The role of estrogen deprivation therapy in premenopausal women with primary unresectable intracardiac leiomyomatosis: a systematic review and meta-analysis.

BACKGROUND: Intracardiac leiomyomatosis (ICLM) is a rare life-threatening form of intravenous leiomyomatosis (IVLM). The incomplete resection and recurrence are associated with high morbidity and mortality. The objective of this study is to identify that whether estrogen deprivation therapies, including bilateral salpingo-oophorectomy (BSO)-based surgery and gonadotrophin releasing hormone agonists (GnRHa) administration, could bring benefits to patients with primary unresectable ICLM. METHODS: PubMed/MEDLINE (Ovid) was searched (up to May 2021) for studies reporting individual patient data on demographics, clinicopathological features, treatment, and follow-up information. Exclusion criteria were patients who may have been included in two or more publications. This study was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: A total of 114 patients from 70 papers were included. Several reports showed that the tumor in the right atrium and inferior vena cava shrank dramatically after BSO-based surgery, or GnRHa administrated preoperatively in premenopausal women. The rate of complete resection was 64.04% in patients with ICLM, which was 85.25% in no/slight adhesion and no pulmonary nodules group, while 22.22% in firm/extensive adhesion and/or pulmonary nodules group (p < 0.0001). Meanwhile, the recurrence rates in patients with complete resection and incomplete resection were 4.29% and 37.84% respectively (p < 0.0001). Furthermore, complete resection with BSO had the lowest recurrence rate of 3.13%, incomplete resection with BSO had a progression rate of 45.45%, while incomplete resection with ovarian preservation had the highest progression rate of 75.00%. CONCLUSIONS: The recurrence rate of ICLM was closely related to firm/extensive adhesion in IVC or above, and/or pulmonary nodules. BSO-based surgery might reduce the recurrence rate no matter ICLM could be completely resected or not. In addition, estrogen deprivation therapies could decrease tumor burden as a primary treatment, and further make a secondary complete resection feasible in premenopausal women with initially unresectable ICLM.

HPV-specific risk assessment of cervical cytological abnormalities.

BACKGROUND: Cytology and HPV genotype screening play an important role in cervical cancer detection. Whether multiple HPV genotyping can predict cytological lesions remains to be further studied. METHODS: Two thousand two hundred twenty-four females were analyzed for cytology and HPV genotypes test. The possibility of predicting cytological lesions by HPV genotypes test was evaluated by multivariate logistic regression and area under the receiver operator characteristic curve (AUC). RESULT: Abnormal cytological results were found in 479 participants. A total of 688 patients were detected with HPV infection, 619 with HR-HPV infection and 112 with LR-HRV infection. HPV-52 was found to be the most common type among these patients, and a relatively higher risk of cervical lesions was found in HPV positive females. HPV-16, 31, 33 and 58 were found to have significantly higher infection rates in patients with HSIL and higher lesions. The prediction model was developed based on age and HPV-specific genotypes, with the AUC of 0.73 for cytological abnormalities and 0.82 for HSIL and higher lesions. CONCLUSION: HPV-16, 31, 33 and 58 infection are significant risk factors for cervical lesions. Combined HPV genotypes test can effectively predict cytological abnormalities.

Mechanism underlying long non­coding RNA ILF3­AS1­mediated inhibition of cervical cancer cell proliferation, invasion and migration, and promotion of apoptosis.

Long non­coding RNA ILF3 divergent transcript (ILF3­AS1) displays a tumor­suppressing effect. StarBase predicted that the potential target microRNA (miR) of ILF3­AS1 was miR­454­3p; therefore, the present study investigated the effect of ILF3­AS1 and its target miR­454­3p on cervical cancer (CC). Gene Expression Profiling Interactive Analysis was used to predict the expression of ILF3­AS1 in CC and the overall survival rate of patients. The present study demonstrated that ILF3­AS1 expression was significantly downregulated in human CC tissues and cells compared with adjacent tissues (ANTs) and normal cervical epithelial cells (NCEs), respectively. Patients with CC with high ILF3­AS1 expression displayed higher survival rates compared with patients with low ILF3­AS1 expression. Cell viability, apoptosis, migration and invasion were detected by performing Cell Counting Kit­8, flow cytometry, wound healing and Transwell assays, respectively. Compared with the negative control (NC) group, ILF3­AS1 overexpression significantly inhibited CC cell viability and migration, but significantly increased CC cell apoptosis. Moreover, ILF3­AS1 overexpression significantly upregulated E­Cadherin expression levels, but significantly downregulated N­Cadherin and snail family transcriptional repressor 1 expression levels compared with the NC group. miR­454­3p expression was negatively correlated with ILF3­AS1, and highly expressed in CC tissues and cells compared with ANTs and NCEs, respectively. PTEN, which was predicted and verified as the target gene for miR­454­3p, was significantly downregulated in CC tissues and cells compared with ANTs and NCEs, respectively. ILF3­AS1 expression was positively correlated with PTEN expression, and ILF3­AS1 overexpression partially reversed the inhibitory effect of miR­454­3p on PTEN expression. In conclusion, the present study indicated that ILF3­AS1 inhibited CC cell proliferation and migration, and promoted CC cell apoptosis by inhibiting epithelial­mesenchymal transition, and ILF3­AS1 overexpression partially reversed the inhibitory effect of miR­454­3p on PTEN expression.

N6-Methyladenosine Associated Silencing of miR-193b Promotes Cervical Cancer Aggressiveness by Targeting CCND1.

OBJECTIVE: Cervical cancer is a frequently encountered gynecological malignancy as a major contributor to cancer-related deaths in women. This study focuses on how miR-193b promotes cervical cancer aggressiveness as well as the role of m6A in miR-193b silencing. METHODS: Cervical cancer samples and the matching adjacent normal cervical tissues were used to determine the significance of miR-193b in cervical cancer. The CCK-8 assay, cell cycle analysis, qRT-PCR, Western blot assay, IHC, RIP, and xenograft models were utilized to explore the impact of miR-193b in cervical cancer and how m6A regulates miR-193b expression. Luciferase reporter assays, qRT-PCR, and Western blotting were enlisted to study the interaction between miR-193b and CCND1. RESULTS: Our study suggested that lower miR-193b expressions were strongly linked to more advanced cervical cancer stages and the presence of deeper stromal invasion. miR-193b functions as a tumor suppressor that is regulated by m6A methylation in cervical tumors. METTL3 modulates miR-193b mature process in an m6A-dependent manner. Reintroduction of miR-193b profoundly inhibits tumorigenesis of cervical cancer cells both in vivo and in vitro through CCND1 targeting. CONCLUSIONS: m6A associated downregulation of miR-193b promotes cervical cancer aggressiveness by targeting CCND1.

Long non-coding RNA AK001903 regulates tumor progression in cervical cancer.

A majority of cervical cancers are squamous cell carcinomas, arising from the squamous (flattened) epithelial cells that line the cervix. Long noncoding RNAs (lncRNAs) are a unique class of messenger RNA-like transcripts of at least 200 nucleotides in length with no significant protein-coding capacity. Aberrant lncRNA expression is emerging as a major component of the cancer transcriptome. In the present study, lncRNA microarrays were conducted to investigate the differentially expression lncRNAs in cervical cancer (CC) tissues compared with peritumoral tissues. Then, the most significantly upregulated lncRNA, which was lncRNA-AK001903 was selected to conduct further experiments. Real-time Quantitative polymerase chain reaction was conducted to investigate lncRNA-AK001903 expression in CC tissues and Hela, Siha, Ca Ski, C33a, H8 (HPV-immortalized cervical epithelial cell line) cell lines, and in situ hybridization histochemistry (ISHH) was performed to detect lncRNA-AK001903 expression level in different CC stages. The effect of lncRNA-AK001903 on cell proliferation, invasion and migration was assessed after knockdown of lncRNA-AK001903. The findings of the study confirmed that lncRNA-AK001903 was upregulated in CC cells and tissues compared with normal cell line H8 and peritumoral tissues. ISHH demonstrated that the expression level of lncRNA-AK001903 was connected with International Federation of Gynecology and Obstetrics (2018) stage of CC. Knockdown of lncRNA-AK001903 inhibited cell proliferation, invasion and migration in Ca Ski cells. In conclusion, lncRNA-AK001903 was demonstrated to be an oncogenic lncRNA that promotes tumor progression and may be an effective target for CC treatment in the near future.

Impaired intestinal barrier function in type 2 diabetic patients measured by serum LPS, Zonulin, and IFABP.

INTRODUCTION: The epithelial tight junctions of intestine were impaired in murine model of type 2 diabetes mellitus (T2DM). The aim of this work was to investigate the alteration of intestinal barrier in T2DM patients. METHODS: 90 patients with T2DM and 28 healthy controls were recruited. Serum lipopolysaccharide (LPS), Zonulin, and intestinal fatty acid binding protein (IFABP) were measured by ELISA, based on which a derived permeability risk score (PRS) was calculated. Subgroup analyses were conducted based on the glycemic control (HbA1c < 7%, or HbA1c ≥ 7%), the amount of chronic diabetic complications, and the use of aspirin at the time. RESULTS: Serum LPS, Zonulin, and IFABP, and PRS of T2DM group were significantly higher than those of the control group (p < 0.05 for all). Serum LPS and PRS was higher in T2DM patients with poor glycemic control (both p < 0.05). Patients with more chronic complications of diabetes had higher serum LPS and IFABP, and PRS (all p < 0.05). No differences were found in these serum markers between T2DM patients being treated with aspirin or not. CONCLUSIONS: Intestinal barrier function was impaired in T2DM patients. Poor glycemic control and more chronic complications of diabetes were associated with worse intestinal barrier function. Treatment with aspirin did not aggravate the impairment of intestinal barrier in T2DM patients.

Real-time infrared image detail enhancement based on fast guided image filter and plateau equalization.

Image detail enhancement is critical to the performance of infrared imaging systems because the original images generally suffer from low contrast and a low signal-to-noise ratio. Although conventional decomposition-based methods have advantages in enhancing image details, they also have clear disadvantages, which include intensive computations, over-enhanced noise, and gradient reversal artifacts. In this paper, we propose to accelerate enhancement processing by using a fast guided filter and plateau equalization. Our method consists of image decomposition, base and detail layers processing, and projection of the enhanced image to an 8-bit dynamic range. Experimental results demonstrated that our proposed method achieves a good balance among detail enhancement performance, noise and gradient reversal artifacts suppression, and computational cost, with a frame rate around 30 fps for 640×512 infrared images.

High-performance concealment of defective pixel clusters in infrared imagers.

Defective pixel concealment is a necessary procedure in infrared image processing and is widely used. However, current approaches are mainly focused on the concealment of isolated pixels and small defective pixel clusters. Consequently, these approaches cannot meet the requirements when applied to infrared detectors with large defective pixel clusters. In this paper, we present a novel and comprehensive approach to processing the image data acquired from infrared imagers with large and small defective pixel clusters. Our approach consists of preprocessing, coarse concealment, high dynamic range enhancement, and fine concealment by generative adversarial networks. Experiments using mid-wave infrared and long-wave infrared images demonstrated that the proposed approach achieves better results than the best conventional approach, known as transforming image completion, with the peak signal-to-noise ratio and structural similarity metrics improved by 2.7063 dB (16.3%) and 0.1951 dB (34.1%), respectively.

ß-Catenin Expression Negatively Correlates with WIF1 and Predicts Poor Clinical Outcomes in Patients with Cervical Cancer.

Aberrant activation of the canonical Wnt pathway plays a significant role in cervical cancer (CC). However, limited data show the correlation between the cancer clinicopathological characteristics and the key molecules such as ß-catenin and Wnt inhibitory factor 1 (WIF1). In this study, ß-catenin and WIF1 expression were analyzed by immunohistochemistry for 196 patients with CC, 39 with cervical intraepithelial neoplasia (CIN), and 41 with normal cervical epithelium (NCE). Significant overexpression of ß-catenin was detected in CC (67.9%) when compared to CIN (43.6%) or NCE (34.1%), p < 0.01, while low WIF1 expression was detected in CC (24.0%) when compared to CIN (59.0%) or NCE (58.5%), p < 0.001. Negative correlation was shown between ß-catenin and WIF1 expression (r = -0.637, p < 0.001). In addition, multivariate analysis revealed that both lymph node metastasis and ß-catenin expression were the independent prognostic factors not only for disease-free survival (HR = 5.029, p < 0.001; HR = 2.588, p = 0.035, resp.), but also for overall survival (HR = 5.058, p < 0.001; HR = 2.873, p = 0.031, resp.). Our findings indicate that, besides lymph node metastasis, ß-catenin expression may also be a poor prognostic factor for CC while WIF1 could be a potential drug target for treatment of advanced CC.

Aldehyde Dehydrogenase 1 Expression Predicts Chemoresistance and Poor Clinical Outcomes in Patients with Locally Advanced Cervical Cancer Treated with Neoadjuvant Chemotherapy Prior to Radical Hysterectomy.

BACKGROUND: Neoadjuvant chemotherapy (NAC) is an important treatment strategy for cervical cancer; however, few predictive markers of the response to NAC exist. Aldehyde dehydrogenase 1 (ALDH1), a cancer stem cell marker, is associated with chemoresistance in a variety of cancers. This study attempted to investigate the value of ALDH1 as a predictive marker of chemosensitivity and its prognostic value in cervical cancer patients treated with NAC. METHODS: Immunohistochemistry was used to evaluate ALDH1 expression in matched pre- and post-NAC tumor samples from 52 patients with cervical cancer. Kaplan-Meier analysis and a Cox proportional hazards regression model were applied to determine overall survival (OS) and disease-free survival (DFS). RESULTS: Fourteen patients (26.9 %) had ALDH1-positive tumors pre-NAC, and ALDH1 expression pre-NAC was significantly associated with a low clinical chemotherapy response rate and clinical non-response. Twenty-two patients (42.3 %) had ALDH1-positive tumors post-NAC, and ALDH1 expression post-NAC was associated with poor DFS and OS (both p = 0.004). Multivariate analysis revealed that ALDH1 expression post-NAC was an independent prognostic factor for OS (hazard ratio 3.513; p = 0.033). Moreover, we observed that ALDH1 expression was increased after NAC in 18 patients (36.7 %). Increased levels of ALDH1 expression after NAC predicted poor DFS and OS (p = 0.013 and p = 0.08, respectively). CONCLUSIONS: Our findings suggest that ALDH1 expression pre-NAC may be a predictive marker for response to NAC, and ALDH1 expression post-NAC could be a prognostic marker for cervical cancer.

Exploration of tumor-suppressive microRNAs silenced by DNA hypermethylation in cervical cancer.

BACKGROUND: Multiple studies proved that miRNAs have a causal role in tumorigenesis. Some miRNAs are regulated by epigenetic alterations in their promoter regions and can be activated by chromatin- modifying drugs. METHODS: We treated cervical cancer cells with 5-aza-2'-deoxycytidine and get a microarray analysis. Dysregulation of miRNAs was measured by qPCR in cervical cell lines and methylation status of them in cervical cancer tissue were performed with MeDIP-qPCR assay. RESULTS: We found hypermethylation of miR-432, miR-1286, miR-641, miR-1290, miR-1287 and miR-95 may have some relationship with HPV infection in cervical cell lines. In primary tumors of cervix with paired normal tissue, expression levels of miRNAs were inversely correlated with their DNA methylation status in the cervical cancer cell lines treated with 5-AZA. CONCLUSIONS: Our results indicate that miRNAs might play a role in the pathogenesis of human cervical cancer with HPV and identify altered miRNA methylation as a possible epigenetic mechanism involved in their aberrant expression.

Neuromedin B and its receptor induce labor onset and are associated with the RELA (NFKB P65)/IL6 pathway in pregnant mice.

Although the neuromedin B receptor (NMBR), a bombesin receptor family member, has been implicated in thermoregulation and in stimulation of both urogenital and gastrointestinal smooth muscle contraction, its underlying role in labor onset and its associated molecular mechanisms remain poorly understood. We examined the relationship between temporal and spatial NMBR expression in the myometrium of pregnant mice and potential mechanistic pathways leading to labor onset. Resultant data indicate that NMBR expression peaked at term and before parturition. Maternal exposure to the NMBR agonist neuromedin B (NMB) shortened the gestational age of pups, an effect that was also observed after oxytocin administration. Both RELA (NFKB P65) DNA-binding activity and interleukin 6 (Il6) mRNA expression were greatest during parturition and after maternal exposure to the highest NMB concentration administered (150 µg/kg). Furthermore, a significant correlation was observed among NMBR mRNA expression, RELA DNA-binding activity, and Il6 mRNA expression. These data demonstrate that NMB and its receptor can induce the onset of labor via a RELA/IL6-mediated pathway.

[Expression of NMBR in myometrium in pregnant mice at different gestational ages and its relation with parturition].

OBJECTIVE: To investigate the spatiotemporal expression of neuromedin B receptor (NMBR) in mice myometrium at different pregnant stages, as well as its mechanism and relation with parturition. METHODS: The pregnant mice were divided into no-pregnancy (NP), early pregnancy (EP), mid-pregnancy (MP), late-pregnancy (LP), parturition (PT) and postpartum (PP) groups (12 mice in each group), according to pregnant stage. The mRNA and protein expression of NMBR, HSP70 and IL-6 were detected in myometrium in pregnant mice by semi-quantitative RT-PCR and Western blot, while NF-kappaB-P65 DNA binding activity was determined by NoShift transcription factor assay kits, respectively. Their relation with parturition was analyzed. RESULTS: The mRNA expression level of NMBR in the PT group was significantly higher than that in the NP, EP, LP and PP groups (P<0.05), but this difference was not observed in the MP group (P>0.05). The NMBR protein in PT group was significantly higher than that in the other 5 groups (P<0.01). NF-kappaB-P65 DNA binding activity at PT group was remarkably higher than that in the NP, LP and PP groups (P<0.05). The expression of IL-6 mRNA was significantly higher than that in the NP, LP and PP groups (P<0.05), its protein expression in PT and LP groups was significantly higher than that in the NP and PP groups (P<0.05). The expression of HSP70 mRNA in the PT group was significantly higher than that in the NP and PP groups (P<0.05), and the protein of HSP70 was significantly up-regulated in PT and PP groups compared with in NP and LP groups (P<0.05). The DNA-binding activity of P65 was positively correlated to the mRNA expression of NMBR and IL-6 (r=0.40, P<0.01; r=0.30, P<0.05), so were positively correlated to DNA-binding activity of P65, mRNA expression of HSP70 and NMBR ( r=0.40, P<0.01; r=0.49, P<0.01). DNA-binding activity of P65 did not correlate with the mRNA expression of HSP70. CONCLUSION: The mRNA and protein expressions of NMBR reach a peak at the onset of labor. NMBR may play an important role in the parturition via NF-kappaB P65-IL-6 signal transduction pathway. It may also influence the onset of labor by regulating HSP70, but this role does not rely on P65 pathway.

[Scanning of drug targets related to uterus contraction from the uterine smooth muscles by cDNA microarray].

OBJECTIVE: To screen the differentially expressed gene profile from the smooth muscles in the fundus uterus at the active stage of labor, and to provide candidate genes for picking out the drug targets related to uterine contraction. METHODS: Differentially expressed genes of uterine smooth muscles in the corpus from pro and post spontaneous parturition and those induced by oxytocin,as well as those from the corpus and the lower portion spontaneous parturition,were scanned respectively by human full-length genetic cDNA microarray with 8064 probe sets. Semi-quantitative RT-PCR was applied to testify the expression of voltage dependent calcium channel-L subtype (CACNA). The differentially expressed genes in the structure and function of the drug targets were picked out by bio-informatics to serve as candidate drug targets related to uterine contraction. RESULTS: The expressions of 29 genes were upregulated in fundus smooth muscles from the pro and post natural parturition, the pro and post inductive parturition of oxytocin, and the natural parturition. The expression of CACNA gene in RT-PCR was in accordance with that in the microarray. Among the 29 genes, neuromedin B receptor (NMBR) gene and neuropeptide Y (NPY) gene were the genes which not only had the targets of uterine contracted medicine, but also could contract the uterine. The differential expression ratios of NMBR in the above 3 types of uterine myometrium were 6.9,11.3, and 9.0, respectively while those of NPY were 6.0,29.8, and 2.9 respectively. CONCLUSION: NMBR, whose expression in the uterine smooth muscles is always up-regulated at different parturition conditions, is likely to be an ideal candidate target of uterotonic drugs.