Interleukin-33 predicts poor prognosis and promotes ovarian cancer cell growth and metastasis through regulating ERK and JNK signaling pathways

Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer, it remains a huge challenge to understand the cellular and molecular mechanisms of the aggressive behavior of EOC cells. Here we investigated the role of an immunomodulatory cytokine IL-33 and its receptor ST2 in mediating the growth and metastasis of EOC. Our data show that both IL-33 and ST2 were highly up-regulated in EOC tumors compared with normal ovary and ovarian benign tumors, and the expression levels were further increased in tumor tissues at the metastatic site. The expression levels of IL-33 and ST2 were positively correlated with the Ki-67 expression, and negatively correlated with the patient survival time. Using EOC cell lines, we observed that cells knocked down of IL-33 gene by siRNA had reduced migratory and invasive potential, while full length human IL-33 (fl-hIL-33) promoted the invasive, migratory and proliferative capacity of EOC cells and this process could be inhibited by IL-33 decoy receptor sST2. Signaling pathway analysis suggested that IL-33 increased the phosphorylation of ERK and JNK which was blocked by sST2. Fl-hIL-33-induced increases in EOC cell migration, invasive potential and proliferation were specifically abrogated by treatment with the ERK inhibitor U0126 while JNK inhibitor SP600125 only disrupted IL-33-induced enhancement of cell viability. Taken together, our data suggest that IL-33/ST2 axis closely associates with poor prognosis of EOC patients, and it promotes ovarian cancer growth and metastasis through regulating ERK and JNK signaling pathways. Thus IL-33/ST2 might be potential prognosis markers and therapeutic targets for EOC patients

Real-Time Monitoring of Tumorigenesis, Dissemination, & Drug Response in a Preclinical Model of Lymphangioleiomyomatosis/Tuberous Sclerosis Complex

Background: TSC2-deficient cells can proliferate in the lungs, kidneys, and other organs causing devastating progressive multisystem disorders such as lymphangioleiomyomatosis (LAM) and tuberous sclerosis complex (TSC). Preclinical models utilizing LAM patient-derived cells have been difficult to establish. We developed a novel animal model system to study the molecular mechanisms of TSC/LAM pathogenesis and tumorigenesis and provide a platform for drug testing. Methods and Findings: TSC2-deficient human cells, derived from the angiomyolipoma of a LAM patient, were engineered to co-express both sodium-iodide symporter (NIS) and green fluorescent protein (GFP). Cells were inoculated intraparenchymally, intravenously, or intratracheally into athymic NCr nu/nu mice and cells were tracked and quantified using single photon emission computed tomography (SPECT) and computed tomography (CT). Surprisingly, TSC2-deficient cells administered intratracheally resulted in rapid dissemination to lymph node basins throughout the body, and histopathological changes in the lung consistent with LAM. Estrogen was found to be permissive for tumor growth and dissemination. Rapamycin inhibited tumor growth, but tumors regrew after the drug treatment was withdrawn. Conclusions: We generated homogeneous NIS/GFP co-expressing TSC2-deficient, patient-derived cells that can proliferate and migrate in vivo after intratracheal instillation. Although the animal model we describe has some limitations, we demonstrate that systemic tumors formed from TSC2-deficient cells can be monitored and quantified noninvasively over time using SPECT/CT, thus providing a much needed model system for in vivo drug testing and mechanistic studies of TSC2-deficient cells and their related clinical syndromes

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead

Exposure to cyclic intermittent hypoxia increases expression of functional NMDA receptors in the rat carotid body

Although large quantities of glutamate are found in the carotid body, to date this excitatory neurotransmitter has not been assigned a role in chemoreception. To examine the possibility that glutamate and its N-methyl-d-aspartate (NMDA) receptors play a role in acclimatization after exposure to cyclic intermittent hypoxia (CIH), we exposed male Sprague-Dawley rats to cyclic hypoxia or to room air sham (Sham) for 8 h/day for 3 wk. Using RT-PCR, Western blot analysis, and immunohistochemistry, we found that ionotropic NMDA receptors, including NMDAR1, NMDAR2A, NMDAR2A/2B, are strongly expressed in the carotid body and colocalize with tyrosine hydroxylase in glomus cells. CIH exposure enhanced the expression of NMDAR1 and NMDAR2A/2B but did not substantially change the level of NMDAR2A. We assessed in vivo carotid sinus nerve activity (CSNA) at baseline, in response to acute hypoxia, in response to infused NMDA, and in response to infused endothelin-1 (ET-1) with and without MK-801, an NMDA receptor blocker. Infusion of NMDA augmented CSNA in CIH rats (124.61 ± 2.64% of baseline) but not in sham-exposed rats. Administration of MK-801 did not alter baseline activity or response to acute hypoxia, in either CIH or sham animals but did reduce the effect of ET-1 infusion on CSNA (CSNA after ET-1 = 160.96 ± 8.05% of baseline; ET-1 after MK-801 = 118.56 ± 9.12%). We conclude that 3-wk CIH exposure increases expression of NMDA functional receptors in rats, suggesting glutamate and its receptors may play a role in hypoxic acclimatization to CIH

Artesunate down-regulates immunosuppression from colorectal cancer Colon26 and RKO cells in vitro by decreasing transforming growth factor beta and interleukin-10

Immunosuppression is the main source of ineffective treatment on tumor, and the study aimed to investigate the effect of artesunate on tumor immunosuppression. Supernatants of re-cultivated murine colorectal cancer cell Colon26 and human colorectal cancer cell RKO after pre-treatment with or without artesunate were enrolled, and their effects on five immune parameters were assessed, including killing activity of natural killer (NK) and lymphocyte proliferation, as measured by MTT, and expressions of interleukin 2 receptor (IL-2R)α, CD3εζ and CD3εζ on lymphocytes, as analyzed by flow cytometry. Six immunosuppressive factors were measured by ELISA, including transforming growth factor (TGF) β, vascular endothelial growth factor (VEGF), IL-4, IL-6, IL-10, and prostaglandin E (PGE). Then, multiple linear regression analysis was applied to reveal the correlation between immunosuppression and immunosuppressive factors, and was used to confirm the findings. It was shown that Colon26 and RKO cells secreted immunosuppressive factors and inhibited these five immune parameters steadily. After pretreatment with artesunate, immunosuppression from the two cells was down-regulated significantly (all P < 0.05), and the concentrations of TGF-β and IL-10 decreased greatly (all P < 0.001). There were positive correlations between the down-regulation of immunosuppression and the decrease in TGF-β or IL-10. Their combined potency attributed to decreased TGF-β and IL-10 with respect to the down-regulating effect of artesunate on immunosuppression of NK killing, lymphocyte proliferation and expressions of IL-2Rα and CD3εζ, was about 60%-90%. The present analysis provides clues that artesunate reverses the immunosuppression from Colon26 and RKO colorectal cancer cells by decreasing TGF-β and IL-10. This is probably one of the anti-tumor mechanisms of artesunate

Cr(VI) Reduction and Fe(II) Regeneration by Penicillium oxalicum SL2-Enhanced Nanoscale Zero-Valent Iron

Nanoscale zero-valent iron (nZVI) faces significant challenges in Cr(VI) remediation through aggregation and passivation. This study identified a Cr(VI)-resistant filamentous fungus (Penicillium oxalicum SL2) for nZVI activation and elucidated the synergistic mechanism in chromium remediation. P. oxalicum SL2 and nZVI synergistically and effectively removed Cr(VI), mainly by extracellular nonenzymatic reduction (89.1%). P. oxalicum SL2 exhibited marked iron precipitate solubilization and Fe(II) regeneration capabilities. The existence of the Fe(II)–Cr(V)-oxalate complex (HCrFeC4O9) indicated that in addition to directly reducing Cr(VI), iron ions generated by nZVI stimulated Cr(VI) reduction by organic acids secreted by P. oxalicum SL2. RNA sequencing and bioinformatics analysis revealed that P. oxalicum SL2 inhibited phosphate transport channels to suppress Cr(VI) transport, facilitated iron and siderophore transport to store Fe, activated the glyoxylate cycle to survive harsh environments, and enhanced organic acid and riboflavin secretion to reduce Cr(VI). Cr(VI) exposure also stimulated the antioxidative system, promoting catalase activity and maintaining the intracellular thiol/disulfide balance. Cr(VI)/Fe(III) reductases played crucial roles in the intracellular reduction of chromium and iron, while nZVI decreased cellular oxidative stress and alleviated Cr(VI) toxicity to P. oxalicum SL2. Overall, the P. oxalicum SL2–nZVI synergistic system is a promising approach for regenerating Fe(II) while reducing Cr(VI)