No abstract available.
Colitis, Ulcerative/*drug therapy ; Female ; Humans ; Janus Kinases/*antagonists & inhibitors ; Male ; Protein Kinase Inhibitors/*administration & dosage ; Pyrimidines/*administration & dosage ; Pyrroles/*administration & dosage

Conventional medical treatment for ulcerative colitis can have limited efficacy or severe adverse reactions requiring additional treatment or colectomy. Hence, different biological agents that target specific immunological pathways are being investigated for treating ulcerative colitis. Anti-tumor necrosis factor (TNF) agents were the first biologics to be used for treating inflammatory bowel disease. For example, infliximab and adalimumab, which are anti-TNF agents, are being used for treating ulcerative colitis. Recently, golimumab, another anti-TNF agent, and vedolizumab, an anti-adhesion therapy, have been approved for ulcerative colitis by the U.S. Food and Drug Administration. In addition, new medications such as tofacitinib, a Janus kinase inhibitor, and etrolizumab, another anti-adhesion therapy, are emerging as therapeutic agents. Therefore, there is a need for further studies to select appropriate patient groups for these biologics and to improve the outcomes of ulcerative colitis treatment through appropriate medical usage.
Antibodies, Monoclonal/therapeutic use ; Antibodies, Monoclonal, Humanized/therapeutic use ; Biological Factors/*therapeutic use ; Cell Adhesion Molecules/antagonists & inhibitors ; Colitis, Ulcerative/*drug therapy ; Humans ; Janus Kinases/antagonists & inhibitors ; Piperidines/therapeutic use ; Pyrimidines/therapeutic use ; Pyrroles/therapeutic use

Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway is one of the downstream pathways of cytokine signaling transduction. It regulates cell development, differentiation, proliferation, apoptosis and so on. The pathway is not only involved in the regulation of normal physiological processes, but also significant in the development of tumors, especially in hematologic malignancies. In recent years, with the further research of JAK/STAT signaling pathway, it has been found that the pathway also plays a key role in the development of solid tumors. Here we reviewed the research advances of JAK/STAT signaling pathway in lung cancer, especially the mechanisms of development, metastasis and drug resistance, and the application of inhibitors which targeting JAK/STAT signaling pathway in the treatment of lung cancer.
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Animals ; Antineoplastic Agents ; therapeutic use ; Biomedical Research ; methods ; trends ; Humans ; Janus Kinases ; antagonists & inhibitors ; metabolism ; Lung Neoplasms ; drug therapy ; metabolism ; pathology ; Neoplasm Metastasis ; STAT Transcription Factors ; antagonists & inhibitors ; metabolism ; Signal Transduction

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by inflammation and joint destruction that causes significant morbidity and mortality. However, the combined use of methotrexate, a synthetic disease-modifying antirheumatic drug (DMARD), and biologic DMARD has revolutionized treatment of RA. Clinical remission is now realistic targets, achieved by a large proportion of RA patients, and rapid and appropriate induction of remission by intensive treatment with biological DMARD and methotrexate is prerequisite to halt joint damage and functional disabilities. However, biological DMARD is limited to intravenous or subcutaneous uses and orally available small but strong molecules have been developed. Oral administration of tofacitinib targeting the Janus kinase (JAK) is significantly effective than placebo in active patients with methotrexatenaive, inadequately responsive to methotrexate or tumor necrosis factor (TNF)-inhibitors. The efficacy was rapid and as strong as adalimumab, a TNF-inhibitor. Meanwhile, association of tofacitinib on carcinogenicity and malignancy is under debate and further investigation on post-marketing survey would be warranted. On the other hand, discontinuation of a biological DMARD without disease flare is our next goal and desirable from the standpoint of risk reduction and cost effectiveness, especially for patients with clinical remission. Recent reports indicate that more than half of early RA patients could discontinue TNF-targeted biological DMARD without clinical flare and functional impairment after obtaining clinical remission. Contrarily, for established RA, fewer patients sustained remission after the discontinuation of biological DMARD and "deep remission" at the discontinuation was a key factor to keep the treatment holiday of biological DMARD.
Administration, Oral ; Antirheumatic Agents/*administration & dosage/adverse effects ; Arthritis, Rheumatoid/diagnosis/*drug therapy/metabolism/physiopathology ; Biological Products/administration & dosage ; Disability Evaluation ; Drug Administration Schedule ; Humans ; Janus Kinases/antagonists & inhibitors/metabolism ; Molecular Targeted Therapy ; Predictive Value of Tests ; Protein Kinase Inhibitors/administration & dosage ; Recovery of Function ; Remission Induction ; Signal Transduction/drug effects ; Treatment Outcome ; Tumor Necrosis Factor-alpha/antagonists & inhibitors/metabolism

BACKGROUND/AIMS: The aim of this study was to assess the efficacy and safety of tofacitinib (5 and 10 mg twice daily) in patients with active rheumatoid arthritis (RA). METHODS: A systematic review of randomized controlled trials (RCTs) that examined the efficacy and safety of tofacitinib in patients with active RA was performed using the Medline, Embase, and Cochrane Controlled Trials Register databases as well as manual searches. RESULTS: Five RCTs, including three phase-II and two phase-III trials involving 1,590 patients, met the inclusion criteria. The three phase-II RCTs included 452 patients with RA (144 patients randomized to 5 mg of tofacitinib twice daily, 156 patients randomized to 10 mg of tofacitinib twice daily, and 152 patients randomized to placebo) who were included in this meta-analysis. The American College of Rheumatology 20% response rate was significantly higher in the tofacitinib 5- and 10-mg groups than in the control group (relative risk [RR], 2.445; 95% confidence interval [CI], 1.229 to 4.861; p = 0.011; and RR, 2.597; 95% CI, 1.514 to 4.455; p = 0.001, respectively). The safety outcomes did not differ between the tofacitinib 5- and 10-mg groups and placebo groups with the exception of infection in the tofacitinib 10-mg group (RR, 2.133; 95% CI, 1.268 to 3.590; p = 0.004). The results of two phase-III trials (1,123 patients) confirmed the findings in the phase-II studies. CONCLUSIONS: Tofacitinib at dosages of 5 and 10 mg twice daily was found to be effective in patients with active RA that inadequately responded to methotrexate or disease-modifying antirheumatic drugs, and showed a manageable safety profile.
Antirheumatic Agents/administration & dosage/adverse effects/*therapeutic use ; Arthritis, Rheumatoid/*drug therapy ; Clinical Trials, Phase II as Topic ; Clinical Trials, Phase III as Topic ; Humans ; Janus Kinases/antagonists & inhibitors ; Methotrexate/therapeutic use ; Piperidines/administration & dosage/adverse effects/*therapeutic use ; Protein Kinase Inhibitors/administration & dosage/adverse effects/therapeutic use ; Pyrimidines/administration & dosage/adverse effects/*therapeutic use ; Pyrroles/administration & dosage/adverse effects/*therapeutic use ; Randomized Controlled Trials as Topic ; Treatment Outcome

OBJECTIVETo investigate the effect and mechanism of blockade of STAT3 signaling pathway by JAK specific inhibitor-AG490 on invasion and metastasis of human highly metastatic pancreatic cancer line SW1990 in vitro.

METHODSAG490 was added into the culture media for SW1990 cells. The invasion ability of SW1990 cells was determined by cell invasion assay kit. Western blot was performed to detect the protein expression of the STAT3, phosphorylated STAT3 (p-STAT3), MMP-2 and VEGF. RT-PCR was performed to detect the mRNA expression of the MMP-2 and VEGF.

RESULTS20 micromol/L AG490 significantly inhibited the invasion ability of SW1990 cells and the inhibitory rate of invasion ability was (77.67 +/- 7.79) %. The use of AG490 not only markedly reduced the protein expression of p-STAT3, MMP-2 and VEGF, but also greatly reduced the mRNA expression of MMP-2 and VEGF.

CONCLUSIONBlocking STAT3 activation with AG490 can inhibit the invasion and metastasis ability of pancreatic cancer cells in vitro through down-regulation of MMP-2 and VEGF expression. Blocking STAT3 signaling pathway may provide a novel strategy in prevention of invasion and metastasis of pancreatic cancer.

Antineoplastic Agents ; pharmacology ; Blotting, Western ; Cell Line, Tumor ; Dose-Response Relationship, Drug ; Gene Expression Regulation, Neoplastic ; drug effects ; Humans ; Janus Kinases ; antagonists & inhibitors ; Matrix Metalloproteinase 2 ; genetics ; metabolism ; Neoplasm Invasiveness ; Neoplasm Metastasis ; Pancreatic Neoplasms ; genetics ; metabolism ; pathology ; Phosphorylation ; drug effects ; RNA, Messenger ; biosynthesis ; genetics ; Reverse Transcriptase Polymerase Chain Reaction ; STAT3 Transcription Factor ; metabolism ; Signal Transduction ; drug effects ; Tyrphostins ; pharmacology ; Vascular Endothelial Growth Factor A ; genetics ; metabolism