Maternal and embryonic signals cause functional differentiation of luminal epithelial cells and receptivity establishment.

Embryo implantation requires temporospatial maternal-embryonic dialog. Using single-cell RNA sequencing for the uterus from 2.5 to 4.5 days post-coitum (DPC) and bulk sequencing for the corresponding embryos of 3.5 and 4.0 DPC pregnant mice, we found that estrogen-responsive luminal epithelial cells (EECs) functionally differentiated into adhesive epithelial cells (AECs) and supporting epithelial cells (SECs), promoted by progesterone. Along with maternal signals, embryonic Pdgfa and Efna3/4 signaling activated AECs and SECs, respectively, enhancing the attachment of embryos to the endometrium and furthering embryo development. This differentiation process was largely conserved between humans and mice. Notably, the developmental defects of SOX9-positive human endometrial epithelial cells (similar to mouse EEC) were related to thin endometrium, whereas functional defects of SEC-similar unciliated epithelial cells were related to recurrent implantation failure (RIF). Our findings provide insights into endometrial luminal epithelial cell development directed by maternal and embryonic signaling, which is crucial for endometrial receptivity.

WDR4/TRIM28 is a novel molecular target linked to lenvatinib resistance that helps retain the stem characteristics in hepatocellular carcinomas.

Hepatocellular carcinoma (HCC) is an aggressive malignancy with few effective treatment options. Lenvatinib is the first-line therapy for HCC but has only limited clinical benefit. Here, we explored the role and mechanism of the WD repeat domain 4 (WDR4) in lenvatinib resistance to improve clinical benefit. We found that lenvatinib-resistant HCC tissues/cells exhibited increased the N7-methylguanosine (m7G) modification and WDR4 expression. By a gain/loss of function experiment, we showed that WDR4 promoted HCC lenvatinib resistance and tumor progress both in vitro and in vivo. By proteomics analysis and RNA immunoprecipitation PCR, we found that tripartite motif protein 28 (trim28) was an important WDR4 target gene. WDR4 promoted TRIM28 expression, further affected target genes expression, and thus increased cell-acquired stemness and lenvatinib resistance. Clinical tissue data showed that TRIM28 expression was correlated with WDR4 levels, and the expression of both was positively correlated with poor prognosis. Our study provides new insight into the role of WDR4, suggesting a potential therapeutic target to enhance the lenvatinib sensitivity of HCC.

CD36+ cancer-associated fibroblasts provide immunosuppressive microenvironment for hepatocellular carcinoma via secretion of macrophage migration inhibitory factor.

Hepatocellular carcinoma (HCC) is an immunotherapy-resistant malignancy characterized by high cellular heterogeneity. The diversity of cell types and the interplay between tumor and non-tumor cells remain to be clarified. Single cell RNA sequencing of human and mouse HCC tumors revealed heterogeneity of cancer-associated fibroblast (CAF). Cross-species analysis determined the prominent CD36+ CAFs exhibited high-level lipid metabolism and expression of macrophage migration inhibitory factor (MIF). Lineage-tracing assays showed CD36+CAFs were derived from hepatic stellate cells. Furthermore, CD36 mediated oxidized LDL uptake-dependent MIF expression via lipid peroxidation/p38/CEBPs axis in CD36+ CAFs, which recruited CD33+myeloid-derived suppressor cells (MDSCs) in MIF- and CD74-dependent manner. Co-implantation of CD36+ CAFs with HCC cells promotes HCC progression in vivo. Finally, CD36 inhibitor synergizes with anti-PD-1 immunotherapy by restoring antitumor T-cell responses in HCC. Our work underscores the importance of elucidating the function of specific CAF subset in understanding the interplay between the tumor microenvironment and immune system.

Serial circulating tumor DNA to predict early recurrence in patients with hepatocellular carcinoma: a prospective study.

We studied the value of circulating tumor DNA (ctDNA) in predicting early postoperative tumor recurrence and monitoring tumor burden in patients with hepatocellular carcinoma (HCC). Plasma-free DNA, germline DNA, and tissue DNA were isolated from 41 patients with HCC. Serial ctDNAs were analyzed by next-generation sequencing before and after operation. Whole-exome sequencing was used to detect the DNA of HCC and adjacent tissues. In total, 47 gene mutations were identified in the ctDNA of the 41 patients analyzed before surgery. ctDNA was detected in 63.4% and 46% of the patient plasma pre- and postoperation, respectively. The preoperative ctDNA positivity rate was significantly lower in the nonrecurrence group than in the recurrence group. With a median follow-up of 17.7 months, nine patients (22%) experienced tumor recurrence. ctDNA positivity at two time-points was associated with significantly shorter recurrence-free survival (RFS). Tumors with NRAS, NEF2L2, and MET mutations had significantly shorter times to recurrence than those without mutations and showed high recurrence prediction performance by machine learning. Multivariate analyses showed that the median variant allele frequency (VAF) of mutations in preoperative ctDNA was a strong independent predictor of RFS. ctDNA is a real-time monitoring indicator that can accurately reflect tumor burden. The median VAF of baseline ctDNA is a strong independent predictor of RFS in individuals with HCC.

MicroRNA-19a-3p regulates cell growth through modulation of the PIK3IP1-AKT pathway in hepatocellular carcinoma.

There are some controversies about the involvement of microRNA (miR)-19a-3p in hepatocellular carcinoma (HCC) biology, even though many studies have shown that it plays an important role in cancer. In this study, we found that miR-19a-3p is usually overexpressed in HCC tissues compared with corresponding peritumorous tissues, and its expression was associated with tumor size and poor overall survival. MiR-19a-3p promoted cell proliferation significantly, and more cells were found in the S phase. In vivo, miR-19a-3p promoted liver tumor growth, and more HCC cells were found in the active cell cycle. Sequencing and bioinformatics analysis predicted that PIK3IP1 is a likely target gene of miR-19a-3p, and we next confirmed it by luciferase and rescue assays. Altogether, our data showed an important role of PIK3IP1 downregulation by miR-19a-3p in HCC progression, and the miR-19a-3p-PIK3IP1-AKT pathway may be a potential therapeutic target.

Far upstream element-binding protein 1 facilitates hepatocellular carcinoma invasion and metastasis.

Previous research suggests that far upstream element-binding protein 1 (FUBP1) plays an important role in various tumors including epatocellular carcinoma (HCC). However, the role of FUBP1 in liver cancer remains controversial, and the regulatory pathway by FUBP1 awaits to be determined. This study aims to identify the role of FUBP1 in HCC progression. Our result shows that the high level of FUBP1 expression in HCC predicts poor prognosis after surgery. Overexpression of FUBP1 promotes HCC proliferation, invasion, and metastasis by activating transforming growth factor-ß (TGF-ß)/Smad pathway and enhancing epithelial-mesenchymal transition (EMT) in vitro and in vivo. Inhibitor of Thrombospondin-1 (LSKL) could inhibit HCC proliferation and invasion in vitro and in vivo by blocking the activation of TGF-ß/Smad pathway mediated by thrombospondin-1 (THBS1). Our study identified the critical role of FUBP1-THBS1-TGF-ß signaling axis in HCC and provides potentially new therapeutic modalities in HCC.

Differential network analysis depicts regulatory mechanisms for hepatocellular carcinoma from diverse backgrounds.

Aim: To elucidate the integrative combinational gene regulatory network landscape of hepatocellular carcinoma (HCC) molecular carcinogenesis from diverse background. Materials & methods: Modified gene regulatory network analysis was used to prioritize differentially regulated genes and links. Integrative comparisons using bioinformatics methods were applied to identify potential critical molecules and pathways in HCC with different backgrounds. Results: E2F1 with its surrounding regulatory links were identified to play different key roles in the HCC risk factor dysregulation mechanisms. Hsa-mir-19a was identified as showed different effects in the three HCC differential regulation networks, and showed vital regulatory role in HBV-related HCC. Conclusion: We describe in detail the regulatory networks involved in HCC with different backgrounds. E2F1 may serve as a universal target for HCC treatment.

Interleukin-22 secreted by ectopic endometrial stromal cells and natural killer cells promotes the recruitment of macrophages through promoting CCL2 secretion.

PROBLEM: During endometriosis, there is an increase in the number of dysfunctional macrophages; however, the mechanisms underlying macrophage recruitment are not well understood. The aim of the present study was to determine the role of natural killer (NK) cell-mediated secretion of chemokine (C-C motif) ligand 2 (CCL2) from endometrial stromal cells (ESCs) in the recruitment of macrophages. METHOD OF STUDY: Normal ESCs (nESC) and ectopic ESCs (eESCs) were separately co-cultured with NK cells for a macrophage chemotaxis assay, and the number of chemotactic macrophages was counted. The expression of interleukin-22 (IL-22) and IL-22 receptors was detected by ELISA and flow cytometry, respectively. eESCs were treated with 0.01, 0.1, and 1 ng/mL recombinant human IL-22 (rhIL-22) to determine the most effective concentration for stimulating CCL2 production. Following treatment with 1 ng/mL rhIL-22, secretion of CCL2 was detected from both the eESC monoculture and the eESC/NK co-culture. RESULTS: Compared with the eESC monoculture, the eESC/NK co-culture recruited a significantly higher number of chemotactic macrophages. There was also an increase in the levels of IL-22 and CCL2 secreted when eESCs were co-cultured compared with the monoculture. Treatment with rhIL-22 resulted in an increase in the levels of CCL2 secreted by eESCs, and the IL-22-induced CCL2 secretion was reversed by the IL-22 antagonist, αIL-22. Increased expression of IL-22 resulted in an increase in the number of chemotactic macrophages, but was reversed by αIL-22 and CCL2 antagonist (αCCL2). CONCLUSION: Interleukin-22 and CCL2 secretion by eESCs stimulated by NK cells contributes to the induction of macrophage recruitment and is thus implicated in the development of endometriosis.

Overexpression of RNF38 facilitates TGF-ß signaling by Ubiquitinating and degrading AHNAK in hepatocellular carcinoma.

BACKGROUND: RING finger protein 38 (RNF38), a member of the RNF protein family, has just emerged as a vital driver of cancer progression. However, the oncogenic mechanisms of RNF38 remain unexplored. METHODS: Using frozen tumor tissue and tissue microarray from hepatocellular carcinoma (HCC) patients, we tried to probe the expression of RNF38 in HCC and its clinical value. Then the biological functions of RNF38 were analyzed in vivo and vitro. Stable isotope labeling with amino acids (SILAC) in cell culture and co-immunoprecipitation proteomic analyses were combined to reveal the potential mechanism of RNF38 in HCC progression. RESULTS: We report that RNF38 expression was markedly higher in HCC tissues than in peritumor tissues. Correspondingly, RNF38 overexpression promoted the HCC cell migration and invasion and inhibited apoptosis both in vitro and in vivo. And elevated RNF38 expression induced HCC cell epithelial-mesenchymal transition by facilitating transforming growth factor-ß (TGF-ß) signaling via ubiquitinating and degrading neuroblast differentiation-associated protein (AHNAK), a well-established inhibitor of TGF-ß signaling. Furthermore, AHNAK interference restored the HCC cell invasion and metastasis deprived by RNF38 downregulation. Clinically, elevated RNF38 and transforming growth factor beta receptor 1 (TGFBR1) expression was related to short overall survival (OS) and high cumulative recurrence rates in HCC patients. CONCLUSIONS: High levels of RNF38 promote HCC by facilitating TGF-ß signaling and are a novel marker for predicting the prognosis of HCC patients and a potential therapeutic target in HCC.

CXCL16/CXCR6 interaction promotes endometrial decidualization via the PI3K/AKT pathway.

Decidualization renders the endometrium transiently receptive to an implanting blastocyst although the underlying mechanisms remain incompletely understood. The aim of this study was to determine the role of chemokine CXCL16 and its receptor CXCR6 in the decidualization during pregnancy. Here, the expression of CXCL16 was investigated in endometrial tissues, decidua and placenta in this study. Compared with endometrial tissue, protein expression of CXCL16 was significantly higher in tissues from the fertile control samples, especially in villus. Meanwhile, the primary trophoblast cells and decidual stromal cells (DSCs) secreted more CXCL16 and expressed higher CXCR6 compared to endometrial stromal cells (ESCs) in vitro. Stimulation with the inducer of decidualization (8-bromoadenosine 3',5'-cyclic with medroxyprogesterone acetate, 8-Br-cAMP plus MPA) significantly upregulated the expression of CXCL16 and CXCR6 in ESCs in vitro. After treatment with exogenous recombinant human CXCL16 (rhCXCL16) or trophoblast-secreted CXLC16, decidualised ESCs showed a significant decidual response, mainly characterised by increased prolactin (PRL) secretion. Simultaneously, PI3K/PDK1/AKT/Cyclin D1 pathway in decidualised ESCs were activated by rhCXCL16, and AKT inhibitor GS 690693 abolished the PRL secretion of ESCs that was triggered by rhCXCL16. Finally, the impaired CXCL16/CXCR6 expression could be observed at the maternal-foetal interface from patients who have experienced spontaneous abortion. This study suggests that the CXCL16/CXCR6 axis contributes to the progression of ESC decidualization by activating PI3K/PDK1/AKT/Cyclin D1 pathway. It unveils a new paradigm at the maternal-foetal interface in which CXCL16 is an initiator for the molecular crosstalk that enhances decidualization of ESCs.

New insight into BIRC3: A novel prognostic indicator and a potential therapeutic target for liver cancer.

BACKGROUND: Prognosis of hepatocellular carcinoma (HCC) remains poor due to high recurrence rate and ineffective treatment options, highlighting the need to better understand the mechanism of recurrence and metastasis in HCC. METHODS: We first collected messenger RNA (mRNA) expression data from 442 cases of HCC patients from The Cancer Genome Atlas (TCGA) database as well as 251 HCC patients from Zhongshan Hospital during 2009 and 2010 to analyze the expression pattern from tissue microarray (TMA) of baculoviral IAP repeat containing 3 (BIRC3). Then, we used BIRC3 gain-of-function (overexpression) and loss-of-function (knockdown) studies to examine the effect of BIRC3 on HCC cell proliferation and invasion. In addition, we also investigated the undying mechanism by which BIRC3 contributes to HCC tumor progression. Functionally, we also used a BIRC3-specific inhibitor AT-406 in HCC xenograft model to explore the potential therapeutic benefit of targeting BIRC3 in liver cancer. RESULTS: BIRC3 serves as a novel prognostic indicator for HCC patients undergoing curative resection. BIRC3 promotes HCC epithelial-mesenchymal transition (EMT), cell migration, and metastasis via upregulating MAP3K7, therefore, inducing ERK1/2 phosphorylation. The specific BIRC3 inhibitor AT-406 can inhibit HCC cell proliferation and reduce pulmonary metastases. CONCLUSION: BIRC3 induces tumor proliferation and metastasis in vitro and in vivo. BIRC3 may serve as a novel therapeutic target for liver cancer.

Differentially expressed miRNAs in hepatocellular carcinoma cells under hypoxic conditions are associated with transcription and phosphorylation.

Hypoxia is a critical aspect of tumor biology and has been associated with poor prognosis and resistance to traditional therapy. In the present study, differentially expressed genes and microRNAs (miRNAs/miRs) were screened for in the hepatocellular carcinoma (HCC) cell line Huh7 under hypoxic conditions. On the basis of microarray data, 11,508 mRNAs and 58 miRNAs exhibiting ≥1.5-fold change in expression under hypoxic conditions were identified. Gene Ontology (GO) and Kyoto Encyclopedia or Genes and Genomes pathway analysis revealed that the differentially expressed genes were primarily involved in cell cycle regulation, cell division, transcription and G-protein-coupled receptor signaling pathways. Using the TargetScan and miRanda software packages with the miRNA-mRNA negative expression network, differentially expressed miRNA targets were predicted. GO analysis revealed that the primary function of these miRNAs was to regulate transcription and phosphorylation. The miRNA-mRNA networks for transcription and phosphorylation were analyzed. Network analysis revealed that the key miRNAs in these networks were miR-19a, miR-34a, miR-29a, mir-196a, miR-25 and miR-1207, whose potential gene targets include DNA-binding proteins, zinc-finger proteins and transcription factors. Certain protein kinases, includingmitogen-activated protein kinase (MAPK) 1, MAPK kinase kinase4 and cyclin-dependent kinase 18, were also revealed to be present in the network. In hypoxic HCC tissue, levels of several key miRNAs implicated in the network analyses (miR-19a, miR-34a, miR-25 and miR-1207) were revealed to exhibit increased expression levels compared with the surrounding tissue. The results of the present study provide evidence that miRNAs serve an important function in transcription and phosphorylation in the hypoxic response of HCC cells.

Upregulation of B7-H4 promotes tumor progression of intrahepatic cholangiocarcinoma.

Recent reports show that B7-H4 is highly expressed in a variety of tumor cells, functions as a negative regulator of T cells and then promotes tumor progression. However, its expression and role in intrahepatic cholangiocarcinoma (ICC) remain unclear. In present study, B7-H4 expression in ICC and peritumoral tissues was determined at the level of mRNA and protein, and its bioactivity in ICC cells was studied after modification of B7-H4 expression. Then, the mechanism related to tumor progression induced by B7-H4 expression in ICC cells was explored. Finally, clinical significance of B7-H4 expression in ICC patients was further analyzed. The results showed that B7-H4 expression in ICC was much higher than that in peritumoral tissues at the level of both mRNA and protein. The high level of B7-H4 in ICC cells induced epithelial-to-mesenchymal transitions and promoted invasion and metastasis of tumor cells through activation of ERK1/2 signaling. The elevated B7-H4 expression was associated with the downregulated Bax, upregulated Bcl-2 expression, and activation of caspase-3. Clinically, high B7-H4 expression in tumor samples was significantly related to malignant phenotype, such as lymph node metastasis, high tumor stage, and poor differentiation. ICC patients with high expression of B7-H4 had shorter overall survival (OS) and disease-free survival. Moreover, the B7-H4 expression was an independent prognostic factor for predicting OS and tumor recurrence of ICC patients after operation. In conclusion, high expression of B7-H4 promotes tumor progression of ICC and may be a novel therapeutic target for ICC patients.

Long non-coding RNA00364 represses hepatocellular carcinoma cell proliferation via modulating p-STAT3-IFIT2 signaling axis.

The effects of long non-coding RNAs (lncRNAs) on hepatocellular carcinoma (HCC) remain largely unclear. In this study, we identified an interferon (IFN)-γ-induced LncRNA, LncRNA00364, in HCC by microarray. LncRNA00364 displays lower expression in HCC tumor samples compared to paired normal controls. Overexpression of LncRNA00364 inhibits cell proliferation, G1/S cell cycle progression and promotes apoptosis in HCC cell lines. Consistently, LncRNA00364 overexpression leads to decreased HCC tumor formation in vivo. Mechanistically, LncRNA00364 specifically binds with STAT3, resulting in inhibition of STAT3 phosphorylation and therefore leads to upregulation of IFIT2. In a clinical setting, LncRNA00364 shows an independent prognostic indicator for overall survival and cumulative recurrence in HCC patients, and correlates with IFIT2. Therefore, our study provides new insights into a novel therapeutic avenue targeting the LncRNA00364 signaling axis in HCC.

HOXB7 promotes tumor progression via bFGF-induced activation of MAPK/ERK pathway and indicated poor prognosis in hepatocellular carcinoma.

The homeobox-containing gene HOXB7 plays an important role in the pathogenesis and progression of many cancers, yet its role in hepatocellular carcinoma (HCC) remains unclear. This study comprehensively analyzed the expression and clinical significance of HOXB7 in HCC and explored its potential mechanism in tumor progression. We found HOXB7 was highly expressed in HCC cell lines with highly metastatic potential and cancerous tissues from patients with tumor recurrence. The abilities of proliferation, migration, and invasion were notably decreased by depletion of HOXB7, and were enhanced by its enforced expression in vitro. HOXB7 expression was positively correlated with tumor progression and lung metastasis in vivo. The gene microarray data implied that HOXB7 affects biological functions of HCC cells through MAPK/ERK pathway activation. Further study confirmed that the effect of HOXB7 in activating MAPK/ERK pathway via induction of basic fibroblast growth factor (bFGF) secretion, and the inhibition of bFGF secretion could abolish MAPK/ERK pathway activation after ectopic expression of HOXB7. Chromatin immunoprecipitation experiments and luciferase reporter assays confirmed that HOXB7 promoted bFGF secretion via binding its promoter directly. Furthermore, the clinical significance of HOXB7 expression was confirmed using tissue microarrays containing 394 HCC tissue specimens. Patients with high HOXB7 expression showed shorter survival times and higher recurrence rates, and HOXB7 was an independent indicator for survival and recurrence. Overall, HOXB7 promotes HCC cell proliferation, migration, and invasion through the bFGF-induced MAPK/ERK pathway activation. It might be a novel prognostic factor in HCC and a promising therapeutic target for tumor metastasis and recurrence.

Immunosuppressive macrophages induced by IDO1 promote the growth of endometrial stromal cells in endometriosis.

It was previously demonstrated that anomalous expression of indoleamine 2,3-dioxygenase-1 (IDO1) in endometrial stromal cells (ESCs) stimulated an inflammatory response that subsequently initiated the activation of immunosuppressive macrophages in endometriosis. The aim of the present study was to clarify the effect of IDO1­induced macrophages on the growth of ESCs in endometriosis. Normal ESCs, ectopic ESCs and normal ESCs treated with plasmid pEGFP­N1­IDO1 or SD11­IDO1 short hairpin RNA were co­cultured with peripheral blood­derived monocyte (PBMC)­driven macrophages directly for 48 h. Compared with normal ESCs, the PBMC­driven macrophages that were co­cultured with ectopic ESCs displayed a lower phagocytic ability. pEGFP­N1­IDO1 transfection of normal ESCs also decreased the phagocytic ability of co­cultured macrophages. Additionally, pEGFP­N1­IDO1­transfected ESC­induced macrophages significantly increased the viability and proliferation of ESCs, while ESC apoptosis was decreased, compared with control ESCs. In conclusion, IDO1 educated-macrophages may facilitate the survival of retrograde endometrial tissues, and be involved in the pathogenesis of endometriosis.

MicroRNA expression profiles and networks in CXCL12­stimulated human endometrial stromal cells.

The chemokine stromal cell-derived factor-1 (C-X-C motif chemokine ligand 12; CXCL12) is important in the recruitment of leukocytes to the peritoneal cavity and the regulation of endometriotic tissue growth in endometriosis patients. However, the alterations in microRNA (miRNA) expression induced by CXCL12 remain to be fully elucidated. The present study evaluated key miRNAs in CXCL12­stimulated endometrial stromal cells (ESCs), and investigated the underlying cellular regulatory mechanisms of CXCL12 in endometriosis by building networks between miRNAs, genes and gene ontologies (GOs). Differential expression of miRNAs and mRNAs induced by CXCL12 stimulation in ESCs was measured using miRNA and gene chips, and it was observed that 35 miRNAs and 1,671 mRNAs were differentially expressed. Using potential target genes of the 35 miRNAs, intersections of these genes were examined and 63 intersection genes were identified. A total of 39 GOs were obtained for these intersection genes, based on information from GO databases, including immune cell chemoattractants, inflammatory and immune responses, and pathological processes of endometriotic lesions in endometriosis. In addition, miRNA­gene networks were built according to the GO and Kyoto Encyclopedia of Genes and Genomes databases. The present study, to the best of our knowledge, provides the most complete miRNAome and mRNAome profiles, and the most detailed investigation of the underlying cellular regulatory mechanisms, of the effects of CXCL12 in endometriosis. These results may facilitate the complete elucidation of the role of CXCL12 in endometriosis, and its underlying epigenetic mechanisms.

Electroacupuncture decreases the progression of ovarian hyperstimulation syndrome in a rat model.

This study aimed to elucidate the effect of electroacupuncture treatment on preventing early ovarian hyperstimulation syndrome (OHSS) and the potential mechanisms involved using an induced rat model. The ovarian response was examined by measuring ovary weight, vascular permeability, levels of inflammation (interleukin-6), tumour necrosis factor alpha, chemokine ligand 2 (also known as monocyte chemoactic protein 1), vascular endothelial growth factor and hormone concentrations (oestradiol, progesterone, testosterone and prolactin). Sprague-Dawley female rats underwent ovarian stimulation to induce OHSS. Hyperstimulated rats received consecutive electroacupuncture treatment from 3 days before the beginning of pregnant mare serum gonadotrophin treatment or the time point of pregnant mare serum gonadotrophin treatment respectively, and last until 3 days after HCG administration. Electroacupuncture treatment reduced ovary weight and vascular permeability in hyperstimulated rats. Electroacupuncture treatment also reduced the levels of serum steroid hormones (progesterone and testosterone), inflammatory cytokines (interleukin-6, tumour necrosis factor alpha and monocyte chemotactic protein 1 and vascular endothelial growth factor in hyperstimulated rats. The results indicate that electroacupuncture can modulate endocrine hormone secretion and affect the secretion of inflammatory cytokines and vascular endothelial growth factor, and thus prevent the progress of OHSS. Electroacupuncture may provide a simple and effective method for the prevention and treatment of OHSS.

A polymeric nanoparticle formulation of curcumin in combination with sorafenib synergistically inhibits tumor growth and metastasis in an orthotopic model of human hepatocellular carcinoma.

Curcumin, a yellow polyphenol extracted from the rhizome of turmeric root (Curcuma longa) has potent anti-cancer properties in many types of tumors with ability to reverse multidrug resistance of cancer cells. However, widespread clinical application of this agent in cancer and other diseases has been limited due to its poor aqueous solubility. The recent findings of polymeric nanoparticle formulation of curcumin (NFC) have shown the potential for circumventing the problem of poor solubility, however evidences for NFC's anti-cancer and reverse multidrug resistance properties are lacking. Here we provide models of human hepatocellular carcinoma (HCC), the most common form of primary liver cancer, in vitro and in vivo to evaluate the efficacy of NFC alone and in combination with sorafenib, a kinase inhibitor approved for treatment of HCC. Results showed that NFC not only inhibited the proliferation and invasion of HCC cell lines in vitro, but also drastically suppressed primary tumor growth and lung metastases in vivo. Moreover, in combination with sorafenib, NFC induced HCC cell apoptosis and cell cycle arrest. Mechanistically, NFC and sorafenib synergistically down-regulated the expression of MMP9 via NF-κB/p65 signaling pathway. Furthermore, the combination therapy significantly decreased the population of CD133-positive HCC cells, which have been reported as cancer initiating cells in HCC. Taken together, NanoCurcumin provides an opportunity to expand the clinical repertoire of this agent. Additional studies utilizing a combination of NanoCurcumin and sorafenib in HCC are needed for further clinical development.

[Clinical outcomes of fresh versus cryopreserved-thawed embryo transfer in high-risk patients with ovarian hyperstimulation syndrome].

OBJECTIVE: To compare the clinical outcomes of fresh embryo transfer and cryopreserved-thawed embryo transfer in high-risk patients with ovarian hyperstimulation syndrome (OHSS). METHODS: We retrospectively analyzed the clinical data of 1784 high-risk OHSS patients undergoing IVF-ET, who were divided into groups A (n=939) and B (n=845). The former received fresh embryo transfer and the latter cryopreserved-thawed embryo transfer. We compared gonadotropin (Gn) administration, body mass index (BMI), the prevalence of polycystic ovary syndrome (PCOS), the number of oocytes retrieved, and the rates of clinical pregnancy, embryo implantation and OHSS incidnece between the two groups. RESULTS: Totally, 657 (69.97%) and 586 (69.35%) pregnancies were achieved in groups A and B, respectively, with 33 cases of moderate OHSS (3.5%) in the former and 30 (3.6%) in the latter. The prevalence of PCOS, the E2 level at hCG trigger, the number of oocytes retrieved, the number of mature oocytes, and the number of quality embryos were significantly lower in group A than in B (P <0.01). No statistically significant differences were found between the two groups in age, infertility duration, BMI, Gn administration, embryo implantation rate, clinical pregnancy rate, abortion rate, and OHSS incidence (P >0.05). CONCLUSION: In IVF-ET cycles, cryopreserved-thawed embryo transfer does not influence the clinical outcome in high-risk OHSS patients and can avoid the incidence of severe OHSS.