Gliclazide Reduces Colitis-Associated Colorectal Cancer Formation by Deceasing Colonic Inflammation and Regulating AMPK-NF-κB Signaling Pathway.

BACKGROUND: Gliclazide is a potential anti-cancer drug candidate for preventing carcinogenesis. However, the effect of gliclazide on colitis-associated colorectal cancer remains unknown. AIMS: We aimed to evaluate whether gliclazide plays a protective role in colitis-associated colorectal cancer and the underlying molecular mechanism. METHODS: The administration of azoxymethane (AOM) followed by dextran sulfate sodium (DSS) aimed to induce colitis-associated colorectal cancer in mice. C57BL mice were gavaged with gliclazide (6 mg/kg by gavage 5 days a week) for 12 weeks immediately following AOM administration. After sacrificing the mice, colon tissues were measured for tumor number and tumor burden. The proliferation- and inflammation-related molecular mechanisms were explored. RESULTS: The administration of gliclazide significantly reduced the tumor number and tumor burden in mice. Cell proliferation decreased in the gliclazide group compared with the control group, as indicated by reduced Ki-67 expression. Furthermore, gliclazide alleviated colonic inflammation, significantly decreased pro-inflammatory factor TNF-α levels and increased anti-inflammatory factor IL-10 levels in vivo. In vivo and vitro, it was shown that gliclazide increased the level of phospho-AMPK (p-AMPK) and inhibited NF-κB activity. Further studies demonstrated that the inhibition of NF-κB activity induced by gliclazide was mediated by p-AMPK in vitro. CONCLUSIONS: Gliclazide effectively alleviated colonic inflammation and prevented colonic carcinogenesis in an AOM-DSS mouse model by modulating the AMPK-NF-κB signaling pathway. Thus, gliclazide holds potential as a chemopreventive agent for colitis-associated colorectal cancer.

SETDB1 promotes gastric carcinogenesis and metastasis via upregulation of CCND1 and MMP9 expression.

SETDB1 is a histone lysine methyltransferase that has critical roles in cancers. However, its potential role in gastric cancer (GC) remains obscure. Here, we mainly investigate the clinical significance and the possible role of SETDB1 in GC. We find that SETDB1 expression is upregulated in GC tissues and its high-level expression was a predictor of poor prognosis in patients. Overexpression of SETDB1 promoted cell proliferation and metastasis, while SETDB1 suppression had an opposite effect both in vitro and in vivo. Mechanistically, SETDB1 was shown to interact with ERG to promote the transcription of cyclin D1 (CCND1) and matrix metalloproteinase 9 (MMP9) through binding to their promoter regions. In addition, the expression of SETDB1 was also enhanced by the transcription factor TCF4 at the transcriptional level in GC. Furthermore, SETDB1 expression was found to be induced by Helicobacter pylori (H. pylori) infection in a TCF4-dependent manner. Taken together, our results indicate that SETDB1 is aberrantly overexpressed in GC and plays key roles in gastric carcinogenesis and metastasis via upregulation of CCND1 and MMP9. Our work also suggests that SETDB1 could be a potential oncogenic factor and a therapeutic target for GC. © 2020 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Thyroid carcinoma producing ß-human chorionic gonadotropin shows different clinical behavior.

Columnar cell variant of papillary thyroid carcinoma (CCV-PTC) is an unusual neoplasm, the clinical behavior of which mainly depends on the encapsulation or infiltration. Patients with extensive extrathyroidal extension usually have an aggressive biological behavior. This study confirmed that beta-human chorionic gonadotropin (ß-hCG) secreting invasive CCV-PTC has good prognosis comparing with a cohort of follicular cell differentiated thyroid carcinoma. On the contrary, positive immunoreaction with ß-hCG was proved in three anaplastic thyroid carcinoma patients showing aggressive clinical courses. The clinicopathologic characteristics of CCV-PTC and the paraneoplastic syndromes in follicular cell differentiated thyroid carcinoma were further summarized using literature review.

Diagnostic pitfalls in pathological diagnosis of infectious disease: patients with syphilitic lymphadenitis often present with inconspicuous history of infection.

Retrospective study was applied to 16 cases of syphilitic lymphadenitis to elucidate the pathological diagnostic features. The typical morphology of syphilitic lymphadenitis includes: (i) well preserved or partially destroyed lymph node structure; (ii) reactive hyperplasia of lymph follicles with broadened germinal centers in the cortex and medulla of the lymph node; (iii) thickened fibrotic lymph node capsules with infiltration of plasma cells; and (iv) phlebitis and endarteritis in varying degree. Additional morphology includes: (i) focal histiocytes with ingested debris; (ii) noncaseating granuloma with epithelioid histiocytes and disperse giant cells; and (iii) hyperplastic centroblast and occasionally isolated mononuclear Reed-Sternberg cell-like giant cells. Treponema pallidum was identified in 15 of the 16 cases by immunohistochemical staining. The histopathological diagnosis of syphilitic lymphadenitis poses difficulty in differentiation from other infectious or neoplastic lymphadenopathies. The newly established Treponema pallidum antibody is sensitive to identification of Treponema pallidum in formalin fixed paraffin embedded tissue.

Case report: A rare case of very well-differentiated gastric adenocarcinoma of gastric type with a lymphovascular invasion.

Background: Very well-differentiated gastric adenocarcinoma (VWDA) is a rare variant of gastric cancer, for which the diagnostic criteria and clinical behavior are not fully established. We reported a case of an intramucosal VWDA of gastric type with a lymphovascular invasion (LVI). Case presentation: A 67-year-old female was diagnosed as intramucosal gastric adenocarcinoma after a biopsy at the local hospital 3 weeks ago and then visited our hospital for further treatment. The endoscopic examination in our hospital showed a rough, slightly faded, 30-mm, flat, and elevated lesion on the lesser curvature of the middle gastric body. Histopathologically, the lesion consisted of superficial foveolar-type papillary adenocarcinoma and deep pyloric gland-type tubular adenocarcinoma. The immunostaining results showed that the foveolar-type papillary adenocarcinoma was positive for MUC5AC and had a high index of Ki-67, but the pyloric gland-type tubular adenocarcinoma was positive for MUC6 and had a low index of Ki-67. Both components were negative for MSH2 and MSH6, which suggested the high microsatellite instability phenotype. Moreover, a LVI was detected in the lesion. The pathological diagnosis was VWDA of gastric type. Conclusion: The case has unique histological and immunophenotypic characteristics, which not only indicates the importance of architectural features in the diagnosis of VWDA but also further proves that the aggressive behavior of VWDA is correlated with tumor histological type and immunophenotype.

Decabromodiphenyl ether exposure reduces dabrafenib sensitivity of papillary thyroid carcinoma harboring BRAFV600E mutation through the EGFR-CRAF-MAPK pathway: An in vitro study.

Decabromodiphenyl ether (BDE209) has been demonstrated to be associated with thyroid dysfunction and thyroid carcinoma risk as a widely used brominated flame retardants. Although dabrafenib has been confirmed to be a promising therapeutic agent for papillary thyroid carcinoma (PTC) harboring BRAFV600E mutation, the rapid acquired dabrafenib resistance has brought a great challenge to clinical improvement and the underpinning mechanisms remain poorly defined. By treating PTC-derived and normal follicular epithelial cell lines with BDE209, we assessed its impact on the MAPK pathway's activation and evaluated the resultant effects on cell viability and signaling pathways, utilizing methods such as Western blot, IF staining, and RNA-seq bioinformatic analysis. Our findings reveal that BDE209 exacerbates MAPK activation, undermining dabrafenib's inhibitory effects by triggering the EGFR pathway, thereby highlighting BDE209's potential to diminish the pharmacological efficacy of dabrafenib in treating BRAF-mutated PTC. This research underscores the importance of considering environmental factors like BDE209 exposure in the effective management of thyroid carcinoma treatment strategies.

KDM6B promotes gastric carcinogenesis and metastasis via upregulation of CXCR4 expression.

KDM6B (Lysine-specific demethylase 6B) is a histone lysine demethyltransferase that plays a key role in many types of cancers. However, its potential role in gastric cancer (GC) remains unclear. Here, we focused on the clinical significance and potential role of KDM6B in GC. We found that the KDM6B expression is upregulated in GC tissues and that its high expression in patients is related to poor prognosis. KDM6B ectopic expression promotes GC cells' proliferation and metastasis, while its inhibition has opposite effects in vitro and in vivo. Mechanistically, KDM6B promotes GC cells proliferation and metastasis through its enzymatic activity through the induction of H3K27me3 demethylation near the CXCR4 (C-X-C chemokine receptor type 4) promoter region, resulting in the upregulation of CXCR4 expression. Furthermore, H. pylori was found to induce KDM6B expression. In conclusion, our results suggest that KDM6B is aberrantly expressed in GC and plays a key role in gastric carcinogenesis and metastasis through CXCR4 upregulation. Our work also suggests that KDM6B may be a potential oncogenic factor and a therapeutic target for GC.

Long-Term Exposure to Decabromodiphenyl Ether Promotes the Proliferation and Tumourigenesis of Papillary Thyroid Carcinoma by Inhibiting TRß.

Polybrominated diphenyl ethers (PBDEs) have been reported to possess endocrine-disrupting and tumour-promoting activity. However, the effects of long-term exposure to decabromodiphenyl ether (BDE209) on thyroid tumourigenesis of papillary thyroid carcinoma (PTC) and the underlying mechanisms remain poorly defined. In this study, functional assays in vitro and mouse models in vivo were used to evaluate the toxic effects of long-term exposure to environmental concentrations of BDE209 on the pathogenesis and progression of PTC. MTS, EdU and colony-forming assays confirmed the chronic toxicity of BDE209 on the proliferation of human normal follicular epithelial cell line (Nthy-ori 3-1) and PTC-derived cell lines (TPC-1 and BCPAP). Wound and Transwell assays showed that BDE209 exacerbated the aggressiveness of PTC cells. BDE209 significantly promoted cell proliferation during the S and G2/M phases of the cell cycle. Mechanistically, BDE209 altered the thyroid system by acting as a competitive inhibitor of thyroid receptor beta (TRß) expression and function, which was further proven by public databases and RNA-seq bioinformation analysis. Taken together, these results demonstrated that BDE209 has chronic toxicity and potential tumourigenic effects on the thyroid by inhibiting TRß.

Efficacy and Safety of Pyrotinib in Human Epidermal Growth Factor Receptor 2-Positive Advanced Breast Cancer: A Multicenter, Retrospective, Real-World Study.

Purpose: Pyrotinib, a novel human epidermal growth factor receptor 2 (HER2)-targeted tyrosine kinase inhibitor (TKI), has led to remarkable survival outcomes in HER2-positive advanced breast cancer (ABC) in clinical trials and was approved for second-line standards of treatment for HER2+ ABC in China. However, the clinical trials could not fully reflect reality of clinical practice, and predictive factors were still lacking. This study aimed to assess the actual efficacy and safety of pyrotinib in HER2+ ABC in real-world setting. Patients and Methods: In this multicenter, retrospective, observational real-world study, we analyzed 171 patients with HER2+ ABC, who received pyrotinib-based treatment from November 2017 to November 2020. The primary end point was progression-free survival (PFS). Secondary end points included overall survival (OS), objective response rate (ORR), clinical benefit rate (CBR) and safety. Results: Up to November 30, 2021, the median PFS (mPFS) was 12.0 months for all patients. One hundred and sixty-two patients (94.7%) with measurable lesions had been included in efficacy assessment. The ORR and CBR were 45.1% and 81.5%, respectively. A significantly longer PFS was reported in patients who received pyrotinib as first-line treatment, had the ECOG-PS of 0-1, as well as those who were lapatinib-naive. In addition, multivariable analysis indicated that ECOG-PS of 2-4, positive hormone receptor (HR) status, and presence of visceral metastasis were independent negative predictors of PFS. As far as we know, this study first reported the survival outcome of pyrotinib cross-line treatment, with a mPFS of 5.0 months. All grades of adverse events (AEs) occurred in 171 patients (100%), and the most common AE was diarrhea (86.5%). Conclusion: This study further demonstrated the outstanding efficacy and safety of pyrotinib and reported the potential predictors of survival in HER2+ ABC.

Pathogen Distribution and Antimicrobial Resistance of Early Onset Sepsis in Very Premature Infants: A Real-World Study.

INTRODUCTION: Early onset sepsis (EOS) remains a potentially fatal newborn condition, especially in very preterm infants. Data on the pathogen distribution and antibiotic susceptibility patterns of EOS among very preterm infants are scarce but essential for the choice of empirical antibiotic administration. We sought to assess the epidemiologic characteristics and antibiotic susceptibility patterns of pathogens causing EOS among a cohort of very preterm infants in China. METHODS: This prospective, observational study included a cohort of infants born at a gestational age (GA) less than 32 weeks of 32 newborn intensive care units (NICUs) in China between January 1, 2018 and December 31, 2020. EOS was defined by isolation of pathogenic species from blood culture within 72 h of birth. RESULTS: A total of 108 EOS cases (18.4 per 1000 admissions) were identified among 5865 very preterm infants. Incidence of EOS increased with the decrease of GA and birthweight. Escherichia coli (n = 44, 40.7%) was the most common pathogen, followed by Klebsiella spp. (n = 10, 9.3%). The distribution and proportion of pathogenic bacteria varied significantly by GA. E. coli and Klebsiella spp. showed high resistance to ampicillin and third-generation cephalosporins, while they showed good susceptibility to carbapenem antibiotics and piperacillin-tazobactam. CONCLUSION: Our data demonstrated that pathogens causing neonatal EOS showed high rates of resistance to ampicillin and third-generation cephalosporins. This raised questions about the best empirical antibiotic choice for preterm infants suspected of having EOS in low- and middle-income countries (LMICs).

A Tumor Progression Related 7-Gene Signature Indicates Prognosis and Tumor Immune Characteristics of Gastric Cancer.

BACKGROUND: Gastric cancer is a common gastrointestinal malignancy. Since it is often diagnosed in the advanced stage, its mortality rate is high. Traditional therapies (such as continuous chemotherapy) are not satisfactory for advanced gastric cancer, but immunotherapy has shown great therapeutic potential. Gastric cancer has high molecular and phenotypic heterogeneity. New strategies for accurate prognostic evaluation and patient selection for immunotherapy are urgently needed. METHODS: Weighted gene coexpression network analysis (WGCNA) was used to identify hub genes related to gastric cancer progression. Based on the hub genes, the samples were divided into two subtypes by consensus clustering analysis. After obtaining the differentially expressed genes between the subtypes, a gastric cancer risk model was constructed through univariate Cox regression, least absolute shrinkage and selection operator (LASSO) regression and multivariate Cox regression analysis. The differences in prognosis, clinical features, tumor microenvironment (TME) components and immune characteristics were compared between subtypes and risk groups, and the connectivity map (CMap) database was applied to identify potential treatments for high-risk patients. RESULTS: WGCNA and screening revealed nine hub genes closely related to gastric cancer progression. Unsupervised clustering according to hub gene expression grouped gastric cancer patients into two subtypes related to disease progression, and these patients showed significant differences in prognoses, TME immune and stromal scores, and suppressive immune checkpoint expression. Based on the different expression patterns between the subtypes, we constructed a gastric cancer risk model and divided patients into a high-risk group and a low-risk group based on the risk score. High-risk patients had a poorer prognosis, higher TME immune/stromal scores, higher inhibitory immune checkpoint expression, and more immune characteristics suitable for immunotherapy. Multivariate Cox regression analysis including the age, stage and risk score indicated that the risk score can be used as an independent prognostic factor for gastric cancer. On the basis of the risk score, we constructed a nomogram that relatively accurately predicts gastric cancer patient prognoses and screened potential drugs for high-risk patients. CONCLUSIONS: Our results suggest that the 7-gene signature related to tumor progression could predict the clinical prognosis and tumor immune characteristics of gastric cancer.

YKT6, as a potential predictor of prognosis and immunotherapy response for oral squamous cell carcinoma, is related to cell invasion, metastasis, and CD8+ T cell infiltration.

Metastasis and immune suppression account for the poor prognosis of oral squamous cell carcinoma (OSCC). YKT6 is a member of the soluble NSF attachment protein receptor (SNARE) family, and the effect of YKT6 in OSCC remains elusive. The purpose of this study was to explore promising prognostic and immune therapeutic candidate biomarkers for OSCC and to understand the expression pattern, prognostic value, immune effects, and biological functions of YKT6. Genes correlated with tumor metastasis and CD8 + T cell levels were identified by weighted gene coexpression network analysis (WGCNA). Next, YKT6 was analyzed through differential expression, prognostic and machine learning analyses. The molecular and immune characteristics of YKT6 were analyzed in independent cohorts, clinical specimens, and in vitro. In addition, we investigated the role of YKT6 at the pan-cancer level. The results suggested that the red module in WGCNA, as a hub module, was associated with lymph node (LN) metastasis and CD8 + T cell infiltration. Upregulation of YKT6 was found in OSCC and linked to adverse prognosis. A nomogram model containing YKT6 expression and tumor stage was constructed for clinical practice. The aggressive and immune-inhibitory phenotypes showed YKT6 overexpression, and the effect of YKT6 on OSCC cell invasion and metastasis in vitro was observed. Moreover, the low expression of YKT6 was correlated with high CD8 + T cell levels and potential immunotherapy response in OSCC. Similar results were found at the pan-cancer level. In total, YKT6 is a promising candidate biomarker for prognosis, molecular, and immune characteristics in OSCC.

miR-106a Regulates Cell Proliferation and Autophagy by Targeting LKB1 in HPV-16-Associated Cervical Cancer.

miR-106a is aberrantly regulated in various tumors and plays an important role in carcinogenesis. However, the biological role and molecular mechanism by which miR-106a contributes to cervical squamous cell carcinoma (CSCC) remains elusive. In this study, we verified that miR-106a was elevated in both human papilloma virus (HPV) 16-positive CSCC tissues and cell lines. ROC curve analysis showed that miR-106a could well distinguish HPV-16-positive CSCC tissues from normal cervical squamous epithelium tissues. High expression of miR-106a was associated with malignant clinicopathologic parameters in CSCC tissues. Exogenous expression of miR-106a greatly promoted cervical cancer cell proliferation while attenuated autophagy. Furthermore, a novel target of miR-106a, liver kinase B1 (LKB1), a proven tumor suppressor in cervical cancer was verified. Here we confirmed LKB1 was negatively correlated with malignant clinicopathologic parameters in CSCC tissues. Overexpression of LKB1 neutralized the effect of miR-106a on proliferation and autophagy in cervical cancer cell lines. In addition, the role of miR-106a in cell proliferation and autophagy was via LKB1 and its downstream pathway AMP-activated protein kinase-mammalian target of rapamycin. Of note, miR-106a was upregulated by HPV-16 E7 protein. The function of HPV-16 E7 to cell proliferation was suppressed when knockdown miR-106a in HPV-16 E7-expressing cells. IMPLICATIONS: Our study highlights the tumorigenic role and regulatory mechanism of miR-106a in CSCC. miR-106a may be a potential therapeutic target in HPV-associated cervical cancer.

HPV E7-mediated NCAPH ectopic expression regulates the carcinogenesis of cervical carcinoma via PI3K/AKT/SGK pathway.

Cervical cancer is one of the most common gynecological tumors in the world, and human papillomavirus (HPV) infection is its causative agent. However, the molecular mechanisms involved in the carcinogenesis of cervical cancer still require clarification. Here we found that knockdown of Non-SMC (Structural Maintenance of Chromosomes) condensin I complex subunit H (NCAPH) gene expression significantly inhibited the proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) of cervical cancer cells in vitro, and restrained xenograft tumor formation in vivo. Intriguingly, HPV E7 could form a positive feedback loop with NCAPH. E7 upregulated NCAPH gene expression via E2F1 which initiated NCAPH transcription by binding to its promoter directly. Silencing of NCAPH reduced E7 transcription via promoting the transition of AP-1 heterodimer from c-Fos/c-Jun to Fra-1/c-Jun. Moreover, the E7-mediated NCAPH overexpression was involved in the activation of the PI3K/AKT/SGK signaling pathway. In vivo, NCAPH expression in cervical cancer tissues was significantly higher than which in normal cervix and high-grade squamous intraepithelial lesion (HSIL) tissues, and its expression was significantly correlated with tumor size, depth of invasion and lymph node metastasis. Patients with high NCAPH expression had a significantly better survival outcomes than those with low-expression, suggesting that NCAPH-induced cell proliferation might sensitize cancer cells to adjuvant therapy. In conclusion, our results revealed the role of NCAPH in the carcinogenesis of cervical cancer in vitro and in vivo. The interaction between E7 and NCAPH expands the mechanism of HPV induced tumorigenesis and that of host genes regulating HPV E7.

Genistein inhibits human papillary thyroid cancer cell detachment, invasion and metastasis.

Papillary thyroid carcinoma (PTC) is the most commonly diagnosed endocrine cancer, and those with BRAFV600E mutation have high recurrence rate and less favorable clinical behavior. Genistein having anti-carcinoma effects in various types of carcinomas as an estrogen analog, but the mechanism of Genistein in the progression of PTC remains unknown. Genistein significantly inhibits the proliferation and the invasion (P < 0.01), and the apoptosis (P < 0.001) of all tumor cell lines, which was probably due to the inducing of the arrest in G2/M phase of the cell cycle (P < 0.001). The anti-proliferation and apoptosis inducing effects are more obvious in BCPAP, IHH4 cell lines harboring BRAFV600E mutation. Genistein significantly decreased the invasion of PTC cell lines and partially reverses epithelial mesenchymal transition in PTC cell lines. Functional study indicated that small interfering RNA (siRNA) knockdown of ß-catenin significantly reverses the effect of genistein on EMT at protein levels. In conclusion, for the first time, our study suggested that genistein has anticarcinoma effect for PTC patients in the range of 2.5 and 80 µg/ml in thyroid carcinoma cells, which was probably through cytoplasmic translocation of ß-catenin. Further study will be needed to determine whether genistein could be used in clinical trial of high-risk PTC.