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D-Mannose 2-epimerase (MEase) catalyzes the bioconversion between D-glucose and D-mannose. It is an important potential biocatalyst for large-scale production of D-mannose, a functional monosaccharide used in pharmaceutical and food industries. In this study, a new microbial MEase was characterized from Runella zeae DSM 19591. The enzyme was purified by one-step nickel-affinity chromatography and determined to be a dimeric protein with two identical subunits of approximately 86.1â¯kDa by gel filtration. The enzyme showed the highest activity at pH 8.0 and 40 °C, with a specific activity of 2.99â¯U/mg on D-glucose and 3.71â¯U/mg on D-mannose. The melting temperature (Tm) was 49.4 °C and the half-life was 115.14 and 3.23â¯h at 35 and 40 °C, respectively. The purified enzyme (1â¯U/mL) produced 115.7â¯g/L of D-mannose from 500â¯g/L of D-glucose for 48â¯h, with a conversion ratio of 23.14â¯%. It was successfully expressed in Bacillus subtilis WB600 via pP43NMK as the vector. The highest fermentation activity was 10.58â¯U/mL after fed-batch cultivation for 28â¯h, and the whole cells of recombinant B. subtilis produced 114.0â¯g/L of D-mannose from 500â¯g/L of D-glucose, with a conversion ratio of 22.8â¯%.
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Proteostasis and genomic integrity are respectively regulated by the endoplasmic reticulum-associated protein degradation (ERAD) and DNA damage repair signaling pathways, with both pathways essential for carcinogenesis and drug resistance. How these signaling pathways coordinate with each other remains unexplored. We found that ER stress specifically induces the DNA-PKcs-regulated nonhomologous end joining (NHEJ) pathway to amend DNA damage and impede cell death. Intriguingly, sustained ER stress rapidly decreased the activity of DNA-PKcs and DNA damage accumulated, facilitating a switch from adaptation to cell death. This DNA-PKcs inactivation was caused by increased KU70/KU80 protein degradation. Unexpectedly, the ERAD ligase HRD1 was found to efficiently destabilize the classic nuclear protein HDAC1 in the cytoplasm, by catalyzing HDAC1's polyubiquitination at lysine 74, at a late stage of ER stress. By abolishing HDAC1-mediated KU70/KU80 deacetylation, HRD1 transmits ER signals to the nucleus. The resulting enhanced KU70/KU80 acetylation provides binding sites for the nuclear E3 ligase TRIM25, resulting in the promotion of polyubiquitination and the degradation of KU70/KU80 proteins. Both in vitro and in vivo cancer models showed that genetic or pharmacological inhibition of HADC1 or DNA-PKcs sensitizes colon cancer cells to ER stress inducers, including the Food and Drug Administration-approved drug celecoxib. The antitumor effects of the combined approach were also observed in patient-derived xenograft models. These findings identify a mechanistic link between ER stress (ERAD) in the cytoplasm and DNA damage (NHEJ) pathways in the nucleus, indicating that combined anticancer strategies may be developed that induce severe ER stress while simultaneously inhibiting KU70/KU80/DNA-PKcs-mediated NHEJ signaling.
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Dano ao DNA , Proteína Quinase Ativada por DNA , Estresse do Retículo Endoplasmático , Ubiquitina-Proteína Ligases , Animais , Humanos , Camundongos , Linhagem Celular Tumoral , Reparo do DNA por Junção de Extremidades , Reparo do DNA , Proteína Quinase Ativada por DNA/metabolismo , Proteína Quinase Ativada por DNA/genética , Retículo Endoplasmático/metabolismo , Histona Desacetilase 1/metabolismo , Histona Desacetilase 1/genética , Autoantígeno Ku/metabolismo , Autoantígeno Ku/genética , Proteólise , Transdução de Sinais , Ubiquitina-Proteína Ligases/metabolismo , Ubiquitina-Proteína Ligases/genética , UbiquitinaçãoRESUMO
BACKGROUND: This study aimed to assess the incidence and risk factors of subsequent carbapenem-resistant Enterobacterales (CRE) infection among rectal carriers, and their association with geographic region and age. METHODS: A meta-analysis of studies investigating incidence and/or risk factors of subsequent CRE infection among rectal carriers was conducted, with subgroup analyses by geographic region and age. PubMed, Embase, Web of Science, and Cochrane Library were searched (published from inception to 31 January 2024). This study is registered with PROSPERO (CRD42023444420). RESULTS: Of 4459 studies identified, 24 studies with 8188 CRE rectal carriers were included. The pooled incidence of subsequent CRE infection was 20.6% (95% CI 15.9-25.8). The highest incidence was seen in America (23.6%, 95% CI 14.2-34.5), followed by Europe (20.9%, 95% CI 12.5-30.8) and Asia (19.8%, 95% CI 12.7-27.9). Children had a greater incidence (26.7%, 95% CI 21.3-32.3) than adults (19.8%, 95% CI 14.9-25.2). Fourteen factors were associated with subsequent CRE infection. In Asia, the most notable risk factor was gastritis (odds ratio [OR] 4.95 95% CI 1.87-13.11). In Europe, admission to the intensive care unit was prominent (OR 2.76 95% CI 1.14-6.65). In the America, the use of a urinary Foley catheter (OR 4.33 95% CI 1.06-17.70) was dominant. Admission to the intensive care unit was most notable in adults (OR 3.01 95% CI 1.80-5.02), while mechanical ventilation was shown the greatest significance in children (OR 15.61 95% CI 4.39-55.47). CONCLUSIONS: Risk of subsequent CRE infection among rectal carriers was critical. Identifying the risk factors for subsequent infection could help in developing more potent prevention and control measures to reduce CRE infection.
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In recent years, with advancements in medicine, the survival period of patients with tumours has significantly increased. The adverse effects of tumour treatment on patients, especially cardiac toxicity, have become increasingly prominent. In elderly patients with breast cancer, treatment-related cardiovascular toxicity has surpassed cancer itself as the leading cause of death. Moreover, in recent years, an increasing number of novel antitumour drugs, such as multitargeted agents, antibodyâdrug conjugates (ADCs), and immunotherapies, have been applied in clinical practice. The cardiotoxicity induced by these drugs has become more pronounced, leading to a complex and diverse mechanism of cardiac damage. The risks of unintended cardiovascular toxicity are increased by high-dose anthracyclines, immunotherapies, and concurrent radiation, in addition to traditional cardiovascular risk factors such as smoking, hypertension, diabetes, hyperlipidaemia, and obesity. However, these factors do not fully explain why only a subset of individuals experience treatment-related cardiac toxicity, whereas others with similar clinical features do not. Recent studies indicate that genetics play a significant role in susceptibility to the development of cardiovascular toxicity from cancer therapies. These genes are involved in drug metabolism, oxidative damage, cardiac dysfunction, and other processes. Moreover, emerging evidence suggests that epigenetics also plays a role in drug-induced cardiovascular toxicity. We conducted a review focusing on breast cancer as an example to help oncologists and cardiologists better understand the mechanisms and effects of genetic factors on cardiac toxicity. In this review, we specifically address the relationship between genetic alterations and cardiac toxicity, including chemotherapy-related genetic changes, targeted therapy-related genetic changes, and immune therapy-related genetic changes. We also discuss the role of epigenetic factors in cardiac toxicity. We hope that this review will improve the risk stratification of patients and enable therapeutic interventions that mitigate these unintended adverse consequences of life-saving cancer treatments.
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Antineoplásicos , Humanos , Antineoplásicos/efeitos adversos , Cardiotoxicidade/etiologia , Neoplasias/genética , Epigênese Genética , Oncologia , Animais , Predisposição Genética para Doença , Cardio-OncologiaRESUMO
Introduction: Non-suicidal self-injury (NSSI) is a prevalent concern among adolescents with depression, yet its relationship with demographic characteristics and physiological indicators remains underexplored. This study aimed to investigate these relationships among inpatient adolescents aged 13 to 18 at a hospital affiliated with Guizhou Medical University. Methods: A cross-sectional study was conducted involving 222 adolescent inpatients diagnosed with depression. Data on NSSI occurrence, demographic variables (gender, only-child status, age), and physiological indicators (ALT, TSH, FT4, PLR, TG, HDLC, LDLC, FT3, NLR, MLR) were collected and analyzed. Statistical analyses, including correlations and group comparisons, were performed to assess the associations between NSSI and these factors. Results: The prevalence of NSSI among the participants was 40.5%. Significant correlations were found between NSSI and several demographic and physiological factors. Specifically, NSSI was significantly associated with female gender, non-only-child status, younger age, lower ALT levels, higher TSH levels, lower FT4 levels, and higher PLR values. However, no significant differences were observed in TG, HDLC, LDLC, FT3, NLR, or MLR between the NSSI and non-NSSI groups. Discussion: The findings highlight distinct demographic and physiological profiles associated with NSSI among adolescents with depression. The prevalence rate of NSSI underscores its significance as a behavioral manifestation in this population. Further research should explore the underlying mechanisms linking these factors to better inform targeted interventions and treatment strategies for adolescents experiencing NSSI in the context of depression.
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Depression's high recurrence rate and severe consequences pose significant challenges to public health. To address this issue effectively, this review explores the innovative application of wearable devices in monitoring and intervening in depression, surpassing the limitations of traditional subjective assessments and patient self-reports. The paper systematically analyzes recent studies utilizing wearable devices to monitor physiological and behavioral indicators of depression, categorizing them by different technological types and evaluating their practical effectiveness in early diagnosis and intervention. The findings indicate that wearable devices can continuously monitor physiological indicators and behavioral patterns related to depression, potentially enabling early detection of depressive episodes and supporting timely interventions. Despite challenges such as data privacy and user acceptance, wearable technology holds immense potential in enhancing clinical outcomes in depression treatment.
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Depressão , Dispositivos Eletrônicos Vestíveis , Humanos , Depressão/terapia , Monitorização Fisiológica/instrumentaçãoRESUMO
It remains unclear whether metronomic chemotherapy is superior to conventional chemotherapy when combined with immune checkpoint blockade. Here we performed a phase 2 clinical trial of metronomic chemotherapy combined with PD-1 blockade to compare the efficacy of combined conventional chemotherapy and PD-1 blockade using Bayesian adaptive randomization and efficacy monitoring. Eligible patients had metastatic HER2-negative breast cancer and had not received more than one prior line of standard chemotherapy. Patients (total n = 97) were randomized to receive (1) metronomic vinorelbine (NVB) monotherapy (n = 11), (2) NVB plus anti-PD-1 toripalimab (n = 7), (3) anti-angiogenic bevacizumab, NVB and toripalimab (n = 27), (4) conventional cisplatin, NVB and toripalimab (n = 26), or (5) metronomic cyclophosphamide, capecitabine, NVB and toripalimab (the VEX cohort) (n = 26). The primary endpoint was disease control rate (DCR). Secondary objectives included progression-free survival (PFS) and safety. The study met the primary endpoint. The VEX (69.7%) and cisplatin (73.7%) cohorts had the highest DCR. The median PFS of patients in the VEX cohort was the longest, reaching 6.6 months, followed by the bevacizumab (4.0 months) and cisplatin (3.5 months) cohorts. In general, the five regimens were well tolerated, with nausea and neutropenia being the most common adverse events. An exploratory mass cytometry analysis indicated that metronomic VEX chemotherapy reprograms the systemic immune response. Together, the clinical and translational data of this study indicate that metronomic VEX chemotherapy combined with PD-1 blockade can be a treatment option in patients with breast cancer. ClinicalTrials.gov Identifier: NCT04389073 .
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Administração Metronômica , Protocolos de Quimioterapia Combinada Antineoplásica , Teorema de Bayes , Neoplasias da Mama , Metástase Neoplásica , Receptor de Morte Celular Programada 1 , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Adulto , Idoso , Ciclofosfamida/administração & dosagem , Ciclofosfamida/uso terapêutico , Ciclofosfamida/efeitos adversos , Inibidores de Checkpoint Imunológico/administração & dosagem , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/efeitos adversos , Vinorelbina/administração & dosagem , Vinorelbina/uso terapêutico , Bevacizumab/administração & dosagem , Bevacizumab/uso terapêutico , Bevacizumab/efeitos adversosRESUMO
BACKGROUND: The risks associated with negative doctor-patient relationships have seriously hindered the healthy development of medical and healthcare and aroused widespread concern in society. The number of public comments on doctor-patient relationship risk events reflects the degree to which the public pays attention to such events. AIM: To explore public emotional differences, the intensity of comments, and the positions represented at different levels of doctor-patient disputes. METHODS: Thirty incidents of doctor-patient disputes were collected from Weibo and TikTok, and 3655 related comments were extracted. The number of comment sentiment words was extracted, and the comment sentiment value was calculated. The Kruskal-Wallis H test was used to compare differences between each variable group at different levels of incidence. Spearman's correlation analysis was used to examine associations between variables. Regression analysis was used to explore factors influencing scores of comments on incidents. RESULTS: The study results showed that public comments on media reports of doctor-patient disputes at all levels are mainly dominated by "good" and "disgust" emotional states. There was a significant difference in the comment scores and the number of partial emotion words between comments on varying levels of severity of doctor-patient disputes. The comment score was positively correlated with the number of emotion words related to positive, good, and happy) and negatively correlated with the number of emotion words related to negative, anger, disgust, fear, and sadness. CONCLUSION: The number of emotion words related to negative, anger, disgust, fear, and sadness directly influences comment scores, and the severity of the incident level indirectly influences comment scores.
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Enzymatic production of D-mannose attracts increasing attention because of the health effects and commercial values of D-mannose. Several kinds of epimerases or isomerases have been used for enzymatic production of D-mannose from D-glucose or D-fructose. D-Mannose epimerase (MEase), belonging to N-acyl-D-glucosamine 2-epimerase superfamily enzymes, catalyzes the C-2 epimerization between D-glucose and D-mannose. In this study, a novel MEase was identified from Cytophagaceae bacterium SJW1-29. Sequence and structure alignments indicate that it is highly conserved with the reported R. slithyformis MEase with the known crystal structure. It was a metal-independent enzyme, with an optimal pH of 8.0 and an optimal temperature of 40⯰C. The specific activities on D-glucose and D-mannose were 2.90 and 2.96â¯U/mg, respectively. The Km, kcat, and kcat/Km on D-glucose were measured to be 194.9â¯mM, 2.72â¯s-1, and 0.014â¯mM-1 s-1, respectively. The purified enzyme produced 23.15â¯g/L of D-mannose from 100â¯g/L of D-glucose at pH 8.0 and 40 °C for 8â¯h, with a conversion rate of 23.15â¯%.
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Carboidratos Epimerases , Glucose , Manose , Manose/metabolismo , Glucose/metabolismo , Especificidade por Substrato , Cinética , Carboidratos Epimerases/metabolismo , Carboidratos Epimerases/genética , Carboidratos Epimerases/química , Proteínas de Bactérias/metabolismo , Proteínas de Bactérias/química , Proteínas de Bactérias/genética , Concentração de Íons de Hidrogênio , Sequência de Aminoácidos , Clonagem Molecular , Proteínas Recombinantes/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/química , Temperatura , Modelos Moleculares , Alinhamento de SequênciaRESUMO
Introduction: This research aims to address the challenges in model construction for the Extended Mind for the Design of the Human Environment. Specifically, we employ the ResNet-50, LSTM, and Object Tracking Algorithms approaches to achieve collaborative construction of high-quality virtual assets, image optimization, and intelligent agents, providing users with a virtual universe experience in the context of visual communication. Methods: Firstly, we utilize ResNet-50 as a convolutional neural network model for generating virtual assets, including objects, characters, and environments. By training and fine-tuning ResNet-50, we can generate virtual elements with high realism and rich diversity. Next, we use LSTM (Long Short-Term Memory) for image processing and analysis of the generated virtual assets. LSTM can capture contextual information in image sequences and extract/improve the details and appearance of the images. By applying LSTM, we further enhance the quality and realism of the generated virtual assets. Finally, we adopt Object Tracking Algorithms to track and analyze the movement and behavior of virtual entities within the virtual environment. Object Tracking Algorithms enable us to accurately track the positions and trajectories of objects, characters, and other elements, allowing for realistic interactions and dynamic responses. Results and discussion: By integrating the technologies of ResNet-50, LSTM, and Object Tracking Algorithms, we can generate realistic virtual assets, optimize image details, track and analyze virtual entities, and train intelligent agents, providing users with a more immersive and interactive visual communication-driven metaverse experience. These innovative solutions have important applications in the Extended Mind for the Design of the Human Environment, enabling the creation of more realistic and interactive virtual worlds.
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BACKGROUND: Glucagon-like peptide-1 receptor agonists (GLP-1RAs) like liraglutide are primarily used for managing blood sugar levels in type 2 diabetes and aiding weight loss. Typically, their adverse effects are gastrointestinal, with limited exploration into their impact on mental health. CASE PRESENTATION: This report examines a 39-year-old male with type 2 diabetes who developed depressive symptoms after starting liraglutide for glycemic control and weight reduction. Symptoms included poor mood, irritability, decreased interest and energy, progressing to sadness, low self-esteem, and physical discomfort. A clinical diagnosis of a depressive episode was made, coinciding with the initiation of liraglutide. INTERVENTION AND OUTCOME: The patient depressive symptoms significantly improved within a week after discontinuing liraglutide and starting antidepressant therapy. This suggests a possible link between liraglutide and depression, despite considering other factors like diabetes-related stress. DISCUSSION: The report explores potential mechanisms, such as GLP-1RA effects on glucose fluctuations and dopamine modulation, which might contribute to depressive symptoms. The influence on the brain reward system and the reduction in cravings for addictive substances after GLP-1RA use is also discussed as a factor in mood regulation. CONCLUSION: This case highlights the necessity of being vigilant about potential psychiatric side effects, particularly depression, associated with GLP-1RAs. The rarity of such reports calls for more research to investigate and understand these implications further.
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Depressão , Diabetes Mellitus Tipo 2 , Hipoglicemiantes , Liraglutida , Humanos , Liraglutida/uso terapêutico , Liraglutida/efeitos adversos , Masculino , Diabetes Mellitus Tipo 2/tratamento farmacológico , Adulto , Depressão/tratamento farmacológico , Depressão/induzido quimicamente , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/uso terapêuticoRESUMO
BACKGROUND: Addressing segmental bone defects remains a complex task in orthopedics, and recent advancements have led to the development of novel drugs to enhance the bone regeneration. However, long-term oral administration can lead to malnutrition and poor patient compliance. Scaffolds loaded with medication are extensively employed to facilitate the restoration of bone defects. METHODS: Inspired by the local application of total flavonoids of Rhizoma Drynariae (TFRD) in the treatment of fracture, a novel 3D-printed HA/CMCS/PDA/TFRD scaffold with anti-infection, biodegradable and induced angiogenesis was designed, and to explore its preclinical value in segmental bone defect of tibia. RESULTS: The scaffold exhibited good degradation and drug release performance. In vitro, the scaffold extract promoted osteogenesis by enhancing bone-related gene/protein expression and mineral deposition in BMSCs. It also stimulated endothelial cell migration and promoted angiogenesis through the upregulation of specific genes and proteins associated with cell migration and tube formation. This may be attributed to the activation of the PI3k/AKT/HIF-1α pathway, facilitating the processes of osteogenesis and angiogenesis. Furthermore, the HA/CMCS/PDA/TFRD scaffold was demonstrated to alleviate infection, enhance angiogenesis, promote bone regeneration, and increase the maximum failure force of new formed bone in a rat model of segmental bone defects. CONCLUSION: Porous scaffolds loaded with TFRD can reduce infection, be biodegradable, and induce angiogenesis, presenting a novel approach for addressing tibial segmental bone defects.
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Regeneração Óssea , Alicerces Teciduais , Animais , Regeneração Óssea/efeitos dos fármacos , Alicerces Teciduais/química , Ratos , Impressão Tridimensional , Osteogênese/efeitos dos fármacos , Porosidade , Ratos Sprague-Dawley , Tíbia/efeitos dos fármacos , Coelhos , Anti-Infecciosos/farmacologia , Anti-Infecciosos/administração & dosagem , Masculino , Modelos Animais de Doenças , Flavonoides/farmacologia , Flavonoides/administração & dosagem , Flavonoides/químicaRESUMO
Breast cancer has become the most prevalent malignancy worldwide; however, therapeutic efficacy is far from satisfactory. To alleviate the burden of this disease, it is imperative to discover novel mechanisms and treatment strategies. Protein phosphatase 2â¯A (PP2A) comprises a family of mammalian serine/threonine phosphatases that regulate many cellular processes. PP2A is dysregulated in several human diseases, including oncological pathologies, and plays a pivotal role in the initiation and progression of tumours. The role of PP2A as a tumour suppressor has been extensively studied, and its regulation can serve as a target for anticancer therapy. Recent studies have shown that PP2A is a tumour promotor. PP2A-mediated anticancer therapy may involve two opposing mechanisms: activation and inhibition. In general, the contradictory roles of PP2A should not be overlooked, and more work is needed to determine the molecular mechanism by which PP2A affects in tumours. In this review, the literature on the role of PP2A in tumours, especially in breast cancer, was analysed. This review describes relevant targets of breast cancer, such as cell cycle control, DNA damage responses, epidermal growth factor receptor, immune modulation and cell death resistance, which may lead to effective therapeutic strategies or influence drug development in breast cancer.
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Neoplasias da Mama , Feminino , Humanos , Neoplasias da Mama/tratamento farmacológico , Proteína Fosfatase 2/genética , Proteína Fosfatase 2/metabolismoRESUMO
The Chinese government has pursued comprehensive ecological conservation and restoration by establishing an ecological barrier system. However, the majority of international research tends to focus on the connectivity between habitats, overlooking the functions that ecological barriers play in ecological conservation and restoration. The existing literature lacks a systematic exploration of the theory and practice of ecological barriers. This study employed the literature analysis tool CiteSpace to present the theoretical and developmental trends in ecological barriers from various perspectives, including research fields, historical evolution, research hotspots, and major research nations. By analyzing the differences in the understanding of ecological barriers between China and other countries, examining the ecological barriers construction history in China, and exploring the types and functions of ecological barriers, this study summarizes the framework of China's ecological barriers construction system as "features-functions-problems." Constructing an ecological barrier system can help achieve ecological conservation and restoration goals in China.
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Conservação dos Recursos Naturais , Ecossistema , Conservação dos Recursos Naturais/métodos , China , Ecologia , Recuperação e Remediação Ambiental/métodosRESUMO
BACKGROUND: Recently, extensively drug-resistant Pseudomonas aeruginosa (XDR-PA) isolates have been increasingly detected and posed great challenges to clinical anti-infection treatments. However, little is known about extensively resistant hypervirulent P. aeruginosa (XDR-hvPA). In this study, we investigate its epidemiological characteristics and provide important basis for preventing its dissemination. METHODS: Clinical XDR-PA isolates were collected from January 2018 to January 2023 and identified using matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry; antibiotic susceptibility testing was performed by broth microdilution method, and minimum inhibitory concentrations (MICs) were evaluated. Virulence was evaluated using the Galleria mellonella infection model; molecular characteristics, including resistance genes, virulence genes, and homology, were determined using whole-genome sequencing. RESULTS: A total of 77 XDR-PA strains were collected; 47/77 strains were XDR-hvPA. Patients aged > 60 years showed a significantly higher detection rate of XDR-hvPA than of XDR-non-hvPA. Among the 47 XDR-hvPA strains, 24 strains carried a carbapenemase gene, including blaGES-1 (10/47), blaVIM-2 (6/47), blaGES-14 (4/47), blaIMP-45 (2/47), blaKPC-2 (1/47), and blaNDM-14 (1/47). ExoU, exoT, exoY, and exoS, important virulence factors of PA, were found in 31/47, 47/47, 46/47, and 29/47 strains, respectively. Notably, two XDR-hvPA simultaneously co-carried exoU and exoS. Six serotypes (O1, O4-O7, and O11) were detected; O11 (19/47), O7 (13/47), and O4 (9/47) were the most prevalent. In 2018-2020, O4 and O7 were the most prevalent serotypes; 2021 onward, O11 (16/26) was the most prevalent serotype. Fourteen types of ST were detected, mainly ST235 (14/47), ST1158 (13/47), and ST1800 (7/47). Five global epidemic ST235 XDR-hvPA carried blaGES and showed the MIC value of ceftazidime/avibactam reached the susceptibility breakpoint (8/4 mg/L). CONCLUSIONS: The clinical detection rate of XDR-hvPA is unexpectedly high, particularly in patients aged > 60 years, who are seemingly more susceptible to contracting this infection. Clonal transmission of XDR-hvPA carrying blaGES, which belongs to the global epidemic ST235, was noted. Therefore, the monitoring of XDR-hvPA should be strengthened, particularly for elderly hospitalized patients, to prevent its spread.
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Antibacterianos , Infecções por Pseudomonas , Idoso , Humanos , Antibacterianos/farmacologia , Antibacterianos/uso terapêutico , Pseudomonas aeruginosa/genética , Infecções por Pseudomonas/epidemiologia , Infecções por Pseudomonas/tratamento farmacológico , Proteínas de Bactérias/genética , beta-Lactamases/genética , Sorogrupo , China/epidemiologia , Testes de Sensibilidade Microbiana , Farmacorresistência Bacteriana Múltipla/genéticaRESUMO
Encapsulating individual mammalian cells with biomimetic materials holds potential in ex vivo cell culture and engineering. However, current methodologies often present tradeoffs between homogeneity, stability, and cell compatibility. Here, inspired by bacteria that use proteins stably anchored on their outer membranes to nucleate biofilm growth, we develop a single-cell encapsulation strategy by using a DNA framework structure as a nucleator (DFN) to initiate the growth of DNA hydrogels under cell-friendly conditions. We find that among the tested structures, the tetrahedral DFN can evenly and stably reside on cell membranes, effectively initiating hybridization chain reactions which generate homogeneously dense yet flexible single-cell encapsulation for diverse cell lines. The encapsulation persists for up to 72â hours in a serum-containing cell culture environment, representing a ~70-fold improvement compared to encapsulations mediated by single-stranded DNA nucleators. The metabolism and proliferation of the encapsulated cells are suppressed, but can be restored to the original efficiencies upon release, suggesting the superior cell compatibility of the encapsulation. We also find that compared to naked cells, the encapsulated cells exhibit a lower autophagy level after undergoing mechanical stress, suggesting the protective effect of the DNA encapsulation. This method may provide a new tool for ex vivo cell engineering.
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Materiais Biomiméticos , Hidrogéis , Animais , Hidrogéis/química , Linhagem Celular , DNA , MamíferosRESUMO
OBJECTIVE: To assess the efficacy of PD-1/PD-L1 inhibitors combined with chemotherapy for early-stage triple-negative breast cancer (TNBC) patients with different clinical characteristics. METHODS: Randomized clinical trials for PD-1/PD-L1 inhibitors and chemotherapy combination were included. Pooled analysis of odds ratio (OR) for pathological complete response (pCR) and hazard ratio (HR) for event-free survival (EFS) was conducted overall and for predefined subgroups. RESULTS: The combination of immunotherapy and chemotherapy significantly improved pCR rate in early TNBC patients (OR, 1.77), and the incidence of events was significantly reduced by 37%. Lymph node metastasis was associated with more benefits on pCR (OR[N0], 1.29; OR[N+], 2.57; P = 0.01), while earlier T stage was related to more benefits on EFS (HR[T1-T2], 0.48; HR[T3-T4], 0.85; P = 0.05). CONCLUSION: The addition of PD-1/PD-L1 inhibitors to chemotherapy offers improved pCR and EFS in early TNBC patients. T and N stages may have implications for the efficacy.
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Inibidores de Checkpoint Imunológico , Neoplasias de Mama Triplo Negativas , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Receptor de Morte Celular Programada 1 , PrognósticoRESUMO
Cytoplasmic vacuolation-associated cell death, known as methuosis, offers a promising nonapoptotic approach for cancer treatment. In this study, we outline the synthesis and evaluation of potent methuosis-inducing compounds. These compounds selectively induce cell death, characterized by extensive cytoplasmic vacuolation in HeLa and MDA-MB-231 cells. Notably, compound L22 exhibited a remarkable interaction with PIKfyve kinase, boasting a Kd value of 0.47 nM, surpassing the positive controls D-13 and MOMIPP in potency. Furthermore, it is important to highlight that cell death induced by compound L22 is unequivocally attributed to methuosis as it differs from apoptosis, necrosis, or autophagy. Importantly, when administered orally, L22 effectively inhibited tumor growth in a HeLa xenograft model without any apparent signs of toxicity. These results underscore the potential of L22 as a valuable tool for in-depth investigations into the mechanisms of methuosis and as a promising lead compound to guide structural optimization.
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Antineoplásicos , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Morte Celular , Apoptose , Fosfatos de Fosfatidilinositol/farmacologiaRESUMO
Extracellular vesicles (EVs) are natural carriers for intercellular transfer of bioactive molecules, which are harnessed for wide biomedical applications. However, a facile yet general approach to engineering interspecies EV-cell communications is still lacking. Here, the use of DNA to encode the heterogeneous interfaces of EVs and cells in a manner free of covalent or genetic modifications is reported, which enables orthogonal EV-cell interkingdom interactions in complex environments. Cholesterol-modified DNA strands and tetrahedral DNA frameworks are employed with complementary sequences to serve as artificial ligands and receptors docking on EVs and living cells, respectively, which can mediate specific yet efficient cellular internalization of EVs via Watson-Crick base pairing. It is shown that based on this system, human cells can adopt EVs derived from the mouse, watermelon, and Escherichia coli. By implementing several EV-cell circuits, it shows that this DNA-programmed system allows orthogonal EV-cell communications in complex environments. This study further demonstrates efficient delivery of EVs with bioactive contents derived from feeder cells toward monkey female germline stem cells (FGSCs), which enables self-renewal and stemness maintenance of the FGSCs without feeder cells. This system may provide a universal platform to customize intercellular exchanges of materials and signals across species and kingdoms.
Assuntos
Vesículas Extracelulares , Nicho de Células-Tronco , Humanos , Animais , Camundongos , Comunicação Celular , DNA , EngenhariaRESUMO
BACKGROUND: Melanoma is a highly aggressive tumor and a significant cause of skin cancer-related death. Timely diagnosis and treatment require identification of specific biomarkers in exosomes secreted by melanoma cells. In this study, label-free surface-enhanced Raman spectroscopy (SERS) method with size-matched selectivity was used to detect membrane proteins in exosomes released from a stimulated environment of fibroblasts (L929) co-cultured with melanoma cells (B16-F10). To promote normal secretion of exosomes, micro-plasma treatment was used to gently induce the co-cultured cells and slightly increase the stress level around the cells for subsequent detection using the SERS method. RESULTS AND DISCUSSION: Firstly, changes in reactive oxygen species/reactive nitrogen species (ROS/RNS) concentrations in the cellular microenvironment and the viability and proliferation of healthy cells are assessed. Results showed that micro-plasma treatment increased extracellular ROS/RNS levels while modestly reducing cell proliferation without significantly affecting cell survival. Secondly, the particle size of secreted exosomes isolated from the culture medium of L929, B16-F10, and co-cultured cells with different micro-plasma treatment time did not increase significantly under single-cell conditions at short treatment time but might be changed under co-culture condition or longer treatment time. Third, for SERS signals related to membrane protein biomarkers, exosome markers CD9, CD63, and CD81 can be assigned to significant Raman shifts in the range of 943-1030 and 1304-1561 cm-1, while the characteristics SERS peaks of L929 and B16-F10 cells are most likely located at 1394/1404, 1271 and 1592 cm-1 respectively. SIGNIFICANCE AND NOVELTY: Therefore, this micro-plasma-induced co-culture model provides a promising preclinical approach to understand the diagnostic potential of exosomes secreted by cutaneous melanoma/fibroblasts. Furthermore, the label-free SERS method with size-matched selectivity provides a novel approach to screen biomarkers in exosomes secreted by melanoma cells, aiming to reduce the use of labeling reagents and the processing time traditionally required.