Design, synthesis and biological evaluation of quinazoline SOS1 inhibitors.

Son of sevenless 1 (SOS1) is a vital guanine nucleotide exchange factor (GEFs) that activates rat sarcoma (Ras) protein in cells. SOS1 inhibitors can effectively inhibit the expression of downstream signaling pathways by blocking the interaction between SOS1 and Ras protein. Here, we designed and synthesized a series of quinazoline-based compounds, and conducted subsequent evaluations of their biological activities. Among them, the comparable compounds I-2 (IC50 = 20 nM, against SOS1) I-5 (IC50 = 18 nM, against SOS1) and I-10 (IC50 = 8.5 nM, against SOS1) have kinase activity equivalent to BAY-293 (IC50 = 6.6 nM, against SOS1), and I-10 also has cell activity equivalent to BAY-293, providing a theoretical reference for subsequent related researches on SOS1 inhibitors.

Pyrizolo[1,5-a]pyrimidine derivatives of the second-generation TRK inhibitor: Design, synthesis and biological evaluation.

As a receptor tyrosine kinase (RTK), tropomyosin receptor kinase (Trk) is a key drug target in solid tumors. However, the use of the First-generation Trk inhibitors was greatly restricted due to mutant drug resistance. Fortunately, the emergence of the Second-generation of Trk inhibitors has brought an effective solution to this mutant resistance, such as TPX-0005 (Repotrectinib). Here, we reported a series of pyrizolo[1,5-a]pyrimidine derivatives as the second-generation Trk inhibitors, and carried out the subsequent biological activity evaluation. Among them, the best compound 14h (IC50 = 1.40, 1.80 nM, against TrkA, TrkAG595R, respectively) and 14j (IC50 = 0.86, 6.92 nM, against TrkA, TrkAG595R, respectively) has a kinase activity comparable to TPX-0005, and 14j (IC50 = 350 nM against ALK) has a higher selectivity of Trk inhibition than TPX-0005, which may be of great significance for reducing toxicity.

Design and synthesis of the novel oleanolic acid-cinnamic acid ester derivatives and glycyrrhetinic acid-cinnamic acid ester derivatives with cytotoxic properties.

Oleanolic acid (OA) and glycyrrhetinic acid (GA) are natural products with anticancer effects. Cinnamic acid (CA) and its derivatives also exhibited certain anticancer activity. In order to improve the anticancer activity of OA and GA, we designed and synthesized a series of novel OA-CA ester derivatives and GA-CA ester derivatives by using molecular hybridization approach. The 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) assay was used to assess their in vitro cytotoxicity on three cell lines (HeLa (cervical cancer), MCF-7 (breast cancer) and L-O2 (a normal hepatic cell)). Among the evaluated compounds, 3o presented the strongest selective cytotoxicity on HeLa cells (IC50 = 1.35 µM) and showed no inhibitory activity against MCF-7 cells (IC50 > 100 µM) and L-O2 cells (IC50 > 100 µM), and 3e presented the strongest selective inhibition of the MCF-7 cells (IC50 = 1.79 µM). What's more, compound 2d also showed very strong selective inhibitory activity against HeLa cells (IC50 = 1.55 µM). The further research using Hoechst 33342, AO/EB dual-staining, flow cytometric analysis and DCFH-DA fluorescent dye staining assay presented that 2d and 3o could induce HeLa cells apoptosis and autophagy.

Phytoextraction potential of soils highly polluted with cadmium using the cadmium/zinc hyperaccumulator Sedum plumbizincicola.

A three-crop repeated phytoextraction experiment was conducted using four soils (S1-S4) highly polluted with cadmium (Cd) and two enhanced phytoextraction pot experiments using the most polluted soil (S4) to investigate the feasibility of Cd removal from highly polluted soils using the Cd/zinc (Zn)-hyperaccumulator Sedum plumbizincicola. Shoot biomass showed no significant difference during the repeated phytoextraction experiment on the four test soils and shoot Cd content showed a decreasing trend with the three consecutive crops in soils S1, S2, and S3 but not in soil S4. The Cd removal rates in soils S1, S2, S3, and S4 were 84.5, 81.6, 45.3, and 32.4%, respectively. Rice straw application increased Cd extraction efficiency by 42.6% but the addition of ethylenediaminedisuccinic acid, biochar or nitrogen had no effect on Cd remediation. Shoot Cd content increased significantly (1.57 and 1.71 times, respectively) at low (S0-1) and high (S0-2) sulfur addition rates. Soil extractable-Cd in S0-1 after the experiment showed no significant difference from the control but was 2.43 times higher in S0-2 than in the control. These results indicate that S. plumbizincicola shows good prospects for the phytoextraction of Cd from highly polluted soils and that the process can be enhanced by adding straw and/or sulfur to the soil.

Parent SMART: Effects of residential treatment and an adjunctive parenting intervention on behavioral health services utilization.

INTRODUCTION: Scant research has examined the impact of residential treatment on adolescent behavioral healthcare utilization post-discharge, even though behavioral healthcare utilization is major driver of healthcare costs. In the primary analyses of a pilot randomized trial, Parent SMART - a technology-assisted intervention for parents of adolescents in residential treatment - was found to improve parental monitoring and parent-adolescent communication, reduce adolescent drinking, and reduce adolescent school-related problems, relative to residential treatment as usual (TAU). The goal of this secondary analysis of the pilot randomized trial was to assess the effects of residential treatment and the adjunctive Parent SMART intervention on both the amount and type of subsequent behavioral healthcare utilization. METHOD: The study randomized sixty-one parent-adolescent dyads to residential TAU (n = 31) or residential TAU plus Parent SMART (n = 30). Of the 61 dyads, 37 were recruited from a short-term residential facility and 24 were recruited from a long-term facility. Adolescents completed a structured clinical interview and self-reported their behavioral health-related visits to the emergency department, nights in residential/inpatient, and outpatient visits over the past 90 days, at baseline, 12-, and 24-weeks post-discharge. Generalized linear mixed models (GLMMs) examined both linear and non-linear (pre- to post- residential treatment) trends, pooled, and stratified by residential facility to examine behavioral health service utilization. RESULTS: Both the linear and pre-post GLMMs revealed that behavioral health-related emergency department visits and residential/inpatient nights decreased across both residential facilities. GLMMs estimating change from the pre- to post period indicated that outpatient visits increased across both facilities. There were no significant effects of the Parent SMART adjunctive intervention in GLMMs, though bivariate tests and the direction of effects signaled that Parent SMART was associated with more nights of residential/inpatient utilization. CONCLUSION: Residential substance use treatment may reduce adolescents' subsequent utilization of costly behavioral healthcare services such as emergency department visits and residential/inpatient nights, while increasing utilization of outpatient services. Parent SMART was not associated with significant changes in behavioral healthcare utilization, but the pattern of results was consistent with prior literature suggesting that stronger parenting skills are associated with greater utilization of non-emergency services.

Refining Parent SMART: User feedback to optimize a multi-modal intervention.

INTRODUCTION: The continuing care period following residential substance use treatment is a time when adolescents are at especially high risk for relapse, yet few families engage in traditional office-based care. Parent SMART (Substance Misuse among Adolescents in Residential Treatment) is a multi-component continuing care intervention for parents that combines three digital health technologies - an "off the shelf" online parenting program, daily phone notifications, and an online parent networking forum - with support from a parent coach. The current study solicited both qualitative and quantitative user feedback about Parent SMART to ensure responsivity to user preferences, refinement, and continuous improvement of the intervention. METHODS: Exit interviews were conducted with 30 parents who received Parent SMART, which includes (1) a parent networking forum; (2) daily text messages reminders of skills, (3) an "off-the-shelf" online parenting program; and (4) in-person or telehealth parent coaching sessions. The study collected qualitative feedback using semi-structured interviews and obtained quantitative feedback via a series of ratings of each Parent SMART component on a 5-point Likert scale administered at each follow-up assessment. RESULTS: Quantitative feedback suggest that parents rated all four elements of Parent SMART as easy to use. Qualitative feedback revealed that parents valued several aspects of Parent SMART including the brevity and structure of the intervention elements, the reminders to use parenting skills, and the sense of social connectedness fostered by different components. Recommended refinements included a number of strategies to enhance personalization and ease of navigation. CONCLUSIONS: Parent feedback informed enhancements to the Parent SMART intervention prior to implementation in a larger, ongoing pragmatic effectiveness trial. The current study serves as a model for applying a staged person-centered approach and eliciting both quantitative and qualitative feedback to refine digital health technologies.

Development of Peptide Paratope Mimics Derived from the Anti-ROR1 Antibody and Long-Acting Peptide-Drug Conjugates for Targeted Cancer Therapy.

Antibody-based targeted therapy in cancer faces a challenge due to uneven antibody distribution in solid tumors, hindering effective drug delivery. We addressed this by developing peptide mimetics with nanomolar-range affinity for Receptor Tyrosine Kinase-Like Orphan Receptor 1 (ROR1) using computational methods. These peptides showed both specific targeting and deep penetration in vitro and in vivo. Additionally, we created peptide-drug conjugates (PDCs) by linking targeting peptides to toxin drugs via various linkers and enhancing their in vivo half-life with fatty side chains for albumin binding. The antitumor candidate II-3 displayed exceptional affinity (KD = 1.72 × 10-9 M), internalization efficiency, anticancer potency (IC50 = 0.015 ± 0.002 µM), and pharmacokinetics (t1/2 = 2.6 h), showcasing a rational approach for designing PDCs with favorable tissue distribution and strong tumor penetration.

The relationship between obsessive-compulsive disorder symptom subtypes and social adjustment.

Background: Although it has been widely established that poor social functioning is a characteristic of obsessive-compulsive disorder (OCD), little research has examined the relationship between OCD symptom subtypes and domains of social functioning. Thus, the present study sought to examine the specific ways in which impairment in social adjustment occurs in each symptom subtype of OCD. Methods: A total of 325 adult participants with a primary diagnosis of OCD were included in the study. Hierarchical linear regressions were used to compare the extent to which OCD symptom subtypes predicted social adjustment domains after controlling for OCD and depression severity. Results: Hoarding was shown to be significantly associated with work functioning. Whereas both contamination and symmetry subtypes were significantly associated with social functioning, only the contamination subtype was associated with functioning within the family unit. The symptom subtypes of doubt and taboo thoughts were not significantly associated with any domains of social adjustment. Conclusion: Consistent with previous research, our results suggest a differential impact of OCD symptom subtypes on social adjustment. They offer important implications for the specific domains to target in treatment for different symptom subtypes.

An updated patent review of GPR40/ FFAR1 modulators (2020 - present).

INTRODUCTION: Free fatty acid receptor 1 (FFAR1) is a potential therapeutic target for type 2 diabetes mellitus (T2DM) because it could clinically stimulate insulin release in a glucose-dependent manner without inducing hypoglycemia. In both the pharmaceutical industry and academic community, FFAR1 agonists have attracted considerable attention. AREAS COVERED: The review presents a patent overview of FFAR1 modulators in 2020-2023, along with chemical structures, the biological activities and therapeutic applications of the representative compounds. Our patent survey used the major electronic databases, namely SciFinder, and Web of Science and Innojoy. EXPERT OPINION: Although FFAR1 agonists exhibit outstanding advantages, they are also associated with significant challenges. At present, reducing the molecular weight and overall lipophilicity and developing tissue-specific FFAR1 agonists may be the strategies for alleviating hepatotoxicity.

Optimized Projection and Fisher Discriminative Dictionary Learning for EEG Emotion Recognition.

Electroencephalogram (EEG)-based emotion recognition (ER) has drawn increasing attention in the brain-computer interface (BCI) due to its great potentials in human-machine interaction applications. According to the characteristics of rhythms, EEG signals usually can be divided into several different frequency bands. Most existing methods concatenate multiple frequency band features together and treat them as a single feature vector. However, it is often difficult to utilize band-specific information in this way. In this study, an optimized projection and Fisher discriminative dictionary learning (OPFDDL) model is proposed to efficiently exploit the specific discriminative information of each frequency band. Using subspace projection technology, EEG signals of all frequency bands are projected into a subspace. The shared dictionary is learned in the projection subspace such that the specific discriminative information of each frequency band can be utilized efficiently, and simultaneously, the shared discriminative information among multiple bands can be preserved. In particular, the Fisher discrimination criterion is imposed on the atoms to minimize within-class sparse reconstruction error and maximize between-class sparse reconstruction error. Then, an alternating optimization algorithm is developed to obtain the optimal solution for the projection matrix and the dictionary. Experimental results on two EEG-based ER datasets show that this model can achieve remarkable results and demonstrate its effectiveness.

Brain Tumor MR Image Classification Using Convolutional Dictionary Learning With Local Constraint.

Brain tumor image classification is an important part of medical image processing. It assists doctors to make accurate diagnosis and treatment plans. Magnetic resonance (MR) imaging is one of the main imaging tools to study brain tissue. In this article, we propose a brain tumor MR image classification method using convolutional dictionary learning with local constraint (CDLLC). Our method integrates the multi-layer dictionary learning into a convolutional neural network (CNN) structure to explore the discriminative information. Encoding a vector on a dictionary can be considered as multiple projections into new spaces, and the obtained coding vector is sparse. Meanwhile, in order to preserve the geometric structure of data and utilize the supervised information, we construct the local constraint of atoms through a supervised k-nearest neighbor graph, so that the discrimination of the obtained dictionary is strong. To solve the proposed problem, an efficient iterative optimization scheme is designed. In the experiment, two clinically relevant multi-class classification tasks on the Cheng and REMBRANDT datasets are designed. The evaluation results demonstrate that our method is effective for brain tumor MR image classification, and it could outperform other comparisons.