• interleukin‐6
• intracellular
• pituitary
• senescence
• signaling
• therapy‐induced senescence
• tumors

• Interleukin-6/metabolism
• Humans
• Cellular Senescence
• Nucleotidyltransferases/metabolism
• Animals
• Mice
• NF-kappa B/metabolism
• Senescence-Associated Secretory Phenotype
• Membrane Proteins/metabolism
• Signal Transduction
• Mice, Inbred NOD
• Mice, SCID

• 20020170100230BA Universidad de Buenos Aires
• PUE-2016 (22920160100010CO) Consejo Nacional de Investigaciones Científicas y Técnicas
• 2012 Max Planck Society, Germany
• PICT2016-1620 Agencia Nacional de Promoción Científica y Tecnológica
• PICT-2018- 03232 Agencia Nacional de Promoción Científica y Tecnológica
• COF 03/11 FOCEM-Mercosur
• Universidad de Buenos Aires
• Consejo Nacional de Investigaciones Científicas y Técnicas
• Max Planck Society, Germany

• combination therapy
• hallmarks of cancer
• radiation
• radio-sensitisation
• rectal cancer
• synergy
• targeted therapy

• Humans
• Rectal Neoplasms/radiotherapy
• Rectal Neoplasms/therapy
• Rectal Neoplasms/pathology
• Rectal Neoplasms/drug therapy
• Molecular Targeted Therapy
• Neoadjuvant Therapy/methods
• Combined Modality Therapy
• Treatment Outcome
• Animals

• MR/T04358X/1 Medical Research Council
• CRUK RRNPSF-JUL21/1D100010 Cancer Research UK
• TCS/22/02 Chief Scientist Office
• GN21ON351 NHS Greater Glasgow and Clyde

• heart failure
• senescence

• 31900502 National Natural Science Foundation of China (National Science Foundation of China)

• ATR
• Apoptosis
• Myeloma
• STAT3

• Humans
• Myeloid Cell Leukemia Sequence 1 Protein/metabolism
• Multiple Myeloma/genetics
• Multiple Myeloma/metabolism
• Ataxia Telangiectasia
• Apoptosis
• Cell Line, Tumor
• bcl-X Protein/genetics
• Phosphorylation
• RNA, Small Interfering/metabolism
• STAT3 Transcription Factor/metabolism

• P30 CA016059 NCI NIH HHS
• Massey’s NIH/NCI Cancer Center Support Grant

• DNA sensing
• STING
• cGAS
• cancer
• immunology
• innate immunity

• Humans
• Immunity, Innate/genetics
• DNA/metabolism
• Nucleotidyltransferases/genetics
• Nucleotidyltransferases/metabolism
• Interferon Type I/genetics
• Interferon Type I/metabolism
• Neoplasms/therapy
• Tumor Microenvironment

• melanoma
• senescence
• senolytic
• skin aging

• Grant No.82060660, 82171558 National Natural Science Foundation of China
• Grant No. 202201AS070038, 202201AS070074 Yunnan Fundamental Research Project

• Cellular senescence
• Hesperidin
• IL/6-STAT3 signaling pathway
• Lung fibroblast
• Pulmonary fibrosis

• Animals
• Mice
• Rats
• Bleomycin
• Cellular Senescence
• Fibroblasts
• Hesperidin/pharmacology
• Idiopathic Pulmonary Fibrosis
• Interleukin-6
• Lung
• Signal Transduction

Activation of the STING pathway upon genotoxic treatment of cancer cells has been shown to lead to anti-tumoral effects, mediated through the acute production of interferon (IFN)-β. Conversely, the pathway also correlates with the expression of NF-κB-driven pro-tumorigenic genes, but these associations are only poorly defined in the context of genotoxic treatment, and are thought to correlate with a chronic engagement of the pathway. We demonstrate here that half of the STING-expressing cancer cells from the NCI60 panel rapidly increased expression of pro-tumorigenic IL-6 upon genotoxic DNA damage, often independent of type-I IFN responses. While preferentially dependent on canonical STING, we demonstrate that genotoxic DNA damage induced by camptothecin (CPT) also drove IL-6 production through non-canonical STING signaling in selected cancer cells. Consequently, pharmacological inhibition of canonical STING failed to broadly inhibit IL-6 production induced by CPT, although this could be achieved through downstream ERK1/2 inhibition. Finally, prolonged inhibition of canonical STING signaling was associated with increased colony formation of MG-63 cells, highlighting the duality of STING signaling in also restraining the growth of selected cancer cells. Collectively, our findings demonstrate that genotoxic-induced DNA damage frequently leads to the rapid production of pro-tumorigenic IL-6 in cancer cells, independent of an IFN signature, through canonical and non-canonical STING activation; this underlines the complexity of STING engagement in human cancer cells, with frequent acute pro-tumorigenic activities induced by DNA damage. We propose that inhibition of ERK1/2 may help curb such pro-tumorigenic responses to DNA-damage, while preserving the anti-proliferative effects of the STING-interferon axis.

• DNA damage
• ERK1/2
• IL-6
• Non-canonical STING
• STING
• STING inhibitor
• cancer

The interplay between mesenchymal stem/stromal cells (MSCs) and preservation conditions is critical to maintain the viability and functionality of these cells before administration. We observed that Ringer lactate (RL) maintained high viability of bone marrow–derived MSCs for up to 72 h at room temperature (18°C–22°C), whereas adipose‐derived and umbilical cord‐derived MSCs showed the highest viability for 72 h at a cold temperature (4°C–8°C). These cells maintained their adherence ability with an improved recovery rate and metabolic profiles (glycolysis and mitochondrial respiration) similar to those of freshly harvested cells. Growth factor and cytokine analyses revealed that the preserved cells released substantial amounts of leukaemia inhibitory factors (LIFs), hepatocyte growth factor (HGF) and vascular endothelial growth factor‐A (VEGF‐A), as well as multiple cytokines (eg IL‐4, IL‐6, IL‐8, MPC‐1 and TNF‐α). Our data provide the simplest clinically relevant preservation conditions that maintain the viability, stemness and functionality of MSCs from perinatal and adult tissue sources.

• Ringer lactate
• adipose tissue
• bone marrow
• cell therapy
• mesenchymal stem/stromal cells
• preservation condition
• sodium chloride
• umbilical cord

Acanthopanax giraldii Harms is commonly used in traditional Chinese medicine to treat rheumatism, improve joints, and strengthen muscles and bones. The polysaccharides present in A. giraldii Harms contain major bioactive substances, which have antioxidant, anticancer, and antiviral activities. In this study, the structural characterization of the homogeneous polysaccharide isolated from A. giraldii Harms, known as AHP-II, and its immunomodulatory effects in vivo will be studied. High-performance ion chromatography (HPIC) and high-performance gel permeation chromatography (HPGPC) based analyses revealed that AHP-II was composed of various monosaccharides, which included rhamnose, arabinose, galactose, glucose, mannose, galacturonic acid, and glucuronic acid in molar ratios of 29.5 : 24.6 : 23.8 : 4.4 : 5.7 : 8.8 : 3.1, respectively, and had a collective molecular weight of 80.21 × 10³ Da. Fourier-transform infrared (FTIR) spectroscopy indicated the presence of a pyranose ring and β-type glycosidic linkages in AHP-II. In addition, immunomodulatory effect analyses of AHP-II that used a cyclophosphamide-induced immunosuppressive mouse model demonstrated that its treatment could significantly restore spleen and thymus indices, promote the proliferation of splenic lymphocytes, elevate CD4⁺ T lymphocyte percentage and CD4⁺ : CD8⁺ ratio in the spleen, promote macrophage phagocytosis, and restore cytokines (IL-6, TNF-α, IgM, and IgG) levels. These results suggested that AHP-II could potentially be used as natural immunomodulator and as an alternative treatment to reduce chemotherapy-induced immunosuppression.

• ACF
• Acriflavine
• anti-leukemic
• anti-tumoral
• chronic myeloid leukemia
• drug repurposing
• leukemia

Cleft lip and palate are amongst the most common congenital malformations worldwide presenting with variable manifestations. Previous research has been primarily focused on the genetical aspects of its complex and multifactorial etiology. In the present study, we investigated the role of cytokines as mediators of epithelial–mesenchymal crosstalk and local site inflammation in cleft affected infants. Lip material was obtained from 12 children aged before primary dentition who suffered from orofacial clefting. The quantification of 12 cytokines (Interleukin-2,4,5,6,10,12,13,17A, Tumor Necrosis Factor-α, Interferon-γ, Transforming Growth Factor beta-1 and Granulocyte-Colony Stimulating Factor) was done using ELISA. Nonparametric Spearman Rho was used to ascertain the correlation between the expression levels of different cytokines. A significantly strong positive correlation was found between IL-2 and IFN-γ coupled with an IL4/IFN-γ ratio favoring IFN-γ. These findings indicate a shift towards the preferential activation of the Th1 differentiation pathway. Further, a pathological reduction in TGFβ-1 levels was noted, which may contribute to mucosal damage. IL-6 was more highly correlated to IFN-γ and IL-12 indicating its potential proinflammatory role in cleft affected tissues. This preferential activation of Th1 cell differentiation and consistent expression of IL-2,6,13 and TNF-α in cleft patients may indicate certain underlying mechanisms for inflammation mediation at the site of clefting.

• ELISA
• cleft lip
• cleft palate
• cytokines
• interleukin
• newborn

• Apoptosis
• JAK/STAT
• caspase
• colon cancer
• gallotannin
• senescence

Acriflavine (ACF) is an antiseptic with anticancer properties, blocking the growth of solid and haematopoietic tumour cells. Moreover, this compound has been also shown to overcome the resistance of cancer cells to chemotherapeutic agents. ACF has been shown to target hypoxia‐inducible factors (HIFs) activity, which are key effectors of hypoxia‐mediated chemoresistance. In this study, we showed that ACF inhibits the growth and survival of chronic myeloid leukaemia (CML) and acute myeloid leukaemia (AML) cell lines in normoxic conditions. We further demonstrated that ACF down‐regulates STAT5 expression in CML and AML cells but activates STAT3 in CML cells in a HIF‐independent manner. In addition, we demonstrated that ACF suppresses the resistance of CML cells to tyrosine kinase inhibitors, such as imatinib. Our data suggest that the dual effect of ACF might be exploited to eradicate de novo or acquired resistance of myeloid leukaemia cells to chemotherapy.

• STAT5
• acriflavine
• apoptosis
• cell cycle
• chronic myeloid leukaemia
• resistance

• Animals
• Anti-Inflammatory Agents/pharmacology
• Anti-Inflammatory Agents/therapeutic use
• Antineoplastic Agents/pharmacology
• Antineoplastic Agents/therapeutic use
• Clinical Trials, Phase II as Topic
• Fibrosis/drug therapy
• Fibrosis/metabolism
• Humans
• Inflammation/drug therapy
• Inflammation/metabolism
• Janus Kinases/antagonists & inhibitors
• Janus Kinases/genetics
• Janus Kinases/metabolism
• Molecular Targeted Therapy
• Neoplasms/drug therapy
• Neoplasms/metabolism
• Phosphorylation
• Protein Kinase Inhibitors/pharmacology
• Protein Kinase Inhibitors/therapeutic use
• STAT3 Transcription Factor/antagonists & inhibitors
• STAT3 Transcription Factor/genetics
• STAT3 Transcription Factor/metabolism

• P50 CA221707 NCI NIH HHS

Reactive oxygen species (ROS) produced during intracellular metabolism or triggered by extrinsic factors can promote neoplastic transformation and malignant microenvironment that mediate tumor development. Oligo-Fucoidan is a sulfated polysaccharide isolated from the brown seaweed. Using human THP-1 monocytes and murine Raw264.7 macrophages as well as human HCT116 colorectal cancer cells, primary C6P2-L1 colorectal cancer cells and human MDA-MB231 breast cancer cells, we investigated the effect of Oligo-Fucoidan on inhibiting M2 macrophage differentiation and its therapeutic potential as a supplement in chemotherapy and tumor prevention. We now demonstrate that Oligo-Fucoidan is an antioxidant that suppresses intracellular ROS and mitochondrial superoxide levels in monocytes/macrophages and in aggressive cancer cells. Comparable to ROS inhibitors (DPI and NAC), Oligo-Fucoidan directly induced monocyte polarization toward M1-like macrophages and repolarized M2 macrophages into M1 phenotypes. DPI and Oligo-Fucoidan also cooperatively prevented M2 macrophage invasiveness. Indirectly, M1 polarity was advanced particularly when DPI suppressed ROS generation and supplemented with Oligo-Fucoidan in the cancer cells. Moreover, cisplatin chemoagent polarized monocytes and M0 macrophages toward M2-like phenotypes and Oligo-Fucoidan supplementation reduced these side effects. Furthermore, Oligo-Fucoidan promoted cytotoxicity of cisplatin and antagonized cisplatin effect on cancer cells to prevent M2 macrophage differentiation. More importantly, Oligo-Fucoidan inhibited tumor progression and M2 macrophage infiltration in tumor microenvironment, thus increasing of anti-tumor immunity.

• M1/M2 macrophages
• Oligo-Fucoidan
• ROS
• antioxidant
• cisplatin
• tumor progression

• fucoidan
• macrophages
• orthodontic tooth movement
• tooth stability

• Astragalus polysaccharide
• Cell apoptosis
• Immunoregulation
• Macrophages activation
• Mitochondria pathway

The present study aimed to investigate the association between methylation and the high expression of the suppressor of cytokine signaling 1 (SOCS1) in ovarian cancer by detecting the methylation rate and the degree of expression. The present study investigated the expression of SOCS1 mRNA and SOCS1 protein in ovarian cancer and normal ovary tissues using reverse transcription-quantitative polymerase chain reaction (PCR) and immunohistochemistry, and the methylation status of the CpG islands of SOCS1 mRNA in ovarian cancer tissue were examined using a methylation-specific PCR. The expression levels of SOCS1 mRNA in ovarian cancer specimens were significantly increased compared with that in the normal ovary tissues (P=0.0215). Consistent with this, the expression levels of SOCS1 protein in ovarian cancer specimens were significantly increased, while the methylation rate of SOCS1 mRNA was significantly decreased compared with that in the normal ovary tissues. Therefore, it may be concluded that the low methylation rate of SOCS1 mRNA in ovarian cancer increased the expression of SOCS1 mRNA, which may serve a role in the development of ovarian cancer.

• gene expression
• methylation
• ovarian cancer
• reverse transcription-quantitative polymerase chain reaction
• suppressor of cytokine signaling 1

• BTK
• Her2 +
• Ibrutinib
• STAT3
• p21

• V600E mutation
• mutations
• -induced senescence
• epidemiology
• genomic instability
• hairy cell leukemia
• hairy morphology
• immunophenotype
• monocytopenia

• CRP
• IL-6
• inflammation
• pNEN
• pNET
• pancreatic neuroendocrine neoplasms
• prognosis

The drug-resistance and relapse of diffuse large B-cell lymphoma (DLBCL), which are related to mesenchymal stem cells (MSCs), have become increasingly common. However, the underlying mechanisms remain elusive.

CCK 8 assay, colony formation assay, and xenograft mouse model were used to investigate the effects of hBMSCs on DLBCL growth. Immunohistochemistry, qRT-PCR, and ELISA were used to study the expressions of IL-6 and IL-17A. Flow cytometry was used to analyze Th17 cells and Treg cells expressions. Western blot analysis, microarray analysis, and bioinformatics analysis were used to analyze the pathways of IL-6 or IL-17A mediated DLBCL growth.

HBMSCs promoted DLBCL growth by secreting IL-6 in vitro and in vivo and simultaneously upregulating IL-17A in vitro. IL-6 and IL-17A synergistically promoted the growth and drug-resistance of DLBCL cells by protecting them from spontaneous or drug-induced apoptosis in vitro. IL-6 or IL-17A activated the JAK2/STAT3 pathway or upregulated cyclin D2 via activation of PI3K/Akt signaling in vitro, respectively.

The present results indicated that hBMSCs might have a “dual effect” on promoting DLBCL progression and drug-resistance by secreting IL-6 and upregulating IL-17A. IL-6, IL-17A, p-STAT3, p-Akt or cyclin D2 may be potential molecular targets for overcoming drug-resistance in patients with relapsed or refractory DLBCL.

• Drug-resistance
• Interleukin-17A
• Interleukin-6
• JAK2/STAT3
• Lymphoma, large B cell, diffuse
• Mesenchymal stem cells
• PI3K/Akt

• IL-6
• epithelial-to-mesenchymal transition
• esophageal adenocarcinoma
• therapy resistance
• tumor stroma

• ATX
• invasion
• pNEN
• pancreatic neuroendocrine neoplasms
• signal transducer and activator of transcription 3

• Cancer immunotherapy
• PD-1/PD-L1
• checkpoint blockade
• combination therapies
• tumor-infiltrating lymphocyte

• IL-6
• Invasion
• NRP-1
• Pancreatic neuroendocrine neoplasms
• Signal transducer and activator of transcription 3
• pNEN

• fibroblast senescence
• idiopathic pulmonary fibrosis
• signal transducer and activator of transcription 3

• Immunohistochemical method
• Pancreatic cancer
• Tim-3

Low-molecular-weight Fucoidan (Oligo-Fucoidan) is a sulfated polysaccharide that has a variety of biological effects and has also been shown to have beneficial health effects. However, the molecular mechanisms underlying the therapeutic effects of Oligo-Fucoidan in patients with cancer remain unclear. Using human colorectal cancer HCT116 cells with (p53^+/+) or without (p53^−/−) normal p53 expression, we found that Oligo-Fucoidan treatment reduces the occurrence of spontaneous DNA lesions. Etoposide induces double strand DNA breaks. Subsequent administration of Oligo-Fucoidan to etoposide-treated cells promotes p53 accumulation, p21 expression and significant decreases in ataxia-telangiectasia-mutated (ATM), checkpoint kinase 1 (Chk1) and γ-H2AX phosphorylation in p53^+/+ cells compared with p53^−/− cells. Similarly, co-administration of Oligo-Fucoidan with etoposide inhibits ATM, Chk1 and γ-H2AX phosphorylation, particularly in the presence of p53. Furthermore, Oligo-Fucoidan supplementation increases cancer cell death and attenuates the adverse effects induced by etoposide that decreases production of the pro-inflammatory cytokine IL-6 and chemokine CCL2/MCP-1. Importantly, Oligo-Fucoidan decreases the tumor-promoting M2 macrophages in microenvironment as well as collaborates with p53 and works in combination with etoposide to prevent HCT116 tumorigenicity. Our results first demonstrate that p53 enables Oligo-Fucoidan to effectively inhibit tumor progression, and Oligo-Fucoidan minimizes the side effects of chemotherapy and alters tumor microenvironment.

• IL-6
• autocrine
• pituitary tumor
• senescence

• Adenoma/genetics
• Adenoma/metabolism
• Adenoma/pathology
• Animals
• Autocrine Communication/genetics
• Cell Cycle/genetics
• Cell Proliferation
• Cellular Senescence/genetics
• Extracellular Matrix/metabolism
• Extracellular Matrix/pathology
• Gene Expression Regulation
• Humans
• Interleukin-6/genetics
• Interleukin-6/metabolism
• Mitogen-Activated Protein Kinase Kinases/genetics
• Mitogen-Activated Protein Kinase Kinases/metabolism
• Neovascularization, Pathologic/genetics
• Neovascularization, Pathologic/metabolism
• Neovascularization, Pathologic/pathology
• Paracrine Communication/genetics
• Phosphatidylinositol 3-Kinases/genetics
• Phosphatidylinositol 3-Kinases/metabolism
• Pituitary Gland, Anterior/metabolism
• Pituitary Gland, Anterior/pathology
• Pituitary Neoplasms/genetics
• Pituitary Neoplasms/metabolism
• Pituitary Neoplasms/pathology
• STAT Transcription Factors/genetics
• STAT Transcription Factors/metabolism

• Hsp90
• STAT-3
• cardiac hypertrophy
• collagen
• myocyte-fibroblast cross talk

• DSBs
• Stat3 activation
• genotoxin
• helicobacter
• tumorigenesis

T cell immunoglobulin mucin-3 (Tim-3) has previously been implicated in the immune response and tumor biology. Colorectal carcinoma (CRC) is a malignancy, which is closely associated with inflammation. However, the role of Tim-3 in the progression of CRC remains to be fully elucidated. The present study aimed to investigate the role of Tim-3 in the progressive activities of human CRC. A total of 30 clinical CRC tissues and their adjacent tissues were collected. Slides from another 112 cases that underwent CRC surgical resection were also obtained. The protein and mRNA levels of Tim-3 in the clinical tissues and in CRC cell lines were initially examined using western blot and reverse transcription-quantitative polymerase chain reaction analyses, respectively. Immunohistochemical staining was performed to detect Tim-3 in the CRC samples. Specific small interfering (si)RNA against Tim-3 (siTim-3) was synthesized to knock down the expression of Tim-3, and the subsequent effects of Tim-3 knockdown on cell proliferation, migration and invasion were assessed. The data obtained showed that Tim-3 was expressed at high levels in the CRC tissues, compared with the non-cancerous tissues. The expression of Tim-3 in the clinical tissues was significantly associated with tumor size (P=0.007), tumor-node-metastasis staging (P<0.0001) and distant metastasis (P<0.0001). Knockdown of Tim-3 significantly reduced the cell proliferative rate of HCT116 and HT-29 cells. Wound closure activity was also inhibited by knockdown of Tim-3 in these two cell lines, and the migration and invasive abilities of these two cell lines were consistently decreased following knockdown of Tim-3. Taken together, Tim-3 was found to be a critical mediator in the progression of CRC and may serve as a potential therapeutic target for the treatment of CRC.

Pulmonary hypertension (PH) is defined by a mean pulmonary arterial pressure over 25 mmHg at rest and is diagnosed by right heart catheterization. Among the different groups of PH, pulmonary arterial hypertension (PAH) is characterized by a progressive obstruction of distal pulmonary arteries, related to endothelial cell dysfunction and vascular cell proliferation, which leads to an increased pulmonary vascular resistance, right ventricular hypertrophy, and right heart failure. Although the primary trigger of PAH remains unknown, oxidative stress and inflammation have been shown to play a key role in the development and progression of vascular remodeling. These factors are known to increase DNA damage that might favor the emergence of the proliferative and apoptosis-resistant phenotype observed in PAH vascular cells. High levels of DNA damage were reported to occur in PAH lungs and remodeled arteries as well as in animal models of PH. Moreover, recent studies have demonstrated that impaired DNA-response mechanisms may lead to an increased mutagen sensitivity in PAH patients. Finally, PAH was linked with decreased breast cancer 1 protein (BRCA1) and DNA topoisomerase 2-binding protein 1 (TopBP1) expression, both involved in maintaining genome integrity. This review aims to provide an overview of recent evidence of DNA damage and DNA repair deficiency and their implication in PAH pathogenesis.

• DNA damage
• DNA-damage response
• inflammation
• oxidative stress
• pulmonary hypertension

Chlamydia trachomatis genital infection in women causes serious adverse reproductive complications, and is a strong co-factor for human papilloma virus (HPV)-associated cervical epithelial carcinoma. We tested the hypothesis that Chlamydia induces epithelial-mesenchyme transition (EMT) involving T cell-derived TNF-alpha signaling, caspase activation, cleavage inactivation of dicer and dysregulation of micro-RNA (miRNA) in the reproductive epithelium; the pathologic process of EMT causes fibrosis and fertility-related epithelial dysfunction, and also provides the co-factor function for HPV-related cervical epithelial carcinoma. Using a combination of microarrays, immunohistochemistry and proteomics, we showed that chlamydia altered the expression of crucial miRNAs that control EMT, fibrosis and tumorigenesis; specifically, miR-15a, miR-29b, miR-382 and MiR-429 that maintain epithelial integrity were down-regulated, while miR-9, mi-R-19a, miR-22 and miR-205 that promote EMT, fibrosis and tumorigenesis were up-regulated. Chlamydia induced EMT in vitro and in vivo, marked by the suppression of normal epithelial cell markers especially E-cadherin but up-regulation of mesenchymal markers of pathological EMT, including T-cadherin, MMP9, and fibronectin. Also, Chlamydia upregulated pro-EMT regulators, including the zinc finger E-box binding homeobox protein, ZEB1, Snail1/2, and thrombospondin1 (Thbs1), but down-regulated anti-EMT and fertility promoting proteins (i.e., the major gap junction protein connexin 43 (Cx43), Mets1, Add1Scarb1 and MARCKSL1). T cell-derived TNF-alpha signaling was required for chlamydial-induced infertility and caspase inhibitors prevented both infertility and EMT. Thus, chlamydial-induced T cell-derived TNF-alpha activated caspases that inactivated dicer, causing alteration in the expression of reproductive epithelial miRNAs and induction of EMT. EMT causes epithelial malfunction, fibrosis, infertility, and the enhancement of tumorigenesis of HPV oncogene-transformed epithelial cells. These findings provide a novel understanding of the molecular pathogenesis of chlamydia-associated diseases, which may guide a rational prevention strategy.

• Cancer prevention
• Cancer therapy
• DNA damage
• Genomic instability
• Nutraceutical

• Centrosome/metabolism
• DNA Damage/genetics
• DNA Repair/genetics
• Diet
• Genomic Instability/drug effects
• Genomic Instability/genetics
• Humans
• Neoplasms/diet therapy
• Neoplasms/genetics
• Neoplasms/pathology
• Prognosis
• Telomerase/antagonists & inhibitors
• Telomerase/genetics

• R01CA172380 NCI NIH HHS
• R03 CA119310 NCI NIH HHS
• R13 CA119920 NCI NIH HHS
• R01 CA132996 NCI NIH HHS
• R01 CA166348 NCI NIH HHS
• RCIRFA0D09009 PHS HHS
• P01 AG024387 NIA NIH HHS
• P50 AT006268 NCCIH NIH HHS
• R21 CA188818 NCI NIH HHS
• 5R01 CA132996-03 NCI NIH HHS
• 1R01CA166348 NCI NIH HHS
• P30CA006973 NCI NIH HHS
• P30 CA006973 NCI NIH HHS
• R01 CA028704 NCI NIH HHS
• P30 DK079626 NIDDK NIH HHS
• P50 CA096784 NCI NIH HHS
• OBC 134038 CIHR
• R01 CA172380 NCI NIH HHS
• P50 DE019032 NIDCR NIH HHS
• R01 CA077355 NCI NIH HHS
• P01 CA077664 NCI NIH HHS

According to the minimal criteria of the International Society of Cellular Therapy, mesenchymal stem cells (MSCs) are a population of undifferentiated cells defined by their ability to adhere to plastic surfaces when cultured under standard conditions, express a certain panel of phenotypic markers and can differentiate into osteogenic, chondrogenic and adipogenic lineages when cultured in specific inducing media. In parallel with their major role as undifferentiated cell reserves, MSCs have immunomodulatory functions which are exerted by direct cell-to-cell contacts, secretion of cytokines and/or by a combination of both mechanisms. There are no convincing data about a principal difference in the profile of cytokines secreted by MSCs isolated from different tissue sources, although some papers report some quantitative but not qualitative differences in cytokine secretion. The present review focuses on the basic cytokines secreted by MSCs as described in the literature by which the MSCs exert immunodulatory effects. It should be pointed out that MSCs themselves are objects of cytokine regulation. Hypothetical mechanisms by which the MSCs exert their immunoregulatory effects are also discussed in this review. These mechanisms may either influence the target immune cells directly or indirectly by affecting the activities of predominantly dendritic cells. Chemokines are also discussed as participants in this process by recruiting cells of the immune systems and thus making them targets of immunosuppression. This review aims to present and discuss the published data and the personal experience of the authors regarding cytokines secreted by MSCs and their effects on the cells of the immune system.

• Mesenchymal stem cells
• Immunomodulation
• Cytokines
• Chemokines
• Dendritic cells

Cellular senescence is an important mechanism for preventing tumor progression. The elevated expression of Bcl-2-interacting cell death suppressor (BIS), an anti-apoptotic and anti-stress protein, often correlates with poor prognosis in several cancers including glioblastoma; however, the role of BIS in the regulation of senescence has not been well defined. Here, we describe for the first time that the depletion of BIS induces G1 arrest and cellular senescence through the accumulation of p27 that is independent of p53, p21 or p16. The increase in p27 expression in BIS-depleted cells was attributable to an impairment of the ubiquitin-mediated degradation of p27, which was caused by a decrease in S-phase kinase-associated protein 2 (SKP2) at the transcriptional level. As an underlying molecular mechanism, we demonstrate that the loss of activity of signal transducer and activator of transcription 3 (STAT3) was specifically linked to the suppression of SKP2 expression. Despite a reduction in phospho-STAT3 levels, total STAT3 levels were unexpectedly increased by BIS depletion, specifically in the insoluble fraction. Our results show that 14-3-3ζ expression is decreased by BIS knockdown and that 14-3-3ζ depletion per se significantly induced senescence phenotypes. In addition, the ectopic expression of 14-3-3ζ blocked senescence caused by BIS depletion, which was paralleled with a decrease in insoluble STAT3 in A172 glioblastoma cells. These findings indicate that the impairment of the protein quality control conferred by BIS and/or 14-3-3ζ is critical for BIS depletion-induced senescence. Moreover, BIS knockdown also induced senescence along with an accumulation of total STAT3 and p27 in several different cell types as well as embryonic fibroblasts derived from Bis-knock out mice with/without variations in 14-3-3ζ levels. Therefore, our findings suggest that a downregulation of BIS expression could serve as a potential strategy for restricting tumor progression via an induction of senescence through the regulation of STAT3/SKP2/p27 pathway.

• Apoptosis
• DNA damage
• Head and Neck Squamous Cell Carcinoma
• Homologous recombination repair
• Linifanib (ABT-869)
• PARP inhibitor
• Veliparib (ABT-888)

• Apoptosis/drug effects
• Benzimidazoles/pharmacology
• Carcinoma, Squamous Cell/drug therapy
• Cell Line, Tumor
• Cell Survival/drug effects
• DNA Breaks/drug effects
• Head and Neck Neoplasms/drug therapy
• Histones/metabolism
• Humans
• Indazoles/pharmacology
• Phenylurea Compounds/pharmacology
• Poly(ADP-ribose) Polymerase Inhibitors
• Poly(ADP-ribose) Polymerases/metabolism
• Rad51 Recombinase/metabolism