Identification of Novel Genes and Pathways of Ovarian Cancer Using a Comprehensive Bioinformatic Framework.

Ovarian cancer (OC) is a significant contributor to gynecological cancer-related deaths worldwide, with a high mortality rate. Despite several advances in understanding the pathogenesis of OC, the molecular mechanisms underlying its development and prognosis remain poorly understood. Therefore, the current research study aimed to identify hub genes involved in the pathogenesis of OC that could serve as selective diagnostic and therapeutic targets. To achieve this, the dataset GEO2R was used to retrieve differentially expressed genes. The study identified a total of five genes (CDKN1A, DKK1, CYP1B1, NTS, and GDF15) that were differentially expressed in OC. Subsequently, a network analysis was performed using the STRING database, followed by the construction of a network using Cytoscape. The network analyzer tool in Cytoscape predicted 276 upregulated and 269 downregulated genes. Furthermore, KEGG analysis was conducted to identify different pathways related to OC. Subsequently, survival analysis was performed to validate gene expression alterations and predict hub genes, using a p-value of 0.05 as a threshold. Four genes (CDKN1A, DKK1, CYP1B1, and NTS) were predicted as significant hub genes, while one gene (GDF15) was predicted as non-significant. The adjusted P values of said predicted genes are 2.85E - 07, 5.49E - 06, 4.28E - 07, 1.43E - 07, and 3.70E - 07 for CDKN1A, DKK1, NTS, GDF15, and CYP1B1 respectively; additionally 6.08, 5.76, 5.74, 5.01, and 4.9 LogFc values of the said genes were predicted in GEO data set. In a boxplot analysis, the expression of these genes was analyzed in normal and tumor cells. The study found that three genes were highly expressed in tumor cells, while two genes (CDKN1A and DKK1) were more elevated in normal cells. According to the boxplot analysis for CDKN1A, 50% of tumor cells ranged between approx 3.8 and 5, while 50% of normal cells ranged between approx 6.9 and 7.9, which is greater than tumor cells. This shows that in normal cells, the CYP1B1 has a high expression level according to the GEPIA boxplot; addtionally the boxplot for DKK1 indicated that 50% of tumor cells ranged between approx 0 and 0.5, which was less than that of normal cells which ranged between approx 0.3 and 0.9. It shows that DKK1 is highly expressed in normal genes. Overall, the current study provides novel insights into the molecular mechanisms underlying OC. The identified hub genes and drug candidate targets could potentially serve as alternative diagnostic and therapeutic options for OC patients. Further research is needed to investigate the clinical significance of these findings and develop effective interventions that can improve the prognosis of patients with OC.

Phase I/II Study of LDE225 in Combination with Gemcitabine and Nab-Paclitaxel in Patients with Metastatic Pancreatic Cancer.

BACKGROUND: Desmoplasia is a central feature of the tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC). LDE225 is a pharmacological Hedgehog signaling pathway inhibitor and is thought to specifically target tumor stroma. We investigated the combined use of LDE225 and chemotherapy to treat PDAC patients. METHODS: This was a multi-center, phase I/II study for patients with metastatic PDAC establishing the maximum tolerated dose of LDE225 co-administered with gemcitabine and nab-paclitaxel (phase I) and evaluating the efficacy and safety of the treatment combination after prior FOLFIRINOX treatment (phase II). Tumor microenvironment assessment was performed with quantitative MRI using intra-voxel incoherent motion diffusion weighted MRI (IVIM-DWI) and dynamic contrast-enhanced (DCE) MRI. RESULTS: The MTD of LDE225 was 200 mg once daily co-administered with gemcitabine 1000 mg/m2 and nab-paclitaxel 125 mg/m2. In phase II, six therapy-related grade 4 adverse events (AE) and three grade 5 were observed. In 24 patients, the target lesion response was evaluable. Three patients had partial response (13%), 14 patients showed stable disease (58%), and 7 patients had progressive disease (29%). Median overall survival (OS) was 6 months (IQR 3.9-8.1). Blood plasma fraction (DCE) and diffusion coefficient (IVIM-DWI) significantly increased during treatment. Baseline perfusion fraction could predict OS (>222 days) with 80% sensitivity and 85% specificity. CONCLUSION: LDE225 in combination with gemcitabine and nab-paclitaxel was well-tolerated in patients with metastatic PDAC and has promising efficacy after prior treatment with FOLFIRINOX. Quantitative MRI suggested that LDE225 causes increased tumor diffusion and works particularly well in patients with poor baseline tumor perfusion.

3-Arylamino-quinoxaline-2-carboxamides inhibit the PI3K/Akt/mTOR signaling pathways to activate P53 and induce apoptosis.

Thirty-eight new 3-arylaminoquinoxaline-2-carboxamide derivatives were in silico designed, synthesized and their cytotoxicity against five human cancer cell lines and one normal cells WI-38 were evaluated. Molecular mechanism studies indicated that N-(3-Aminopropyl)-3-(4-chlorophenyl) amino-quinoxaline-2-carboxamide (6be), the compound with the most potent anti-proliferation can inhibit the PI3K-Akt-mTOR pathway via down regulating the levels of PI3K, Akt, p-Akt, p-mTOR and simultaneously inhibit the phosphorylation of Thr308 and Ser473 residues in Akt kinase to servers as a dual inhibitor. Further investigation revealed that 6be activate the P53 signal pathway, modulated the downstream target gene of Akt kinase such p21, p27, Bax and Bcl-2, caused the fluctuation of intracellular ROS, Ca2+ and mitochondrial membrane potential to induce cell cycle arrest and apoptosis in MGC-803 cells. 6be also display moderate anti-tumor activity in vivo while displaying no obvious adverse signs during the drug administration. The results suggest that 3-arylaminoquinoxaline-2-carboxamide derivatives might server as new scaffold for development of PI3K-Akt-mTOR inhibitor.

Lipocalin 2 serum levels correlate with age and bone turnover biomarkers in healthy subjects but not in postmenopausal osteoporotic women.

PURPOSE: Lipocalin 2 (LCN2) is an adipokine involved in many physiological functions, including bone metabolism. We previously demonstrated its implication in mouse models of mechanical unloading-induced osteoporosis and in a cohort of bed rest volunteers. We therefore aimed at studying its involvement in postmenopausal osteoporosis. METHODS: We measured serum LCN2 and correlated its levels to Dickkopf WNT Signaling Pathway Inhibitor 1 (DKK1), Tartrate Resistant Acid Phosphatase 5B (TRAcP5B), sclerostin, urinary N-terminal telopeptide of type I collagen (NTX), serum C-terminal telopeptide of type I collagen (CTX), parathyroid hormone and vitamin K by ELISA performed in a cohort of younger (50-65 years) and older (66-90 years) osteoporotic women in comparison to healthy subjects. A cohort of male healthy and osteoarthritic patients was also included. Sobel mediation analysis was used to test indirect associations among age, LCN2 and DKK1 or NTX. RESULTS: LCN2 levels were unchanged in osteoporotic and in osteoarthritis patients when compared to healthy subjects and did not correlate with BMD. However, serum LCN2 correlated with age in healthy women (R = 0.44; P = 0.003) and men (R = 0.5; P = 0.001) and serum concentrations of DKK1 (R = 0.47; P = 0.003) and urinary NTX (R = 0.34; P = 0.04). Sobel mediation analysis showed that LCN2 mediates an indirect relationship between age and DKK1 (P = 0.02), but not with NTX, in healthy subjects. CONCLUSIONS: Taken together, the results suggest a hitherto unknown association between LCN2, DKK1 and age in healthy individuals, but not in postmenopausal osteoporotic women.

Mining the 99 Lives Cat Genome Sequencing Consortium database implicates genes and variants for the Ticked locus in domestic cats (Felis catus).

Tabby patterns of fur coats are defining characteristics in wild and domestic felids. Historically, three autosomal alleles at one locus (Tabby): Abyssinian (Ta ; a.k.a. ticked), mackerel (Tm ; a.k.a. striped) and blotched (tb ; a.k.a. classic, blotched) were thought to control these patterns in domestic cats and their breeds. Currently, at least three loci influence cat tabby markings, two of which are designated Tabby and Ticked. The Tabby locus is laeverin (LVRN) and affects the mackerel and blotched patterns. The unidentified gene for the Ticked locus on cat chromosome B1 was suggested to control the presence or absence of the ticked pattern (Tabby - Abyssinian (Ta ; a.k.a. ticked). The cat reference genome (Cinnamon, the Abyssinian) has the ticked phenotype and the variant dataset and coat phenotypes from the 99 Lives Cat Genome Consortium (195 cats) were used to identify candidate genes and variants associated with the Ticked locus. Two strategies were used to find the Ticked allele(s), one considered Cinnamon with the reference allele or heterozygous (Strategy A) and the other considered Cinnamon as having the variant allele or heterozygous (Strategy B). For Strategy A, two variants in Dickkopf Wnt Signaling Pathway Inhibitor 4 (DKK4), a p.Cys63Tyr (B1:41621481, c.188G>A) and a less common p.Ala18Val (B1:42620835, c.53C>T) variant are suggested as two alleles influencing the Ticked phenotype. Bioinformatic and molecular modeling analysis suggests that these changes disrupt a key disulfide bond in the Dkk4 cysteine-rich domain 1 or Dkk4 signal peptide cleavage respectively. All coding variants were excluded as Ticked alleles using Strategy B.

Inhibition of persimmon tannin extract on guinea pig skin pigmentation.

BACKGROUND: In daily life, excessive exposure to ultraviolet light can lead to pigmentation. AIMS: This study is to determine the mechanism of persimmon tannin extract in inhibiting pigmentation, to investigate whether the effect of persimmon tannin extract is superior to that of arbutin, and to detect the optimal concentration. METHODS: In this study, the guinea pig pigmentation model was established by ultraviolet B (UVB) irradiation. With arbutin as a positive control, Masson-Fontana silver staining was used to observe the effects of persimmon tannin extract on melanin distribution in guinea pigs' skin tissue. Then, the tyrosinase activity was measured, and an Enzyme-linked immunosorbent assay was used to investigate the contents of antioxidant enzymes, inflammatory factors, and signaling pathway inhibitors in guinea pigs' skin tissue. RESULTS: The results showed that compared with the model group, superoxide dismutase, catalase, glutathione peroxidase, DKK1 content of Wnt/-catenin signaling pathway inhibitors levels, and inhibitory tyrosinase activity were increased by 24.3%, 33.3%, 59.3%, 36.81%, and 17.16%, respectively. Meanwhile, the interleukin-6 and interleukin-8 expression were reduced by approximately 22.2% and 54%. The results also showed that persimmon tannin extract could significantly reduce melanin density. The differences in experimental results were statistically significant (P < .01). CONCLUSIONS: Compared with the arbutin group, the medium-dose group (persimmon tannin extract of 20%) had a more significant effect on inhibiting pigmentation. Persimmon tannin could serve as a promising agent for preventing skin pigmentation. It is expected to provide ideas for the development of deep-processed persimmon products related to functional foods and cosmetics.

Progress in evidence-based research on the clinical treatment of infantile hemangioma and vascular malformations / 口腔疾病防治

@#Hemangiomas and vascular malformations are common clinical diseases. According to their clinical and imaging characterizations, the International Society for the Study of Vascular Anomalies (ISSVA) has systematically classified infantile hemangioma and vascular malformations, and the classification has been widely recognized and applied. To date, most vascular malformations involve the following important signaling pathways: PI3K/Akt/mTOR and RAS/MAPK/ERK. This discovery has major impacts on the diagnosis and treatment of vascular malformations including the following: the understanding of the biology of vascular malformations has been increased; the understanding of vascular malformations based on genotype has been refined; and the development of targeted drugs for the treatment of vascular malformations has been promoted. Despite facing many challenges, with the development of gene sequencing, molecular biology and imaging technology, the relevance of vascular malformation classification and the accuracy of diagnosis are improving, and this is accompanied by innovations in surgical treatment and sclerotherapy, interventional embolization, and continuous progress in targeted therapy. At present, investigations on vascular malformations are mostly retrospective clinical studies or low-level clinical trials. The purpose of this paper is to review the literature on the treatment of infantile hemangioma, lymphatic malformation, venous malformation and arteriovenous malformation and to review the research progress in evidence-based treatment of infantile hemangioma and vascular malformation.

TNF­α treatment increases DKK1 protein levels in primary osteoblasts via upregulation of DKK1 mRNA levels and downregulation of miR­335­5p.

Elucidation of the underlying mechanisms governing osteogenic differentiation is of significant importance to the improvement of therapeutics for bone­related inflammatory diseases. Tumor necrosis factor­α (TNF­α) is regarded as one of the major agents during osteogenic differentiation in an inflammatory environment. miR­335­5p post­transcriptionally downregulates the Dickkopf WNT signaling pathway inhibitor 1 (DKK1) protein level by specifically binding to the DKK1 3'UTR and activating Wnt signaling. The role of miR­335­5p in TNF­α­induced post­transcriptional regulation of DKK1 remains to be elucidated. In the present study, the mRNA and protein levels of DKK1 and the level of miR­335­5p were determined in MC3T3­E1 cells and the primary calvarial osteoblasts treated with or without TNF­α. The role of NF­κB signaling in TNF­α­induced post­transcriptional regulation of DKK1 was also evaluated. The present study determined that although TNF­α treatment exhibited cell­specific effects on DKK1 mRNA expression, the stimulation of TNF­α time­ and concentration­dependently upregulated the protein levels of DKK1. In primary calvarial osteoblasts, the decreased miR­335­5p level induced by TNF­α­activated NF­κB signaling served an important role in mediating the post­transcriptional regulation of DKK1 by TNF­α treatment. In MC3T3­E1 cells, the post­transcriptional regulation of DKK1 by TNF­α treatment was more complicated and involved other molecular signaling pathways in addition to the NF­κB signaling. In conclusion, TNF­α treatment served an important role in the post­transcriptional regulation of DKK1 expression, which requires further investigation. The results of the present study not only provided new insights into the regulatory effects of miR­335­5p on osteogenic differentiation in an inflammatory microenvironment, but may also promote the development of potential therapeutic strategies for the treatment of bone­related inflammatory diseases.

miR-1303 promotes the proliferation, migration and invasion of prostate cancer cells through regulating the Wnt/ß-catenin pathway by targeting DKK3.

MicroRNA-1303 (miR-1303) is involved in the tumorigenesis and progression of several cancers, and yet the role of miR-1303 in prostate cancer (PCa) and its underlying mechanism are unknown. To explore this issue, the present study aimed to use PCa tissues, cell lines and a PCa-engrafted mouse model to determine the expression and roles of miR-1303 in PCa. Furthermore, a series of experiments were conducted to explore the underlying mechanisms of action of miR-1303 in PCa cells. miR-1303 was demonstrated to be highly expressed in PCa tissues and cell lines. The level of miR-1303 expression was closely associated with higher Gleason scores and a more developed tumor stage in patients with PCa, and patients with higher levels of miR-1303 displayed a reduced overall survival rate. miR-1303 overexpression promoted the proliferation, migration and invasion of PCa cells. In vivo experiments showed that miR-1303 inhibition suppressed the growth of PCa tumors in mice. Additionally, dickkopf Wnt signaling pathway inhibitor 3 (DKK3) was identified as a target of miR-1303. Knockdown of miR-1303 suppressed the proliferation, migration and invasion of PCa cells, increased DKK3 expression, and inhibited the activity of the Wnt/ß-catenin pathway. In conclusion, miR-1303 may promote proliferation, migration and invasion of PCa cells through activating the Wnt/ß-catenin pathway by regulating DKK3 expression. These results indicated that miR-1303 may be considered as a potential biomarker for PCa treatment.

PD-L1 Distribution and Perspective for Cancer Immunotherapy-Blockade, Knockdown, or Inhibition.

Cancer immunotherapy involves blocking the interactions between the PD-1/PD-L1 immune checkpoints with antibodies. This has shown unprecedented positive outcomes in clinics. Particularly, the PD-L1 antibody therapy has shown the efficiency in blocking membrane PD-L1 and efficacy in treating some advanced carcinoma. However, this therapy has limited effects on many solid tumors, suspecting to be relevant to PD-L1 located in other cellular compartments, where they play additional roles and are associated with poor prognosis. In this review, we highlight the advances of 3 current strategies on PD-1/PD-L1 based immunotherapy, summarize cellular distribution of PD-L1, and review the versatile functions of intracellular PD-L1. The intracellular distribution and function of PD-L1 may indicate why not all antibody blockade is able to fully stop PD-L1 biological functions and effectively inhibit tumor growth. In this regard, gene silencing may have advantages over antibody blockade on suppression of PD-L1 sources and functions. Apart from cancer cells, PD-L1 silencing on host immune cells such as APC and DC can also enhance T cell immunity, leading to tumor clearance. Moreover, the molecular regulation of PD-L1 expression in cells is being elucidated, which helps identify potential therapeutic molecules to target PD-L1 production and improve clinical outcomes. Based on our understandings of PD-L1 distribution, regulation, and function, we prospect that the more effective PD-L1-based cancer immunotherapy will be combination therapies.

Hypertension in the Cardio-Oncology Clinic.

As cancer therapies improve, the population of survivors of cancer has increased, and the long-term effects of cancer treatments have become more apparent. Cardiotoxicity is a well-established adverse effect of many antineoplastic agents. Hypertension is common in survivors of cancer, can be caused or worsened by certain agents, and has been shown to increase the risk of other cardiovascular diseases including heart failure. Pretreatment risk assessment and careful monitoring of blood pressure during therapy is essential. Aggressive management of preexisting or incident hypertension in survivors of cancer is paramount to decrease the risk of heart failure and other cardiovascular diseases in these patients.

miR-25-3p promotes glioma cell proliferation and migration by targeting FBXW7 and DKK3.

MicroRNAs (miRs) serve important roles in glioma. However, the underlying molecular mechanism of miR-25 in glioma progression remains largely unknown; therefore, it was investigated in the present study. RT-qPCR analysis revealed that miR-25 expression levels were markedly increased in human glioma tissue and glioma cell lines compared with normal brain tissues and normal human astrocytes, respectively. miR-25 upregulation exhibited an association with glioma progression, and the knockdown of miR-25 significantly inhibited glioma cell proliferation and migration. F-box and WD repeat domain containing 7 (FBXW7) and dickkopf WNT signaling pathway inhibitor 3 (DKK3) were identified as target genes of miR-25. FBXW7 and DKK3 expression levels were significantly downregulated in glioma tissue samples compared with normal brain tissue, and their expression levels were negatively regulated by miR-25 expression in glioma cells. Furthermore, inhibition of FBXW7 and DKK3 expression suppressed the miR-25-induced effects on glioma cell proliferation and migration. The findings of the present study suggest that miR-25 may promote glioma cell proliferation and migration by inhibiting the expression of FBXW7 and DKK3. Therefore, miR-25 may serve as a promising molecular target for the treatment of glioma.

Progress in the genetics research of infantile hemangioma and vascular malformations / 口腔疾病防治

@#The etiology and pathogenesis of hemangiomas and vascular malformations are still unclear and face many challenges in terms of treatment. This article focuses on the etiology and genetic mechanism of common vascular tumors (such as infantile hemangiomas, congenital hemangioma and pyogenic granuloma) and vascular abnormalities (such as sporadic venous malformations, blue rubber bleb nevus syndrome, hereditary cutaneomucosal venous malformations, glomuvenous malformations, verrucous venous malformations, lymphatic malformations, and arteriovenous malformations). Some gene mutations have been identified and established. Several mutations in key proteins in the signaling pathways of endothelial cells (ECs) have been shown to play a major role in the pathogenesis of vascular abnormalities. Mutations in PIK3CA and G-protein coupled receptors were most frequently identified. The detection of genetic or somatic gene mutations is important for elucidating the underlying molecular mechanisms and developing effective therapeutic approaches.

Effects of SB202190 on expression levels of IL-6 and NF-κB in flap ischemia-reperfusion injury.

The aim of the current study was to investigate the effect of SB202190, a specific inhibitor of p38 MAPK signaling pathway, on the expression levels of IL-6 and NF-κB in flap ischemia-reperfusion injury. Healthy Sprague-Dawley rats were randomly divided into four groups of 12 each. For the ischemia-reperfusion group, the flap was constructed and then sutured after 8 h of ischemia. For the saline group, rats were intraperitoneally infused with saline at regular intervals after flap ischemia-reperfusion. For the inhibitor group, rats were intraperitoneally infused with SB202190 at regular intervals after flap ischemia-reperfusion. For the control group, the flap was constructed and then sutured immediately. The flap survival rate of each group was measured after 7 days. The concentration of IL-6 in serum was measured by ELISA kit. The mRNA and protein expression levels of IL-6 and NF-κB in the flap were measured using RT-PCR and western blot analysis, respectively. In the ischemia-reperfusion group and the saline group, the flap survival rates were much lower than that in the control group (P<0.05). By contrast, the mRNA and protein expression levels of IL-6 and NF-κB in the flap and the concentration of IL-6 in serum were much higher (P<0.05). In the inhibitor group, the flap survival rate was significantly higher than those in the ischemia-reperfusion and saline groups (P<0.05). By contrast, the concentration of IL-6 in serum and the mRNA and protein expression levels of NF-κB and IL-6 in the flap were significantly decreased (P<0.05). The results show that, SB202190 played a role in the protection of the flap by reducing the inflammatory response in flap ischemia-reperfusion injury.

Garlic-derived compound S-allylmercaptocysteine inhibits hepatocarcinogenesis through targeting LRP6/Wnt pathway.

Whether and how garlic-derived S-allylmercaptocysteine (SAMC) inhibits hepatocellular carcinoma (HCC) is largely unknown. In the current study, the role of low-density lipoprotein receptor (LDLR)-related protein 6 (LRP6) in HCC progression and the anti-HCC mechanism of SAMC was examined in clinical sample, cell model and xenograft/orthotopic mouse models. We demonstrated that SAMC inhibited cell proliferation and tumorigenesis, while induced apoptosis of human HCC cells without influencing normal hepatocytes. SAMC directly interacted with Wnt-pathway co-receptor LRP6 on the cell membrane. LRP6 was frequently over-expressed in the tumor tissue of human HCC patients (66.7% of 48 patients) and its over-expression only correlated with the over-expression of ß-catenin, but not with age, gender, tumor size, stage and metastasis. Deficiency or over-expression of LRP6 in hepatoma cells could partly mimic or counteract the anti-tumor properties of SAMC, respectively. In vivo administration of SAMC significantly suppressed the growth of Huh-7 xenograft/orthotopic HCC tumor without causing undesirable side effects. In addition, stable down-regulation of LRP6 in Huh-7 facilitated the anti-HCC effects of SAMC. In conclusion, LRP6 can be a potential therapeutic target of HCC. SAMC is a promising specific anti-tumor agent for treating HCC subtypes with Wnt activation at the hepatoma cell surface.

Tumor necrosis factor-α downregulates the REIC/Dkk-3 tumor suppressor gene in normal human skin keratinocytes.

Our previous studies revealed that REIC/Dkk-3 was expressed various tissues, including skin keratinocytes. The aim of the present study was to identify the factors that regulate the expression of the dickkopf Wnt signaling pathway inhibitor 3 (REIC/Dkk­3) tumor suppressor gene in normal human skin keratinocytes (NHKs). Several growth factors and cytokines that have previously been reported to be involved in the growth and differentiation of keratinocytes were screened as potential regulators. Western blot analysis was performed using protein from NHKs cultured with/without various factors including the epidermal growth factor, tumor necrosis factor­α, transforming growth factor­ß, interleukin (IL)­1F9, IL­6, IL­8 and Ca2+. The results indicated that only TNF­α downregulated REIC/Dkk­3 expression in NHKs. Subsequently, TNF­α was confirmed to reduce the expression levels of REIC/Dkk­3 in mouse skin tissue and hair culture models. TNF­α­mediated downregulation of REIC/Dkk­3 expression in NHKs was abrogated by the addition of a TNF­α­specific antibody. In conclusion, the results indicate that TNF­α downregulates REIC/Dkk­3 expression in normal skin keratinocytes.

Garlic-derived compound -allylmercaptocysteine inhibits hepatocarcinogenesis through targeting LRP6/Wnt pathway

Whether and how garlic-derived -allylmercaptocysteine (SAMC) inhibits hepatocellular carcinoma (HCC) is largely unknown. In the current study, the role of low-density lipoprotein receptor (LDLR)-related protein 6 (LRP6) in HCC progression and the anti-HCC mechanism of SAMC was examined in clinical sample, cell model and xenograft/orthotopic mouse models. We demonstrated that SAMC inhibited cell proliferation and tumorigenesis, while induced apoptosis of human HCC cells without influencing normal hepatocytes. SAMC directly interacted with Wnt-pathway co-receptor LRP6 on the cell membrane. LRP6 was frequently over-expressed in the tumor tissue of human HCC patients (66.7% of 48 patients) and its over-expression only correlated with the over-expression of -catenin, but not with age, gender, tumor size, stage and metastasis. Deficiency or over-expression of LRP6 in hepatoma cells could partly mimic or counteract the anti-tumor properties of SAMC, respectively. administration of SAMC significantly suppressed the growth of Huh-7 xenograft/orthotopic HCC tumor without causing undesirable side effects. In addition, stable down-regulation of LRP6 in Huh-7 facilitated the anti-HCC effects of SAMC. In conclusion, LRP6 can be a potential therapeutic target of HCC. SAMC is a promising specific anti-tumor agent for treating HCC subtypes with Wnt activation at the hepatoma cell surface.

Arylurea Derivatives: A Class of Potential Cancer Targeting Agents.

Arylurea derivatives, an important class of small molecules, have received considerable attention in recent years due to their wide range of biological applications. Various molecular targeted agents with arylurea scaffold as potential enzyme/receptor inhibitors were constructed with the successful development of sorafenib and regorafenib. This review focuses on those arylureas possessing anti-cancer activities from 2010 to date. According to their different mechanisms of action, these arylureas are divided into the following six categories: (1) Ras/Raf/MEK/ERK signaling pathway inhibitors; (2) tumor angiogenesis inhibitors, their targets include Vascular Endothelial Growth Factor Receptors (VEGFRs), Fibroblast Growth Factor Receptors (FGFRs), Platelet-Derived Growth Factor Receptors (PDGFRs), Epidermal Growth Factor Receptors (EGFRs), Insulin-Like Growth Factor 1 Receptor (IGF-1R), Fmslike Tyrosine Kinase 3 (FLT3), c-Kit, MET, and Smoothened (Smo); (3) PI3K/AKT/mTOR signaling pathway inhibitors; (4) cell cycle inhibitors, their targets include Checkpoint Kinases (Chks), Cyclin- Dependent Kinases (CDKs), Aurora, SUMO activating enzyme 1 (SUMO E1), tubulin, and DNA; (5) tumor differentiation, migration, and invasion inhibitors, their targets include Matrix Metalloproteinases (MMPs), LIM kinase (Limk), Nicotinamide Phosphoribosyltransferase (Nampt), and Histone Deacetylase (HDAC); (6) arylureas from the rational modification of natural products. This review focuses on the Structure-Activity Relationships (SARs) of these arylureas. The structural evolution and current status of some typical anti-cancer agents used in clinic and/or in clinical trials are emphasized.

Mechanisms of resistance to PBK-Akt-mTOR signaling pathway inhibitors / 中国药学杂志

The resistance to PBK-Akt-mTOR pathway inhibitors has close relationship to the negative feedback of its context-dependent signal pathways. According to our current understanding, the resistant mechanisms could be divided into the following basic conditions: related to FOXO and hormone receptor, MYC-dependence, β-catenin-dependence, JAK/STAT pathway-dependence, MAPK pathway-dependence and related to AXL. The emergence of drug resistance to PBK-Akt-mTOR pathway inhibitors has greatly limited their curative effect. The reported resistance mechanisms to PBK-Akt-mTOR pathway inhibitors to search for potential strategies for overcoming resistance by drug combination were summarized.

Novelties in the management of B-cell malignancies: B-cell receptor signaling inhibitors and lenalidomide.

B-cell lymphoproliferative disorders comprise 85% of Non-Hodgkin's lymphomas. Despite successful chemoimmunotherapy regimens, responses are not durable and the outcome is fatal in a considerable portion of patients. There is an inevitable need for less toxic and more potent therapeutic agents. Over the recent years, a plethora of agents including monoclonal antibodies, Bcl-2 antagonists, tyrosine kinase inhibitors, cyclin-dependent kinase inhibitors, mTOR inhibitors and immunomodulatory drugs have been developed in B-cell malignancies. The aim of this paper is to focus on B-cell receptor signaling inhibitors and lenalidomide as an immunomodulatory drug and to provide insight on how and when to incorporate these agents into the treatment algorithms.