Abstract Tumor budding (TB) is a small tumor cell cluster with highly aggressive behavior located ahead of the invasive tumor front. However, the molecular and biological characteristics of TB and the regulatory mechanisms governing TB phenotypes remain unclear. This study reveals that TB exhibits a particular dynamic gene signature with stemness and partial epithelial‐mesenchymal transition (p‐EMT). Importantly, nuclear expression of CYTOR is identified to be the key regulator governing stemness and the p‐EMT phenotype of TB cells, and targeting CYTOR significantly inhibits TB formation, tumor growth and lymph node metastasis in head and neck squamous cell carcinoma (HNSCC). Mechanistically, CYTOR promotes tumorigenicity and metastasis of TB cells by facilitating the formation of FOSL1 phase‐separated condensates to establish FOSL1‐dependent super enhancers (SEs). Depletion of CYTOR leads to the disruption of FOSL1‐dependent SEs, which results in the inactivation of cancer stemness and pro‐metastatic genes. In turn, activation of FOSL1 promotes the transcription of CYTOR . These findings indicate that CYTOR is a super‐lncRNA that controls the stemness and metastasis of TB cells through facilitating the formation of FOSL1 phase separation and SEs, which may be an attractive target for therapeutic interventions in HNSCC.
Tofacitinib is an oral small molecule Janus kinase inhibitor for the treatment of ulcerative colitis.To report efficacy and infection rates in patients receiving tofacitinib induction treatment, by baseline corticosteroid status.We evaluated efficacy and safety data from OCTAVE Induction 1&2 in patients with moderately-to-severely active ulcerative colitis who received tofacitinib 10 mg twice daily or placebo for 8 weeks, based on induction baseline oral corticosteroid use (Corticosteroid-Yes/No) and dose (< 20/ ≥ 20 mg/day). Infections of interest included serious infections, herpes zoster (HZ), and adjudicated opportunistic infections (OIs).At OCTAVE Induction 1&2 baseline, 478/1092 (43.8%) patients were receiving corticosteroids. Tofacitinib demonstrated significant induction efficacy versus placebo for both Corticosteroid-Yes and Corticosteroid-No. With adjustment for prior tumor necrosis factor inhibitor and immunosuppressant failure, there were no statistically significant differences in remission and clinical response rates for Corticosteroid-Yes versus Corticosteroid-No. Among tofacitinib-treated patients, HZ and OIs occurred more frequently in Corticosteroid-Yes versus Corticosteroid-No, regardless of dose (< 20 mg vs. ≥ 20 mg). Infection incidence rates (regardless of severity/seriousness) during tofacitinib induction were generally similar regardless of baseline corticosteroid use. The proportion of tofacitinib-treated patients with HZ was 0.2% for Corticosteroid-No versus 1.1% for Corticosteroid-Yes < 20 mg and 1.0% for Corticosteroid-Yes ≥ 20 mg. Two out of three patients had HZ OIs.Tofacitinib induction efficacy (clinical response and remission) was similar in baseline corticosteroid subgroups. Infections of interest were rare; HZ and OIs occurred more frequently among those receiving tofacitinib and corticosteroids versus those receiving tofacitinib without corticosteroids.http://www.gov (NCT01465763[21/10/2011]; NCT01458951[21/10/2011]).
Summary Background Tofacitinib is an oral, small molecule Janus kinase inhibitor that is being investigated for inflammatory bowel disease. Aims This 48‐week open‐label extension study primarily investigated long‐term safety of tofacitinib 5 and 10 mg b.d. and secondarily investigated efficacy as maintenance therapy in patients with Crohn's disease. Methods Patients who had completed the phase 2b maintenance study, or withdrawn due to treatment failure, were enrolled. Patients in remission (Crohn's disease activity index <150) at baseline received tofacitinib 5 mg b.d.; all others received 10 mg b.d. A single dose adjustment was allowed after 8 weeks’ fixed, open‐label treatment. Results Sixty‐two patients received tofacitinib 5 mg b.d.; 88 received 10 mg b.d. Both groups had similar rates of adverse events and serious infections. Crohn's disease worsening was the most frequent adverse event for tofacitinib 5 (33.9%) and 10 mg b.d. (19.3%). Patients not in remission at baseline, receiving 10 mg b.d., had higher rates of serious adverse events (19.3%) and discontinuation attributed to insufficient clinical response (30.7%) vs 5 mg b.d. (8.1% and 9.7%, respectively). At week 48, of patients with baseline remission receiving 5 mg b.d., 87.9% maintained remission and 75.0% sustained remission as observed (46.8% and 38.7%, respectively, by non‐responder imputation). Study design prevented between‐dose efficacy comparisons. Conclusions No new safety signals emerged. Although both doses showed generally similar safety outcomes for overall adverse events, serious adverse events were more frequent for tofacitinib 10 than 5 mg b.d. Discontinuation due to insufficient clinical response was lower among patients in remission at baseline. ClinicalTrials.gov: NCT01470599.
Tofacitinib is an oral, small molecule Janus kinase inhibitor for the treatment of ulcerative colitis (UC). The efficacy and safety of tofacitinib were demonstrated in a dose-ranging phase 2 induction trial, 3 phase 3 randomized, placebo-controlled trials (OCTAVE Induction 1 and 2; and OCTAVE Sustain), and an ongoing, open-label, long-term extension trial (OCTAVE Open) in patients with moderately to severely active UC. Here, we assessed short- and long-term efficacy and safety of extended induction (16 weeks) with tofacitinib 10 mg twice daily (BID) in patients who failed to respond to initial induction (8 weeks) treatment.In patients who achieved a clinical response following extended induction (delayed responders), the efficacy and safety of tofacitinib were evaluated up to Month 36 of OCTAVE Open.52.2% of patients who did not achieve clinical response to 8 weeks' treatment with tofacitinib 10 mg BID in the induction studies achieved a clinical response following extended induction (delayed responders). At Month 12 of OCTAVE Open, 70.3%, 56.8%, and 44.6% of delayed responders maintained clinical response and achieved endoscopic improvement and remission, respectively. Corresponding values at Month 36 were 56.1%, 52.0%, and 44.6%. The safety profile of the subsequent 8 weeks was similar to the initial 8 weeks.Overall, the majority of patients achieved a clinical response after 8 or 16 weeks' induction therapy with tofacitinib 10 mg BID. Tofacitinib 10 mg BID, administered as induction therapy for up to 16 weeks, had a comparable safety profile to 8 weeks' induction therapy. Most delayed responders at Month 36 were in remission.gov: NCT00787202; NCT01465763; NCT01458951; and NCT01470612.
Abstract Activation of the cyclic GMP‐AMP synthase‐stimulator of the interferon gene (cGAS‐STING) pathway is a potent anticancer immunotherapeutic strategy, and the induction of pyroptosis is a feasible way to stimulate the anticancer immune responses. Herein, two Pt II complexes ( Pt1 and Pt2 ) were designed as photoactivators of the cGAS‐STING pathway. In response to light irradiation, Pt1 and Pt2 could damage mitochondrial/nuclear DNA and the nuclear envelope to activate the cGAS‐STING pathway, and concurrently induce pyroptosis in cancer cells, which evoked an intense anticancer immune response in vitro and in vivo. Overall, we present the first photoactivator of the cGAS‐STING pathway, which may provide an innovative design strategy for anticancer immunotherapy.
INTRODUCTION: Tofacitinib is an oral, small molecule JAK inhibitor for the treatment of UC. Patients (pts) may need to temporarily suspend tofacitinib treatment for several reasons, such as adverse events (AEs), pregnancy or surgery; thus, it is key to assess the efficacy/safety of retreatment after treatment interruption. METHODS: We provide an update (1) of tofacitinib retreatment efficacy and safety data after treatment interruption in the ongoing, open-label, long-term extension (OLE) study (NCT01470612; data as of May 2019, database not locked). We analyzed pts in the OLE study who had a clinical response after 8 wks of tofacitinib 10 mg twice daily (BID) in OCTAVE Induction 1&2 (NCT01465763; NCT01458951) then received placebo in OCTAVE Sustain (NCT01458574) and had treatment failure after Wk8 up to Wk52 and subsequently received tofacitinib 10 mg BID in the OLE study. Treatment failure was defined as a ≥ 3-point increase from OCTAVE Sustain baseline total Mayo score plus a ≥ 1-point increase in rectal bleeding subscore and endoscopic subscore (ES) and an absolute ES ≥ 2 points after ≥ 8 wks' treatment. We evaluated efficacy up to Month (Mo) 36 of the OLE study and AEs throughout the study. RESULTS: Of 917 pts treated for ≥ 2 mo in the OLE study, 100 entered the study with a clinical response to tofacitinib 10 mg BID in OCTAVE Induction 1 or 2 followed by treatment failure on placebo during OCTAVE Sustain; median time to treatment failure was 135 days. After receiving tofacitinib 10 mg BID in the OLE study, clinical response was recaptured at Mo2 in 74.3% (non-responder imputation and last observation carried forward [NRI-LOCF]) and 85.2% of pts (observed data; Table 1). At Mo 12, 24 and 36, 43.6%, 40.6% and 37.0% (NRI-LOCF) and 62.0%, 69.5% and 72.0% (observed data) of pts were in remission, respectively. In pts with prior TNFi failure, 80.4% had a clinical response at Mo 2 and 47.8%, 37.0% and 28.3% were in remission at Mo 12, 24 and 36 (NRI-LOCF), respectively. Corresponding observed data were 92.5%, 66.7%, 70.8% and 63.2%, respectively. Incidence rates for AEs are reported (Table 1). CONCLUSION: In this post hoc analysis, in pts with prior response to tofacitinib induction, retreatment with 10 mg BID after 8–52 wks' treatment interruption was efficacious and well-tolerated, with clinical response recaptured in the majority of pts by Mo 2 and in half of pts at Mo 36. The safety profile was generally consistent with that in the overall study population.Table 1
Introduction: Gastric cancer is among the leading causes of cancer-related death worldwide, especially in Eastern Asia, Eastern Europe and South America. Statin is one of the most widely used medications for hypercholesterolemia. Several meta-analyses have failed to determine the relationship between statins and gastric cancer. Aims: A meta-analysis of case control studies is conducted to evaluate the association of statin exposure and risk of gastric cancer. Materials and Methods: Eight electronic databases (The Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 12, 2012), PubMed, EMBASE, ISI Web of Knowledge, CNKI, CBM, CSJD and Wanfang Database) were searched for relevant publications through September 2013. Two reviewers determined the eligibility of articles and abstracted the data independently. RevMan 5.2 software was used for statistical analysis. Results: 146 items were retrieved from the databases and 6 studies were identified in this meta-analysis, which included 5,993 cases and 54,800 matched controls. Results from the meta-analysis demonstrated that statins were inversely related to the risk of gastric cancer (RR = 0.56, 95% CI: 0.35-0.90). There was no significant difference for cumulative duration of statin exposure and gastric cancer, nor participants from Asia, Europe, or USA. Conclusion: This meta-analysis suggests that statins have favorable effects on gastric cancer, rigorously designed and executed observational studies and randomized control trials with longer duration of follow-up are warranted to determine effects in clinical practice.
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