TNFR2 and Regulatory T Cells: Potential Immune Checkpoint Target in Cancer Immunotherapy

TNF has both proinflammatory and antiinflammatory effects. It binds to two structurally related but functionally distinct receptors TNFR1 and TNFR2. Unlike TNFR1 that is ubiquitously expressed, TNFR2 expression is more limited to myeloid and lymphoid cell lineages including a fraction of regulatory T cells (Treg). In general, TNFR1 is responsible for TNF-mediated cell apoptosis and death, and mostly induces proinflammatory reactions. However, TNFR2 mainly leads to functions related to cell survival and immune suppression. Treg play an indispensable role in maintaining immunological self-tolerance and restraining excessive immune reactions deleterious to the host. Impaired Treg-mediated immune regulation has been observed in various autoimmune diseases as well as in cancers. Therefore, Treg might provide an ideal therapeutic target for diseases where the immune balance is impaired and could benefit from the regulation of Treg properties. TNFR2 is highly expressed on Treg in mice and in humans, and TNFR2+ Treg reveal the most potent suppressive capacity. TNF-TNFR2 ligation benefits Treg proliferation, although the effect on Treg suppressive function remains controversial. Here, we will describe in detail the TNF-mediated regulation of Treg and the potential clinical applications in cancer immunotherapy as well as in autoimmune diseases, with the focus on human Treg subsets

Re-ranking Method Based on Topic Word Pairs

PACLIC 20 / Wuhan, China / 1-3 November, 200

Światowa produktywność badań w dziedzinie endokrynologii i metabolizmu — analiza bibliometryczna

  Introduction: Recently, significant contributions to the study of endocrinology and metabolism have been made. The national contribution, however, has not been reported. The aim of this study was to assess national efforts in the field of endocrinology and metabolism. Material and methods: A Web of Science search was performed using subject categories “endocrinology & metabolism” to identify articles published from 2010 to 2014. The total and per capita numbers of articles and citations were analysed for different countries. Results: A total of 79,394 articles were published on endocrinology and metabolism from 2010 to 2014. Most were published in North America, East Asia, and Europe. The majority (82.28%) were reported by authors in high-income countries, 17.64% were published in middle-income countries, and only 0.08% were published in low-income countries. Authors in the United States published the most articles (27.38%), followed by China (7.22%), Italy (5.70%), the United Kingdom (5.6%), and Japan (5.54%). Articles published by authors in the United States had the most citations (260,934). A positive correlation was found between the number of publications and population/gross domestic product (GDP; p < 0.01). When normalised to population size, the ranking for the most publications was Denmark, Sweden, and the Netherlands; when normalised to GDP, the ranking was Denmark, Greece, and the Netherlands. Conclusions: The majority of endocrinology and metabolism articles were published by authors from high-income countries with few from low-income countries. The United States was the most productive country. However, when population size and GDP were considered, some European countries were ranked higher. (Endokrynol Pol 2015; 66 (5): 434–442)    Wstęp: Ostatnio pojawiło się wiele znaczących publikacji na temat badań z dziedziny endokrynologii i metabolizmu. Narodowy wkład na tym polu został jednak pominięty. Celem niniejszego badania była ocena krajowych badań w dziedzinie endokrynologii i metabolizmu. Materiał i metody: Wyszukiwanie za pomocą Web of Science przeprowadzono z wykorzystaniem kategorii podmiotowych „endokrynologia i metabolizm”, aby zidentyfikować artykuły opublikowane w latach 2010–2014. Analizie poddano łączną liczbę artykułów i cytowań, a także ich liczbę przypadającą na osobę w odniesieniu do różnych krajów. Wyniki: W latach 2010–2014 opublikowano łącznie 79 394 artykułów na temat endokrynologii i metabolizmu. Większość artykułów pochodziła z Ameryki Północnej, Azji Wschodniej i Europy. Większość artykułów (82,28%) napisali autorzy z krajów o wysokich dochodach, 17,64% opublikowano w krajach średnio zamożnych, a jedynie 0,08% artykułów opublikowano w krajach o niskich dochodach. Najwięcej artykułów publikowali autorzy ze Stanów Zjednoczonych (27,38%), następnie z Chin (7,22%), Włoch (5,70%), Wielkiej Brytanii (5,6%) i Japonii (5,54%). Prace publikowane przez amerykańskich autorów zawierały największą liczbę cytowań (260 934). Stwierdzono pozytywny związek między liczbą publikacji i populacją/produktem krajowym brutto (PKB; p < 0,01). Po unormalizowaniu do liczebności populacji, w rankingu krajów o najwyższej liczbie publikacji znalazły się Dania, Szwecja oraz Holandia. Gdy znormalizowano wyniki pod względem PKB, w rankingu znalazły się Dania, Grecja oraz Holandia. Wnioski: Większość artykułów z dziedziny endokrynologii i metabolizmu została opublikowana przez autorów z krajów o wysokich dochodach; w krajach o niskich dochodach ukazało się niewiele artykułów. Stany Zjednoczone wykazały największą produktywność, jednak kiedy brano pod uwagę liczebność populacji i PKB, niektóre kraje europejskie zajmowały wyższą pozycję. (Endokrynol Pol 2015; 66 (5): 434–442)

Virome and metagenomic analysis reveal the distinct distribution of microbiota in human fetal gut during gestation

Studies have shown that fetal immune cell activation may result from potential exposure to microbes, although the presence of microbes in fetus has been a controversial topic. Here, we combined metagenomic and virome techniques to investigate the presence of bacteria and viruses in fetal tissues (small intestine, cecum, and rectum). We found that the fetal gut is not a sterile environment and has a low abundance but metabolically rich microbiome. Specifically, Proteobacteria and Actinobacteria were the dominant bacteria phyla of fetal gut. In total, 700 species viruses were detected, and Human betaherpesvirus 5 was the most abundant eukaryotic viruses. Especially, we first identified Methanobrevibacter smithii in fetal gut. Through the comparison with adults’ gut microbiota we found that Firmicutes and Bacteroidetes gradually became the main force of gut microbiota during the process of growth and development. Interestingly, 6 antibiotic resistance genes were shared by the fetus and adults. Our results indicate the presence of microbes in the fetal gut and demonstrate the diversity of bacteria, archaea and viruses, which provide support for the studies related to early fetal immunity. This study further explores the specific composition of viruses in the fetal gut and the similarities between fetal and adults’ gut microbiota, which is valuable for understanding human fetal immunity development during gestation

Overexpression of miR-489 enhances efficacy of 5-fluorouracil-based treatment in breast cancer stem cells by targeting XIAP

Population of cancer stem cells (CSCs) in breast cancer is reported to be resistant to chemotherapy. Furthermore, many cases of treatment failure are induced by the chemoresistance of CSCs in breast cancer patients. Therefore, novel strategies should be explored urgently to reverse drug-resistance in breast cancer stem cells (BCSCs). In this study, we isolated and cultured the BCSCs from the T-47D and SKBR3 breast cancer cell lines. We observed significant resistance to 5-fluorouracil in BCSCs. Mechanically, we found that expression of miR-489 was decreased in BCSCs. Furthermore, overexpression of miR-489 was found to increase the cytotoxicity of 5-fluorouracil to BCSCs. XIAP, a key anti-apoptotic protein, was proved to be the target of miR-489. We found that enforced expression of XIAP through its recombinant expression vector abolished the effect of miR-489 on reversing the 5-fluorouracil resistance. On the contrary, embelin, a XIAP specific inhibitor, was found to sensitize BCSCs to 5-fluorouracil similarly with miR-489. In summary, our data demonstrate that introduction with miR-489 represents a novel strategy to enhance efficacy of 5-fluorouracil-based treatment in BCSCs

ADAM12-L confers acquired 5-fluorouracil resistance in breast cancer cells

5-FU-based combinatory chemotherapeutic regimens have been routinely used for many years for the treatment of breast cancer patients. Recurrence and chemotherapeutic drug resistance are two of the most prominent factors that underpin the high mortality rates associated with most breast cancers (BC). Increasing evidence indicates that overexpression of ADAMs could correlate with cancer progression. However, the role of ADAMs in the chemoresistance of cancer cells has rarely been reported. In this study, we observed that 5-FU induces expression of the ADAM12 isoform ADAM12-L but not ADAM12-S in BC cells and in recurrent BC tissues. The overexpression of ADAM12-L in BC cells following 5-FU treatment results in the acquisition of resistance to 5-FU. ADAM12-L overexoression also resulted in increased levels of p-Akt but not p-ERK. These alterations enhanced BC cell growth and invasive abilities. Conversely, ADAM12 knockdown attenuated the levels of p-Akt and restored 5-FU sensitivity in 5-FU-resistant BC cells. ADAM12 knockdown also reduced BC cell survival and invasive abilities. These findings suggest that ADAM12-L mediates chemoresistance to 5-FU and 5-FU-induced recurrence of BC by enhancing PI3K/Akt signaling. The results of this study suggest that specific ADAM12-L inhibition could optimize 5-FU-based chemotherapy of BC, thereby preventing BC recurrence in patients