RESUMEN

With the development of comprehensive treatment, locoregional transarterial chemotherapy has become an alternative conversion therapy, palliative therapy, and neoadjuvant therapy for many solid malignant tumors. Locoregional transarterial chemotherapy, which is most frequently used for treating liver cancer, has the characteristics of high regional efficacy and few systemic adverse reactions. In recent years, the number of relevant reports of locoregional chemotherapy for treating initially inoperable colorectal cancer (CRC), including non-metastatic and metastatic CRC, has gradually increased. However, the specific treatment options for such locoregional therapy are not the same, and its indications, medication regimens and combined treatments have not reached any consensus. In this review, the application status of locoregional transarterial chemotherapy in primary and metastatic CRC patients has been reviewed and summarized to provide a reference for future clinical work and scientific research.

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BACKGROUND: Glucose fluctuations may be involved in the pathophysiological process of cardiomyocyte apoptosis, but the exact mechanism remains elusive. This study focused on exploring the mechanisms related to glucose fluctuation-induced cardiomyocyte apoptosis. METHODS: Diabetic rats established via an injection of streptozotocin were randomized to five groups: the controlled diabetic (CD) group, the uncontrolled diabetic (UD) group, the glucose fluctuated diabetic (GFD) group, the GFD group rats with the injection of 0.9% sodium chloride (NaCl) (GFD + NaCl) and the GFD group rats with the injection of N-acetyl-L-cysteine (NAC) (GFD + NAC). Twelve weeks later, cardiac function and apoptosis related protein expressions were tested. Proteomic analysis was performed to further analyze the differential protein expression pattern of CD and GFD. RESULTS: The left ventricular ejection fraction levels and fractional shortening levels were decreased in the GFD group, compared with those in the CD and UD groups. Positive cells tested by DAB-TUNEL were increased in the GFD group, compared with those in the CD group. The expression of Bcl-2 was decreased, but the expressions of Bax, cleaved caspase-3 and cleaved caspase-9 were increased in response to glucose fluctuations. Compared with CD, there were 527 upregulated and 152 downregulated proteins in GFD group. Txnip was one of the differentially expressed proteins related to oxidative stress response. The Txnip expression was increased in the GFD group, while the Akt phosphorylation level was decreased. The interaction between Txnip and Akt was enhanced when blood glucose fluctuated. Moreover, the application of NAC partially reversed glucose fluctuations-induced cardiomyocyte apoptosis. CONCLUSIONS: Glucose fluctuations lead to cardiomyocyte apoptosis by up-regulating Txnip expression and enhancing Txnip-Akt interaction.

Asunto(s)

Proteínas Reguladoras de la Apoptosis , Apoptosis , Glucemia , Proteínas Portadoras , Diabetes Mellitus Experimental , Miocitos Cardíacos , Proteínas Proto-Oncogénicas c-akt , Ratas Sprague-Dawley , Transducción de Señal , Animales , Miocitos Cardíacos/patología , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/efectos de los fármacos , Apoptosis/efectos de los fármacos , Proteínas Proto-Oncogénicas c-akt/metabolismo , Diabetes Mellitus Experimental/metabolismo , Masculino , Proteínas Portadoras/metabolismo , Glucemia/metabolismo , Proteínas Reguladoras de la Apoptosis/metabolismo , Fosforilación , Función Ventricular Izquierda/efectos de los fármacos , Tiorredoxinas/metabolismo , Cardiomiopatías Diabéticas/metabolismo , Cardiomiopatías Diabéticas/patología , Cardiomiopatías Diabéticas/fisiopatología , Cardiomiopatías Diabéticas/etiología , Proteómica , Ratas , Mapas de Interacción de Proteínas , Proteínas de Ciclo Celular

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Extracellular vesicles (EVs) are considered as promising candidates for predicting patients who respond to immunotherapy. Nevertheless, simultaneous detection of multiple EVs markers still presents significant technical challenges. In this work, we developed a high-throughput microdroplet-enhanced chip (MEC) platform, which utilizes thousands of individual microchambers (∼pL) as reactors, accelerating the detection efficiency of the CRISPR/Cas systems and increasing the sensitivity by up to 100-fold (aM level). Ten biomarkers (including 5 RNAs and 5 proteins) from patients' EVs are successfully detected on one chip, and the comprehensive markers show increased accuracy (AUC 0.911) than the individual marker for the efficacy prediction of immunotherapy. This platform provides a high-throughput yet sensitive strategy for screening immunotherapy markers in clinical.

RESUMEN

Cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6 inhibitors) can significantly extend tumor response in patients with metastatic luminal A breast cancer, yet intrinsic and acquired resistance remains a prevalent issue. Understanding the molecular features of CDK4/6 inhibitor sensitivity and the potential efficacy of their combination with novel targeted cell death inducers may lead to improved patient outcomes. Herein, we demonstrate that ferroptosis, a form of regulated cell death driven by iron-dependent phospholipid peroxidation, partly underpins the efficacy of CDK4/6 inhibitors. Mechanistically, CDK4/6 inhibitors downregulate the cystine transporter SLC7A11 by inhibiting SP1 binding to the SLC7A11 promoter region. Furthermore, SLC7A11 is identified as critical for the intrinsic sensitivity of luminal A breast cancer to CDK4/6 inhibitors. Both genetic and pharmacological inhibition of SP1 or SLC7A11 enhances cell sensitivity to CDK4/6 inhibitors and synergistically inhibits luminal A breast cancer growth when combined with CDK4/6 inhibitors in vitro and in vivo. Our data highlight the potential of targeting SLC7A11 in combination with CDK4/6 inhibitors, supporting further investigation of combination therapy in luminal A breast cancer.

RESUMEN

Understanding the genetic basis of neuro-related proteins is essential for dissecting the molecular basis of human behavioural traits and the disease aetiology of neuropsychiatric disorders. Here the SCALLOP Consortium conducted a genome-wide association meta-analysis of over 12,000 individuals for 184 neuro-related proteins in human plasma. The analysis identified 125 cis-regulatory protein quantitative trait loci (cis-pQTL) and 164 trans-pQTL. The mapped pQTL capture on average 50% of each protein's heritability. At the cis-pQTL, multiple proteins shared a genetic basis with human behavioural traits such as alcohol and food intake, smoking and educational attainment, as well as neurological conditions and psychiatric disorders such as pain, neuroticism and schizophrenia. Integrating with established drug information, the causal inference analysis validated 52 out of 66 matched combinations of protein targets and diseases or side effects with available drugs while suggesting hundreds of repurposing and new therapeutic targets.

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Objective: To investigate the prevalence of subthreshold depression among Chinese college students and to explore the related factors. Methods: The research subjects were Chinese college students participating in the "2022 Psychology and Behavior Investigation of Chinese Residents (PBICR-2022)". Data on respondents' general characteristics, quality of life, perceived pressure, family communication, perceived social support, self-efficacy, and depression status were gathered. To investigate the association between each variable and the risk of subthreshold depression, statistical analyses, including chi-square tests and rank sum tests were conducted. Furthermore, a binary stepwise logistic regression was employed to establish the regression model of the factors related to subthreshold depression among Chinese college students. Results: A prevalence of subthreshold depression of about 39.7 % was found among the 8934 respondents. Logistic regression analysis revealed that respondents who are female, have chronic diseases, are in debt, experience significant impacts from epidemic control policies, have lower self-assessed quality of life, experience challenges in family communication, perceive lower social support, have lower self-efficacy, and feel higher perceived pressure are more likely to develop subthreshold depression compared to the control group. (P < 0.05). Conclusion: The prevalence rate of subthreshold depression among Chinese college students was found to be approximately 40 %. Female college students suffering from chronic diseases, with households in debt, greatly impacted by epidemic control policies, and experiencing high perceived stress, may be at risk for subthreshold depression among Chinese college students. On the other hand, strong family communication, perceived social support, and self-efficacy were identified as potential protective factors. In order to facilitate timely screening, diagnosis, and treatment of subthreshold depression in Chinese college students, it is crucial for the government, local communities, colleges, and families to prioritize the mental health of college students and implement targeted measures accordingly.

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INTRODUCTION: Aplastic anemia (AA) and hypoplastic myelodysplastic syndrome (MDS-h) are bone marrow failure disease and difficult to distinguish merely by morphological analysis. In this study, we investigated the value of flow cytometry (FCM) in the differential diagnosis of AA and MDS-h. METHODS: We included 822 patients (626 control, 69 AA, 22 MDS-h and 105 dilution patients) from January 2017 to December 2022 for a retrospective study. Bone marrow myeloid progenitor (MP) cell and mature lymphocytes proportions were analyzed by FCM. The ratio of MP cell proportion and mature lymphocytes proportion, MPLR, was calculated. Data were compared by Kruskal-Wallis test. Differential diagnostic efficacy was evaluated by receiver operating characteristic (ROC) curve. Cutoff value was determined by the maximum Youden index. RESULTS: Bone marrow MP cell proportion and MPLR of MDS-h patients were higher than AA patients. Mature lymphocytes proportion of MDS-h patients was lower than AA patients. Area under ROC curve (AUC of ROC) of MP cell proportion, MPLR and mature lymphocytes proportion to distinguish AA from MDS-h were 0.992, 0.988, and 0.850, respectively. Moreover, MPLR of dilution patients was higher than AA patients but lower than MDS-h patients. The AUC of ROC curves of MPLR to distinguish MDS-h and AA from dilution were 0.854 and 0.871, respectively. CONCLUSION: Bone marrow MP cell proportion and MPLR can effectively discriminate AA from MDS-h with similar differential efficacy, which is higher than mature lymphocytes proportion. Moreover, MPLR can evaluate the quality of bone marrow aspirates, which would interfere with the differential diagnosis.

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Myeloid cells are vital components of the immune system and have pivotal functions in orchestrating immune responses. Understanding their functions within the tumor microenvironment and their interactions with tumor-infiltrating lymphocytes presents formidable challenges across diverse cancer types, particularly with regards to cancer immunotherapies. Here, we explore tumor-infiltrating myeloid cells (TIMs) by conducting a pan-cancer analysis using single-cell transcriptomics across eight distinct cancer types, encompassing a total of 192 tumor samples from 129 patients. By examining gene expression patterns and transcriptional activities of TIMs in different cancer types, we discern notable alterations in abundance of TIMs and kinetic behaviors prior to and following immunotherapy. We also identify specific cell-cell interaction targets in immunotherapy; unique and shared regulatory profiles critical for treatment response; and TIMs associated with survival outcomes. Overall, our study illuminates the heterogeneity of TIMs and improves our understanding of tissue-specific and cancer-specific myeloid subsets within the context of tumor immunotherapies.

Asunto(s)

Inhibidores de Puntos de Control Inmunológico , Inmunoterapia , Células Mieloides , Neoplasias , Análisis de la Célula Individual , Microambiente Tumoral , Humanos , Células Mieloides/inmunología , Células Mieloides/metabolismo , Análisis de la Célula Individual/métodos , Neoplasias/inmunología , Neoplasias/genética , Neoplasias/terapia , Neoplasias/patología , Microambiente Tumoral/inmunología , Microambiente Tumoral/genética , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacología , Inmunoterapia/métodos , Linfocitos Infiltrantes de Tumor/inmunología , Regulación Neoplásica de la Expresión Génica , Transcriptoma , Perfilación de la Expresión Génica

RESUMEN

Background: The western region of China has a dense population, relatively underdeveloped economy, and a significant number of left-behind children. Currently, the prevalence of adolescent psychological abuse, neglect, and the factors associated with these issues in the region remain unclear. This study aims to evaluate the current status of adolescent psychological abuse and neglect and its associated factors in this region.Methods: Data were collected from 50 schools in western China through cluster sampling to target adolescents aged 12 to 18. A comprehensive survey form was used to collect socio-demographic characteristics of adolescents. The Child Psychological Abuse and Neglect Scale was employed to assess the current psychological abuse and neglect of adolescents. Independent samples t-tests were used for inter-group comparisons. A Directed Acyclic Graph was constructed for controlling confounding variables. Subsequently, binary logistic regression analysis was performed, and a nomogram risk factors model was developed using R Studio.Results: This study included 12,743 teenagers, with an average age of 15.53(±1.39) years. Among them, 4,965 individuals, accounting for 39.0%, reported experiences of psychological abuse, while 4,167 individuals, accounting for 32.7%, reported experiences of neglect. The rates of psychological abuse and neglect in adolescents are influenced by gender, grade, left-behind experience, parental marital status, and living on campus (P < .05).Conclusion: Adolescents in western China exhibit higher rates of psychological abuse and neglect compared to those in the eastern and northern regions of China. Gender, grade, left-behind experience, and family factors significantly influence the psychological abuse and neglect of adolescents.

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This study is the first large-scale, multi-centre, cross-sectional analysis of psychological abuse and neglect among youth in Western China, a region with relatively underdeveloped economic and social conditions.This article fills in the gap in the region's research on psychological abuse and neglect by addressing the issues of small sample size, limited coverage, and a lack of variables included.This provides a crucial theoretical foundation for enhancing the mental well-being of youth in this region and preventing psychological and mental illnesses among youth.

Asunto(s)

Maltrato a los Niños , Humanos , Adolescente , China/epidemiología , Masculino , Femenino , Estudios Transversales , Prevalencia , Factores de Riesgo , Maltrato a los Niños/estadística & datos numéricos , Maltrato a los Niños/psicología , Encuestas y Cuestionarios , Niño , Abuso Emocional/estadística & datos numéricos , Abuso Emocional/psicología , Instituciones Académicas

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Glucocorticoids (GCs) are potent anti-inflammatory and immunosuppressant medications and remain the cornerstone of systemic lupus erythematosus (SLE) therapy. However, ongoing exposure to GCs has the potential to elicit multiple adverse effects. Considering the irreplaceability of GCs in SLE therapy, it is important to explore the optimal regimen of GCs. Here, we compared the long-term efficacy and safety of pulsed and oral GC therapy in a lupus-prone mouse model. Mice were grouped using a randomized block design. We monitored survival rates, proteinuria, serum autoantibodies, and complement 3 (C3) levels up to 28 weeks of age, and assessed renal damage, bone quality, lipid deposition in the liver and marrow, glucose metabolic parameters, and levels of hormones of the hypothalamic-pituitary-adrenal (HPA) axis. Finally, we explored the mechanisms underlying the superior efficacy of the pulse regimen over oral prednisone regimen. We found that both GC regimens alleviated the poor survival rate, proteinuria, and glomerulonephritis, while also reducing serum autoantibodies and increasing the level of C3. The pulsed GC regimen showed less resistance to insulin, less suppression of the HPA axis, less bone loss, and less bone marrow fat deposition than the oral GC regimen. Additionally, GC-induced leucine zipper (GILZ) was significantly overexpressed in the GC pulse group. These results suggest that the GC pulse regimen ameliorated symptoms in lupus-prone mice, with fewer side effects, which may be related to GILZ overexpression. Our findings offer a potentially promising GC treatment option for SLE.

Asunto(s)

Glucocorticoides , Lupus Eritematoso Sistémico , Metilprednisolona , Ratones Endogámicos MRL lpr , Prednisona , Animales , Lupus Eritematoso Sistémico/tratamiento farmacológico , Metilprednisolona/farmacología , Metilprednisolona/administración & dosificación , Glucocorticoides/farmacología , Glucocorticoides/administración & dosificación , Glucocorticoides/efectos adversos , Prednisona/farmacología , Prednisona/efectos adversos , Prednisona/administración & dosificación , Ratones , Femenino , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Autoanticuerpos/sangre , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/metabolismo , Complemento C3/metabolismo , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Sistema Hipófiso-Suprarrenal/metabolismo , Proteinuria/tratamiento farmacológico

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The carbon skeleton of any organic molecule serves as the foundation for its three-dimensional structure, playing a pivotal role in determining its physical and biological properties1. As such, taxane diterpenes are one of the most well-known natural product families, primarily owing to the success of their most prominent compound, paclitaxel, an effective anticancer therapeutic for more than 25 years2-6. In contrast to classical taxanes, the bioactivity of cyclotaxanes (also referred to as complex taxanes) remains significantly underexplored. The carbon skeletons of these two groups of taxanes differ significantly, and so would typically their own distinct synthetic approaches. Here we report a versatile synthetic strategy based on the interconversion of complex molecular frameworks, providing general access to the wider taxane diterpene family. A range of classical and cyclotaxane frameworks was prepared including, among others, the total syntheses of taxinine K (2), canataxapropellane (5) and dipropellane C from a single advanced intermediate. The synthetic approach deliberately eschews biomimicry, emphasizing instead the power of stereoelectronic control in orchestrating the interconversion of polycyclic frameworks.

Asunto(s)

Hidrocarburos Aromáticos con Puentes , Técnicas de Química Sintética , Diterpenos , Taxoides , Productos Biológicos/síntesis química , Productos Biológicos/química , Hidrocarburos Aromáticos con Puentes/síntesis química , Hidrocarburos Aromáticos con Puentes/química , Carbono/química , Diterpenos/síntesis química , Diterpenos/química , Estereoisomerismo , Taxoides/química , Taxoides/síntesis química , Paclitaxel/química

RESUMEN

Antibiotics are widely utilized in agriculture for the prevention and treatment of animal diseases. How-ever, the abuse and overuse of antibiotics progressively increase the risks of antibiotic residues and antibiotic resis-tance. The bioaccumulation and biomagnification of antibiotics through food chains will negatively affect ecological safety, and finally threaten human health. There are many shortages of traditional antibiotic detection techniques, such as complex procedures, complicated operation and time consuming, and thus are difficult to meet the demand of instant, efficient and accurate on-site detection. Therefore, it is crucial to develop rapid detection techniques of antibiotics to manage the application of antibiotics in agriculture. We reviewed the utilization, and management of antibiotics in animal husbandry, residual characteristics, and potential hazards of antibiotics in agricultural products, summarized the advancements in rapid detection techniques of antibiotics in agricultural products over the past five years, compared the advantages and disadvantages of different rapid detection techniques, and prospected the future development in this area. This review would provide a valuable reference to the control and point-of-care test of antibiotics in agricultural products.

Asunto(s)

Antibacterianos , Productos Agrícolas , Residuos de Medicamentos , Antibacterianos/análisis , Residuos de Medicamentos/análisis , Productos Agrícolas/química , Productos Agrícolas/crecimiento & desarrollo , Contaminación de Alimentos/análisis , Animales

RESUMEN

Toll-like receptor 4 (TLR4) acts as a double-edged sword in the occurrence and development of periodontitis. While the activation of TLR4 in macrophages aids in clearing local pathogens, it can also disrupt innate immune responses, upsetting microecological balance and accelerating the destruction of periodontal bone tissues. To date, the effects of TLR4 on osteogenesis and osteoclastogenesis in periodontitis have not been comprehensively studied. In this study, we investigated the development of periodontitis in the Tlr4-/- mice by ligating their second molars with silk threads. Compared to wild-type (WT) mice, Tlr4-/- mice demonstrated increased resistance to periodontitis-associated bone destruction, as evidenced by decreased bone resorption and enhanced bone regeneration. Mechanistically, the deletion of Tlr4 not only inhibited osteoclast formation by reducing the expression of NFATc1, CTSK and TRAP, but also enhanced osteogenic abilities through increased expression of OCN, OPN and RUNX2. In conclusion, TLR4 tips the balance of osteoclastogenesis and osteogenesis, thereby promoting periodontal bone destruction in periodontitis.

Asunto(s)

Ratones Noqueados , Osteoblastos , Osteoclastos , Osteogénesis , Periodontitis , Receptor Toll-Like 4 , Animales , Receptor Toll-Like 4/metabolismo , Receptor Toll-Like 4/genética , Periodontitis/inmunología , Periodontitis/genética , Periodontitis/patología , Osteoclastos/fisiología , Osteoclastos/inmunología , Ratones , Osteoblastos/metabolismo , Osteoblastos/inmunología , Ratones Endogámicos C57BL , Masculino , Factores de Transcripción NFATC/metabolismo , Factores de Transcripción NFATC/genética , Humanos , Pérdida de Hueso Alveolar/inmunología , Pérdida de Hueso Alveolar/patología

RESUMEN

Seven undescribed abietane diterpenoids [abietamethinols A-G (1-7)] were isolated from the twigs and leaves of Isodon amethystoides. Their structures were elucidated on the basis of spectroscopic methods including 2D NMR, and they were further confirmed by X-ray crystallographic data. Lophanic acid was considered as the precursor of 1-7 in the biosynthesis pathway hypothesis. These compounds were evaluated for their cytotoxic, anti-bacterial and anti-AIV (avian influenza virus) activities. Compound 5 showed 42.9% inhibitory activity against the cancer cell line SMMC-7721 at the concentration of 40 µM, 3 and 4 could inhibit the bacterial growth of Streptococcus sobrinus by 55.3% and 63.2% at the concentrations of 148.6 and 141.9 µM, respectively, and 4 was demonstrated with antiviral activity against AIV with the inhibitory effect of 68.4% at 25 µM.

Asunto(s)

Abietanos , Antibacterianos , Antineoplásicos Fitogénicos , Antivirales , Isodon , Pruebas de Sensibilidad Microbiana , Abietanos/farmacología , Abietanos/química , Abietanos/aislamiento & purificación , Humanos , Antivirales/farmacología , Antivirales/química , Antivirales/aislamiento & purificación , Antibacterianos/farmacología , Antibacterianos/química , Antibacterianos/aislamiento & purificación , Isodon/química , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/aislamiento & purificación , Estructura Molecular , Ensayos de Selección de Medicamentos Antitumorales , Línea Celular Tumoral , Relación Estructura-Actividad , Hojas de la Planta/química , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Conformación Molecular , Virus de la Influenza A/efectos de los fármacos

RESUMEN

BACKGROUND: This study was an introduction to the Swedish ALSrisc Study and explored the association of lifestyle and medical conditions, with risk and progression of amyotrophic lateral sclerosis (ALS). METHODS: We included 265 newly diagnosed ALS patients during 2016-2022 in Stockholm and 207 ALS-free siblings and partners of the patients as controls. Information on body mass index (BMI), smoking, and history of head injuries, diabetes mellitus, hypercholesterolemia, and hypertension was obtained through the Euro-MOTOR questionnaire at recruitment. Patients were followed from diagnosis until death, invasive ventilation, or November 30, 2022. RESULTS: Higher BMI at recruitment was associated with lower risk for ALS (OR 0.89, 95%CI 0.83-0.95), especially among those diagnosed after 65 years. One unit increase in the average BMI during the 3 decades before diagnosis was associated with a lower risk for ALS (OR 0.94, 95%CI 0.89-0.99). Diabetes was associated with lower risk of ALS (OR 0.38, 95%CI 0.16-0.90), while hypercholesterolemia was associated with higher risk of ALS (OR 2.10, 95%CI 1.13-3.90). Higher BMI at diagnosis was associated with lower risk of death (HR 0.91, 95%CI 0.84-0.98), while the highest level of smoking exposure (in pack-years) (HR 1.90, 95%CI 1.20-3.00), hypercholesterolemia (HR 1.84, 95%CI 1.06-3.19), and hypertension (HR 1.76, 95%CI 1.03-3.01) were associated with higher risk of death, following ALS diagnosis. CONCLUSIONS: Higher BMI and diabetes were associated with lower risk of ALS. Higher BMI was associated with lower risk of death, whereas smoking (especially in high pack-years), hypercholesterolemia, and hypertension were associated with higher risk of death after ALS diagnosis.

Asunto(s)

Esclerosis Amiotrófica Lateral , Índice de Masa Corporal , Progresión de la Enfermedad , Estilo de Vida , Humanos , Esclerosis Amiotrófica Lateral/epidemiología , Esclerosis Amiotrófica Lateral/diagnóstico , Masculino , Suecia/epidemiología , Femenino , Persona de Mediana Edad , Anciano , Adulto , Factores de Riesgo , Fumar/epidemiología , Diabetes Mellitus/epidemiología , Hipertensión/epidemiología , Hipercolesterolemia/epidemiología

RESUMEN

The development of non-precious metal electrocatalysts with excellent activity and durability for electrochemical water splitting has always been a goal. Transition metal sulfides are attractive electrocatalysts for both hydrogen evolution reaction (HER) and oxygen evolution reaction (OER). In this article, we designed and constructed efficient catalysts with multiple synergistic interactions and synthesized Ce-NiS2@NF nanosphere using a solvothermal method. Ce-NiS2@NF exhibits excellent HER performance, OER performance, and overall water splitting capability in alkaline electrolytes, demonstrating good stability. The addition of Ce influences the activity of the catalysts, attributed to the synergistic interactions creating more active sites and higher intrinsic activity through the introduction of Ce heteroatoms. Additionally, the self-supported conductive substrate promotes electron transfer, enhancing the intrinsic activity and active site density of the catalyst. This study provides an in-depth investigation into structural design and performance enhancement, offering ideas for designing efficient catalysts for overall water electrolysis. This work provides an in-depth study in terms of structural design performance enhancement and provides ideas for designing efficient alkaline bifunctional catalysts. Valuable insights have been provided in elucidating the intrinsic mechanism of the catalytic activity of cerium-doped nickel sulfide nanospheres, thus providing new guidance in the field of energy conversion technology.

RESUMEN

Loss-of-function mutations in CREBBP, which encodes for a histone acetyltransferase, occur frequently in B-cell malignancies, highlighting CREBBP deficiency as an attractive therapeutic target. Using established isogenic cell models, we demonstrated that CREBBP-deficient cells are selectively vulnerable to AURKA inhibition. Mechanistically, we found that co-targeting CREBBP and AURKA suppressed MYC transcriptionally and post-translationally to induce replication stress and apoptosis. Inhibition of AURKA dramatically decreased MYC protein level in CREBBP-deficient cells, implying a dependency on AURKA to sustain MYC stability. Furthermore, in vivo studies showed that pharmacological inhibition of AURKA was efficacious in delaying tumor progression in CREBBP-deficient cells and was synergistic with CREBBP inhibitors in CREBBP-proficient cells. Our study sheds light on a novel synthetic lethal interaction between CREBBP and AURKA, indicating that targeting AURKA represents a potential therapeutic strategy for high-risk B-cell malignancies harboring CREBBP inactivating mutations.

Asunto(s)

Aurora Quinasa A , Proteína de Unión a CREB , Proteínas Proto-Oncogénicas c-myc , Mutaciones Letales Sintéticas , Proteína de Unión a CREB/genética , Proteína de Unión a CREB/metabolismo , Aurora Quinasa A/genética , Aurora Quinasa A/metabolismo , Aurora Quinasa A/antagonistas & inhibidores , Humanos , Animales , Ratones , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Apoptosis/genética , Ensayos Antitumor por Modelo de Xenoinjerto

RESUMEN

The emergence of XBB.1.16 has gained rapid global prominence. Previous studies have elucidated that the infection of SARS-CoV-2 induces alterations in the mitochondrial integrity of host cells, subsequently influencing the cellular response to infection. In this study, we compared the differences in infectivity and pathogenicity between XBB.1.16 and the parental Omicron sublineages BA.1 and BA.2 and assessed their impact on host mitochondria. Our findings suggest that, in comparison with BA.1 and BA.2, XBB.1.16 exhibits more efficient spike protein cleavage, more efficient mediating syncytia formation, mild mitochondriopathy, and less pathogenicity. Altogether, our investigations suggest that, based on the mutation of key sites, XBB.1.16 exhibited enhanced infectivity but lower pathogenicity. This will help us to further investigate the biological functions of key mutation sites.

Asunto(s)

COVID-19 , Mitocondrias , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , SARS-CoV-2/genética , SARS-CoV-2/metabolismo , SARS-CoV-2/patogenicidad , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/metabolismo , Glicoproteína de la Espiga del Coronavirus/química , Humanos , COVID-19/virología , Mitocondrias/metabolismo , Animales , Mutación , Chlorocebus aethiops , Células Vero , Ratones , Células HEK293

RESUMEN

Matrix Gla protein (MGP) and trichorhinophalangeal syndrome type 1 (TRPS1) have recently emerged as novel breast-specific immunohistochemical (IHC) markers, particularly for triple-negative breast cancer (TNBC) and metaplastic carcinoma. The present study aimed to validate and compare the expression of MGP, TRPS1 and GATA binding protein 3 (GATA3) in metastatic breast carcinoma (MBC), invasive breast carcinoma (IBC) with special features, including special types of invasive breast carcinoma (IBC-STs) and invasive breast carcinoma of no special type with unique features, and mammary and non-mammary salivary gland-type tumours (SGTs). Among all enrolled cases, MGP, TRPS1 and GATA3 had comparable high positivity for ER/PR-positive (p=0.148) and HER2-positive (p=0.310) breast carcinoma (BC), while GATA3 positivity was significantly lower in TNBC (p<0.001). Similarly, the positive rates of MGP and TRPS1 in MBCs (99.4%), were higher than in GATA3 (90.9%, p<0.001). Among the IBC-STs, 98.4% of invasive lobular carcinomas (ILCs) were positive for all three markers. Among neuroendocrine tumours (NTs), all cases were positive for TRPS1 and GATA3, while MGP positivity was relatively low (81.8%, p=0.313). In the neuroendocrine carcinoma (NC) subgroup, all cases were positive for GATA3 and MGP, while one case was negative for TRPS1. All carcinomas with apocrine differentiation (APOs) were positive for GATA3 and MGP, while only 60% of the cases demonstrated moderate staining for TRPS1. Among mammary SGTs, MGP demonstrated the highest positivity (100%), followed by TRPS1 (96.0%) and GATA3 (72.0%). Positive staining for these markers was also frequently observed in non-mammary SGTs. Our findings further validate the high sensitivity of MGP and TRPS1 in MBCs, IBC-STs, and breast SGTs. However, none of these markers are capable of distinguishing between mammary and non-mammary SGTs.

Asunto(s)

Biomarcadores de Tumor , Neoplasias de la Mama , Factor de Transcripción GATA3 , Proteína Gla de la Matriz , Neoplasias de las Glándulas Salivales , Factores de Transcripción , Femenino , Humanos , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/análisis , Neoplasias de la Mama/patología , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/metabolismo , Proteínas de Unión al Calcio/metabolismo , Proteínas de Unión al Calcio/análisis , Proteínas de Unión al ADN/metabolismo , Proteínas de la Matriz Extracelular/metabolismo , Factor de Transcripción GATA3/metabolismo , Factor de Transcripción GATA3/análisis , Inmunohistoquímica , Proteínas Represoras/metabolismo , Neoplasias de las Glándulas Salivales/patología , Neoplasias de las Glándulas Salivales/diagnóstico , Neoplasias de las Glándulas Salivales/metabolismo , Sensibilidad y Especificidad , Factores de Transcripción/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/diagnóstico , Neoplasias de la Mama Triple Negativas/metabolismo

RESUMEN

Single-cell sequencing datasets are key in biology and medicine for unraveling insights into heterogeneous cell populations with unprecedented resolution. Here, we construct a single-cell multi-omics map of human tissues through in-depth characterizations of datasets from five single-cell omics, spatial transcriptomics, and two bulk omics across 125 healthy adult and fetal tissues. We construct its complement web-based platform, the Single Cell Atlas (SCA, www.singlecellatlas.org ), to enable vast interactive data exploration of deep multi-omics signatures across human fetal and adult tissues. The atlas resources and database queries aspire to serve as a one-stop, comprehensive, and time-effective resource for various omics studies.

Asunto(s)

Ascomicetos , Multiómica , Adulto , Humanos , Bases de Datos Factuales , Feto , Perfilación de la Expresión Génica