Interferon-γ in the tumor microenvironment promotes the expression of B7H4 in colorectal cancer cells, thereby inhibiting cytotoxic T cells.

The bioactivity of interferon-γ (IFN-γ) in cancer cells in the tumor microenvironment (TME) is not well understood in the current immunotherapy era. We found that IFN-γ has an immunosuppressive effect on colorectal cancer (CRC) cells. The tumor volume in immunocompetent mice was significantly increased after subcutaneous implantation of murine CRC cells followed by IFN-γ stimulation, and RNA sequencing showed high expression of B7 homologous protein 4 (B7H4) in these tumors. B7H4 promotes CRC cell growth by inhibiting the release of granzyme B (GzmB) from CD8+ T cells and accelerating apoptosis in CD8+ T cells. Furthermore, interferon regulatory factor 1 (IRF1), which binds to the B7H4 promoter, is positively associated with IFN-γ stimulation-induced expression of B7H4. The clinical outcome of patients with CRC was negatively related to the high expression of B7H4 in cancer cells or low expression of CD8 in the microenvironment. Therefore, B7H4 is a biomarker of poor prognosis in CRC patients, and interference with the IFN-γ/IRF1/B7H4 axis might be a novel immunotherapeutic method to restore the cytotoxic killing of CRC cells.

Strengthened Interficial Adhesive Fracture Energy by Young's Modulus Matching Degree Strategy in Carbon-Based HTM Free MAPbI3 Perovskite Solar Cell with Enhanced Mechanical Compatibility.

Carbon-based hole transport layer-free perovskite solar cells (PSCs) based on methylammonium lead triiodide (MAPbI3 ) have become one of the research focus due to low cost, easy preparation, and good optoelectronic properties. However, instability of perovskite under vacancy defects and stress-strain makes it difficult to achieve high-efficiency and stable power output. Here, a soft-structured long-chain 2D pentanamine iodide (abbreviated as "PI") is used to improve perovskite quality and interfacial mechanical compatibility. PI containing CH3 (CH2 )4 NH3 + and I- ions not only passivate defects at grain boundaries, but also effectively alleviate residual stress during high temperature annealing via decreasing Young's modulus of perovskite film. Most importantly, PI effectively increases matching degree of Young's modulus between MAPbI3 (47.1 GPa) and carbon (6.7 GPa), and strengthens adhesive fracture energy (Gc ) between perovskite and carbon, which is helpful for outward release of nascent interfacial stress generated under service conditions. Consequently, photoelectric conversion efficiency (PCE) of optimal device is enhanced from 10.85% to 13.76% and operational stability is also significantly improved. 83.1% output is maintained after aging for 720 h at room temperature and 25-60% relative humidity (RH). This strategy of regulation from chemistry and physics provides a strategy for efficient and stable carbon-based PSCs.

Cdc42 subcellular relocation in response to VEGF/NRP1 engagement is associated with the poor prognosis of colorectal cancer.

Microscopic indications of malignancy and hallmark molecules of cancer are pivotal to determining cancer patient prognosis and subsequent medical intervention. Here, we found that compared to apical expression of Cdc42, which indicated that basal expression of Cdc42 occurred at the migrating cell front, glandular basal expression of Cdc42 (cell division cycle 42) in tissues indicated poorer prognoses for colorectal cancer (CRC) patients. The current study shows that activated Cdc42 was rapidly recruited to the migrating CRC cell front after VEGF stimulation through engagement of membrane-anchored neuropilin-1 (NRP1). When VEGF signalling was blocked with NRP1 knockdown or ATWLPPR (A7R, antagonist of VEGF/NRP1 interaction), Cdc42 activation and relocation to the cell front was attenuated, and filopodia and invadopodia formation was inhibited. The VEGF/NRP1 axis regulates directional migration, invasion, and metastasis through Cdc42 activation and relocation resulting from actin filament polymerisation of the extensions of membrane protrusions. Collectively, the immuno-micromorphological pattern of subcellular Cdc42 at the cell front indicated aggressive behaviours and predicted poor prognosis in CRC patients. Disruption of the intra- and extracellular interactions of the VEGF/NRP1 axis or Cdc42 relocation could be performed in clinical practice because it might inhibit cancer cell motility and metastasis.

High expression of PRKDC promotes breast cancer cell growth via p38 MAPK signaling and is associated with poor survival.

BACKGROUND: DNA-Dependent Protein Kinase Catalytic Subunit (PRKDC), a key component of the DNA damage repair pathway, is associated with chemotherapy resistance and tumor progression. METHODS: Here we analyzed transcriptome data of ~2,000 breast cancer patients and performed functional studies in vitro to investigate the function of PRKDC in breast cancer. RESULTS: Our results revealed overexpression of PRKDC in multiple breast cancer subtypes. Consistent with patients' data, overexpression of PRKDC was also observed in breast cancer cell lines compared to normal breast epithelial cells. Knockdown of PRKDC in MCF-7 and T47D breast cancer cell lines resulted in proliferation inhibition, reduced colony formation and G2/M cell cycle arrest. Furthermore, we showed that PRKDC knockdown induced proliferation inhibition through activation of p38 MAPK, but not ERK MAPK, signaling pathway in breast cancer cells. Blockage of p38 MAPK signaling could largely rescue proliferation inhibition and cell cycle arrest induced by PRKDC knockdown. Moreover, we analyzed gene expression and clinical data from six independent breast cancer cohorts containing ~1,000 patients. In all cohorts, our results consistently showed that high expression of PRKDC was significantly associated with poor survival in both treated and untreated breast cancer patients. CONCLUSION: Together, our results suggest that high expression of PRKDC facilitates breast cancer cell growth via regulation of p38 MAPK signaling, and is a prognostic marker for poor survival in breast cancer patients.

PRKDC is a prognostic marker for poor survival in gastric cancer patients and regulates DNA damage response.

A hallmark of gastric cancer is the high rate of genomic instability associated with deregulation of DNA damage repair pathways. DNA-Dependent Protein Kinase Catalytic Subunit (PRKDC) is a key component of the non-homologous end-joining (NHEJ) pathway. By reanalyzing transcriptome data of 80 pairs of gastric cancer tumors and the adjacent normal tissues from non-treated patients, we identified PRKDC as the top upregulated DNA damage repair genes in gastric cancer. High expression of PRKDC is associated with poor survival of gastric cancer patients, and genomic amplification of the gene is frequently observed across most gastric cancer subtypes. Knockdown of PRKDC in gastric cell lines resulted in reduced proliferation and cell cycle arrest. Furthermore, we showed that loss of PRKDC induced DNA damage and enhanced gastric cancer cell chemosensitivity to DNA-damaging reagents. Together, our results suggest that PRKDC is a prognostic marker of poor survival and is a putative target to overcome chemoresistance in gastric cancer.

Comparative medical characteristics of ZDF-T2DM rats during the course of development to late stage disease.

BACKGROUND: There are few reports on the comparative medical characteristics of type 2 diabetes models in late stage. An analysis of comparative medical characteristics of Zucker diabetic fatty type 2 diabetes mellitus (ZDF-T2DM) rats during the course of development to late stage disease was performed. METHODS: In this study, ZDF rats were fed with high-sugar and high-fat diets to raise the fasting blood glucose, and develop of type 2 diabetes. At the late stage of T2DM, the preliminary comparative medical characteristics of the T2DM model were analyzed through the detection of clinical indicators, histopathology, related cytokine levels, and insulin-related signaling molecule expression levels. RESULTS: In the T2DM group, the fasting blood glucose was higher than 6.8 mmol/L, the serum insulin, leptin, and adiponectin levels were significantly decreased, and glucose intolerance and insulin resistance were measured as clinical indicators. Regarding pathological indicators, a large number of pancreatic islet cells showed the reduction of insulin secretion, resulting in damaged glycogen synthesis and liver steatosis. At the molecular level, the insulin signal transduction pathway was inhibited by decreasing the insulin receptor substrate 1 (IRS1), insulin receptor substrate 2 (IRS2), phosphatidylinositol 3 kinase (PI3K), and glycogen synthesis kinase 3ß (GSK-3ß) expression levels. CONCLUSION: The results show that the ZDF/T2DM rats have typical clinical, histopathological, and molecular characteristics of human T2DM and thus can be used as an effective model for T2DM drug development and treatment of advanced T2DM.

[Photo-induced Phosphate Release from Organic Phosphorus Decomposition Driven by Fe(â ¢)-oxalate Complex in Lake Water].

The phosphate released from organic phosphorus photo-decomposition has a significantly influence on the phosphorus levels in the water column in lakes. In order to reveal the effect of organic phosphorus photo-decomposition on phosphate level in lake water, the phosphate released from organic phosphorus photo-decomposition driven by Fe(Ⅲ)-oxalate complex under UV-Vis and sunlight irradiation was investigated in natural lake water using glyphosate as the model organic phosphorus. The effects of pH and initial concentration of Fe(Ⅲ), oxalate and glyphosate on the phosphate released from glyphosate photolysis were studied. The results showed that phosphate could be released from glyphosate degradation by Fe(Ⅲ)-oxalate complex under UV-Vis and sunlight irradiation. The concentration of phosphate reached 0.25 mg·L-1 and 0.18 mg·L-1 under UV-Vis and sunlight irradiation for 60 and 720 min, respectively. The amount of phosphate released increased with the increase of the initial concentration of Fe(Ⅲ), as well as the increasing oxalate and glyphosate concentration in lake water. However, the increase of pH could significantly inhibit this process in the reaction system. The concentration of phosphorus decreased with the addition of isopropanol, which indicated that the hydroxyl radical (·OH) was one of the main active oxygen species of Fe(Ⅲ)-oxalate complex. The rates of·OH production for Fe(Ⅲ)-oxalate/UV-Vis and Fe(Ⅲ)-oxalate/sunlight systems were 0.52×10-2 µmol·(L·min)-1 and 0.03×10-2 µmol·(L·min)-1, respectively. The steady-state concentrations of hydroxyl radical (·OH) for the Fe(Ⅲ)-oxalate/UV-Vis conditions were 4.74×10-16 mol·L-1 and 0.27×10-16 mol·L-1 for the Fe(Ⅲ)-oxalate/sunlight system.

Phylogenomic analyses reveal subclass Scuticociliatia as the sister group of subclass Hymenostomatia within class Oligohymenophorea.

Scuticociliates and hymenostomes are two groups of the ciliate class Oligohymenophorea, a diverse clade that includes two model genera, Tetrahymena and Paramecium, which have been intensively studied due to their ease of culture and their amenability to a wide range of biochemical and genetic investigations. However, phylogenetic relationships among the subclasses of the Oligohymenophorea, and especially between the Scuticociliatia and Hymenostomatia, are not clearly resolved. Here, we investigate the phylogenetic relationship between the subclasses Scuticociliatia and Hymenostomatia based on omics data. The transcriptomes of five species, comprising four oligohymenophoreans and one colpodean, were sequenced. A supermatrix was constructed for phylogenomic analyses based on 113 genes encoding 43,528 amino acid residues from 26 taxa, including ten representatives of the class Oligohymenophorea. Our phylogenomic analyses revealed that the monophyletic Scuticociliatia is sister to the monophyletic Hymenostomatia, which together form the terminal branch within the monophyletic class Oligohymenophorea. Competing hypotheses for this relationship were rejected by topological tests. Our results provide corroborative evidence for the close relationship between the subclasses Scuticociliatia and Hymenostomatia, justifying the possible use of the model hymenostome T. thermophila as an effective experimental system to study the molecular and cellular biology of the scuticociliates.