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Objective: Highly malignant pancreatic ductal adenocarcinoma (PDAC) is characterised by an abundant immunosuppressive and fibrotic tumour microenvironment (TME). Future therapeutic attempts will therefore demand the targeting of tumours and stromal compartments in order to be effective. Here we investigate whether dual specificity and tyrosine phosphorylation-regulated kinase 1B (DYRK1B) fulfil these criteria and represent a promising anticancer target in PDAC., Design: We used transplantation and autochthonous mouse models of PDAC with either genetic Dyrk1b loss or pharmacological DYRK1B inhibition, respectively. Mechanistic interactions between tumour cells and macrophages were studied in direct or indirect co-culture experiments. Histological analyses used tissue microarrays from patients with PDAC. Additional methodological approaches included bulk mRNA sequencing (transcriptomics) and proteomics (secretomics)., Results: We found that DYRK1B is mainly expressed by pancreatic epithelial cancer cells and modulates the influx and activity of TME-associated macrophages through effects on the cancer cells themselves as well as through the tumour secretome. Mechanistically, genetic ablation or pharmacological inhibition of DYRK1B strongly attracts tumoricidal macrophages and, in addition, downregulates the phagocytosis checkpoint and 'don't eat me' signal CD24 on cancer cells, resulting in enhanced tumour cell phagocytosis. Consequently, tumour cells lacking DYRK1B hardly expand in transplantation experiments, despite their rapid growth in culture. Furthermore, combining a small-molecule DYRK1B-directed therapy with mammalian target of rapamycin inhibition and conventional chemotherapy stalls the growth of established tumours and results in a significant extension of life span in a highly aggressive autochthonous model of PDAC., Conclusion: In light of DYRK inhibitors currently entering clinical phase testing, our data thus provide a novel and clinically translatable approach targeting both the cancer cell compartment and its microenvironment., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Copyright of Der Pathologe is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Abstract Background Ghana introduced the monovalent rotavirus vaccine (Rotarix) into its national paediatric vaccination programme in May2012. Vaccine introduction was initiated nationwide and achieved >85% coverage within a few months. Rotavirus strain distribution pre- and post-RV vaccine introduction is reported. Methods Stool samples were collected from diarrhoeic children <5 years of age hospitalized between 2009 and 2016 at sentinel sites across Ghana and analyzed for the presence of group A rotavirus by enzyme immunoassay. Rotavirus strains were characterized by RT-PCR and sequencing. Results A total of 1363 rotavirus EIA-positive samples were subjected to molecular characterization. These were made up of 823 (60.4%) and 540 (39.6%) samples from the pre- and post-vaccine periods respectively. Rotavirus VP7 genotypes G1, G2 and G3, and VP4 genotypes P[6] and P[8] constituted more than 65% of circulating G and P types in the pre–vaccine period. The common strains detected were G1P[8] (20%), G3P[6] (9.2%) and G2P[6] (4.9%). During the post-vaccine period, G12, G1 and G10 genotypes, constituted more than 65% of the VP7 genotypes whilst P[6] and P[8] made up more than 75% of the VP4 genotypes. The predominant circulating strains were G12P[8] (26%), G10P[6] (10%) G3P[6] (8.1%) and G1P[8] (8.0%). We also observed the emergence of the unusual rotavirus strain G9P[4] during this period. Conclusion Rotavirus G1P[8], the major strain in circulation during the pre-vaccination era, was replaced by G12P[8] as the most predominant strain after vaccine introduction. This strain replacement could be temporary and unrelated to vaccine introduction since an increase in G12 was observed in countries yet to introduce the rotavirus vaccine in West Africa. A continuous surveillance programme in the post-vaccine era is necessary for the monitoring of circulating rotavirus strains and the detection of unusual/emerging genotypes. [ABSTRACT FROM AUTHOR]

In the treatment of penile cancer, there is a need for prognostic and predictive factors allowing assessment of the likelihood of lymph node metastasis, as this would greatly facilitate clinical decision-making for invasive staging of inguinal nodes. Furthermore, systemic chemotherapy in metastatic disease has limited efficacy and more effective additional or second-line therapies are needed. There is a great interest in personalised and targeted therapies at present, but do we have any indications that these will be useful in penile cancer? This review examines the well-proven predictors of prognosis that pathologists can take from specimens, and reports which molecular markers are of proven value in penile cancer. [ABSTRACT FROM AUTHOR]

Background Few studies have addressed prognostic markers and none has correlated molecular status and prognosis in vulvar melanomas. Objectives To evaluate the clinicopathological features of 95 cases of vulvar melanoma. Methods p53, CD117, Ki-67, neurofibromin, brafv600e and nrasq61r immunostains, and molecular analyses by either targeted next-generation or direct sequencing, were performed on available archival materials. Results Molecular testing detected mutations in KIT (44%), BRAF (25%), NF1 (22%), TP53 (17%), NRAS (9%) and TERT promoter (9%). Co-mutation of KIT and NF1 and of KIT and NRAS were identified in two and one cases, respectively. KIT mutations were significantly associated with better progression-free survival in univariate analyses. In multivariate analyses CD117 expression was significantly associated with better progression-free survival. Tumour thickness was significantly associated with worse progression-free and overall survival, and perineural invasion significantly correlated with reduced melanoma-specific survival and reduced overall survival. Cases were from multiple centres and only a subset of samples was available for molecular testing. Conclusions KIT mutations and CD117 overexpression are markers of better progression-free survival. In addition to its prognostic value, molecular testing may identify cases that might respond to targeted agents or immunotherapeutic approaches. [ABSTRACT FROM AUTHOR]

Background & Aims Our increasing understanding of hepatocellular carcinoma (HCC) biology holds promise for personalized care, however its translation into clinical practice requires a precise knowledge of its relationship to tumour phenotype. Methods We aimed at investigating molecular-phenotypic correlations in a large series of HCC. To this purpose, 343 surgically resected HCC samples were investigated by pathological review, immunohistochemistry, gene expression profiling and sequencing. Results CTNNB1 (40%) and TP53 (21%) mutations were mutually exclusive and defined two major groups of HCC characterized by distinct phenotypes. CTNNB1 mutated tumours were large ( p = 0.002), well-differentiated ( p <0.001), cholestatic ( p <0.001), with microtrabecular ( p <0.001) and pseudoglandular ( p <0.001) patterns and without inflammatory infiltrates ( p <0.001). TP53 mutated tumours were poorly differentiated ( p <0.001) with a compact pattern ( p = 0.02), multinucleated ( p = 0.01) and pleomorphic ( p = 0.02) cells and frequent vascular invasion ( p = 0.02). World Health Organization (WHO) classification of histological subtypes were also strongly related to molecular features. The scirrhous subtype was associated with TSC1/TSC2 mutations ( p = 0.005), epithelial-to-mesenchymal transition and a progenitor expression profile. The steatohepatitic subtype showed frequent IL-6/JAK/STAT activation without CTNNB1 , TERT and TP53 pathway alterations ( p = 0.01). Pathological review identified a novel subtype, designated as “macrotrabecular-massive” associated with poor survival ( p <0.001), high alpha-fetoprotein serum level ( p = 0.02), vascular invasion ( p <0.001), TP53 mutations ( p <0.001) and FGF19 amplifications ( p = 0.02), features also validated in The Cancer Genome Atlas (TCGA) data. Finally, integration of HCC pathological characteristics with its transcriptomic classification showed phenotypically distinct tumour subclasses closely related to G1-G6 subgroups. Conclusion HCC phenotypes are tightly associated with gene mutations and transcriptomic classification. These findings may help in translating our knowledge of HCC biology into clinical practice. Lay summary: HCC is a very heterogenous tumour, both at the pathological and molecular levels. We show here that HCC phenotype is tightly associated to its molecular alterations and underlying oncogenic pathways. [ABSTRACT FROM AUTHOR]

Penile cancer (PeCa) is a rare malignancy with potentially devastating effects. Squamous cell carcinoma is the most common variant with distinct precancerous lesions before development into invasive disease. Involvement of the inguinal lymph nodes is the most important prognostic factor in PeCa, and once disease is present outside the groin, prognosis is poor. Metastatic PeCa is challenging to treat and often requires multidisciplinary approaches in management. Due to its rarity, molecular understanding of the disease continues to be limited with most studies based on small, single center series. Thus far, it appears PeCa has diverse mechanisms of carcinogenesis affecting similar molecular pathways. In this review, we evaluate the current landscape of the molecular carcinogenesis of PeCa and explore ongoing research on potential actionable targets of therapy. The emergence of anti-epidermal growth factor receptor (EGFR) and other immunotherapeutic strategies may improve outcomes for PeCa patients. [ABSTRACT FROM AUTHOR]

With ever-increasing molecular information about colorectal cancer (CRC), there is an expectation to detect more sensitive and specific molecular markers for new advanced diagnostic methods that can surpass the limitations of current screening tests. Moreover, enhanced molecular pathology knowledge about cancer has led to the development of targeted therapies, designed to interfere with specific aberrant biological pathways in cancer. Furthermore, biotechnology has opened a new window in CRC diagnosis and treatment by introducing different application of antibodies, antibody fragments, non-Ig scaffold proteins, and aptamers in targeted therapy and drug delivery. This review summarizes the molecular diagnostic and therapeutic approaches in CRC with a focus on genetic and epigenetic alterations, protein and metabolite markers as well as targeted therapy and drug delivery by Ig-scaffold proteins, non-Ig scaffold proteins, nanobodies, and aptamers. [ABSTRACT FROM AUTHOR]

Background: OPCML belongs to the IgLON family of Ig domain-containing GPI-anchored cell adhesion molecules and was recently found to be involved in carcinogenesis, while its role in gastric cancer remains unclear.Methods: We assessed expression and biological behavior of OPCML in gastric cancer.Results: OPCML expression was markedly reduced in tumor tissues and cancer cell lines. Decreased OPCML expression had a significant association with unfavorable tumor stage (p = 0.007) and grading (p < 0.001). Furthermore, the results revealed that OPCML was an independent prognostic factor for overall survival in gastric cancer (p = 0.002). In addition, ectopic expression of OPCML in cancer cells significantly inhibited cell viability (p < 0.01) and colony formation (p < 0.001), arrest cell cycle in G0/G1 phase and induced apoptosis, and suppressed tumor formation in nude mice. The alterations of phosphorylation status of AKT and its substrate GSK3β, up-regulation of pro-apoptotic regulators including caspase-3, caspase-9 and PARP, and up-regulation of cell cycle regulator p27, were implicated in the biological activity of OPCML in cancer cells.Conclusion: Down-regulated OPCML expression might serve as an independent predictor for unfavorable prognosis of patients, and the biological behavior supports its role as a tumor suppressor in gastric cancer. [ABSTRACT FROM AUTHOR]

Colon cancer is one of the leading causes of morbidity and mortality throughout the world. Some of the most common presenting signs are a change in bowel habits, alteration of fecal contour or consistency, blood in stool, fatigue, and weight loss. However, it may present insidiously. This is the case of an 81-year-old female with Clostridium septicum bacteremia as the primary presenting sign of metastatic colon cancer. In further literature review, we discuss the genomic associations that contribute to the severity of the disease and explore the potential links between the gut microbiome and colorectal carcinoma. This article highlights risk factor modifications and lab abnormalities that may be useful for the primary care provider and acute care practitioner., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Abraham et al.)

Objectives: To test miR-223 upregulation during gastric (intestinal-type) and Barrett esophageal carcinogenesis.Methods: miR-223 expression was assessed by quantitative reverse transcription polymerase chain reaction in a series of 280 gastroesophageal biopsy samples representative of the whole spectrum of phenotypic changes involved in both carcinogenetic cascades. The results were further validated by in situ hybridization on multiple tissue specimens obtained from six surgically treated gastroesophageal adenocarcinomas. miR-223 expression was also assessed in plasma samples from 30 patients with early stage (ie, stages I and II) gastroesophageal adenocarcinoma and relative controls.Results: In both gastric and esophageal models, miR-223 expression significantly increased along with the severity of the considered lesions (analysis of variance, P  <   .001). Among atrophic gastritis and long-segment Barrett esophagus samples, miR-223 overexpression was significantly associated with the score of intestinal metaplasia. miR-223 plasma levels were significantly upregulated in patients with cancer compared with controls ( t test, both P  <   .001).Conclusions: miR-223 early upregulation observed in tissue samples and its diagnostic value in discriminating patients with early adenocarcinoma by plasma testing provide a solid rationale for further exploring the diagnostic reliability of this microRNA as a novel biomarker in gastroesophageal adenocarcinoma secondary prevention strategies. [ABSTRACT FROM AUTHOR]

Trichloroethylene (TCE), commonly used as an industrial solvent, is ubiquitous in our living environment. TCE exposure can induce hepatocellular carcinoma (HCC) in mice, but the underlying mechanisms remain elusive. To understand the role of miRNA in the hepatocarcinogenesis of TCE, we examined the miRNA expression profiles by microarray in the liver of B6C3F1 male mice exposed to TCE at 0 or 1000 mg/kg b.w. Nine differentially expressed miRNAs were identified, out of which miR-182-5p exhibited the highest increase in expression. Moreover, the TCE-induced upregulation of miR182-5p in mouse liver was dose dependent and correlated with promoter DNA hypomethylation. Treatment of mouse liver cell lines (BNL CL.2 and Hepa1-6) with TCE at non-toxic doses (0.1 and/or 0.3mM) significantly increased the expression level of miR-182-5p accompanied with elevated cell proliferation. The TCE-induced cell proliferation was further found to be mediated by miR-182-5p overexpression. Additionally, tumor suppressor gene Cited2, which was downregulated in TCE exposed mouse liver cells, was proved to be a direct target of miR-182-5p. In conclusion, TCE might up-regulate miR-182-5p expression by DNA hypomethylation, which could suppress Cited2 and improve cell proliferation rate, resulting in liver tumor. [ABSTRACT FROM AUTHOR]

Long interspersed nuclear element 1 (LINE-1 or L1) belongs to the non-long terminal repeat (non-LTR) retrotransposon family, which has been implicated in carcinogenesis and disease progression. Circulating tumor cells (CTCs) are also known to be involved in cancer progression. The present study aimed to compare the L1 expression between circulating tumor cells and non-cancerous samples. Blood samples were collected from 10 healthy individuals and 22 patients with different types of cancer. The whole blood cells were isolated using enrichment protocols and the DNA and RNA were extracted. RT-qPCR was performed for L1-ORF1 (open reading frame 1) and L1-ORF2, using 18S rRNA as the reference gene. The data were analyzed with the Livak method and statistical analyses were carried out with the Mann-Whitney and Kruskal-Wallis tests. In parallel with the above molecular biology experiments, FISH experiments were performed on the interphase nuclei of the cells for the detection of ORF2 RNA. DNA analysis revealed the presence of both ORF1 and ORF2 in all samples. RNA expression experiments demonstrated that ORF1 was not expressed in all samples, while ORF2 was expressed at varying levels in the non-cancer samples and the samples representing the different cancer types. A significant difference in ORF2 expression was observed between the CTCs and non-cancer samples (p = 0,00043), and significant differences were also observed between normal and lung (p = 0,034), pancreatic (p = 0,022), prostate (p = 0,014), and unknown primary of origin (p = 0,0039) cancer samples. Cytogenetic analysis revealed higher levels of ORF2 in the nuclei of CTCs than in normal samples. This study highlights the significant difference in L1-ORF2 expression between CTCs and normal samples. The increased expression levels observed for CTCs may be correlated with the characteristic features of these cells. [ABSTRACT FROM AUTHOR]

3-Nitrobenzanthrone (3-NBA), a potential human carcinogen, is present in diesel exhaust. The main metabolite of 3-NBA, 3-aminobenzanthrone, was detected in urine of miners occupationally exposed to diesel emissions. Environmental and occupational factors play an important role in development of bladder cancer (BC), one of the most frequent malignancies. It is expected that exposure of urothelium to 3-NBA and its metabolites may induce BC initiation and/or progression. To test this hypothesis, we studied geno- and cytotoxicity of 3-NBA using an in vitro BC model. 3-NBA induced higher levels of DNA adducts, reactive oxygen species and DNA breaks in aggressive T24 cells than in more differentiated RT4 cells. To understand the nature of this difference we examined the role of several enzymes that were identified as 3-NBA bio activators. However, the difference in DNA adduct formation cannot be directly linked to the different activity of any of the examined enzymes. Conversely, the difference of tested cell lines in p53 status can partly explain the distinct levels of 3-NBA-DNA adducts and DNA damage induced by 3-NBA. Therefore, we assume that more aggressive T24 cells are more predisposed for DNA adduct formation, DNA damage and, possibly, mutations and as a result further tumorigenesis. [ABSTRACT FROM AUTHOR]

Long non-coding RNAs (lncRNAs) emerged as key regulators of diverse roles during colorectal cancer (CRC) carcinogenesis, but their specific function still remains to be explored. The present study aimed to re-annotate the Affymetrix Human Exon 1.0 ST Array for defining differential lncRNAs in CRC. Their prognostic relevance was also developed for screening key regulators in CRC. The CRC datasets E-GEOD-31737, E-MATB-829, Affymetrix colon cancer dataset and E-GEOD-24550 were re-purposed for searching differential lncRNAs and exploring their association with overall survival (OS). The identified lncRNAs were validated in CRC tissues or cell lines. As a result, 462, 286 and 166 differential lncRNAs were identified, respectively, in three predictive datasets. Among them, 48 lncRNAs were commonly observed to exhibit differential expression in the three datasets. Notably, the overexpression of family with sequence similarity 83 member H (FAM83H)-antisense (AS) 1 (P=0.038) and VPS9 domain containing 1 (VPS9D1)-AS1 (P=0.020) indicated shorter OS time than lower expression. The overexpression of FAM83H-AS1 (P=0.033) and VPS9D1-AS1 (P=0.011) was validated in cancerous tissues. Thus, FAM83H-AS1 and VPS9D1-AS1 may potentially enhance carcinogenesis or may be developed as prognostic biomarkers for CRC. In conclusion, a total of 48 CRC-related lncRNAs were identified, the majority of which were confirmed to exhibit dysregulation. FAM83H-AS1 and VPS9D1-AS1 could have a potential use as prognostic biomarkers for CRC patients. [ABSTRACT FROM AUTHOR]

Although hepatocellular carcinoma (HCC) is associated with poor prognosis worldwide, the molecular mechanisms underlying the carcinogenesis and progression of this disease remain unclear. Several tumor characteristics have previously been demonstrated to be prognostic factors of survival following hepatic resection, or the recurrence of HCC or other types of cancer. Comparisons of normal tissues and HCC tumor tissues have revealed the presence of numerous molecular alterations in HCC, including genetic and epigenetic mechanisms, particularly mutations in certain genes and DNA methylation in the promoter regions of tumor-suppressor genes. A number of studies have previously used array analysis to detect variations in the expression levels of cancer-associated genes and microRNAs, and in DNA methylation. However, an investigation of HCC tumor tissues may not determine the effect of noncancerous liver tissues (background liver) in patients with HCC. As HCC may recur multicentrically following resection, a damaged or chronically diseased HCC background liver may be considered as a pre-cancerous organ. Therefore, the influence of the background liver on HCC requires further study. Detailed studies regarding the background liver may be essential for the improved understanding of the carcinogenesis and progression of this malignancy; however only a few studies have investigated the microenvironment of the HCC background liver. The present review discusses prior molecular studies of hepatocarcinogenesis that focus on HCC and background liver tissues. [ABSTRACT FROM AUTHOR]

Purpose: There is accumulating evidence that oxidative stress is an important contributor to carcinogenesis. We hypothesized that genetic variation in genes involved in maintaining antioxidant/oxidant balance would be associated with overall oxidative stress. Methods: We examined associations between single nucleotide polymorphisms (SNPs) in MnSOD, GSTP1, GSTM1, GPX1, GPX3, and CAT genes and thiobarbituric acid-reactive substances (TBARS), a blood biomarker of oxidative damage, in healthy white women randomly selected from Western New York (n = 1402). We used general linear models to calculate age-adjusted geometric means of TBARS across the variants. We also examined the associations within strata of menopausal status. Results: For MnSOD, being heterozygous was associated with lower geometric means of TBARS (less oxidative stress), 1.28 mg/dL, compared to homozygous T-allele or homozygous C-allele,1.35 mg/dL, and 1.31 mg/dL correspondingly (p for trend = 0.01). This difference remained among postmenopausal women, 1.40 mg/dL for TT, 1.32 mg/dL for TC, and 1.34mg/dL for CC (p for trend 0.015); it was attenuated among premenopausal women. SNPs in the other genes examined (GSTP1, GSTM1, GPX1, GPX3, and CAT) were not associated with TBARS. Conclusions: Our findings suggest that genetic variation in MnSOD gene may be associated with oxidative status, particularly among postmenopausal women. [ABSTRACT FROM AUTHOR]

The last 5 years have seen significant advances in our understanding of the molecular pathogenesis of B-cell lymphomas. This has led to the emergence of a large number of new therapeutic agents exploiting precise aspects of the tumor cell's signaling pathways, surface antigens or microenvironment. The purpose of this comprehensive review is to provide a detailed analysis of the breakthrough agents in the field, with a focus on recent clinical data. We describe agents targeting the B-cell receptor pathway, Bcl-2 inhibitors, emerging epigenetic therapies, new monoclonal antibodies and antibody drug conjugates, selective inhibitors of nuclear export, agents targeting the programmed cell death axis and chimeric antigen receptor T cells. [ABSTRACT FROM AUTHOR]

Mortalin/mthsp70 (HSPA9) is a stress chaperone enriched in many cancers that has been implicated in carcinogenesis by promoting cell proliferation and survival. In this study, we examined the clinical relevance of mortalin upregulation in carcinogenesis. Consistent with high mortalin expression in various human tumors and cell lines, we found that mortalin overexpression increased the migration and invasiveness of breast cancer cells. Expression analyses revealed that proteins involved in focal adhesion, PI3K-Akt, and JAK-STAT signaling, all known to play key roles in cell migration and epithelial-to-mesenchymal transition (EMT), were upregulated in mortalin-expressing cancer cells. We further determined that expression levels of the mesenchymal markers vimentin (VIM), fibronectin (FN1), β-catenin (CTNNB1), CK14 (KRT14), and hnRNP-K were also increased upon mortalin overexpression, whereas the epithelial markers E-cadherin (CDH1), CK8 (KRT8), and CK18 (KRT18) were downregulated. Furthermore, shRNA-mediated and pharmacologic inhibition of mortalin suppressed the migration and invasive capacity of cancer cells and was associated with a diminished EMT gene signature. Taken together, these findings support a role for mortalin in the induction of EMT, prompting further investigation of its therapeutic value in metastatic disease models. Cancer Res; 76(9); 2754-65. [ABSTRACT FROM AUTHOR]

Recent transcriptome studies using next-generation sequencing have detected aberrant changes in the expression of noncoding RNAs (ncRNAs) associated with cancer. For prostate cancer, the expression levels of ncRNAs including microRNAs and long noncoding RNAs are strongly associated with diagnosis, carcinogenesis and tumor growth. Moreover, androgen and its cognate receptor, androgen receptor (AR), regulate various signaling pathways for prostate tumor growth. In addition, progression to lethal castration-resistant prostate cancer (CRPC) is also owing to AR function. Systematic analysis of AR-binding sites and their regulated transcripts revealed that many ncRNAs are widely regulated at the transcriptional level. Thus, recent studies provide new insight into the complicated molecular mechanism of prostate cancer progression. This review focused on the role of various ncRNAs in prostate cancer and the association between their expression and CRPC. [ABSTRACT FROM AUTHOR]

Background and objectives The development of HCC is multifactorial, resulting from the interaction of environmental factors (possibly hepatitis viruses) and host factors (genetic factors). So identification of risk factors that contribute to HCC and thus early diagnosis and therapy is necessary. This study aimed to investigate the role of tumor suppressor genes RASSF1A Ala133Ser and RECK rs11788747polymorphisms and their haplotypes in HCC. Subjects and methods 104 cases of HCC and 100 healthy controls were included in a case-control study. RASSF1A and RECK genotypes, allele and haplotypes were detected by PCR-RFLP. Results Risk of HCC was significantly associated with carriers of A1a/Ser, Ser/Ser, Ser allele and A1a/Ser +GA haplotypes (OR = 20.57, p < 0.001, OR = 7.26, p = 0.05, OR = 10.64, p < 0.001, OR = 12.52, p = 0.005) respectively. More over RECK GG, G allele and haplotype A1a/A1a + GG were protective to HCC (OR = 0.11, p < 0.001, & OR = 0.53, p = 0.001 & OR = 0.16, p = 0.002) respectively. Also, it was found that RASSF1A gene polymorphism significantly associated with bad pathological features but no association with RECK gene polymorphism. Conclusions The RASSF1AAla133Ser polymorphism, RECK gene polymorphism and for the first time haplotype of both genes influence molecular carcinogenesis and clinic pathological features of HCC within the Egyptian population. [ABSTRACT FROM AUTHOR]

Farnesoid X receptor (FXR) belongs to the nuclear receptor superfamily with its endogenous ligands bile acids. Mice with whole body FXR deficiency develop liver tumors spontaneously, but the underlying mechanism is unclear. Moreover, it is unknown whether FXR deficiency in liver alone serves as a tumor initiator or promoter during liver carcinogenesis. This study aims to evaluate the effects of hepatocyte-specific FXR deficiency (FXRhep-/-) in liver tumor formation. The results showed that FXRhep-/- mice did not show spontaneous liver tumorigenesis with aging (up to 24 mo of age). Therefore FXRhep-/- mice were fed a bile acid (cholic acid)-containing diet alone or along with a liver tumor initiator, diethylnitrosamine (DEN). Thirty weeks later, no tumors were found in wild-type or FXRhep-/- mice without any treatment or with DEN only. However, with cholic acid, while only some wild-type mice developed tumors, all FXRhep-/- mice presented with severe liver injury and tumors. Interestingly, FXRhep-/- mouse livers increased basal expression of tumor suppressor p53 protein, apoptosis, and decreased basal cyclin D1 expression, which may prevent tumor development in FXRhep-/- mice. However, cholic acid feeding reversed these effects in FXRhep-/- mice, which is associated with an increased cyclin D1 and decreased cell cycle inhibitors. More in-depth analysis indicates that the increased in cell growth might result from disturbance of the MAPK and JAK/Stat3 signaling pathways. In conclusion, this study shows that hepatic FXR deficiency may only serve as a tumor initiator, and increased bile acids is required for tumor formation likely by promoting cell proliferation. [ABSTRACT FROM AUTHOR]

Background and aims Helicobacter pylori is the causative agent of gastric diseases and the main risk factor in the development of gastric adenocarcinoma. In vitro studies with this bacterial pathogen largely rely on the use of transformed cell lines as infection model. However, this approach is intrinsically artificial and especially inappropriate when it comes to investigating the mechanisms of cancerogenesis. Moreover, common cell lines are often defective in crucial signalling pathways relevant to infection and cancer. A long-lived primary cell system would be preferable in order to better approximate the human in vivo situation. Methods Gastric glands were isolated from healthy human stomach tissue and grown in Matrigel containing media supplemented with various growth factors, developmental regulators and apoptosis inhibitors to generate long-lasting normal epithelial cell cultures. Results Culture conditions were developed which support the formation and quasi-indefinite growth of three dimensional (3D) spheroids derived from various sites of the human stomach. Spheroids could be differentiated to gastric organoids after withdrawal of Wnt3A and R-spondin1 from the medium. The 3D cultures exhibit typical morphological features of human stomach tissue. Transfer of sheared spheroids into 2D culture led to the formation of dense planar cultures of polarised epithelial cells serving as a suitable in vitro model of H. pylori infection. Conclusions A robust and quasi-immortal 3D organoid model has been established, which is considered instrumental for future research aimed to understand the underlying mechanisms of infection, mucosal immunity and cancer of the human stomach. [ABSTRACT FROM AUTHOR]

Background: Several lines of evidence support the involvement of the lectin pathway of complement (LP) in the pathogenesis of acute ischemic stroke. The aim of this multicenter observational study was to assess the prognostic value of different circulating LP initiators in acute stroke.Methods: Plasma levels of the LP initiators ficolin-1, -2, and -3 and mannose-binding lectin (MBL) were measured in 80 stroke patients at 6 h only and in 85 patients at 48 h and later. Sixty-one age- and sex-matched healthy individuals served as controls. Stroke severity was measured on admission using the National Institutes of Health Stroke Scale (NIHSS). The outcome was measured at 90 days by the modified Rankin Scale (mRS).Results: Ficolin-1 was decreased in patients compared with controls measured at 6 h (median 0.13 vs 0.33 μg/ml, respectively, p < 0.0001). At 48 h, ficolin-1 was significantly higher (0.45 μg/ml, p < 0.0001) compared to the 6 h samples and to controls. Likewise, ficolin-2 was decreased at 6 h (2.70 vs 4.40 μg/ml, p < 0.0001) but not at 48 h. Ficolin-3 was decreased both at 6 and 48 h (17.3 and 18.23 vs 21.5 μg/ml, p < 0.001 and <0.05, respectively). For MBL no difference was detected between patients and controls or within patients at the different time points. In multivariate analysis, early ficolin-1 was independently associated with unfavorable mRS outcome (adjusted odds ratio (OR): 2.21, confidence interval (CI) 95 % 1.11-4.39, p = 0.023). Early ficolin-1 improved the discriminating ability of an outcome model including NIHSS and age (area under the curve (AUC) 0.95, CI 95 % 0.90-0.99, p = 0.0001).Conclusions: The ficolins are consumed within 6 h after stroke implicating activation of the LP. Early ficolin-1 is selectively related to 3-month unfavorable outcome. [ABSTRACT FROM AUTHOR]

Copyright of Der Onkologe is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Potent chemotherapy for advanced gastric cancer has not been completely established. Many molecularly targeted therapies are under investigation, but their therapeutic outcomes are not promising because they do not target specific and/or critical targets of gastric carcinogenesis. Although the molecular basis of gastric carcinogenesis remains poorly understood, nuclear localization of β-catenin was observed in approximately 50 % of gastric cancer specimens. Recent studies have suggested that activation of signal transducer and activator of transcription 3 (STAT3) contributes to gastric carcinogenesis in a mouse model. A newly synthesized curcumin analog has inhibitory potential against β-catenin and STAT3. Methods: Using a transgenic mouse model of gastric cancer in which β-catenin, cyclooxygenase 2, and microsomal prostaglandin E synthase 1 activation is induced, we examined a curcumin analog with the most enhanced potential for treating gastric cancer through oral administration. Inhibition of these targets was demonstrated using microarray and immunohistochemical analyses. Results: The curcumin analog GO-Y031 decreased the incidence of gastric carcinogenesis to 54.5 % of that of the control (50.0 % vs 91.7 %, p = 0.043), and tumor size was reduced to 51.6 % of that of the control (1.6 mm vs 3.1 mm, p = 0.03). β-Catenin and STAT3 levels were suppressed to 26.2 % ( p = 0.00023) and 44.8 % ( p = 0.025), respectively, of those of the control. Moreover, macrophage infiltration was suppressed with GO-Y031. Conclusion: β-Catenin and STAT3 can be pharmacologically inhibited in vivo with a curcumin analog, which effectively inhibits β-catenin and STAT3. [ABSTRACT FROM AUTHOR]

Background/Aims: Effective treatment of gastric cancer (GC) requires better understanding of the molecular regulation of its carcinogenesis. Identification of cancer stem cells (CSCs) in GC appears to be a critical question. Methods: We analyzed Lgr5 expression in GC specimen. We used an adeno-associated virus (AAV) that carries diphtheria toxin fragment A (DTA) under the control of Lgr5 promoter (AAV-pLgr5-DTA) to transduce human GC cells. The growth of GC cells with/without depletion of Lgr5-positive cells was studied in vitro in an MTT assay, and in vivo by analyzing bioluminescence levels. Results: A portion of GC cells in the resected specimen expressed Lgr5. GC cells that formed tumor spheres expressed high Lgr5. Selective depletion of Lgr5-positive GC cells resulted in significant growth inhibition of GC cells in vitro and in vivo. Conclusion: Lgr5-positive cells may be CSCs-like cells in GC and may play a pivotal role in the tumorigenesis of GC. Treating Lgr5-positive GC cells may substantially improve the therapeutic outcome. [ABSTRACT FROM AUTHOR]

The recent exponential increase in our knowledge of cellular and molecular mechanisms involved in carcinogenesis has largely failed to translate into new therapies and clinical practices. This lack of success may result in part from the fact that most studies focus on tumor cells as potential therapeutic targets and neglect the complex microenvironment that undergoes profound changes during tumor development. Furthermore, an unfortunate association of factors such as tumor genetic complexity, overestimation of biomarker and drug potentials, as well as a poor understanding of tumor microenvironment in diagnosis and prognosis leads to the current levels of treatment failure regarding a vast majority of cancer types. A growing body of evidence points to the importance of the functional diversity of immune and structural cells during tumor development. In this sense, the lack of technologies that would allow for molecular screening of individual stromal cell types poses a major challenge for the development of therapies targeting the tumor microenvironment. Progress in microenvironment genetic studies represents a formidable opportunity for the development of new selective drugs because stromal cells have lower mutation rates than malignant cells, and should prove to be good targets for therapy. [ABSTRACT FROM AUTHOR]

Rapid growth in knowledge of cell and molecular biology led to the increased usage of molecular techniques in anatomical pathology. This is also due to the advances achieved in the techniques introduced in the last few years which are less laborious as compared to the techniques used at the beginning of the "molecular era". The initial assays were also very expensive and were not performed except for selected centers. Moreover, the clinicians were not sure how to make use of the accumulating molecular information. That situation has also changed and molecular techniques are being performed in a wide variety of medical settings which also has a reflection on the endocrine system pathology among other organ systems. This review will provide an update of genetic changes observed in different endocrine system pathologies and their diagnostic, therapeutic and prognostic values. [ABSTRACT FROM AUTHOR]

The pathogenesis of hepatocellular carcinoma (HCC) is thought to involve the interaction of numerous genes. Identification of these genes and proteins which regulate liver carcinogenesis is critical for the exploration of novel targeted therapies. Yes-associated protein (YAP) and large tumor suppressor 1 (LATS1) are associated with HCC cells. LATS1 is an upstream inhibitory factor of YAP in the Hippo pathway. The aim of the present study was to measure the expression of LATS1 in Yap-downregulated cancer cells. Immunohistochemistry was used to determine YAP and LATS1 levels in HCC tissue samples. High YAP-expressing cell lines were selected from two human hepatocellular carcinoma cells with different metastatic potential. In addition, changes in cell growth rates and LATS1 expression in human HCC 97H cells, in which YAP had been knocked down using RNA interference (RNAi). The proliferation of cells was evaluated using an MTS assay and changes in the progression of cell division were assessed through cell cycle analysis. Western blot analysis was then used to determine YAP and LATS1 expression levels in 97H cells. The results of the present study demonstrated that overexpression of YAP was negatively correlated with LATS1 expression in HCC cells (P=0.016). Knockdown of YAP using lentivirus-small hairpin (sh)RNA significantly inhibited 97H cell growth; in addition, the downregulation of YAP protein levels (33.4%) was accompanied by downregulation of LATS1 protein levels (68.5%). In conclusion, these results demonstrated that as an inhibitor of YAP, LATS1 was decreased via downregulation of YAP using RNAi. This therefore indicated that the change in YAP levels in HCC cells may regulate LATS1 in a feedback manner. [ABSTRACT FROM AUTHOR]

High aldehyde dehydrogenase (ALDH) activity is a feature of stem cells from normal and cancerous tissues and a reliable universal marker used to isolate them. There are numerous ALDH isoforms with preferred substrate specificity variably expressed depending on tissue, cell type, and organelle and cell status. On the other hand, a given substrate may be metabolized by several enzyme isoforms. Currently ALDH activity is evidenced by using Aldefluor, a fluorescent substrate likely to be metabolized by numerous ALDH isoforms. Therefore, isolation techniques based on ALDH activity detection select a heterogeneous population of stem or progenitor cells. Despite active research in the field, the precise role(s) of different ALDH isoforms in stem cells remains enigmatic. Understanding the metabolic role of different ALDH isoform in the control of stem cell phenotype and cell fate during development, tissue homeostasis, or repair, as well as carcinogenesis, should open perspectives to significant discoveries in tissue biology. In this perspective, novel ALDH substrates are being developed. Here we describe how new substrates could be instrumental for better isolation of cell population with stemness potential and for defining hierarchy of cell populations in tissue. Finally, we speculate on other potential applications. [ABSTRACT FROM AUTHOR]