Guanidino quinazolines and pyrimidines promote readthrough of premature termination codons in cells with native nonsense mutations.

Using small molecules to induce readthrough of premature termination codons is a promising therapeutic approach to treating genetic diseases and cancers caused by nonsense mutations, as evidenced by the widespread use of ataluren to treat nonsense mutation Duchene muscular dystrophy. Herein we describe a series of novel guanidino quinazoline and pyrimidine scaffolds that induce readthrough in both HDQ-P1 mammary carcinoma cells and mdx myotubes. Linkage of basic, tertiary amines with aliphatic, hydrophobic substituents to the terminal guanidine nitrogen of these scaffolds led to significant potency increases. Further potency gains were achieved by flanking the pyrimidine ring with hydrophobic substituents, inducing readthrough at concentrations as low as 120 nM and demonstrating the potential of these compounds to be used either in combination with ataluren or as stand-alone therapeutics.

Nickel-promoted oxidative domino Csp3-H/N-H bond double-isocyanide insertion reaction to construct pyrrolin-2-ones.

The first nickel-catalyzed oxidative domino Csp3-H/N-H double isocyanide insertion reaction of acetamides with isocyanides has been developed for the synthesis of pyrrolin-2-one derivatives. A wide range of acetamides bearing various functional groups are compatible with this reaction system by utilizing Ni(acac)2 as a catalyst. In this transformation, isocyanide could serve as a C1 connector and insert into the inactive Csp3-H bond, representing an effective way to construct heterocycles.

Sarcopenia predicts prognosis of patients with renal cell carcinoma: A systematic review and meta-analysis.

Sarcopenia, a concept reflecting the loss of skeletal muscle mass, was reported to be associated with the prognosis of several tumors. However, the prognostic value of sarcopenia in patients with renal cancer remains unclear. We carried out this meta-analysis and systematic review to evaluate the prognostic value of sarcopenia in patients with renal cell carcinomas. We comprehensively searched PubMed, Embase, and Cochrane Library from inception to December 2018. Hazard ratio (HR) and 95% confidence interval (CI) were pooled together. A total of 5 studies consisting of 771 patients were enrolled in this quantitative analysis, 347 (45.0%) of which had sarcopenia. Patients with sarcopenia had a worse OS compared with those without sarcopenia (HR=1.76; 95%CI, 1.35-2.31; P<0.001). In the subgroup of patients with localized and advanced/metastatic diseases, sarcopenia was also associated with poor OS (HR=1.48, P=0.039; HR=2.14, P<0.001; respectively). With a limited sample size, we did not observe difference of PFS between two groups (HR=1.56, 95% CI, 0.69-3.50, P=0.282). In the present meta-analysis, we observed that patients with sarcopenia had a worse OS compared with those without sarcopenia in RCC. Larger, preferably prospective studies, are needed to confirm and update our findings.

Positioning Locality Using Cognitive Directions Based on Indoor Landmark Reference System.

Locality descriptions are generally communicated using reference objects and spatial relations that reflect human spatial cognition. However, uncertainty is inevitable in locality descriptions. Positioning locality with locality description, with a mapping mechanism between the qualitative and quantitative data, is one of the important research issues in next-generation geographic information sciences. Spatial relations play an important role in the uncertainty of positioning locality. In indoor landmark reference systems, the nearest landmarks can be selected when describing localities by using direction relations indoors. By using probability operation, we combine a set of uncertainties, that is, near and direction relations to positioning locality. Some definitions are proposed from cognitive and computational perspectives. We evaluate the performance of our method through indoor cognitive experiments. Test results demonstrate that a positioning accuracy of 3.55 m can be achieved with the semantically derived direction relationships in indoor landmark reference systems.

4-Hydroxy-2-pyridones: Discovery and evaluation of a novel class of antibacterial agents targeting DNA synthesis.

The continued emergence of bacteria resistant to current standard of care antibiotics presents a rapidly growing threat to public health. New chemical entities (NCEs) to treat these serious infections are desperately needed. Herein we report the discovery, synthesis, SAR and in vivo efficacy of a novel series of 4-hydroxy-2-pyridones exhibiting activity against Gram-negative pathogens. Compound 1c, derived from the N-debenzylation of 1b, preferentially inhibits bacterial DNA synthesis as determined by standard macromolecular synthesis assays. The structural features of the 4-hydroxy-2-pyridone scaffold required for antibacterial activity were explored and compound 6q, identified through further optimization of the series, had an MIC90 value of 8 µg/mL against a panel of highly resistant strains of E. coli. In a murine septicemia model, compound 6q exhibited a PD50 of 8 mg/kg in mice infected with a lethal dose of E. coli. This novel series of 4-hydroxy-2-pyridones serves as an excellent starting point for the identification of NCEs treating Gram-negative infections.

SAR exploration at the C-3 position of tetrahydro-ß-carboline sstr3 antagonists.

MK-4256, a tetrahydro-ß-carboline sstr3 antagonist, was discontinued due to a cardiovascular (CV) adverse effect observed in dogs. Additional investigations revealed that the CV liability (QTc prolongation) was caused by the hERG off-target activity of MK-4256 and was not due to sstr3 antagonism. In this Letter, we describe our extensive SAR effort at the C3 position of the tetrahydro-ß-carboline structure. This effort resulted in identification of 5-fluoro-pyridin-2-yl as the optimal substituent on the imidazole ring to balance sstr3 activity and the hERG off-target liability.

Cascaded-TOARNet: A cascaded framework based on mixed attention and multiscale information for thoracic OARs segmentation.

BACKGROUND: Accurate and automated segmentation of thoracic organs-at-risk (OARs) is critical for radiotherapy treatment planning of thoracic cancers. However, this has remained a challenging task for four major reasons: (1) thoracic OARs have diverse morphologies; (2) thoracic OARs have low contrast with the background; (3) boundaries of thoracic OARs are blurry; (4) class imbalance issue caused by small organs. PURPOSE: To overcome the above challenges and achieve accurate and automated segmentation of thoracic OARs on thoracic CT. METHODS: A novel cascaded framework based on mixed attention and multiscale information for thoracic OARs segmentation, called Cascaded-TOARNet. This cascaded framework comprises two stages: localization and segmentation. During the localization stage, TOARNet locates each organ to crop the regions of interest (ROIs). During the segmentation stage, TOARNet accurately segments the ROIs, and the segmentation results are merged into a complete result. RESULTS: We evaluated our proposed method and other common segmentation methods on two public datasets: the AAPM Thoracic Auto-Segmentation Challenge dataset and the Segmentation of Thoracic Organs at Risk (SegTHOR) dataset. Our method demonstrated superior performance, achieving a mean Dice score of 92.6% on the SegTHOR dataset and 90.8% on the AAPM dataset. CONCLUSIONS: This segmentation method holds great promise as an essential tool for enhancing the efficiency of thoracic radiotherapy planning.

[Dynamic study of correspondence of prescription and syndrome system: a system with combination of disease and syndrome, correspondence of prescription and syndrome].

By analyzing the present situation and existing problems in the material bases of syndrome and Chinese materia medica, we think that either syndrome or prescription is a complex whole system. Studies of the material bases of syndrome and prescription should be established on the combination of disease and syndrome, following the holistic and dynamic principles. Departure from the holistic principle, separating the syndrome from the prescription, ignoring the dynamic concepts may possibly lose the features and advantages of syndrome typing and Chinese medicine preparations. The metabolomics research bridges the study of prescription and syndrome. It is of great significance in finding out the agreeable point of disease-syndrome-efficacy, establishing a dynamic research method with combination of disease and syndrome, correspondence of prescription and syndrome.

Advances in AR-targeting chimeras: a case study of proteolysis-targeting chimeras from bench to bedside.

Proteolysis-targeting chimera (PROTAC) is an emerging revolutionary technology that promotes degradation of target proteins by proteolysis. AR-targeting PROTACs marked many milestones in the history of PROTAC development. In this review, the author discusses the development of AR-targeting PROTACs over the last two decades. Also included in this focused review are medicinal chemistry strategies, pharmacokinetic profiles and clinical development. Taking AR targeting PROTACs for case study, this review provides a target specific overview of how PROTAC technology has advanced from a revolutionary concept and achieved proof of concept leading to drug candidates that benefit patients.

D-dimer/fibrinogen ratio for the prediction of progressive hemorrhagic injury after traumatic brain injury.

BACKGROUND: Progressive hemorrhagic injury (PHI) greatly affects prognosis of traumatic brain injury (TBI). D-dimer/fibrinogen ratio (D/F ratio) may be a potential predictor for venous thromboembolism. This study sought to describe and evaluate any relationship between D/F ratio and PHI after TBI. METHODS: This retrospective study included a cohort of 192 TBI patients. Plasma D-dimer and fibrinogen were measured, and subsequently D/F ratio was calculated. Multivariate logistic regression analysis was applied to identify predictors of PHI. Receiver operating characteristic (ROC) curve was conFig.d to analyze predictive capability for PHI. RESULTS: A total of 43 patients (22.4%) experienced PHI. Both Glasgow coma scale (GCS) score (odds ratio [OR], 0.565; 95% CI, 0.464-0.689) and D/F ratio (OR, 4.026; 95% CI, 2.219-7.305) were the two independent predictor for PHI. Area under ROC curve (AUC) of D/F ratio was similar to that of GCS score (AUC, 0.816; 95% CI, 0.754-0.868 vs. AUC, 0.834; 95% CI, 0.773-0.883; P = 0.699). Moreover, D/F ratio significantly improved AUC of GCS score to 0.928 (95% CI, 0.881-0.960; P < 0.001). CONCLUSIONS: D/F ratio was strongly predictive of PHI in the studied cohort and, thereby should be considered in the clinical management of TBI patients.