Siah2 control of T-regulatory cells limits anti-tumor immunity.

Understanding the mechanisms underlying anti-tumor immunity is pivotal for improving immune-based cancer therapies. Here, we report that growth of BRAF-mutant melanoma cells is inhibited, up to complete rejection, in Siah2-/- mice. Growth-inhibited tumors exhibit increased numbers of intra-tumoral activated T cells and decreased expression of Ccl17, Ccl22, and Foxp3. Marked reduction in Treg proliferation and tumor infiltration coincide with G1 arrest in tumor infiltrated Siah2-/- Tregs in vivo or following T cell stimulation in culture, attributed to elevated expression of the cyclin-dependent kinase inhibitor p27, a Siah2 substrate. Growth of anti-PD-1 therapy resistant melanoma is effectively inhibited in Siah2-/- mice subjected to PD-1 blockade, indicating synergy between PD-1 blockade and Siah2 loss. Low SIAH2 and FOXP3 expression is identified in immune responsive human melanoma tumors. Overall, Siah2 regulation of Treg recruitment and cell cycle progression effectively controls melanoma development and Siah2 loss in the host sensitizes melanoma to anti-PD-1 therapy

The effect of bacteriophages T4 and HAP1 on in vitro melanoma migration

<p>Abstract</p> <p>Background</p> <p>The antibacterial activity of bacteriophages has been described rather well. However, knowledge about the direct interactions of bacteriophages with mammalian organisms and their other, i.e. non-antibacterial, activities in mammalian systems is quite scarce. It must be emphasised that bacteriophages are natural parasites of bacteria, which in turn are parasites or symbionts of mammals (including humans). Bacteriophages are constantly present in mammalian bodies and the environment in great amounts. On the other hand, the perspective of the possible use of bacteriophage preparations for antibacterial therapies in cancer patients generates a substantial need to investigate the effects of phages on cancer processes.</p> <p>Results</p> <p>In these studies the migration of human and mouse melanoma on fibronectin was inhibited by purified T4 and HAP1 bacteriophage preparations. The migration of human melanoma was also inhibited by the HAP1 phage preparation on matrigel. No response of either melanoma cell line to lipopolysaccharide was observed. Therefore the effect of the phage preparations cannot be attributed to lipopolysaccharide. No differences in the effects of T4 and HAP1 on melanoma migration were observed.</p> <p>Conclusion</p> <p>We believe that these observations are of importance for any further attempts to use bacteriophage preparations in antibacterial treatment. The risk of antibiotic-resistant hospital infections strongly affects cancer patients and these results suggest the possibility of beneficial phage treatment. We also believe that they will contribute to the general understanding of bacteriophage biology, as bacteriophages, extremely ubiquitous entities, are in permanent contact with human organisms.</p

Vitamin D-VDR signaling inhibits Wnt/beta-catenin-mediated melanoma progression and promotes anti-tumor immunity

1α,25-dihydroxyvitamin D3 signals via the Vitamin D Receptor (VDR). Higher serum vitamin D is associated with thinner primary melanoma and better outcome, although a causal mechanism has not been established. As melanoma patients commonly avoid sun exposure, and consequent vitamin D deficiency might worsen outcomes, we interrogated 703 primary melanoma transcriptomes to understand the role of vitamin D-VDR signalling and replicated the findings in TCGA metastases. VDR expression was independently protective for melanoma death in both primary and metastatic disease. High tumor VDR expression was associated with upregulation of pathways mediating anti-tumor immunity and correspondingly with higher imputed immune cell scores and histologically detected tumor infiltrating lymphocytes (TILs). High VDR expressing tumors had downregulation of proliferative pathways, notably Wnt/beta-catenin signaling. Deleterious low VDR levels resulted from promoter methylation and gene deletion in metastases. Vitamin D deficiency (< 25 nmol/l ~ 10 ng/ml) shortened survival in primary melanoma in a VDR-dependent manner. In vitro functional validation studies showed that elevated vitamin D-VDR signaling inhibited Wnt/beta-catenin signaling genes. Murine melanoma cells overexpressing VDR produced fewer pulmonary metastases than controls in tail vein metastasis assays. In summary, vitamin D-VDR signaling contributes to controlling pro-proliferative/immunosuppresive Wnt/beta-catenin signaling in melanoma and this is associated with less metastatic disease and stronger host immune responses. This is evidence of the causal relationship between vitamin D-VDR signaling and melanoma survival which should be explored as a therapeutic target in primary resistance to checkpoint blockade

Role of social infrastructure in sustainable development of rural areas

Artykuł wskazuje rolę infrastruktury społecznej jako jeden z najważniejszych czynników w zrównoważonym rozwoju obszarów wiejskich. Pomiędzy infrastrukturą społeczną a zrównoważonym rozwojem, istnieje ścisły związek, ponieważ wyposażenie infrastrukturalne determinuje tempo rozwoju. W artykule przedstawiony został także temat pojęcia infrastruktury jak i zrównoważonego rozwoju.The article indicates the role of social infrastructure as one of the most important factors in the sustainable development of rural areas. There is a close relationship between the social infrastructure and sustainable development, because infrastructural equipment determines the pace of development. The article also presents the topic of the concept of infrastructure and sustainable development

Doświadczenia kliniczne w diagnozowaniu zmian patologicznych krtani z zastosowaniem obrazowania w wąskiej wiązce światła

Wprowadzenie: Jedną z najnowszych metod stosowanych w obrazowaniu krtani jest endoskopia wąskopasmowa (NBI). Umożliwia ona ocenę architektoniki naczyń błony śluzowej, uwidocznienie ognisk nieprawidłowej angiogenezy a tym samym zidentyfikowanie zmian patologicznych na wczesnym etapie kancerogenezy. Celem pracy było porównanie wartości diagnostycznej endoskopii w świetle białym oraz w wąskiej wiązce obrazowania (NBI) w ocenie zmian patologicznych błony śluzowej krtani. Materiał i metody: 333 pacjentów ze zmianami patologicznymi w krtani poddano ocenie w świetle białym oraz NBI. Obliczono czułość, swoistość, PPV, NPV dla obu metod. Wartość diagnostyczną WLE i NBI oceniono dla założeń, że wynik pozytywny stanowi dysplazja dużego stopnia i rak; oraz tylko rak. Wyniki: Czułość, swoistość, PPV, NPV dla założenia, że wynik pozytywny stanowi dysplazja dużego stopnia i rak wynosiły odpowiednio dla światła białego w porównaniu do NBI: 95,4% vs 98,5%; 84,2% vs 98,5%; 79,6% vs 97,7% oraz 96,6% vs 99,0%. Z kolei dla założenia, że wynikiem pozytywnym jest tylko rak powyższe wartości wynosiły: 97,4% vs 100%; 79,3% vs 93,5%; 72,6% vs 89,4% oraz 98,2% vs 100,0%. W przypadku obu wariantów wykazano, że czułość, PPV i NPV były wyższe dla NBI w porównaniu do światła białego. Stwierdzono ponadto znamiennie wyższą swoistość NBI w porównaniu do światła białego w różnicowaniu zmian patologicznych krtani (p<0,001). Wnioski: Zastosowanie NBI umożliwia zarówno rozpoznanie jak i różnicowanie zmian patologicznych w krtani, niewidocznych w świetle białym. Badanie endoskopowe, szczególnie wzmocnione NBI jest nieinwazyjne, powtarzalne i pozostaje przydatnym narzędziem w diagnostyce zmian rozrostowymi krtani. Badaniem decydującym o ostatecznym rozpoznaniu pozostaje badanie histopatologiczne

Clinical experience of narrow band imaging (NBI) usage in diagnosis of laryngeal lesions

Introduction: One of the most recent methods used in imaging of the larynx is NBI. NBI allows to detect specific patterns of pathological angiogenesis suggestive of premalignant or neoplastic lesions. Aim: The aim of the study was to compare imaging of laryngeal lesions in WLE and NBI in relation to histopathological examination. Material and methods: 333 patients with laryngeal lesions underwent endoscopic evaluation in WLE and NBI. Sensitivity, specificity, PPV, NPV for both methods were calculated. The diagnostic value for WLE and NBI was evaluated for two assumptions: a positive result indicates (1) severe dysplasia and cancer, or (2) only cancer. Results: Sensitivity, specificity, PPV, NPV for the first assumption were, respectively for white light compared to NBI: 95.4% vs 98.5%; 84.2% vs 98.5%; 79.6% vs 97.7% and 96.6% vs 99.0%. The values for the second assumption were: 97.4% vs 100%; 79.3% vs 93.5%; 72.6% vs 89.4% and 98.2% vs 100.0%. Higher sensitivity was observed for the second assumption, while higher specificity was recorded for the first assumption. Specificity was significantly higher for NBI than for WLE (p < 0.001). Conclusions: NBI allows to detect and differentiate laryngeal lesions, which are invisible in WLE. Endoscopic examination, especially in NBI mode, is non-invasive, repeatable and remains a useful tool in the daily practice and diagnosis of patients with pathological lesions in the larynx

Expression of pre-selected TMEMs with predicted ER localization as potential classifiers of ccRCC tumors

BACKGROUND: VHL inactivation is the most established molecular characteristic of clear cell renal cell carcinoma (ccRCC), with only a few additional genes implicated in development of this kidney tumor. In recently published ccRCC gene expression meta-analysis study we identified a number of deregulated genes with limited information available concerning their biological role, represented by gene transcripts belonging to transmembrane proteins family (TMEMs). TMEMs are predicted to be components of cellular membranes, such as mitochondrial membranes, ER, lysosomes and Golgi apparatus. Interestingly, the function of majority of TMEMs remains unclear. Here, we analyzed expression of ten TMEM genes in the context of ccRCC progression and development, and characterized these proteins bioinformatically. METHODS: The expression of ten TMEMs (RTP3, SLC35G2, TMEM30B, TMEM45A, TMEM45B, TMEM61, TMEM72, TMEM116, TMEM207 and TMEM213) was measured by qPCR. T-test, Pearson correlation, univariate and multivariate logistic and Cox regression were used in statistical analysis. The topology of studied proteins was predicted with Metaserver, together with PSORTII, Pfam and Localizome tools. RESULTS: We observed significant deregulation of expression of 10 analyzed TMEMs in ccRCC tumors. Cluster analysis of expression data suggested the down-regulation of all tested TMEMs to be a descriptor of the most advanced tumors. Logistic and Cox regression potentially linked TMEM expression to clinical parameters such as: metastasis, Fuhrman grade and overall survival. Topology predictions classified majority of analyzed TMEMs as type 3 and type 1 transmembrane proteins, with predicted localization mainly in ER. CONCLUSIONS: The massive down-regulation of expression of TMEM family members suggests their importance in the pathogenesis of ccRCC and the bioinformatic analysis of TMEM topology implies a significant involvement of ER proteins in ccRCC pathology

Tumor endothelial cell autophagy is a key vascular‐immune checkpoint in melanoma

Abstract Tumor endothelial cells (TECs) actively repress inflammatory responses and maintain an immune‐excluded tumor phenotype. However, the molecular mechanisms that sustain TEC‐mediated immunosuppression remain largely elusive. Here, we show that autophagy ablation in TECs boosts antitumor immunity by supporting infiltration and effector function of T‐cells, thereby restricting melanoma growth. In melanoma‐bearing mice, loss of TEC autophagy leads to the transcriptional expression of an immunostimulatory/inflammatory TEC phenotype driven by heightened NF‐kB and STING signaling. In line, single‐cell transcriptomic datasets from melanoma patients disclose an enriched InflammatoryHigh/AutophagyLow TEC phenotype in correlation with clinical responses to immunotherapy, and responders exhibit an increased presence of inflamed vessels interfacing with infiltrating CD8+ T‐cells. Mechanistically, STING‐dependent immunity in TECs is not critical for the immunomodulatory effects of autophagy ablation, since NF‐kB‐driven inflammation remains functional in STING/ATG5 double knockout TECs. Hence, our study identifies autophagy as a principal tumor vascular anti‐inflammatory mechanism dampening melanoma antitumor immunity