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Background: Aumolertinib demonstrated superior progression-free survival (PFS) and a well-tolerated toxicity profile compared to gefitinib in front-line treatment of locally advanced or metastatic non-small cell lung cancer (NSCLC) in the AENEAS trial. However, patient-reported outcomes (PROs) of aumolertinib have not been published. Methods: In this real-world study, the efficacy was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) 1.0. PROs were evaluated using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 (QLQ-C30) and the EORTC Quality of Life lung cancer-specific module (QLQ-LC13) in advanced NSCLC patients receiving aumolertinib as initial therapy. Pre-specified key symptoms were cough, hemoptysis, dyspnea, sore mouth or tongue, dysphagia, hair loss, tingling in hands or feet, chest pain, arm or shoulder pain, and pain at other sites. Results: A total of 33 patients were included, 23 of whom had efficacy information up to January 2024. The median follow-up time was 264 days (interval: 36-491 days). The objective response rate and disease control rate were 65.2% and 91.3%, respectively. The EORTC QLQ-LC30 general health status scale showed that functional scales increased and symptom scales decreased during aumolertinib treatment. Symptom scales assessed by the EORTC QLQ-LC13 showed that improvements in cough, sore mouth or tongue, tingling in hands or feet, chest pain, arm or shoulder pain, and other pain sites were both clinically and statistically significant after 6 months of aumolertinib treatment (p < 0.05). Conclusion: In this real-world study, aumolertinib showed comparable disease control and objective response rates as reported in the AENEAS trial for advanced NSCLC patients with EGFR-sensitizing mutations. Aumolertinib treatment improved PROs, further supporting it in first-line clinical practice.
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Inspired by ecological floating beds to treat water pollution through photosynthesis, we employed a combination of calcination and hydrothermal methods to construct a photothermal-assisted photocatalysis system based on a floating monolithic porous mesh of g-C3N4 (MPMCN) loaded with the excellent photothermal material Bi2MoO6 (BMO), forming a BMO/MPMCN S-scheme heterojunction. This approach improved the utilization efficiency of solar light by BMO/MPMCN, minimized heat loss, and enhanced the overall temperature of the material during the reaction process, thereby accelerating interfacial electron transfer. The unique floating structure confers a larger specific surface area to BMO/MPMCN, providing more reaction sites for TC pollutants and efficiently removing TC contamination from water. BMO/MPMCN degradated 99.3% of TC after 90 min of photothermal reaction, and exhibited good recyclability and reusability. Structural and performance characterizations of the material were carried out using techniques such as XRD, TEM, electrochemical testing, and ESR. Furthermore, the corresponding band structure and S-scheme electron transfer mechanism of the BMO/MPMCN heterojunction were deduced through the combination of in-situ XPS and UPS. The possible degradation pathways of TC and the ecological toxicity changes of intermediate products were analyzed. Finally, a mechanistic model for the photothermal-assisted photocatalytic degradation of TC in water by the BMO/MPMCN S-scheme heterojunction was established, providing a novel approach for the practical application of photocatalysis technology.
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The RNA N6-methyladenosine (m6A) regulator METTL3 is an important regulatory gene in various progressive processes of prostate cancer (PCa). METTL3 inhibitors have been reported to possess potent tumor suppression capacity in some cancer types. Nevertheless, the detailed influence and mechanism of METTL3 inhibitors on PCa progression and their potential synergy with other drugs are poorly understood. In this study, we demonstrated that METTL3 was overexpressed and associated with poor survival in most PCa patients. METTL3 inhibitor STM2457 reduced m6A levels of PCa cells, thus inhibiting their proliferation, colony formation, migration, invasion, and stemness in vitro. Furthermore, STM2457 suppressed PCa progression in both the CDX and PDX models in vivo. MeRIP-seq analysis coupled with biological validation revealed that STM2457 influenced multiple biological processes in PCa cells, mainly through the IGFBP3/AKT pathway. We also proved that STM2457 induced DNA damage and showed synergistic anti-PCa effects with the PARP inhibitor olaparib both in vitro and in vivo. All in all, this work provides a novel therapeutic strategy for targeting RNA m6A modifications for the treatment of PCa and provides a meaningful reference for further clinical trials.
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Proliferación Celular , Progresión de la Enfermedad , Sinergismo Farmacológico , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina , Metiltransferasas , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Neoplasias de la Próstata , Proteínas Proto-Oncogénicas c-akt , Transducción de Señal , Masculino , Humanos , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Metiltransferasas/metabolismo , Metiltransferasas/antagonistas & inhibidores , Animales , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Línea Celular Tumoral , Transducción de Señal/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/farmacología , Ratones , Ensayos Antitumor por Modelo de Xenoinjerto , Ratones Desnudos , Movimiento Celular/efectos de los fármacos , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Adenosina/análogos & derivados , Adenosina/farmacologíaRESUMEN
Over the past two decades, molecular glues (MGs) have gradually attracted the attention of the pharmaceutical community with the advent of MG degraders such as IMiDs and indisulam. Such molecules degrade the target protein by promoting the interaction between the target protein and E3 ligase. In addition, as a chemical inducer, MGs promote the dimerization of homologous proteins and heterologous proteins to form ternary complexes, which have great prospects in regulating biological activities. This review focuses on the application of MGs in the field of drug development including protein-protein interaction (PPI) stability and protein degradation. We thoroughly analyze the structure of various MGs and the interactions between MGs and various biologically active molecules, thus providing new perspectives for the development of PPI stabilizers and new degraders.
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Proteínas , Humanos , Proteínas/química , Proteínas/metabolismo , Proteínas/antagonistas & inhibidores , Desarrollo de Medicamentos , Unión Proteica , Estructura Molecular , Proteolisis/efectos de los fármacosRESUMEN
Lattice-confined single-atom catalyst (LC SAC), featuring exceptional activity, intriguing stability and prominent selectivity, has attracted extensive attention in the fields of various reactions (e.g., hydrogen evolution reaction (HER), oxygen evolution reaction (OER), oxygen reduction reaction (ORR), etc.). To design a "smart" LC SAC for catalytic applications, one must systematically comprehend updated advances in the preparation, the application, and especially the peculiar electron regulation mechanism of LC SAC. In this review, the specific preparation methods of LC SAC based on general coordination strategy are updated, and its applications in HER, OER, ORR, N2 reduction reaction (NRR), advanced oxidation processes (AOPs) and so forth are summarized to display outstanding activity, stability and selectivity. Uniquely, the electron regulation mechanisms are first and deeply discussed and can be primarily categorized as electron transfer bridge with monometallic active sites, novel catalytic centers with polymetallic active sites, and positive influence by surrounding environments. In the end, the existing issues and future development directions are put forward with a view to further optimize the performance of LC SAC. This review is expected to contribute to the in-depth understanding and practical application of highly efficient LC SAC.
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Aqueous zinc-ion batteries are emerging as promising sustainable energy-storage devices. However, their cyclic stability is still a great challenge due to the inevitable parasitic reaction and dendrite growth induced by water. Herein, a cosolvent strategy based on competitive effect is proposed to address the aforementioned challenges. Ethanol with a higher Gutmann donor number demonstrates lower polarity and better wettability on the Zn surface compared with water, which endows ethanol with the ability of minimizing water activity by weakening H bonds and preferentially adsorbing on the Zn electrode. The above competitive advantages synergistically contribute to inhibiting the decomposition of free water and dendrite growth. Besides, an organic-inorganic hybrid solid-electrolyte interphase layer is in situ built based on ethanol additives, where organic matrix suppresses water corrosion while inorganic fillers promote fast Zn2+ diffusion. Consequently, the electrolyte with ethanol additives boosts a high reversibility of Zn deposition, long-term durability, as well as superior Zn2+ diffusibility in both Zn half-cells (Zn||Cu and Zn||Zn batteries) and Zn full cells (Zn||PTCDA and Zn||VO2 batteries). This work sheds light on a universal strategy to design a high-reversible and dendrite-free Zn anode for stable aqueous batteries.
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BACKGROUND: Patients with extensive-stage small cell lung cancer (ES-SCLC) have an exceptionally poor prognosis and immune checkpoint inhibitors (ICIs) combined with etoposide-platinum is recommended as standard first-line therapy. However, which combination pattern is the best still remains unknown. This network meta-analysis was performed to compare the efficacy and safety of currently available patterns including an antiangiogenic agent containing regimen and probed into the most appropriate therapy for patients. METHODS: Hazard ratios (HRs) and odds ratios (ORs) were generated using R software. The outcomes of overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and adverse events of grade 3 or higher (grade ≥ 3 adverse events [AEs]) were analyzed. RESULTS: A total of 10 randomized controlled trials (RCTs) involving 5544 patients were included for analysis. Drug combination patterns included adebrelimab, atezolizumab, durvalumab, durvalumab plus tremelimumab, ipilimumab, pembrolizumab, serplulimab, benmelstobart plus anlotinib, tislelizumab, tiragolumab plus atezolizumab and toripalimab in combination with chemotherapy. The novel antiangiogenic agent containing regimen benmelstobart + anlotinib + chemotherapy showed the highest possibility to present the best PFS and OS versus chemotherapy. Compared with ICI plus chemotherapy, it also achieved significantly better PFS and presented a tendency of OS benefit. As for safety and toxicity, patients treated with benmelstobart + anlotinib + chemotherapy and durvalumab + tremelimumab + chemotherapy suffered a higher likelihood of more grade ≥ 3 AEs without unexpected AEs. CONCLUSION: PD-1/PD-L1 inhibitors-based combinations are associated with significant improvement in both PFS and OS for treatment-naïve ES-SCLC patients. Benmelstobart plus anlotinib with chemotherapy (CT) yielded better survival benefit versus CT alone or other ICIs + CT with caution for more adverse effects along with the addition of an antiangiogenic agent.
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Protocolos de Quimioterapia Combinada Antineoplásica , Inhibidores de Puntos de Control Inmunológico , Neoplasias Pulmonares , Metaanálisis en Red , Carcinoma Pulmonar de Células Pequeñas , Humanos , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/patología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéuticoRESUMEN
The development of a solid-state electrolyte (SSE) is crucial for overcoming the side reactions of metal potassium anodes and advancing the progress of K-ion batteries (KIBs). Exploring the diffusion mechanism of the K ion in SSE is important for deepening our understanding and promoting its development. In this study, we conducted static calculations and utilized deep potential molecular dynamics (DeepMD) to investigate the behavior of cubic K3SbS4. The original K3SbS4 exhibited poor ionic conductivity, but we discovered that introducing heterovalent tungsten doping created vacancies, which significantly reduced the activation energy to 0.12 eV and enhanced the ionic conductivity to 1.80 × 10-2 S/cm. The diffusion of K-ions in K3SbS4 primarily occurs through the exchange of positions with K vacancies. This research provides insights into the design of SSE with high ionic conductivity. Furthermore, it highlights the effectiveness of DeepMD as a powerful tool for studying the SSE.
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Infection, autoimmunity, and cancer are principal human health challenges of the 21st century. Often regarded as distinct ends of the immunological spectrum, recent studies hint at potential overlap between these diseases. For example, inflammation can be pathogenic in infection and autoimmunity. T resident memory (TRM) cells can be beneficial in infection and cancer. However, these findings are limited by size and scope; exact immunological factors shared across diseases remain elusive. Here, we integrate large-scale deeply clinically and biologically phenotyped human cohorts of 526 patients with infection, 162 with lupus, and 11,180 with cancer. We identify an NKG2A+ immune bias as associative with protection against disease severity, mortality, and autoimmune/post-acute chronic disease. We reveal that NKG2A+ CD8+ T cells correlate with reduced inflammation and increased humoral immunity and that they resemble TRM cells. Our results suggest NKG2A+ biases as a cross-disease factor of protection, supporting suggestions of immunological overlap between infection, autoimmunity, and cancer.
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Enfermedades Autoinmunes , Enfermedades Transmisibles , Neoplasias , Humanos , Linfocitos T CD8-positivos , Neoplasias/patología , Autoinmunidad , Inflamación/patología , Enfermedades Autoinmunes/patología , Enfermedades Transmisibles/patología , Memoria InmunológicaRESUMEN
Cyano-containing electrodes usually promise high theoretical potentials while suffering from uncontrollable self-dissolution and sluggish reaction kinetics. Herein, to remedy their limitations, an unprecedented core-shell heterostructured electrode of carbon nanotubes encapsulated in poly(1,4-dicyanoperfluorobenzene sulfide) (CNT@PFDCB) is rationally crafted via molecule and microstructure modulations. Specifically, the linkage of sulfide bridges of PFDCB prevents the active cyano groups from dissolving, resulting in a robust structure. The fluorinations modulate the electronic configurations in frontier orbitals, allowing higher electrical conductivity and elevated output voltage. Combined with the core-shell architecture to unlock the sluggish diffusion kinetics for both electrons and guest ions, the CNT@PFDCB exhibits an impressive capacity (203.5â mAh g-1), remarkable rate ability (127.6â mAh g-1 at 3.0â A g-1), and exceptional cycling stability (retaining 81.1 % capacity after 3000â cycles at 1.0â A g-1). Additionally, the Li-storage mechanisms regarding PFDCB are thoroughly revealed by in situ attenuated total reflection infrared spectroscopy, in situ Raman spectroscopy, and theoretical simulations, which involve the coordination interaction between Li ions and cyano groups and the electron delocalization along the conjugated skeleton. More importantly, a practical fully organic cell based on the CNT@PFDCB is well-validated that demonstrates a tremendous potential of cyanopolymer as the cathode to replace its inorganic counterparts.
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Androgen receptor (AR) antagonists play important roles in the treatment of castration-resistant prostate cancer (CRPC). The glucocorticoid receptor (GR) upregulation leads to drug resistance for clinically used antiandrogens. Therefore, blocking AR/GR signaling simultaneously has become an efficient strategy to overcome the drug resistance of CRPC. Our previous work indicated that Z19 could inhibit the activity of both AR and GR. Herein, we optimized the structure of Z19 and identified GA32 as a potent AR/GR dual inhibitor. GA32 efficiently reduced the mRNA and protein levels of AR/GR downstream genes. GA32 efficiently inhibited the proliferation of enzalutamide resistance CRPC both in vitro and in vivo. GA32 could directly bind to AR and GR, and the predicted binding modes for GA32 with AR/GR suggested that GA32 binds to the AR or GR hormone binding pocket. This work provides a potential lead compound with dual AR/GR inhibitory activity to conquer the drug resistance of CRPC.
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Neoplasias de la Próstata Resistentes a la Castración , Receptores Androgénicos , Masculino , Humanos , Receptores Androgénicos/metabolismo , Antagonistas de Andrógenos/farmacología , Antagonistas de Andrógenos/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Receptores de Glucocorticoides/metabolismo , Resistencia a Antineoplásicos , Antagonistas de Receptores Androgénicos/farmacología , Antagonistas de Receptores Androgénicos/uso terapéutico , Nitrilos/uso terapéutico , Línea Celular TumoralRESUMEN
Infection, autoimmunity, and cancer are the principal human health challenges of the 21st century and major contributors to human death and disease. Often regarded as distinct ends of the immunological spectrum, recent studies have hinted there may be more overlap between these diseases than appears. For example, pathogenic inflammation has been demonstrated as conserved between infection and autoimmune settings. T resident memory (TRM) cells have been highlighted as beneficial for infection and cancer. However, these findings are limited by patient number and disease scope; exact immunological factors shared across disease remain elusive. Here, we integrate large-scale deeply clinically and biologically phenotyped human cohorts of 526 patients with infection, 162 with lupus, and 11,180 with cancer. We identify an NKG2A+ immune bias as associative with protection against disease severity, mortality, and autoimmune and post-acute chronic disease. We reveal that NKG2A+ CD8+ T cells correlate with reduced inflammation, increased humoral immunity, and resemble TRM cells. Our results suggest that an NKG2A+ bias is a pan-disease immunological factor of protection and thus supports recent suggestions that there is immunological overlap between infection, autoimmunity, and cancer. Our findings underscore the promotion of an NKG2A+ biased response as a putative therapeutic strategy.
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Ferroptosis is a newly discovered iron-dependent form of regulated cell death driven by phospholipid peroxidation and associated with processes including iron overload, lipid peroxidation, and dysfunction of cellular antioxidant systems. Ferroptosis is found to be closely related to many diseases, including cancer at every stage. Epithelial-mesenchymal transition (EMT) in malignant tumors that originate from epithelia promotes cancer-cell migration, invasion, and metastasis by disrupting cell-cell and cell-cell matrix junctions, cell polarity, etc. Recent studies have shown that ferroptosis appears to share multiple initiators and overlapping pathways with EMT in cancers and identify ferroptosis as a potential predictor of various cancer grades and prognoses. Cancer metastasis involves multiple steps, including local invasion of cancer cells, intravasation, survival in circulation, arrest at a distant organ site, extravasation and adaptation to foreign tissue microenvironments, angiogenesis, and the formation of "premetastatic niche". Numerous studies have revealed that ferroptosis is closely associated with cancer metastasis. From the cellular perspective, ferroptosis has been implicated in the regulation of cancer metastasis. From the molecular perspective, the signaling pathways activated during the two events interweave. This review briefly introduces the mechanisms of ferroptosis and discusses how ferroptosis is involved in cancer progression, including EMT, cancer angiogenesis, invasion, and metastasis.
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Ferroptosis , Neoplasias , Humanos , Neoplasias/patología , Hierro/metabolismo , Transición Epitelial-Mesenquimal/fisiología , Peroxidación de Lípido , Microambiente TumoralRESUMEN
In order to reduce the digestion rate of starch in human body and improve the content of slowly digestible starch (SDS) and resistant starch (RS), millimeter calcium alginate beads encapsulated with different proportions of recrystallized starch were constructed in this study. First, we prepared recrystallized starch (RS3) by debranching waxy corn starch and retrogradation, and then encapsulated RS3 in calcium alginate beads by the ionic gel method. The microstructure of the beads was observed by scanning electron microscope, and the gel texture properties, swelling properties, and in vitro digestibility of the beads were studied. The results showed that the beads after cooking still maintained high hardness and chewiness, and the swelling power and solubility of the beads were lower than that of native starch. Compared with native starch, the content of rapidly digestible starch (RDS) in beads decreased, while the content of SDS and RS increased. The sample with the highest content of RS is RS31@Alginate1, whose content of RS is 70.10%, 52.11 times higher than that of waxy corn starch and 1.75 times higher than that of RS3. RS3 encapsulated in calcium alginate beads has a good encapsulation effect, and the content of SDS and RS is greatly increased. This study has important implications for reducing the digestion rate of starch and regulating the health of people with diabetes and obesity.
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MoS2 is regarded as a hopeful anode candidate for sodium-ion batteries (SIBs) due to their various merits such as high specific capacity, abundant raw material reserves and low cost. However, their practical application is impeded by unsatisfied cycling ability due to the intense mechanical stress and unstable solid electrolyte interphase (SEI) during Na+ insertion/extraction process. Herein, spherical MoS2@polydopamine derived highly conductive N-doped carbon (NC) shell composites (MoS2@NC) are designed and synthesized to promote the cycling stability. The internal MoS2 core is optimized and restructured from the original micron-sized block to the ultra-fine nanosheets during initial 100-200 cycles, which not only improves the utilization of electrode materials but also shortens the ion transport distance. The outer flexible NC shell effectively maintains the original spherical structure of the overall electrode material and prevents the occurrence of large-scale agglomeration, which is conducive to form a stable SEI layer. Therefore, the core-shell MoS2@NC electrode presents a remarkable cyclic stability and a capable rate performance. Under a high rate of 20 A g-1, the high capacity of 428 mAh g-1 can be acquired after over ultra-long 10,000 cycles without obvious capacity loss. Moreover, the MoS2@NCâNa3V2(PO4)3 full-cell assembled by employing commercial Na3V2(PO4)3 cathode can achieve a high capacity retention of 91.4% after 250 cycles at 0.4 A g-1. This work reveals the promising prospect of MoS2-based materials as anode of SIBs, and also has some inspirations on the structural design for conversion-type electrode materials.
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The discovery and characterization of antigen-specific CD8+ T cell clonotypes typically involves the labor-intensive synthesis and construction of peptide-MHC tetramers. We adapt single-chain trimer (SCT) technologies into a high throughput platform for pMHC library generation, showing that hundreds can be rapidly prepared across multiple Class I HLA alleles. We use this platform to explore the impact of peptide and SCT template mutations on protein expression yield, thermal stability, and functionality. SCT libraries were an efficient tool for identifying T cells recognizing commonly reported viral epitopes. We then construct SCT libraries to capture SARS-CoV-2 specific CD8+ T cells from COVID-19 participants and healthy donors. The immunogenicity of these epitopes is validated by functional assays of T cells with cloned TCRs captured using SCT libraries. These technologies should enable the rapid analyses of peptide-based T cell responses across several contexts, including autoimmunity, cancer, or infectious disease.
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Linfocitos T CD8-positivos , COVID-19 , Humanos , SARS-CoV-2/genética , Antígenos , Epítopos , Péptidos/genéticaRESUMEN
In patients with castration-resistant prostate cancer (CRPC), clinical resistances such as androgen receptor (AR) mutation, AR overexpression, and AR splice variants (ARVs) limit the effectiveness of second-generation antiandrogens (SGAs). Several strategies have been implemented to develop novel antiandrogens to circumvent the occurring resistance. Here, we found and identified a bifunctional small molecule Z15, which is both an effective AR antagonist and a selective AR degrader. Z15 could directly interact with the ligand-binding domain (LBD) and activation function-1 region of AR, and promote AR degradation through the proteasome pathway. In vitro and in vivo studies showed that Z15 efficiently suppressed AR, AR mutants and ARVs transcription activity, downregulated mRNA and protein levels of AR downstream target genes, thereby overcoming AR LBD mutations, AR amplification, and ARVs-induced SGAs resistance in CRPC. In conclusion, our data illustrate the synergistic importance of AR antagonism and degradation in advanced prostate cancer treatment.
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Neoplasias de la Próstata Resistentes a la Castración , Receptores Androgénicos , Masculino , Humanos , Receptores Androgénicos/metabolismo , Antagonistas de Andrógenos/farmacología , Antagonistas de Andrógenos/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/metabolismo , Transducción de Señal , Antagonistas de Receptores Androgénicos/farmacología , Antagonistas de Receptores Androgénicos/uso terapéutico , Línea Celular Tumoral , Resistencia a Antineoplásicos , Nitrilos/farmacología , Nitrilos/uso terapéuticoRESUMEN
The androgen receptor (AR) is dominant in prostate cancer (PCa) pathology. Current therapeutic agents for advanced PCa include androgen synthesis inhibitors and AR antagonists that bind to the hormone binding pocket (HBP) at the ligand binding domain (LBD). However, AR amplification, AR splice variants (AR-Vs) expression, and intra-tumoral de novo synthesis of androgens result in the reactivation of AR signalling. The AR N-terminal domain (NTD) plays an essential role in AR transcriptional activity. The AR inhibitor targeting NTD could potentially block the activation of both full-length AR and AR-Vs, thus overcoming major resistance mechanisms to current treatments. This review discusses the progress of research in various NTD inhibitors and provides new insight into the development of AR-NTD inhibitors.
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Neoplasias de la Próstata Resistentes a la Castración , Neoplasias de la Próstata , Masculino , Humanos , Receptores Androgénicos/metabolismo , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Andrógenos/metabolismo , Andrógenos/uso terapéutico , Antagonistas de Receptores Androgénicos/farmacología , Antagonistas de Receptores Androgénicos/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Dominios ProteicosRESUMEN
CD8 + cytotoxic T cell responses against viral infection represent a major element of the adaptive immune response. We describe the development of a peptide antigen - major histompatibility complex (pMHC) library representing the full SARS-CoV-2 viral proteome, and comprised of 634 pMHC multimers representing the A*02.01, A*24.02, and B*07.02 HLA alleles, as well as specific antigens associated with the cytomegalovirus (CMV). These libraries were used to capture non-expanded CD8 + T cells from blood samples collected from 64 infected individuals, and then analyzed using single cell RNA-seq. The discovery and characterization of antigen-specific CD8 + T cell clonotypes typically involves the labor-intensive synthesis and construction of peptide-MHC tetramers. We adapted single-chain trimer (SCT) technologies into a high throughput platform for pMHC library generation, showing that hundreds can be rapidly prepared across multiple Class I HLA alleles. We used this platform to explore the impact of peptide and SCT template mutations on protein expression yield, thermal stability, and functionality. SCT libraries were an efficient tool for identifying T cells recognizing commonly reported viral epitopes. We then constructed SCT libraries designed to capture SARS-CoV-2 specific CD8 + T cells from COVID-19 participants and healthy donors. The immunogenicity of these epitopes was validated by functional assays of T cells with cloned TCRs captured using SCT libraries. These technologies should enable the rapid analyses of peptide-based T cell responses across several contexts, including autoimmunity, cancer, or infectious disease.
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Prostate cancer (PCa) is the most frequently diagnosed male malignant tumor and remains the second leading cause of male cancer mortality in western countries. The development of novel antiandrogens to circumvent the drug resistance in anti-PCa treatment is highly demanded. Herein, we identified that gossypol (GOS) specificly inhibited the AR signaling. Further optimization of GOS derivatives led to the discovery of compound XY-32. XY-32 efficiently inhibits AR signaling with the IC50 of 1.23 µM. XY-32 downregulates both the full-length AR and the AR variable splice AR-V7 via suppressing the mRNA expression. It inhibits the proliferation of CRPC cells such as the LNCaP cells, the PC-3 cells, and enzalutamide resistance 22Rv1 cells. The work demonstrates the GOS derivatives represent a novel series of anti-androgen to conquer the acquired AR mutations or AR splice variants induced drug resistance of mCRPC.