rs11615 polymorphism increases susceptibility to breast cancer: a meta-analysis of 4547 individuals.

Excision repair cross-complementation group 1 (ERCC1), a DNA repair protein, is vital for maintaining genomic fidelity and integrity. Despite the fact that a mounting body of case-control studies has concentrated on investigating the association of the ERCC1 rs11615 polymorphism and breast cancer risk, there is still no consensus on it. We conducted the current meta-analysis of all eligible articles to reach a much more explicit conclusion on this ambiguous association. A total of seven studies involving 2354 breast cancer cases and 2193 controls were elaborately selected for this analysis from the Embase, EBSCO, PubMed, WanFang, and China National Knowledge Infrastructure (CNKI) databases. Pooled odds ratios (ORs) and their 95% confidence intervals (CIs) were estimated in our meta-analysis. We found that the ERCC1 rs11615 polymorphism was significantly associated with breast cancer risk under all genetic models. When excluded, the studies that deviated from Hardy-Weinberg equilibrium (HWE), the pooled results of what remained significantly increase the risk of breast cancer under the allele model (OR = 1.14, 95% CI = 1.02-1.27, P=0.02), heterozygote model (OR = 1.24, 95% CI = 1.06-1.44, P=0.007), and dominant model (OR = 1.21, 95% CI = 1.05-1.41, P=0.01). This increased breast cancer risk was found in Asian population as well as under the heterozygote model (OR = 1.24, 95% CI = 1.05-1.48, P=0.013) and dominant model (OR = 1.20, 95% CI = 1.02-1.42, P=0.03). Our results suggest that the ERCC1 rs11615 polymorphism is associated with breast cancer susceptibility, and in particular, this increased risk of breast cancer existence in Asian population.

NOTCH4 is a possible novel susceptibility gene for dilated cardiomyopathy in the Chinese population: A case-control study.

BACKGROUND: The incidence of dilated cardiomyopathy (DCM) has increased in recent years, and many studies have sought to further improve the general understanding of this condition. Previous studies have demonstrated that some single nucleotide polymorphisms (SNPs) associated with systemic lupus erythematosus also affect susceptibility to DCM, suggesting that immune-related diseases may share similar genetic susceptibility. Recent large-scale and genome-wide association studies have identified NCR3, NOTCH4, CYP1A2, ITGA1, OPRM1, ST8SIA2, and LINC00704 as genetic risk factors associated with cardiac manifestations of neonatal lupus. Here, we aimed to determine whether these SNPs conferred susceptibility to DCM in the Chinese Han population. METHODS: We investigated the relationship between these polymorphisms and DCM risk in 273 patients with DCM and 548 healthy controls. Genotyping was performed using MassArray iPLEX system. RESULTS: Logistic regression analysis indicated that the T allele of rs3134942 in NOTCH4 gene increased the risk of DCM by 61% compared with the G allele (Pa  = 6.57 × 10-3 ). The SNP rs3134942 was also significantly associated with increased DCM risk in the additive (Pa  = 6.57 × 10-3 ) and dominant models (Pa  = 1.01 × 10-2 ). Additionally, rs2472299 in CYP1A2 gene showed suggestive association with reduced risk of DCM in the dominant model (Pa  = 4.24 × 10-2 ) and was correlated with smoking status in patients with DCM (Pa  = 1.56 × 10-2 ). CONCLUSIONS: Our findings suggested that rs3134942 in NOTCH4 may be involved in DCM risk. Further, studies in larger and ethnically diverse populations are required to confirm the results reported in this study.

A facile supramolecular approach to fabricate multifunctional upconversion nanoparticles as a versatile platform for drug loading, in vivo delivery and tumor imaging.

Multifunctional upconversion nanoparticles (UCNPs) that can be implemented in theranostic applications are particularly attractive scaffolds for precise drug delivery. However, most of the current methods for drug formulation are technically complicated, thereby impeding their use in the clinic. Here, we report on the preparation of a lipophilic cytotoxic prodrug-integrated and polyethylene glycol (PEG)-cloaked UCNPs scaffold through a facile one-pot supramolecular approach. By choosing 7-ethyl-10-hydroxycamptothecin (SN38)-derived prodrug 1 as a model chemotherapeutic, we show that this lipophilic prodrug can be feasibly self-assembled onto the surface of UCNPs, which are cooperatively solubilized by PEGylated phospholipids. The resulting SN38 prodrug 1-encapsulated UCNPs (designated 1@pUCNPs) produce a stable colloidal system in aqueous solution, making it suitable for intravenous injection. The SN38 drug loading capacity in pUCNPs is as high as ∼12.3 wt%, and a sustained drug release profile is observed, indicating that the drug payloads can be transported to targeted tumor sites via the enhanced permeability and retention (EPR) effect. Upconversion luminescence (UCL) imaging, including in vivo and ex vivo imaging, suggests that the drug-loaded pUCNPs remain stable in tumors over a long time and preferentially accumulate in tumors presumably via the EPR effect. Furthermore, the 1@pUCNPs show superior therapeutic outcomes compared with the clinically approved SN38 prodrug CPT-11 in the Bcap-37 mouse model of breast cancer. Collectively, our results demonstrate that pUCNPs facilely constructed in a one-pot self-assembly manner may be used as a versatile platform, enabling synchronous in vivo delivery of poorly water-soluble drugs and tumor imaging.

[Effect of DAPT on proliferation and apoptosis of human multiple myeloma cell line RPMI8226].

The aim of this study was to explore the effect of DAPT (N-[N-(3,5-difluorophenacetyl)-L-alanyl]-S-phenylglycinet-butyl ester) on proliferation in vitro of human multiple myeloma cell line RPMI8226 and its underlying mechanism. The proliferation of RPMI8226 cells was detected by CCK-8 method; flow cytometry was employed to assay the cell apoptosis rate;the expressions of Notch1 and Hes1 proteins were detected by Western blot. The results indicated that the proliferation of human RPMI8226 cells significantly decreased after treatment with DAPT 0.5 - 5.0 µmol/L for 24 - 72 h (P < 0.05) in a concentration- and time-dependent manner. DAPT significantly induced apoptosis of RPMI8226 cells (P < 0.05). The expressions of Notch1 and Hes1 proteins were gradually downregulated with the increase of DAPT concentration. It is concluded that the DAPT can inhibit the proliferation of RPMI8226 cells, which may be related with the down-regulation of the protein expression of Notchl and Hes1.