Long-term GnRH agonist pretreatment before frozen embryo transfer improves pregnancy outcomes in women with adenomyosis.

RESEARCH QUESTION: Do frozen embryo transfer (FET) cycles following long-term gonadotrophin-releasing hormone agonist (GnRHa) pretreatment have better pregnancy outcomes than fresh embryo transfer cycles with long or ultra-long GnRHa protocol in these patients? DESIGN: This study included 537 women with adenomyosis divided into three groups: (Group A) FET cycles following long-term GnRHa pretreatment (192 patients); (Group B) fresh embryo transfer cycles with the ultra-long GnRHa protocol (241 patients); (Group C) fresh embryo transfer cycles with the long GnRHa protocol (104 patients). RESULTS: The total gonadotrophin dose and stimulation duration were significantly lower in Group A than in Groups B and C. The implantation and live birth rates were significantly higher in Group A than in Groups B and C. In the long-term GnRHa pretreatment and FET treatment of Group A, implantation (odds ratio [OR] 1.729, 95% confidence interval [CI] 1.073-2.788, P = 0.025), clinical pregnancy (OR 1.665, 95% CI 1.032-2.686, P = 0.037) and live birth rates (OR 1.694, 95% CI 1.045-2.746, P = 0.033) increased and miscarriage rate (OR 0.203, 95% CI 0.078-0.530, P = 0.001) decreased when compared with Group C. Comparison of Groups A and B showed that with the long-term GnRHa pretreatment, FET was a protective factor for live birth rate (OR 1.350, 95% CI 1.017-1.792, P = 0.038). CONCLUSION: FET following long-term GnRHa pretreatment has a better IVF/intracytoplasmic sperm injection outcome, and a potential benefit in terms of a lower gonadotrophin dose, and a shorter stimulation duration than fresh embryo transfer combined with a long or ultra-long GnRHa protocol.

Long noncoding RNA AK023096 interacts with hnRNP-K and contributes to the maintenance of self-renewal in bladder cancer stem-like cells.

LncRNA contribution to self-renewal of bladder cancer stem-like cells (CSLCs) remains largely unknown. We investigated the expression profile and biological function of lncRNAs in urothelial CSLCs by microarray analysis. Among these, lncRNA-AK023096 was identified as potentially playing a role in maintaining self-renewal of CSLCs. Knockdown of this transcript inhibited spheroid formation and tumor formation. We found that AK023096 mediates recruitment of hnRNP-K to SOX2 promoter and increases H3K4 trimethylation status on SOX2 promoter, leading to a robust change in SOX2 mRNA and protein levels. Moreover, AK023096 expression in primary tumors was found to be a powerful predictor of recurrence following transurethral resection in patients with nonmuscle-invasive bladder cancer, highlighting the critical role of lncRNA in the bladder cancer regulatory network.

A nomogram prognostic index for risk-stratification in diffuse large B-cell lymphoma in the rituximab era: a multi-institutional cohort study.

BACKGROUND: We aimed to establish a predictive prognostic risk-stratification model for diffuse large B-cell lymphoma (DLBCL) in the rituximab era. METHODS: The data of 1406 primary DLBCL patients from the Sun Yat-Sen University Cancer Center were analysed to establish a nomogram prognostic index (NPI) model for predicting overall survival (OS) based on pre-treatment indicators. An independent cohort of 954 DLBCL patients from three other hospitals was used for external validation. RESULTS: Age, performance status, stage, lactate dehydrogenase, number of extranodal sites, BCL2, CD5 expression, B symptoms and absolute lymphocyte and monocyte count were the main factors of the NPI model and could stratify the patients into four distinct categories based on their predicted OS. The calibration curve demonstrated satisfactory agreement between the predicted and actual 5-year OS of the patients. The concordance index of the NPI model (0.794) was higher than the IPI (0.759) and NCCN-IPI (0.750), and similar results were obtained upon external validation. For CD5 + DLBCL patients, systemic treatment with high-dose methotrexate was associated with superior OS compared to R-CHOP-based immunochemotherapy alone. CONCLUSIONS: We established and validated an accurate prediction model, which performed better than IPI and NCCN-IPI for prognostic stratification of DLBCL patients.

Upfront autologous stem cell transplantation for untreated diffuse large B cell lymphoma patients in rituximab era: a systematic review and meta-analysis.

To assess the survival outcomes and adverse events (AEs) of high-intermediate- or high-risk patients with diffuse large B cell lymphoma (DLBCL) who underwent conventional chemotherapy plus rituximab with or without first-line autologous stem cell transplantation (ASCT). Related studies published on Medline, Embase, Cochrane Library, and Web of science were searched, comprising both retrospective and randomized clinical trials (RCTs). The primary endpoints were overall survival (OS) and progression-free survival (PFS). The meta-analysis was performed using the software RevMan v5.3. Four RCTs and six retrospective trials with a total of 1811 patients were identified. Pooled data indicated that conventional chemotherapy plus rituximab followed by ASCT as the first-line therapy contributed to better PFS (HR = 0.73, 95% CI 0.62-0.86, p = 0.0002) but did not significantly improve OS (HR = 0.74, 95% CI 0.55-1.01, p = 0.06) of high-intermediate/high-risk patients. Subgroup analyses of patients with complete remission after induction chemotherapy may benefit from the upfront ASCT (OS, HR = 0.48, 95% CI 0.28-0.82, p = 0.008). The incidences of grade ≥ 3 hematological and non-hematological AEs occurred more frequently in the transplantation group. High-intermediate or high-risk untreated patients with DLBCL only achieved short-term survival benefit with the upfront ASCT.

Heterogeneous nuclear ribonucleoprotein K is associated with poor prognosis and regulates proliferation and apoptosis in bladder cancer.

Heterogeneous nuclear ribonucleoprotein K (hnRNPK) is an essential RNA- and DNA-binding protein that regulates diverse biological events, especially DNA transcription. hnRNPK overexpression is related to tumorigenesis in several cancers. However, both the expression patterns and biological mechanisms of hnRNPK in bladder cancer are unclear. We investigated hnRNPK expression by immunohistochemistry in 188 patients with bladder cancer, and found that hnRNPK expression levels were significantly increased in bladder cancer tissues and that high-hnRNPK expression was closely correlated with poor prognosis. Loss- and gain-of-function assays demonstrated that hnRNPK promoted proliferation, anti-apoptosis, and chemoresistance in bladder cancer cells in vitro, and hnRNPK knockdown suppressed tumorigenicity in vivo. Mechanistically, hnRNPK regulated various functions in bladder cancer by directly mediating cyclin D1, G0/G1 switch 2 (G0S2), XIAP-associated factor 1, and ERCC excision repair 4, endonuclease catalytic subunit (ERCC4) transcription. In conclusion, we discovered that hnRNPK plays an important role in bladder cancer, suggesting that it is a potential prognostic marker and a promising target for treating bladder cancer.

Polycystic ovary syndrome is associated with anogenital distance, a marker of prenatal androgen exposure.

Study question: Is the presence of polycystic ovary syndrome (PCOS) associated with anogenital distance (AGD), a biomarker for the prenatal hormonal environment? Summary answer: The presence of PCOS is associated with longer AGD. What is known already: Although the aetiology of PCOS is unclear, emerging data suggest that the natural history of PCOS may originate from intrauterine life. Prenatal exposure to androgen hormones is considered an important factor of PCOS. AGD is the distance measured from the anus to the genital tubercle and there is considerable evidence in humans and animals to support AGD as a sensitive biomarker of prenatal androgen activity. Study design, size, duration: This case-control study of 156 PCOS patients and 180 reproductively healthy women (control subjects) was performed from October 2015 to July 2016. Participants/materials, setting, methods: The patients and controls were recruited from the out-patient Department of Gynecology of Sun Yat-sen Memorial Hospital. Participants completed health questionnaires and provided a blood sample for evaluation of serum reproductive hormone profiles. Anthropometric indices of AGDAF (anus-fourchette) and AGDAC (anus-clitoris) were measured in all subjects. We used logistic regression to estimate the association between the presence of PCOS and AGD measurements while accounting for important confounders, including age and BMI. Multiple linear regression was used to analyse the relationships between PCOS characteristics (e.g. polycystic ovaries and total testosterone (T)) and two measurements of AGD in the PCOS group and controls. Main results and the role of chance: Overall, logistic regression showed that women with AGDAF in the highest tertile were 18.8 times (95% CI 9.6-36.6; P < 0.001) more likely to have PCOS compared with those in the lowest tertile. Women with AGDAC in the highest tertile were 6.7 times (95% CI 3.7-12.1; P < 0.001) more likely to have PCOS than those in the lowest tertile. In the PCOS group, multiple linear regression analyses revealed that both AGD measurements were positively associated with T levels (ß = 0.246 for AGDAC, ß = 0.368 for AGDAF; P = 0.003 and P < 0.001, respectively), and AGDAF was positively associated with the presence of polycystic ovaries (ß = 0.279; P < 0.001). In the controls, a positive association was found only between T levels with AGDAF (ß = 0.177, P = 0.020), whereas no associations were found between the remaining covariates and AGD measurements. Limitations, reasons for caution: As this was an observational study, causal inference cannot be obtained. Wider implications of the findings: This study suggests that PCOS may originate in intrauterine life, and be affected by prenatal exposure to androgens. Study funding/competing interest(s): This study was supported by funds obtained from the Science Technology Research Project of Guangdong Province (2010B031600058 and 2015A030310083) and the Major Science Technology Research Project of Guangdong Province (ZKM05602S). The authors have no competing interests to declare. Trial registration number: Not applicable.

An NKX3.1 binding site polymorphism in the l-plastin promoter leads to differential gene expression in human prostate cancer.

The L-plastin gene is involved in the invasion and metastasis of prostate cancer. However, the molecular mechanisms underlying L-plastin transcription are unclear. We hypothesize that the occurrence of polymorphic genetic variations in the L-plastin promoter might affect an individual's susceptibility to prostate cancer. In this study, we identified a single nucleotide polymorphism (SNP) at position -1,687 in the L-plastin promoter by genotype sequencing. The SNP -1,687 showed different transcriptional activity in the luciferase assay in vitro. The TRANSFAC software was applied to predict the multiple cis-elements, and luciferase assay was used to further identify the L-plastin regulatory region. We performed EMSAs, supershift assays and ChIP-qPCR demonstrated that the transcriptional suppressor NKX3.1 binds to the SNP site of the L-plastin promoter. SNP -1,687 (T/T) led to an increase in the affinity of NKX3.1 for L-plastin promoter, resulted in lower levels of L-plastin RNA and protein expression. Furthermore, we collected and sequenced samples from 640 individuals (372 prostate cancer patients and 268 healthy controls) from 2000 to 2013. The results showed that SNP -1,687 (T/T) occurred more frequently in the healthy individuals than that in the prostate cancer patients compared to SNP -1,687 (C/C). Similarly, SNP -1,687 (T/T) genotype occurred more frequently compared to SNP -1,687 (C/C) genotype in the patients with low and moderately differentiated tumors. In conclusion, SNP -1,687, located in the NKX3.1 binding site within the L-plastin promoter, might reduce the expression of L-plastin and potentially decrease the tumorigenesis and progression of prostate cancer. This SNP could be a potential prognostic factor for prostate cancer.

Methylation of neurofilament light polypeptide promoter is associated with cell invasion and metastasis in NSCLC.

The role of NEFL in NSCLC remains largely unknown. Immunohistochemistry was performed to investigate the expression of NEFL in 108 lung cancer specimens. NEFL expression was associated with decreased lymph node metastases and favorable prognosis. Furthermore, real-time PCR and Western blot were used to investigate the expression of the NEFL gene in NSCLC cell lines. Subsequently, lentivirus-mediated RNA interference and overexpression were used to demonstrate that knocked-down of NEFL enhanced the invasion and migration of A549 and H460 NSCLC cells, whereas NEFL overexpression resulted in a suppression of the invasion and migration of GLC-82 and L78 cells in vitro. In addition, bisulfite sequence PCR assay demonstrated that NEFL downregulation was associated with promoter methylation, and NEFL expression was restored after treatment with 5-Aza-dC. Finally, we demonstrated that NEFL inhibited the NF-κB pathway, thereby suppressing the expression of uPA and decreasing NSCLC invasiveness and migration. Our studies suggest that NEFL methylation is a novel mechanism for NSCLC invasion and metastasis and that NEFL may represent a candidate biomarker for recurrence and survival in patients with NSCLC.

lncRNA Up-Regulated in Nonmuscle Invasive Bladder Cancer Facilitates Tumor Growth and Acts as a Negative Prognostic Factor of Recurrence.

PURPOSE: While lncRNAs (long noncoding RNAs) have been shown to have critical regulatory roles in cancer biology, the biological functions and prognostic values in nonmuscle invasive bladder cancer remain largely unknown. We identified a lncRNA termed lncRNA-UNMIBC (up-regulated in nonmuscle invasive bladder cancer) and evaluated its prognostic value in patients with primary nonmuscle invasive bladder cancer. MATERIALS AND METHODS: We analyzed the expression of lncRNA-UNMIBC in the tissues of 75 cases of primary nonmuscle invasive bladder cancer and adjacent normal mucosa by quantitative real-time polymerase chain reaction. Data were compared with clinicopathological parameters using the Kaplan-Meier method and multivariate Cox regression analysis. The functions of lncRNA-UNMIBC were assessed by silencing the lncRNA in vitro and in vivo. RNA immunoprecipitation was performed to assay whether lncRNA-UNMIBC could be physically associated with EZH2 (enhancer of zeste homolog 2) and SUZ12 (SUZ12 polycomb repressive complex 2 subunit), which are core components of PRC2 (polycomb repressive complex 2). Chromatin immunoprecipitation was done to examine histone modification status. RESULTS: The expression level of lncRNA-UNMIBC was up-regulated in the tissues of 45 cases of primary nonmuscle invasive bladder cancer compared with normal mucosa. Kaplan-Meier estimates showed that lncRNA-UNMIBC expression was significantly associated with recurrence (log rank test p = 0.0151). We also found that lncRNA-UNMIBC had a key role in G0/G1 arrest. Furthermore, RNA and chromatin immunoprecipitation assays demonstrated that lncRNA-UNMIBC was physically associated with EZH2 and SUZ12, leading to an altered histone H3 lysine 27 methylation status of target genes. CONCLUSIONS: These findings indicate that lncRNA-UNMIBC can facilitate tumor growth and may act as a negative prognostic factor of recurrence.

linc-UBC1 physically associates with polycomb repressive complex 2 (PRC2) and acts as a negative prognostic factor for lymph node metastasis and survival in bladder cancer.

OBJECTIVES: The human genome encodes many long intergenic noncoding RNAs (lincRNAs). However, their biological functions, molecular mechanisms and prognostic values associated with bladder cancer remain to be elucidated. Here we investigated a lincRNA termed linc-UBC1 (Up-regulated in bladder cancer 1) and evaluated its prognostic value in bladder cancer patients. MATERIALS AND METHODS: Expression of linc-UBC1 was evaluated by quantitative reverse transcription PCR (qRT-PCR) in 102 bladder cancer tissue samples and normal adjacent tissues. The functions of linc-UBC1 on cell proliferation, migration, invasion, colony formation, tumorigenicity and metastatic potential were evaluated by knockdown strategy in vitro and in vivo. RNA immunoprecipitation (RIP) was performed to confirm that linc-UBC1 physically associates with EZH2 and SUZ12, core components of polycomb repressive complex 2 (PRC2). Chromatin immunoprecipitation (ChIP) was conducted to examine histone modification status. RESULTS: qRT-PCR confirmed that linc-UBC1 expression is up-regulated in 60 cases (58.8%) in bladder cancer tissues compared with normal adjacent tissues, and its overexpression correlates with lymph node metastasis and poor survival. Further functional analysis demonstrated that knockdown of linc-UBC1 attenuates bladder cancer cell proliferation, motility, invasion, colony formation ability, tumorigenicity and metastatic potential. Importantly, the inhibitory effect of linc-UBC1 on cell proliferation was also observed in primary bladder cancer cells obtained from patients. RIP and ChIP assay confirmed that linc-UBC1 physically associates with PRC2 complex and regulates histone modification status of target genes. CONCLUSIONS: Frequently overexpressed linc-UBC1 physically associates with PRC2 complex, and acts as a negative prognostic factor for lymph node metastasis and survival in bladder cancer.

Up-regulated microRNA-143 in cancer stem cells differentiation promotes prostate cancer cells metastasis by modulating FNDC3B expression.

BACKGROUND: Metastatic prostate cancer is a leading cause of cancer-related death in men. Cancer stem cells (CSCs) are involved in tumor progression and metastasis, including in prostate cancer. There is an obvious and urgent need for effective cancer stem cells specific therapies in metastatic prostate cancer. MicroRNAs (miRNAs) are an important class of pervasive genes that are involved in a variety of biological functions, especially in cancer. The goal of this study was to identify miRNAs involved in prostate cancer metastasis and cancer stem cells. METHODS: A microarray and qRT-PCR were performed to investigate the miRNA expression profiles in PC-3 sphere cells and adherent cells. A transwell assay was used to evaluate the migration of PC-3 sphere cells and adherent cells. MiR-143 was silenced with antisense oligonucleotides in PC-3, PC-3-M and LNCaP cells. The role of miR-143 in prostate cancer metastasis was measured by wound-healing and transwell assays in vitro and bioluminescence imaging in vivo. Bioinformatics and luciferase report assays were used to identify the target of miR-143. RESULTS: The expression of miR-143 and the migration capability were reduced in PC-3 sphere cells and progressively increased during sphere re-adherent culture. Moreover, the down-regulation of miR-143 suppressed prostate cancer cells migration and invasion in vitro and systemically inhibited metastasis in vivo. Fibronectin type III domain containing 3B (FNDC3B), which regulates cell motility, was identified as a target of miR-143. The inhibition of miR-143 increased the expression of FNDC3B protein but not FNDC3B mRNA in vitro and vivo. CONCLUSIONS: These data demonstrate for the first time that miR-143 was up-regulated during the differentiation of prostate cancer stem cells and promoted prostate cancer metastasis by repressing FNDC3B expression. This sheds a new insight into the post-transcriptional regulation of cancer stem cells differentiation by miRNAs, a potential approach for the treatment of prostate cancer.

Ordinal Regression With Pinball Loss.

Ordinal regression (OR) aims to solve multiclass classification problems with ordinal classes. Support vector OR (SVOR) is a typical OR algorithm and has been extensively used in OR problems. In this article, based on the characteristics of OR problems, we propose a novel pinball loss function and present an SVOR method with pinball loss (pin-SVOR). Pin-SVOR is fundamentally different from traditional SVOR with hinge loss. Traditional SVOR employs the hinge loss function, and the classifier is determined by only a few data points near the class boundary, called support vectors, which may lead to a noise sensitive and re-sampling unstable classifier. Distinctively, pin-SVOR employs the pinball loss function. It attaches an extra penalty to correctly classified data that lies inside the class, such that all the training data is involved in deciding the classifier. The data near the middle of each class has a small penalty, and that near the class boundary has a large penalty. Thus, the training data tend to lie near the middle of each class instead of on the class boundary, which leads to scatter minimization in the middle of each class and noise insensitivity. The experimental results show that pin-SVOR has better classification performance than state-of-the-art OR methods.

Estrogen-increased SGK1 Promotes Endometrial Stromal Cell Invasion in Adenomyosis by Regulating with LPAR2.

Adenomyosis is an estrogen-dependent gynecological disorder. The abnormal migration and invasion of the eutopic endometrium is thought to be the primary role in the pathogenesis of adenomyosis. However, the exact underlying mechanism remains unclear. This study investigated involvement of serum and glucocorticoid-regulated kinase 1 (SGK1) in the pathogenesis of adenomyosis. The SGK1 expression level was higher in the eutopic endometrium of adenomyosis. Upregulation of SGK1 can promote the migration, invasion of human stromal endometrial cells (HESC). Through RNA sequencing and other technical methods, we found that SGK1 regulates the expression of the important downstream molecule Lysophosphatidic acid receptor 2 (LPAR2), and ultimately regulates the expression level of functional proteins such as matrix metalloproteinase 2 and matrix metalloproteinase 9, which are related to migration and invasion. Then, we found that 17ß-estradiol (E2) upregulated the expression of SGK1 in endometrial cells in a dose-dependent manner. Furthermore, SGK1 shRNA significantly suppressed the migration and invasion induced by E2 in endometrial cells, as well as the related factors. Our study revealed the possible role of SGK1 in the migration and invasion in the development of adenomyosis.

Pelvic reconstruction and lateral prostate capsule sparing techniques improve early continence of robot-assisted radical cystectomy with orthotopic ileal neobladder.

PURPOSE: To evaluate urinary outcomes of pelvic construction and lateral capsule sparing techniques in robot-assisted radical cystectomy with orthotopic ileal neobladder (RARC-OIN). METHODS: A total of 107 male patients who underwent RARC-OIN during January 2017 and February 2021 in Sun Yat-sen Memorial Hospital were analyzed retrospectively. Standard RARC-OIN with or without nerve sparing technique was performed in 44 patients (standard group), lateral prostate capsule sparing technique was performed in 20 patients (LCS group), combined pelvic reconstruction (CPR) technique including anterior suspension and posterior reconstruction were performed in 43 patients (CPR group). The urinary function was assessed by the use of pads and the Bladder Cancer Index (BCI). Continence was defined as the use of 0-1 pad during daytime or night-time. RESULTS: There was no statistical difference between the three groups regarding demographic, perioperative, and pathological data. Continence rates were 6.8, 50.0 and 34.9% for daytime, 4.6, 40.0 and 32.6% for night-time in the standard group, LCS group and CPR group at 1 month post-operation, respectively. Continence rates were 34.1, 80.0 and 69.8% for daytime, 27.3, 75.0 and 65.1% for night-time in the standard group, LCS group and CPR group at 3 month post-operation, respectively. No statistically significant difference was observed in the daytime and night-time continence rates at 12 months. CONCLUSIONS: Lateral capsule-sparing and combined pelvic reconstruction techniques are feasible to improve early daytime and night-time continence rates in RARC with orthotopic neobladder. CLINICAL TRIAL REGISTRATION: The trial registration number: ChiCTR2100047606.

Migraine Is More Prevalent in Advanced-Stage Endometriosis, Especially When Co-Occuring with Adenomoysis.

Background: Emerging data suggest a significant association between migraine and endometriosis, however the relationship between migraine and endometriosis severity or adenomyosis is unclear. Our objectives were to explore the relationship between migraine and endometriosis, according to the endometriosis severity and co-exist with adenomyosis or not. Methods: This case-control study of 167 endometriosis patients verified by surgery and 190 patients for other benign gynecological conditions (control subjects) was performed from September 2017 and January 2021. There is 49 adenomyosis detected by transvaginal ultrasound or histologic diagnosis among the endometriosis patients. Besides, we also included 41 adenomyosis but without endometriosis patients as a subgroup. All women completed a self-administered headache questionnaire and diagnosed as migraine according to the International Headache Society classification. The severity and stage of endometriosis was evaluated with revised American Society of Reproductive Medicine (rASRM) score. We used logistic regression to estimate the association between the presence of migraine and endometriosis severity while accounting for important confounders, including age, body mass index (BMI) and family history of migraine. We also estimate the risk of adenomyosis alone and adenomyosis with co-occurring endometriosis in migrainous women. Results: Migraine was significantly more prevalent in endometriosis patients compared with controls (29.9% vs. 12.1%, p<0.05), but the prevalence was similar between isolated adenomyosis patients and controls (9.8% vs.12.1%, p>0.05). For all endometriosis and control participants, migraineurs were 4.6-times (OR=4.6; 95% CI 2.7-8.1) more likely to have severe endometriosis. However, the strength of the association decreased when the analysis examined in moderate stage (OR=3.6, 95% CI 2.1-6.2). The risk of mild and minimal endometriosis was not significant (OR=1.9, 95%CI 0.9-4.0; OR=1.6, 95% CI 0.8-3.4; respectively). When we divided the endometriosis patients according to whether co-occurring with adenomyosis. We found in migrainous women, the risk of endometriosis co-exist with adenomyosis increased, with nearly fivefold greater odds compared with control (OR=5.4;95% CI 3.0-9.5), and nearly two times higher than the risk of endometriosis without co-exist adenomyosis patients (OR=2.2; 95% CI 1.2-3.8). Conclusion: Our study supports the strong association between migraine and endometriosis. We found migrainous women suffer more frequently from sever endometriosis, especially endometriosis with co-occurring adenomyosis. It is advisable to heighten suspicion for patients who presenting with either these conditions in order to optimize therapy.

Systemic chemotherapy and sequential locoregional radiotherapy in initially metastatic nasopharyngeal carcinoma: Retrospective analysis with 821 cases.

BACKGROUND: We designed this retrospective study to explore the best treatment modality for patients with initially metastatic nasopharyngeal carcinoma (NPC). METHODS: From 2008 to 2017, 821 patients were enrolled. Treatment modalities and prognostic factors were analyzed. RESULTS: Compared with chemotherapy alone and radiotherapy-based treatment, systemic chemotherapy-sequential locoregional radiotherapy to the nasopharyngeal primary tumor site were associated with a significantly increased 3-year overall survival (OS) rate (40.3%, 11.7%, and 22.9%, P < .001). The overall response rate of the paclitaxel combined with platinum and fluorouracil (TPF) regimen as first-line chemotherapy was higher than that of the paclitaxel plus platinum (TP) regimen (78.2% vs 70.0%, P = .038). A better OS was achieved in the TPF group compared to doublet drug regimens (3-year OS, 35.7% vs 25.3%, P < .001). CONCLUSIONS: Systemic chemotherapy-sequential locoregional radiotherapy may prolong OS and progression-free survival for selected patients with initially metastatic NPC.

Exosomal long noncoding RNA LNMAT2 promotes lymphatic metastasis in bladder cancer.

Patients with bladder cancer (BCa) with clinical lymph node (LN) metastasis have an extremely poor prognosis. VEGF-C has been demonstrated to play vital roles in LN metastasis in BCa. However, approximately 20% of BCa with LN metastasis exhibits low VEGF-C expression, suggesting a VEGF-C-independent mechanism for LN metastasis of BCa. Herein, we demonstrate that BCa cell-secreted exosome-mediated lymphangiogenesis promoted LN metastasis in BCa in a VEGF-C-independent manner. We identified an exosomal long noncoding RNA (lncRNA), termed lymph node metastasis-associated transcript 2 (LNMAT2), that stimulated human lymphatic endothelial cell (HLEC) tube formation and migration in vitro and enhanced tumor lymphangiogenesis and LN metastasis in vivo. Mechanistically, LNMAT2 was loaded to BCa cell-secreted exosomes by directly interacting with heterogeneous nuclear ribonucleoprotein A2B1 (hnRNPA2B1). Subsequently, exosomal LNMAT2 was internalized by HLECs and epigenetically upregulated prospero homeobox 1 (PROX1) expression by recruitment of hnRNPA2B1 and increasing the H3K4 trimethylation level in the PROX1 promoter, ultimately resulting in lymphangiogenesis and lymphatic metastasis. Therefore, our findings highlight a VEGF-C-independent mechanism of exosomal lncRNA-mediated LN metastasis and identify LNMAT2 as a therapeutic target for LN metastasis in BCa.

Downregulation of long noncoding RNA FENDRR predicts poor prognosis in renal cell carcinoma.

Long noncoding RNA FOXF1 adjacent non-coding developmental regulatory RNA (FENDRR) dysregulation associates with multiple types of human cancer. However, the biological functions of FENDRR in renal cell carcinoma are unresolved. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to determine the expression level of FENDRR in renal cell carcinoma tissues. An RNA interference assay and ectopic expression experiments were conducted to evaluate the effects of FENDRR on cell proliferation, migration, invasion and colony formation in vitro. RNA immunoprecipitation was conducted to identify proteins associated with FENDRR. It was observed that FENDRR is frequently downregulated in renal cell carcinoma and overexpression of FENDRR attenuated proliferation, migration, invasion and colony growth of renal carcinoma cells. Conversely, knockdown of FENDRR promotes proliferation and invasiveness of renal carcinoma cells. Downregulation of FENDRR associates with poor prognosis of renal cell carcinoma. Mechanistically, it was identified that FENDRR may bind to Polycomb Repressive Complex 2 and lysin methyltransferase 2A histone modifying complexes. In summary, FENDRR acts as an tumor suppressor in renal cell carcinoma and may serve as a candidate target for gene therapy.

Long Noncoding RNA LBCS Inhibits Self-Renewal and Chemoresistance of Bladder Cancer Stem Cells through Epigenetic Silencing of SOX2.

PURPOSE: Chemoresistance and tumor relapse are the leading cause of deaths in bladder cancer patients. Bladder cancer stem cells (BCSCs) have been reported to contribute to these pathologic properties. However, the molecular mechanisms underlying their self-renewal and chemoresistance remain largely unknown. In the current study, a novel lncRNA termed Low expressed in Bladder Cancer Stem cells (lnc-LBCS) has been identified and explored in BCSCs. EXPERIMENTAL DESIGN: Firstly, we establish BCSCs model and explore the BCSCs-associated lncRNAs by transcriptome microarray. The expression and clinical features of lnc-LBCS are analyzed in three independent large-scale cohorts. The functional role and mechanism of lnc-LBCS are further investigated by gain- and loss-of-function assays in vitro and in vivo. RESULTS: Lnc-LBCS is significantly downregulated in BCSCs and cancer tissues, and correlates with tumor grade, chemotherapy response, and prognosis. Moreover, lnc-LBCS markedly inhibits self-renewal, chemoresistance, and tumor initiation of BCSCs both in vitro and in vivo. Mechanistically, lnc-LBCS directly binds to heterogeneous nuclear ribonucleoprotein K (hnRNPK) and enhancer of zeste homolog 2 (EZH2), and serves as a scaffold to induce the formation of this complex to repress SRY-box 2 (SOX2) transcription via mediating histone H3 lysine 27 tri-methylation. SOX2 is essential for self-renewal and chemoresistance of BCSCs, and correlates with the clinical severity and prognosis of bladder cancer patients. CONCLUSIONS: As a novel regulator, lnc-LBCS plays an important tumor-suppressor role in BCSCs' self-renewal and chemoresistance, contributing to weak tumorigenesis and enhanced chemosensitivity. The lnc-LBCS-hnRNPK-EZH2-SOX2 regulatory axis may represent a therapeutic target for clinical intervention in chemoresistant bladder cancer.