The heterochronic gene let-7 serves as a tumor suppressor microRNA by targeting various oncogenic pathways in cancer cells. Considerable evidence indicates that reduced expression of let-7 might be associated with poor clinical outcome in patients with cancer. Here, we report that the expression levels of three let-7 family members, let-7a, let-7b, and let-7g, were significantly decreased in the breast cancer patients with lymph node metastasis compared to those without lymph node metastasis. Enforced expression of let-7b significantly inhibits breast cancer cell motility and affects actin dynamics. Using bioinformatic and experimental approaches, four genes in the actin cytoskeleton pathway, including PAK1, DIAPH2, RDX, and ITGB8, were identified as let-7 direct targets. Blocking the expression of PAK1, DIAPH2, and RDX significantly inhibits breast cancer cell migration induced by let-7b repression. Our results indicate reconstitution of let-7 expression in tumor cells could provide a novel therapeutic strategy for the treatment of metastatic disease.

Effective and safe analgesics represent an unmet medical need for the treatment of acute and chronic pain. A series of N-cyclopropylmethyl-7α-phenyl-6,14-endoethano­tetrahydro­northebaines were designed, synthesized, and assayed, leading to the discovery of a benzylamine derivative (compound 4, SLL-039) as a highly selective and potent κ opioid agonist (κ, K i = 0.47 nM, κ/μ = 682, κ/δ = 283), which was confirmed by functional assays in vitro and antinociceptive assays in vivo. The in vivo effect could be blocked by pretreatment with the selective κ antagonist nor-BNI. Moreover, this compound did not induce sedation, a common dose limiting effect of κ opioid receptor agonists, at its analgesic dose compared to U50,488H. The dissociation of sedation/antinociception found in SLL-039 was assumed to be correlated with the occupation of its benzamide motif in a unique subsite involving V1182.63, W124EL1, and E209EL2.

BackgroundLarge-size data on type-specific HPV prevalence in Southwest China are required to estimate the cervical cancer burden in the country and to prepare for HPV-based cervical screening program and further HPV vaccination of China. This HPV study is a pooled analysis of data from five years in Chongqing of China, which is cross-sectional in design using data collecting.ResultsThe positivity of HPV was 26.2% (10542/40311), single type was 25.7% (10360/40311), multiple type was 8.2% (3306/40311), high-risk HPV was 30.9% (12490/40311), and low-risk HPV was 2.9%(1169/40311). The most common genotypes were HPV16,52,58 and 18. HPV-positive women (n = 10542) were triaged by cytology, colposcopy or histological diagnosis. Among HPV-positive women, 43.8% had normal, 22.5% had ASCUS, 0.2% had LSIL, 12.6% had HSIL and 6.0% had ICC. The most common HPV genotypes were HPV16, 58 and 18 in ASCUS, HPV16, 18 and 58 in LSIL, HPV16, 58 and 33 in HSIL, and HPV16, 58 and 18 in ICC. The prevalence of Group 1/2A HPV types increased with increasing CIN grade and accounted for 96.05% of the CIN 3+ lesions, while HPV16 accounted for 71.1%. HPV-positive women steadily increased with age, peaking at 31–40 years.ConclusionThe type-specific prevalence rate of HPV 16 and HPV 18 were a little lower than the mean of international meta-analyses. Single HPV genotype infection was predominantly detected in different groups of cervical lesions in Chongqing, and HPV16, 52, 58 were the priority HPV types. The HPV genotyping study was found to be valuable for planning further preventive program for cervical cancer.

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Microglia activation plays an important role in neuroinflammation. Sirtuin1 (SIRT1) has been shown to play a role in regulation of inflammation. Resveratrol, a potent SIRT1 activator, has anti-inflammation property. MicroRNA (miRNA or miR) related to inflammation pathways has been shown to be a promising therapeutic approach for septic encephalopathy (SE). The miR mediated mechanism of regulation of SIRT1 expression in encephalitis. However, the mechanism of was unknown. To address this question, we investigated whether miRNAs and resveratrol regulate the SIRT1 and the functional changes of mice microglia cell lines pre-treated with or without lipopolysaccharide (LPS). The research about direct role of miR-204 and resveratrol on expression of SIRT1 in mice microglia cell lines (N9 and BV2) pre-treated with or without LPS had been performed. Mice microglia cell lines were transfected with miR-204 mimics and inhibitors or treated with resveratrol, and the effects on cell growth, proliferation, and apoptosis of cells were assessed. LPS induced inflammation and activation of mice microglia. Through overexpression of SIRT1, resveratrol, and inhibitor of miR-204 inhibited inflammation process, proliferation of mice microglia cells and promoted its apoptosis. We identified if resveratrol and miR-204 could repress inflammation process and proliferation of mice microglia cell through promoting the expression of SIRT1.

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T he cellular oncogene KRAS encodes two splice isoforms, KRAS4A and the predominant form KRAS4B (here referred to as KRAS), which is a small GTPase that links extracellular stimuli to intracellular signaling pathways regulating developmental processes and diseases, especially cancers (1-5). KRAS protein has been widely reported to bear activating mutations (e.g., G12D, G13D, and Q61L) in cancers derived from lung, colon, and pancreas (1-5). These mutations impair the GTPase activity of KRAS and enable constitutive activation of downstream pathways independent of exogenous regulatory signals. The abnormal activation of downstream effectors in KRAS pathways, such as RAF-extracellular signal-regulated kinase (ERK) and phosphatidylinositol 3-kinase (PI3K)/AKT, had been found to contribute to KRASdriven tumorigenesis, which is characterized by cellular transformation, resistance to apoptosis, and metastasis (1-6). Moreover, downstream transcription factors of KRAS pathways, such as FOS, JUN, nuclear factor B (NF-B), and Fra1, are required for cancer cell survival, proliferation, migration, and invasion (7-10). Although the molecular mechanisms dictating how the aberrant activation of KRAS pathways affects transformed phenotypes and tumorigenesis have been well studied, the role of noncoding genes in mediating KRAS function is still largely unknown (11).MicroRNAs (miRNAs) are endogenous 18-to 25-nucleotide noncoding small RNAs that regulate gene expression in a sequence-specific manner via the degradation of target mRNAs or inhibition of protein translation (12)(13)(14). MicroRNA 200 (mir-200) is a well-characterized, highly conserved miRNA family, consisting of five members that are located in two miRNA gene clusters (mir-200b/a/429 and mir-200c/141) on different chromosomes. Each cluster is transcribed into a single primary miRNA transcript (pri-miRNA) and processed by the Drosha/ DGCR8 complex into individual precursor transcripts (premiRNA), which are further sliced by Dicer into mature miRNAs. The five mature miRNAs of the family contain highly similar seed sequences, which leads them to share a wide range of biological functions, such as regulation of development (15-17), cellular senescence (18), apoptosis (19), tumor metastasis (20-27), angiogenesis (28), and immunosuppression of lymphocytes (29). These biological functions of mir-200 were disclosed by the discovery of its target genes, such as those coding for ZEB1/2 (21, 22, 24-26), SEC23 (30), CXCL1/IL-8 (28), and PD-L1 (29), in different cellular contexts. Similar to other miRNAs involved in tumorigenesis (31), the expression levels of mir-200 family members were deregulated in cancer cells by different mechanisms, implying their crit-

Key Points CML patients can be stratified into 4 subgroups with different risk of blastic transformation based on cytogenetic abnormalities. TKI therapy mitigates risk of blastic transformation associated with low-risk ACAs or no ACAs but not that associated with HR ACAs.