Human Papillomaviruses and Epstein-Barr Virus Interactions in Colorectal Cancer: A Brief Review.

Human papillomaviruses (HPVs) and the Epstein-Barr virus (EBV) are the most common oncoviruses, contributing to approximately 10%-15% of all malignancies. Oncoproteins of high-risk HPVs (E5 and E6/E7), as well as EBV (LMP1, LMP2A and EBNA1), play a principal role in the onset and progression of several human carcinomas, including head and neck, cervical and colorectal. Oncoproteins of high-risk HPVs and EBV can cooperate to initiate and/or enhance epithelial-mesenchymal transition (EMT) events, which represents one of the hallmarks of cancer progression and metastasis. Although the role of these oncoviruses in several cancers is well established, their role in the pathogenesis of colorectal cancer is still nascent. This review presents an overview of the most recent advances related to the presence and role of high-risk HPVs and EBV in colorectal cancer, with an emphasis on their cooperation in colorectal carcinogenesis

Synchronous or collision solid neoplasms and lymphomas: A systematic review of 308 case reports.

The presence of a lymphoma associated with a solid synchronous neoplasm or collision neoplasm has been rarely in the literature, and a detailed characterization of these cases is lacking to date. To describe the main clinicopathological features of synchronous/collision tumors. A systematic search in PubMed, Scielo, and Virtual Health Library literature databases for cases or case series of synchronous or collision lymphoma and other solid neoplasms reported up to March 2021 was performed. Three reviewers independently screened the literature, extracted data, and assessed the quality of the included studies. The systematic review was performed following the Preferred Reporting Items for Systematic Meta-Analyses guidelines. Mean age of patients was 62.9 years (52.9% men). A total of 308 cases were included (62% synchronous and 38% collision). The most frequent location of both synchronous and collision tumors was the gastrointestinal tract with the most common solid neoplasm being adenocarcinoma, and the most frequent lymphoma diffuse large B-cell lymphoma (21.7%) and mucosa-associated lymphoid tissue lymphoma (20.4%). Of the total number of mucosa-associated lymphoid tissue lymphomas and gastric adenocarcinomas, the presence of Helicobacter pylori infection was documented in 47.3% of them. Only 2% of all cases had a previous history of lymphoma. Thus, in most cases (98%), lymphoma was discovery incidentally. In addition, nodal lymphoma was associated with metastasis in 29 (9.4%) cases as collision tumor, most commonly (90%) in locoregional lymph nodes of the solid neoplasm. The frequent association of some type of B-cell lymphoma and adenocarcinoma in synchronous/collision tumors of the gastrointestinal tract points to common pathogenic mechanisms in both neoplasia, particularly related to chronic inflammation in this location. In most cases, lymphoma identified in locoregional lymph nodes or distant of a carcinoma seems to represent an incidental finding during the carcinoma diagnostic/therapeutic approach. A synergy between carcinoma and lymphoma (involving inflammation and immunosuppression mechanisms) may favor tumor progression and dissemination. A better understating of the interactions lymphoma/carcinoma in the setting of synchronous/collision tumors may help to improve patient management and prognosis

Pathologic aspects of skull base tumors

Skull base tumors form a highly heterogeneous group. As there are several structures in this anatomical site, a large number of different primary malignancies might develop, as well as a variety of secondary (metastatic) tumors. In this article, the most common malignancies are presented, along with a short histopathologic description. For some entities, an immunohistochemical profile is also given that should be helpful in proper diagnosis. As many pathologic diagnoses nowadays also include genetic studies, the most common genetic abnormalities in skull base tumors are presented

The HBP1 tumor suppressor is a negative epigenetic regulator of MYCN driven neuroblastoma through interaction with the PRC2 complex

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Visualizing the Productive Program of HPV in Differentiating Squamous Epithelial Tissue

The human papillomavirus (HPV) establishes persistent infections in the basal stratum of squamous epithelia, while productive amplification of viral DNA occurs in differentiated keratinocytes prior to virion assembly in the superficial strata. Until recently, only in situ hybridization (ISH) of low-grade HPV lesions could be used to reveal a snap shot of the viral life cycle. There has been a critical need to reproducibly propagate HPV infections in culture for consistent genetic analyses. Organotypic raft cultures recapitulate a differentiated squamous epithelium. Our lab utilized in vivo Cre-mediated recombination to reconstitute the entire HPV-18 genome in primary human keratinocytes (PHKs). My fluorescent in situ hybridization (FISH) to examine HPV DNA and RNA revealed robust differentiation-dependent viral activities and enabled a redesign that ultimately generated abundant progeny virus. Crucially, harvested virus elicited a new cycle of the productive infectious program in PHKs. The contextual progression of raft cultures containing HPV-18 replicons was consistent with known patterns of viral DNA amplification. Importantly, a detailed view of virus-host interactions was achieved by simultaneous in situ probing for viral DNA, viral proteins and host cell biomarkers. S-phase reentry was induced in numerous differentiated suprabasal epithelial cells on days 8 and 10. Unexpectedly, the patterns of HPV DNA amplification did not parallel those of the stochastic S phase cells. Rather, I show that viral DNA amplification initiated from G2 arrested on days 10 and 12 in the spinous strata. These cells accumulated high levels of cytoplasmic cyclin B1. While ectopic expression of HPV E1^E4 leads to G2 arrest in cell lines, I demonstrate that this viral protein accumulated following cyclin B stabilization and coincidental with the high amplification of viral DNA. Interestingly, such differentiated cells with high copies of viral DNA lost HPV E7 activity and transitioned to express capsid proteins for virion morphogenesis. An immortalization-null HPV-18 E6*I mutant genome was deficient in viral DNA amplification and failed to express the major capsid protein. These observations emphasize the value of simultaneous multiplexed detections in discerning the subtle interplay between naturally progressing HPV pathogenesis within its differentiating environment

Molecular biomarkers in head and neck cancer: Evaluation of biomarkers in prognostication and radiotherapy response prediction

Radiotherapy plays an integral part in the treatment of head and neck squamous cell carcinoma (HNSCC). Despite rigorous investigation spanning several decades, no molecular biomarkers are currently available for the prediction of radiotherapy response of an individual HNSCC tumour. Several radioresistance mechanisms have been acknowledged, including p53 alterations, hypoxia, and cancer stem cells. In this thesis, the overall purpose, role, and interpretation of molecular biomarkers in the context of HNSCC is discussed, and the clinical problem-field is emphasized. Putative radioresistance related molecular biomarkers were selected for investigation in HNSCC cell lines and patient materials. For clinical investigation, all HNSCC patients treated in the tertiary referral centre of Turku University Hospital during 2005-2010 were retrospectively collected. Clinical patient data was gathered, patient tumour samples were collected and processed into a tissue microarray. Immunohistochemistry and in situ hybridization were used for detection of biomarker expression and their relation to patient survival was analysed in multivariable survival models. Copy number alterations of stemness associated cancerous inhibitor of protein phosphatase 2A (CIP2A) were demonstrated in HNSCC cell lines and the presence of copy number alterations was found to be associated with a poor prognosis in HNSCC patients. Putative radioresistance biomarkers were investigated in several HNSCC cell lines after construction of a cell microarray. Stem cell marker OCT4 was revealed to be significantly associated with intrinsic radioresistance. The representativeness of the clinical tissue microarray was carefully confirmed using a novel population validation method. Using immunohistochemical stains, putative prognostic biomarkers were shown to perform poorly in the population-validated tissue microarray (PV-TMA). Finally, using the PV-TMA, OCT4 was found to predict for poor radiotherapy response and improved chemoradiotherapy response. In conclusion, using HNSCC cell line microarray and highly representative PVTMA patient material, OCT4 was established as a stratification biomarker between radiotherapy and cisplatin-based chemoradiotherapy.Molekulaariset biomarkkerit pään ja kaulan alueen syövässä Sädehoidolla on keskeinen rooli pään ja kaulan alueen levyepiteelisyöpien hoidossa. Vuosikymmenten tutkimuksesta huolimatta yksittäisen pään ja kaulan alueen levyepiteelisyövän sädehoitovastetta ennustavaa molekulaarista biomarkkeria ei ole käytettävissä. Nykyisin tunnetaan lukuisia huonoa sädeherkkyyttä selittäviä mekanismeja kuten p53-geenin mutaatiot, kasvaimen hypoksiset olosuhteet ja syöpäkantasolut. Tässä työssä tarkastellaan molekulaarisen biomarkkerin tehtävää, tarkoitusta ja tulkintaa pään ja kaulan alueen levyepiteelisyövän yhteydessä korostaen kliinistä ongelmakenttää. Sädeherkkyyteen liitettyjä biomarkkeriehdokkaita tutkittiin pään ja kaulan levyepiteelisyöpäsolulinjoja ja potilasaineistoja hyödyntäen. Kliinisenä tutkimuksena kerättiin kaikki vuosina 2005–2010 Turun yliopistollisessa keskussairaalassa hoidetut pään ja kaulan alueen levyepiteelisyöpäpotilaat käsittävä aineisto. Potilasnäytteet kerättiin ja niistä valmistettiin kudosmikrosiru. Biomarkkerien ilmentymistä tutkittiin immunohistokemiallisilla menetelmillä ja in situ hybridisaatiolla ja niiden yhteyttä potilaiden ennusteeseen selvitettiin monimuuttujaisilla ennustemalleilla. CIP2A-proteiinin kopiolukumuutoksia todettiin pään ja kaulan alueen levyepiteelisyöpäsolulinjoissa, ja kopiolukumuutosten havaittiin olevan yhteydessä pään ja kaulan levyepiteelisyöpäpotilaiden heikentyneeseen ennusteeseen. Pään ja kaulan alueen levyepiteelisyöpäsolulinjoista kootussa solumikrosiruaineistossa havaittiin kantasolutekijä OCT4:n olevan merkitsevästi yhteydessä solujen sädeherkkyyteen. Kliinisen kudosmikrosiruaineiston todettiin olevan edustava. Biomarkkeriehdokkaat suoriutuivat huonosti potilaiden ennusteen määrittämisestä, mutta OCT4 ennusti levyepiteelikasvaimen huonoa sädehoitovastetta, mutta hyvää ennustetta sisplatiinipohjaisen kemosädehoidon jälkeen. Tutkimuksessa todettiin pään ja kaulan levyepiteelisoluja ja edustavaksi havaittua väestövarmennettua kudosmikrosiruaineistoa hyödyntäen, että OCT4 soveltuu sädehoidon ja sisplatiinipohjaisen kemosädehoidon valintaa ohjaavaksi biomarkkeriksi

Prognostički značaj nuklearne morfometrije i imunohistohemijskih parametara kod melanoma kože

The goal was to prove the prognostic significance of nuclear-morphometric and immunohistochemical parameters in skin melanoma. Methodology: Epidemiological parameters (sex, age and localization) and biological properties (recidives, metastases) were analyzed (timespan from 2002 to 2016). Nuclear-morphometric and immunohistochemical parameters were also analyzed. Statistical data processing provided the connection between the evaluated parameters and their prognostic value. Significance of the research: The existence of a link between the biological course of skin melanoma and nuclear-morphometric and immunohistochemical parameters has been established. The increase in total intratumoral concentrations of CD4 and CD8 positive cells, as well as the increased proportion of these cells compared to the unstained cells of the same morphological characteristics, led to a good prognosis. The intensity of CD4 staining was also positively correlated with good prognosis. The increased count of CD15 positive cells along with the increase of Area, Circularity, IntDen, and Roundness predicts a good prognosis. The increase in Circularity and Roundness, as well as the increased concentration of peritumor CD15 cells, led to a worse prognosis. The lower CD117 level with increasing circularity and roundness may also indicate a poor prognosis of the disease. The CD8 parameters correlated with CD4 and CD15 parameters. Roundness showed a negative relation with the CD117 parameters. This represents the original scientific contribution of this dissertation

Colorectal Cancer Biology

Colorectal cancer is a common disease, affecting millions worldwide and represents a global health problem. Effective therapeutic solutions and control measures for the disease will come from the collective research efforts of clinicians and scientists worldwide. This book presents the current status of the strides being made to understand the fundamental scientific basis of colorectal cancer. It provides contributions from scientists, clinicians and investigators from 20 different countries. The four sections of this volume examine the evidence and data in relation to genes and various polymorphisms, tumor microenvironment and infections associated with colorectal cancer. An increasingly better appreciation of the complex inter-connected basic biology of colorectal cancer will translate into effective measures for management and treatment of the disease. Research scientists and investigators as well as clinicians searching for a good understanding of the disease will find this book useful

Medical-Data-Models.org:A collection of freely available forms (September 2016)

MDM-Portal (Medical Data-Models) is a meta-data repository for creating, analysing, sharing and reusing medical forms, developed by the Institute of Medical Informatics, University of Muenster in Germany. Electronic forms for documentation of patient data are an integral part within the workflow of physicians. A huge amount of data is collected either through routine documentation forms (EHRs) for electronic health records or as case report forms (CRFs) for clinical trials. This raises major scientific challenges for health care, since different health information systems are not necessarily compatible with each other and thus information exchange of structured data is hampered. Software vendors provide a variety of individual documentation forms according to their standard contracts, which function as isolated applications. Furthermore, free availability of those forms is rarely the case. Currently less than 5 % of medical forms are freely accessible. Based on this lack of transparency harmonization of data models in health care is extremely cumbersome, thus work and know-how of completed clinical trials and routine documentation in hospitals are hard to be re-used. The MDM-Portal serves as an infrastructure for academic (non-commercial) medical research to contribute a solution to this problem. It already contains more than 4,000 system-independent forms (CDISC ODM Format, www.cdisc.org, Operational Data Model) with more than 380,000 dataelements. This enables researchers to view, discuss, download and export forms in most common technical formats such as PDF, CSV, Excel, SQL, SPSS, R, etc. A growing user community will lead to a growing database of medical forms. In this matter, we would like to encourage all medical researchers to register and add forms and discuss existing forms