A novel lncRNA-hidden polypeptide regulates malignant phenotypes and pemetrexed sensitivity in A549 pulmonary adenocarcinoma cells.

The advance of high-throughput sequencing enhances the discovery of short ORFs embedded in long non-coding RNAs (lncRNAs). Here, we uncovered the production and biological activity of lncRNA-hidden polypeptides in lung adenocarcinoma (LUAD). In the present study, bioinformatics was used to screen the lncRNA-hidden polypeptides in LUAD. Analysis of protein expression was done by western blot or immunofluorescence assay. The functions of the polypeptide were determined by detecting its effects on cell viability, proliferation, migration, invasion, and pemetrexed (PEM) sensitivity. The protein interactors of the polypeptide were analyzed by mass spectrometry after Co-immunoprecipitation (Co-IP) assay. The results showed that the lncRNA LINC00954 was confirmed to encode a novel polypeptide LINC00954-ORF. The polypeptide had tumor-suppressor features in A549 cells by repressing cell growth, motility and invasion. Moreover, the polypeptide enhanced PEM sensitivity and suppressed growth in A549/PEM cells. The protein interactors of this polypeptide had close correlations with RNA processing, amide metabolic process, translation, RNA binding, RNA transport, and DNA replication. As a conclusion, the LINC00954-ORF polypeptide embedded in lncRNA LINC00954 possesses tumor-suppressor features in A549 and PEM-resistant A549 cells and sensitizes PEM-resistant A549 cells to PEM, providing evidence that the LINC00954-ORF polypeptide is a potential anti-cancer agent in LUAD.

Transgenerational inheritance of wing development defects in Drosophila melanogaster induced by cadmium.

The transgenerational inheritance of phenotype induced by environmental factors is a new focus in epigenetic research. In this study, Drosophila melanogaster (F0) was cultured in the medium containing cadmium (Cd, 4.5 mg/kg) from eggs to adults, and offspring (F1-F4) were continuously kept in standard medium (without cadmium). The phenotype analysis showed that cadmium induced developmental defects on wings and apoptosis in the wing disc cells of Drosophila (F0). The wing defects were transmitted for at least four generations even without Cd afterwards. And the effect on the mRNA expression of wing development related genes (shg, omb, F-actin, Mekk1) can be maintained for at least two or three generations. More importantly, under cadmium stress, the post-translational modification (PTM) on the histones H3K4me3 in the third instar larvae and ovaries or testes of adult flies increased significantly, while the levels of H3K9me3 and H3K27me3 decreased significantly. The expression of histone methylation related genes (dSet-1, ash1, Lsd1) increased significantly and these changes can be transmitted to offspring from one or two generations in ovaries or testes. These results suggest that the phenotypic defects of wings caused by cadmium can be inherited to the offspring, and this transgenerational inheritance effect may be related to the epigenetic regulation of histone methylation. Therefore, the adaptability of offspring should be considered when evaluating the toxicity and environmental risk of cadmium.

Adjuvant chemotherapy versus adjuvant concurrent chemoradiotherapy after radical surgery for early-stage cervical cancer: a randomized, non-inferiority, multicenter trial.

We conducted a prospective study to assess the non-inferiority of adjuvant chemotherapy alone versus adjuvant concurrent chemoradiotherapy (CCRT) as an alternative strategy for patients with early-stage (FIGO 2009 stage IB-IIA) cervical cancer having risk factors after surgery. The condition was assessed in terms of prognosis, adverse effects, and quality of life. This randomized trial involved nine centers across China. Eligible patients were randomized to receive adjuvant chemotherapy or CCRT after surgery. The primary end-point was progression-free survival (PFS). From December 2012 to December 2014, 337 patients were subjected to randomization. Final analysis included 329 patients, including 165 in the adjuvant chemotherapy group and 164 in the adjuvant CCRT group. The median follow-up was 72.1 months. The three-year PFS rates were both 91.9%, and the five-year OS was 90.6% versus 90.0% in adjuvant chemotherapy and CCRT groups, respectively. No significant differences were observed in the PFS or OS between groups. The adjusted HR for PFS was 0.854 (95% confidence interval 0.415-1.757; P = 0.667) favoring adjuvant chemotherapy, excluding the predefined non-inferiority boundary of 1.9. The chemotherapy group showed a tendency toward good quality of life. In comparison with post-operative adjuvant CCRT, adjuvant chemotherapy treatment showed non-inferior efficacy in patients with early-stage cervical cancer having pathological risk factors. Adjuvant chemotherapy alone is a favorable alternative post-operative treatment.

Human papillomavirus integration perspective in small cell cervical carcinoma.

Small cell cervical carcinoma (SCCC) is a rare but aggressive malignancy. Here, we report human papillomavirus features and genomic landscape in SCCC via high-throughput HPV captured sequencing, whole-genome sequencing, whole-transcriptome sequencing, and OncoScan microarrays. HPV18 infections and integrations are commonly detected. Besides MYC family genes (37.9%), we identify SOX (8.4%), NR4A (6.3%), ANKRD (7.4%), and CEA (3.2%) family genes as HPV-integrated hotspots. We construct the genomic local haplotype around HPV-integrated sites, and find tandem duplications and amplified HPV long control regions (LCR). We propose three prominent HPV integration patterns: duplicating oncogenes (MYCN, MYC, and NR4A2), forming fusions (FGFR3-TACC3 and ANKRD12-NDUFV2), and activating genes (MYC) via the cis-regulations of viral LCRs. Moreover, focal CNA amplification peaks harbor canonical cancer genes including the HPV-integrated hotspots within MYC family, SOX2, and others. Our findings may provide potential molecular criteria for the accurate diagnosis and efficacious therapies for this lethal disease.

Effects of cadmium on oxidative stress and cell apoptosis in Drosophila melanogaster larvae.

With the increase of human activities, cadmium (Cd) pollution has become a global environmental problem affecting biological metabolism in ecosystem. Cd has a very long half-life in humans and is excreted slowly in organs, which poses a serious threat to human health. In order to better understand the toxicity effects of cadmium, third instar larvae of Drosophila melanogaster (Canton-S strain) were exposed to different concentrations (1.125 mg/kg, 2.25 mg/kg, 4.5 mg/kg, and 9 mg/kg) of cadmium. Trypan blue staining showed that intestinal cell damage of Drosophila larvae increased and the comet assay indicated significantly more DNA damage in larvae exposed to high Cd concentrations. The nitroblue tetrazolium (NBT) experiments proved that content of reactive oxygen species (ROS) increased, which indicated Cd exposure could induce oxidative stress. In addition, the expression of mitochondrial adenine nucleotide transferase coding gene (sesB and Ant2) and apoptosis related genes (Debcl, hid, rpr, p53, Sce and Diap1) changed, which may lead to increased apoptosis. These findings confirmed the toxicity effects on oxidative stress and cell apoptosis in Drosophila larvae after early cadmium exposure, providing insights into understanding the effects of heavy metal stress in animal development.

The Ability of Zika virus Intravenous Immunoglobulin to Protect From or Enhance Zika Virus Disease.

The closely related flaviviruses, dengue and Zika, cause significant human disease throughout the world. While cross-reactive antibodies have been demonstrated to have the capacity to potentiate disease or mediate protection during flavivirus infection, the mechanisms responsible for this dichotomy are still poorly understood. To understand how the human polyclonal antibody response can protect against, and potentiate the disease in the context of dengue and Zika virus infection we used intravenous hyperimmunoglobulin (IVIG) preparations in a mouse model of the disease. Three IVIGs (ZIKV-IG, Control-Ig and Gamunex®) were evaluated for their ability to neutralize and/or enhance Zika, dengue 2 and 3 viruses in vitro. The balance between virus neutralization and enhancement provided by the in vitro neutralization data was used to predict the IVIG concentrations which could protect or enhance Zika, and dengue 2 disease in vivo. Using this approach, we were able to define the unique in vivo dynamics of complex polyclonal antibodies, allowing for both enhancement and protection from flavivirus infection. Our results provide a novel understanding of how polyclonal antibodies interact with viruses with implications for the use of polyclonal antibody therapeutics and the development and evaluation of the next generation flavivirus vaccines.

Identification of proteins related with pemetrexed resistance by iTRAQ and PRM-based comparative proteomic analysis and exploration of IGF2BP2 and FOLR1 functions in non-small cell lung cancer cells.

Pemetrexed (PEM), a multi-target folate antagonist, has been extensively used for the treatment of non-small cell lung cancer (NSCLC). However, the therapeutic efficacy of PEM is limited by tumor resistance. In this project, iTRAQ and parallel reaction monitoring (PRM)-based LC-MS/MS comparative proteomic analysis was performed to identify protein determinants of PEM resistance in A549/PEM cells versus A549 parental cells. A total of 567 differentially expressed proteins (DEPs) were identified by iTRAQ analysis. The function and classification of DEPs were analyzed through GO and KEGG Pathway databases. Moreover, PRM analysis further validated the expression changes of 14 DEPs identified by iTRAQ analysis. Moreover, insulin-like growth factor (IGF) 2 mRNA-binding protein 2 (IGF2BP2) or folate receptor alpha (FOLR1) knockdown weakened PEM resistance, reduced cell viability and promoted cell apoptosis in A549/PEM cells. IGF2BP2 depletion inhibited cell migration, invasion and epithelial-mesenchymal transition (EMT), while FOLR1 loss had no much effect on cell migration, invasion and EMT in A549/PEM cells. Our study can provide a deep insight into molecular mechanisms of PEM resistance in NSCLC and contribute to the development of more effective therapeutic schedules. SIGNIFICANCE: Our study can provide deeper insight into molecular mechanisms of PEM resistance in NSCLC and contribute to the development of more effective therapeutic schedules.

RHPN1-AS1 promotes cell proliferation and migration via miR-665/Akt3 in ovarian cancer.

Recent efforts have revealed that long non-coding RNAs exert crucial roles in cancer initiation and progression. RHPN1-AS1 is a 2030 bp transcript from human chromosome 8q24, and involved in tumorigenesis in uveal melanoma and non-small cell lung cancer, but it remains unknown in ovarian cancer. This study focused on the role of RHPN1-AS1 in ovarian cancer and found that RHPN1-AS1 was up-regulated in ovarian cancer tissues and cell lines. Overexpression of RHPN1-AS1 promoted ovarian cancer cell proliferation, migration, and invasion. Mechanistically, overexpression of RHPN1-AS1 decreased the expression of miR-665 and subsequently promoted the expression of Akt3 at posttranscriptional level. Taken together, RHPN1-AS1 positively regulated the expression of Akt3 through sponging miR-665, and exerted an oncogenic role in ovarian cancer progression, and indicates that RHPN1-AS1 may be a potential therapeutic target in ovarian cancer.

MicroRNA-127 Inhibits the Progression of Melanoma by Downregulating Delta-Like Homologue 1.

OBJECTIVE: Melanoma is the most common form of skin cancer with low survival rate and poor prognosis. MicroRNAs (miRNAs) have been reported to play essential roles in progression of melanoma. However, the role and mechanism of miR-127 in the process of melanoma remain poorly understood. METHODS: The expressions of miR-127 and delta-like homologue 1 (DLK1) were measured in melanoma tissues and cells by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. Cell proliferation and apoptosis were measured by MTT assay, flow cytometry, and Western blot. The interaction between miR-127 and DLK1 was investigated by bioinformatics analysis, luciferase activity assay, and RNA immunoprecipitation (RIP). Murine xenograft model was conducted to investigate the effect of miR-127 on tumor growth in vivo. RESULTS: miR-127 was inhibited and DLK1 mRNA was enhanced in melanoma tissues and cells. Low abundance of miR-127 in melanoma tissues predicted a poor prognosis and was associated with the malignant clinicopathological features. Overexpression of miR-127 inhibited cell proliferation and induced apoptosis in melanoma cells. Moreover, DLK1 was targeted by miR-127 and its restoration reversed the regulatory effect of miR-127 on the process of melanoma. Besides, the addition of miR-127 suppressed xenograft tumor growth via suppressing DLK1 protein level in nude mice. CONCLUSION: miR-127 blocked the development of melanoma by targeting DLK1, providing a novel biomarker for the treatment of melanoma.

The PVT1/miR-216b/Beclin-1 regulates cisplatin sensitivity of NSCLC cells via modulating autophagy and apoptosis.

PURPOSE: The efficacy of cisplatin-based chemotherapy remains an open question for chemo-resistance in non-small cell lung cancer (NSCLC). This study aimed to explore the role and mechanism of long noncoding RNA plasmacytoma variant translocation 1 (PVT1) in cisplatin sensitivity of NSCLC. METHODS: Paired tumor and adjacent tissues were collected from forty patients with NSCLC. The clinical value of PVT1 was investigated according to clinicopathological parameters of patients. Cisplatin-sensitive or -resistant cells (A549 or A549/DDP) were used for in vitro experiments. Cell viability, apoptosis, autophagy and animal experiments were conducted to investigate cisplatin sensitivity. The expressions of PVT1, microRNA-216b (miR-216b) and apoptosis- or autophagy-related proteins were measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR) or western blot assay, respectively. Luciferase reporter assay and RNA immunoprecipitation (RIP) assay were conducted to probe the interaction between miR-216b and PVT1 or Beclin-1. RESULTS: PVT1 was highly expressed and associated with poor prognosis of NSCLC patients (*P < 0.05). PVT1 knockdown enhanced cisplatin-induced viability inhibition and apoptosis induction in A549/DDP cells, but addition of PVT1 caused an opposite effect in A549 cells (*P < 0.05, #P < 0.05). Moreover, accumulation of PVT1 facilitated autophagy of NSCLC cells and tumor growth in vivo (*P < 0.05, #P < 0.05). In addition, miR-216b interacted with PVT1 or Beclin-1. Beclin-1 reversed miR-216b-mediated effect on autophagy and apoptosis of NSCLC cells (*P < 0.05,#P < 0.05). Besides, Beclin-1 protein expression was regulated by PVT1 and miR-216b (*P < 0.05, #P < 0.05). CONCLUSIONS: PVT1 may function as a competing endogenous RNA for miR-216b to inhibit cisplatin sensitivity of NSCLC through regulating apoptosis and autophagy via miR-216b/Beclin-1 pathway, providing a novel target for improving chemo-therapy efficacy of NSCLC.

The safety and effectiveness of volumetric magnetic resonance-guided high-intensity focused ultrasound treatment of symptomatic uterine fibroids: early clinical experience in China.

BACKGROUND: Uterine fibroids are the most common benign tumor in women, and surgical intervention is still the main fibroid treatment. Patient demands have encouraged development of less-invasive methods such as high-intensity focused ultrasound (HIFU). This study aimed to evaluate the safety and effectiveness of magnetic resonance-guided high-intensity focused ultrasound therapy using a volumetric ablation technique in the treatment of symptomatic uterine fibroids in China. METHODS: One hundred and seven patients were enrolled and treated with magnetic resonance-guided high-intensity focused ultrasound in this study. Clinical efficacy was based on the proportion of patients with fibroid shrinkage (10 % volume reduction or more compared to baseline) at 6 months post treatment as measured with magnetic resonance imaging. The quality of life and symptom outcome was assessed using the uterine fibroid symptom and quality of life questionnaire with symptom severity scoring. Safety was primarily assessed by evaluating the reported adverse events. RESULTS: Ninety nine of the 107 treated patients had fibroid shrinkage at 6 months post treatment. Resulting in an overall 93 % (95 % confidence interval 86-97 %) treatment success rate, p value <0.001; the symptom severity scoring and health-related quality of life at 6 months was statistically different from the screening symptom severity scoring at 0.05 level. Of 366 adverse events reported, there were no study procedure-related or device-related serious adverse events were in the study. CONCLUSIONS: This study demonstrated that the volumetric magnetic resonance-guided high-intensity focused ultrasound device is safe and technically effective and can be utilized in clinically efficient treatments of symptomatic uterine fibroids. TRIAL REGISTRATION: NCT01588899.

The Stability and Expression Level of Bok Are Governed by Binding to Inositol 1,4,5-Trisphosphate Receptors.

Bok is a member of the Bcl-2 protein family that governs the intrinsic apoptosis pathway, although the role that Bok plays in this pathway is unclear. We have shown previously in cultured cell lines that Bok interacts strongly with inositol 1,4,5-trisphosphate receptors (IP3Rs), suggesting that it may contribute to the structural integrity or stability of IP3R tetramers. Here we report that Bok is similarly IP3R-assocated in mouse tissues, that essentially all cellular Bok is IP3R bound, that it is the helical nature of the Bok BH4 domain, rather than specific amino acids, that mediates binding to IP3Rs, that Bok is dramatically stabilized by binding to IP3Rs, that unbound Bok is ubiquitinated and degraded by the proteasome, and that binding to IP3Rs limits the pro-apoptotic effect of overexpressed Bok. Agents that stimulate IP3R activity, apoptosis, phosphorylation, and endoplasmic reticulum stress did not trigger the dissociation of mature Bok from IP3Rs or Bok degradation, indicating that the role of proteasome-mediated Bok degradation is to destroy newly synthesized Bok that is not IP3R associated. The existence of this unexpected proteolytic mechanism that is geared toward restricting Bok to that which is bound to IP3Rs, implies that unbound Bok is deleterious to cell viability and helps explain the current uncertainty regarding the cellular role of Bok.

Development and validation of a surgical-pathologic staging and scoring system for cervical cancer.

BACKGROUND: Most cervical cancer patients worldwide receive surgical treatments, and yet the current International Federation of Gynecology and Obstetrics (FIGO) staging system do not consider surgical-pathologic data. We propose a more comprehensive and prognostically valuable surgical-pathologic staging and scoring system (SPSs). METHODS: Records from 4,220 eligible cervical cancer cases (Cohort 1) were screened for surgical-pathologic risk factors. We constructed a surgical-pathologic staging and SPSs, which was subsequently validated in a prospective study of 1,104 cervical cancer patients (Cohort 2). RESULTS: In Cohort 1, seven independent risk factors were associated with patient outcome: lymph node metastasis (LNM), parametrial involvement, histological type, grade, tumor size, stromal invasion, and lymph-vascular space invasion (LVSI). The FIGO staging system was revised and expanded into a surgical-pathologic staging system by including additional criteria of LNM, stromal invasion, and LVSI. LNM was subdivided into three categories based on number and location of metastases. Inclusion of all seven prognostic risk factors improves practical applicability. Patients were stratified into three SPSs risk categories: zero-, low-, and high-score with scores of 0, 1 to 3, and ≥4 (P=1.08E-45; P=6.15E-55). In Cohort 2, 5-year overall survival (OS) and disease-free survival (DFS) outcomes decreased with increased SPSs scores (P=9.04E-15; P=3.23E-16), validating the approach. Surgical-pathologic staging and SPSs show greater homogeneity and discriminatory utility than FIGO staging. CONCLUSIONS: Surgical-pathologic staging and SPSs improve characterization of tumor severity and disease invasion, which may more accurately predict outcome and guide postoperative therapy.

Establishing a Nomogram for Stage IA-IIB Cervical Cancer Patients after Complete Resection.

BACKGROUND: This study aimed to establish a nomogram by combining clinicopathologic factors with overall survival of stage IA-IIB cervical cancer patients after complete resection with pelvic lymphadenectomy. MATERIALS AND METHODS: This nomogram was based on a retrospective study on 1,563 stage IA-IIB cervical cancer patients who underwent complete resection and lymphadenectomy from 2002 to 2008. The nomogram was constructed based on multivariate analysis using Cox proportional hazard regression. The accuracy and discriminative ability of the nomogram were measured by concordance index (C-index) and calibration curve. RESULTS: Multivariate analysis identified lymph node metastasis (LNM), lymph-vascular space invasion (LVSI), stromal invasion, parametrial invasion, tumor diameter and histology as independent prognostic factors associated with cervical cancer survival. These factors were selected for construction of the nomogram. The C-index of the nomogram was 0.71 (95% CI, 0.65 to 0.77), and calibration of the nomogram showed good agreement between the 5-year predicted survival and the actual observation. CONCLUSIONS: We developed a nomogram predicting 5-year overall survival of surgically treated stage IA-IIB cervical cancer patients. More comprehensive information that is provided by this nomogram could provide further insight into personalized therapy selection.

Functional-segregated coumarin-containing telodendrimer nanocarriers for efficient delivery of SN-38 for colon cancer treatment.

Four coumarin-containing telodendrimers (denoted as P-I, P-II, P-III and P-IV) were designed and synthesized to self-assemble into the corresponding nanoparticles. Of those, two nanoparticles (P-II and P-IV micelles) were screened and selected for targeted drug delivery of 7-ethyl-10-hydroxy camptothecin (SN-38), a prominent and efficacious anticancer agent, for the treatment of colon cancers. The nanoparticle encapsulation significantly increased the solubility of SN-38 in aqueous solution. Dynamic light scattering (DLS) showed the size of these SN-38 nanoparticles to be around 50 nm, and rod-shaped micelles were observed using transmission electron microscopy (TEM). These two novel nanoformulations of SN-38/P-II and SN-38/P-IV were found to exhibit similar in vitro cytotoxic activity against colon cancer cells as the free drug (SN-38 in DMSO) and were 500-fold more potent than irinotecan (a prodrug of SN-38). In addition, near infrared fluorescent (NIRF) optical imaging was utilized to monitor the tumor targeted delivery of SN-38/NPs via co-loading a NIRF dye. It was demonstrated that these NPs preferentially accumulated in tumors when compared to healthy tissue. A pharmacokinetics study showed that SN-38 micelle formulations had a longer circulating time in blood than irinotecan. Furthermore, SN-38 loaded nanoformulations exhibit superior anti-tumor efficacy when compared with irinotecan at equivalent SN-38 dose in HT-29 human colon cancer xenograft models.

Knockdown of S100A11 expression suppresses ovarian cancer cell growth and invasion.

As a member of the S100 protein family, S100A11 expression is often upregulated in human cancer tissues. Numerous studies have demonstrated that S100A11 plays an important role in the progression of cancer. However, the function of S100A11 in ovarian cancer remains elusive. In the present study, the expression levels of S100A11 were found to be significantly increased in ovarian cancer cells. Subsequently, the expression of S100A11 in ovarian cancer HO8910 cells was knocked down using short hairpin (sh)RNA in order to investigate the biological effects of S100A11 on the progression of the disease. The results demonstrated that knockdown of S100A11 by shRNA inhibited the proliferation, anchorage-independent growth, invasion and migration of HO8910 cells. In addition, knockdown of S100A11 increased the expression of E-cadherin and decreased the expression of Snail in HO8910 cells. Collectively, these results indicated that S100A11 was able to promote the growth, invasion and migration of ovarian cancer cells. Therefore, S100A11 may serve as a potential molecular target for the diagnosis and treatment of ovarian cancer.

An ovarian cancer model with positive ER: Reversion of ER antagonist resistance by Src blockade.

Approximately 60% of ovarian cancers are positive for the estrogen receptor (ER); however, ER-targeted treatment is disappointing due to drug resistance as compared with breast cancer. In estrogen-sensitive cancers, estrogen activates Src to phosphorylate p27 promoting its degradation and increasing cell cycle progression. Since Src is frequently activated in ovarian cancers, we investigated whether combined Src and ER blockade by saracatinib and fulvestrant would circumvent anti-estrogen resistance. In 20 out of 40 enrolled patients with immunohistochemically ER-positive ovarian cancer, phosphorylated Src (p-Src) at the site of 416 tyrosine was expressed with a propensity for metastasis and a poorer disease-free survival (DFS) at 3 years following ER antagonist treatment. The effects of ER and Src blockade on cell cycle were assayed in estrogen receptor α (ERα)-positive ovarian cancer. We observed that Src activity was fairly greater in anti-estrogen-resistant ovarian cancer cells than that in the anti-estrogen-sensitive cell line. Estrogen activated Src via ER-Src binding and ER translocation from cytoplasm to nucleus. Mitogenesis was mediated via ERα, not ERß. Combined saracatinib and fulvestrant increased p27 and inhibited cell cycle progression. Furthermore, dual therapy induced autophagy and inhibited ovarian cancer xenograft growth more effectively than monotherapy. Saracatinib facilitated the therapeutic effects of fulvestrant by antagonizing the estrogen-mediated Src activation. These are supportive of further preclinical assessment of combined fulvestrant and saracatinib in patients with ovarian cancer.

A genome-wide association study identifies two new cervical cancer susceptibility loci at 4q12 and 17q12.

To identify new genetic risk factors for cervical cancer, we conducted a genome-wide association study in the Han Chinese population. The initial discovery set included 1,364 individuals with cervical cancer (cases) and 3,028 female controls, and we selected a 'stringently matched samples' subset (829 cases and 990 controls) from the discovery set on the basis of principal component analysis; the follow-up stages included two independent sample sets (1,824 cases and 3,808 controls for follow-up 1 and 2,343 cases and 3,388 controls for follow-up 2). We identified strong evidence of associations between cervical cancer and two new loci: 4q12 (rs13117307, Pcombined, stringently matched=9.69×10(-9), per-allele odds ratio (OR)stringently matched=1.26) and 17q12 (rs8067378, Pcombined, stringently matched=2.00×10(-8), per-allele ORstringently matched=1.18). We additionally replicated an association between HLA-DPB1 and HLA-DPB2 (HLA-DPB1/2) at 6p21.32 and cervical cancer (rs4282438, Pcombined, stringently matched=4.52×10(-27), per-allele ORstringently matched=0.75). Our findings provide new insights into the genetic etiology of cervical cancer.

Development of a novel class of tubulin inhibitors with promising anticancer activities.

UNLABELLED: We have developed a novel class (2-amino-4-phenyl-4H-chromene-3-carboxylate) of inhibitors of tubulin assembly by modifying HA14-1, which is a Bcl-2 inhibitor discovered by our group. Three of these compounds, mHA1, mHA6, and mHA11, showed in vitro cytotoxicities against tumor cells that were more potent and more stable than the backbone compound HA14-1, with nM IC50 values. In contrast, the cytotoxic effects of these compounds on normal cells were minimal. Computational docking, colchicine-tubulin competitive binding, and tubulin polymerization studies demonstrated that these compounds bind at the colchicine-binding site on tubulin and inhibit the formation of microtubules. Treatment of HL-60/Bcl-2 leukemia and CRL5908 lung cancer cells with these mHA compounds led to pronounced microtubule density decreases, G2/M cell cycle arrest, and apoptosis, as determined by immunofluorescence microscopy, flow cytometry, and DNA fragmentation analysis. Combined, these data identify a novel class of compounds that inhibit tubulin assembly and limit cancer cell phenotypes. IMPLICATIONS: This study supports the continued development of novel anti-tubulin assembly inhibitors as potential anticancer agents.

Development of criteria for ovarian preservation in cervical cancer patients treated with radical surgery with or without neoadjuvant chemotherapy: a multicenter retrospective study and meta-analysis.

BACKGROUND: There is no consensus on the selection criteria for ovarian preservation in cervical cancer, and the role of neoadjuvant chemotherapy (NACT) on ovarian metastasis (OM) is also unknown. METHODS: A total of 1,889 cervical cancer patients with International Federation of Gynecology and Obstetrics (FIGO) stages IB to IIB who underwent radical hysterectomy, pelvic lymphadenectomy, and bilateral salpingo-oophorectomy with or without NACT were enrolled. Clinicopathologic variables were studied by univariate and multivariate analyses. Meta-analyses of published data for risk factors of OM were also performed. RESULTS: Twenty-two (1.2%) of 1,889 patients were diagnosed as OM: 12 squamous cell carcinomas (SCC, 0.7%), five adenocarcinomas (2.7%), four adenosquamous carcinomas (5.6%), and one small cell carcinoma (7.7%). Multivariate analysis revealed that lymph node metastasis (LNM; odds ratio 5.75, 95% confidence interval 2.16-15.28), corpus uteri invasion (CUI; 5.53, 2.11-14.53), parametrial invasion (PMI; 8.24, 3.01-22.56), and histology and NACT (0.40, 0.13-1.22) were associated with OM. Furthermore, OM in patients with SCC was associated with PMI (5.67, 1.63-19.72), CUI (3.25, 0.88-12.01), and LNM (9.44, 2.43-36.65). FIGO stage (IIB vs. IB; 31.78, 1.41-716.33), bulky tumor size (12.71, 1.31-123.68), PMI (51.21, 4.10-639.19), NACT (0.003, 0.00-0.27), and CUI (44.49, 2.77-714.70) were independent clinicopathologic factors for OM in adenocarcinomas. In the meta-analysis, we identified six risk factors for OM: LNM, CUI, PMI, adenocarcinoma, large tumor size, and lymphovascular space involvement. CONCLUSIONS: Ovarian preservation surgery may be safe in SCC patients without suspicious LNM, PMI, and CUI, and in adenocarcinomas in patients who received NACT without FIGO stage IIB disease, bulky tumor size (>4 cm), suspicious PMI, and CUI.