Tumor associated inflammation predicts response to immune checkpoint blockade in human melanoma. Current theories on regulation of inflammation center on anti-tumor T cell responses. Here we show that tumor associated B cells are vital to melanoma associated inflammation. Human B cells express pro- and anti-inflammatory factors and differentiate into plasmablast-like cells when exposed to autologous melanoma secretomes in vitro. This plasmablast-like phenotype can be reconciled in human melanomas where plasmablast-like cells also express T cell-recruiting chemokines CCL3, CCL4, CCL5. Depletion of B cells in melanoma patients by anti-CD20 immunotherapy decreases tumor associated inflammation and CD8+ T cell numbers. Plasmablast-like cells also increase PD-1+ T cell activation through anti-PD-1 blockade in vitro and their frequency in pretherapy melanomas predicts response and survival to immune checkpoint blockade. Tumor associated B cells therefore orchestrate and sustain melanoma inflammation and may represent a predictor for survival and response to immune checkpoint blockade therapy.

Colloidal perovskite quantum dots represent one of the most promising materials for applications in solar cells and photoluminescences. These devices require a low density of crystal defects and a high yield of photogenerated carriers, which are difficult to realize in tin-halide perovskite because of the intrinsic instability of tin during nucleation. Here, an enhancement in the luminescent property of tin-halide perovskite nanoplates (TPNPs) that are composed of strongly coupled layered structures with the chemical formula of PEA SnX (PEA = C H (CH ) NH , X = Br, I) is reported. TPNPs (X = I) show an emission at a wavelength of 640 nm, with high quantum yield of 6.40 ± 0.14% and full width at half maximum (FWHM) as small as 36 nm. The presence of aliphatic carboxylic acid is found to play a key role in reducing the tin perovskite defect density, which significantly improves the emission intensity and stability of TPNPs. Upon mixing iodo- and bromo- precursors, the emission wavelength is successfully tuned from 640 nm (PEA SnI ) to 550 nm (PEA SnBr ), with a corresponding emission quantum yield and FWHM of 0.16-6.40% and 36-80 nm, respectively. The results demonstrate a major advance for the emission yield and tunability of tin-halide perovskites.

Reactive oxygen species, endothelial dysfunction, inflammation, and mitogen-activated protein kinases have important roles in the pathogenesis of ischemia/reperfusion kidney injury. Stanniocalcin-1 (STC1) suppresses superoxide generation in many systems through induction of mitochondrial uncoupling proteins and blocks the cytokine-induced rise in endothelial permeability. Here we tested whether transgenic overexpression of STC1 protects from bilateral ischemia/reperfusion kidney injury. This injury in wild type mice caused a halving of the creatinine clearance; severe tubular vacuolization and cast formation; increased infiltration of macrophages and T cells; higher vascular permeability; greater production of superoxide and hydrogen peroxide; and higher ratio of activated ERK/activated JNK and p38, all compared to sham-treated controls. Mice transgenic for human STC1 expression, however, had resistance to equivalent ischemia/reperfusion injury indicated as no significant change from controls in any of these parameters. Tubular epithelial cells in transgenic mice expressed higher mitochondrial uncoupling protein 2 and lower superoxide generation. Pre-treatment of transgenic mice with paraquat, a generator of reactive oxygen species, before injury restored the susceptibility to ischemia/reperfusion kidney injury, suggesting that STC1 protects by an anti-oxidant mechanism. Thus, STC1 may be a therapeutic target for ischemia/reperfusion kidney injury.

Tumor associated inflammation predicts response to immune checkpoint blockade in human melanoma. Established mechanisms that underlie therapy response and resistance center on anti-tumor T cell responses.Here we show that tumor-associated B cells are vital to tumor associated inflammation.Autologous B cells were directly induced by melanoma conditioned medium, expressed proand anti-inflammatory factors, and differentiated towards a plasmablast-like phenotype in vitro .We could identify this phenotype as a distinct cluster of B cells in an independent public single-cell RNA-seq dataset from melanoma tumors. There, plasmablast-like tumor-associated B cells showed expression of CD8+T cell-recruiting chemokines such as CCL3, CCL4, CCL5 and CCL28. Depletion of tumor associated B cells in metastatic melanoma patients by anti-CD20 immunotherapy decreased overall inflammation and CD8+T cell numbers in the human melanoma TME. Conversely, the frequency of plasmablast-like B cells in pretherapy melanoma samples predicted response and survival to immune checkpoint blockade in two independent cohorts. Tumor-associated B cells therefore orchestrate and sustain tumor inflammation, recruit CD8+ T effector cells and may represent a predictor for response and survival to immune checkpoint blockade in human melanoma.2 Cancers such as melanoma, lung, and kidney cancer often present with an inflamed but immunosuppressive tumor microenvironment (TME). Immune checkpoint blocking (ICB) antibodies have significantly improved cancer therapy by overcoming inhibition of T cell effector functions. Yet, a considerable number of patients does not benefit from ICB therapy 1 . It is therefore key to understand the mechanisms that regulate inflammation within the TME to develop novel therapies and improve patient survival. B cells promote both acute immune-associated inflammation for protection against foreign pathogens as well as chronic inflammation in autoimmune diseases and persistent infection. Mouse cancer models show that tumor-associated B cells (TAB) promote tumor inflammation 2,3 but may also inhibit anti-tumor T cell-dependent therapy responses 4-7 . The immuno-inhibitory function of TAB in these models resembles that of regulatory B cells (Breg), which are an established source of inhibitory cytokines such as IL-10 and TGF-b (reviewed in 8 ). In human cancer, Breg were described by either phenotyping, direct detection of immunoinhibitory cytokines or surface molecules, and/or immunosuppressive function 4,[9][10][11][12][13] .Often Breg frequencies increase with tumor progression and are enriched in tumors compared to peripheral blood or adjacent normal tissue. Increased IL-10 + B cell numbers can also be accompanied by increased numbers of CD4 + CD25 +/high CD127 low/and Foxp3 + Tregs in tumor tissues 10,12,14,15 which were independently associated with tumor progression or reduced patient survival.In human melanoma, up to 33% of the immune cells can be TAB 16,17 and phenotypic analysis has revealed CD20+ TAB (reviewed in 18 ) and CD1...

Population structures and genetic diversity of the small eukaryotic plankton from the coastal waters of the Nansha Islands in China were investigated. Two genes libraries using 18S rDNA of the marine small eukaryotes were constituted, and 323 clones were identified within alveolates (more than 43%), acanthareas, viridiplantaes, and stramenopiles. Many novel clones were detected in the two libraries, including two groups of alveolates and two clades related to both acanthareas and polycystineas. Several sequences unrelated to any other known eukaryotes may represent early branches in the phylogenetic tree. Our results reveal that there is a high diversity and abundance of small eukaryotes in the marine regions of China.

Extracellular signal-regulated kinase 3 (ERK3) is an atypical mitogen-activated protein kinase (MAPK), whose biological activity is tightly regulated by its cellular abundance. Recent studies have revealed that ERK3 is upregulated in multiple cancers and promotes cancer cell migration/invasion and drug resistance. Little is known, however, about how ERK3 expression level is upregulated in cancers. Here we have identified the oncogenic polycomb group protein BMI1 as a positive regulator of ERK3 level in head and neck cancer cells. Mechanistically, BMI1 upregulates ERK3 expression by suppressing the tumor suppressive microRNA (miRNA) let-7i which directly targets ERK3 mRNA. ERK3 then acts as an important downstream mediator of BMI1 in promoting cancer cell migration. Importantly, ERK3 protein level is positively correlated with BMI1 level in head and neck tumor specimens of human patients. Taken together, our study revealed a molecular pathway consisting of BMI1, miRNA let-7i and ERK3 which controls the migration of head and neck cancer cells, and suggests that ERK3 kinase is a potential new therapeutic target in head and neck cancers, particularly those with BMI1 overexpression.

The internal elastic lamina (IEL) of vein grafts may be modified when exposed to arterialized hemodynamics. We investigated changes of the IEL in the inferior vena cava (IVC) of rats with aortocaval fistulae (ACF). In the IVC of ACF rats, both a markedly increased flow velocity and a mildly increased pressure were demonstrated. In the lower segment where hemodynamic changes were prominent, neointimal hyperplasia was prominently found. The IEL of the IVC in sham-operated rats, observed by confocal microscopy, was composed of parallel elastic fibers. In ACF rats, the IEL degenerated progressively after surgery. The elastic fibers were stretched and gradually became sparse, a change that was more prominent in the lower segment. Eight weeks after surgery, the IEL hardly existed in some areas of the lower segment. Electron microscopy revealed decreased densities and diameters of elastic fibers. Reverse transcriptase-polymerase chain reaction analysis revealed an up-regulation of potent elastases, cathepsins K and S, and matrix metalloproteinase-2 in the IVC of ACF rats. Results of immunohistochemical studies localized cathepsin expression predominantly to the luminal endothelium lining the IEL, suggesting involvement of elastinolysis in the degradation of the IEL. We demonstrated the degradation of the IEL in the vein graft of ACF rats, especially in the segment exposed to prominent hemodynamic changes. IEL degradation may contribute to the development of neointimal hyperplasia in vein grafts.

BackgroundIntersubspecific autotetraploid rice hybrids possess high hybrid vigor; however, low pollen fertility is a critical hindrance in its commercial utilization. Our previous study demonstrated that polyploidy could increase the multi-loci interaction and cause high pollen abortion in autotetraploid rice hybrids. However, there is little known about the critical role of pollen sterility locus or loci in the intersubspecific hybrids. We developed autotetraploid rice hybrids harboring heterozygous genotypes (S i S i S j S j) at different pollen sterility loci by using the near isogenic lines of Taichung65-4×. Moreover, autotetraploid lines carrying double neutral genes, Sa n and Sb n, were used to assess their effect on fertility restoration.ResultsCytological studies showed that the deleterious genetic interactions at Sa and Sb pollen sterility loci resulted in higher pollen sterility (76.83%) and abnormal chromosome behavior (24.59%) at metaphase I of meiosis in autotetraploid rice hybrids. Transcriptome analysis revealed 1092 differentially expressed genes (DEG) in a hybrid with the pervasive interactions at Sa and Sb pollen sterility loci, and most of the genes (about 83%) exhibited down regulation. Of the DEG, 60 were associated with transcription regulation and 18 genes were annotated as meiosis-related genes. Analysis on the hybrids developed by using autotetraploid rice harboring double neutral genes, Sa n and Sb n, revealed normal pollen fertility, and transcriptome analysis showed non-significant difference in number of DEG among different hybrids.ConclusionsOur finding revealed that pervasive interactions at Sa and Sb pollen sterility loci cause high sterility in the autotetraploid hybrids that lead to the down-regulation of important meiosis-related genes and transcription regulation factors. Moreover, we also found that the hybrids sterility could be overcome by double neutral genes, Sa n and Sb n, in autotetraploid rice hybrids. The present study provided a strong evidence for the utilization of heterosis in autotetraploid rice hybrids.Electronic supplementary materialThe online version of this article (10.1186/s12284-017-0188-8) contains supplementary material, which is available to authorized users.