URI alleviates tyrosine kinase inhibitors-induced ferroptosis by reprogramming lipid metabolism in p53 wild-type liver cancers.

The clinical benefit of tyrosine kinase inhibitors (TKIs)-based systemic therapy for advanced hepatocellular carcinoma (HCC) is limited due to drug resistance. Here, we uncover that lipid metabolism reprogramming mediated by unconventional prefoldin RPB5 interactor (URI) endows HCC with resistance to TKIs-induced ferroptosis. Mechanistically, URI directly interacts with TRIM28 and promotes p53 ubiquitination and degradation in a TRIM28-MDM2 dependent manner. Importantly, p53 binds to the promoter of stearoyl-CoA desaturase 1 (SCD1) and represses its transcription. High expression of URI is correlated with high level of SCD1 and their synergetic expression predicts poor prognosis and TKIs resistance in HCC. The combination of SCD1 inhibitor aramchol and deuterated sorafenib derivative donafenib displays promising anti-tumor effects in p53-wild type HCC patient-derived organoids and xenografted tumors. This combination therapy has potential clinical benefits for the patients with advanced HCC who have wild-type p53 and high levels of URI/SCD1.

Phase II trial of natalizumab with corticosteroids as initial treatment of gastrointestinal acute graft-versus-host disease.

The α4ß7 integrin is upregulated on naive and memory T cell subsets in patients who subsequently develop gastrointestinal (GI) acute GVHD. Natalizumab (Tysabri®, Biogen Inc.) acts against the α4 subunit that mediates homing of lymphocytes to the GI tract. We initiated a phase II study of natalizumab with corticosteroids for initial treatment of acute GI GVHD. In total, 300 mg IV of natalizumab was given, with steroids initiated up to 3 days prior. Twenty-one subjects were treated, median age was 63 years (range 38-74), and 15 (71%) were male. Eighteen (86%) underwent RIC, 15 (71%) received MUD, and all received PBSCs. Overall GVHD at enrollment was grade II in 4 and grade III in 17. The primary endpoint, day 56 GVHD-free survival rate, was attained in 33.3%. The overall response rate at day 28 and 56 was 57% and 52%, respectively. Six of eight CRs were durable for 1 year. Five experienced toxicity possibly related to natalizumab and ten had infections before day 100. 2-year OS was 43% (95% CI 22-62%) and 2-year NRM was 52% (95% CI 29-71%). Natalizumab with corticosteroids as initial treatment of acute GI GVHD is safe, effective, and durable.

Haematopoietic cell transplantation with and without sorafenib maintenance for patients with FLT3-ITD acute myeloid leukaemia in first complete remission.

We performed a retrospective study analysing the effect of sorafenib, an oral fms-Like Tyrosine Kinase 3 (FLT3)/multikinase inhibitor, as post-transplant maintenance in adult patients with FLT3-internal tandem duplication (ITD) acute myeloid leukaemia (AML). We identified consecutive patients with FLT3-ITD AML diagnosed between 2008 and 2014 who received haematopoietic cell transplantation (HCT) in first complete remission (CR1). Post-HCT initiation of sorafenib (yes/no) was evaluated as a time-varying covariate in the overall survival/progression-free survival (OS/PFS) analysis and we performed a landmark analysis of controls alive without relapse at the median date of sorafenib initiation. We identified 26 sorafenib patients and 55 controls. Median follow-up was 27·2 months post-HCT for sorafenib survivors, and 38·4 months for controls (P = 0·021). The median time to initiating sorafenib was 68 days post-HCT; 43 controls were alive without relapse at this cut-off. Sorafenib patients had improved 2-year OS in the d+68 landmark analysis (81% vs. 62%, P = 0·029). Sorafenib was associated with improved 2-year PFS (82% vs. 53%, P = 0·0081) and lower 2-year cumulative incidence of relapse (8·2% vs. 37·7%, P = 0·0077). In multivariate analysis, sorafenib significantly improved OS [Hazard ratio (HR) 0·26, P = 0·021] and PFS (HR 0·25, P = 0·016). There was no difference in 2-year non-relapse mortality (9·8% vs. 9·3%, P = 0·82) or 1-year chronic graft-versus-host disease (55·5% vs. 37·2%, P = 0·28). These findings suggest potential benefit of post-HCT sorafenib in FLT3-ITD AML, and support further evaluation of post-HCT FLT3 inhibition.

[Study on the stability of resveratrol in rhizoma polygoni cuspidati].

OBJECTIVE: The stability of resveratrol in Rhizoma Polygoni Cuspidati is evaluated all-roundly. METHODS: We not only increase influence intensity by physical, chemical and biological methods but also parallel analyzing the influence results to elicit the opinions. RESULTS: The content of resveratrol is declied greatly by lighting, heating, wet-heating or oxidizing. The content is increased in Rhizoma Polygoni Cuspidati treated with acid or alkali only using sodium hydroxide until pH=11. The content is not increased when its own activated microbe is destroyed. CONCLUSION: Resveratrol is unstable against light, heat, wet-heating and oxidizer. Its own activated microbe has not influenced to it. It has not benefit with acidification. Its solubility and stability increase formed sodium salt with basification.

[Experimental study on treatment of immune ulcerative colitis in mice by Changlu Enema].

OBJECTIVE: To observe the therapeutic effect of Chinese compound, Changlu Enema (CE), on immune ulcerative colitis (UC) in mice. METHODS: Mice were randomly divided into the normal group, the model group, the CE high dose (CE-H) and low dose (CE-L) group and the salicylazosulfapyridine (SASP) group. All mice, except those in the normal group, were made into UC model by colonic mucosa protein immunization. After 21 days of medication, the changes of UC activity index and body weight in mice were observed, and the condition of colonic inflammation and histomorphological changes in colonic tissue were observed also. RESULTS: UC activity index was lower and body weight was higher in the two CE groups than those in the model group respectively, showing significant difference (P < 0.05 or P < 0.01); pathological examination showed the pathological changes and inflammatory response in colonic tissue were relieved significantly after treatment, and the improvement in the CE-H group was better than that in the SASP group. CONCLUSION: TCM compound CE is markedly effective in treating UC rats.

[Clinical study on effects of kangwei granule on precancerous lesion in patients with chronic atrophic gastritis].

UNLABELLED: (GPL) in patients suffered from chronic atrophic gastritis (CAG) differentiated as Pi-deficiency with damp-heat retention and blood stasis in TCM Syndrome differentiation. METHODS: Sixty-eight patients fitting to the admission criteria were randomly divided into two groups, 36 patients were treated with KWG in the treated group and 32 were treated with Weifuchun in the control group, all were treated for 2 treatment courses (12 weeks as one course). RESULTS: The curative effects on gastroscopy and pathologic changes in the treated group were significantly superior to those in the control group (P < 0.05). The comparison of clinical efficacy, symptom improvement, anti-Helicobactor pylori effect between the two groups was insignificantly different (P > 0.05). CONCLUSION: KWG is an effective drug for GPL.