Cancer gene therapy – state-of-the-art

A number of gene therapy clinical trials are being carried out the world over. Gene therapy is being applied in (I) cancer diseases, involving the largest number of patients, (II) monogenic diseases, (III) infectious diseases, (IV) vascular diseases, (V) autoimmune diseases and others. In the last decade, several strategies of cancer gene therapy have emerged due to a rapid development of gene delivery systems, both viral (recombinant retroviruses, adenoviruses, AAVs, herpes viruses) and nonviral (liposomes, gene guns, electroporation). To date four main strategies of cancer gene therapy have been evaluated in clinical trials: (I) immunogene therapy, (II) suicide gene therapy, (III) antiangiogenic gene therapy, (IV) and administration of tumour suppressor genes.These strategies mostly involve: malignant melanoma, prostate cancer, renal cell cancer, colon cancer, breast and ovarian cancers, lung cancers, neoplastic diseases of the blood and brain tumours.At the Department of Cancer Immunology at the GreatPoland Cancer Center Gene Modified Tumour Vaccine has been tested in malignant melanoma patients for more than six years. Due to encouraging results from phase I and II of clinical trials a phase III was designed and will be started in 2003

Skin dysfunction in diabetes. Part 2 — microangiopathy and neuropathy

Znalezienie wiarygodnych metod oceniających wczesne zmiany w mikrokrążeniu oraz wczesne wykładniki neuropatii cukrzycowej ma istotne znaczenie kliniczne. W pracy przedstawiono patogenezę zaburzeń funkcji skóry w cukrzycy jako obrazu zmian zarówno mikroangiopatycznych, jak i w obrębie nerwów obwodowych. Opisano również aktualnie dostępne metody badania skóry.Searching for reliable methods for evaluating early changes in the microcirculation and early markers of diabetic neuropathy has important clinical significance. The paper presents the pathogenesis of skin changes in diabetes as a result of microangiopathy and pathology in the peripheral nerves. We also describe currently available methods to evaluate skin dysfunction

239. Ocena efektu przeciwnowotworowego genetycznie modyfikowanej szczepionki komórkowej w mysim modelu raka nerki

CelGenetycznie modyfikowane szczepionki komórkowe (GMTV) mają za zadanie indukcję efektywnej odpowiedzi przeciwnowotworowej. Postanowiliśmy ocenić efekt protekcyjny dwóch różnych GMTV w mysim modelu raka jasnokomórkowego nerki, oraz rolę komórek dendrytycznych w fazie indukcji przeciwnowotworowej odpowiedzi komórkowej.MetodyPrzy wykorzystaniu wektorów retrowirusowych DCCMV-IRES-Neo-H-6 oraz DCCMV-IRES-Neo-IL-6 wprowadzono do komórek mysiego raka jasnokomórkowego (RenCa) skonstruowano dwa rodzaje GMTV: (i) Komórki RenCa wykazujące ekspresję genu Interleukiny-6, (ii) komórki RenCa wykazujące ekspresję genu Hyper-lnterleukiny-6 (sztuczna cytokina będąca białkiem fuzyjnym składającym się z IL-6 powiązanej sztucznym linkerem z agonistycznym rozpuszczalnym receptorem) W celu oceny efektu protekcyjnego GMTV, myszy Balb/c w wieku 8–12 tygodni (8 osobników w jednej grupie eksperymentalnej) immunizowano podając podskórnie w lewe udo, 1×10^6 naświetlonych (80 Gy) komórek (RenCa w/t, RenCa-IL-6, Renca-H6). Po 14 dniach myszom podawano podskórnie w prawe udo wyjściowe komórki RenCa w/t w ilości 5×10^5. Następnie oceniano dynamikę pojawiania się guzów oraz kinetykę ich wzrostu. W celu oceny mechanizmów indukcji odpowiedzi immunologicznej postanowiono ocenić in situ wpływ poszczególnych rodzajów GMTV na komórki dendrytyczne. Myszy Balb/c otrzymywały w okolicy śródbrzusza, podskórnie 2×10^6 napromienionych (80 Gy) komórek Renca w/t, Renca-IL-6, Renca H-6 zawieszonych w Matrigelu™. Po 7 dniach przy pomocy cytometru przepływowego analizowano komórki naciekające Matrigel.Wyniki i podsumowanieImmunizacja myszy komórkami RenCa-H6 okazała się najbardziej efektywna w porównaniu do komórek RenCa w/t i RenCa-IL-6. Jakkolwiek nie przeciwdziałała wzrostowi guzów. Aktywowane komórki DC naciekały najsilniej komórki RenCa-H6. Efekt protekcyjny wyraźnie korelował z ilością aktywowanych komórek DC naciekających miejsce podania GMTV. Intensywna infiltracja miejsca podania GMTV przez komórki DC o wysokim poziomie aktywacji wskazuje na silną role Hyper-Interleukiny-6 w procesie indukcji funkcjonalnej przeciwnowotworowej odpowiedzi immunologicznej

Skin dysfunction in diabetes. Part 1 — function of skin cells

Skóra jest jednym z największych narządów w ustroju. Zbudowana jest z naskórka, skóry właściwej i tkanki podskórnej. Zmiany skórne w cukrzycy przypominają przyspieszony proces jej starzenia. W pracy przedstawiono zmiany funkcji poszczególnych komórek skóry w warunkach hiperglikemii. Opisano również mechanizmy glikacji białek skóry, a także ich wpływ na jej właściwości. Różnorodność komórek skóry, uzależnienie ich czynności od stężeń glukozy we krwi oraz łatwa dostępność do przeprowadzania badań powinny czynić zmiany czynności skóry w cukrzycy wczesnym ekwiwalentem powikłań choroby.Skin is one of the largest organs in the body. It is composed of epidermis, dermis and subcutaneous tissue. Skin changes in diabetes are similar to accelerated aging process. This paper presents the changes in the skin cells functions in the presence of hyperglycemia. We also describe the mechanisms of assessment of glycation of skin proteins, and the impact of the formation of advanced glycation end products on the properties of the skin. The variety of skin cells, glucose dependence, and their easy availability should make changes in the skin an equivalent of late diabetic complications

In vivo differentiation of common basal cell carcinoma subtypes by microvascular and structural imaging using dynamic optical coherence tomography

The subtype of basal cell carcinoma (BCC) influences the choice of treatment. Optical coherence tomography (OCT) is a non-invasive imaging tool, and a recent development of an angiographic version of OCT has extended the application of OCT to image the cutaneous microvasculature (so-called dynamic OCT, D-OCT). This study explores D-OCT's ability to differentiate the common BCC subtypes by microvascular and structural imaging. Eighty-one patients with 98 BCC lesions, consisting of three subtypes: 27 superficial BCC (sBCC), 55 nodular BCC (nBCC) and 16 infiltrative BCC (iBCC) were D-OCT scanned at three European dermatology centres. Blinded evaluations of microvascular and structural features were performed, followed by extensive statistical analysis of risk ratio (RR) and multiple correspondence analysis. nBCC lesions displayed most characteristic structural and vascular features. Serpiginous vessels, branching vessels, vessels creating a circumscribed figure and sharply demarcated hyporeflective ovoid structures in the dermis were all associated with a higher risk of the subtype being nBCC. The presence of highly present lines and dark peripheral borders at the margin of ovoid structures was negatively associated with iBCC. Lastly, the finding of hyporeflective ovoid structures protruding from epidermis correlated with sBCC. We identified various microvascular and structural D-OCT features that may aid non-invasive identification of BCC subtypes. This would allow clinicians to individualize and optimize BCC treatment as well as aid follow-up of non-surgical treatment

Multicenter, real-life experience with checkpoint inhibitors and targeted therapy agents in advanced melanoma patients in Switzerland.

Metastatic melanoma is a highly aggressive disease. Recent progress in immunotherapy (IT) and targeted therapy (TT) has led to significant improvements in response and survival rates in metastatic melanoma patients. The current project aims to determine the benefit of the introduction of these new therapies in advanced melanoma across several regions of Switzerland. This is a retrospective multicenter analysis of 395 advanced melanoma patients treated with standard chemotherapy, checkpoint inhibitors, and kinase inhibitors from January 2008 until December 2014. The 1-year survival was 69% (n=121) in patients treated with checkpoint inhibitors (IT), 50% in patients treated with TTs (n=113), 85% in the IT+TT group (n=66), and 38% in patients treated with standard chemotherapy (n=95). The median overall survival (mOS) from first systemic treatment in the entire study cohort was 16.9 months. mOS of patients treated either with checkpoint or kinase inhibitors (n=300, 14.6 months) between 2008 and 2014 was significantly improved (P<0.0001) compared with patients treated with standard chemotherapy in 2008-2009 (n=95, 7.4 months). mOS of 61 patients with brain metastases at stage IV was 8.1 versus 12.5 months for patients without at stage IV (n=334), therefore being significantly different (P=0.00065). Furthermore, a significant reduction in hospitalization duration compared with chemotherapy was noted. Treatment with checkpoint and kinase inhibitors beyond clinical trials significantly improves the mOS in real life and the results are consistent with published prospective trial data

Odbiór emocji wyrażonych w prozodii u dzieci z uszkodzonym narządem słuchu

Reception of Emotions Expressed in the Prosy by Children with Damaged Hearing SystemHearing damage causes difficulties in perception not only of segmented speech components but also of suprasegmental structures. As a result, many functions performed by the prosody of speech, which are important for the understanding and interpretation of language communication, become unavailable to people with impaired hearing. The article presents the results of own research on perception of emotions encoded in the prosody of speech (happiness, sadness and anger) by children with prelingual hearing damage. The obtained results indicate that children’s ability to perceive emotions expressed prosodically is significantly reduced when compared with normal-hearing children’s. Difficulties in this respect increase proportionally to the hearing loss severity.Key words: prosody, hearing damage, perception of prosodic phenomen

Music and Intonation in the Perception of Children Using Hearing Aids

Cechy wspólne mowy i muzyki są szczególnie widoczne w prozodii. Wyniki badań nad powiązaniami procesów percepcji obydwu tych zjawisk, choć istotne w perspektywie zastosowania muzyki w działaniach służących kształtowaniu prozodii mowy, opisywane są w literaturze stosunkowo rzadko. Niewiele jest również doniesień na ten temat w odniesieniu do osób z uszkodzonym narządem słuchu. W artykule zaprezentowano wyniki badań własnych nad odbiorem zjawisk muzycznych – melodii i rytmu oraz intonacji w mowie przez dzieci z prelingwalnym uszkodzeniem narządu słuchu korzystające z aparatów słuchowych. Wskazują one na obniżoną, w porównaniu z grupą kontrolną, sprawność percepcyjną badanych w zakresie wszystkich tych zjawisk. Najmniejsze zaburzenia dotyczą odbioru struktur intonacyjnych, największe zaś – melodii instrumentalnych.The features shared by speech and music are particularly noticeable in prosody. The results of studies on the connections between perception processes of the two phenomena, although important from the perspective of the use of music in measures serving to shape the prosody of speech, are described comparatively seldom in literature. There are also few reports concerning persons with impaired hearing. The article presents the results of the authors’ own research on the perception of musical phenomena – melody and rhythm as well as intonation in speech by fitting prelingual hearing-impaired children with hearing aids. As compared with the control group, the results show a lower perception skill of the subjects in respect of all these phenomena. The weakest disorders are reported in the perception of intonation structures, while the strongest – in the perception of instrumental melodies

Oncogenic BRAF mutations and p16 expression in melanocytic nevi and melanoma in the Polish population

Introduction: Twenty-five – fifty percent of skin melanomas arise from nevi. Melanocyte proliferation is activated by BRAF V600E , then is arrested, but single nevi transform to melanomas. p16 controls arrest, and p16 loss may promote transformation. Aim : To analyze BRAF V600E , p16 expression and melanocyte proliferation in dermal, compound and dysplastic nevi, cells of primary and metastatic melanoma in the Polish population. Material and methods : One hundred and thirty-two nevi (dermal, compound, dysplastic) and 41 melanomas (in situ, primary, metastatic) were studied. BRAF was assessed by cobas® 4800 BRAFV600 Mutation Test, High Resolution Melting Assay validated with: pyrosequencing and immunohistochemistry. p16 and Ki67 expression was analyzed by IHC. Results : Eighty-two percent of nevi and 57% of melanomas display BRAF V600E expression. Most dermal and compound nevi had > 50% of p16(+) cells. BRAF V600E dysplastic nevi had a low number of p16(+) cells. Nevi without BRAF V600E (WT), had 90% of cells p16(+). In 60% of in situ and primary melanomas, there was a low number of cells of p16(+). Fifty percent of WT metastatic melanoma and 33% of BRAF V600E showed a high level of p16. The number of Ki67(+) cells in dysplastic nevi was very low. In 25% of BRAF V600E melanomas in situ and 55% of WT, > 10% cells were Ki67(+). All BRAF V600E primary melanomas and 66% of WT had > 10% Ki67(+) cells. Twenty percent of BRAF V600E and WT metastases had > 10% of Ki67(+), however, 62% of BRAF V600E and 32% of WT samples had > 50% of Ki67(+) cells. Conclusions : BRAF V600E and p16 are more frequent in nevi than in melanoma in vivo. A significantly higher p16 expression was observed in mutated nevi than in WT, while in melanoma it was just the opposite. The proliferation rate of melanoma cells negatively correlated with p16 expression