Abstract Li-Fraumeni syndrome (LFS) is characterized by germline mutations occurring on one allele of genome guardian TP53 . It is a severe cancer predisposition syndrome with a poor prognosis, partly due to the frequent development of subsequent primary tumors following DNA-damaging therapies. Here we explored, for the first time, the effectiveness of mutant p53 rescue compound in treating LFS-mimicking mice harboring a deleterious p53 mutation. Among the ten p53 hotspot mutations in IARC LFS cohorts, R282W is one of the mutations predicting the poorest survival prognosis and the earliest tumor onset. Among the six clinical-stage mutant p53 rescue compounds, arsenic trioxide (ATO) effectively restored transactivation activity to p53-R282W. We thus constructed a heterozygous Trp53 R279W (corresponding to human R282W) mouse model for the ATO treatment study. The p53 R279W/+ (W/+) mice exhibited tumor onset and overall survival well mimicking the ones of human LFS. Further, 35 mg/L ATO addition in drink water significantly extended the median survival of W/+ mice (from 460 to 596 days, hazard ratio = 0.4003, P = 0.0008). In the isolated tumors from ATO-treated W/+ mice, the representative p53 targets including Cdkn1a , Mdm2 , and Tigar were significantly upregulated, accompanying with a decreased level of the proliferation marker Ki67 and increased level of apoptosis marker TUNEL. Together, the non-genotoxic treatment of p53 rescue compound ATO holds promise as an alternative for LFS therapeutic.
Arsenic trioxide (ATO) targets PML/RARα and leads to miraculous success in treating acute promyelocytic leukemia. Notably, ATO also targets p53, the most frequently mutated protein in cancers, through a similar binding mechanism. However, p53-targeting ATO trials are challenging due to the poor cellular uptake and cancer selectivity of ATO. Here, we analyzed the structure–activity relationship of arsenicals and rationally developed a novel arsenical (designated AcGlcAs) by conjugating arsenic to sulfur atoms and tetraacetyl-β-d-thioglucose. AcGlcAs exhibited remarkable cellular uptake through a thiol-mediated pathway (maximally 127-fold higher than ATO), thereby potently targeting PML/RARα and mutant p53. Among the 55 tested cell lines, AcGlcAs preferentially killed cancer lines rather than normal lines. In preclinical studies, AcGlcAs significantly extended the survival of mice bearing a xenograft tumor with p53 mutation while showing high plasma stability and oral bioavailability. Thus, AcGlcAs is a potential clinical candidate for precisely treating numerous p53-mutated cancers.
Accurate prognostic stratification of patients can provide guidance for personalized therapy. Many prognostic models for acute myeloid leukemia (AML) have been reported, but most have considerable inaccuracies due to contained variables with insufficient capacity of predicting survival and lack of adequate verification. Here, 235 genes strongly related to survival in AML were systematically identified through univariate Cox regression analysis of eight independent AML datasets. Pathway enrichment analysis of these 235 genes revealed that the IL-2/STAT5 signaling pathway was the most highly enriched. Through Cox proportional-hazards regression model and stepwise algorithm, we constructed a six-gene STAT5-associated signature based on the most robustly survival-related genes related to the IL-2/STAT5 signaling pathway. Good prognostic performance was observed in the training cohort (GSE37642-GPL96), and the signature was validated in seven other validation cohorts. As an independent prognostic factor, the STAT5-associated signature was positively correlated with patient age and ELN2017 risk levels. An integrated score based on these three prognostic factors had higher prognostic accuracy than the ELN2017 risk category. Characterization of immune cell infiltration indicated that impaired B-cell adaptive immunity, immunosuppressive effects, serious infection, and weakened anti-inflammatory function tended to accompany high-risk patients. Analysis of in-house clinical samples revealed that the STAT5-assocaited signature risk scores of AML patients were significantly higher than those of healthy people. Five chemotherapeutic drugs that were effective in these high-risk patients were screened in silico. Among the five drugs, MS.275, a known HDAC inhibitor, selectively suppressed the proliferation of cancer cells with high STAT5 phosphorylation levels in vitro. Taken together, the data indicate that the STAT5-associated signature is a reliable prognostic model that can be used to optimize prognostic stratification and guide personalized AML treatments.
The tumor suppressor p53 is inactivated by over hundreds of heterogenous mutations in cancer. Here, we purposefully selected phenotypically reversible temperature-sensitive (TS) p53 mutations for pharmacological rescue with thermostability as the compound-screening readout. This rational screening identified antiparasitic drug potassium antimony tartrate (PAT) as an agent that can thermostabilize the representative TS mutant p53-V272M via noncovalent binding. PAT met the three basic criteria for a targeted drug: availability of a co-crystal structure, compatible structure-activity relationship, and intracellular target specificity, consequently exhibiting antitumor activity in a xenograft mouse model. At the antimony dose in clinical antiparasitic therapy, PAT effectively and specifically rescued p53-V272M in patient-derived primary leukemia cells in single-cell RNA sequencing. Further scanning of 815 frequent p53-missense mutations identified 65 potential PAT-treatable mutations, most of which were temperature sensitive. These results lay the groundwork for repurposing noncovalent antiparasitic antimonials for precisely treating cancers with the 65 p53 mutations.
To compare and analyse the recommendations from clinical practice guidelines (CPGs) on gout worldwide, examine the consistency across CPGs, and provide suggestions to develop and update gout guidelines.We conducted systematic searches in MEDLINE, CBM, GIN, NICE, NGC, WHO, SIGN, DynaMed, UpToDate, and Best Practice databases, from their inception to August 2019 to identify and select CPGs related to gout. We used the search terms "gout", "hyperuricaemia" and "guideline". After two rounds of screening, we included the eligible CPGs of gout according to the pre-defined inclusion and exclusion criteria. Methodological quality of included guidelines was assessed with the AGREE-II instrument. The general characteristics of included guidelines and the recommendations were extracted, and the consistency of recommendations across guidelines was compared and analysed.A total of 15 gout guidelines including 359 recommendations were retrieved. The main topics covered by the recommendations were diagnosis, pharmacologic treatment of gout flares, pharmacologic urate-lowering therapy (ULT) of chronic gouty arthritis, lifestyle interventions, prophylaxis, and management of asymptomatic hyperuricaemia. The results of AGREE-II appraisal showed that only two guidelines achieved high scores (≥50%) in all six domains. There was substantial discrepancy between the guidelines in recommendations covering the value of computed tomography (CT) and x-rays for diagnosis, the use of corticosteroids as a first-line treatment for flare, the use of colchicine, indications for ULT, the use of febuxostat as first-line ULT, the administration of allopurinol, and the timing of ULT initiation.A number of countries are devoting themselves to the development of gout guidelines, but the process of updating guidelines is slower than that suggested by the WHO. Methodological quality is not satisfactory in most guidelines, and recommendations between guidelines are not consistent.
We explored the therapeutic effects of liraglutide combined with metformin and Diamicron in elderly patients with type 2 diabetes mellitus (T2DM) and the effects of this regimen on glucose – lipid metabolism and islet β-cell function. Ninety-two elderly patients with T2DM admitted to our hospital were selected as research participants. Of these, 42 patients treated with metformin and Diamicron were included in the control group (CG) and the remaining 50 patients treated with liraglutide combined with metformin and Diamicron were enrolled in the research group (RG). The total rate of efficacy in RG was significantly higher than that in CG (P < 0.05); however, there was no significant difference in the incidence of adverse reactions (P > 0.05). Moreover, no marked differences were observed in glucose–lipid metabolism indexes and islet β-cell function between the two groups before treatment (P > 0.05). After treatment, fasting plasma glucose, 2-h postprandial blood glucose, and glycosylated hemoglobin levels remarkably decreased in both groups, and these levels were significantly lower in RG than in CG (P < 0.001). Liraglutide combined with metformin and Diamicron can effectively improve glucose – lipid metabolism in elderly patients with T2DM and enhance islet β-cell function with improved clinical efficacy.
Summary: Pharmacologically targeting tumor suppressors necessitates an unprecedented strategy of restoring, rather than conventionally inhibiting, protein function, and p53, the most commonly mutated protein in cancer, has thus remained undruggable. In this study, we address long-standing misconceptions in the field and gaps in the scientific logic for a p53 function–restoration strategy, identify four barriers for drugging mutant p53, and accordingly propose effectiveness evaluation criteria, clinical-translating norms, and prospects for mutant p53 rescue compounds.
Objective: The aim of this review is to evaluate the efficacy of available Purtscher's Retinopathy treatments.Materials and Methods: In order to collect single-case reports, electronic searches were conducted in several databases including PubMed, Embase, Web of Science, China National Knowledge Infrastructure, SinoMed, VIP, and WanFang in the Electronic Theses and Dissertations Center. In VIP and Wanfang, we also traced the references of included articles. Risk of bias was evaluated using a tool adapted from the Cochrane Risk of Bias Tool. Statistical analysis was done in SPSS19.0. Evidence was evaluated and graded with GRADE system.Results: In total, 76 studies were included involving 88 cases and 139 eyes. Serious bias existed in 90% of the included studies. Current treatments for Purtscher's retinopathy included glucocorticoid therapy (63.29%), traditional Chinese medicine therapy (10.13%), glucocorticoid integrative medicine therapy (7.60%), and integrative medicine therapy (6.33%). Patients' eyesight with (56.83%) or without (43.17%) treatment both improved in the follow-up within 1–3 months, 4–6 months, and more than 6 months; however, conditions without treatment became better compared to the treatment groups in after 4–6 months and more than 6 months. All results were "very low" in the GRADE system. None of the studies reported adverse reactions in any patient.Conclusions: Both treatment and no treatment improve vision in Purtscher's retinopathy patients, but the difference between no treatment and glucocorticoid therapy had no statistical significance. The evidence quality for this conclusion was "very low" and had large bias. Further research is required to understand the safety of Purtscher's retinopathy treatment.
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