Drugging p53: Barriers, Criteria, and Prospects.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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).

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.

Success of I-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 I seeds in our department, because surgery and chemotherapy were not possible due to low platelets, leaving radiotherapy as the lone therapeutic option.

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 ( < 0.

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".

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

L. is one of the major medicinal plants used to treat cancer. However, the functional mechanism of L.

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.

: 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.

Preclinical study of the antitumor effect of sphingosine-1-phosphate receptor 1 antibody (S1PR-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 S1PR 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 S1PR (S1PR-antibody) could impose any effect on cell growth of human breast cancer SK-BR-3 and MDA-MB-231 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.