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BACKGROUND: The combination of immune checkpoint inhibitors and antiangiogenic agents has been effective in treating multiple cancers. This was further explored in an open-label, multicenter phase 2 basket study (NCT04346381), which evaluated the antitumor activity and safety of camrelizumab (an anti-PD-1 antibody) plus famitinib (a receptor tyrosine kinase inhibitor) in patients with advanced solid tumors. We herein report the findings from the cohort of advanced NSCLC patients who progressed after treatment with platinum-doublet chemotherapy and immunotherapy. METHODS: Eligible patients were enrolled and treated with camrelizumab (200 mg once every 3 weeks via intravenous infusion) and oral famitinib (20 mg once daily). The primary endpoint was the objective response rate (ORR). Secondary endpoints included the disease control rate (DCR), duration of response (DoR), progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Forty patients were enrolled in this cohort, with a median follow-up duration of 11.5 months. Three patients (7.5%) achieved a partial response, and 29 patients (72.5%) achieved stable disease. The ORR and DCR with this combination regimen were 7.5% (95% CI, 1.6-20.4) and 80.0% (95% CI, 64.4-90.9), respectively. The median DoR was 12.1 months (95% CI, 10.3-not reached). The median PFS was 5.4 months (95% CI, 4.1-7.5), and the median OS was 12.1 months (95% CI, 9.1-16.7). The estimated 12-month OS rate was 51.5% (95% CI, 34.9-65.9). The most frequent grade 3 or higher treatment-related adverse events occurring in more than 5% of patients included hypertension (27.5%), palmar-plantar erythrodysesthesia syndrome (10%), decreased neutrophil count (10%), and proteinuria (7.5%). CONCLUSION: Camrelizumab plus famitinib demonstrated favorable benefits in PFS and OS, along with manageable safety profiles, in patients with advanced NSCLC who progressed after platinum-doublet chemotherapy and immunotherapy. This finding warrants further exploration.
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Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Masculino , Femenino , Persona de Mediana Edad , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Anciano , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Adulto , Sulfonamidas/uso terapéutico , Sulfonamidas/administración & dosificación , Inmunoterapia/métodos , Indoles , PirrolesRESUMEN
1,4-BN-doped polycyclic aromatic hydrocarbons (PAHs) have emerged as very promising emitters in organic light-emitting diodes (OLEDs) due to their narrowband emission spectra that may find application in high-definition displays. While considerable research has focused on investigating the properties of these materials, less attention has been placed on their synthetic methodology. Here we developed an efficient synthetic method for 1,4-BN-doped PAHs, which enables sustainable production of narrowband organic emitting materials. By strategically introducing substituents, such as methyl, tert-butyl, phenyl, and chloride, at the C5 position of the 1,3-benzenediamine substrates, we achieved remarkable regioselective borylation in the para-position of the substituted moiety. This approach facilitated the synthesis of a diverse range of 1,4-BN-doped PAHs emitters with good yields and exceptional regioselectivity. The synthetic method demonstrated excellent scalability for large-scale production and enabled late-stage transformation of the borylated products. Mechanistic investigations provided valuable insights into the pivotal roles of electron effect and steric hindrance effect in achieving highly efficient regioselective borylation. Moreover, the outstanding device performance of the synthesized compounds 10 b and 6 z, underscores the practicality and significance of the developed method.
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Saposhnikovia divaricata is an authentic Chinese herbal medicine in Northeast China named Guanfangfeng, which is made from very high quality plants for sufficient efficacy. However, leaf spot causes a very large reduction in the yield and quality of S. divaricata in Shuangyashan (126°54'E, 45°81'N), Northeast China. A total of 18 isolates were isolated from the diseased leaves of S. divaricata, following Koch's postulates, and identified as Fusarium acuminatum based on morphological, molecular biological, and phylogenetic tree analyses. To the authors' knowledge, this is the first report of F. acuminatum causing S. divaricata leaf spot in China. F. acuminatum infected perilla and mung beans, but not foxtail millet, peanuts, wheat, peas, rye, red beans, or sorghum. Susceptibility assessment of F. acuminatum to fungicides using the mycelial growth rate method showed that isolates of F. acuminatum were most sensitive to prochloraz, with EC50 values of 0.0005413-0.0009523 µg·ml-1. In the two field experiments, the average control efficacy of prochloraz at 0.450 g/l on S. divaricata leaf spot caused by F. acuminatum was 75.42%. Therefore, non-host plant rotation or intercropping with suitable chemical fungicides may be used to control S. divaricata leaf spot. This study's results provide a theoretical basis for controlling S. divaricata leaf spot and will facilitate the development of effective disease management programs.
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White clover (Trifolium repens L.) is an excellent quality forage legume species with superior planting efficiency, which reduces the cost of artificial weeding and nitrogen fertilizer inputs and has feeding and economic value. However, from June to September 2022, severe stem rot affected the yield and quality of white clover crops in Harbin, Heilongjiang Province, China. The aim of this study was to identify the causative agents of the disease. Overall, Colletotrichum truncatum (6 isolates) and C. destructivum (10 isolates) were obtained from rotten white clover stems and identified according to morpho-molecular characteristics and phylogenetic analyses. Pathogenicity tests of the isolates revealed that C. destructivum had a higher pathogenicity to white clover than C. truncatum. In addition, all isolates were highly pathogenic to broad bean, fodder soybean, soybean, pak choi, and chickpea, pathogenic to mint, and did not infect corn, wheat, or cilantro. C. destructivum and C. truncatum isolates were very sensitive to tebuconazole and pyraclostrobin, with EC50 values of 0.54 to 0.70 µg/ml and 0.42 to 0.62 µg/ml, respectively, efficacies ranging between 93.2 to 94.9% and 90.2 to 95.2% at 600 µg/ml and 450 µg/ml, respectively, and EC90 values of 1.88 to 13.36 µg/ml and 1.32 to 23.39 µg/ml, respectively. Therefore, intercropping of host and non-host plants and chemicals can be considered to control stem rot in white clover. These results provide a basis for controlling C. destructivum and C. truncatum in white clover in China.
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BACKGROUND: Juvenile xanthogranuloma (JXG) is a kind of non-Langerhans cell histiocytosis, usually with skin lesions as the main manifestation. It rarely occurs in other tissues or organs and even more rarely is it found in the skull. Here, we report a case of xanthogranuloma derived from the temporal bone that was not present in any other parts of the body. CASE PRESENTATION: A 15-year-old boy had an unaccountable right migraine for 7 months. A mass with tenderness was located behind his right ear. The mass gradually increased in size, and his headache continued. Eventually, he came to our hospital for treatment. A computed tomography (CT) scan and magnetic resonance imaging (MRI) revealed a cystic solid mass in the right temporo-occipital region with skull destruction. The clinical diagnosis was haemangiopericytoma and skull-derived tumour. Haematological and biochemical results were as follows: alanine aminotransferase (ALT) 7 U/L; aspartate aminotransferase (AST) 12 U/L; basophil percentage (BASO%) 1.2%; normal coagulation. The patient was successfully treated with total surgical resection of the tumour. Postoperative histopathology examination showed xanthogranuloma, and his prognosis after surgery was good. CONCLUSIONS: Because JXG rarely occurs in the skull and lacks typical imaging findings, an accurate diagnosis is difficult. The diagnosis of this disease mainly depends on pathological examination and immunohistochemistry. If feasible, many intracranial lesions can be cured through complete resection.
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Xantogranuloma Juvenil , Adolescente , Cabeza/patología , Humanos , Imagen por Resonancia Magnética , Masculino , Hueso Temporal/diagnóstico por imagen , Hueso Temporal/patología , Tomografía Computarizada por Rayos X , Xantogranuloma Juvenil/diagnóstico por imagen , Xantogranuloma Juvenil/cirugíaRESUMEN
We report the first purely chemical method for the resolution of C, N-unprotected racemic α-substituted ß-amino acids (ß2-AAs) using thermodynamically stable and recyclable chiral proline-derived ligands. The ligands and racemic ß2-AAs along with Ni(II) could form a pair of Ni(II) complex diastereoisomers with a desirable diastereoselectivity (dr up to 91:9). Enantiomerically pure C, N-unprotected ß2-AAs could be obtained by simple hydrolysis of an isolated favored Ni(II) complex. The method featured unique versatility compared with enzymatic approaches and characterized by its broad synthetic generality, good stereochemical outcome, and mild reaction conditions, thus making it a powerful supplement in the field of chemical resolution of ß2-AAs.
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Unnatural (R)-α-amino acids (α-AAs) are in growing demand in the biomedical research and pharmaceutical industries. In this work, we present development of a purely chemical approach for preparation of (R)-α-AAs via (S)-to-(R)-interconversion of natural and tailor-made (S)-α-AAs. The method can be used on free, unprotected α-AAs and features a remarkable structural generality including substrates bearing tertiary alkyl chains and reactive functional groups. These attractive characteristics, combined with simplicity of reaction conditions and virtually complete stereochemical outcome, constitute a true methodological advance in this area, rivaling previously reported chemical and biocatalytic approaches.
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Aminoácidos/química , Biocatálisis , EstereoisomerismoRESUMEN
Described here is an advanced, general method for purely chemical dynamic thermodynamic resolution and S/R interconversion of unprotected tailor-made α-amino acids (α-AAs) through intermediate formation of the corresponding nickel(II)-chelated Schiff bases. The method features virtually complete stereochemical outcome, broad substrate generality (35 examples), and operationally convenient conditions allowing for large-scale preparation of the target α-AAs in enantiomerically pure form. Furthermore, the new type of nonracemizable axially chiral ligands can be quantitatively recycled and reused, rendering the whole process economically and synthetically attractive.
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Aminoácidos/química , Termodinámica , Estructura Molecular , EstereoisomerismoRESUMEN
Structurally simple and inexpensive chiral tridentate ligands were employed for substantially advancing the purely chemical dynamic kinetic resolution (DKR) of unprotected racemic tailor-made α-amino acids (TM-α-AAs), enabling the first DKR of TM-α-AAs bearing tertiary alkyl chains as well as multiple unprotected functional groups. Owing to the operationally convenient conditions, virtually complete stereoselectivity, and full recyclability of the source of chirality, this method should find wide applications for the preparation of TM-α-AAs, especially on large scale.
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Aminoácidos/química , Aminoácidos/metabolismo , Níquel/química , Compuestos Organometálicos/química , Termodinámica , Cinética , Ligandos , Estructura Molecular , Compuestos Organometálicos/síntesis químicaRESUMEN
Reported herein is the first purely chemical method for the dynamic kinetic resolution (DKR) of unprotected racemic α-amino acids (α-AAs), a method which can rival the economic efficiency of the enzymatic reactions. The DKR reaction principle can be readily applied for S/Râ interconversions of α-AAs, the methodological versatility of which is unmatched by biocatalytic approaches. The presented process features a virtually complete stereochemical outcome, fully recyclable source of chirality, and operationally simple and convenient reaction conditions, thus allowing its ready scalability. A quite unique and novel mode of the thermodynamic control over the stereochemical outcome, including an exciting interplay between axial, helical, and central elements of chirality is proposed.
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Aminoácidos/química , Catálisis , Cinética , EstereoisomerismoRESUMEN
A new narrowband thermally activated delayed fluorescence emitter, PhCzBN-PO, was developed by incorporating the diphenylphosphine oxide (DPPO) group into a multi-resonance core. The unique properties of DPPO enabled PhCzBN-PO to achieve pure green emission and a nonplanar structure. The resulting electroluminescent devices achieved high external quantum efficiencies up to 32.4% with extremely low efficiency roll-off and pure-green emission with Commission Internationale de L'Eclairage (CIE) coordinates of (0.24, 0.67).
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BACKGROUND: The combination of immune-checkpoint inhibitors and antiangiogenic agents can synergistically modulate the tumor microenvironment and represents a promising treatment option. Here, we evaluated the efficacy and safety of camrelizumab plus famitinib (a receptor tyrosine kinase inhibitor) as a first-line treatment for advanced or metastatic NSCLC patients with a programmed death ligand-1 (PD-L1) tumor proportion score (TPS) of ≥1%, in an open-label, multicenter, phase 2 basket trial. METHODS: Eligible patients received camrelizumab (200 mg once every 3 weeks via intravenous infusion) plus oral famitinib at an initial dose of 20 mg once daily. The primary endpoint was the objective response rate (ORR), as assessed by the investigator per Response Evaluation Criteria in Solid Tumors V.1.1. Key secondary endpoints included disease control rate (DCR), duration of respons, progression-free survival (PFS), overall survival (OS), 12-month OS rate, and safety profile. RESULTS: Of the enrolled 41 patients, 21 (51.2%) had a PD-L1 TPS of 1-49%. As of the cut-off date on June 22, 2022, the combination regimen of camrelizumab and famitinib achieved an ORR of 53.7% (95% CI 37.4% to 69.3%) and a DCR of 92.7% (95% CI 80.1% to 98.5%). The median PFS was 16.6 months (95% CI 8.3 to not reached), and OS data were not yet mature, with an estimated 12-month OS rate of 76.8% (95% CI 60.0% to 87.3%). The most common treatment-related adverse events of grade 3 or higher included hypertension (22.0%), increased alanine aminotransferase (12.2%), decreased neutrophil count (9.8%), proteinuria (7.3%), decrease platelet count (7.3%), and hypokalemia (7.3%). One (2.4%) patient died from grade 5 hemoptysis, which was considered possibly related to the study treatment by the investigator. CONCLUSION: Camrelizumab plus famitinib demonstrated promising antitumor activity in advanced or metastatic NSCLC patients and had an acceptable safety profile. These findings suggest that this combination regimen could be an alternative therapeutic option and warrant further investigation. TRIAL REGISTRATION NUMBER: NCT04346381.
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Anticuerpos Monoclonales Humanizados , Carcinoma de Pulmón de Células no Pequeñas , Indoles , Neoplasias Pulmonares , Pirroles , Humanos , Antígeno B7-H1/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Microambiente TumoralRESUMEN
Eosinophilic solid and cystic renal cell carcinoma (ESC-RCC) is a rare type of renal cell carcinoma with inert biological behavior that has not yet been included in the 2016 World Health Organization (WHO) classification, and its imaging manifestations are unclear due to its rarity. Although there have only been a few cases, the CT and MRI findings of ESC-RCC are characterized by its cystic solid structure, according to the proportion of cystic and solid components observed on images, ESC-RCC can be categorized into three types. Especially the Type I, when the cystic-solid components are almost equal, the imaging findings are illustrated as "lotus root-like," which may be helpful in the differential diagnosis of ESC-RCC from other types of renal tumors. In fact, ESC-RCC has diverse radiological appearances, and the differentiation of clear cell renal cell carcinoma, renal oncocytoma, chromophobe renal cell carcinoma, and renal angiomyolipoma remains challenging. This review aims to discuss ESC-RCC with a focus on the radiological findings and differential diagnosis of ESC-RCC.
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Angiomiolipoma , Carcinoma de Células Renales , Neoplasias Renales , Humanos , Neoplasias Renales/diagnóstico por imagen , Neoplasias Renales/patología , Carcinoma de Células Renales/diagnóstico por imagen , Carcinoma de Células Renales/patología , Angiomiolipoma/patología , Diagnóstico Diferencial , Imagen por Resonancia MagnéticaRESUMEN
Background: Lymphocyte-activation gene 3 (LAG-3), a checkpoint molecule contributing to immune suppressive microenvironment, is regarded as a promising target in cancer treatment. SHR-1802 is a novel anti-LAG-3 monoclonal antibody. Objectives: To evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of SHR-1802. Design: A phase I dose-escalation and expansion trial of SHR-1802 in patients with advanced solid tumors. Methods: Patients with confirmed advanced solid tumors who failed previous standard-of-care or for whom no effective therapy was available were enrolled to receive SHR-1802 once every 21-day cycle. Dose escalation was performed in an accelerated titration design followed by a 3 + 3 scheme at escalating doses from 0.3 to 10 mg/kg. On the basis of results from dose-escalation phase, one or two dose levels were expanded to establish the recommended phase II dose (RP2D). The primary end points were dose-limiting toxicity (DLT) and RP2D. Results: Between 01 July 2020, and 07 September 2021, 28 patients were enrolled. No DLTs were observed, and all doses investigated were well tolerated. Treatment-related adverse events occurred in 20 patients (71.4%), all grade 1 or 2, with the most common ones being anemia (14.3%), asthenia (14.3%), electrocardiogram QT prolonged (14.3%), followed by increased blood fibrinogen (10.7%), infusion-related reaction (10.7%), and hypoalbuminemia (10.7%). No adverse event-related discontinuation occurred. Three patients died from adverse events, but none of the deaths were deemed related to study treatment. SHR-1802 exposure enhanced with the increasing doses in a greater than dose-proportional manner over the investigated dose range. The disease control rate was 32.0% (95% CI 14.9%-53.5%). The median progression-free survival was 2.0 months (95% CI 1.2-6.1). Conclusions: SHR-1802 demonstrated a tolerable safety profile and preliminary antitumor activity in patients with advanced solid tumors. Further studies with larger sample size and in combination forms are warranted for future clinical application. Registration ClinicalTrialsgov: NCT04414150.
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Microplastic contamination is ubiquitous in aquatic environments. As global plastic production increases, the abundance of microplastic contaminants released into the environment has also continued to soar. The hydrophobic surfaces of plastic particles can adsorb a variety of chemical pollutants, and could therefore facilitate toxin accumulation through the food chain. In this study, the adsorption behavior of aniline, a priority environmental pollutant from industrial production, on the surface of polystyrene microplastics (mPS) was investigated. The results showed that the maximum adsorption capacity of mPS was 0.060 mg/g. Adsorption equilibrium was reached after 24 h, and the pseudo-second-order model was employed to explain the adsorption kinetics of aniline on the mPS particles. The Freundlich models could describe the adsorption isotherms. The potential adsorption mechanisms may include π-π interactions and hydrophobic interactions. pH, ionic strength, and ambient temperature of the solution played important roles in the adsorption process.
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Contaminantes Ambientales , Contaminantes Químicos del Agua , Microplásticos/química , Plásticos/química , Poliestirenos/química , Adsorción , Compuestos de Anilina , Contaminantes Químicos del Agua/análisisRESUMEN
Background: Treatment options for patients with recurrent/metastatic nasopharyngeal carcinoma (RM-NPC) are not clear after progression on previous treatment with PD-(L)1 inhibitor; critical gaps in evidence remain for such cases. Immunotherapy combined with antiangiogenic therapy has been reported to have synergistic antitumor activity. Therefore, we evaluated the efficacy and safety of camrelizumab plus famitinib in patients with RM-NPC who failed treatment with PD-1 inhibitor-containing regimens. Methods: This multicenter, adaptive Simon minimax two-stage, phase II study enrolled patients with RM-NPC refractory to at least one line of systemic platinum-containing chemotherapy and anti-PD-(L)1 immunotherapy. The patient received camrelizumab 200 mg every 3 weeks and famitinib 20 mg once per day. The primary endpoint was objective response rate (ORR), and the study could be stopped early as criterion for efficacy was met (>5 responses). Key secondary endpoints included time to response (TTR), disease control rate (DCR), progression-free survival (PFS), duration of response (DoR), overall survival (OS), and safety. This trial was registered with ClinicalTrials.gov, NCT04346381. Findings: Between October 12, 2020, and December 6, 2021, a total of 18 patients were enrolled since six responses were observed. The ORR was 33.3% (90% CI, 15.6-55.4) and the DCR was 77.8% (90% CI, 56.1-92.0). The median TTR was 2.1 months, the median DoR was 4.2 months (90% CI, 3.0-not reach), and the median PFS was 7.2 months (90% CI, 4.4-13.3), with a median follow-up duration of 16.7 months. Treatment-related adverse events (TRAEs) of grade ≥3 were reported in eight (44.4%) patients, with the most common being decreased platelet count and/or neutropenia (n = 4, 22.2%). Treatment-related serious AEs occurred in six (33.3%) patients, and no deaths occurred due to TRAEs. Four patients developed grade ≥3 nasopharyngeal necrosis; two of them developed grade 3-4 major epistaxis, and they were cured by nasal packing and vascular embolization. Interpretation: Camrelizumab plus famitinib exhibited encouraging efficacy and tolerable safety profiles in patients with RM-NPC who failed frontline immunotherapy. Further studies are needed to confirm and expand these findings. Funding: Jiangsu Hengrui Pharmaceutical Co., Ltd.
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LSD1 is identified as an essential drug target, which is closely correlated to the development of several tumor types. In this work, on the basis of comprehensive analysis of the binding site of LSD1 and other FAD-dependent enzymes, a novel series of potent and selective LSD1 inhibitors were designed by incorporation of privileged indoline scaffold strategies. Representative compound 7e (LSD1; IC50 = 24.43 nM, selectivity over LSD2 and MAOs of >200- and 4000-fold) possessed selective antiproliferative activities against MV-4-11 cell lines. Further study indicates that 7e could activate CD86 expression (EC50 = 470 nM) and induce differentiation of AML cell lines. More importantly, compound 7e demonstrated an acceptable oral PK profile and good in vivo antitumor efficacy with a T/C value of 30.89% in an MV-4-11 xenograft mouse model. Collectively, this work provides a promising lead compound for the development of novel LSD1 inhibitors for the treatment of AML.
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Antineoplásicos , Leucemia Mieloide Aguda , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Proliferación Celular , Inhibidores Enzimáticos/química , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Histona Demetilasas , Humanos , Indoles , Leucemia Mieloide Aguda/tratamiento farmacológico , Lisina/farmacología , Ratones , Relación Estructura-ActividadRESUMEN
Approximately 20% of multiple myeloma (MM) are caused by a chromosomal translocation t (4; 14) that leads to the overexpression of the nuclear receptor binding SET domain-protein 2 (NSD2) histone methyltransferase. NSD2 catalyzes the methylation of lysine 36 on histone H3 (H3K36me2) and is associated with transcriptionally active regions. Using high-throughput screening (HTS) with biological analyses, a series of 5-aminonaphthalene derivatives were designed and synthesized as novel NSD2 inhibitors. Among all the prepared compounds, 9c displayed a good NSD2 inhibitory activity (IC50 = 2.7 µM) and selectivity against both SET-domain-containing and non-SET-domain-containing methyltransferases. Preliminary research indicates the inhibition mechanism of compound 9c by significantly suppressed the methylation of H3K36me2. Compound 9c specifically inhibits the proliferation of the human B cell precursor leukemia cell line RS4:11 and the human myeloma cell line KMS11 by inducing cell cycle arrest and apoptosis with little cytotoxicity. It has been reported that the anti-cancer effect of compound 9c is partly achieved by completely suppressing the transcriptional activation of NSD2-targeted genes. When administered intraperitoneally at 25 mg/kg, compound 9c suppressed the tumor growth of RS4:11 xenografts in vivo and no body weight loss was detected in the tested SCID mice.