Showing papers in "Pathology Research and Practice in 2019"

Curcumin inhibits NF-kB and Wnt/β-catenin pathways in cervical cancer cells.

Abstract: Curcumin is a natural non-toxic phenol which is isolated from Curcumin longa L. Mounting evidence has revealed the anticancer properties of curcumin in various tumors, but the underlying molecular mechanisms of this suppression in cervical cancer is still remained unclear. Here we assessed the antitumor effects of curcumin compared with 5-Fluorouracil in Hella cells in spheroids models and monolayer cell cultures. The anti-proliferative effects of curcumin and 5-Fluorouracil were as examined in spheroid and monolayer models. The expression levels of Wnt/β-catenin and NF-kB pathways as well as the influence of the cell cycle were evaluated. Curcumin inhibited cell growth in Hella cells through the regulation of NF-kB and Wnt pathways. Also, cells developed a G2/M cell cycle arrest followed by sub-G1 apoptosis with 5-Fluorouracil and curcumin. It was also shown that curcumin either considerably affects the Wnt/β-catenin and NF-kB pathways. We showed that curcumin inhibits invasion and proliferation of cervical cancer cells via impairment of NF-kB and Wnt/β-catenin pathways, proposing further studies on the potential impacts of this compound on cancer therapy.

The RNA m6A methyltransferase METTL3 promotes pancreatic cancer cell proliferation and invasion.

Abstract: Epigenetic modifications are involved in carcinogenesis and METTL3 is involved in RNA methylation. This study aimed to explore the role of the RNA m6A methyltransferase METTL3 in pancreatic cancer cells. The m6A modification was analyzed in human pancreatic cancer and paracancerous specimens, as well as in the normal HPDE6-C7 pancreatic cell line and the MIA-PaCa-2 and BxPC-3 pancreatic cancer cell lines. Immunohistochemistry (IHC), western blotting, and RT-qPCR were used to detect the expression of METTL3. Cell lines were transfected with siRNAs against METLL3. Proliferation, invasion, and migration were examined. The functions of METTL3 were predicted by bioinformatics analysis. In the 40 patients included, high METTL3 expression was associated with high pathological stage (P = 0.02) and high N stage (P = 0.02). Survival was better in patients with low METTL3 expression compared with those with high MTTL3 expression (P

Inhibition of hsa_circ_0001313 (circCCDC66) induction enhances the radio-sensitivity of colon cancer cells via tumor suppressor miR-338-3p: Effects of cicr_0001313 on colon cancer radio-sensitivity.

Abstract: Circular RNA_0001313 (circ_0001313), also known as circCCDC66, is a novel circRNA that recently found to be upregulated in colon cancer tissues and promote colon cancer progression. However, the role of circ_0001313 in regulating radio-sensitivity of colon cancer and its molecular mechanism remain undetermined. Here we found circ_0001313 was significantly upregulated and miR-338-3p was downregulated in radio-resistant colon cancer tissues compared to radio-sensitive tissues. Radiation treatment in colon cells triggered a remarkable upregulation of circ_0001313 and a downregulation of miR-338-3p. Knockdown of circ_0001313 reduced cell viability, colony formation rate and increased caspase-3 activity in colon cancer cells under irradiation. Moreover, circ_0001313 act as a sponge for miR-338-3p in colon cancer cells. Furthermore, miR-338-3p could reverse the effects of circ_0001313 knockdown on cell viability, colony formation, and caspase-3 activity. These findings revealed that knockdown of circ_0001313 could induce radio-sensitivity of colon cancer cells by negatively regulating miR-338-3p.

The metalloprotease ADAM17 in inflammation and cancer.

Abstract: Proteolytic cleavage of transmembrane proteins is an important post-translational modification that regulates the biological function of numerous transmembrane proteins. Among the 560 proteases encoded in the human genome, the metalloprotease A Disintegrin and Metalloprotease 17 (ADAM17) has gained much attention in recent years and has emerged as a central regulatory hub in inflammation, immunity and cancer development. In order to do so, ADAM17 cleaves a variety of substrates, among them the interleukin-6 receptor (IL-6R), the pro-inflammatory cytokine tumor necrosis factor α (TNFα) and most ligands of the epidermal growth factor receptor (EGFR). This review article provides an overview of the functions of ADAM17 with a special focus on its cellular regulation. It highlights the importance of ADAM17 to understand the biology of IL-6 and TNFα and their role in inflammatory diseases. Finally, the role of ADAM17 in the formation and progression of different tumor entities is discussed.

lncRNAPVT1 targets miR-152 to enhance chemoresistance of osteosarcoma to gemcitabine through activating c-MET/PI3K/AKT pathway.

Abstract: Background: LncRNA PVT1 has been reported to be involved in a variety of biological processes, including cell proliferation, cell differentiation and cancer progression. However, the mechanism by which LncRNA PVT1 contributes to chemoresistance of osteosarcoma cell, has not been fully elucidated. Methods: We first generatedLncRNA PVT1-overexpressed MG63 cells and LncRNA PVT1 knockdown MG63/DOX cells. Then, we examined the effect of LncRNA PVT1 on cell viability and colony formation ability by MTT assay and soft agar assay, respectively. In addition, we performed flow cytometry analysis to detect apoptosis induced by GEM. Dual luciferase reporter assay and RIP were used to confirmed the interaction between LncRNA PVT1 and miR-152. Finally, we determined protein level of c-MET, p-PI3K, and p-AKT by westernblot. Results: LncRNA PVT1 overexpression promoted cell proliferation and exhibited the anti-apoptotic property in LncRNA PVT1-overexpressing MG63 cells treated with gemcitabine. While, LncRNA PVT1-depleted MG63/DOX cells treated with gemcitabine exhibited significant lower survival rate and high percentage of apoptosis. Next, we found that LncRNA PVT1 could target and downregulated the level of miR-152. Interestingly, miR-152 greatly rescued the biological outcomes of LncRNA PVT1 not only in MG63 but also in MG63/DOX cells. We observed that LncRNA PVT1 markedly induced PI3K/AKT pathway activation, which was abolished by miR-152 mimics overexpression. Finally, c-MET inhibitor was used to confirm the essential role of c-MET in LncRNA PVT1 and miR-152-regulated PI3K/AKT signaling. Conclusion: We showed thatlncRNA PVT1 played a contributory role in chemoresistance of osteosarcoma cells through c-MET/PI3K/AKT pathway activation, which was largely dependent on miR-152. Our findings advance our understanding of how lncRNA PVT1 promotes chemoresistance of osteosarcoma cells and facilitate development of novel strategies for treating osteosarcoma.

Detection of circulating exosomal miR-17-5p serves as a novel non-invasive diagnostic marker for non-small cell lung cancer patients.

Abstract: Exosome-shuttled bioactive miRNAs act as novel non-invasive biomarkers for cancer diagnosis have received increasing attention. In this study, we aimed to investigate the expression signatures of exosomal miRNAs and develop a serum exosome-derived miRNA panel for diagnosis of non-small cell lung cancer (NSCLC). The miR-17-92 cluster including 6 miRNAs (miR-17-5p, miR-18a-5p, miR-19a-3p, miR-19b-1-5p, miR-20a-5p and miR-92a-1-5p) was selected as potential diagnostic candidate molecule. Then, expression profiles of the candidate miRNAs were firstly analyzed in 43 pairs of serum samples from the training set by quantitative real-time PCR, and the dysregulated miRNA along with three tumor markers (carcinoembryonic antigen, CEA; cytokeratin 19 fragment, CYFRA21-1; squamous cell carcinoma antigen, SCCA) were further validated in two independent cohorts, which consisted of training set (including 100 NSCLC patients and 90 healthy controls) and validation set (including 72 NSCLC patients and 47 healthy controls). The expression of miR-17-5p was significantly up-regulated in NSCLC patients compared with the healthy controls (P

LncRNA SNHG14 promotes the progression of cervical cancer by regulating miR-206/YWHAZ.

Abstract: Accumulating evidence suggests that lncRNAs play key roles in many cancers. It has been reported that long non-coding RNA SNHG14 promotes cell proliferation and metastasis in multiple cancers. However, the role and underlying molecular mechanism of SNHG14 in cervical cancer (CC) remain largely unclear. In this study, we discovered that the relative expression of SNHG14 was significantly upregulated in CC tissues and cells, and associated with the overall survival of CC patients. Moreover, knockdown of SNHG14 significantly inhibited cell proliferation, migration and invasion, and promoted cell apoptosis in CC. Molecular mechanism explorations revealed that SNHG14 acted as a sponge of miR-206 and that YWHAZ was a downstream target gene of miR-206 in CC. Spearman's correlation analysis uncovered a significantly negative correlation between SNHG14 (or YWHAZ) and miR-206 expression, while a significantly positive correlation between SNHG14 and YWHAZ expression in CC tissues. We also found that the effect of SNHG14 knockdown on the CC progression could be partly rescued by overexpression of YWHAZ at the same time. Our findings revealed that SNHG14 acted as a sponge of miR-206 to regulate the expression of YWHAZ in CC, hinting the promising therapeutic target role of SNHG4 for CC patients.

LncRNA NEAT1/miR-29b-3p/BMP1 axis promotes osteogenic differentiation in human bone marrow-derived mesenchymal stem cells

Abstract: Osteogenic differentiation of human bone marrow-derived mesenchymal stem cells (hBMSCs) is quite important for the bone formation. Bone morphogenetic proteins (BMPs) are important to the skeleton formation. As a member of BMPs, BMP1 can induce bone and cartilage development. This study revealed the biological effect of BMP1 on the osteogenic differentiation. Firstly, the relative lower expression of BMP1 was detected in hBMSCs obtained from osteoporosis patients. The expression levels of osteoporosis-related genes (ALP, OCN, and OPN) were found to be decreased in hBMSCs treated with sh-BMP1. Mechanically, BMP1 was demonstrated to be the target mRNA of miR-29b-3p. Moreover, increasing studies indicate that long non-coding RNAs (lncRNAs) are crucial regulators in hBMSCs osteogenic differentiation by exerting ceRNA function. Further mechanism investigation revealed that lncRNA NEAT1 could regulate miR-29b-3p-BMP1 axis in hBMSCs. Finally, rescue assays were performed to validate the specific function of NEAT1-miR-29b-3p-BMP1 axis in the osteogenic differentiation of hBMSCs. In conclusion, NEAT1 promotes osteogenic differentiation in hBMSCs by regulating miR-29b-3p/BMP1 axis.

Knockdown of LncRNA SNHG7 inhibited epithelial-mesenchymal transition in prostate cancer though miR-324-3p/WNT2B axis in vitro

Abstract: It is identified that long non-coding RNAs (lncRNAs) play important roles in cancer progression and metastasis. LncRNA SNHG7 was reported to play an oncogenic role in the progression of cancers including prostate cancer. However, its potential regulatory mechanism of endothelial-mesenchymal transition in PCa remains unclear. In this study, We found a lncRNA SNHG7 was overexpressed in PCa cell lines and tissues. LncRNA SNHG7 promotes prostate cancer migration and invasion by modulating EMT. Further study indicated that lncRNA SNHG7 acts as a sponge for miRNA-324-3p and positively regulates WNT2B by a sponge effect. Moreover, We confirmed that WNT2B, an important protein in the Wnt signal pathway, promotes the malignant phenotype of PCa cells and mediated the biological effects exerted by lncRNA SNHG7. Overall, our study suggested that lncRNA SNHG7 could promote PCa EMT via miR-324-3p and WNT2B in vitro. The lncRNA SNHG7/miR-324-3p /WNT2B axis regulatory network might provide a potential new therapeutic strategy for PCa treatment.

miR-129-5p attenuates cell proliferation and epithelial mesenchymal transition via HMGB1 in gastric cancer.

Abstract: Background The miR-129-5p has been reported to be aberrant expression and exert vital roles in tumor progression of various malignancies. However, the effects on EMT in gastric cancer and its precise molecular mechanism in gastric cancer remain unclear. Methods and materials RT-qPCR was performed to evaluate the expression level of miR-129-5p and HMGB1 in cell lines. Cell proliferation was detected via CCK-8. The epithelial mesenchymal transition (EMT) related proteins and the expression of HMGB1 were detected by western blot analysis. Luciferase assays were used to validate binding seeds between miR-129-5p and HMGB1. Results miR-129-5p was downregulated in gastric cancer cells compared with GES-1. At the same time EMT was promoted in gastric cancer cells compared to GES-1. Overexpression of miR-129-5p inhibited EMT and proliferation. MiR-129-5p negatively and directly targeted HMGB1. HMGB1 was upregulated in gastric cancer cells and HMGB1 knocked-down inhibited EMT and cell proliferation. Conclusion Taken together, upregulation of miR-129-5p associated with gastric cancer proliferation and EMT, and serves as a potential diagnostic and therapeutic target via miR-129-5p/HMGB1 pathway in gastric cancer.

"… a life broken in two" Walter Pagel (1898-1983)-Famous pathologist and victim of Nazi Germany.

Abstract: There is no doubt that Walter Pagel (1898–1983) is one of the most outstanding figures in the history of pathology. Not only his fundamental research on tuberculosis and various other fields of pathology but also his historicomedical publications set international standards and earned him numerous honors throughout the scientific world. Far less known is the fact that Pagel, as a German Jew, was one of the victims of the “Third Reich”: He was dismissed from his job in Heidelberg, felt forced to emigrate in 1933 and fought for reparation after 1945. Accordingly, this article deals with Pagel’s role and fate as a politically persecuted and disenfranchised Jew. It focuses on the general circumstances of his dismissal and forced emigration, but also on Pagel’s treatment in post-war Germany. In addition, the influences of this biographical break on Pagel’s further research career are investigated. The study is based on archival sources and on a re-analysis of the relevant research literature. It points out that Pagel’s emigration took place under difficult circumstances and without clear job prospects. Enormous discipline and mental strength as well as successful networking with supporting mentors allowed Pagel to continue his career in his exile country of England despite poor health. The way in which Pagel was treated in post-war Germany, on the other hand, was less satisfactory: the University of Heidelberg did not offer him any prospect of employment and the “reparation procedure” (“Wiedergutmachungsverfahren”) resulted in only small pension payments. Instead, Pagel was awarded an honorary doctorate at his home university in 1966. Of the numerous “stumbling blocks” (n = 183) laid in Heidelberg, not one reminds us of Walter Pagel to date.

EZH2 promotes gastric cancer cells proliferation by repressing p21 expression.

Abstract: EZH2 is a core component of the polycomb repressive complex 2 (PRC2), which catalyzes trimethylation of histone H3 lysine 27 (H3K27me3) and promotes carcinogenesis by epigenetically silencing many tumor suppressor genes. Increased EZH2 expression is a marker of advanced and metastatic in many cancers, including lung, prostate and breast cancer, and it has been considered as a potential novel therapeutic target. However, the clinical significance and molecular mechanisms of EZH2 controlling gastric cancer cell proliferation and invasion are not well documented. In this study, immunohistochemical analysis was conducted to investigate the EZH2 expression in gastric cancer. We found that EZH2 levels were increased in gastric cancer tissues compared with adjacent normal tissues. Moreover, patients with high levels of EZH2 expression had a relatively poor prognosis. Furthermore, knockdown of EZH2 expression by siRNA could impair cell proliferation and invasion both in vitro and vivo. Finally, we found that EZH2 influences gastric cancer cells proliferation partly through regulating p21 expression. Our findings present that EZH2 over-expression can be identified as a poor prognostic biomarker in gastric cancer.

MiR-138-5p suppresses lung adenocarcinoma cell epithelial-mesenchymal transition, proliferation and metastasis by targeting ZEB2.

Abstract: Background MiR-138-5p is regarded as a tumour suppressor in many cancers. Transforming growth factor beta (TGF-β) often acts as a tumor promotor at the late stages of human cancers. However, the function of miR-138-5p on lung adenocarcinoma cells induced by TGF-β remains to be further confirmed. Methods RT-qPCR was used to detect the expression of human lung adenocarcinoma tissues, adjacent normal tissues, and relative cell lines. When the lung adenocarcinoma cells A549 and H1299 were transfected with negative control (NC), miR-138-5p mimics and miR-138-5p inhibitor by lipofectamine3000 and treated with or without TGF-β1, the lung adenocarcinoma cell function was detected by Immunofluorescence, Western blotting (WB), cell counting Kit-8 (CCK8), colony formation, EdU, Wound-healing and Transwell assays. The relation between miR-138-5p and zinc finger E-box-binding homeobox 2 (ZEB2) was detected by RT-qPCR, WB, and Luciferase reporter assays. When ZEB2 was knocked down, the lung adenocarcinoma cell function was detected by WB, CCK8 and Transwell assays. Results The expression of miR-138-5p was decreased in lung adenocarcinoma tissues and cell lines. When treated with or without TGF-β1, overexpression of miR-138-5p suppressed EMT, proliferation and metastasis of A549 and H1299. ZEB2 was verified as the direct target of miR-138-5p. Downregulation of ZEB2 suppressed EMT, proliferation and metastasis of lung adenocarcinoma cell, which could be reversed by miR-138-5p inhibitor. Conclusions MiR-138-5p inhibits epithelial-mesenchymal transition, growth and metastasis of lung adenocarcinoma cells through targeting ZEB2.

Disfranchisement, expulsion and persecution of pathologists in the Third Reich – A sociodemographic study

Abstract: This sociodemographic study focuses on the disenfranchisement, expulsion and persecution of pathologists in the Third Reich – a group that has, until now, received little systematic attention in scholarly research. The paper attempts to determine the number of pathologists who suffered persecution, the characteristics they shared, and the effects the repression had on their lives – both in the period from 1933 to 1945 and in the post-war period. The study is based on primary sources from numerous archives as well as on a systematic re-analysis of published secondary literature on the history of Nazi medicine. A total of 89 disenfranchised pathologists were identified and have been included. The vast majority of these pathologists (90%) were persecuted due to their Jewish ancestry or their relation to Jews. A good two-thirds of these pathologists were employed at a university until their disenfranchisement. For two-thirds of these pathologists (n = 62; 70%), documentation of emigration was found. Twenty-four pathologists remained in their home country; of these, five died in concentration camps and two others committed suicide. The preferred country for direct immigration was the United States (n = 19), followed by Great Britain (n = 13). Most of these pathologists were able to establish themselves professionally in their destination country, and little inclination to return to Germany after 1945 was shown. The reasons for this were a lack of career options in their home country, the lack of a welcoming culture among colleagues and universities, and the stigmatizing experiences of individual pathologists had during academic appointments and reparations proceedings in Germany. However, especially in recent decades and in part posthumously, these pathologists are being granted honorary, intangible recognition in Germany and Austria. Even though this recognition can no longer provide tangible reparations, it is nevertheless a sign of a gradual change in consciousness.

The role of oxidative stress in the biology of melanoma: A systematic review.

Abstract: Melanoma is the most aggressive skin tumour, which incidence is rising fast over the year. The metastatic stage of disease is extremely difficult to treat and the mortality rate is still high. Emerging evidence suggested that oxidative stress (OS) is involved in the pathophysiological pathways of several chronic diseases and in the transformation and progression of many common cancers, including melanoma. In particular, it has emerged that OS interacts with inflammatory and immune response, all taking part in the melanomagenic process. In light of the interest shown by the scientific community for this topic, it was analysed the association between melanoma and oxidative stress. A systematic review was performed according to PRISMA guideline employing PubMed database. It identified n = 29 articles which investigated this aspect. Melanoma cells resulted to have adaptive mechanisms to overcome effects of high reactive oxygen species (ROS) levels. Furthermore, OS influences the metastatic ability of melanoma cells and their resistance to therapy. Nonetheless, the included studies were conducted on heterogeneous patient population and with differences in the design of the studies and in the protocols. Therefore, it is mandatory performing further studies which analyze all the aspect of OS pathways: ROS imbalance, its effect to proliferation and metastasis, role of microenvironment, ROS effect to drug resistance. All this in order to understand the role of oxidative stress in the complex biology of melanoma and to provide possibilities of defining new strategy of therapy.

Long non-coding RNAs in retinoblastoma.

Abstract: Retinoblastoma represents 3% of all childhood cancers and is the most common intraocular malignant tumor with a highly aggressive and metastatic phenotype. While recent genetic and epigenetic studies have reported new insights into the mechanism of retinoblastoma development, the involvement of regulatory non-coding RNAs remains unclear. Long non-coding RNAs (lncRNAs) are a group of endogenous non-protein-coding RNAs with the capacity to regulate gene expression at multiple levels. Recent evidence has shown that lncRNAs can regulate many cellular processes, such as cell proliferation, differentiation, migration, and invasion. Several lncRNAs, including BANCR, AFAP1-AS1, NEAT1, XIST, ANRIL, PlncRNA-1, HOTAIR, PANDAR, DANCR, and THOR, promote the progression and metastasis of retinoblastoma. However, some lncRNAs, such as MEG3, MT1JP, and H19, play a tumor suppressive role. Our review summarizes the functional role of lncRNAs in retinoblastoma and their potential clinical applications for diagnosis, prognosis, and treatment.

Carl August Krauspe (1895-1983)-Founder and honorary member of the "European Society of Pathology" and "politically reliable" National Socialist.

Abstract: The name of the Hamburg pathologist Carl August Krauspe (1895–1983) is closely linked to the history of the “European Society of Pathology” (ESP) and the “German Pathological Society” (DGP): He was one of the founding fathers of the ESP, became its vice president, and was appointed an honorary member in 1983. From 1953–1962 he also served as secretary of the DGP and editor of the association's proceedings. In 1962/63 he finally held the chairmanship of the DGP. Most of the publications about Carl Krauspe accordingly pay tribute to these professional functions and offices. Hardly mentioned – let alone critically discussed – is the fact that Krauspe joined the “Nazi Party” (NSDAP), the Storm Detachment (SA) and other Nazi organizations after Hitler's “seizure of power”. The content and tenor of Krauspe’s reports on politically exposed colleagues have also hardly been examined. With this in mind, the present study pursues the goal of exploring Krauspe’s political role and his possible involvement in National Socialism. It is based on previously unexamined archival sources and a reanalysis of the relevant research literature. The paper points out that Krauspe willingly served the Nazi regime during the Third Reich. Thanks to his “loyalty to the party” he was able to significantly advance his own career after 1933. In addition, individual examples show that Krauspe’s “expert reports” on colleagues before 1945, but also in post-war Germany, were obviously ideologically influenced. After 1945 he failed to make a late personal contribution to the making of amends for Nazi injustice.

LncRNA TRG-AS1 promotes glioblastoma cell proliferation by competitively binding with miR-877-5p to regulate SUZ12 expression.

Abstract: Glioblastoma is one of the most fatal diseases in human central nerve system. However, the prognosis and treatment of glioblastoma still call for steady improvement. In recent years, increasing studies have revealed that the abnormal expression of long non-coding RNA (lncRNA) is closely related to carcinogenesis and prognosis. Unfortunately, many lncRNAs still need further research in their function and molecule mechanism. LncRNA TRG-AS1 hasn't been detected in any types of cancers before. TRG-AS1 is associated with poor prognosis and is upregulated in glioblastoma tissues and cells. TRG-AS1 can also accelerate glioblastoma cell proliferation in return. On the other hand, miRNA-877-5p expresses low in glioblastoma and contains binding sites with both TRG-AS1 and SUZ12. Furthermore, TRG-AS1 suppresses the expression of miR-877-5p while miR-877-5p suppresses SUZ12 expression. Overexpression of TRG-AS1 could promote the expression of SUZ12.Rescue assays demonstrates that overexpression of SUZ12 can counteract the decline of glioblastoma cell proliferation induced by knockdown of TRG-AS1. Based on all these assays, TRG-AS1 promotes glioblastoma cell proliferation by acting as a ceRNA of miR-877-5p to regulate SUZ12 expression. TRG-AS1 might serve as a new target in glioblastoma treatment.

Integrin subunit alpha V promotes growth, migration, and invasion of gastric cancer cells.

Abstract: Integrin subunit alpha V (ITGAV), a member of integrin family of extracellular matrix receptors, is involved in many types of cancer. In this study, the expression levels, clinical features and prognosis of ITGAV in gastric cancer (GC) patients were investigated, and the functional roles of ITGAV were also investigated. Cell Counting Kit-8 (CCK-8) assay was performed to examine the proliferation of GC cells. Transwell assays and wound-healing assays were conducted to explore the effect of ITGAV expression on GC cell migration and invasion. We found that ITGAV was overexpressed in both GC tissues and GC cells. ITGAV expression was positively correlated with lymph node metastasis and TNM stage of GC. High expression of ITGAV was associated with shorter overall survival (OS) and disease-free survival (DFS). Interestingly, the downregulation of ITGAV resulted in suppression of proliferation, migration, and invasion in GC cells. In conclusion, ITGAV is overexpressed in gastric cancer and is associated with poorer prognostic outcomes. ITGAV may serve as an important prognostic marker for GC staging and progression.

Exosome plays an important role in the development of hepatocellular carcinoma.

Abstract: Hepatocellular carcinoma (HCC) is one of the most malignant cancers around the world. However, the early biomarkers for its detection and treatment are limited currently. Exosomes, classified as intercellular messenger shuttling their cargoes between cells, regulate cell differentiation and tissue development. They contain messenger RNA (mRNA), microRNA (miRNA), long non-coding RNA (lncRNA), circular RNA (circRNA), proteins, lipids and transcription factors. Therefore, exosomes play a crucial role in the development of HCC. In this review, we highlight the exosomal cargoes which could serve as biomarkers for the prediction and diagnosis of HCC. Exosomes are involved in metastases of HCC and they show great potential in immunotherapy and drug resistance mechanism. In summary, exosome suggests new clues in clinical application of HCC.

Expression and significance of CD47, PD1 and PDL1 in T-cell acute lymphoblastic lymphoma/leukemia.

Abstract: Although dose intensification strategies achieve a favorable prognosis for pediatric patients of T-lmphoblastic lymphoma/leukemia (T-LBL/ALL), numerous side effects have been followed. Molecular targeted therapies will be needed to optimize the current treatment strategy for T-LBL/ALL. The aim of this study was to analyse expression and significance of CD47, PD1 and PDL1 in. T-LBL/ALL. We performed immunohistochemistry staining and real time fluorescence quantitative PCR (qRT-PCR) on FFPE tissues. Immunohistochemistry results showed that the high expression rate of CD47 protein was 46.4% (26/56) and the positive expression rate of PDL1 protein was 37.5% (21/56). PD1 expression was observed in tumor infiltrating lymphocytes in approximately 20% of T-LBL/ALL patients, but not expressed on tumor cells of T-LBL/ALL. And the results of qRT-PCR showed that the relative expression levels of CD47, PDL1 and PD1 mRNA in 56 cases of T LBL/ALL were significantly higher than those in control group (6.915 vs 4.050, 12.255 vs 2.575, 37.990 vs 3.615), and the differences were all statistically significant (p all 25 years old. Multivariate Cox regression analysis showed that the high expression of CD47 and PDL1 protein were independent prognostic factors (both p

"Jüdisch versippt" and "materialistic": The marginalization of Walther E. Berblinger (1882-1966) in the Third Reich.

Abstract: The pathologist Walther Berblinger (1882-1966) became famous for his scientific studies on internal secretion, namely on the pathology of the pituitary and the pineal gland. The results of his research on the hormonal control of the reproductive system contributed significantly to the consolidation of the young discipline of endocrinology. His later pioneering work on the use of chemotherapeutics in tuberculosis was similarly important. Despite his "Aryan" ancestry, Berblinger was targeted by the National Socialists and forced to emigrate to Switzerland due to the pressure of political events - a fact that has only been partially investigated by researchers to date. Accordingly, this essay focuses on Berblinger's professional exclusion and on the implications and consequences associated with it. It also examines why Berblinger decided not to return to Germany after 1945. Primary documents from the University Archives Jena and the Main State Archives Weimar served as the central source for this study; they were supplemented and compared with the research literature available to date on Walther Berblinger and on the history of pathology and medicine under National Socialism. The study documents that Berblinger - unlike his Jewish colleagues - was initially able to continue his career in the Third Reich almost without restriction, but was dismissed from service when he refused to separate from his Jewish wife in 1937. Subsequently, the National Socialists' victimization of Berlinger even reached him in Swiss exile. Notwithstanding the hostile treatment and harassment from Germany, Berblinger succeeded in continuing his scientific career in Switzerland. After 1945, he decided against remigration - not least because negative experiences with German authorities made led him doubt the rule of law in post-war Germany. It was not until the last phase of his life that Berblinger was "rediscovered" by his homeland, as is shown by a series of late honors.

Naringin inhibits thyroid cancer cell proliferation and induces cell apoptosis through repressing PI3K/AKT pathway.

Abstract: The present study aimed to investigate the anti-tumor effects of naringin in thyroid cancer (TC), and to explore the underlying mechanisms. TC cell lines TPC-1 and SW1736 were treated with 6, 12 or 25 μg/ml naringin for indicated times. Then, cell proliferation was determined using 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay, and cell apoptosis was analyzed by flow cytometer. Moreover, cell proliferation and apoptosis related genes (cyclin D1, c-Myc, survivin, Caspase3, Bcl-2, and Bax) were measured by western blot assay and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) respectively. Cleaved Caspase3 was measured using western blot assay. Phosphatidylinositol 3-kinase (PI3K)/AKT pathway was also analyzed in this study. Results indicated that naringin dose- and time-dependently inhibited TPC-1 and SW1736 cell proliferation, and naringin dose-dependently induced TPC-1 and SW1736 cell apoptosis. In addition, we found that naringin dose-dependently enhanced the expression of Caspase3, cleaved Caspase3 and Bax, and reduced the expression of cyclin D1, c-Myc, survivin, and Bcl-2 in TPC-1 and SW1736 cells. Moreover, we found that naringin dose-dependently suppressed PI3K/AKT pathway activation in TC cells. In conclusion, the data of this study suggested that naringin presented anti-tumor effects in TC cells through inhibiting TC cell proliferation and inducing cell apoptosis via regulating the expression of cell proliferation and apoptosis related genes and PI3K/AKT pathway activation. Our study suggested the potential value of naringin in the treatment of TC and provided more theoretical evidence for the treatment of TC.

MicroRNA-301b-3p accelerates the growth of gastric cancer cells by targeting zinc finger and BTB domain containing 4.

Abstract: MicroRNAs (miRNAs) have been found to be aberrantly expressed and exert essential roles in the tumorigenesis and progression of gastric cancer (GC). miR-301b-3p has been recognized as a cancer-related miRNA in lung cancer, bladder cancer and hepatocellular carcinoma. However, the function of miR-301b-3p in GC progression and its underlying mechanism have not been studied yet. In this study, we found that miR-301b-3p expression was up-regulated in GC tissues compared to adjacent noncancerous tissues. Furthermore, the elevated levels of miR-301b-3p were detected in GC cell lines (SGC-7901, AGS, MKN-45 and MGC-803) as compared with GES-1 cells. Interestingly, GC tissues from patients with tumor size ≥ 5 cm and advanced tumor stages showed obvious higher levels of miR-301b-3p compared to matched controls. Functionally, miR-301b-3p knockdown prominently inhibited cell proliferation, and induced cell cycle arrest at G1 phase and apoptosis in MGC-803 cells. Meanwhile, ectopic expression of miR-301b-3p conversely regulated these biological behaviors of MKN-45 cells. Next, we found that miR-301b-3p knockdown increased, whereas miR-301b-3p overexpression reduced the expression of zinc finger and BTB domain containing 4 (ZBTB4) in GC cells. Accordingly, luciferase reporter assay identified ZBTB4 as a direct target of miR-301b-3p. ZBTB4 overexpression markedly restrained the growth of MGC-803 cells. More importantly, ZBTB4 silencing partially reversed miR-301b-3p knockdown-induced tumor suppressive effects on MGC-803 cells. In conclusion, we firstly revealed that miR-301-3p was highly expressed in GC and contributed to tumor progression via attenuating ZBTB4, which might provide a novel molecular-targeted strategy for GC treatment.

KRT15, INHBA, MATN3, and AGT are aberrantly methylated and differentially expressed in gastric cancer and associated with prognosis.

Abstract: Aim: The present study aims to identify aberrantly methylated and differentially expressed genes (DEGs) in gastric cancer (GC) and explore their potential role in the carcinogenesis and development of GC. Methods: The original RNA-Seq, clinical information and Illumina Human Methylation 27 Chip data associated with GC were downloaded from The Cancer Genome Atlas (TCGA) database using the gdc-client tool. The DEGs and aberrantly methylated genes (AMGs) were screened with edgeR and limma package in R, respectively. The cut-off criteria for DEG identification were P 2.0, and for AMG identification were P 2.0. Genes which were both DEGs and AMGs were considered to be regulated by aberrant DNA methylation in GC. The common genes were used for further functional enrichment analysis in the categories of cellular component, molecular function, biological process and biological pathway. Results: In total 465 genes including 336 down-regulated genes with hyper-methylation (DGs-Hyper) and 129 up-regulated genes with hypo-methylation (UGs-Hypo) were identified. Cellular component analysis showed that these genes were mainly expressed in the cytoplasm and plasma membrane. Molecular function and biological process analysis indicated that the genes primarily participate in cell communication, signal transduction, cell growth/maintenance and function as transcription factors, receptor, cell adhesion molecules, and transmembrane receptor protein tyrosine kinases. Biological pathway analysis revealed that the genes are involved in some crucial pathways including epithelial-to-mesenchymal transition, IL3-mediated signaling, mTOR signaling, VEGF/VEGFR and c-Met signaling. KRT15, INHBA, MATN3, and AGT are significantly associated with the prognosis of GC patients. Conclusion: Our study identified several DEGs regulated by aberrant DNA methylation in GC. The mechanism of DNA methylation in the carcinogenesis and development of GC could be further explored in these genes, especially KRT15, INHBA, MATN3, and AGT.

Expression of programmed cell death-ligand 1 in oral squamous cell carcinoma and oral leukoplakia is associated with disease progress and CD8+ tumor-infiltrating lymphocytes.

Abstract: Objective In recent years, monoclonal antibodies targeting programmed cell death-ligand 1 (PD-L1) have become a promising cancer immunotherapy. However, the role of PD-L1 in oral squamous cell carcinoma (OSCC) and oral potentially malignant disorders (OPMDs), including oral leukoplakia (OLK), remains controversial. The aim of the present study was to investigate the expression level of PD-L1 in OSCC and OPMDs, and examine its relationship with CD8 expression and different clinicopathological features. Method Expression of PD-L1 and CD8 were conducted in 41 OSCC, 21 OLK, and 25 normal mucosa samples by immunohistochemistry. Then, the density of PD-L1 expression was measured, and its correlation with CD8 expression and different clinicopathological features was analyzed. Results PD-L1 protein was detected in 97.6% of OSCC, 61.9% of OLK, and 0% of normal tissues. PD-L1 was highly expressed in human OSCC tissue (P 0.05). Also, there was a significant upregulation of PD-L1 expression observed in the OLK group compared to the control group (P 0.05). Conclusion The upregulation of PD-L1 may be associated with disease progress and CD8+ tumor-infiltrating lymphocytes in oral premalignant and malignant lesions.

Knockdown of lncRNA SNHG7 inhibited cell proliferation and migration in bladder cancer through activating Wnt/β-catenin pathway.

Abstract: It is identified that long non-coding RNAs (lncRNAs) play important roles in tumorigenesis. LncRNA SNHG7 has been found to be an oncogene in varieties of tumors including bladder cancer. However, its potential regulatory mechanism in bladder cancer still remains unknown. In this study, we discovered that the expression levels of SNHG7 were significantly increased in bladder cancer tissues and cell lines. Patients with high expression level of SNHG7 suffered from poor prognosis. Additionally, knockdown of SNHG7 induced declined cell viability, proliferation as well as G0/G1 cell cycle arrest. Furthermore, we found that cell migratory ability was markedly reduced after silencing SNHG7. Next, we verified that knockdown of SNHG7 reduced the protein level of β-catenin and thus decreased the level of its downstream targets including c-myc, cyclin D1 and E-cadherin, implying that SNHG7 might impact bladder cancer via Wnt/β-catenin pathway. Subsequently, the rescue assays performed in SNHG7 silenced T24 cells by using activator of Wnt/β-catenin signaling elucidated that re-activation of this pathway partly restored the inhibitory effects of SNHG7 suppression on biological behaviors of T24 cells. Collectively, SNHG7 elicited carcinogenic functions in bladder cancer partially via activating Wnt/β-catenin signaling pathway, suggesting a potential target for the treatment and prognosis of bladder cancer.

LncRNA CASC7 inhibits the progression of glioma via regulating Wnt/β-catenin signaling pathway.

Abstract: Increasing evidence reveal the important role of long non-coding RNAs (lncRNAs) in the initiation and progression of glioma. However, the role of lncRNA cancer susceptibility candidate 7 (CASC7) in glioma is largely unknown. At first, the expression level of CASC7 was tested in glioma tissues and cell lines by using qRT-PCR. We applied Kaplan-Meier method to analyze the correlation between the expression level between CASC7 expression and the overall survival rate of glioma patients. We found that CASC7 was downregulated in glioma tissues and cell liens and predicted poor prognosis for patients with glioma. To determine the involvement of CASC7 in the biological processes of glioma, we conducted gain or loss-of function assays in two glioma patients. We found that CASC7 suppressed glioma cell proliferation and induced glioma cell apoptosis. Mechanistically, the expression level of CASC7 was negatively correlated with the expression levels of core factors of Wnt/β-catenin signaling pathway in glioma cells. Moreover, TOP flash luciferase activity further revealed the negative effect of CASC7 on the activity of Wnt/β-catenin signaling pathway. Finally, rescue assays were carried out to determine that Wnt/β-catenin signaling pathway involved in CASC7-mediated glioma progression. Taken together, all research findings suggested that CASC7 inhibited the progression of glioma via regulating Wnt/β-catenin signaling pathway.

Comprehensive analysis of tumor immune infiltration associated with endogenous competitive RNA networks in lung adenocarcinoma.

Abstract: Cancer immunotherapy has achieved unprecedented success in the treatment of cancer. However, different patients have different responses to immunotherapy. More and more studies have shown that tumor immune heterogeneity has an important influence on the prognosis of cancer. Therefore, understanding the clinical impact of tumor immune infiltration and the regulatory mechanism of RNA molecules is crucial for exploring the pathogenesis of lung adenocarcinoma (LUAD) and the development of immunotherapy protocols.The endogenous competitive RNA hypothesis provides new ideas for studying immune heterogeneity. Therefore, by using the method of immune genomics, this article explores the relationship between immune infiltration and prognosis of patients with lung adenocarcinoma, and found that B-cell immune infiltration highly affects the survival of patients. Through differential analysis, differential mRNAs, lncRNAs and miRNAs were extracted, and 318 differentially expressed mRNAs related to B cell immunity were screened by correlation analysis, and prognosis of patients with COX risk regression model was predicted and analyzed. Through multiple database searches, an immune-related ceRNA regulatory network was constructed, containing 3 key mRNAs, 4 miRNAs, and 50 lncRNAs. Three mRNAs and most miRNAs, lncRNAs, are significantly associated with LUAD prognosis. Bioinformatics analysis of the network showed that LINC00337 may up-regulate the expression of PBK and KIF23 through competitive binding of has-mir-373 and has-mir-519d. The competitive binding of has-mir-373 and has-mir-372 can up-regulate the expression of SLC7A11. The interaction between these RNAs may have an important regulatory role in the immune infiltration in lung adenocarcinoma, thereby affecting the patient's prognosis and immunotherapy efficacy.

Impact of the 2018 ASCO/CAP HER2 guidelines update for HER2 testing by FISH in breast cancer.

Abstract: Recently, the American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) updated the guidelines on HER2 testing for invasive breast cancer. Little is known about the impact of the guidelines update. We aimed to study the impact of the 2018 ASCO/CAP HER2 testing guidelines update. We compared the HER2 FISH results interpreted by 2013 and 2018 ASCO/CAP guidelines in 331 cases of invasive breast cancers. We also analyzed the pathological features and clinical outcomes of these cases. In comparing to the 2013 ASCO/CAP guidelines, the HER2 negative rate was increased significantly from 62.5% to 75.8%(P