Humán daganatokban termelődő fehérjék alap és alkalmazott klinikai kutatásai = The basic and applied clinical research of proteins expressed in human tumors

Korábban már beszámoltunk egy új kis molekulasúlyú fehérje azonosításáról (Hsp16.2). Vizsgáltuk a fehérje expresszióját különféle humán neuroectodermalis tumorokban. Végül azt találtuk, hogy a Hsp16.2 megjelenése a különféle neuroectodermális agytumorokban korrelál a szövettani grádussal. A fehérje további pathológiás szöveti vizsgálatai folyamatban vannak egyéb tumorokban (rectum-, nyelőcső- tumorok). Munkacsoportunk írta le a „tail-interacting protein of 47 kDa TIP47” fehérjét, feltételezett funkcióját. Előzetes publikációink alapján vizsgáltuk a fehérje esetleges klinikai alkalmazását nőgyógyászati dysplasiakban, primer tumorokban és metasztázisok esetén. Vizsgálataink alapján a TIP47 szérumszintjének monitorozása alkalmas lehet a cervix daganat nyomon követésére, esetleges recidívák észlelésére. A TIP47 fehérje funkcionális vizsgálatait tovább folytatjuk a molekuláris biológia módszereivel. A fehérjének a védelmi oldalon van szerepe, antiapoptótikus hatása van. Vizsgáltuk az általunk publikált „heme-binding protein 2/ SOUL” fehérje funkcióját. Eredmények alapján a fehérje fő szerepe a nekrotikus útvonalak aktiválása. Célkitűzésünk volt nyelőcső-daganatos betegek szövettani mintájában tumor asszociált fehérjék keresése, amelyek expressziója utalhat a kemo-radioterápiára adott válaszra. Hsp16.2, Hsp90, pAKT, bax/bcl-2 arány és SOUL fehérjék ígéretes markereknek tűnnek. Korábban mi írtuk le PP13/galectin 13 fehérjét, mely funkcionális vizsgálatait folytattuk. A fehérje overexpressziója elsősorban az apoptotikus útvonalak aktivációját eredményezte. | We’d previously reported the characterisation of a novel small molecular weight protein, Hsp 16.2. We examined its expression in different types of human neuroectodermal tumors. We found, that the appearance of Hsp 16.2 in the various types of neuroectodermal brain tumors correlated with the histologic grade of the tumor. Our work group described the „tail-interacting protein of 47 kDa TIP47” and its assumed function. Based on our previous publications we investigated the possible clinical utilisation of the protein in gynecological dysplasias, primary tumors as well as in the cases of metastases. According to our findings, the monitoring of the serumlevel of TIP47 could be suitable for the follow up of patients suffering from cervical cancer as well as for the detection of possible recurrences. We are continuing the functional investigation of TIP47 protein using the methods of molecular biology. The protein has an antiapoptotic effect in cells. We examined the function of the „heme-binding protein 2/ SOUL” protein, which was published earlier by our work group. According to our results, the main role of the protein is the activation of the necrotic pathways. It was our goal to find tumor-associated proteins in the histologic samples of patients afflicted by esophageal cancer, whose expression could be related to the response of chemo-radiotherapy. Hsp 16.2, Hsp 90, pAkt, bax/bcl-2 ratio and SOUL proteins seemed promising markers. Earlier we described the PP13/galectin 13 protein, whose functional investigation we continued. The overexpression of the protein primarily resulted in the activation of the apoptotic pathways

The state of Hungarian radiotherapy

BackgroundHungary suffers from one of the highest levels of cancer morbidity, with over 700 new cases per 100000 inhabitants per year. This situation necessitates, among others, investigation of the current state of radiotherapeutic care, and its infrastructural and staffing conditions.AimThe aim of this paper is to present the current state of Hungarian radiotherapy.ResultsAlthough the number of radiation treatments increased substantially between 1995 and 2003 (16544 vs. 26316), together with a considerable increase in the linear accelerator equivalent (LAE) value (15.9 vs 29.45), about one-third of the patients who would profit from radiotherapy do not receive this form of treatment. Radiotherapeutic care is provided at 13 centers in 7 geographical regions, with widely varying infrastructural and staffing conditions, characterized by a mean LAE value of 4.2 (range: 0–8.45), a 1 LAE value for a mean of 343500 inhabitants (range: 0–731500), and a mean annual workload of 353 patients per radiation oncologist (range: 255–424), 532 patients per physicist (range: 255–911) and 149 per radiation technologist (range: 71–300). These conditions result in a waiting list of between 0 and 42 days for non-emergency cases and a mean of 260 radiotherapy-treated patients per 100000 inhabitants (range: 111–434) in the different geographical regions, which is far below the expected Hungarian value of 403 radiotherapy-treated cases/year.ConclusionsAttainment of an adequate radiotherapeutic service with an acceptable waiting time throughout Hungary requires the creation of 2 additional centers and the reconstruction of 1 existing center, the provision of 9 new linacs, the replacement of 10 functioning telecobalt units with linacs, and increases of 54% in the number of radiation oncologists, 51% in the number of physicists and 65% in the number of radiation technologists

Correlation between the progressive cytoplasmic expression of a novel small heat shock protein (Hsp16.2) and malignancy in brain tumors

<p>Abstract</p> <p>Background</p> <p>Small heat shock proteins are molecular chaperones that protect proteins against stress-induced aggregation. They have also been found to have anti-apoptotic activity and to play a part in the development of tumors. Recently, we identified a new small heat shock protein, Hsp16.2 which displayed increased expression in neuroectodermal tumors. Our aim was to investigate the expression of Hsp16.2 in different types of brain tumors and to correlate its expression with the histological grade of the tumor.</p> <p>Methods</p> <p>Immunohistochemistry with a polyclonal antibody to Hsp16.2 was carried out on formalin-fixed, paraffin-wax-embedded sections using the streptavidin-biotin method. 91 samples were examined and their histological grade was defined. According to the intensity of Hsp16.2 immunoreactivity, low (+), moderate (++), high (+++) or none (-) scores were given.</p> <p>Immunoblotting was carried out on 30 samples of brain tumors using SDS-polyacrylamide gel electrophoresis and Western-blotting.</p> <p>Results</p> <p>Low grade (grades 1–2) brain tumors displayed low cytoplasmic Hsp16.2 immunoreactivity, grade 3 tumors showed moderate cytoplasmic staining, while high grade (grade 4) tumors exhibited intensive cytoplasmic Hsp16.2 staining. Immunoblotting supported the above mentioned results. Normal brain tissue acted as a negative control for the experiment, since the cytoplasm did not stain for Hsp16.2. There was a positive correlation between the level of Hsp16.2 expression and the level of anaplasia in different malignant tissue samples.</p> <p>Conclusion</p> <p>Hsp16.2 expression was directly correlated with the histological grade of brain tumors, therefore Hsp16.2 may have relevance as becoming a possible tumor marker.</p

Visualization of mucosal field in HPV positive and negative oropharyngeal squamous cell carcinomas: combined genomic and radiology based 3D model

The aim of this study was to visualize the tumor propagation and surrounding mucosal field in radiography-based 3D model for advanced stage HNSCC and combine it with HPV genotyping and miRNA expression characterization of the visualized area. 25 patients with T1-3 clinical stage HNSCC were enrolled in mapping biopsy sampling. Biopsy samples were evaluated for HPV positivity and miR-21-5p, miR-143, miR-155, miR-221-5p expression in Digital Droplet PCR system. Significant miRNA expression differences of HPV positive tumor tissue biopsies were found for miR-21-5p, miR-143 and miR-221-5p compared to the HPV negative tumor biopsy series. Peritumoral mucosa showed patchy pattern alterations of miR-21-5p and miR-155 in HPV positive cases, while gradual change of miR-21-5p and miR-221-5p was seen in HPV negative tumors. In our study we found differences of the miRNA expression patterns among the HPV positive and negative tumorous tissues as well as the surrounding mucosal fields. The CT based 3D models of the cancer field and surrounding mucosal surface can be utilized to improve proper preoperative planning. Complex evaluation of HNSCC tissue organization field can elucidate the clinical and molecular differentiation of HPV positive and negative cases, and enhance effective organ saving therapeutic strategies

Retrospective study of cancer patients’ predictive factors of care in a large, Hungarian tertiary care centre

Objectives To identify predictive factors of multiple emergency department (ED) visits, hospitalisation and potentially preventable ED visits made by patients with cancer in a Hungarian tertiary care centre. Design Observational, retrospective study. Setting A large, public tertiary hospital, in Somogy County, Hungary, with a level 3 emergency and trauma centre and a dedicated cancer centre. Participants Patients above 18 years with a cancer diagnosis (International Classification of Diseases, 10th Revision codes of C0000–C9670) who visited the ED in 2018, who had received their diagnosis of cancer within 5 years of their first ED visit in 2018 or received their diagnosis of cancer latest within the study year. Cases diagnosed with cancer at the ED (new cancer diagnosis- related ED visits) were also included, constituting 7.9% of visits. Primary outcome measures Demographic and clinical characteristics were collected and the predictors of multiple (≥2) ED visits within the study year, admission to inpatient care following the ED visit (hospitalisation), potentially preventable ED visits and death within 36 months were determined. Results 2383 ED visits made by 1512 patients with cancer were registered. Predictive factors of multiple (≥2) ED visits were residing in a nursing home (OR 3.09, 95% CI 1.88 to 5.07) and prior hospice care (OR 1.87, 95% CI 1.05 to 3.31). Predictive factors for hospitalisation following an ED visit included a new cancer diagnosis- related visit (OR 1.86, 95% CI 1.30 to 2.66) and complaint of dyspnoea (OR 1.61, 95% CI 1.22 to 2.12). Conclusions Being a resident of a nursing home and receiving prior hospice care significantly increased the odds of multiple ED visits, while new cancer-related ED visits independently increased the odds of hospitalisation of patients with cancer. This is the first study to report these associations from a Central-Eastern European country. Our study may shed light on the specific challenges of EDs in general and particularly faced by countries in the region

Expression Levels of GHRH-Receptor, pAkt and Hsp90 Predict 10-Year Overall Survival in Patients with Locally Advanced Rectal Cancer

Rectal cancer constitutes nearly one-third of all colorectal cancer diagnoses, and certain clinical and molecular markers have been studied as potential prognosticators of patient survival. The main objective of our study was to investigate the relationship between the expression intensities of certain proteins, including growth-hormone-releasing hormone receptor (GHRH-R), Hsp90, Hsp16.2, p-Akt and SOUL, in specimens of locally advanced rectal cancer patients, as well as the time to metastasis and 10-year overall survival (OS) rates. We also investigated whether these outcome measures were associated with the presence of other clinical parameters.In total, 109 patients were investigated retrospectively. Samples of pretreatment tumors were stained for the proteins GHRH-R, Hsp90, Hsp16.2, p-Akt and SOUL using immunhistochemistry methods. Kaplan-Meier curves were used to show the relationships between the intensity of expression of biomarkers, clinical parameters, the time to metastasis and the 10-year OS rate.High levels of p-Akt, GHRH-R and Hsp90 were associated with a significantly decreased 10-year OS rate (p = 0.001, p = 0.000, p = 0.004, respectively) and high expression levels of p-Akt and GHRH-R were correlated with a significantly shorter time to metastasis. Tumors localized in the lower third of the rectum were linked to both a significantly longer time to metastasis and an improved 10-year OS rate.Hsp 90, pAkt and GHRH-R as well as the lower-third localization of the tumor were predictive of the 10-year OS rate in locally advanced rectal cancer patients. The GHRH-R and Hsp90 expression levels were independent prognosticators of OS. Our results imply that GHRH-R could play a particularly important role both as a molecular biomarker and as a target for the anticancer treatment of advanced rectal cancer

GHRH antagonists reduce the invasive and metastatic potential of human cancer cell lines \u3ci\u3ein vitro\u3c/i\u3e

We investigated the effect of a GHRH antagonist, MIA-602 on the metastatic cascade in vitro of three human cancers, DBTRG-05 glioblastoma, MDA-MB-468 estrogen-independent breast, and ES-2 clear cell ovarian cancer. GHRH receptors and their main splice variant, SV1 were detected on all three cell lines. After treatment with MIA-602, the cell viability decreased significantly, significant inhibition of cell invasion was observed and the release of MMPs was significantly decreased. The attachment of cancer cells to fibronectin and matrigel was severely hindered. Wound-healing experiments demonstrated a reduced cellular motility in all three cell lines. The up regulation of caveolin-1 and E-cadherin, and the powerful down regulation of NF-ĸB and β-catenin was detected. Our study suggests that the clinical application of highly potent GHRH antagonists in cancer therapy would be desirable since they inhibit proliferation and metastasis development as well