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To determine the clinicopathologic and immunohistochemical predictors of the persistence/recurrence of cervical intraepithelial neoplasia (CIN) after cervical conization. Medical records of 502 patients who received cervical conization treatment of CIN between 2005 and 2012 were reviewed. The clinicopathologic parameters were analyzed using Cox hazard regression. Fifty patients with CIN persistence/recurrence were matched to 50 cases without CIN persistence/recurrence. These 100 cervical specimens were assessed for expression of insulin-like growth factor II messenger RNA (mRNA)-binding protein 3 (IMP3), targeting protein for xenopus kinesin-like protein 2 (TPX2), and programmed cell death-1 ligand-1 (PD-L1) using immunohistochemical staining. Multivariate analysis found that the independent predictors of CIN persistence/recurrence were positive surgical margin (hazard ratio 5.777, 95% confidence interval 2.334-14.301, p < 0.001) and human papilloma virus persistence for 6 months (hazard ratio 20.685, 95% confidence interval 7.350-57.657, p < 0.001). Co-expression of TPX2 and PD-L1 was significantly higher in CIN persistence/recurrence group than the group without CIN persistence/recurrence (p = 0.013). The depth of glandular involvement (GI) was less than 3mm in about 86.8% (59/68) CIN2-3 lesions, However, No statistically significant associations between GI and persistence/recurrence were observed (P = 0.58). Positive surgical margin, HPV persistence, and expression of both TPX2 and PD-L1 are associated with persistence/recurrence of cervical intraepithelial neoplasia after cervical conization.

Liver metastasis is the main cause of death in patients with colorectal cancer (CRC); thus, necessitating effective biomarkers and therapeutic targets for colorectal cancer liver metastasis (CRLM). Fibroblast growth factor 19 (FGF19) is a protumorigenic gene in numerous human malignancies. In this study, it is shown that FGF19 plays an indispensable role in CRLM. FGF19 expression and secretion are markedly correlated with liver metastasis and lower overall survival rates of patients with CRC. An in vivo metastasis model shows that FGF19 overexpression confers stronger liver‐metastatic potential in CRC cells. Mechanistically, FGF19 exerts an immunomodulatory function that creates an environment conducive for metastasis in CRLM. FGF19 mediates the polarization of hepatic stellate cells to inflammatory cancer‐associated fibroblasts (iCAFs) by activating the autocrine effect of IL‐1α via the FGFR4‐JAK2‐STAT3 pathway. FGF19‐induced iCAFs promote neutrophil infiltration and mediate neutrophil extracellular trap (NET) formation in liver metastatic niches via the production of complement C5a and IL‐1β, which in turn accelerates the liver colonization of CRC cells. Importantly, targeting FGF19 signaling with fisogatinib efficiently suppresses FGF19‐induced liver metastasis in a mouse model. In summary, this study describes the mechanism by which FGF19 regulates CRLM, thereby providing a novel target for CRLM intervention. Liver metastasis is the main cause of colorectal cancer (CRC)‐related deaths in humans. Tumor‐secreted FGF19 mediates the polarization of hepatic stellate cells to inflammatory cancer‐associated fibroblasts (iCAFs), thereby modulating neutrophil infiltration and the metastasis‐supporting neutrophil extracellular traps (NETs) in liver metastatic niches. These promote liver colonization of CRC cells and support FGF19‐targeting therapy for colorectal cancer liver metastasis.

Purpose Squamous cell carcinomas and adenocarcinomas are the most common types of cervical cancer. Compared to squamous cell carcinomas, adenocarcinomas are more common in younger women and have a poorer prognosis. Yet, so far, no useful biomarkers have been developed for these two types of cancer. In the following study, we examined the combination of cytokeratin 5/6, p63, p40 and MUC5AC for distinguishing squamous cell carcinoma (SCC) from adenocarcinoma of the cervix (AEC). Materials and methods A total of 101 SCC and 108 AEC were collected. Immunohistochemical analyses were conducted to determine the expression of CK5/6, p63, p40, CK7 and MUC5AC. One pathologist who was blinded to the patient’s clinical and pathological data interpreted the staining results. Results MUC5AC and CK7 were detected in 81.48 and 82.41% of AEC cases compared to 9.9 and 49.50% of SCC cases ( P  < 0.05); the specificity of MUC5AC was higher than that of CK7 in AEC (P < 0.05). The sensitivity of MUC5AC combined with p40 or p63 was similar to that of CK7, but the specificity was slightly higher than that of CK7 in AEC. Moreover, the expression of MUC5AC was correlated with the degree of tumor differentiation in adenocarcinomas ( P  = 0.036) and was not related to the prognosis of cervical adenocarcinoma and subtypes. Conclusions MUC5AC may be useful as a biomarker for differential diagnoses between squamous carcinoma and adenocarcinoma of the cervix.

Spatial heterogeneity and plasticity of the mammalian liver are critical for systemic metabolic homeostasis in response to fluctuating nutritional conditions. Here, a spatially resolved transcriptomic landscape of mouse livers across fed, fasted and refed states using spatial transcriptomics is generated. This approach elucidated dynamic temporal‐spatial gene cascades and how liver zonation—both expression levels and patterns—adapts to shifts in nutritional status. Importantly, the pericentral nuclear receptor Nr1i3 (CAR) as a pivotal regulator of triglyceride metabolism is pinpointed. It is showed that the activation of CAR in the pericentral region is transcriptionally governed by Pparα. During fasting, CAR activation enhances lipolysis by upregulating carboxylesterase 2a, playing a crucial role in maintaining triglyceride homeostasis. These findings lay the foundation for future mechanistic studies of liver metabolic heterogeneity and plasticity in response to nutritional status changes, offering insights into the zonated pathology that emerge during liver disease progression linked to nutritional imbalances. Spatial transcriptomics reveals how mouse liver zonation adapts to nutritional changes, highlighting the pericentral nuclear receptor CAR as a key regulator of triglyceride metabolism. CAR activation, transcriptionally governed by PPARα, enhances lipolysis during fasting by upregulating carboxylesterase 2a, crucial for maintaining triglyceride homeostasis. This study provides insights into the liver's metabolic heterogeneity and plasticity.

Background Genetic and epigenetic alterations are the two key mechanisms in the development of hepatocellular carcinoma (HCC). However, how they contribute to hepatocarcinogenesis and the correlation between them has not been fully elucidated. Methods A total of 48 paired HCCs and noncancerous tissues were used to detect loss of heterozygosity (LOH) and the methylation profiles of five tumor suppressor genes ( RASSF1A , BLU , FHIT , CRBP1 , and HLTF ) on chromosome 3 by using polymerase chain reaction (PCR) and methylation-specific PCR. Gene expression was analyzed by immunohistochemistry and reverse transcription (RT)-PCR. Results Sixteen of 48 (33.3 %) HCCs had LOH on at least one locus on chromosome 3, and two smallest common deleted regions (3p22.3-24.3 and 3p12.3-14.2) were identified. RASSF1A , BLU, and FHIT showed very high frequencies of methylation in HCCs (100, 81.3, and 64.6 %, respectively) and noncancerous tissues, but not in liver tissues from control patients. Well-differentiated HCCs showed high methylation frequencies of these genes but very low frequencies of LOH. Furthermore, BLU methylation was associated with an increased level of alpha-fetoprotein, and FHIT methylation was inversely correlated with HCC recurrence. In comparison, CRBP1 showed moderate frequencies of methylation, while HLTF showed low frequencies of methylation, and CRBP1 methylation occurred mainly in elderly patients. Treatment with 5-aza-2′-deoxycytidine demethylated at least one of these genes and restored their expression in a DNA methylation-dependent or -independent manner. Conclusions Hypermethylation of RASSF1A , BLU, and FHIT is a common and very early event in hepatocarcinogenesis; CRBP1 methylation may also be involved in the later stage. Although LOH was not too frequent on chromosome 3, it may play a role as another mechanism in hepatocarcinogenesis.

Background E2F1 transcription factor plays a vital role in the regulation of diverse cellular processes including cell proliferation, apoptosis, invasion and metastasis. E2F1 overexpression has been demonstrated in small cell lung cancer (SCLC), and extensive metastasis in early phase is the most important feature of SCLC. In this study, we investigated the involvement of E2F1 in the process of invasion and metastasis in SCLC by regulating the expression of matrix metalloproteinases (MMPs). Methods Immunohistochemistry was performed to evaluate the expression of E2F1 and MMPs in SCLC samples in a Chinese Han population. The impact of E2F1 on invasion and metastasis was observed by transwell and wound healing experiments with depletion of E2F1 by specific siRNA. The target genes regulated by E2F1 were identified by chromatin immunoprecipitation (ChIP)-to-sequence, and the expressions of target genes were detected by real time PCR and western blotting. The dual luciferase reporter system was performed to analyze the regulatory relationship between E2F1 and MMPs. Results E2F1 is an independent and adverse prognosis factor that is highly expressed in SCLC in a Chinese Han population. Knockdown of E2F1 by specific siRNA resulted in the downregulation of migration and invasion in SCLC. The expressions of MMP-9 and −16 in SCLC were higher than other MMPs, and their expressions were most significantly reduced after silencing E2F1. ChIP-to-sequence and promoter-based luciferase analysis demonstrated that E2F1 directly controlled MMP-16 expression via an E2F1 binding motif in the promoter. Although one E2F1 binding site was predicted in the MMP-9 promoter, luciferase analysis indicated that this binding site was not functionally required. Further study demonstrated that E2F1 transcriptionally controlled the expression of Sp1 and p65, which in turn enhanced the MMP-9 promoter activity in SCLC cells. The associations between E2F1, Sp1, p65, and MMP-9 were validated by immunohistochemistry staining in SCLC tumors. Conclusions E2F1 acts as a transcriptional activator for MMPs and directly enhances MMP transcription by binding to E2F1 binding sequences in the promoter, or indirectly activates MMPs through enhanced Sp1 and NF-kappa B as a consequence of E2F1 activation in SCLC.

Purpose Alteration of CyclinD1 was suggested to relate with development of endometrial carcinogenesis before, however CyclinD1 expression is not well defined in endometrial hyperplasia lesions. We checked the relationship between its expression and clinic-pathological variables of endometrial lesions to explore the possibility for CyclinD1 as a potential diagnostic and prognostic marker. Methods Cyclin D1 immunohistochemical analysis (IHC) was used to evaluate 201 fixed, paraffin-embedded endometrial samples which included simple hyperplasia (n = 27), atypical complex hyperplasia (ACH) (n = 41), endometrioid carcinoma (n = 103), endometrial serous carcinoma (ESC) (n = 21) and clear cell carcinoma (CCC) (n = 9). A breast cancer with known CyclinD1 expression was selected as a positive control in each immunohistochemistry run. We also performed follow-up study to estimate patients’ prognosis. Results CyclinD1 was significantly overexpressed in atypical complex hyperplasia (ACH), endometrioid carcinoma and clear cell carcinoma (CCC). The positive signaling of CyclinD1 was showed less than 40% in simple hyperplasia and endometrial serous carcinoma (ESC). The high expression of CyclinD1 was observed in metastasis carcinoma group more significantly than non-metastasis carcinoma group. Kaplan Meier analysis demonstrated that patients with high CyclinD1 expression had an obviously poor prognosis than patients without CyclinD1 staining ( p  < 0.05). Moreover, according to multivariate Cox regression analysis, CyclinD1 expression, as crucial as metastasis, was a risk marker for overall survival rate. Conclusion CyclinD1 exhibited a promising potential to predict the prognosis of patients with endometrial carcinoma. However, the statistical analysis demonstrated that CyclinD1 exhibited a poor ability to differentiate neoplastic lesions from non-neoplastic lesions; thus, the application of CyclinD1 only is not so credible for differentiation between benign and malignant lesions. Virtual slides The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1871063048950173 .

Protein arginine methyltransferase 5 (PRMT5) has previously been reported to be upregulated in many malignant tumors. This study investigated the significance of PRMT5 in endometrial carcinoma (EC) and explored its function in tumorigenesis. Immunohistochemistry was performed to evaluate PRMT5 expression in 62 EC and 66 endometrial hyperplasia samples. The functions of PRMT5 were investigated by cell counting kit‐8, plate colony formation, wound healing, and transwell and flow cytometry assays. Quantitative reverse transcription‐polymerase chain reaction and western blotting were used to measure the expression of PRMT5, changes in estrogen receptor α (ERα), and related functional proteins. Coimmunoprecipitation was performed to examine the interaction of PRMT5 with ERα and its coactivator steroid receptor coactivator‐1 (SRC1). Compared to endometrial hyperplasia tissue, PRMT5 was overexpressed in endometrioid adenocarcinoma (EAC) but not overexpressed in mucinous EC. The main expression pattern of PRMT5 in EAC was cytoplasmic. However, the positive cases of endometrial hyperplasia showed both cytoplasmic and nuclear positivity in the endometrial glands or were mainly positive in stromal cells. Knockdown of PRMT5 significantly inhibited the growth and migration ability of EAC cells and promoted their apoptosis by regulating cyclin D1, c‐myc, p53, and Bcl2 proteins. Furthermore, PRMT5 could form a complex with ERα and SRC1 to promote the expression of ERα. In conclusion, PRMT5 plays a significant role in the progression of EAC by interacting with ERα and impacting the cell cycle signaling pathways.

Diagnosis of a glioblastoma (GBM) is triggered by the onset of symptoms and is based on cerebral imaging and histological examination. Serum-based biomarkers may support detection of GBM. Here, we explored serum protein concentrations of GBM patients and used data mining to explore profiles of biomarkers and determine whether these are associated with the clinical status of the patients. Gene and protein expression data for astrocytoma and GBM were used to identify secreted proteins differently expressed in tumors and in normal brain tissues. Tumor expression and serum concentrations of 14 candidate proteins were analyzed for 23 GBM patients and nine healthy subjects. Data-mining methods involving all 14 proteins were used as an initial evaluation step to find clinically informative profiles. Data mining identified a serum protein profile formed by BMP2, HSP70, and CXCL10 that enabled correct assignment to the GBM group with specificity and sensitivity of 89 and 96%, respectively ( p  < 0.0001, Fischer’s exact test). Survival for more than 15 months after tumor resection was associated with a profile formed by TSP1, HSP70, and IGFBP3, enabling correct assignment in all cases ( p  < 0.0001, Fischer’s exact test). No correlation was found with tumor size or age of the patient. This study shows that robust serum profiles for GBM may be identified by data mining on the basis of a relatively small study cohort. Profiles of more than one biomarker enable more specific assignment to the GBM and survival group than those based on single proteins, confirming earlier attempts to correlate single markers with cancer. These conceptual findings will be a basis for validation in a larger sample size.

Drug resistance in breast cancer remains a major cause for the failure of chemotherapy. Glucosylceramide synthase (GCS) plays an important role in multidrug resistance (MDR) in breast cancer. P-glycoprotein (P-gp) also confers a cross-resistance of many unrelated drugs. In this study, we studied the MDR effect and potential mechanisms of breast cancer after constructing permanent breast cancer cell lines with GCS knockout by using recombinant vectors targeting GCS (pSUPER-GCSshRNAs). The GCSshRNA stably transfected cells were successfully established and significant lower levels of GCS mRNA and protein expression were confirmed. In in vitro experiments, the GCSshRNA stably transfected cells showed a significantly reduced level of MDR1 and P-gp expression and decreased drug efflux ability. Reduced level of GCS expression conveyed a significant reversal of drug resistance by MTT assay and increased caspase-3 activity. In in vivo experiments by using nude mice with xenograft tumors, a significant inhibition of tumor growth was observed after comparing with the control group. Furthermore, enhanced response of chemotherapy was acquired by reduced expression of GCS as well as MDR1 in vivo. In conclusion, GCSshRNA could efficiently suppress GCS and MDR1 expression in vitro and in vivo and these findings may be used as one of the methods to reverse MDR in breast cancer.