Natural killer cell-based signature: Prognostic analysis in head and neck squamous cell carcinoma.

BACKGROUND: Head and neck squamous cell carcinoma (HNSC) is a challenging cancer with significant clinical implications. Natural killer (NK) cells have emerged as important players in tumor immunosurveillance, yet their role and potential as prognostic biomarkers in HNSC remain unclear. METHODS: Quantitative analysis using multiple algorithms identified FCRL1, KIR3DL2 and ZNF541 as molecules significantly associated with local NK cell infiltration and patient survival. A prognostic model based on these molecules demonstrated robust predictive performance. RESULTS: Analysis of high- and low-risk patient groups revealed distinct differences in the tumor microenvironment, indicating an inhibitory immune microenvironment in high-risk patients. Notably, low-risk patients exhibited potential sensitivity to immunotherapy and showed favorable responses to specific drugs such as axitinib, methotrexate, rapamycin and vorinostat. NK cells, important effectors of the innate immune response, were found to play a crucial role in HNSC immunity. The present study provides valuable insights into the correlation between FCRL1, KIR3DL2, ZNF541 and NK cell infiltration, paving the way for future investigations into their roles in HNSC. Activation of NOTCH signaling, MYC targets, DNA repair, E2F targets, epithelial-mesenchymal transition, G2M checkpoint and mitotic spindle pathways in high-risk patients suggests their involvement in disease progression and poor prognosis. CONCLUSIONS: The present study reveals the significance of NK cells in HNSC and their potential as prognostic biomarkers. The CFKZ score offers a promising approach for predicting patient outcomes and guiding personalized treatment decisions in HNSC. These findings contribute to our understanding of HNSC immunobiology and hold implications for precision medicine in HNSC management.

Multiple Equine Therapies for the Treatment of Gross Motor Function in Children with Cerebral Palsy: A Systematic Review.

PURPOSE: This study aimed to evaluate the impact of three equine therapy approaches on gross motor function in children with cerebral palsy. METHODS: The studies were retrieved from PubMed, Web of Science, Science Direct, and the Cochrane Library, in accordance with the style commonly found in scientific journal publications:(1) peer-reviewed articles written in English; (2) experimental or quasi-experimental; (3) three Equine Therapy Interventions as experiment's independent variable; (4) children with cerebral palsy; and (5) measurement of outcomes related to Gross Motor Function. RESULTS: The study examined 596 patients with cerebral palsy, whose average age was 8.03 years. The three types of horse therapy interventions had a significant impact on gross motor function in children with cerebral palsy (SMD = 0.19, 95% CI 0.02-0.36, p = 0.031). Additionally, the interventions positively affected dimensions C (SMD = 0.31, 95% CI 0.00-0.62, p = 0.05), D (SMD = 0.30, 95% CI 0.06-0.56, p = 0.017), and B (SMD = 0.72, 95% CI 0.10-1.34, p = 0.023). The Gross Motor Function Measure (GMFM) consists of 88 or 66 items, which are divided into five functional dimensions: GMFM-A (lying down and rolling), GMFM-B (sitting), GMFM-C (crawling and kneeling), GMFM-D (standing), and GMFM-E (walking, running, and jumping). Each subsection of the GMFM can be used separately to evaluate motor changes in a specific dimension of interest. Subgroup analysis revealed that different horse-assisted therapy approaches, types of cerebral palsy, exercise duration, frequency, and intervention periods are important factors influencing treatment outcomes. CONCLUSION: The intervention period ranged from 8 to 12 weeks, with session durations of 30 to 45 minutes, 2 to 3 times per week. Equine-assisted therapy (EAT) demonstrated significant improvements in the overall gross motor function score, Dimension B, Dimension C, and Dimension D among children with cerebral palsy. The most effective treatment is provided by Equine-Assisted Therapy, followed by Horseback Riding Simulator (HRS). Due to its economic practicality, HRS plays an irreplaceable role. CLINICAL EVIDENCE: Equine-Assisted Therapy (EAT) demonstrates the most effective treatment outcomes, suggesting that hospitals and healthcare professionals can form specialized teams to provide rehabilitation guidance. 2. Within equine-assisted therapy, Horseback Riding Simulator (HRS) exhibits treatment efficacy second only to Equine-Assisted Therapy (EAT), making it a cost-effective and practical option worthy of promotion and utilization among healthcare institutions and professionals. 3. In equine-assisted therapy, Therapeutic Horseback Riding (THR) holds certain value in rehabilitation due to its engaging and practical nature.

Discovery of 1-arylpyrrolidone derivatives as potent p53-MDM2 inhibitors based on molecule fusing strategy.

Introducing an aryl moiety to our previous pyrrolidone scaffold by molecule fusing strategy afforded two sets of isopropylether-pyrrolidone and α-phenylethylamine-pyrrolidone derivatives. Two novel compounds 8b and 8g of the latter serial showed potent p53-MDM2 inhibitory activities with Ki values of 90nM which were three-time higher than that of the parent compound. We also confirmed compound 8b can activate p53 proteins in lung cancer A549 cells. The results offered us valuable information for further lead optimization.

Design, synthesis and biological evaluation of sulfamide and triazole benzodiazepines as novel p53-MDM2 inhibitors.

A series of sulfamide and triazole benzodiazepines were obtained with the principle of bioisosterism. The p53-murine double minute 2 (MDM2) inhibitory activity and in vitro antitumor activity were evaluated. Most of the novel benzodiazepines exhibited moderate protein binding inhibitory activity. Particularly, triazole benzodiazepines showed good inhibitory activity and antitumor potency. Compound 16 had promising antitumor activity against the U-2 OS human osteosarcoma cell line with an IC50 value of 4.17 µM, which was much better than that of nutlin-3. The molecular docking model also successfully predicted that this class of compounds mimicked the three critical residues of p53 binding to MDM2.

Synthesis and biological assays of 9-(acylamino) homocamptothecins as DNA topoisomerase I inhibitors.

In an effort to improve the stability of homocamptothecin and reduce the toxicity, novel homocamptothecin analogs with acylamino groups at C(9) were designed and synthesized. The cytotoxic activities of all the synthetic compounds against three cancer cell lines were evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay, and irinotecan was used as reference compound. Compound 7c with a piperidinylacetamido group and 10a with phenylacetamido group at C(9) showed potent activities both in vitro and in vivo. In addition, they also revealed remarkable topoisomerase I inhibitions which were exhibited with well-established bonds with amino acid residues Arg364 and Asp533 in the active pocket. On the basis of the biological activities, 7c and 10a would be potential candidates for further studies.

Artificial Intelligence for Classifying and Archiving Orthodontic Images.

One of the main requirements for orthodontic treatment is continuous image acquisition. However, the conventional system of orthodontic image acquisition, which includes manual classification, archiving, and monitoring, is time-consuming and prone to errors caused by fatigue. This study is aimed at developing an effective artificial intelligence tool for the automated classification and monitoring of orthodontic images. We comprehensively evaluated the ability of a deep learning model based on Deep hidden IDentity (DeepID) features to classify and archive photographs and radiographs. This evaluation was performed using a dataset of >14,000 images encompassing all 14 categories of orthodontic images. Our model automatically classified orthodontic images in an external dataset with an accuracy of 0.994 and macro area under the curve of 1.00 in 0.08 min. This was 236 times faster than a human expert (18.93 min). Furthermore, human experts with deep learning assistance required an average of 8.10 min to classify images in the external dataset, much shorter than 18.93 min. We conclude that deep learning can improve the accuracy, speed, and efficiency of classification, archiving, and monitoring of orthodontic images.

Double-edged swords as cancer therapeutics: novel, orally active, small molecules simultaneously inhibit p53-MDM2 interaction and the NF-κB pathway.

Simultaneous inactivation of p53 and hyperactivation of nuclear factor-κB (NF-κB) is a common occurrence in human cancer. Currently, antitumor agents are being designed to selectively activate p53 or inhibit NF-κB. However, there is no concerted effort yet to deliberately design inhibitors that can simultaneously do both. This paper provided a proof-of-concept study that p53-MDM2 interaction and NF-κB pathway can be simultaneously targeted by a small-molecule inhibitor. A series of pyrrolo[3,4-c]pyrazole derivatives were rationally designed and synthesized as the first-in-class inhibitors of p53-MDM2 interaction and NF-κB pathway. Most of the compounds were identified to possess nanomolar p53-MDM2 inhibitory activity. Compounds 5q and 5s suppressed NF-κB activation through inhibition of IκBα phosphorylation and elevation of the cytoplasmic levels of p65 and phosphorylated IKKα/ß. Biochemical assay for the kinases also supported the fact that pyrrolo[3,4-c]pyrazole compounds directly targeted the NF-κB pathway. In addition, four compounds (5j, 5q, 5s, and 5u) effectively inhibited tumor growth in the A549 xenograft model. Further pharmacokinetic study revealed that compound 5q exhibited excellent oral bioavailability (72.9%).

Synthesis and preliminary bioevaluation of novel E-ring modified acetal analog of camptothecin as cytotoxic agents.

In an effort to improve the metabolic stability of the E-ring and decrease the toxicity of camptothecin (CPT), a novel cytotoxic acetal analog with 21-alkoxy groups was designed and synthesized. The preliminary results revealed that this class of compounds showed superior antiproliferative activity in vitro and moderate in vivo activity, while their topoisomerase I (Topo I) inhibitory activity was weakened significantly. The implications of these results within the current understanding of the structure-activity relationship of camptothecin are analyzed in detail. The obtained information provides insight into the role of the 21-carbonyl group in the binding of CPT to Topo I-DNA complex.

New tricks for an old natural product: discovery of highly potent evodiamine derivatives as novel antitumor agents by systemic structure-activity relationship analysis and biological evaluations.

Evodiamine is a quinazolinocarboline alkaloid isolated from the fruits of traditional Chinese herb Evodiae fructus . Previously, we identified N13-substituted evodiamine derivatives as potent topoisomerase I inhibitors by structure-based virtual screening and lead optimization. Herein, a library of novel evodiamine derivatives bearing various substitutions or modified scaffold were synthesized. Among them, a number of evodiamine derivatives showed substantial increase of the antitumor activity, with GI(50) values lower than 3 nM. Moreover, these highly potent compounds can effectively induce the apoptosis of A549 cells. Interestingly, further computational target prediction calculations in combination with biological assays confirmed that the evodiamine derivatives acted by dual inhibition of topoisomerases I and II. Moreover, several hydroxyl derivatives, such as 10-hydroxyl evodiamine (10j) and 3-amino-10-hydroxyl evodiamine (18g), also showed good in vivo antitumor efficacy and low toxicity at the dose of 1 mg/kg or 2 mg/kg. They represent promising candidates for the development of novel antitumor agents.

Discovery, synthesis, and biological evaluation of orally active pyrrolidone derivatives as novel inhibitors of p53-MDM2 protein-protein interaction.

The p53-MDM2 interaction has been proved to be a valuable target to develop effective antitumor agents. Novel p53-MDM2 inhibitors bearing pyrrolidone scaffolds were successfully identified by structure-based design. The nanomolar inhibitor 5 possessed good p53-MDM2 inhibitory activity (K(i) = 780 nM) due to its hydrophobic and hydrogen bonding interactions with MDM2. Further hit optimization led to the discovery of a number of highly potent pyrrolidone derivatives with improved p53-MDM2 inhibitory activity and in vitro antiproliferative potency. Compounds 41 (K(i) = 260.0 nM) and 60a (K(i) = 150.0 nM) showed good and selective activity against tumor cells with deleted p53. In addition, these two compounds also effectively inhibited the tumor growth in the A549 xenograft model. Interestingly, compound 41 was proved to be a potent MDM2/MDMX dual inhibitor. The novel pyrrolidone p53-MDM2 inhibitors represent promising lead structures for the development of novel antitumor agents.

Structure-activity relationship and antitumor activity of thio-benzodiazepines as p53-MDM2 protein-protein interaction inhibitors.

In order to discuss the structure-activity relationship (SAR) of the thio-benzodiazepine compounds which showed excellent activity against p53-MDM2 protein-protein interaction, we designed and synthesized twenty compounds with electrophilic and nucleophilic groups on the benzene ring. Among them, compounds 8i (K(i) = 91 nM) and 8n (K(i) = 89 nM) showed better binding activity than that of the reference drug Nutlin-3a (K(i) = 121 nM). In addition, in vitro antitumor activity against Saos-2, U-2 OS, A549 and NCI-H1299 cell-lines were assayed by the MTT method. Especially, compounds 8i and 8n possessed excellent biological activity and good selectivity comparable to Nutlin-3a, which were promising candidates for further evaluation.

Synthesis and biological evaluation of thio-benzodiazepines as novel small molecule inhibitors of the p53-MDM2 protein-protein interaction.

A series of thio-benzodiazepine p53-MDM2 inhibitors were designed and synthesized based on the principle of bioisosterism. Most of the thio-benzodiazepines had nanomolar to micromolar affinity toward MDM2. Particularly, compounds 8a (K(i) = 0.52µM) and 8f (K(i) = 0.32 µM) showed binding activity comparable to the positive drug nutlin-3a (K(i) = 0.23 µM). Meanwhile, compound 8j exhibited excellent antitumor activity against the U-2 OS human osteosarcoma cell line with an IC(50) value of 1.06 µM, which was about 23 times higher than that of nutlin-3a. The docking model also successfully predicted that this class of compounds mimicked three p53 critical residues binding to MDM2. The thio-benzodiazepines represent a promising class of non-peptide inhibitors of the p53-MDM2 interaction.