Developmental arsenic exposure impairs cognition, directly targets DNMT3A, and reduces DNA methylation.

Developmental arsenic exposure has been associated with cognitive deficits in epidemiological studies, but the underlying mechanisms remain poorly understood. Here, we establish a mouse model of developmental arsenic exposure exhibiting deficits of recognition and spatial memory in the offspring. These deficits are associated with genome-wide DNA hypomethylation and abnormal expression of cognition-related genes in the hippocampus. Arsenic atoms directly bind to the cysteine-rich ADD domain of DNA methyltransferase 3A (DNMT3A), triggering ubiquitin- and proteasome-mediated degradation of DNMT3A in different cellular contexts. DNMT3A degradation leads to genome-wide DNA hypomethylation in mouse embryonic fibroblasts but not in non-embryonic cell lines. Treatment with metformin, a first-line antidiabetic agent reported to increase DNA methylation, ameliorates the behavioral deficits and normalizes the aberrant expression of cognition-related genes and DNA methylation in the hippocampus of arsenic-exposed offspring. Our study establishes a DNA hypomethylation effect of developmental arsenic exposure and proposes a potential treatment against cognitive deficits in the offspring of pregnant women in arsenic-contaminated areas.

Recommendations in clinical practice guidelines on gout: systematic review and consistency analysis.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONLUSIONS: 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.

Preclinical study of the antitumor effect of sphingosine-1-phosphate receptor 1 antibody (S1PR1-antibody) against human breast cancer cells.

Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite, which regulates a broad range of physiological and pathophysiological processes. The signaling of S1P via its cell surface receptor S1PR1 has been identified to play an important role in carcinogenesis, cancer growth and survival, and tumor metastasis. In this study, we evaluated whether a monoclonal antibody against S1PR1 (S1PR1-antibody) could impose any effect on cell growth of human breast cancer SK-BR-3 and MDA-MB-231 cells. The S1PR1-antibody exhibited cytostatic effect against both cell lines at the concentration of 4000 ng/mL. Co-administration of 4000 ng/mL of the S1PR1-antibody not only potentiated the cytotoxicity of carboplatin towards the MDA-MB-231 cells but also increased the anti-proliferative effect of S1P towards the SK-BR-3 cells. Furthermore, we showed that co-administration of S1P did not sensitize the SK-BR-3 and MDA-MB-231 cells towards carboplatin.

Characterization of the generic mutant p53-rescue compounds in a broad range of assays.

Dozens of compounds that rescue tumor-associated mutant p53 have been reported. Xiao et al. perform 10 assays to evaluate effectiveness of the mutant p53-rescue compounds side-by-side but do not detect reliable rescue in any assay for the evaluated compounds, except for ATO and its analog PAT.

AcGlcAs: A Novel P53-Targeting Arsenical with Potent Cellular Uptake and Cancer Cell Selectivity.

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-ß-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.

Arsenic trioxide extends survival of Li-Fraumeni syndrome mimicking mouse.

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 p53R279W/+ (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.

Diverse rescue potencies of p53 mutations to ATO are predetermined by intrinsic mutational properties.

Tumor suppressor p53 is inactivated by thousands of heterogeneous mutations in cancer, but their individual druggability remains largely elusive. Here, we evaluated 800 common p53 mutants for their rescue potencies by the representative generic rescue compound arsenic trioxide (ATO) in terms of transactivation activity, cell growth inhibition, and mouse tumor-suppressive activities. The rescue potencies were mainly determined by the solvent accessibility of the mutated residue, a key factor determining whether a mutation is a structural one, and the temperature sensitivity, the ability to reassemble the wild-type DNA binding surface at a low temperature, of the mutant protein. A total of 390 p53 mutants were rescued to varying degrees and thus were termed as type 1, type 2a, and type 2b mutations, depending on the degree to which they were rescued. The 33 type 1 mutations were rescued to amounts comparable to the wild type. In PDX mouse trials, ATO preferentially inhibited growth of tumors harboring type 1 and type 2a mutants. In an ATO clinical trial, we report the first-in-human mutant p53 reactivation in a patient harboring the type 1 V272M mutant. In 47 cell lines derived from 10 cancer types, ATO preferentially and effectively rescued type 1 and type 2a mutants, supporting the broad applicability of ATO in rescuing mutant p53. Our study provides the scientific and clinical communities with a resource of the druggabilities of numerous p53 mutations (www.rescuep53.net) and proposes a conceptual p53-targeting strategy based on individual mutant alleles rather than mutation type.

Advances in Assistive Electronic Device Solutions for Urology.

Recent technology advances have led urology to become one of the leading specialities to utilise novel electronic systems to manage urological ailments. Contemporary bladder management strategies such as urinary catheters can provide a solution but leave the user mentally and physically debilitated. The unique properties of modern electronic devices, i.e., flexibility, stretchability, and biocompatibility, have allowed a plethora of new technologies to emerge. Many novel electronic device solutions in urology have been developed for treating impaired bladder disorders. These disorders include overactive bladder (OAB), underactive bladder (UAB) and other-urinary-affecting disorders (OUAD). This paper reviews common causes and conservative treatment strategies for OAB, UAB and OUAD, discussing the challenges and drawbacks of such treatments. Subsequently, this paper gives insight into clinically approved and research-based electronic advances in urology. Advances in this area cover bladder-stimulation and -monitoring devices, robot-assistive surgery, and bladder and sphincter prosthesis. This study aims to introduce the latest advances in electronic solutions for urology, comparing their advantages and disadvantages, and concluding with open problems for future urological device solutions.

A Prognostic Model for Acute Myeloid Leukemia Based on IL-2/STAT5 Pathway-Related Genes.

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.

Repurposing antiparasitic antimonials to noncovalently rescue temperature-sensitive p53 mutations.

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.

Effect of high-quality nursing on negative psychological moods and quality of life of elderly patients with hypertension.

OBJECTIVE: This study was designed to determine the effect of high-quality nursing on negative psychological moods and quality of life of elderly patients with hypertension. METHODS: In this prospective research, 89 hypertensive elderly patients were divided via random number table method, into a control group (n=44) with routine basic nursing and a research group (n=45) with high-quality nursing. The two groups were compared with respect to psychological status, quality of life, self-management ability and blood pressure control, as well as medication compliance and complications, before and after intervention. RESULTS: Scores of Hamilton anxiety scale (HAMA) and Hamilton depression scale (HAMD) decreased in both groups after intervention, and the reduction was more significant in the research group (both P<0.05). After intervention, scores of various dimensions of generic quality of life inventory-74 (GQOLI-74), self-management ability and Morisky medication compliance scale (MMAS) increased in both groups, and the increase was more evident in the research group (all P<0.05). Systolic blood pressure (SBP) and diastolic blood pressure (DBP) decreased in both groups after intervention, with lower parameters in the research group (both P<0.05). The total incidence of complications in the research group was lower than that in the control group (P<0.05). CONCLUSION: High-quality nursing for elderly hypertensive patients can significantly relieve their negative emotions and improve their quality of life, with a low incidence of complications.

Correlation of CD3+/CD4+, and serum CK-18 fragment levels with glucose and lipid metabolism in elderly type 2 diabetes patients with nonalcoholic fatty liver disease.

OBJECTIVE: To test the correlation of helper T lymphocytes (CD3+/CD4+), and cytokeratin 18 fragment (CK-18) with glucose and lipid metabolism in elderly patients with type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD). METHODS: A total of 108 patients with T2DM hospitalized in Geriatrics, Taizhou People's Hospital from August 2019 to December 2020 were obtained and grouped into' Non-NAFLD group (58 patients) and NAFLD group (50 patients) according to the patients' conditions. Another 50 healthy people were obtained as the control group (CG). The BMI was tested, and the elbow venous blood was collected. The indexes of blood glucose, liver and kidney function (ALT, AST, creatinine, urea nitrogen), blood lipid (triglyceride, total cholesterol, low density lipoprotein cholesterol, high density lipoprotein cholesterol) and blood uric acid were detected. CD3+/CD4+ in elbow venous blood was tested using flow cytometry, and CK-18 was tested using ELISA. Pearson correlation coefficient was applied to test the correlation of CD3+/CD4+, CK-18 with glucose and lipid metabolism in NAFLD group. RESULTS: Compared with the CG, CK-18 in the other two groups were elevated, and CK-18 in the NAFLD group were elevated compared to the Non-NAFLD group. Compared with the CG, CD3+ and CD4+ in the other two groups were decreased, and CD3+ and CD4+ in the NAFLD group decreased compared to the Non-NAFLD group. Correlation analysis revealed that both CD3+ and CD4+ had a negative correlation with FPG, HbA1C, FINS, HOMA-IR, TG, TC, HDL and LDL, while CK-18 had a positive correlation with these indexes. ROC curve revealed that the AUC values of CK-18, CD3+ and CD4+ for NAFLD in elderly T2DM patients were 0.875, 0.867, and 0.871, respectively. Logistic regression analysis revealed that FINS, HOMA-IR, CK-18, CD3+ and CD4+ were all related factors leading to NAFLD in elderly T2DM patients. CONCLUSION: CD3+/CD4+, and CK-18 were correlated with glucose and lipid metabolism in elderly T2DM patients with NAFLD. They may be related to the development of T2DM and NAFLD, and these indexes can be used as biological diagnostic indicators for elderly T2DM patients with NAFLD.

Arsenic Trioxide Rescues Structural p53 Mutations through a Cryptic Allosteric Site.

TP53 is the most frequently mutated gene in cancer, yet these mutations remain therapeutically non-actionable. Major challenges in drugging p53 mutations include heterogeneous mechanisms of inactivation and the absence of broadly applicable allosteric sites. Here we report the identification of small molecules, including arsenic trioxide (ATO), an established agent in treating acute promyelocytic leukemia, as cysteine-reactive compounds that rescue structural p53 mutations. Crystal structures of arsenic-bound p53 mutants reveal a cryptic allosteric site involving three arsenic-coordinating cysteines within the DNA-binding domain, distal to the zinc-binding site. Arsenic binding stabilizes the DNA-binding loop-sheet-helix motif alongside the overall ß-sandwich fold, endowing p53 mutants with thermostability and transcriptional activity. In cellular and mouse xenograft models, ATO reactivates mutant p53 for tumor suppression. Investigation of the 25 most frequent p53 mutations informs patient stratification for clinical exploration. Our results provide a mechanistic basis for repurposing ATO to target p53 mutations for widely applicable yet personalized cancer therapies.

Success of 125I-Seed Treatment in Vulvar Squamous-Cell Carcinoma with Aplastic Anemia: A Case Report.

Vulvar squamous-cell carcinoma (SCC) is a rare disease that occurs mainly in postmenopausal women. Chemo/radiotherapy with or without surgery is the most important modality for treatment of advanced vulvar cancer. A case of vulvar SCC with aplastic anemia was treated using 125I seeds in our department, because surgery and chemotherapy were not possible due to low platelets, leaving radiotherapy as the lone therapeutic option. 125I seeds present an alternative option for treatment of patients with vulvar SCC and local relapse with lymph-node metastasis following previous radiotherapy.

Modeling the effect of vibration on the quality of stirred yogurt during transportation.

When transporting yogurt, vibrations and sharp movements can damage its quality. This study developed a model to connect the changes in yogurt quality with the transportation distance as simulated by the total number of vibrations. Linear regression analysis showed that there was a significant negative correlation between the water holding capacity and hardness of the yogurt over the same transport distance (p < 0.05). The yogurt vibration model was established by combining principal component analysis with a Back-Propagation Artificial Neural Network model. The number of training iterations was 2669, with a correlation coefficient of 0.96611, indicating that the model was reliable. The optimal transportation distance was determined to be within the range from 20 rpm for 8 h to 100 rpm for 4 h.

Probing the Antitumor Mechanism of Solanum nigrum L. Aqueous Extract against Human Breast Cancer MCF7 Cells.

Solanum nigrum L. is one of the major medicinal plants used to treat cancer. However, the functional mechanism of S. nigrum L. extract is still unknown in spite of numerous studies on its active components. In this study, we probed the potential anticancer mechanism of the aqueous extract of S. nigrum L. (AESN) towards human breast cancer cell line MCF7. At a concentration of 10 g/L, AESN caused 43% cytotoxicity, inhibited the migration, and suppressed the activities of hexokinase and pyruvate kinase by about 30% and 40%, respectively, towards the MCF7 cells. RT2-PCR analysis of a panel of 89 caner-related genes identified 13 upregulated and eight downregulated genes (>2-folds) in MCF7 cells upon AESN treatment. Gene ontology (GO) and functional disease ontology (FunDO) analyses show that the antitumor function of S. nigrum L. involves multiple genes and these genes are shared across other diseases or disorders.

Downregulated lncRNA UCA1 acts as ceRNA to adsorb microRNA-498 to repress proliferation, invasion and epithelial mesenchymal transition of esophageal cancer cells by decreasing ZEB2 expression.

Objective: Esophageal cancer (EC) is one of the most general malignant tumors in humans. There were few studies researching the connections between lncRNA UCA1 and EC. This study is to research the effect of lncRNA UCA1 adsorbing microRNA-498 (miR-498) as a ceRNA to regulate ZEB2 expression on epithelial mesenchymal transition (EMT), invasion and migration of EC cells. Methods: UCA1, miR-498 and ZEB2 expression in EC tissues and cells was detected by RT-qPCR or western blot analysis. EC cells were transfected with siRNA-UCA1, miR-498 mimics or their controls to determine cell colony, proliferation, cycle distribution, apoptosis, migration and invasion by colony formation assay, CCK-8 assay, flow cytometry, and Transwell assay, respectively. The protein expression of PCNA, c-Myc, E-cadherin, N-cadherin, MMP-2 and MMP-9 was detected by Western blot analysis. The growth rate and weight of transplanted tumor in nude mice were observed. Results: There were overly expressed UCA1 and ZEB2 and lowly expressed miR-498 in EC tissues and cells. LncRNA UCA1 acted as ceRNA to inhibit miR-498 expression and thereby increasing ZEB2 expression. With down-regulated UCA1 and up-regulated miR-498, ZEB2 expression, cell proliferation, colony formation, invasion, migration ability, EMT, tumor growth rate and weight in nude mice were apparently reduced. Conclusion: This study demonstrates that inhibited UCA1 up-regulated miR-498 and down-regulated ZEB2, thereby repressing proliferation activity, invasion, migration, and EMT of EC cells.

Efficacy of Purtscher's Retinopathy Treatments: A Systematic Review.

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.