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Biomass-encapsulated liquid metals (LMs) composite gels have aroused tremendous attention as epidermal smart materials due to their biocompatibility and sustainability. However, they can still not simultaneously possess toughness, adhesion, and recoverability. In this work, the tough, sticky, and recyclable protein-encapsulated LMs organogels (GLMx) are fabricated through the micro-interfacial stabilization of LMs by lignin and the following preparation of food-making inspired gels. With the help of lignin modification, the LMs micro-drops demonstrated uniform dispersion in the protein matrix, as well as dense non-covalent interactions (e.g., Hâbond and hydrophobic interaction) with amino acid residues in peptide chains, which endowed the GLMx with high conductivity (≈5.4 S m-1), toughness (≈738.2 kJ m-3), self-adhesiveness (a maximal lap-shear strength of ≈58.3 kPa), and recoverability. By tightly adhering onto human skin, the GLMx can act as epidermal sensors to detect drastic (e.g., joint bending) and subtle body movements (e.g., swallowing) and even recognize handwriting and speaking in real-time. Moreover, the organogels can also harvest solar energy and convert it into heat and electricity, which is promising in self-powered intelligent devices. Thus, this work paves a facile way to prepare protein/LMs composite organogels that are suitable for multiple applications like healthcare, human-robot interactions, and solar energy conversion.
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BACKGROUND: Chimeric antigen receptor (CAR)-T cell therapy has been used to treat pediatric refractory or relapsed mature B-cell non-Hodgkin lymphoma (r/r MB-NHL) with significantly improved outcomes, but a proportion of patients display no response or experience relapse after treatment. To investigate whether tumor-intrinsic somatic genetic alterations have an impact on CAR-T cell treatment, the genetic features and treatment outcomes of 89 children with MB-NHL were analyzed. METHODS: 89 pediatric patients treated at multiple clinical centers of the China Net Childhood Lymphoma (CNCL) were included in this study. Targeted next-generation sequencing for a panel of lymphoma-related genes was performed on tumor samples. Survival rates and relapse by genetic features and clinical factors were analyzed. Survival curves were calculated using a log-rank (Mantel-Cox) test. The Wilcox sum-rank test and Fisher's exact test were applied to test for group differences. RESULTS: A total of 89 driver genes with somatic mutations were identified. The most frequently mutated genes were TP53 (66%), ID3 (55%), and ARID1A (31%). The incidence of ARID1A mutation and co-mutation of TP53 and ARID1A was high in patients with r/r MB-NHL (P = 0.006; P = 0.018, respectively). CAR-T cell treatment significantly improved survival in r/r MB-NHL patients (P = 0.00081), but patients with ARID1A or ARID1A and TP53 co-mutation had poor survival compared to those without such mutations. CONCLUSION: These results indicate that children with MB-NHL harboring ARID1A or TP53 and ARID1A co-mutation are insensitive to initial conventional chemotherapy and subsequent CAR-T cell treatment. Examination of ARID1A and TP53 mutation status at baseline might have prognostic value, and risk-adapted or more effective therapies should be considered for patients with these high-risk genetic alterations.
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Two-dimensional (2D) sheet-like biochar as promising alternatives to graphene nanosheets has gained significant attention in materials science while being highly restricted by its complicated synthetic steps. In this study, the dimethyl sulfoxide/potassium hydroxide (DMSO/KOH) superbase system was first used to pretreat sweet sorghum residues (SS) and then carbonized to prepare sheet-like biochar. Ascribing to the strong nucleophilicity of DMSO/KOH, a synergistic effect was achieved by partially removing non-cellulosic components in SS and swelling the amorphous region of cellulose, leaving more layered cellulose behind (â¼46.5 wt %), which was favorable for the formation of 2D biochar nanosheets with high graphitization degrees (â¼93.1%). This strategy was also suitable for other biomass fibers (e.g., straw, wood powders, and nuclear shells) to obtain sheet-like biochar. The resulting sheet-like biochar could be compounded with cellulose nanofibers to achieve the structural design of composites and solve the molding problem of biochar, which was beneficial for dyeing wastewater treatment. Thus, this work provides insight into a simple strategy for developing 2D ultrathin sheet-like biochar from sustainable biomass wastes.
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Sorghum , Dimetil Sulfóxido , Carvão Vegetal/química , CeluloseRESUMO
Immune checkpoint blockade (ICB) of the programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) immune checkpoint pathway has led to unprecedented advances in cancer therapy. However, the overall response rate of anti-PD-1/PD-L1 monotherapy is still unpromising, underscoring the need for predictive biomarkers. In this retrospective study, we collected pretreatment plasma samples from two independent cohorts of patients receiving ICB. To determine whether a signature of plasma cytokines could be associated with therapeutic efficacy, we systemically profiled cytokine clusters and functional groups in the discovery and validation datasets by using 59 multiplexed bead immunoassays and bioinformatics analysis. We first attempted to functionally classify the 59 immunological factors according to their biological classification or functional roles in the cancer-immunity cycle. Surprisingly, we observed that two signatures, the "checkpoint signature" and "trafficking of T-cell signature", were higher in the response subgroup than in the nonresponse subgroup in both the discovery and validation cohorts. Moreover, enrichment of the "checkpoint signature" was correlated with improved overall survival and progression-free survival in both datasets. In addition, we demonstrated that increased baseline levels of three checkpoint molecules (PD-L1, T-cell immunoglobulin mucin receptor 3 and T-cell-specific surface glycoprotein CD28) were common peripheral responsive correlates in both cohorts, thus rendering this "refined checkpoint signature" an ideal candidate for future verification. In the peripheral blood system, the "refined checkpoint signature" may function as a potential biomarker for anti-PD-1/PD-L1 monotherapy in gastrointestinal (GI) cancers.
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Biomarcadores Tumorais , Citocinas/metabolismo , Neoplasias Gastrointestinais/etiologia , Proteínas de Checkpoint Imunológico/metabolismo , Biologia Computacional , Citocinas/genética , Neoplasias Gastrointestinais/diagnóstico , Neoplasias Gastrointestinais/tratamento farmacológico , Neoplasias Gastrointestinais/metabolismo , Perfilação da Expressão Gênica , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Proteínas de Checkpoint Imunológico/genética , Imuno-Histoquímica , Estimativa de Kaplan-Meier , Masculino , Prognóstico , Reprodutibilidade dos Testes , Resultado do TratamentoRESUMO
NotF from Aspergillus sp. MF297-2 and BrePT from Aspergillus versicolor catalyze a reverse C2-prenylation of brevianamide F in the biosynthetic pathway of brevianamides and notoamides. NotF was reported to use only brevianamide F as substrate while BrePT demonstrated broad substrate promiscuity. With high identity at amino acid level, it is interesting to reinvestigate the catalytic activities of these two prenyltransferases in vitro toward 14 cyclodipeptides. Product identification of the in vitro assays by MS proved that NotF and BrePT share similar catalytic ability and substrate promiscuity.
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Aspergillus/metabolismo , Dimetilaliltranstransferase/metabolismo , Alcaloides Indólicos/metabolismo , Aspergillus/genética , Dimetilaliltranstransferase/química , Dimetilaliltranstransferase/genética , Prenilação , Especificidade por SubstratoRESUMO
In eukaryotic cells, Endoplasmic Reticulum (ER) is an interconnected membranous organelle and plays important roles in protein synthesis and lipid metabolism. We have previously demonstrated that TMCO1 is an ER Ca2+ channel actively preventing ER Ca2+ overloading. Recently, we also found that TMCO1 deficiency in mouse granulosa cells (GCs) caused abnormal Ca2+ signaling, ER stress and enhanced reactive oxygen species (ROS). In this study, we further examined the roles of TMCO1 in lipid metabolism and mitochondrial functions. Intriguingly, we found that TMCO1 deletion reduced the number of lipid droplets (LDs) and the content of triglyceride (TG), which was due to ER stress associated degradation (ERAD) of the important enzyme in catalyzing TG synthesis, diacylglycerol acyltransferase 2 (DGAT2). Hypofunction in transforming non-esterification fatty acid (NEFA) to TG caused NEFA deposit, a potential risk of mitochondrial dysfunction. Furthermore, in TMCO1 deficient cells, mitochondria volume decreased and inefficient oxidative phosphorylation was detected, which underlined enhanced mitophagy and impaired mitochondrial functions. Taken these data together, we for the first time revealed the role of TMCO1 in regulating lipid-metabolism and mitochondrial function. This study may provide new insights into understanding TMCO1 defect syndrome.
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Canais de Cálcio/metabolismo , Diacilglicerol O-Aciltransferase/metabolismo , Estresse do Retículo Endoplasmático/fisiologia , Mitocôndrias/metabolismo , Animais , Canais de Cálcio/genética , Ácidos Graxos/metabolismo , Fibroblastos/metabolismo , Técnicas de Silenciamento de Genes , Células HeLa , Humanos , Gotículas Lipídicas/metabolismo , Camundongos Knockout , Mitocôndrias/patologia , Mitofagia/genética , Consumo de Oxigênio , Triglicerídeos/metabolismoRESUMO
Protein-based hydrogels with promising biocompatibility and biodegradability have attracted considerable interest in areas of epidermal sensing, whereas, which are still difficult to synchronously possess high mechanical strength, self-adhesion, and recoverability. Hence, the bio-polymer lignosulfonate-reinforced gluten organohydrogels (GOHLx) are fabricated through green and simple food-making processes and the following solvent exchange with glycerol/water binary solution. Ascribing to the uniform distribution of lignosulfonate in gluten networks, as well as the noncovalent interactions (e.g., H-bond) between them, the resultant GOHLx exhibit favorable conductivity (â¼14.3 × 10-4 S m-1), toughness (â¼711.0 kJ m-3), self-adhesion (a maximal lap-shear strength of â¼33.5 kPa), high sensitivity (GF up to â¼3.04), and durability (â¼3000 cycles) toward shape deformation, which are suitable for the detection of both drastic (e.g., elbow and wrist bending) and subtle (e.g., swallowing and speaking) human movements even under -20 °C. Furthermore, the GOHLx is also biocompatible, degradable, and recoverable (by a simple kneading process). Thus, this work may pave a simple, green, and cheap way to prepare all-biomass-based, tough, sticky, and recoverable protein-based organohydrogels for epidermal strain sensing even in harsh environments.
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Adesivos , Dispositivos Eletrônicos Vestíveis , Humanos , Lignina , Temperatura , Glutens , Condutividade Elétrica , HidrogéisRESUMO
Phase change materials (PCMs) have attracted considerable attention as a thermal energy management technology for thermal storage. However, achieving high energy-storing abilities, low leakage rates, and solar absorption abilities simultaneously in PCMs remains greatly challenging. This research proposed a green strategy for preparing sorghum straw-based PCMs. By facile delignification and solvothermal process, delignified sorghum straw (DSS) and carbon quantum dots (CQDs) derived from removal lignin are prepared. The obtained PEG@CQDs/DSS possessed considerable reusable stabilities, excellent photo-thermal conversion properties, and thermal energy management capacities due to the delicate micropores and intrinsic noncovalent interactions among components. Especially, the PEG@CQDs-7.5/DSS exhibited superior solar-thermal conversion capabilities (with conducive photo-thermal conversion efficiency ~90.84%), and kept stable after 100 cycles of heating and cooling, in which the melting enthalpy value is ~168.1 J/g (enthalpy efficiency of ~91.11%). In conclusion, the synthesized PCMs showed potential for application in energy-saving and building thermal management.
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Energia Solar , Sorghum , Polietilenoglicóis , Carbono , Temperatura Baixa , Grão ComestívelRESUMO
Liquid free ion-conductive elastomers (ICEs) have demonstrated promising potential in various advanced application scenarios including sensor, artificial skin, and human-machine interface. However, ICEs that synchronously possess toughness, adhesiveness, stability, and anti-bacterial capability are still difficult to achieve yet highly demanded. Here, a one-pot green and sustainable strategy was proposed to fabricate multifunctional ICEs by extracting non-cellulose components (mainly lignin and hemicellulose) from lignocellulose with polymerizable deep eutectic solvents (PDES) and the subsequent in-situ photo-polymerization process. Ascribing to the uniform dispersion of non-cellulose components in PDES, the resultant ICEs demonstrated promising mechanical strength (a tensile strength of ~1200 kPa), high toughness (~9.1 MJ m-3), favorable adhesion (a lap-shear strength up to ~61.5 kPa toward metal), conducive stabilities, and anti-bacterial capabilities. With the help of such advantages, the ICEs exhibited sensitive (a gauge factor of ~23.5) and stable (~4000 cycles) performances in human motion and physiological signal detection even under sub-zero temperatures (e.g., -20 °C). Besides, the residue cellulose can be mechanically isolated into nanoscale fibers, which matched the idea of green chemistry.
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Solventes Eutéticos Profundos , Dietilestilbestrol/análogos & derivados , Lignina , Humanos , Celulose , ElastômerosRESUMO
BACKGROUND: In December 2022, a large-scale epidemic occurred in China due to Omicron variant of SARS-CoV-2. This study explored risk factors for Omicron infection in transplant recipients at our institution and investigated the factors influencing the severity of SARS-CoV-2 Omicron infection among recipients of allo-HSCT. METHODS: This single-center study investigated totally 63 allogeneic hematopoietic stem cell transplant patients infected with Omicron variant at the Beijing GoBroad Boren Hospital Transplant Center during December 2022 and analyzed their risk factors. RESULTS: The study included 63 allogeneic hematopoietic stem cell transplant patients who developed Omicron infection. There were 34 mild and 29 moderate to severe cases. Their median age was 22 years (range, 1-65 years), with the male-to-female ratio being 1:1.1. Acute myeloid leukemia (53.97%), acute lymphoblastic leukemia (42.86%), and non-Hodgkin lymphoma (3.17%) were underlying diseases. The median time between HCT and Omicron infection was 8.45 months. Significant predictive factors for moderate to severe Omicron infection included older age (p < .0001), cGVHD (p = .0195), concurrent bacterial infection (p < .0001), low absolute lymphocyte count (p = .026), low CD4/CD8 ratio (p = .0091), high CRP (p < .0001), high serum ferritin (p = .0023), high D-dimer (p < .0001), low CD4 absolute count (p = .0057), and low B-cell absolute count (p = .0154). A moderate to high HCT-CI score tended to be associated with moderate to severe infection (p = .0596). CONCLUSION: This study indicates that risk factors for severe Omicron infection include certain clinical characteristics, such as age, cGVHD, and inflammatory response.
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COVID-19 , Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , SARS-CoV-2 , Humanos , COVID-19/epidemiologia , COVID-19/complicações , Masculino , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Feminino , Adulto , Pessoa de Meia-Idade , Adolescente , Fatores de Risco , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/epidemiologia , SARS-CoV-2/isolamento & purificação , Adulto Jovem , Criança , Idoso , Pré-Escolar , Lactente , China/epidemiologia , Transplante Homólogo/efeitos adversos , Índice de Gravidade de Doença , Estudos RetrospectivosRESUMO
BACKGROUND: Adult neurogenesis occurs in the subventricular zone (SVZ) and the subgranular zone of the dentate gyrus in the hippocampus. The neuronal stem cells in these two neurogenic niches respond differently to various physiological and pathological stimuli. Recently, we have found that the decrement of carboxypeptidase E (CPE) with aging impairs the maturation of brain-derived neurotrophic factor (BDNF) and neurogenesis in the SVZ. However, it remains unknown whether these events occur in the hippocampus, and what the role of CPE is in the adult hippocampal neurogenesis in the context of Alzheimer's disease (AD). METHODS: In vivo screening was performed to search for miRNA mimics capable of upregulating CPE expression and promoting neurogenesis in both neurogenic niches. Among these, two agomirs were further assessed for their effects on hippocampal neurogenesis in the context of AD. We also explored whether these two agomirs could ameliorate behavioral symptoms and AD pathology in mice, using direct intracerebroventricular injection or by non-invasive intranasal instillation. RESULTS: Restoration of CPE expression in the hippocampus improved BDNF maturation and boosted adult hippocampal neurogenesis. By screening the miRNA mimics targeting the 5'UTR region of Cpe gene, we developed two agomirs that were capable of upregulating CPE expression. The two agomirs significantly rescued adult neurogenesis and cognition, showing multiple beneficial effects against the AD-associated pathologies in APP/PS1 mice. Of note, noninvasive approach via intranasal delivery of these agomirs improved the behavioral and neurocognitive functions of APP/PS1 mice. CONCLUSIONS: CPE may regulate adult hippocampal neurogenesis via the CPE-BDNF-TrkB signaling pathway. This study supports the prospect of developing miRNA agomirs targeting CPE as biopharmaceuticals to counteract aging- and disease-related neurological decline in human brains.
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Doença de Alzheimer , Carboxipeptidase H , Hipocampo , Transtornos da Memória , Neurogênese , Regulação para Cima , Animais , Neurogênese/efeitos dos fármacos , Neurogênese/fisiologia , Doença de Alzheimer/genética , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Carboxipeptidase H/genética , Carboxipeptidase H/biossíntese , Camundongos , Transtornos da Memória/genética , Transtornos da Memória/etiologia , Fator Neurotrófico Derivado do Encéfalo/biossíntese , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , MicroRNAs/genética , MicroRNAs/biossíntese , Masculino , Camundongos Transgênicos , Camundongos Endogâmicos C57BL , Modelos Animais de DoençasRESUMO
It is crucial to quickly bridge to allogeneic hematopoietic stem cell transplantation (allo-HSCT) for hematopoietic reconstitution. Here we report on the efficacy and safety of donor CD7 chimeric antigen receptor (CAR) T cell therapy (CAR-T) bridging to allo-HSCT in treating 12 patients with relapsed/refractory (r/r) T-ALL or T-cell lymphoblastic lymphoma (T-LBL). The median time from CAR-T infusion to allo-HSCT was 33.5 days (range, 30 to 55 days). With reduced-intensity conditioning, all patients except 1 successfully engrafted. With a mean follow-up of 301 days (range, 238 to 351 days), the remaining 11 patients were alive and disease-free at their last follow-up. Acute graft-versus-host disease (GVHD) was observed in 3 patients, and chronic GVHD developed in 3 patients, all with a limited pattern. Under the current protocol, infection was the main complication post-transplantation, and all infections were well controlled except in 1 patient, who died of multiple organ failure caused by an infection-induced inflammatory cytokine storm at days 14 post-transplantation. One patient relapsed (CD7+), and 3 patients became minimal residual disease (MRD) positive (CD7+ in 1, CD7- in 1, fusion gene positive only in 1). Subsequently, all 3 of these patients achieved an MRD-negative complete remission with either CD7 CAR-T reinfusion or immunosuppressive agent withdrawal. Our study shows for the first time that a novel strategy of donor CD7 CAR-T bridging to allo-HSCT can be highly effective and feasible in improving disease-free survival for patients with r/r T-ALL or T-LBL.
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Doença Enxerto-Hospedeiro , Neoplasias Hematológicas , Transplante de Células-Tronco Hematopoéticas , Leucemia-Linfoma Linfoblástico de Células Precursoras , Leucemia-Linfoma Linfoblástico de Células T Precursoras , Receptores de Antígenos Quiméricos , Humanos , Antígenos CD7 , Leucemia-Linfoma Linfoblástico de Células T Precursoras/etiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Linfócitos T , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Doença Enxerto-Hospedeiro/terapiaRESUMO
BACKGROUND: Maintaining homeostasis of Ca2+ stores in the endoplasmic reticulum (ER) is crucial for proper Ca2+ signaling and key cellular functions. Although Ca2+ depletion has been known to cause ER stress which in turn activates the unfolded protein response (UPR), how UPR sensors/transducers respond to excess Ca2+ when ER stores are overloaded remain largely unclear. RESULTS: Here, we report for the first time that overloading of ER Ca2+ can directly sensitize the IRE1α-XBP1 axis. The overloaded ER Ca2+ in TMCO1-deficient cells can cause BiP dissociation from IRE1α, promote the dimerization and stability of the IRE1α protein, and boost IRE1α activation. Intriguingly, attenuation of the over-activated IRE1α-XBP1s signaling by a IRE1α inhibitor can cause a significant cell death in TMCO1-deficient cells. CONCLUSIONS: Our data establish a causal link between excess Ca2+ in ER stores and the selective activation of IRE1α-XBP1 axis, underscoring an unexpected role of overload of ER Ca2+ in IRE1α activation and in preventing cell death.
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Background: Overexpression of the cytokine receptor-like factor 2 (CRLF2) gene is the most common feature in the Philadelphia chromosome (Ph)-like subtype of B-cell acute lymphoblastic leukemia (B-ALL). However, the predictive value of CRLF2 overexpression for the prognosis of pediatric B-ALL patients remain controversial. The molecular mechanisms that upregulate CRLF2 expression level in patients has not been fully elucidated. Methods: In this study, the prognostic impact of CRLF2 expression level on molecular types of B-ALL in pediatric patients from Zhujiang Hospital (n = 111) was retrospectively analyzed. Youden index analysis was used to categorize CRLF2 expression into 3 groups, and these categories more precisely described the differences in the prognosis of patients with varying expression levels of CRLF2 in both the Zhujiang Hospital cohort and the TARGET cohort. Results: We used the Zhujiang Hospital cohort as a discovery cohort to determine the cutoff value of CRLF2 expression. CRLF2-high patients accounted for approximately 6%. In addition, the percentage of bone marrow blast cells and initial white blood cell count in CRLF2-high patients were higher than those in CRLF2-low patients, and MRD turned negative slower. The results were validated in the TARGET cohort and indicated that CRLF2 overexpression could be subdivided by CRLF2 expression levels into 2 categories: CRLF2-high with a poor survival and CRLF2-medium with a good OS and EFS. Such heterogeneity was attributed to the different molecular mechanisms leading to CLRF2 upregulation, where the CRLF2 overexpression level was high in Ph-like B-ALL and medium in high hyperdiploid B-ALL. Conclusion: This study highlights the importance of the molecular mechanisms of the upregulation of CRLF2 expression in predicting the prognosis of pediatric B-ALL patients.
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Bone morphogenetic protein (BMP) signaling has been shown to be intimately associated with adult neurogenesis in the subventricular zone (SVZ) and subgranular zone (SGZ). Adult neurogenesis declines in aging rodents and primates. However, the role of BMP signaling in the age-related neurogenesis decline remains elusive and the effect of BMP4 on adult SVZ neurogenesis remains controversial. Here, the expression of BMP4 and its canonical effector phosphorylated-Smad1/5/8 (p-Smad1/5/8) in the murine SVZ and SGZ were found to be increased markedly with age. We identified Id3 as a major target of BMP4 in neuronal stem cells (NSCs) of both neurogenic regions, which exhibited a similar increase during aging. Intracerebroventricular infusion of BMP4 activated Smad1/5/8 phosphorylation and upregulated Id3 expression, which further restrained NeuroD1, leading to attenuated neurogenesis in both neurogenic regions and defective differentiation in the SGZ. Conversely, noggin, a potent inhibitor of BMP4, demonstrated opposing effects. In support of this, BMP4 treatment or lentiviral overexpression of Id3 resulted in decreased NeuroD1 protein levels in NSCs of both neurogenic regions and significantly inhibited neurogenesis. Thus, our findings revealed that the increased BMP4 signaling with age inhibited adult neurogenesis in both SVZ and SGZ, which may be attributed at least in part, to the changes in the Id3-NeuroD1 axis.
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Transmembrane of coiled-coil domains 1 (TMCO1) plays an important role in maintaining homeostasis of calcium (Ca2+) stores in the endoplasmic reticulum (ER). TMCO1-defect syndrome shares multiple features with human cerebro-facio-thoracic (CFT) dysplasia, including abnormal corpus callosum (CC). Here, we report that TMCO1 is required for the normal development of CC through sustaining Ca2+ homeostasis. Tmco1-/- mice exhibit severe agenesis of CC with stalled white matter fiber bundles failing to pass across the midline. Mechanistically, the excessive Ca2+ signals caused by TMCO1 deficiency result in upregulation of FGFs and over-activation of ERK, leading to an excess of glial cell migration and overpopulated midline glia cells in the indusium griseum which secretes Slit2 to repulse extension of the neural fiber bundles before crossing the midline. Supportingly, using the clinical MEK inhibitors to attenuate the over-activated FGF/ERK signaling can significantly improve the CC formation in Tmco1-/- brains. Our findings not only unravel the underlying mechanism of abnormal CC in TMCO1 defect syndrome, but also offer an attractive prevention strategy to relieve the related agenesis of CC in patients.
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Corpo Caloso , Deficiência Intelectual , Animais , Canais de Cálcio/metabolismo , Corpo Caloso/metabolismo , Retículo Endoplasmático/metabolismo , MAP Quinases Reguladas por Sinal Extracelular , Homeostase , Humanos , Sistema de Sinalização das MAP Quinases , Camundongos , NeurogêneseRESUMO
Background: Patients with refractory/relapsed (r/r) acute B lymphocytic leukemia (B-ALL) can achieve complete response (CR) after chimeric antigen receptor T-cell (CAR-T) therapy, but recurrence occurs in the short term. To reduce recurrence and improve survival, CAR-T therapy followed by transplantation is a feasible option. We analyzed the long-term follow-up outcomes and the risk factors for allogeneic hematopoietic stem cell transplantation (allo-HSCT) after CR by CAR-T therapy in this study. Methods: A total of 144 patients who underwent allo-HSCT after CAR-T therapy in our hospital were enrolled in this study. Target gene analysis was performed in 137 r/r B-ALL patients receiving allo-HSCT after CR by CAR-T therapy. Among the 137 patients, 87 were evaluated for germline predisposition gene mutations, and 92 were evaluated for tumor somatic gene mutations using NGS. The clinical factors, germline predisposition gene and somatic gene mutations associated with the prognosis of patients receiving transplantation after CAR-T therapy were analyzed using univariate Cox regression. Factors related to disease-free survival (DFS) and overall survival (OS) were analyzed using multivariate Cox regression analysis. Results: In 137 r/r B-ALL patients, the 2-year cumulative incidence of recurrence (CIR), OS and DFS in patients receiving allo-HSCT after CAR-T therapy was 31.5%, 71.4%, and 60.5%, respectively. The 2-year OS and DFS in MRD-negative patients were 80.9% and 69.3%, respectively. Univariate Cox analysis showed that pretransplant MRD positivity, fungal infection, germline EP300 mutation and somatic TP53 mutation were associated with a poor prognosis after transplantation; a TBI-based regimen was a protective factor for survival and recurrence after transplantation. Multivariate Cox regression analysis showed that the TBI-based regimen was an independent protective factor for DFS, fungal infection and MRD positivity were independent risk factors for DFS, and tumor somatic TP53 mutation and germline EP300 mutation were independent risk factors for DFS and OS. Conclusion: Germline EP300 mutation and tumor somatic TP53 mutation are poor prognostic factors for posttransplant recurrence and survival in r/r B-ALL patients achieving CR after CAR-T therapy. The prognostic risk factors should be considered in adjusting treatment strategies to improve the efficacy of clinical diagnosis and treatment.
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BACKGROUND: This study was designed to screen potential biomarkers in plasma cell-free DNA (cfDNA) for predicting the clinical outcome of immune checkpoint inhibitor (ICI)-based therapy in advanced hepatobiliary cancers. METHODS: Three cohorts including 187 patients with hepatobiliary cancers were recruited from clinical trials at the Peking Union Medical College Hospital. Forty-three patients received combination therapy of programmed cell death protein 1 (PD-1) inhibitor with lenvatinib (ICI cohort 1), 108 patients received ICI-based therapy (ICI cohort 2) and 36 patients received non-ICI therapy (non-ICI cohort). The plasma cfDNA and blood cell DNA mutation profiles were assessed to identify efficacy biomarkers by a cancer gene-targeted next-generation sequencing panel. RESULTS: Based on the copy number variations (CNVs) in plasma cfDNA, the CNV risk score model was constructed to predict survival by using the least absolute shrinkage and selection operator Cox regression methods. The results of the two independent ICI-based therapy cohorts showed that patients with lower CNV risk scores had longer overall survival (OS) and progression-free survival (PFS) than those with high CNV risk scores (log-rank p<0.01). In the non-ICI cohort, the CNV risk score was not associated with PFS or OS. Furthermore, the results indicated that 53% of patients with low CNV risk scores achieved durable clinical benefit; in contrast, 88% of patients with high CNV risk scores could not benefit from combination therapy (p<0.05). CONCLUSIONS: The CNVs in plasma cfDNA could predict the clinical outcome of the combination therapy of PD-1 inhibitor with lenvatinib and other ICI-based therapies in hepatobiliary cancers.
Assuntos
Neoplasias do Sistema Biliar/tratamento farmacológico , Biomarcadores Tumorais/genética , DNA Tumoral Circulante/genética , Variações do Número de Cópias de DNA , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Hepáticas/tratamento farmacológico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Pequim , Neoplasias do Sistema Biliar/sangue , Neoplasias do Sistema Biliar/genética , Neoplasias do Sistema Biliar/imunologia , Biomarcadores Tumorais/sangue , DNA Tumoral Circulante/sangue , Ensaios Clínicos como Assunto , Análise Mutacional de DNA , Feminino , Humanos , Inibidores de Checkpoint Imunológico/efeitos adversos , Neoplasias Hepáticas/sangue , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/imunologia , Masculino , Pessoa de Meia-Idade , Mutação , Valor Preditivo dos Testes , Intervalo Livre de Progressão , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Adulto JovemRESUMO
BACKGROUND: The human leukocyte antigen class I (HLA-I) genotype has been linked with differential immune responses to infectious disease and cancer. However, the clinical relevance of germline HLA-mediated immunity in gastrointestinal (GI) cancer remains elusive. METHODS: This study retrospectively analyzed the genomic profiling data from 84 metastatic GI cancer patients treated with immune checkpoint blockade (ICB) recruited from Peking University Cancer Hospital (PUCH). A publicly available dataset from the Memorial Sloan Kettering (MSK) Cancer Center (MSK GI cohort) was employed as the validation cohort. For the PUCH cohort, we performed HLA genotyping by whole exome sequencing (WES) analysis on the peripheral blood samples from all patients. Tumor tissues from 76 patients were subjected to WES analysis and immune oncology-related RNA profiling. We studied the associations of two parameters of germline HLA as heterozygosity and evolutionary divergence (HED, a quantifiable measure of HLA-I evolution) with the clinical outcomes of patients in both cohorts. RESULTS: Our data showed that neither HLA heterozygosity nor HED at the HLA-A/HLA-C locus correlated with the overall survival (OS) in the PUCH cohort. Interestingly, in both the PUCH and MSK GI cohorts, patients with high HLA-B HED showed a better OS compared with low HLA-B HED subgroup. Of note, a combinatorial biomarker of HLA-B HED and tumor mutational burden (TMB) may better stratify potential responders. Furthermore, patients with high HLA-B HED were characterized with a decreased prevalence of multiple driver gene mutations and an immune-inflamed phenotype. CONCLUSIONS: Our results unveil how HLA-B evolutionary divergence influences the ICB response in patients with GI cancers, supporting its potential utility as a combinatorial biomarker together with TMB for patient stratification in the future.
Assuntos
Neoplasias Gastrointestinais/genética , Neoplasias Gastrointestinais/terapia , Células Germinativas , Antígenos HLA-B/genética , Inibidores de Checkpoint Imunológico/uso terapêutico , Imunoterapia/métodos , Biomarcadores Tumorais/genética , Estudos de Coortes , Genótipo , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Mutação , Estudos RetrospectivosRESUMO
An eco-friendly and novel water treatment material was synthesized using sodium lignosulfonate modified polystyrene (SLPS), which can be used to eliminate phenols in aqueous solution. SLPS was characterized by BET, FTIR, SEM, and EDS. The effect of the initial pH value, phenol content, adsorption time, and temperature on the absorbability of phenol in SLPS was investigated through adsorption experiments. It was found that SLPS could efficiently adsorb phenol in aqueous solution at a pH value of about 7. The test results revealed that the kinetic adsorption and isotherm adsorption could be successfully described using the pseudo second-order and Langmuir models, respectively. It was illustrated that the phenol adsorption on SLPS was dominated by chemisorption and belonged to monolayer adsorption. The max. phenol adsorption value of SLPS was 31.08 mg/g at 30 °C. Therefore, SLPS displayed a great potential for eliminating phenol from polluted water as a kind of novel and effective adsorbent.