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Adult oligodendrocyte progenitors (aOPCs) generate myelinating oligodendrocytes like neonatal progenitors (nOPCs), and they also display unique functional features. Here, using unbiased histone proteomics analysis and ChIP sequencing analysis of PDGFRα+ OPCs sorted from neonatal and adult Pdgfra-H2B-EGFP reporter mice, we identify the activating H4K8ac histone mark as enriched in the aOPCs. We detect increased occupancy of the H4K8ac activating mark at chromatin locations corresponding to genes related to the progenitor state (e.g., Hes5, Gpr17), metabolic processes (e.g., Txnip, Ptdgs), and myelin components (e.g., Cnp, Mog). aOPCs showed higher levels of transcripts related to lipid metabolism and myelin, and lower levels of transcripts related to cell cycle and proliferation compared with nOPCs. In addition, pharmacological inhibition of histone acetylation decreased the expression of the H4K8ac target genes in aOPCs and decreased their proliferation. Overall, this study identifies acetylation of the histone H4K8 as a regulator of the proliferative capacity of aOPCs.
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Proliferación Celular , Histonas , Células Precursoras de Oligodendrocitos , Animales , Histonas/metabolismo , Histonas/genética , Acetilación , Células Precursoras de Oligodendrocitos/metabolismo , Células Precursoras de Oligodendrocitos/citología , Ratones , Oligodendroglía/metabolismo , Oligodendroglía/citología , Diferenciación Celular , Células Cultivadas , Ratones Endogámicos C57BLRESUMEN
Proneural gliomas are brain tumors characterized by enrichment of oligodendrocyte progenitor cell (OPC) transcripts and genetic alterations. In this study we sought to identify transcriptional and epigenetic differences between OPCs with Trp53 deletion and PDGF-BB overexpression (BB-p53n), which form tumors when transplanted in mouse brains, and those carrying only p53 deletion (p53n), which do not. We used unbiased histone proteomics and RNA-seq analysis on these two genetically modified OPC populations and detected higher levels of H3K27me3 in BB-p53n compared to p53n OPCs. The BB-p53n OPC were characterized by higher levels of transcripts related to proliferation and lower levels of those related to differentiation. Pharmacological inhibition of histone H3K27 trimethylation in BB-p53n OPC reduced cell cycle transcripts and increased the expression of differentiation markers. These data suggest that PDGF-BB overexpression in p53 null OPC results in histone post-translational modifications and consequent transcriptional changes favoring proliferation while halting differentiation, thereby promoting the early stages of transformation.
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SUMMARY Dansu et al. identify distinct histone H4 modifications as potential mechanism underlying the functional differences between adult and neonatal progenitors. While H4K8ac favors the expression of differentiation genes, their expression is halted by H4K20me3. Adult oligodendrocyte progenitors (aOPCs) generate myelinating oligodendrocytes, like neonatal progenitors (nOPCs), but they also display unique functional features. Here, using RNA-sequencing, unbiased histone proteomics analysis and ChIP-sequencing, we define the transcripts and histone marks underlying the unique properties of aOPCs. We describe the lower proliferative capacity and higher levels of expression of oligodendrocyte specific genes in aOPCs compared to nOPCs, as well as the greater levels of H4 histone marks. We also report increased occupancy of the H4K8ac mark at chromatin locations corresponding to oligodendrocyte-specific transcription factors and lipid metabolism genes. Pharmacological inhibition of H4K8ac deposition reduces the levels of these transcripts in aOPCs, rendering their transcriptome more similar to nOPCs. The repressive H4K20me3 mark is also higher in aOPCs compared to nOPCs and pharmacological inhibition of its deposition results in increased levels of genes related to the mature oligodendrocyte state. Overall, this study identifies two histone marks which are important for the unique transcriptional and functional identity of aOPCs.
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Two-dimensional (2D) van der Waals (vdW) materials offer rich tuning opportunities generated by different stacking configurations or by introducing intercalants into the vdW gaps. Current knowledge of the interplay between stacking polytypes and intercalation often relies on macroscopically averaged probes, which fail to pinpoint the exact atomic position and chemical state of the intercalants in real space. Here, by using atomic-resolution electron energy-loss spectroscopy in a scanning transmission electron microscope, we visualize a stacking-selective self-intercalation phenomenon in thin films of the transition-metal dichalcogenide (TMDC) Nb1+xSe2. We observe robust contrasts between 180°-stacked layers with large amounts of Nb intercalants inside their vdW gaps and 0°-stacked layers with little detectable intercalants inside their vdW gaps, coexisting on the atomic scale. First-principles calculations suggest that the films lie at the boundary of a phase transition from 0° to 180° stacking when the intercalant concentration x exceeds ~0.25, which we could attain in our films due to specific kinetic pathways. Our results offer not only renewed mechanistic insights into stacking and intercalation, but also open up prospects for engineering the functionality of TMDCs via stacking-selective self-intercalation.
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Protein clustering is a powerful form of optogenetic control, yet remarkably few proteins are known to oligomerize with light. Recently, the photoreceptor BcLOV4 was found to form protein clusters in mammalian cells in response to blue light, although clustering coincided with its translocation to the plasma membrane, potentially constraining its application as an optogenetic clustering module. Herein we identify key amino acids that couple BcLOV4 clustering to membrane binding, allowing us to engineer a variant that clusters in the cytoplasm and does not associate with the membrane in response to blue light. This variant-called BcLOVclust-clustered over many cycles with substantially faster clustering and de-clustering kinetics compared to the widely used optogenetic clustering protein Cry2. The magnitude of clustering could be strengthened by appending an intrinsically disordered region from the fused in sarcoma (FUS) protein, or by selecting the appropriate fluorescent protein to which it was fused. Like wt BcLOV4, BcLOVclust activity was sensitive to temperature: light-induced clusters spontaneously dissolved at a rate that increased with temperature despite constant illumination. At low temperatures, BcLOVclust and Cry2 could be multiplexed in the same cells, allowing light control of independent protein condensates. BcLOVclust could also be applied to control signaling proteins and stress granules in mammalian cells. While its usage is currently best suited in cells and organisms that can be cultured below â¼30 °C, a deeper understanding of BcLOVclust thermal response will further enable its use at physiological mammalian temperatures.
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Proteínas Adaptadoras Transductoras de Señales , Criptocromos , Proteínas de la Matriz de Golgi , Optogenética , Animales , Membrana Celular/química , Membrana Celular/efectos de la radiación , Análisis por Conglomerados , Citoplasma/química , Citoplasma/efectos de la radiación , Luz , Criptocromos/química , Criptocromos/efectos de la radiación , Proteínas de la Matriz de Golgi/química , Proteínas de la Matriz de Golgi/efectos de la radiación , Proteínas Adaptadoras Transductoras de Señales/química , Proteínas Adaptadoras Transductoras de Señales/efectos de la radiación , Multimerización de ProteínaRESUMEN
Cancer vaccines have attracted widespread interest in tumor therapy because of the potential to induce an effective antitumor immune response. However, many challenges including weak immunogenicity, off-target effects, and immunosuppressive microenvironments have prevented their broad clinical translation. To overcome these difficulties, effective delivery systems have been designed for cancer vaccines. As carriers in cancer vaccine delivery systems, hydrogels have gained substantial attention because they can encapsulate a variety of antigens/immunomodulators and protect them from degradation. This enables hydrogels to simultaneously reverse immunosuppression and stimulate the immune response. Meanwhile, the controlled release properties of hydrogels allow for precise temporal and spatial release of loads in situ to further enhance the immune response of cancer vaccines. Therefore, this review summarizes the classification of cancer vaccines, highlights the strategies of hydrogel-based cancer vaccines, and provides some insights into the future development of hydrogel-based cancer vaccines.
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Vacunas contra el Cáncer , Neoplasias , Humanos , Hidrogeles , Inmunoterapia , Adyuvantes Inmunológicos , Inmunidad , Neoplasias/terapia , Microambiente TumoralRESUMEN
Maternal stress during pregnancy exerts long-term effects on the mental well-being of the offspring. However, the long-term effect of prenatal exposure on the offspring's mental status is only partially understood. The placenta plays a vital role in connecting the maternal side to the fetus, thereby serving as an important interface between maternal exposure and fetal development. Here, we profiled the placental transcriptome of women who were pregnant during a hurricane (Superstorm Sandy), which struck New York City in 2012. The offspring were followed longitudinally and their temperament was assessed during the first 6-12 months of age. The data identified a significant correlation between a Superstorm Sandy stress factor score and infant temperament. Further, analysis of the placental transcriptomes identified an enrichment of functional pathways related to inflammation, extracellular matrix integrity and sensory perception in the specimen from those infants with "Slow-to-Warm-up" temperament during the first year of life. Together, these findings provide initial evidence that maternal exposure to climate-related disasters results in altered placental transcriptome, which may be related to long-term emotional and behavioral consequences in children.
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Cells elaborate transcriptional programs in response to external signals. In the peripheral nerves, Schwann cells (SC) sort axons of given caliber and start the process of wrapping their membrane around them. We identify Actin-like protein 6a (ACTL6a), part of SWI/SNF chromatin remodeling complex, as critical for the integration of axonal caliber recognition with the transcriptional program of myelination. Nuclear levels of ACTL6A in SC are increased by contact with large caliber axons or nanofibers, and result in the eviction of repressive histone marks to facilitate myelination. Without Actl6a the SC are unable to coordinate caliber recognition and myelin production. Peripheral nerves in knockout mice display defective radial sorting, hypo-myelination of large caliber axons, and redundant myelin around small caliber axons, resulting in a clinical motor phenotype. Overall, this suggests that ACTL6A is a key component of the machinery integrating external signals for proper myelination of the peripheral nerve.
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Aim: To explore the relationship between mutations in cfDNA and response to afatinib. Patients & methods: In total, 64 patients from one Chinese site with locally advanced/metastatic EGFRm+ non-small-cell lung cancer, who received afatinib 40 mg once daily, were included. Results: Overall, 33 (82.5%) patients became EGFRm- by visit 3; median progression-free survival was longer in these patients vs those who did not (11.0 vs 5.5 months). Progression-free survival was shorter in 42 (45.2%) patients with non-EGFR co-mutations at baseline vs those without (8.1 vs 12.5 months). Neither difference was significant. Conclusion: Afatinib provided clinical benefit for patients with EGFRm+ non-small-cell lung cancer across all subgroups. EGFRm status assessment in plasma cfDNA is a useful method of monitoring treatment.
We conducted a study in 64 Chinese patients with non-small-cell lung cancer to investigate the relationship between cancer mutations detected in the blood and the response to treatment with afatinib, which is known to be effective against EGFR mutations. Technology is now available to detect these mutations in the blood, as an alternative to obtaining and testing lung tissue samples. All 64 patients had EGFR mutations (and some patients had additional types of mutations) when afatinib was started (visit 1 in the study). By visit 3, most patients (82.5%) no longer had EGFR mutations detected in their blood, and these patients responded better to afatinib than those who still had EGFR mutations in their blood. Patients with additional types of mutations generally did not respond as well as those who had only EGFR mutations. Although results showed clinical benefit with afatinib using assessment of mutation status in the blood, statistical significance could not be shown due to the small size of the study. Clinical Trial Registration: NCT01953913 (ClinicalTrials.gov).
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Afatinib/uso terapéutico , Biomarcadores , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Mutación , Inhibidores de Proteínas Quinasas/uso terapéuticoRESUMEN
BACKGROUND: Afatinib has been shown as a suitable option for the treatment of epidermal growth factor receptor mutation-positive (EGFRm+) non-small-cell lung cancer (NSCLC) in randomized controlled trials. However, patients treated in real-world clinical practice, including elderly patients, and those with brain metastases or poor Eastern Cooperative Oncology Group (ECOG) performance statuses, are often excluded from these studies. OBJECTIVE: To report the final results, with a particular focus on patients enrolled in China, from a prospective phase IIIb, "near real-world" study of afatinib in tyrosine kinase inhibitor (TKI)-naïve Asian patients with EGFRm+ NSCLC. PATIENTS AND METHODS: NCT01953913 was conducted at 34 centers across Asia. Entry criteria were broad to reflect real-world settings. Patients received afatinib 40 mg/day until tumor progression, lack of clinical benefit, or poor tolerability. Assessments included safety, time to symptomatic progression (TTSP), and progression-free survival (PFS). RESULTS: 541 patients were treated, of whom 412 were enrolled in China. Dose reductions were implemented in 28.7% of patients overall, and 17.7% of patients from China. Safety findings were consistent with phase III studies of afatinib. Median TTSP in all patients was 14.0 months (95% CI 12.9-15.9), and median PFS was 12.1 months (95% CI 11.0-13.6). Median TTSP (13.8 months, 95% CI 12.7-16.1) and PFS (11.4 months, 95% CI 10.9-13.7) were similar in patients from China to the overall population. Among patients from China who had dose reductions, TTSP was numerically longer than in those who did not (16.4 vs. 13.8 months; P = 0.0703), while PFS was significantly longer (13.9 vs. 11.1 months; P = 0.0275). Among patients from China with brain metastases, TTSP was numerically shorter than in those without (11.0 vs. 14.4 months; P = 0.0869), whereas PFS was significantly shorter (9.2 vs. 12.9 months; P = 0.0075). CONCLUSIONS: Safety data for afatinib when used in a "near real-world" setting in patients with EGFRm+ NSCLC was consistent with the known safety profile of afatinib. Supporting efficacy data of afatinib were provided in all patients, and in those enrolled in China. Tolerability-guided afatinib dose reduction allowed patients to remain on treatment and continue to experience clinical benefit. TRIAL REGISTRATION NUMBER AND DATE OF REGISTRATION: NCT01953913 (1 October 2013).
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Neoplasias Encefálicas , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Afatinib/farmacología , Afatinib/uso terapéutico , Anciano , Neoplasias Encefálicas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/patología , Mutación , Estudios Prospectivos , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Resultado del TratamientoRESUMEN
The considerable development of carrier-free nanodrugs has been achieved due to their high drug-loading capability, simple preparation method, and offering "all-in-one" functional platform features. However, the native defects of carrier-free nanodrugs limit their delivery and release behavior throughout the in vivo journey, which significantly compromise the therapeutic efficacy and hinder their further development in cancer treatment. In this review, we summarized and discussed the recent strategies to enhance drug delivery and release of carrier-free nanodrugs for improved cancer therapy, including optimizing the intrinsic physicochemical properties and external modification. Finally, the corresponding challenges that carrier-free nanodrugs faced are discussed and the future perspectives for its application are presented. We hope this review will provide constructive information for the rational design of more effective carrier-free nanodrugs to advance therapeutic treatment.
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SPOP, an E3 ubiquitin ligase, acts as a prostate-specific tumor suppressor with several key substrates mediating oncogenic function. However, the mechanisms underlying SPOP regulation are largely unknown. Here, we have identified G3BP1 as an interactor of SPOP and functions as a competitive inhibitor of Cul3SPOP, suggesting a distinctive mode of Cul3SPOP inactivation in prostate cancer (PCa). Transcriptomic analysis and functional studies reveal a G3BP1-SPOP ubiquitin signaling axis that promotes PCa progression through activating AR signaling. Moreover, AR directly upregulates G3BP1 transcription to further amplify G3BP1-SPOP signaling in a feed-forward manner. Our study supports a fundamental role of G3BP1 in disabling the tumor suppressive Cul3SPOP, thus defining a PCa cohort independent of SPOP mutation. Therefore, there are significantly more PCa that are defective for SPOP ubiquitin ligase than previously appreciated, and these G3BP1high PCa are more susceptible to AR-targeted therapy.
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Proteínas Cullin/antagonistas & inhibidores , ADN Helicasas/metabolismo , Proteínas Nucleares/antagonistas & inhibidores , Proteínas de Unión a Poli-ADP-Ribosa/metabolismo , Neoplasias de la Próstata/metabolismo , ARN Helicasas/metabolismo , Proteínas con Motivos de Reconocimiento de ARN/metabolismo , Receptores Androgénicos/metabolismo , Proteínas Represoras/antagonistas & inhibidores , Antagonistas de Receptores Androgénicos/farmacología , Animales , Carcinogénesis , Línea Celular Tumoral , Movimiento Celular , Supervivencia Celular/efectos de los fármacos , Proteínas Cullin/metabolismo , ADN Helicasas/genética , Regulación Neoplásica de la Expresión Génica , Humanos , Masculino , Ratones , Mutación , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas de Unión a Poli-ADP-Ribosa/genética , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , ARN Helicasas/genética , Proteínas con Motivos de Reconocimiento de ARN/genética , Proteínas Represoras/genética , Proteínas Represoras/metabolismo , Transducción de Señal/efectos de los fármacos , Ubiquitina-Proteína Ligasas/antagonistas & inhibidores , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismoRESUMEN
The normal androgen receptor (AR) cistrome and transcriptional program are fundamentally altered in prostate cancer (PCa). Here, we profile the chromatin landscape and AR-directed transcriptional program in normal prostate cells and show the impact of SPOP mutations, an early event in prostate tumorigenesis. In genetically normal mouse prostate organoids, SPOP mutation results in accessibility and AR binding patterns similar to that of human PCa. Consistent with dependence on AR signaling, castration of SPOP mutant mouse models results in the loss of neoplastic phenotypes, and human SPOP mutant PCa shows a favorable response to AR-targeted therapies. Together, these data validate mouse prostate organoids as a robust model for studying epigenomic and transcriptional alterations in normal prostate, provide valuable datasets for further studies, and show that a single genomic alteration may be sufficient to reprogram the chromatin of normal prostate cells toward oncogenic phenotypes, with potential therapeutic implications for AR-targeting therapies.
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Cromatina/metabolismo , Regulación Neoplásica de la Expresión Génica/genética , Próstata/metabolismo , Neoplasias de la Próstata/metabolismo , Andrógenos/inmunología , Animales , Carcinogénesis/genética , Masculino , Ratones Transgénicos , Neoplasias de la Próstata/genética , Receptores Androgénicos/metabolismo , Proteínas Represoras/metabolismo , Transducción de Señal/fisiologíaRESUMEN
INTRODUCTION: Insulin-like growth factor signaling has been implicated in acquired resistance to EGFR tyrosine kinase inhibitors (TKIs) in NSCLC. This phase 1 trial (NCT02191891) investigated the combination of xentuzumab (an insulin-like growth factor-ligand neutralizing monoclonal antibody) and afatinib (an EGFR TKI) in patients with previously treated EGFR mutation-positive NSCLC. METHODS: The trial comprised dose escalation (part A) and expansion (part B). Patients had advanced or metastatic NSCLC that had progressed on EGFR TKI monotherapy or platinum-based chemotherapy (nonadenocarcinoma only, part A) or irreversible EGFR TKI monotherapy (part B). Absence of EGFR T790M mutation was required in part B. Part A used a 3 + 3 design, with a starting dose of xentuzumab 1000 mg/wk (intravenous) and afatinib 30 mg/d (oral). Primary endpoints were the maximum tolerated dose of the combination (part A) and objective response (part B). RESULTS: A total of 16 patients each were treated in parts A and B. Maximum tolerated dose was xentuzumab 1000 mg/wk plus afatinib 40 mg/d. No patients in part B had an objective response, but 10 had stable disease (median [range] duration of disease control: 2.3 [0.8-10.9] mo). The most common drug-related adverse events were diarrhea (75 %), paronychia (69 %), and rash (69 %) in part A and diarrhea (31 %), rash (19 %), paronychia (19 %), and fatigue (19 %) in part B. CONCLUSIONS: There were no new safety issues; xentuzumab and afatinib could be safely coadministered. Nevertheless, the combination revealed only modest activity in patients with EGFR mutation-positive, T790M-negative NSCLC after progression on afatinib.
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BACKGROUND: Afatinib is approved for first-line treatment of patients with epidermal growth factor receptor mutation-positive (EGFRm+) non-small-cell lung cancer (NSCLC). Here, we report findings from a combined analysis of three phase IIIb studies of afatinib in EGFR tyrosine kinase inhibitor (TKI)-naïve patients. METHODS: EGFR-TKI-naïve patients with EGFRm+ NSCLC received afatinib 40 mg/day. Dose reductions were permitted for adverse events (AEs). Efficacy endpoints included progression-free survival (PFS), time to symptomatic progression (TTSP), and tumor response. Subgroup analyses were performed by Eastern Cooperative Oncology Group performance status (ECOG PS), presence of brain metastasis, age and common/uncommon EGFR mutations (plus other factors). RESULTS: 1108 patients were treated. Median age was 61 years (range, 25-89); 19.2% had baseline brain metastases, 4.4% had ECOG PS ≥2, and 17.9% had tumors harboring uncommon mutations. Treatment-related AEs (TRAEs) were reported in 97.2%, most commonly diarrhea and rash. 41.6% had AEs leading to dose reduction. Median PFS was 13.0 months [95% confidence interval (CI): 12.0-13.8]; median TTSP was 14.8 months (95% CI: 13.9-16.1). Objective response rate (ORR) was 55.0%. Age, presence of baseline brain metastases, major (G719X, L861Q, S768I) or compound uncommon mutations had little/no effect on PFS, TTSP, or ORR, while outcomes were poorer in patients with ECOG PS 2 or exon 20 insertion/T790M mutations. CONCLUSIONS: Afatinib was tolerable with no new safety signals. Afatinib demonstrated encouraging efficacy in a broad patient population, including those with brain metastases or uncommon EGFR mutations.
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The mechanisms regulating myelin repair in the adult central nervous system (CNS) are unclear. Here, we identify DNA hydroxymethylation, catalyzed by the Ten-Eleven-Translocation (TET) enzyme TET1, as necessary for myelin repair in young adults and defective in old mice. Constitutive and inducible oligodendrocyte lineage-specific ablation of Tet1 (but not of Tet2), recapitulate this age-related decline in repair of demyelinated lesions. DNA hydroxymethylation and transcriptomic analyses identify TET1-target in adult oligodendrocytes, as genes regulating neuro-glial communication, including the solute carrier (Slc) gene family. Among them, we show that the expression levels of the Na+/K+/Cl- transporter, SLC12A2, are higher in Tet1 overexpressing cells and lower in old or Tet1 knockout. Both aged mice and Tet1 mutants also present inefficient myelin repair and axo-myelinic swellings. Zebrafish mutants for slc12a2b also display swellings of CNS myelinated axons. Our findings suggest that TET1 is required for adult myelin repair and regulation of the axon-myelin interface.
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Metilación de ADN , Proteínas de Unión al ADN/genética , Perfilación de la Expresión Génica/métodos , Vaina de Mielina/genética , Proteínas Proto-Oncogénicas/genética , Remielinización/genética , Animales , Animales Modificados Genéticamente , Células Cultivadas , Proteínas de Unión al ADN/metabolismo , Ratones Noqueados , Ratones Transgénicos , Mutación , Vaina de Mielina/metabolismo , Oligodendroglía/citología , Oligodendroglía/metabolismo , Proteínas Proto-Oncogénicas/metabolismo , RNA-Seq/métodos , Miembro 2 de la Familia de Transportadores de Soluto 12/genética , Miembro 2 de la Familia de Transportadores de Soluto 12/metabolismo , Pez Cebra/genéticaRESUMEN
Nanoparticle-based drug delivery faces challenges from the imprecise targeted delivery and the low bioavailability of drugs due to complex biological barriers. Here, we designed cascade-targeting, dual drug-loaded, core-shell nanoparticles (DLTPT) consisting of CD44-targeting hyaluronic acid shells decorated with doxorubicin (HA-DOX) and mitochondria-targeting triphenylphosphonium derivative nanoparticle cores loaded with lonidamine (LND) dimers (LTPT). DLTPT displayed prolonged blood circulation time and efficiently accumulated at the tumor site due to the tumor-homing effect and negatively charged hyaluronic acid. Subsequently, the HA-DOX shell was degraded by extracellular hyaluronidase, resulting in decreased particle size and negative-to-positive charge reversal, which would increase tumor penetration and internalization. The degradation of HA-DOX further accelerated the release of DOX and exposed the positively charged LTPT core for rapid endosomal escape and mitochondria-targeted delivery of LND. Notably, when DLTPT was used in combination with anti-PD-L1, the tumor growth was inhibited, which induced immune response against tumor metastasis.
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BACKGROUND: Xentuzumab-a humanised IgG1 monoclonal antibody-binds IGF-1 and IGF-2, inhibiting their growth-promoting signalling and suppressing AKT activation by everolimus. This phase Ib/II exploratory trial evaluated xentuzumab plus everolimus and exemestane in hormone receptor-positive, locally advanced and/or metastatic breast cancer (LA/MBC). METHODS: Patients with hormone receptor-positive/HER2-negative LA/MBC resistant to non-steroidal aromatase inhibitors were enrolled. Maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of xentuzumab/everolimus/exemestane were determined in phase I (single-arm, dose-escalation). In phase II (open-label), patients were randomised 1:1 to the RP2D of xentuzumab/everolimus/exemestane or everolimus/exemestane alone. Randomisation was stratified by the presence of visceral metastases. Primary endpoint was progression-free survival (PFS). RESULTS: MTD was determined as xentuzumab 1000 mg weekly plus everolimus 10 mg/day and exemestane 25 mg/day. A total of 140 patients were enrolled in phase II (70 to each arm). Further recruitment was stopped following an unfavourable benefit-risk assessment by the internal Data Monitoring Committee appointed by the sponsor. Xentuzumab was discontinued; patients could receive everolimus/exemestane if clinically indicated. Median PFS was 7.3 months (95% CI 3.3-not calculable) in the xentuzumab/everolimus/exemestane group and 5.6 months (3.7-9.1) in the everolimus/exemestane group (hazard ratio 0.97, 95% CI 0.57-1.65; P = 0.9057). In a pre-specified subgroup of patients without visceral metastases at screening, xentuzumab/everolimus/exemestane showed evidence of PFS benefit versus everolimus/exemestane (hazard ratio 0.21 [0.05-0.98]; P = 0.0293). Most common any-cause adverse events in phase II were diarrhoea (29 [41.4%] in the xentuzumab/everolimus/exemestane group versus 20 [29.0%] in the everolimus/exemestane group), mucosal inflammation (27 [38.6%] versus 21 [30.4%]), stomatitis (24 [34.3%] versus 24 [34.8%]), and asthenia (21 [30.0%] versus 24 [34.8%]). CONCLUSIONS: Addition of xentuzumab to everolimus/exemestane did not improve PFS in the overall population, leading to early discontinuation of the trial. Evidence of PFS benefit was observed in patients without visceral metastases when treated with xentuzumab/everolimus/exemestane, leading to initiation of the phase II XENERA™-1 trial (NCT03659136). TRIAL REGISTRATION: ClinicalTrials.gov, NCT02123823 . Prospectively registered, 8 March 2013.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/etiología , Adulto , Anciano , Anciano de 80 o más Años , Androstadienos/administración & dosificación , Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores de Tumor , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/mortalidad , Manejo de la Enfermedad , Everolimus/administración & dosificación , Femenino , Humanos , Dosis Máxima Tolerada , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Pronóstico , Receptor ErbB-2 , Receptores de Estrógenos , Receptores de Progesterona , Resultado del TratamientoRESUMEN
Molecular targeted-photodynamic combinational therapy is a promising strategy to enhance antitumor effects; meanwhile, current nanocarriers face challenges of limited selective delivery and release of therapeutic agents to specific tumor sites, which significantly compromises their therapeutic efficacy. Herein, we report active-targeting, enzyme- and ROS-dual responsive nanoparticles (HPGBCA) consisting of CD44-targeting hyaluronic acid (HA) shells and afatinib (AFT)-loaded, ROS-sensitive poly(l-lysine)-conjugated chlorin e6 (Ce6) derivative nanoparticle cores (PGBCA). HPGBCA can actively carry AFT and Ce6 specifically to tumor cells due to the negatively charged HA and CD44-mediated active targeting. Subsequently, hyaluronidase in the endosome will further spur the degradation of the HA shell to prompt exposure of the positively charged PGBCA core for rapid endosomal escape and intracellular delivery of AFT and Ce6. Furthermore, the generation of ROS produced by Ce6 under NIR irradiation can trigger the rapid oxidation of the thioether linker to facilitate the release of AFT into the cytoplasm. In vitro and in vivo studies demonstrated that the released AFT and excessive ROS at the local site can synergistically induce cell apoptosis to enhance the therapeutic efficacy without side effects. Our developed intelligent nanoparticle provides new avenues to achieve on-demand, specific intracellular drug release for improved molecular targeted-photodynamic combination therapeutic efficacy.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas/patología , Liberación de Fármacos , Receptores ErbB/antagonistas & inhibidores , Espacio Intracelular/metabolismo , Neoplasias Pulmonares/patología , Nanopartículas/química , Inhibidores de Proteínas Quinasas/metabolismo , Afatinib/química , Afatinib/metabolismo , Afatinib/farmacología , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Línea Celular Tumoral , Clorofilidas , Portadores de Fármacos/química , Humanos , Ácido Hialurónico/química , Luz , Neoplasias Pulmonares/tratamiento farmacológico , Terapia Molecular Dirigida , Fotoquimioterapia , Porfirinas/química , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Especies Reactivas de Oxígeno/metabolismoRESUMEN
BACKGROUND: Despite 1-4 % of NSCLC tumors harboring mutations in the HER2 gene, there are no approved HER2-pathway-targeted treatments available. We report an open-label, single-arm, multicenter phase II study investigating the efficacy and safety of afatinib in Asian patients with HER2-mutation positive (HER2m+) NSCLC. METHODS: Eligible patients for Part A had confirmed stage IIIb/IV HER2mâ¯+â¯NSCLC, had failed one or two prior lines of chemotherapy, and were EGFR/HER2-inhibitor naïve. Patients received oral afatinib 40â¯mg/day in continuous 28-day cycles, until disease progression or intolerable adverse events (AEs). Patients qualified for Part B if they had > 12 weeks' clinical benefit and Eastern Cooperative Oncology Group performance status ≤ 2. In Part B, patients were to receive afatinib at the last received dose, plus paclitaxel 80â¯mg/m2 weekly, until disease progression or intolerable AEs. The primary endpoint in Part A was objective response (OR); secondary endpoints included disease control (DC), progression-free survival (PFS), and overall survival (OS). Further exploratory endpoints were OR, DC, and PFS in Part B. RESULTS: Eighteen patients received afatinib in Part A. No patient achieved an OR; 11 patients (61.1 %) achieved stable disease, and six patients (33.3 %) had progressive disease. DC rate was therefore 61.1 % (95 % confidence interval [CI]: 35.7, 82.7). A decrease in tumor size from baseline of > 0 to < 30 % was observed in eight patients. At the time of analysis, 16 patients (88.9 %) had progressed or died. Median PFS was 2.76 months (95 % CI: 1.87, 4.60) and median OS was 10.02 months (95 % CI: 8.47, 10.08). All patients experienced ≥ 1 AE, most commonly diarrhea (66.7 %) and rash (33.3 %). No patients met the inclusion criteria for Part B, and recruitment was slow; therefore, the study was terminated. CONCLUSIONS: This study found no clinical benefit of afatinib for EGFR TKI-naïve patients with HER2mâ¯+â¯NSCLC.