Allergic hyper-carcinoembryonic antigen syndrome: A syndrome summarized by case series.

Allergic respiratory diseases can increase serum carcinoembryonic antigen levels. We report three cases experiencing allergic symptoms that proved refractory to inhaled corticosteroids but exhibited a positive response to long-term treatment with oral corticosteroids. This response was characterized by a synchronous alteration in serum eosinophil counts and carcinoembryonic antigen levels. Immunofluorescence assays indicated localized carcinoembryonic antigen production within eosinophils. In addition, we conducted a systematic review of patients exhibiting similar characteristics on PubMed. After comprehensively reviewing this unique pathophysiological condition, we herein introduced a novel term "Allergic hyper-carcinoembryonic antigen syndrome," defined by the following criteria: (1) recurrent asthmatic attacks; (2) eosinophilia or pulmonary eosinophilic infiltrations accompanied by elevated serum carcinoembryonic antigen levels; (3) pulmonary lesions determined by imaging or biopsy; (4) exclusion of malignancy and infections; and (5) responsive to systemic corticosteroids. Allergic hyper-carcinoembryonic antigen syndrome suggests systemic corticosteroids should be introduced early when managing allergic patients with both eosinophilia and elevated serum carcinoembryonic antigen levels.

A functional loop between YTH domain family protein YTHDF3 mediated m6A modification and phosphofructokinase PFKL in glycolysis of hepatocellular carcinoma.

BACKGROUND & AIMS: N6-methyladenosine (m6A) modification plays a critical role in progression of hepatocellular carcinoma (HCC), and aerobic glycolysis is a hallmark of cancer including HCC. However, the role of YTHDF3, one member of the core readers of the m6A pathway, in aerobic glycolysis and progression of HCC is still unclear. METHODS: Expression levels of YTHDF3 in carcinoma and surrounding tissues of HCC patients were evaluated by immunohistochemistry. Loss and gain-of-function experiments in vitro and in vivo were used to assess the effects of YTHDF3 on HCC cell proliferation, migration and invasion. The role of YTHDF3 in hepatocarcinogenesis was observed in a chemically induced HCC model with Ythdf3-/- mice. Untargeted metabolomics and glucose metabolism phenotype assays were performed to evaluate relationship between YTHDF3 and glucose metabolism. The effect of YTHDF3 on PFKL was assessed by methylated RNA immunoprecipitation assays (MeRIP). Co-immunoprecipitation and immunofluorescence assays were performed to investigate the connection between YTHDF3 and PFKL. RESULTS: We found YTHDF3 expression was greatly upregulated in carcinoma tissues and it was correlated with poor prognosis of HCC patients. Gain-of-function and loss-of-function assays demonstrated YTHDF3 promoted proliferation, migration and invasion of HCC cells in vitro, and YTHDF3 knockdown inhibited xenograft tumor growth and lung metastasis of HCC cells in vivo. YTHDF3 knockout significantly suppressed hepatocarcinogenesis in chemically induced mice model. Mechanistically, YTHDF3 promoted aerobic glycolysis by promoting phosphofructokinase PFKL expression at both mRNA and protein levels. MeRIP assays showed YTHDF3 suppressed PFKL mRNA degradation via m6A modification. Surprisingly, PFKL positively regulated YTHDF3 protein expression, not as a glycolysis rate-limited enzyme, and PFKL knockdown effectively rescued the effects of YTHDF3 overexpression on proliferation, migration and invasion ability of Sk-Hep-1 and HepG2 cells. Notably, co-immunoprecipitation assays demonstrated PFKL interacted with YTHDF3 via EFTUD2, a core subunit of spliceosome involved in pre-mRNA splicing process, and ubiquitination assays showed PFKL could positively regulate YTHDF3 protein expression via inhibiting ubiquitination of YTHDF3 protein by EFTUD2. CONCLUSIONS: our study uncovers the key role of YTHDF3 in HCC, characterizes a positive functional loop between YTHDF3 and phosphofructokinase PFKL in glucose metabolism of HCC, and suggests the connection between pre-mRNA splicing process and m6A modification.

Anti-galectin-3 antibodies induce skin vascular inflammation via promoting local production of IL-1ß in systemic lupus erythematosus.

Vascular inflammation could occur in all organs and tissues in patients with systematic lupus erythematosus (SLE), of which skin is the most frequent one. Our previous research identified anti-galectin-3 (Gal3) antibodies (Abs) as an important mediator of lupus cutaneous vasculopathy. Herein, we showed that anti-Gal3 Abs dysregulated the function of vascular endothelial cells with higher transcript levels of IL-1ß and increased expression of mature IL-1ß. The enhanced production of IL-1ß secreted by endothelial cells was dependent on NLRP3 inflammasome. Intradermal injection of anti-Gal3 Abs in mice induced local inflammation with perivascular infiltration of T cells and neutrophils, which was inhibited by IL-1ß blockade. Induction of anti-Gal3 Abs in circulation by immunization of Gal3 antigen not only led to histopathologic changes in the skin, including focal keratinocytes vacuolization and thickening of blood vessels, but also a systemic autoimmune phenotype that involves autoantibody production and kidney damage. Intriguingly, local overexpression of IL-1ß was primarily associated with skin lesions but not with other internal organs in mice. Finally, we showed that the serum levels of IL-1ß were comparable between SLE patients and healthy donors. Whilst the expression of IL-1ß was enriched in local area with perivascular inflammation in lupus skin lesion compared to healthy normal skin. The results strongly suggest that IL-1ß plays an important role in mediating anti-Gal3 Ab-induced skin vascular inflammation and raised the prospect for using IL-1ß blocking therapies to treat lupus cutaneous damage.

Development and validation of a transcriptomics-based gene signature to predict distant metastasis and guide induction chemotherapy in locoregionally advanced nasopharyngeal carcinoma.

AIM: Metastasis is the primary cause of treatment failure in nasopharyngeal carcinoma (NPC); however, the current tumour-node-metastasis staging system has limitations in predicting distant metastasis and guiding induction chemotherapy (IC) application. Here, we established a transcriptomics-based gene signature to assess the risk of distant metastasis and guide IC in locoregionally advanced NPC. METHODS: Transcriptome sequencing was performed on NPC biopsy samples from 12 pairs of patients with different metastasis risks. Bioinformatics and qPCR were used to identify differentially expressed genes (DEGs), while univariate and multivariate analyses were used to select prognostic indicators for the gene signature. A signature-based nomogram was established in a training cohort (n = 191) and validated in an external cohort (n = 263). RESULTS: Eleven DEGs were identified between metastatic and non-metastatic NPC. Four of these (AK4, CPAMD8, DDAH1 and CRTR1) were used to create a gene signature that effectively categorised patients into low- and high-risk metastasis groups (training: 91.1 versus 70.4%, p < 0.0001, C-index = 0.752; validation: 88.4 versus 73.9%, p = 0.00057, C-index = 0.741). IC with concurrent chemoradiotherapy (CCRT) improved distant metastasis-free survival in low-risk patients (94.4 versus 85.0%, p = 0.043), whereas patients in the high-risk group did not benefit from IC (72.6 versus 74.9%, p = 0.946). CONCLUSIONS: Our transcriptomics-based gene signature was able to reliably predict metastasis in locoregionally advanced NPC and could be used to identify candidates that could benefit from IC + CCRT.

Clinical characteristics of Hepatoid adenocarcinoma of the lung: Four case reports and literature review.

PURPOSE: Hepatoid adenocarcinoma of the lung (HAL) is a rare form of lung cancer, which is characterized by its morphologic hepatoid features. The clinical characteristics and prognosis of this rare form of lung cancer remain obscure. METHODS: The clinical courses of four cases of HAL were reported. A literature search was performed up to December 31, 2020, using the electronic databases PubMed and Web of Science. RESULTS: Including the present 4 cases, a total of 42 cases of HAL have been reported in the literature. The median age was 58.5 years old (range, 36-73 years). 36 (85.7%) patients were male. 26 (61.9%) patients had a history of smoking, the median amount of smoking was 40 pack years (range, 8-180). The most common site of the primary tumor was the right upper lobe (22 cases, 52.3%) and the left upper lobe (10 cases, 23.8%). 21 patients (50%) had pretreatment serum AFP levels higher than the upper limit, and 4 patients (9.5%) had normal pretreatment serum AFP levels. Treatment of HAL included surgery, chemotherapy, radiotherapy, tyrosine kinase inhibitors (TKIs), anti-angiogenesis therapy, and anti-PD-1/PD-L1 monoclonal antibody. Overall, the prognosis of HAL was poor, with median overall survival (OS) of 14 months. CONCLUSIONS: HAL is an aggressive tumor, with a poor prognosis and male predominance, which tends to occur in heavy smokers and affects the right upper lobe of the lung.

Alantolactone: A sesquiterpene lactone with diverse pharmacological effects.

Alantolactone (Ala) is a sesquiterpene lactone that can be isolated from many herbal plants belonging to Asteraceae. Besides the antimicrobial activities against bacteria, fungi and viruses, Ala has also demonstrated significant anti-inflammatory effects in various models by inhibiting NF-κB and MAPKs to decrease the pro-inflammatory cytokines such as IL-1ß, IL-6 and TNF-α. The antitumor effects of Ala have been demonstrated in vitro and in vivo via inducing intrinsic apoptosis, oxidative stress, ER stress, cell cycle arrest and inhibiting autophagy and STAT3 phosphorylation, which are also involved in its combination or synergy with other antitumor drugs. Ala also has neuroprotective activity through attenuating oxidative stress and inflammation, besides its modulation of glucose and lipid metabolism. This review summarizes the recent advances of the pharmacological effects of Ala, including anti-inflammatory, antitumor, antimicrobial, neuroprotective activities, as well as the underlying mechanisms. Ala might be employed as a potential lead to develop drugs for multiple diseases.

Circular RNA hsa_circ_0061395 accelerates hepatocellular carcinoma progression via regulation of the miR-877-5p/PIK3R3 axis.

BACKGROUND: Circular RNA hsa_circ_0061395 (circ_0061395) has been reported to accelerate the advancement of hepatocellular carcinoma (HCC). However, the regulatory mechanism by which circ_0061395 modulates the progression of HCC is unclear. METHODS: The morphology and size of exosomes were analyzed by transmission electron microscope (TEM) and nanoparticle-tracking analysis (NTA). Protein levels were detected by western blotting. Expression levels of circ_0061395, microRNA (miR)-877-5p, and phosphoinositide-3-kinase regulatory subunit 3 (PIK3R3) mRNA were assessed by quantitative real time polymerase chain reaction (qRT-PCR). The proliferation, invasion, migration, cell cycle progression, and apoptosis were analyzed by cell counting kit-8 (CCK-8), plate clone, transwell, or flow cytometry assays. The targeting relationship between circ_0061395 or PIK3R3 and miR-877-5p was verified using the dual-luciferase reporter and/or RNA immunoprecipitation (RIP) assays. Xenograft assay was performed to confirm the biological function of circ_0061395 in HCC. RESULTS: Circ_0061395 was upregulated in HCC tissues, serum, cells, and serum-derived exosomes. Circ_0061395 silencing decreased tumor growth in vivo, and induced cell cycle arrest, apoptosis, repressed proliferation, invasion, and migration of HCC cells in vitro. MiR-877-5p was downregulated while PIK3R3 was upregulated in HCC. Circ_0061395 regulated PIK3R3 expression via competitively binding to miR-877-5p. MiR-877-5p inhibitor overturned circ_0061395 knockdown-mediated influence on malignant behaviors of HCC cells. PIK3R3 overexpression reversed the suppressive influence of miR-877-5p mimic on malignant behaviors of HCC cells. CONCLUSION: Circ_0061395 facilitated HCC progression via regulating the miR-877-5p/PIK3R3 axis, providing a new perspective on the advancement of HCC.

A Case Report of Non-Bacterial Cystitis Caused by Immune Checkpoint Inhibitors.

We report a case of non-bacterial cystitis after treatment with programmed death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) antibodies, which was considered an immune-related adverse event (irAE). A 48-year-old male patient with intrahepatic cholangiocarcinoma (ICC) was treated with nivolumab after postoperative multi-line treatment. This patient recurred worsening of psoriasis and repeated urinary tract discomfort. The drug was discontinued and surgery was performed due to the recurrence of the tumor suggested by imaging. After receiving three cycles of chemotherapy treatment combined with atezolizumab, urinary tract discomfort reappeared. No bacteria were found in multiple urine cultures, and non-bacterial bladder inflammation was considered after cystoscopy biopsy. This is a report of non-bacterial inflammation of the urinary tract caused by immunotherapy.

Development and validation of the immune signature to predict distant metastasis in patients with nasopharyngeal carcinoma.

BACKGROUND: The tumor immune microenvironment has clinicopathological significance in predicting prognosis and therapeutic efficacy. We aimed to develop an immune signature to predict distant metastasis in patients with nasopharyngeal carcinoma (NPC). METHODS: Using multiplexed quantitative fluorescence, we detected 17 immune biomarkers in a primary screening cohort of 54 NPC tissues presenting with/without distant metastasis following radical therapy. The LASSO (least absolute shrinkage and selection operator) logistic regression model used statistically significant survival markers in the training cohort (n=194) to build an immune signature. The prognostic and predictive accuracy of it was validated in an external independent group of 304 patients. RESULTS: Eight statistically significant markers were identified in the screening cohort. The immune signature consisting of four immune markers (PD-L1+ CD163+, CXCR5, CD117) in intratumor was adopted to classify patients into high and low risk in the training cohort and it showed a high level of reproducibility between different batches of samples (r=0.988 for intratumor; p<0.0001). High-risk patients had shorter distant metastasis-free survival (HR 5.608, 95% CI 2.619 to 12.006; p<0.0001) and progression-free survival (HR 2.798, 95% CI 1.498 to 5.266; p=0·001). The C-indexes which reflected the predictive capacity in training and validation cohort were 0.703 and 0.636, respectively. Low-risk patients benefited from induction chemotherapy plus concurrent chemoradiotherapy (IC+CCRT) (HR 0.355, 95% CI 0.147 to 0.857; p=0·021), while high-risk patients did not (HR 1.329, 95% CI 0.543 to 3.253; p=0·533). To predict the individual risk of distant metastasis, nomograms with the integration of both immune signature and clinicopathological risk factors were developed. CONCLUSIONS: The immune signature provided a reliable estimate of distant metastasis risk in patients with NPC and might be applied to identify the cohort which benefit from IC+CCRT.

Ischemic Preconditioning Preventing Downregulation of miR-182 Protects Intestine Against Ischemia/Reperfusion Injury by Inhibiting Apoptosis.

BACKGROUND: Intestinal ischemia/reperfusion (I/R) injury is a severe condition associated with high morbidity and mortality. Ischemic preconditioning (IPC) had been found to be the most promising strategies against I/R injury. However, the potential molecular mechanisms underlying the protective effect of IPC have not been fully disclosed. MicroRNA182 (miR-182) is closely related to apoptosis and plays an important role in I/R injury. Our recent study demonstrated that miR-182 was down-regulated in the intestinal mucosa after I/R injury. However, whether miR-182 is involved in the protective effects of IPC in the setting of intestinal I/R injury is unknown. AIMS: To investigate the role of miR-182 in the protective effect of IPC in intestine after I/R injury and potential mechanisms. METHODS: AntagomiR-182 was pretreated before IPC in mice with intestinal I/R injury. MiR-182 mimic was administered before oxygen and glucose deprivation and reperfusion (OGD/R) in mice intestinal mucosa epithelial (MIME) cells. RESULTS: IPC partially prevented the downregulation of miR-182 in mice, which was blocked by pretreatment with antagomiR-182. Compared with the IPC group, pretreatment with antagomiR-182 further increased Chiu's scores and diamine oxidase activities. Meanwhile, apoptotic cells and cleaved caspase-3 expression were increased. Compared with the OGD/R group, pretreatment with miR-182 mimic prevented the downregulation of miR-182, improved cell survival, reduced apoptosis and cleaved caspase-3 expression in MIME cells. CONCLUSIONS: The downregulation of miR-182 was partially prevented by IPC, which was involved in IPC induced intestinal protection, and the mechanisms may be associated with inhibition of apoptosis.

Factors associated with delay in presentation among patients for oral cancer.

Aim: This study aimed to determine factors that influence delay in presentation among oral cancer patients. Materials & methods: A cross-sectional study with 128 Oral cancer patients receiving treatment from the Hospital of Stomatology, at Jilin University, in China, was conducted. Results: A total of 78 patients delayed seeking treatment for more than 3 weeks after noticing symptoms of oral anomaly. Patients who were male, farmers (Odds ratio [OR] = 2.617; 95% CI: 1.90-3.64), or currently smoking (OR = 4.651; 95% CI: 1.21-9.46), were more likely to delay. Patients alerted to the problem at a physical exam had much lower risk of delay than patients who discovered the disease independently (OR = 0.029; 95% CI: 0.01-0.30). Higher coping style scores (OR = 0.747; 95% CI: 0.47-1.18) and oral cancer knowledge scores (OR = 0.886; 95% CI: 0.60-2.01) were significantly correlated with shorter delays. Conclusion: Delay in presentation may be achieved through regular oral health screening and improved public education about factors influencing delay.

EBV-associated myoid tumor with lipoblast-like cells in a patient with normal immunity.

EBV-associated myoid tumor (EBVMT) comprises a specific group of soft tissue tumors with divergent histologic appearances, which typically occur in immunocompromised patients. To the best of our knowledge, there have been no previous reported of EBVMT in patients with normal immunity. EBVMT with lipoblast-like cells (EBVMT-LIC) is an extremely rare variant of EBVMT. Here, a male patient with normal immunity and EBVMT-LIC is presented. Comprehensive EBV latency expression pattern and tumorigenesis molecular analyses are performed to detail the pathologic features of this disease. Our patient was a 14-year-old who suffered from Burkitt's lymphoma 6 years ago and got complete remission for 5 years. At his last visit, he presented with pain and weakness in arms and legs. Subsequent MRI revealed an extramedullary mass at the cervical areas. CT-guided resection was then performed and comprehensive histopathologic examination was conducted. We found a haemangiopericytoma-like pattern with EBER-positive lipoblasts exist in this neoplasm and these features were in accordance with the diagnosis of EBVMT-LIC. Also, the EBV type I latency pattern was observed and the activation of Akt/mTOR pathway and Bcl-2 overexpression were found to be involved in the tumorigenesis of EBVMT-LIC. In conclusion, the results of this study suggest that EBVMT can occur in patients with normal immunity. EBV could achieve a latency type I pattern and may promote the development of EBVMT by activation of Akt/mTOR pathway and Bcl-2 overexpression. The role of chronic latent EBV infection in the development of EBVMT may be more important than previously thought.

Treatment Approach and Prognosis of Pediatric and Adolescent Nonepithelial Malignant Ovarian Tumors: A Retrospective Prognosis Analysis.

STUDY OBJECTIVE: Nonepithelial malignant ovarian tumors are rare in the pediatric and adolescent population. The aim of this study was to observe the spectrum of pathology, presentation, outcome, and risk factors for survival of pediatric nonepithelial malignant ovarian tumors in a Chinese pediatric population. DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: This was a retrospective study of 171 girls (median age at presentation of 14 years) diagnosed with primary malignant ovarian tumors between 1990 and 2014 at the Yat-Sen Memorial Hospital and Cancer Center of Sun Yat-sen University. Symptoms, pathological data, treatments, and outcomes were obtained retrospectively from the medical records. RESULTS: Most (85.96%, 147/171) tumors occurred in patients aged 10-18 years and most cases were International Federation of Gynecology and Obstetrics stage I (68.42%, 117/171). The predominant pathological type was germ cell tumors (87.13%, 149/171). All patients underwent surgery, and 87 (50.88%, 87/171) underwent conservative incomplete staging surgery (unilateral salpingo-oophorectomy or tumor excision). The 5-year progression-free survival (PFS) was 59.2%. The 5-year overall survival (OS) was 88.7%. Surgical hospital (hazard ratio, 0.388; 95% confidence interval, 0.213-0.706; P = .002) was independently associated with PFS. Recurrence state (hazard ratio, 163.26; 95% confidence interval, 1.321-20,181.875; P = .038) was independently associated with OS. CONCLUSION: Ovarian cancers in children and adolescents have features of good prognosis. Girls who received their first surgery in a tertiary hospital had better PFS. Patients who did not suffer recurrence had better OS.

Epithelial-Mesenchymal Transition is Superior to Vessels-Encapsulate Tumor Cluster in Promoting Metastasis of Hepatocellular Carcinoma: a Morphological Evidence.

Purpose Vessels-encapsulate tumor cluster (VETC) is a vascular pattern distinct from classical capillary-like pattern. It is reported that VETC structure is common in hepatocellular carcinoma (HCC) and can promote HCC metastasis in an epithelial-mesenchymal transition (EMT)-independent but VETC-dependent manner. However, the main metastatic manner of HCC containing both VETC and classical vascular structure (we called VETC±) is unknown. Methods Vascular pattern types and E-cadherin expression were evaluated by immunohistochemical staining in 168 HCC tissues, 50 pairs of primary HCC tissues and intrahepatic metastatic lesions, as well as 12 pairs of primary HCC tissues and major portal vein tumor thrombus. Survival and recurrence rates were evaluated using Kaplan-Meier analysis. The multivariate Cox proportional hazards model was used to determine the independent prognostic factors of HCC. Results VETC± cases were more common than VETC+ cases (HCC tissues with a VETC pattern fully distributed in the HCC section) in HCC. Statistical analysis showed that VETC± was an independent predictor of survival and recurrence. Furthermore, E-cadherin was positively correlated with the presence of VETC structure. In the case of HCCs with VETC±, their metastases (both intrahepatic and major vascular) were more likely to be VETC negative. Conclusions Our findings suggest that EMT may be superior to VETC in promoting HCC metastasis. Thus, both anti-EMT and anti-VETC agents should be considered in the case of HCC with VETC±.

Laparoscopic Partial Nephrectomy for T1 Renal Cell Carcinoma: Comparison of Two Resection Techniques in a Multi-institutional Propensity Score-Matching Analysis.

BACKGROUND: Enucleoresection is defined as presence of a minimal paratumor parenchyma that allows for clear visualization of the tumor's contours during partial nephrectomy (PN). Because there is variability in published reports regarding resection techniques during PN before the surface-intermediate-base (SIB) margin score reporting system, the association between postoperative outcomes and resection techniques are rarely reported. This study was designed to compare the perioperative, oncologic, and functional outcomes between laparoscopic enucleoresection (LER) (SIB score 1 + 1 + 1 = 3) and traditional laparoscopic partial nephrectomy (TLPN) (SIB score 1 + 2 + 2 = 5). METHODS: Data from 270 consecutive patients who underwent laparoscopic partial nephrectomy for single T1 RCC at 3 medical centers were prospectively collected. Propensity score matching was performed on age, gender, body mass index, American Society of Anesthesiologists score, preoperative estimated glomerular filtration rate (eGFR), tumor size, RENAL nephrometry score, Charlson score, and solitary kidney status. Normal parenchyma width of each patient was evaluated right after the surgery, and SIB score was assigned retrospectively. Ninety-eight matched patients undergoing LER or TLPN were compared for perioperative, oncologic, and functional outcomes. RESULTS: After matching, warm ischemia time (WIT) and operative time were significantly shorter in LER than TLPN group (20.8 vs. 23.8 min, P = 0.003 and 130.8 vs. 152.1 min, P = 0.005, respectively). Estimated blood loss (EBL) also was lower in LER than TLPN group (50 vs. 90 mL, P = 0.045). Complication rates, positive surgical margin rates, and local recurrence rates were comparable between groups (P = 0.3, P = 0.62, and P = 1.0, respectively). At last follow-up, the eGFRs also were comparable in both groups (P = 0.6). CONCLUSIONS: LER has similar oncologic, functional outcomes and complication rates with the advantage of a shorter WIT, operative time, and lower EBL compared with TLPN.

Levonorgestrel Inhibits Human Endometrial Cell Proliferation through the Upregulation of Gap Junctional Intercellular Communication via the Nuclear Translocation of Ser255 Phosphorylated Cx43.

OBJECTS: To assess whether LNG exerts antiproliferation effects on human endometrial cells through changes of GJIC function and the phosphorylated Cx43. METHODS: Cell proliferation and apoptosis of human endometrial stromal cells (HESCs) and glandular cells (HEGCs) treated with LNG in a dose- and time-dependent manner. GJIC change and further total Cx43 and serine 368 and 255 phosphorylated Cx43 were measured. RESULTS: 5 × 10(-5) mol/L LNG revealed a time-dependent inhibition of cell proliferation and an increase of apoptosis in both HESCs and HEGCs. Furthermore, these cells demonstrated a significant GJIC enhancement upon treatment with 5 × 10(-5) mol/L for 48 hours. The effects of LNG were most noticeable in HESCs rather than in HEGCs. Associated with these changes, LNG induced a relative increase in total Cx43 in a time-dependent manner but not Ser368 phosphorylated Cx43. Moreover, laser scanning confocal microscope confirmed the increased expression of total Cx43 in the cytoplasm and, interestingly, the nuclear translocation of Ser255 phosphorylated Cx43. CONCLUSIONS: LNG likely inhibits the proliferation and promotes apoptosis in HESCs and HEGCs though an increase in gap junction permeability in vitro, which is achieved through the upregulation of Cx43 expression and the translocation of serine 255 phosphorylated Cx43 from the plasma to the nuclear compartment.

DICER1 mutations in a patient with an ovarian Sertoli-Leydig tumor, well-differentiated fetal adenocarcinoma of the lung, and familial multinodular goiter.

DICER1 syndrome, a recently described tumor-predisposition syndrome, often involves multiple organs and is characterized by pleuropulmonary blastoma (PPB), cystic nephroma, ovarian Sertoli-Leydig tumors, familial multinodular goiter, etc. Germline DICER1 mutations have been identified in individuals with a variety of malignant conditions. However, in a review of the reported DICER1 syndrome cases that feature an unusual array of neoplastic and hyperplastic phenotypes, no mentions are made of these patients also presenting well-differentiated fetal adenocarcinoma of the lung. Here, we present a 16-year-old Chinese adolescent suffering from an ovarian Sertoli-Leydig cell tumor,well-differentiated fetal adenocarcinoma of the lung, and familial multinodular goiter with a nonsense mutation (c.3540C > A; p.Tyr1180*) in exon 21 of DICER1. This report presents the first case in which the clinical features of DICER1 syndrome appear in combination with well-differentiated fetal adenocarcinoma of the lung. We hypothesize that this case may suggest that well-differentiated fetal adenocarcinoma of the lung falls within the wide spectrum of manifestations of the DICER1 syndrome. Remarkably, this mutation is reported in a patient from The International PPB Registry.

Overexpression of hypoxia-inducible factor-1α is a predictor of poor prognosis in cervical cancer: a clinicopathologic study and a meta-analysis.

BACKGROUND: Published data on the prognostic value of hypoxia-inducible factor-1α (HIF-1α) expression in cervical cancer are conflicting and heterogeneous. We aimed to derive a more precise estimation of them. METHODS: We conducted a clinicopathologic study in 74 patients with early-stage cervical cancer treated through surgery and performed a meta-analysis among patients with cervical cancer of all stages to estimate the prognostic importance of HIF-1α expression for disease-free survival (DFS) and overall survival (OS). Expression of HIF-1α was evaluated through immunohistochemistry. RESULTS: A positive nuclear expression of HIF-1α was found in 94.6% of all specimens. There were significant associations between HIF-1α expression and International Federation of Gynecology and Obstetrics stage (P = 0.024), tumor size (P = 0.003), and anemia (P = 0.010), respectively. Log-rank tests revealed significant correlations between HIF-1α expression, International Federation of Gynecology and Obstetrics stages, tumor grade, tumor size and DFS/OS, respectively. The multivariate Cox regression analyses revealed HIF-1α overexpression and high tumor grade to be independent predictors for impaired DFS (HIF-1α overexpression: hazard ratio [HR], 2.67; 95% confidence interval [CI], 1.10-6.47; high tumor grade: HR, 5.56; 95% CI, 1.47-21.13) and OS (HIF-1α overexpression: HR, 2.57; 95% CI, 1.06-6.23; high tumor grade: HR, 6.23; 95% CI, 1.49-25.97). The results of 10 studies indicated that HIF-1α overexpression predicted poor DFS (HR, 1.98; 95% CI, 1.22-3.21) and OS (HR, 2.58; 95% CI, 1.86-3.56) for cervical cancer. CONCLUSIONS: The present clinicopathologic study and meta-analysis showed that HIF-1α overexpression is associated with poor survival of cervical cancer and emphasized the importance of HIF-1α as a predictor for cervical cancer.

Altered expression of E-cadherin by hepatocyte growth factor and effect on the prognosis of nasopharyngeal carcinoma.

BACKGROUND AND PURPOSE: Hepatocyte growth factor (HGF)-related E-cadherin expression and prognosis of patients with nasopharyngeal carcinoma (NPC) are not fully understood. This study investigated HGF-induced altered expression of E-cadherin and the relationship between prognosis and modulation of E-cadherin by HGF in NPC. METHODS: 135 cases of NPC were collected, and expression of HGF, c-Met, and E-cadherin in tissue microarray was evaluated by immunohistochemical staining. Correlation between immunostainings and clinicopathological parameters, as well as the follow-up data of patients, was analyzed statistically. The association and alteration of E-cadherin by HGF treatment in NPC cell lines were evaluated by immunocytochemical staining, Western blot, and invasion assay. RESULTS: Both high HGF expression in tumor cells (62.9%, 85/135 cases) and nonmembranous E-cadherin expression (61.5%, 83/135 cases) were significantly associated with advanced clinical stage, lymph node metastasis, and worse prognosis of NPC patients. However, only abnormal E-cadherin expression (P = 0.001) and lymph node metastasis (P = 0.004) emerged as strong independent prognostic factors for overall survival of NPC patients. In vitro, exogenous HGF decreased and internalized E-cadherin expression from cell membrane to cytoplasm, with obvious cellular morphological change. HGF-treated NPC cells exhibited significantly enhanced invasive ability in Matrigel matrix-coated Transwell chamber assay. CONCLUSION: HGF may contribute to cell invasion in NPC by modulating E-cadherin-mediated cell-cell adhesion through downregulation and internalization of E-cadherin. Altered expression of E-cadherin by HGF is a valuable predictor for prognostic evaluation of NPC patients.

Co-elevated expression of hepatocyte growth factor and Interleukin-8 contributes to poor prognosis of patients with primary nasopharyngeal carcinoma.

Hepatocyte growth factor (HGF) related tumor angiogenesis and prognosis of patients with nasopharyngeal carcinoma (NPC) has not been identified. The expressions of HGF and IL-8, as well as microvessels density were evaluated in 127 NPC biopsies by immunohistochemical staining. The correlation between these parameters and patient's clinicopathological features was analyzed statistically. In vitro, IL-8 concentration was evaluated in exogenous HGF-treated NPC cell lines by ELISA assay. The presence of EBV was also detected in NPC cells by PCR for Bam HI-W fragment. Both 54.3% (69/127) cases of HGF high-expression in tumor cells and 80.3% (102/127) of HGF high-expression in stromal cells were significantly associated with increased microvessels density, advanced clinical stage, lymph node metastasis and high-expression of IL-8. Angiogenesis exhibited in relation to overall survival of NPC patients (P=0.001), and the patients with HGF and IL-8 dual high-expression tumors had a significantly worse prognosis than those with single protein high-expression and dual low expression tumors (P=0.011 and P=0.026, respectively). Exogenous HGF was observed to promote induction of IL-8 in NPC cells without EBV infection. Co-operating with IL-8, HGF might contribute to a poor prognosis of NPC by inducing angiogenesis through both autocrine and paracrine EBV-independent pathways.