IL-27 Mediates PD-L1 Expression and Release by Human Mesothelioma Cells

Malignant mesothelioma (MM) is a rare tumor with an unfavorable prognosis. MM genesis involves asbestos-mediated local inflammation, supported by several cytokines, including IL-6. Recent data showed that targeting PD-1/PD-L1 is an effective therapy in MM. Here, we investigated the effects of IL-6 trans-signaling and the IL-6-related cytokine IL-27 on human MM cells in vitro by Western blot analysis of STAT1/3 phosphorylation. The effects on PD-L1 expression were tested by qRT-PCR and flow-cytometry and the release of soluble (s)PD-L1 by ELISA. We also measured the concentrations of sPD-L1 and, by multiplexed immunoassay, IL-6 and IL-27 in pleural fluids obtained from 77 patients in relation to survival. IL-27 predominantly mediates STAT1 phosphorylation and increases PD-L1 gene and surface protein expression and sPD-L1 release by human MM cells in vitro. IL-6 has limited activity, whereas a sIL-6R/IL-6 chimeric protein mediates trans-signaling predominantly via STAT3 phosphorylation but has no effect on PD-L1 expression and release. IL-6, IL-27, and sPD-L1 are present in pleural fluids and show a negative correlation with overall survival, but only IL-27 shows a moderate albeit significant correlation with sPD-L1 levels. Altogether these data suggest a potential role of IL-27 in PD-L1-driven immune resistance in MM.

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Specificity of the HIV-1 Protease on Substrates Representing the Cleavage Site in the Proximal Zinc-Finger of HIV-1 Nucleocapsid Protein

Viruses ◽

10.3390/v13061092 ◽

2021 ◽

Vol 13 (6) ◽

pp. 1092

Author(s):

János András Mótyán ◽

Márió Miczi ◽

Stephen Oroszlan ◽

József Tőzsér

Keyword(s):

Amino Acid ◽

Zinc Finger ◽

Cleavage Site ◽

Potential Role ◽

Binding Mode ◽

Interaction Energies ◽

Vitro Assay ◽

Hiv 1

To explore the sequence context-dependent nature of the human immunodeficiency virus type 1 (HIV-1) protease’s specificity and to provide a rationale for viral mutagenesis to study the potential role of the nucleocapsid (NC) processing in HIV-1 replication, synthetic oligopeptide substrates representing the wild-type and modified versions of the proximal cleavage site of HIV-1 NC were assayed as substrates of the HIV-1 protease (PR). The S1′ substrate binding site of HIV-1 PR was studied by an in vitro assay using KIVKCF↓NCGK decapeptides having amino acid substitutions of N17 residue of the cleavage site of the first zinc-finger domain, and in silico calculations were also performed to investigate amino acid preferences of S1′ site. Second site substitutions have also been designed to produce “revertant” substrates and convert a non-hydrolysable sequence (having glycine in place of N17) to a substrate. The specificity constants obtained for peptides containing non-charged P1′ substitutions correlated well with the residue volume, while the correlation with the calculated interaction energies showed the importance of hydrophobicity: interaction energies with polar residues were related to substantially lower specificity constants. Cleavable “revertants” showed one residue shift of cleavage position due to an alternative productive binding mode, and surprisingly, a double cleavage of a substrate was also observed. The results revealed the importance of alternative binding possibilities of substrates into the HIV-1 PR. The introduction of the “revertant” mutations into infectious virus clones may provide further insights into the potential role of NC processing in the early phase of the viral life-cycle.

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CD133 Promotes Adhesion to the Ovarian Cancer Metastatic Niche

Cancer Growth and Metastasis ◽

10.1177/1179064418767882 ◽

2018 ◽

Vol 11 ◽

pp. 117906441876788 ◽

Cited By ~ 16

Author(s):

Lynn Roy ◽

Alexander Bobbs ◽

Rachel Sattler ◽

Jeffrey L Kurkewich ◽

Paige B Dausinas ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Metastasis ◽

Ex Vivo ◽

Surface Protein ◽

Ovarian Cancer Cells ◽

Metastatic Niche ◽

Attractive Therapeutic Target ◽

Peritoneal Mesothelium

Cancer stem cells (CSCs) are an attractive therapeutic target due to their predicted role in both metastasis and chemoresistance. One of the most commonly agreed on markers for ovarian CSCs is the cell surface protein CD133. CD133+ ovarian CSCs have increased tumorigenicity, resistance to chemotherapy, and increased metastasis. Therefore, we were interested in defining how CD133 is regulated and whether it has a role in tumor metastasis. Previously we found that overexpression of the transcription factor, ARID3B, increased the expression of PROM1 (CD133 gene) in ovarian cancer cells in vitro and in xenograft tumors. We report that ARID3B directly regulates PROM1 expression. Importantly, in a xenograft mouse model of ovarian cancer, knockdown of PROM1 in cells expressing exogenous ARID3B resulted in increased survival time compared with cells expressing ARID3B and a control short hairpin RNA. This indicated that ARID3B regulation of PROM1 is critical for tumor growth. Moreover, we hypothesized that CD133 may affect metastatic spread. Given that the peritoneal mesothelium is a major site of ovarian cancer metastasis, we explored the role of PROM1 in mesothelial attachment. PROM1 expression increased adhesion to mesothelium in vitro and ex vivo. Collectively, our work demonstrates that ARID3B regulates PROM1 adhesion to the ovarian cancer metastatic niche.

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High Expression of GSDMC Is Associated with Poor Survival in Kidney Clear Cell Cancer

BioMed Research International ◽

10.1155/2021/5282894 ◽

2021 ◽

Vol 2021 ◽

pp. 1-10

Author(s):

Yun-Qian Cui ◽

Fei Meng ◽

Wen-Li Zhan ◽

Zhou-Tong Dai ◽

Xinghua Liao

Keyword(s):

Potential Role ◽

Clear Cell ◽

Cell Cancer ◽

Progression Free Survival ◽

Renal Clear Cell Carcinoma ◽

High Expression ◽

Poor Survival ◽

Free Survival

This study is aimed at exploring the potential role of GSDMC in kidney renal clear cell carcinoma (KIRC). We analyzed the expression of GSDMC in 33 types of cancers in TCGA database. The results showed that the expression of GSDMC was upregulated in most cancers. We found a significant association between high expression of GSDMC and shortened patient overall survival, progression-free survival, and disease-specific survival. In vitro experiments have shown that the expression of GSDMC was significantly elevated in KIRC cell lines. Moreover, decreased expression of GSDMC was significantly associated with decreased cell proliferation. In summary, we believe that this study provides valuable data supporting future clinical treatment.

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Ozone Therapy as Adjuvant for Cancer Treatment: Is Further Research Warranted?

Evidence-based Complementary and Alternative Medicine ◽

10.1155/2018/7931849 ◽

2018 ◽

Vol 2018 ◽

pp. 1-11 ◽

Cited By ~ 11

Author(s):

Bernardino Clavo ◽

Norberto Santana-Rodríguez ◽

Pedro Llontop ◽

Dominga Gutiérrez ◽

Gerardo Suárez ◽

...

Keyword(s):

Cancer Treatment ◽

Immune Modulation ◽

Animal Studies ◽

Potential Role ◽

Randomized Clinical Trials ◽

Tumor Hypoxia ◽

Tumor Resection ◽

Ozone Therapy

Introduction. This article provides an overview of the potential use of ozone as an adjuvant during cancer treatment.Methods. We summarize the findings of the most relevant publications focused on this goal, and we include our related clinical experience.Results. Over several decades, prestigious journals have publishedin vitrostudies on the capacity of ozone to induce direct damage on tumor cells and, as well, to enhance the effects of radiotherapy and chemotherapy. Indirect effects have been demonstrated in animal models: immune modulation by ozone alone and sensitizing effect of radiotherapy by concurrent ozone administration. The effects of ozone in modifying hemoglobin dissociation curve, 2,3-diphosphoglycerate levels, locoregional blood flow, and tumor hypoxia provide additional support for potential beneficial effects during cancer treatment. Unfortunately, only a few clinical studies are available. Finally, we describe some works and our experience supporting the potential role of local ozone therapy in treating delayed healing after tumor resection, to avoid delays in commencing radiotherapy and chemotherapy.Conclusions.In vitroand animal studies, as well as isolated clinical reports, suggest the potential role of ozone as an adjuvant during radiotherapy and/or chemotherapy. However, further research, such as randomized clinical trials, is required to demonstrate its potential usefulness as an adjuvant therapeutic tool.

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Potential Role of the Chemokine Macrophage Inflammatory Protein 1α in Human and Experimental Schistosomiasis

Infection and Immunity ◽

10.1128/iai.73.4.2515-2523.2005 ◽

2005 ◽

Vol 73 (4) ◽

pp. 2515-2523 ◽

Cited By ~ 23

Author(s):

Adriano L. S. Souza ◽

Ester Roffê ◽

Vanessa Pinho ◽

Danielle G. Souza ◽

Adriana F. Silva ◽

...

Keyword(s):

Potential Role ◽

Severe Disease ◽

Experimental Studies ◽

Interleukin 4 ◽

Enzyme Linked Immunosorbent Assay ◽

Inflammatory Protein ◽

Macrophage Inflammatory Protein ◽

Deficient Mice

ABSTRACT In human schistosomiasis, the concentrations of the chemokine macrophage inflammatory protein 1α (MIP-1α/CCL3) is greater in the plasma of patients with clinical hepatosplenic disease. The objective of the present study was to confirm the ability of CCL3 to detect severe disease in patients classified by ultrasonography (US) and to evaluate the potential role of CCL3 in Schistosoma mansoni-infected mice. CCL3 was measured by enzyme-linked immunosorbent assay in the plasma of S. mansoni-infected patients. CCL3-deficient mice were infected with 25 cercariae, and various inflammatory and infectious indices were evaluated. The concentration of CCL3 was higher in the plasma of S. mansoni-infected than noninfected patients. Moreover, CCL3 was greater in those with US-defined hepatosplenic than with the intestinal form of the disease. In CCL3-deficient mice, the size of the granuloma and the liver eosinophil peroxidase activity and collagen content were diminished compared to wild-type mice. In CCL3-deficient mice, the worm burden after 14 weeks of infection, but not after 9 weeks, was consistently smaller. The in vitro response of mesenteric lymph node cells to antigen stimulation was characterized by lower levels of interleukin-4 (IL-4) and IL-10. CCL3 is a marker of disease severity in infected humans, and experimental studies in mice suggest that CCL3 may be a causative factor in the development of severe schistosomiasis.

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Role for the Related Poly(ADP-Ribose) Polymerases Tankyrase 1 and 2 at Human Telomeres

Molecular and Cellular Biology ◽

10.1128/mcb.22.1.332-342.2002 ◽

2002 ◽

Vol 22 (1) ◽

pp. 332-342 ◽

Cited By ~ 197

Author(s):

Brandoch D. Cook ◽

Jasmin N. Dynek ◽

William Chang ◽

Grigoriy Shostak ◽

Susan Smith

Keyword(s):

Potential Role ◽

Telomere Maintenance ◽

Telomeric Dna ◽

Continuous Growth ◽

Telomere Elongation ◽

Bona Fide ◽

Tankyrase 1 ◽

Growth Of Tumor

ABSTRACT Telomere maintenance is essential for the continuous growth of tumor cells. In most human tumors telomeres are maintained by telomerase, a specialized reverse transcriptase. Tankyrase 1, a human telomeric poly(ADP-ribose) polymerase (PARP), positively regulates telomere length through its interaction with TRF1, a telomeric DNA-binding protein. Tankyrase 1 ADP-ribosylates TRF1, inhibiting its binding to telomeric DNA. Overexpression of tankyrase 1 in the nucleus promotes telomere elongation, suggesting that tankyrase 1 regulates access of telomerase to the telomeric complex. The recent identification of a closely related homolog of tankyrase 1, tankyrase 2, opens the possibility for a second PARP at telomeres. We therefore sought to establish the role of tankyrase 1 at telomeres and to determine if tankyrase 2 might have a telomeric function. We show that endogenous tankyrase 1 is a component of the human telomeric complex. We demonstrate that telomere elongation by tankyrase 1 requires the catalytic activity of the PARP domain and does not occur in telomerase-negative primary human cells. To investigate a potential role for tankyrase 2 at telomeres, recombinant tankyrase 2 was subjected to an in vitro PARP assay. Tankyrase 2 poly(ADP-ribosyl)ated itself and TRF1. Overexpression of tankyrase 2 in the nucleus released endogenous TRF1 from telomeres. These findings establish tankyrase 2 as a bona fide PARP, with itself and TRF1 as acceptors of ADP-ribosylation, and suggest the possibility of a role for tankyrase 2 at telomeres.

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Malaria and red cell genetic defects

Blood ◽

10.1182/blood.v74.4.1213.1213 ◽

1989 ◽

Vol 74 (4) ◽

pp. 1213-1221 ◽

Cited By ~ 75

Author(s):

RL Nagel ◽

EF Jr Roth

Keyword(s):

Culture System ◽

Potential Role ◽

Dna Analysis ◽

Red Cell ◽

Metabolic Products ◽

Recombinant Technology ◽

Host Parasite ◽

Made In

Abstract The study of inherited RBC resistance to malaria has increased our knowledge of the biochemistry and physiology of the host-parasite interaction and suggested potential sites for therapeutic intervention. Discovery by Jensen and Trager of the in vitro culture system for P falciparum has facilitated research in this area. Known RBC defects may affect invasion, growth, or merozoite liberation (Fig 1). Significant advances made in understanding mechanisms underlying protection against malaria should not obscure the fact that the data are far from complete. More knowledge is needed about the influence of the erythrocyte cytoskeleton on invasion and growth of parasites as well as the potential role of phospholipids, erythrocyte enzymes other than G6PD, or other metabolic products. Application of DNA analysis and recombinant technology may have an increasing impact on study of the interaction of RBC defects with malarial parasites.

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Intestinal miRNAs regulated in response to dietary lipids

Scientific Reports ◽

10.1038/s41598-020-75751-w ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Judit Gil-Zamorano ◽

João Tomé-Carneiro ◽

María-Carmen Lopez de las Hazas ◽

Lorena del Pozo-Acebo ◽

M. Carmen Crespo ◽

...

Keyword(s):

Small Intestine ◽

Lipid Metabolism ◽

Chronic Exposure ◽

Potential Role ◽

In Vitro Models ◽

Dietary Lipids ◽

Metabolism Regulation

Abstract The role of miRNAs in intestinal lipid metabolism is poorly described. The small intestine is constantly exposed to high amounts of dietary lipids, and it is under conditions of stress that the functions of miRNAs become especially pronounced. Approaches consisting in either a chronic exposure to cholesterol and triglyceride rich diets (for several days or weeks) or an acute lipid challenge were employed in the search for intestinal miRNAs with a potential role in lipid metabolism regulation. According to our results, changes in miRNA expression in response to fat ingestion are dependent on factors such as time upon exposure, gender and small intestine section. Classic and recent intestinal in vitro models (i.e. differentiated Caco-2 cells and murine organoids) partially mirror miRNA modulation in response to lipid challenges in vivo. Moreover, intestinal miRNAs might play a role in triglyceride absorption and produce changes in lipid accumulation in intestinal tissues as seen in a generated intestinal Dicer1-deletion murine model. Overall, despite some variability between the different experimental cohorts and in vitro models, results show that some miRNAs analysed here are modulated in response to dietary lipids, hence likely to participate in the regulation of lipid metabolism, and call for further research.

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Mechanisms of angiotensin II stimulation of NCC are time-dependent in mDCT15 cells

AJP Renal Physiology ◽

10.1152/ajprenal.00465.2014 ◽

2015 ◽

Vol 308 (7) ◽

pp. F720-F727 ◽

Cited By ~ 16

Author(s):

Benjamin Ko ◽

Abinash Mistry ◽

Lauren Hanson ◽

Rickta Mallick ◽

Robert S. Hoover

Keyword(s):

Angiotensin Ii ◽

Cell Model ◽

Surface Protein ◽

Early Time ◽

Dependent Manner ◽

Ang Ii ◽

Biphasic Effect ◽

Surface Protein Expression ◽

Stimulation Of

Angiotensin II (ANG II) increases thiazide-sensitive sodium-chloride cotransporter (NCC) activity both acutely and chronically. ANG II has been implicated as a switch that turns WNK4 from an inhibitor of NCC into an activator of NCC, and ANG II's effect on NCC appears to require WNK4. Chronically, ANG II stimulation of NCC results in an increase in total and phosphorylated NCC, but the role of NCC phosphorylation in acute ANG II actions is unclear. Here, using a mammalian cell model with robust native NCC activity, we corroborate the role that ANG II plays in WNK4 regulation and clarify the role of Ste20-related proline alanine-rich kinase (SPAK)-induced NCC phosphorylation in ANG II action. ANG II was noted to have a biphasic effect on NCC, with a peak increase in NCC activity in the physiologic range of 10−11 M ANG II. This effect was apparent as early as 15 min and remained sustained through 120 min. These changes correlated with significant increases in NCC surface protein expression. Knockdown of WNK4 expression sharply attenuated the effect of ANG II. SPAK knockdown did not affect ANG II action at early time points (15 and 30 min), but it did attenuate the response at 60 min. Correspondingly, NCC phosphorylation did not increase at 15 or 30 min, but increased significantly at 60 min. We therefore conclude that within minutes of an increase in ANG II, NCC is rapidly trafficked to the cell surface in a phosphorylation-independent but WNK4-dependent manner. Then, after 60 min, ANG II induces SPAK-dependent phosphorylation of NCC.

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