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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: 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
BACKGROUND: Xentuzumab, an insulin-like growth factor (IGF)-1/IGF-2-neutralising antibody, binds IGF-1 and IGF-2, inhibiting their growth-promoting signalling. Two first-in-human trials assessed the maximum-tolerated/relevant biological dose (MTD/RBD), safety, pharmacokinetics, pharmacodynamics, and activity of xentuzumab in advanced/metastatic solid cancers. METHODS: These phase 1, open-label trials comprised dose-finding (part I; 3 + 3 design) and expansion cohorts (part II; selected tumours; RBD [weekly dosing]). Primary endpoints were MTD/RBD. RESULTS: Study 1280.1 involved 61 patients (part I: xentuzumab 10-1800 mg weekly, n = 48; part II: 1000 mg weekly, n = 13); study 1280.2, 64 patients (part I: 10-3600 mg three-weekly, n = 33; part II: 1000 mg weekly, n = 31). One dose-limiting toxicity occurred; the MTD was not reached for either schedule. Adverse events were generally grade 1/2, mostly gastrointestinal. Xentuzumab showed dose-proportional pharmacokinetics. Total plasma IGF-1 increased dose dependently, plateauing at ~1000 mg/week; at ≥450 mg/week, IGF bioactivity was almost undetectable. Two partial responses occurred (poorly differentiated nasopharyngeal carcinoma and peripheral primitive neuroectodermal tumour). Integration of biomarker and response data by Bayesian Logistic Regression Modeling (BLRM) confirmed the RBD. CONCLUSIONS: Xentuzumab was well tolerated; MTD was not reached. RBD was 1000 mg weekly, confirmed by BLRM. Xentuzumab showed preliminary anti-tumour activity. CLINICAL TRIAL REGISTRATION: NCT01403974; NCT01317420.
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Anticuerpos Monoclonales Humanizados/administración & dosificación , Factor II del Crecimiento Similar a la Insulina/antagonistas & inhibidores , Factor I del Crecimiento Similar a la Insulina/antagonistas & inhibidores , Neoplasias/tratamiento farmacológico , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/inmunología , Anticuerpos Neutralizantes/administración & dosificación , Anticuerpos Neutralizantes/inmunología , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Factor I del Crecimiento Similar a la Insulina/inmunología , Factor II del Crecimiento Similar a la Insulina/inmunología , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Neoplasias/genética , Neoplasias/patología , Adulto JovenRESUMEN
Differentiation of oligodendrocytes (OL) from progenitor cells (OPC) is the result of a unique program of gene expression, which is further regulated by the formation of topological domains of association with the nuclear lamina. In this study, we show that cultured OPC were characterized by progressively declining levels of endogenous Lamin B1 (LMNB1) during differentiation into OL. We then identify the genes dynamically associated to the nuclear lamina component LMNB1 during this transition, using a well established technique called DamID, which is based on the ability of a bacterially-derived deoxyadenosine methylase (Dam), to modify genomic regions in close proximity. We expressed a fusion protein containing Dam and LMNB1 in OPC (OPCLMNB1-Dam) and either kept them proliferating or differentiated them into OL (OLLMNB1-Dam) and identified genes that were dynamically associated to LMNB1 with differentiation. Importantly, we identified Lss, the gene encoding for lanosterol synthase, a key enzyme in cholesterol synthesis, as associated to the nuclear lamina in OLLMNB1-Dam. This finding could at least in part explain the lipid dysregulation previously reported for mouse models of ADLD characterized by persistent LMNB1 expression in oligodendrocytes.
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Lamina Tipo B/genética , Lamina Tipo B/metabolismo , Células Precursoras de Oligodendrocitos/fisiología , Animales , Diferenciación Celular/fisiología , Núcleo Celular/genética , Núcleo Celular/metabolismo , Perfilación de la Expresión Génica , Ratones , Ratones Endogámicos C57BL , Neurogénesis/fisiología , Lámina Nuclear/genética , Lámina Nuclear/metabolismo , Células Precursoras de Oligodendrocitos/citología , Células Precursoras de Oligodendrocitos/metabolismoRESUMEN
The ability to produce nanotherapeutics at large-scale with high drug loading efficiency, high drug loading capacity, high stability, and high potency is critical for clinical translation. However, many nanoparticle-based therapeutics under investigation suffer from complicated synthesis, poor reproducibility, low stability, and high cost. In this work, a simple method for preparing multifunctional nanoparticles is utilized that act as both a contrast agent for magnetic resonance imaging and a photosensitizer for photodynamic therapy for the treatment of cancer. In particular, the photosensitizer protoporphyrin IX (PpIX) is used to solubilize small nanoclusters of superparamagnetic iron oxide nanoparticles (SPIONs) without the use of any additional carrier materials. These nanoclusters are characterized with a high PpIX loading efficiency; a high loading capacity, stable behavior; high potency; and a synthetic approach that is amenable to large-scale production. In vivo studies of photodynamic therapy (PDT) efficacy show that the PpIX-coated SPION nanoclusters lead to a significant reduction in the growth rate of tumors in a syngeneic murine tumor model compared to both free PpIX and PpIX-loaded poly(ethylene glycol)-polycaprolactone micelles, even when injected at 1/8th the dose. These results suggest that the nanoclusters developed in this work can be a promising nanotherapeutic for clinical translation.
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The multidrug resistance profiles of Klebsiella pneumoniae carbapenemase (KPC) producers have led to increased clinical polymyxin use. Combination therapy with polymyxins may improve treatment outcomes, but it is uncertain which combinations are most effective. Clinical successes with intravenous minocycline-based combination treatments have been reported for infections caused by carbapenemase-producing bacteria. The objective of this study was to evaluate the in vitro activity of polymyxin B and minocycline combination therapy against six KPC-2-producing K. pneumoniae isolates (minocycline MIC range, 2 to 32 mg/liter). Polymyxin B monotherapy (0.5, 1, 2, 4, and 16 mg/liter) resulted in a rapid reduction of up to 6 log in bactericidal activity followed by regrowth by 24 h. Minocycline monotherapy (1, 2, 4, 8, and 16 mg/liter) showed no reduction of activity of >1.34 log against all isolates, although concentrations of 8 and 16 mg/liter prolonged the time to regrowth. When the therapies were used in combination, rapid bactericidal activity was followed by slower regrowth, with synergy (60 of 120 combinations at 24 h, 19 of 120 combinations at 48 h) and additivity (43 of 120 combinations at 24 h, 44 of 120 combinations at 48 h) against all isolates. The extent of killing was greatest against the more susceptible polymyxin B isolates (MICs of ≤0.5 mg/liter) regardless of the minocycline MIC. The pharmacodynamic activity of combined polymyxin B-minocycline therapy against KPC-producing K. pneumoniae is dependent on polymyxin B susceptibility. Further in vitro and animal studies must be performed to fully evaluate the efficacy of this drug combination.
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Antibacterianos/farmacología , Proteínas Bacterianas/metabolismo , Klebsiella pneumoniae/efectos de los fármacos , Klebsiella pneumoniae/enzimología , Minociclina/farmacología , Polimixina B/farmacología , beta-Lactamasas/metabolismo , Proteínas Bacterianas/genética , Farmacorresistencia Bacteriana Múltiple/genética , Pruebas de Sensibilidad Microbiana , beta-Lactamasas/genéticaRESUMEN
BACKGROUND: Speckle-type POZ protein (SPOP) is an E3 ubiquitin ligase adaptor protein that functions as a potential tumor suppressor, and SPOP mutations have been identified in ~10% of human prostate cancers. However, it remains unclear if mutant SPOP proteins can be utilized as biomarkers for early detection, diagnosis, prognosis or targeted therapy of prostate cancer. Moreover, the SPOP mutation sites are distributed in a relatively short region with multiple lysine residues, posing significant challenges for bottom-up proteomics analysis of the SPOP mutations. METHODS: To address this issue, PRISM (high-pressure, high-resolution separations coupled with intelligent selection and multiplexing)-SRM (selected reaction monitoring) mass spectrometry assays have been developed for quantifying wild-type SPOP protein and 11 prostate cancer-derived SPOP mutations. RESULTS: Despite inherent limitations due to amino acid sequence constraints, all the PRISM-SRM assays developed using Arg-C digestion showed a linear dynamic range of at least two orders of magnitude, with limits of quantification ranged from 0.1 to 1 fmol/µg of total protein in the cell lysate. Applying these SRM assays to analyze HEK293T cells with and without expression of the three most frequent SPOP mutations in prostate cancer (Y87N, F102C or F133V) led to confident detection of all three SPOP mutations in corresponding positive cell lines but not in the negative cell lines. Expression of the F133V mutation and wild-type SPOP was at much lower levels compared to that of F102C and Y87N mutations; however, at present, it is unknown if this also affects the biological activity of the SPOP protein. CONCLUSIONS: In summary, PRISM-SRM enables multiplexed, isoform-specific detection of mutant SPOP proteins in cell lysates, providing significant potential in biomarker development for prostate cancer.
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Espectrometría de Masas/métodos , Mutación/genética , Proteínas Nucleares/genética , Neoplasias de la Próstata/genética , Proteómica/métodos , Proteínas Represoras/genética , Secuencia de Aminoácidos , Células HEK293 , Humanos , Límite de Detección , Masculino , Péptidos/química , Péptidos/metabolismoRESUMEN
BACKGROUND: The spread of carbapenemase-producing K. pneumoniae (CPKP) has become a significant problem worldwide. Combination therapy for CPKP is encouraging, but polymyxin resistance to many antibiotics is hampering effective treatment. Combination therapy with three or more antibiotics is being increasingly reported, therefore we performed a systematic review of triple combination cases in an effort to evaluate their clinical effectiveness for CPKP infections. METHODS: The PubMed database was searched to identify all published clinical outcomes of CPKP infections treated with triple combination therapy. Articles were stratified into two tiers depending on the level of clinical detail provided. A tier 1 study included: antibiotic regimen, regimen-specific outcome, patient status at onset of infection, and source of infection. Articles not reaching these criteria were considered tier 2. RESULTS: Thirty-three studies were eligible, 23 tier 1 and ten tier 2. Among tier 1 studies, 53 cases were included in this analysis. The most common infection was pneumonia (31%) followed by primary or catheter-related bacteremia (21%) and urinary tract infection (17%). Different combinations of antibiotic classes were utilized in triple combinations, the most common being a polymyxin (colistin or polymyxin B, 86.8%), tigecycline (73.6%), aminoglycoside (43.4%), or carbapenem (43.4%). Clinical and microbiological failure occurred in 14/39 patients (35.9%) and 22/42 patients (52.4%), respectively. Overall mortality for patients treated with triple combination therapy was 35.8% (19/53 patients). CONCLUSIONS: Triple combination therapy is being considered as a treatment option for CPKP. Polymyxin-based therapy is the backbone antibiotic in these regimens, but its effectiveness needs establishing in prospective clinical trials.
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Antibacterianos/uso terapéutico , Proteínas Bacterianas/metabolismo , Infecciones por Klebsiella/tratamiento farmacológico , Klebsiella pneumoniae/efectos de los fármacos , beta-Lactamasas/metabolismo , Aminoglicósidos/administración & dosificación , Aminoglicósidos/uso terapéutico , Antibacterianos/administración & dosificación , Bacteriemia/tratamiento farmacológico , Bacteriemia/microbiología , Carbapenémicos/administración & dosificación , Carbapenémicos/uso terapéutico , Colistina/administración & dosificación , Colistina/uso terapéutico , Combinación de Medicamentos , Femenino , Humanos , Infecciones por Klebsiella/microbiología , Infecciones por Klebsiella/mortalidad , Klebsiella pneumoniae/enzimología , Masculino , Pruebas de Sensibilidad Microbiana , Minociclina/administración & dosificación , Minociclina/análogos & derivados , Minociclina/uso terapéutico , Neumonía/tratamiento farmacológico , Neumonía/microbiología , Polimixina B/administración & dosificación , Polimixina B/uso terapéutico , Polimixinas/administración & dosificación , Polimixinas/uso terapéutico , Tigeciclina , Resultado del Tratamiento , Infecciones Urinarias/tratamiento farmacológico , Infecciones Urinarias/microbiologíaRESUMEN
The properties of iron-based superconductors (Fe-SCs) can be varied dramatically with the introduction of dopants and atomic defects. As a pressing example, FeSe, parent phase of the highest-Tc Fe-SC, exhibits prevalent defects with atomic-scale "dumbbell" signatures as imaged by scanning tunneling microscopy (STM). These defects spoil superconductivity when their concentration exceeds 2.5%. Resolving their chemical identity is a prerequisite to applications such as nanoscale patterning of superconducting/nonsuperconducting regions in FeSe as well as fundamental questions such as the mechanism of superconductivity and the path by which the defects destroy it. We use STM and density functional theory to characterize and identify the dumbbell defects. In contrast to previous speculations about Se adsorbates or substitutions, we find that an Fe-site vacancy is the most energetically favorable defect in Se-rich conditions and reproduces our observed STM signature. Our calculations shed light more generally on the nature of Se capping, the removal of Fe vacancies via annealing, and their ordering into a â5 × â5 superstructure in FeSe and related alkali-doped compounds.
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We use scanning tunneling spectroscopy to investigate the filled and empty electronic states of superconducting single-unit-cell FeSe deposited on SrTiO3(001). We map the momentum-space band structure by combining quasiparticle interference imaging with decay length spectroscopy. In addition to quantifying the filled-state bands, we discover a Γ-centered electron pocket 75 meV above the Fermi energy. Our density functional theory calculations show the orbital nature of empty states at Γ and explain how the Se height is a key tuning parameter of their energies, with broad implications for electronic properties.
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The highest-temperature superconductors are electronically inhomogeneous at the nanoscale, suggesting the existence of a local variable that could be harnessed to enhance the superconducting pairing. Here we report the relationship between local doping and local strain in the cuprate superconductor Bi(2)Sr(2)CaCu(2)O(8+x). We use scanning tunneling microscopy to discover that the crucial oxygen dopants are periodically distributed in correlation with local strain. Our picoscale investigation of the intraunit-cell positions of all oxygen dopants provides essential structural input for a complete microscopic theory.
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Cobre/química , Conductividad Eléctrica , Nanopartículas del Metal/química , Nanopartículas del Metal/ultraestructura , Modelos Químicos , Simulación por Computador , Módulo de Elasticidad , Calor , Ensayo de Materiales , Resistencia a la TracciónRESUMEN
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) and those carrying only p53 deletion (p53n). In culture, the BB-p53n OPCs display growth characteristics more similar to glioma cells than p53n OPCs. When injected in mouse brains, BB-p53n OPC form tumors, while the p53n OPCs do not. Unbiased histone proteomics and transcriptomic analysis on these OPC populations identified higher levels of the histone H3K27me3 mark and lower levels of the histone H4K20me3. The transcriptome of the BB-p53n OPCs was characterized by higher levels of transcripts related to proliferation and cell adhesion compared to p53n OPCs. Pharmacological inhibition of the enzyme responsible for histone H3K27 trimethylation (EZH2i) in BB-p53n OPCs, reduced cell cycle transcripts and increased the expression of differentiation markers, but was not sufficient to restore their growth characteristics. This suggests that PDGF-BB overexpression in p53n OPCs favors the early stages of transformation, by promoting proliferation and halting differentiation in a H3K27me3-dependent pathway, and favoring growth characteristics in a H3K27me3 independent manner.
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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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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
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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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
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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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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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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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.