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BACKGROUND: Neuroendocrine tumors (NETs) arise from the body's diffuse endocrine system. Coexisting primary adenocarcinoma of the colon and NETs of the duodenum (D-NETs) is a rare occurrence in clinical practice. The classification and treatment criteria for D-NETs combined with a second primary cancer have not yet been determined. CASE SUMMARY: We report the details of a case involving female patient with coexisting primary adenocarcinoma of the colon and a D-NET diagnosed by imaging and surgical specimens. The tumors were treated by surgery and four courses of chemotherapy. The patient achieved a favorable clinical prognosis. CONCLUSION: Coexisting primary adenocarcinoma of the colon and D-NET were diagnosed by imaging, laboratory indicators, and surgical specimens. Surgical resection combined with chemotherapy was a safe, clinically effective, and cost-effective treatment.

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BACKGROUND: Savolitinib has been approved in China for advanced or metastatic non-small-cell lung cancer (NSCLC) with MET exon 14 (METex14) skipping alterations in previously treated patients and those unable to receive platinum-based chemotherapy. We report results from a treatment-naive cohort of a phase 3b study that was designed to evaluate the efficacy and safety of savolitinib in locally advanced or metastatic METex14-mutated NSCLC. METHODS: This single-arm, multicohort, multicentre, open-label, phase 3b study was done at 48 hospitals in China in adult (≥18 years) patients with locally advanced or metastatic METex14-mutated NSCLC who had not received previous systemic antitumour therapy. Patients with a bodyweight of 50 kg or more and those with a bodyweight of less than 50 kg received savolitinib once daily at 600 mg or 400 mg, respectively, in 21-day cycles. The primary endpoint was objective response rate assessed by independent review committee (IRC) per Response Evaluation Criteria in Solid Tumours, version 1.1. The full analysis set comprised all patients who received at least one dose of study medication, which was used to assess the efficacy endpoints and baseline and safety data. This study is registered with ClinicalTrials.gov (NCT04923945) and is closed to accrual. FINDINGS: Between Aug 31, 2021, and Oct 20, 2023, 125 treatment-naive patients were assessed for eligibility, of whom 87 were enrolled and received savolitinib. The median age of patients was 70·0 years (IQR 65·2-75·8) and 51 (59%) of 87 patients were male and 36 (41%) were female. In the full analysis set, the IRC-assessed objective response rate was 62% (95% CI 51-72) and the investigator-assessed objective response rate was 60% (49-70), showing a high concordance rate (84%). Treatment-related adverse events were reported in 85 (98%) of 87 patients, with peripheral oedema (54 [62%]) being the most common. Two of these treatment-related adverse events led to death (cardiac failure n=1, unknown reasons n=1). INTERPRETATION: Savolitinib showed manageable toxicity and promising efficacy in treatment-naive patients with advanced or metastatic METex14-mutated NSCLC. FUNDING: HUTCHMED and AstraZeneca.

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Adsorptive ethylene separation from the C2H2/C2H4/C2H6/CO2 four-component gas mixture provides a low-energy input solution for industrial ethylene purification, yet it is still a great challenge. Herein, we report a facile scaled-up synthesis of a stable ultramicroporous coordination network of Zn-CO3-datz (Hdatz = 3,5-diamine-1,2,4-triazole), which enables selective adsorption of C2H2, C2H4 and CO2 over C2H4, thanks to its specific pore environment supported by GCMC simulation of gas adsorption sites. Dynamic breakthrough experiments exhibited efficient one-step production of polymer-grade (≥99.95%) C2H4 from the quaternary C2H4/C2H2/C2H6/CO2 (1/1/1/1) mixture, with excellent C2H4 productivity of 0.12 mol kg-1 at 298 K. Moreover, it can be easily synthesized in kilogram scale with an affordable and low-cost ligand, rendering its further potential industrial applications.

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BACKGROUND: Colorectal cancer is the third most common cancer and the second leading cause of cancer death. There are limited therapeutic options for the treatment of locally advanced or metastatic colorectal cancers which fail first-line chemotherapy. Phase I/II studies showed that the combined application of the raltitrexed and irinotecan has significant synergistic effect and acceptable toxicity. However, most of these previous studies have relatively small sample size. METHODS: This is a prospective open-label, single-arm, multi-center, Phase II trial. Brief inclusion criteria: patients were aged 18 to 75 years with locally advanced or metastatic colorectal cancer after failure of 5-FU and oxaliplatin therapy. Enrolled patients received raltitrexed (3 mg/m2, d1) and irinotecan (180 mg/m2, d1) each 21-day cycle until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival, and the secondary endpoints were disease control rate, objective response rate, overall survival and safety. RESULTS: A total of 108 patients were enrolled between September 2016 and May 2020. The median age was 61 years, ECOG 1 score accounts for 67.6%, the rest were ECOG 0. A total of 502 cycles were completed, with an average of 4.6 cycles and a median of 4 cycles. 108 patients were evaluated, with an objective response rate of 17.6%, and disease control rate of 76.9%. The median follow-up time was 27 months (range:3.1-61.0 m) at data cut-off on March 2023. Median progression-free survival was 4.9 months (95% CI 4.1-5.7) and median overall survival was 13.1 months (95% CI 12.2-15.5). The most common adverse events that were elevated are alanine aminotransferase increased, aspartate aminotransferase increased, fatigue, diarrhoea, neutrocytopenia, thrombocytopenia, hypohemoglobin, and leukocytopenia. Most of the adverse events were Grade I/II, which were relieved after symptomatic treatment, and there were no treatment-related cardiotoxicities and deaths. CONCLUSIONS: The combination of raltitrexed and irinotecan as second-line treatment for mCRC could be a reliable option after failure of standard 5-Fu-first-line chemotherapy in locally advanced or metastatic colorectal cancers, especially for patients with 5-FU intolerance (cardiac events or DPD deficiency patients). TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03053167, registration date was 14/2/2017.

Asunto(s)

Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias Colorrectales , Irinotecán , Quinazolinas , Tiofenos , Humanos , Persona de Mediana Edad , Quinazolinas/uso terapéutico , Quinazolinas/efectos adversos , Masculino , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/mortalidad , Irinotecán/uso terapéutico , Irinotecán/administración & dosificación , Anciano , Femenino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Tiofenos/uso terapéutico , Tiofenos/administración & dosificación , Tiofenos/efectos adversos , Estudios Prospectivos , Adulto , Supervivencia sin Progresión , Adulto Joven

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Artificial rabbits optimization (ARO) is a metaheuristic algorithm based on the survival strategy of rabbits proposed in 2022. ARO has favorable optimization performance, but it still has some shortcomings, such as weak exploitation capacity, easy to fall into local optima, and serious decline of population diversity at the later stage. In order to solve these problems, we propose an improved multi-strategy artificial rabbits optimization, called IMARO, based on ARO algorithm. In this paper, a roulette fitness distance balanced hiding strategy is proposed so that rabbits can find better locations to hide more reasonably. Meanwhile, in order to improve the deficiency of ARO which is easy to fall into local optimum, an improved non-monopoly search strategy based on Gaussian and Cauchy operators is designed to improve the ability of the algorithm to obtain the global optimal solution. Finally, a covariance restart strategy is designed to improve population diversity when the exploitation is stagnant and to improve the convergence accuracy and convergence speed of ARO. The performance of IMARO is verified by comparing original ARO algorithm with six basic algorithms and seven improved algorithms. The results of CEC2014, CEC2017, CEC2022 show that IMARO has a good exploitation and exploration ability and can effectively get rid of local optimum. Moreover, IMARO produces optimal results on six real-world engineering problems, further demonstrating its efficiency in solving real-world optimization challenges.

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BACKGROUND: This prospective study aimed to evaluate the outcomes of the use of dermal templates for lengthy volar soft tissue defects (1.5-4 cm) in the fingers. METHODS: The volar soft tissue defects of 15 patients (19 fingers) were treated with Lando dermal template coverage between June 2022 and November 2022. We evaluated sensory recovery, scar formation, and overall appearance of the repair site at an average of 13 months (range, 12-17 months) of follow-up. RESULTS: The defect healed in all cases. We found an average static 2-point discrimination of 7 mm (range 4 to 14 mm). Scar formation was evident in all cases. The repair did not restore the bulkiness of the volar finger, especially in the finger with the bony exposure. Nail deformities and joint contracture were observed in some cases. CONCLUSION: Dermal template repair does not restore normal sensation and inevitably leads to scar formation when the defect is longer (>1.5 cm). Bulkiness of the volar finger is not restored in most patients, especially when there was bone or tendon exposure in the initial wound site.

Asunto(s)

Cicatriz , Traumatismos de los Dedos , Humanos , Masculino , Femenino , Adulto , Traumatismos de los Dedos/cirugía , Estudios Prospectivos , Persona de Mediana Edad , Traumatismos de los Tejidos Blandos/cirugía , Piel Artificial , Adolescente , Adulto Joven , Dedos/cirugía , Trasplante de Piel/métodos

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The P-glycoprotein (ABCB1)-mediated multidrug resistance (MDR) has emerged as a significant impediment to the efficacy of cancer chemotherapy in clinical therapy, which could promote the development of effective agents for MDR reversal. In this work, we reported the exploration of novel pyrazolo [1,5-a]pyrimidine derivatives as potent reversal agents capable of enhancing the sensitivity of ABCB1-mediated MDR MCF-7/ADR cells to paclitaxel (PTX). Among them, compound 16q remarkably increased the sensitivity of MCF-7/ADR cells to PTX at 5 µM (IC50 = 27.00 nM, RF = 247.40) and 10 µM (IC50 = 10.07 nM, RF = 663.44). Compound 16q could effectively bind and stabilize ABCB1, and does not affect the expression and subcellular localization of ABCB1 in MCF-7/ADR cells. Compound 16q inhibited the function of ABCB1, thereby increasing PTX accumulation, and interrupting the accumulation and efflux of the ABCB1-mediated Rh123, thus resulting in exhibiting good reversal effects. In addition, due to the potent reversal effects of compound 16q, the abilities of PTX to inhibit tubulin depolymerization, and induce cell cycle arrest and apoptosis in MCF-7/ADR cells under low-dose conditions were restored. These results indicate that compound 16q might be a promising potent reversal agent capable of revising ABCB1-mediated MDR, and pyrazolo [1,5-a]pyrimidine might represent a novel scaffold for the discovery of new ABCB1-mediated MDR reversal agents.

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Subfamilia B de Transportador de Casetes de Unión a ATP , Antineoplásicos , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Pirazoles , Pirimidinas , Humanos , Pirimidinas/farmacología , Pirimidinas/química , Pirimidinas/síntesis química , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Subfamilia B de Transportador de Casetes de Unión a ATP/metabolismo , Subfamilia B de Transportador de Casetes de Unión a ATP/antagonistas & inhibidores , Resistencia a Antineoplásicos/efectos de los fármacos , Pirazoles/farmacología , Pirazoles/química , Pirazoles/síntesis química , Relación Estructura-Actividad , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Estructura Molecular , Paclitaxel/farmacología , Paclitaxel/química , Células MCF-7 , Descubrimiento de Drogas , Relación Dosis-Respuesta a Droga , Proliferación Celular/efectos de los fármacos , Apoptosis/efectos de los fármacos

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OBJECTIVE: To investigate potential mechanisms of anti-atherosclerosis by berberine (BBR) using ApoE-/- mice. METHODS: Eight 8-week-old C57BL/6J mice were used as a blank control group (normal), and 56 8-week-old AopE-/- mice were fed a high-fat diet for 12 weeks, according to a completely random method, and were divided into the model group, BBR low-dose group (50 mg/kg, BBRL), BBR medium-dose group (100 mg/kg, BBRM), BBR high-dose group (150 mg/kg, BBRH), BBR+nuclear factor erythroid 2-related factor 2 (NRF2) inhibitor group (100 mg/kg BBR+30 mg/kg ML385, BBRM+ML385), NRF2 inhibitor group (30 mg/kg, ML385), and positive control group (2.5 mg/kg, atorvastatin), 8 in each group. After 4 weeks of intragastric administration, samples were collected and serum, aorta, heart and liver tissues were isolated. Biochemical kits were used to detect serum lipid content and the expression levels of malondialdehyde (MDA) and superoxide dismutase (SOD) in all experimental groups. The pathological changes of atherosclerosis (AS) were observed by aorta gross Oil Red O, aortic sinus hematoxylin-eosin (HE) and Masson staining. Liver lipopathy was observed in mice by HE staining. The morphology of mitochondria in aorta cells was observed under transmission electron microscope. Flow cytometry was used to detect reactive oxygen species (ROS) expression in aorta of mice in each group. The content of ferrous ion Fe2+ in serum of mice was detected by biochemical kit. The mRNA and protein relative expression levels of NRF2, glutathione peroxidase 4 (GPX4) and recombinant solute carrier family 7 member 11 (SLC7A11) were detected by quantitative real time polymerase chain reaction (RT-qPCR) and Western blot, respectively. RESULTS: BBRM and BBRH groups delayed the progression of AS and reduced the plaque area (P<0.01). The characteristic morphological changes of ferroptosis were rarely observed in BBR-treated AS mice, and the content of Fe2+ in BBR group was significantly lower than that in the model group (P<0.01). BBR decreased ROS and MDA levels in mouse aorta, increased SOD activity (P<0.01), significantly up-regulated NRF2/SLC7A11/GPX4 protein and mRNA expression levels (P<0.01), and inhibited lipid peroxidation. Compared with the model group, the body weight, blood lipid level and aortic plaque area of ML385 group increased (P<0.01); the morphology of mitochondria showed significant ferroptosis characteristics; the serum Fe2+, MDA and ROS levels increased (P<0.05 or P<0.01), and the activity of SOD decreased (P<0.01). Compared with BBRM group, the iron inhibition effect of BBRM+ML385 group was significantly weakened, and the plaque area significantly increased (P<0.01). CONCLUSION: Through NRF2/SLC7A11/GPX4 pathway, BBR can resist oxidative stress, inhibit ferroptosis, reduce plaque area, stabilize plaque, and exert anti-AS effects.

RESUMEN

BACKGROUND: Severe bacterial infections can trigger acute lung injury (ALI) and acute respiratory distress syndrome, with bacterial pathogen-associated molecular patterns (PAMPs) exacerbating the inflammatory response, particularly in COVID-19 patients. Cyclic-di-GMP (CDG), one of the PAMPs, is synthesized by various Gram-positve and Gram-negative bacteria. Previous studies mainly focused on the inflammatory responses triggered by intracellular bacteria-released CDG. However, how extracellular CDG, which is released by bacterial autolysis or rupture, activates the inflammatory response remains unclear. METHODS: The interaction between extracellular CDG and myeloid differentiation protein 2 (MD2) was investigated using in vivo and in vitro models. MD2 blockade was achieved using specific inhibitor and genetic knockout mice. Site-directed mutagenesis, co-immunoprecipitation, SPR and Bis-ANS displacement assays were used to identify the potential binding sites of MD2 on CDG. RESULTS: Our data show that extracellular CDG directly interacts with MD2, leading to activation of the TLR4 signalling pathway and lung injury. Specific inhibitors or genetic knockout of MD2 in mice significantly alleviated CDG-induced lung injury. Moreover, isoleucine residues at positions 80 and 94, along with phenylalanine at position 121, are essential for the binding of MD2 to CDG. CONCLUSION: These results reveal that extracellular CDG induces lung injury through direct interaction with MD2 and activation of the TLR4 signalling pathway, providing valuable insights into bacteria-induced ALI mechanisms and new therapeutic approaches for the treatment of bacterial co-infection in COVID-19 patients.

Asunto(s)

Lesión Pulmonar Aguda , COVID-19 , GMP Cíclico , Antígeno 96 de los Linfocitos , Lesión Pulmonar Aguda/metabolismo , Antígeno 96 de los Linfocitos/metabolismo , Animales , Ratones , GMP Cíclico/metabolismo , GMP Cíclico/análogos & derivados , Humanos , COVID-19/metabolismo , COVID-19/complicaciones , Ratones Noqueados , Inflamación/metabolismo , SARS-CoV-2 , Receptor Toll-Like 4/metabolismo , Ratones Endogámicos C57BL , Transducción de Señal , Masculino

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We summarize the attention that has been drawn to and the thought process about the complexity of current classification zones of extensor tendons. A possible new, simpler classification was proposed by the lead author and discussed with the co-author. A simplified classification is presented with rationale, mainly based on the simplified treatment strategies used by the authors. We also discuss the possible drawbacks and call for investigations on this topic to make the current treatment strategies less complex. An updated system should be based on improved understandings of clinical treatment, including an increasing trend of using conservative treatment for closed injuries and strong surgical repair methods for open injuries of extensor tendons.

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Background: At present, the few photothermal/chemotherapy studies about retinoblastoma that have been reported are mainly restricted to ectopic models involving subcutaneous implantation. However, eyeball is unique physiological structure, the blood-retina barrier (BRB) hinders the absorption of drug molecules through the systemic route. Moreover, the abundant blood circulation in the fundus accelerates drug metabolism. To uphold the required drug concentration, patients must undergo frequent chemotherapy sessions. Purpose: To address these challenges above, we need to develop a secure and effective drug delivery system (FA-PEG-PDA-DOX) for the fundus. Methods: We offered superior therapeutic efficacy with minimal or no side effects and successfully established orthotopic mouse models. We evaluated cellular uptake performance and targeting efficiency of FA-PEG-PDA-DOX nanosystem and assessed its synergistic antitumor effects in vitro and vivo. Biodistribution assessments were performed to determine the retention time and targeting efficiency of the NPs in vivo. Additionally, safety assessments were conducted. Results: Cell endocytosis rates of the FA-PEG-PDA-DOX+Laser group became 5.23 times that of the DOX group and 2.28 times that of FA-PEG-PDA-DOX group without irradiation. The fluorescence signal of FA-PEG-PDA-DOX persisted for more than 120 hours at the tumor site. The number of tumor cells (17.2%) in the proliferative cycle decreased by 61.6% in the photothermal-chemotherapy group, in contrast to that of the saline control group (78.8%). FA-PEG-PDA-DOX nanoparticles(NPs) exhibited favorable biosafety and high biocompatibility. Conclusion: The dual functional targeted nanosystem, with the effects of DOX and mild-temperature elevation by irradiation, resulted in precise chemo/photothermal therapy in nude mice model.

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Doxorrubicina , Indoles , Terapia Fototérmica , Polímeros , Retinoblastoma , Animales , Retinoblastoma/terapia , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacología , Doxorrubicina/administración & dosificación , Ratones , Terapia Fototérmica/métodos , Humanos , Indoles/química , Indoles/farmacocinética , Indoles/farmacología , Línea Celular Tumoral , Polímeros/química , Distribución Tisular , Polietilenglicoles/química , Polietilenglicoles/farmacocinética , Ratones Desnudos , Nanopartículas/química , Sistemas de Liberación de Medicamentos/métodos , Neoplasias de la Retina/terapia , Neoplasias de la Retina/tratamiento farmacológico , Ratones Endogámicos BALB C , Antibióticos Antineoplásicos/farmacología , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/administración & dosificación , Modelos Animales de Enfermedad , Ensayos Antitumor por Modelo de Xenoinjerto , Sistema de Administración de Fármacos con Nanopartículas/química , Sistema de Administración de Fármacos con Nanopartículas/farmacocinética

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The introduction of heterogeneous components within one single coordination network leads to the multifunctionality of the final material. However, it is hard to precisely control the local distribution of these different components in such a coordination network, especially for different components with identical topological connectivity. In this study, we successfully achieved the ordered assembly of [Mn3(µ3-O)] nodes and [Mn6(µ3-O)2(CH3COO)3] nodes within one pacs coordination network. The resulting new structure (NPU-6) with heterogeneous metal nodes simultaneously inherits the advantages of both parent networks (good thermal stability and high pore volume). The significant effect of the reaction concentration of competing ligand CH3COO- on the mixed assembly of these two nodes in NPU-6 is revealed by a series of control experiments. This method is anticipated to offer a valuable reference for orderly assembling heterogeneous components in coordination networks.

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Introduction: Primary central nervous system lymphoma (PCNSL) is a rare type of non-Hodgkin's lymphoma that affects brain parenchyma, eyes, cerebrospinal fluid, and spinal cord. Diagnosing PCNSL can be challenging because imaging studies often show similar patterns as other brain tumors, and stereotactic brain lesion biopsy conformation is invasive and not always possible. This study aimed to validate a previous proteomic profiling (PMID: 32610669) of cerebrospinal fluid (CSF) and develop a CSF-based proteomic panel for accurate PCNSL diagnosis and differentiation. Methods: CSF samples were collected from patients of 30 PCNSL, 30 other brain tumors, and 31 tumor-free/benign controls. Liquid chromatography tandem-mass spectrometry targeted proteomics analysis was used to establish CSF-based proteomic panels. Results: Final proteomic panels were selected and optimized to diagnose PCNSL from tumor-free controls or other brain tumor lesions with an area under the curve (AUC) of 0.873 (95%CI: 0.723-0.948) and 0.937 (95%CI: 0.807- 0.985), respectively. Pathways analysis showed diagnosis panel features were significantly enriched in pathways related to extracellular matrices-receptor interaction, focal adhesion, and PI3K-Akt signaling, while prion disease, mineral absorption and HIF-1 signaling were significantly enriched with differentiation panel features. Discussion: This study suggests an accurate clinical test panel for PCNSL diagnosis and differentiation with CSF-based proteomic signatures, which may help overcome the challenges of current diagnostic methods and improve patient outcomes.

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Biomarcadores de Tumor , Neoplasias Encefálicas , Proteómica , Humanos , Proteómica/métodos , Biomarcadores de Tumor/líquido cefalorraquídeo , Neoplasias Encefálicas/líquido cefalorraquídeo , Neoplasias Encefálicas/diagnóstico , Femenino , Masculino , Persona de Mediana Edad , Anciano , Diagnóstico Diferencial , Adulto , Linfoma no Hodgkin/líquido cefalorraquídeo , Linfoma no Hodgkin/diagnóstico

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Focal adhesion kinase (FAK) is considered as a pivotal intracellular non-receptor tyrosine kinase, and has garnered significant attention as a promising target for anticancer drug development. As of early 2024, a total of 12 drugs targeting FAK have been approved for clinical or preclinical studies worldwide, including three PROTAC degraders. In recent three years (2021-2023), significant progress has been made in designing targeted FAK anticancer agents, including the development of a novel benzenesulfofurazan type NO-releasing FAK inhibitor and the first-in-class dual-target inhibitors simultaneously targeting FAK and HDACs. Given the pivotal role of FAK in the discovery of anticancer drugs, as well as the notable advancements achieved in FAK inhibitors and PROTAC degraders in recent years, this review is underbaked to present a comprehensive overview of the function and structure of FAK. Additionally, the latest findings on the inhibitors and PROTAC degraders of FAK from the past three years, along with their optimization strategies and anticancer activities, were summarized, which might help to provide novel insights for the development of novel targeted FAK agents with promising anticancer potential and favorable pharmacological profiles.

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Antineoplásicos , Proteína-Tirosina Quinasas de Adhesión Focal , Neoplasias , Inhibidores de Proteínas Quinasas , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/síntesis química , Proteína-Tirosina Quinasas de Adhesión Focal/antagonistas & inhibidores , Proteína-Tirosina Quinasas de Adhesión Focal/metabolismo , Neoplasias/tratamiento farmacológico , Animales , Estructura Molecular

RESUMEN

As a highly conserved signaling network across different species, the Hippo pathway is involved in various biological processes. Dysregulation of the Hippo pathway could lead to a wide range of diseases, particularly cancers. Extensive researches have demonstrated the close association between dysregulated Hippo signaling and tumorigenesis as well as tumor progression. Consequently, targeting the Hippo pathway has emerged as a promising strategy for cancer treatment. In fact, there has been an increasing number of reports on small molecules that target the Hippo pathway, exhibiting therapeutic potential as anticancer agents. Importantly, some of Hippo signaling pathway inhibitors have been approved for the clinical trials. In this work, we try to provide an overview of the core components and signal transduction mechanisms of the Hippo signaling pathway. Furthermore, we also analyze the relationship between Hippo signaling pathway and cancers, as well as summarize the small molecules with proven anti-tumor effects in clinical trials or reported in literatures. Additionally, we discuss the anti-tumor potency and structure-activity relationship of the small molecule compounds, providing a valuable insight for further development of anticancer agents against this pathway.

Asunto(s)

Antineoplásicos , Vía de Señalización Hippo , Neoplasias , Proteínas Serina-Treonina Quinasas , Transducción de Señal , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Transducción de Señal/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , Relación Estructura-Actividad , Animales , Estructura Molecular , Bibliotecas de Moléculas Pequeñas/química , Bibliotecas de Moléculas Pequeñas/farmacología

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ETHNOPHARMACOLOGICAL RELEVANCE: Hyssopus cuspidatus Boriss., a classic Uyghur medicine, is used to treat inflammatory lung diseases such as asthma. But the therapeutic effect and mechanism of the volatile oil of Hyssopus cuspidatus Boriss.(HVO) in asthma therapy remain unclear. AIM OF THE STUDY: We aim to characterize the constituents of HVO, investigate the therapeutic effect in OVA-induced allergic asthmatic mice and further explore the molecular mechanism. MATERIALS AND METHODS: In this study, we applied two-dimensional gas chromatography quadrupole time-of-flight mass spectrometry (GC × GC-QTOF MS) to identify the ingredients of HVO. We established OVA-induced asthmatic model to investigate the therapeutic effect of HVO. To further explore the potential molecular pathways, we used network pharmacology approach to perform GO and KEGG pathways enrichment, and then built an ingredient-target-pathway network to identify key molecular pathways. Finally, LPS-induced RAW 264.7 macrophages and OVA-induced asthmatic model were used to validate the potential signaling pathways. RESULTS: GC × GC-QTOF MS analysis revealed the presence of 123 compounds of HVO. The sesquiterpenes and monoterpenes are the main constituents. The in vivo study indicated that HVO suppressed OVA-induced eosinophilic infiltration in lung tissues, inhibited the elevation of IgE, IL-4, IL-5, and IL-13 levels, downregulated the expressions of phosphorylated PI3K, Akt, JNK and P38, and maintained epithelial barrier integrity via reducing the degradation of occludin, Zo-1, Zo-2, and E-cadherin. The in vitro study also revealed an inhibition of NO release and downregulation of phosphorylated PI3K, Akt, JNK and P38 levels. CONCLUSION: HVO alleviates airway inflammation in OVA-induced asthmatic mice by inhibiting PI3K/Akt/JNK/P38 signaling pathway and maintaining airway barrier integrity via reducing the degradation of occludin, Zo-1, Zo-2, and E-cadherin.

Asunto(s)

Asma , Aceites Volátiles , Ovalbúmina , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Animales , Femenino , Ratones , Antiasmáticos/farmacología , Asma/tratamiento farmacológico , Asma/inducido químicamente , Modelos Animales de Enfermedad , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Ratones Endogámicos BALB C , Aceites Volátiles/farmacología , Aceites Volátiles/química , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Pyroglyphidae/inmunología , Células RAW 264.7 , Transducción de Señal/efectos de los fármacos

RESUMEN

The design of boron-based molecular rotors stems from boron-carbon binary clusters containing multiple planar hypercoordinate carbons (phCs, such as C2B8). However, the design of boron-coordinated phCs is challenging due to boron's tendency to occupy hypercoordinate centers more than carbon. Although this challenge has been addressed, the designed clusters of interest have not exhibited dynamic fluxionality similar to that of the initial C2B8. To address this issue, we report a σ/π doubly aromatic CB2H5 + cluster, the first global minimum containing a boron-coordinated planar tetracoordinate carbon atom with dynamic fluxionality. Dynamics simulations show that two ligand H atoms exhibit alternate rotation, resulting in an intriguing dynamic fluxionality in this cluster. Electronic structure analysis reveals the flexible bonding positions of the ligand H atoms because they do not participate in π delocalized bonding nor bond to any other non-carbon atom, highlighting this rotational fluxionality. Unprecedentedly, the fluxional process involves not only the usual conversion of the number of bonding atoms, but also the type of bonding (3c π bonds ↔4c σ bonds), which is an uncommon fluxional mechanism. The cluster represents an effort to apply phC species to molecular machines.

RESUMEN

Bile acids (BAs) play a crucial role in lipid metabolism of children. However, the association between per- and polyfluoroalkyl substance (PFAS) exposure and BAs in children is scarce. To address this need, we selected 252 children from the Maoming Birth Cohort and measured 32 PFAS, encompassing short- and long-chain perfluorocarboxylic acids (PFCAs) and perfluorosulfonic acids (PFSAs) in the cord blood. Additionally, we analyzed nine primary and eight secondary BAs in the serum of three-year-old children. Generalized linear models with FDR-adjusted and Bayesian kernel machine regression (BKMR) were used to explore the associations of individual and mixture effects of PFAS and BAs. We found negative associations between cord blood long-chain PFCAs exposure and serum primary BAs in three-year-old children. For example, one ln-unit (ng/mL) increase of perfluoro-n-tridecanoic acid (PFTrDA), perfluoro-n-undecanoic acid (PFUnDA) and perfluoro-n-decanoic acid (PFDA) were associated with decreased taurochenodeoxycholic acid, with estimated percentage change of -24.28% [95% confidence interval (CI): -36.75%, -9.35%], -25.84% (95% CI: -39.67%, -8.83%), and -22.97% (95% CI: -34.45%, -9.47%) respectively. Notably, the observed associations were more pronounced in children with lower vegetable intake. Additionally, the BKMR model also demonstrated a monotonical decline in primary BAs as the PFAS mixture increased. We provided the first evidence of the association between intrauterine exposure to PFAS and its mixture with BAs in children. Further large-sample-size studies are needed to verify this finding.

Asunto(s)

Ácidos y Sales Biliares , Contaminantes Ambientales , Fluorocarburos , Humanos , Fluorocarburos/sangre , Preescolar , Femenino , Estudios Prospectivos , Masculino , Contaminantes Ambientales/sangre , Cohorte de Nacimiento , Embarazo , Sangre Fetal/química , Efectos Tardíos de la Exposición Prenatal , Exposición Materna/estadística & datos numéricos , Ácidos Carboxílicos

RESUMEN

TFE3-rearranged renal cell cancer (tRCC) is a rare form of RCC that involves chromosomal translocation of the Xp11.2 TFE3 gene. Despite its early onset and poor prognosis, the molecular mechanisms of the pathogenesis of tRCC remain elusive. This study aimed to identify novel therapeutic targets for patients with primary and recurrent tRCC. We collected 19 TFE3-positive RCC tissues that were diagnosed by immunohistochemistry and subjected them to genetic characterization to examine their genomic and transcriptomic features. Tumor-specific signatures were extracted using whole exome sequencing (WES) and RNA sequencing (RNA-seq) data, and the functional consequences were analyzed in a cell line with TFE3 translocation. Both a low burden of somatic single nucleotide variants (SNVs) and a positive correlation between the number of somatic variants and age of onset were observed. Transcriptome analysis revealed that four samples (21.1%) lacked the expected fusion event and clustered with the genomic profiles of clear cell RCC (ccRCC) tissues. The fusion event also demonstrated an enrichment of upregulated genes associated with mitochondrial respiration compared with ccRCC expression profiles. Comparison of the RNA expression profile with the TFE3 ChIP-seq pattern data indicated that PPARGC1A is a metabolic regulator of the oncogenic process. Cell proliferation was reduced when PPARGC1A and its related metabolic pathways were repressed by its inhibitor SR-18292. In conclusion, we demonstrate that PPARGC1A-mediated mitochondrial respiration can be considered a potential therapeutic target in tRCC. This study identifies an uncharacterized genetic profile of an RCC subtype with unique clinical features and provides therapeutic options specific to tRCC.

Asunto(s)

Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice , Carcinoma de Células Renales , Secuenciación del Exoma , Neoplasias Renales , Humanos , Carcinoma de Células Renales/genética , Carcinoma de Células Renales/patología , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Neoplasias Renales/genética , Neoplasias Renales/patología , Femenino , Masculino , Persona de Mediana Edad , Anciano , Adulto , Reordenamiento Génico , Regulación Neoplásica de la Expresión Génica , Línea Celular Tumoral , Perfilación de la Expresión Génica , Translocación Genética , Transcriptoma , Polimorfismo de Nucleótido Simple , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma

RESUMEN

This research delves into the preparation of heteronuclear bimetallic catalysts and explores their catalytic properties in the thermal decomposition of ammonium perchlorate (AP). The study's central focus is on enhancing the thermal decomposition characteristics of AP and, consequently, the combustion performance of composite solid propellants. The synthesized materials underwent structural characterization by XRD, XPS, SEM, and FTIR. Catalytic properties were examined using DTA tests. Notably, catalysts derived from calcination at 500 °C exhibited heightened catalytic activity. They advanced the pyrolysis temperature by 135.4 °C and reduced the activation energy by 82.38 kJ/mol compared with pure AP. To further elucidate the decomposition mechanism of AP, the investigation also employed a combined approach involving DSC-TG-FTIR-MS analysis.