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1.
J Environ Sci (China) ; 148: 420-436, 2025 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-39095177

RESUMO

Mercury (Hg) pollution has been a global concern in recent decades, posing a significant threat to entire ecosystems and human health due to its cumulative toxicity, persistence, and transport in the atmosphere. The intense interaction between mercury and selenium has opened up a new field for studying mercury removal from industrial flue gas pollutants. Besides the advantages of good Hg° capture performance and low secondary pollution of the mineral selenium compounds, the most noteworthy is the relatively low regeneration temperature, allowing adsorbent regeneration with low energy consumption, thus reducing the utilization cost and enabling recovery of mercury resources. This paper reviews the recent progress of mineral selenium compounds in flue gas mercury removal, introduces in detail the different types of mineral selenium compounds studied in the field of mercury removal, reviews the adsorption performance of various mineral selenium compounds adsorbents on mercury and the influence of flue gas components, such as reaction temperature, air velocity, and other factors, and summarizes the adsorption mechanism of different fugitive forms of selenium species. Based on the current research progress, future studies should focus on the economic performance and the performance of different carriers and sizes of adsorbents for the removal of Hg0 and the correlation between the gas-particle flow characteristics and gas phase mass transfer with the performance of Hg0 removal in practical industrial applications. In addition, it remains a challenge to distinguish the oxidation and adsorption of Hg0 quantitatively.


Assuntos
Poluentes Atmosféricos , Mercúrio , Mercúrio/química , Adsorção , Poluentes Atmosféricos/química , Selênio/química , Gases/química , Compostos de Selênio/química
2.
Eur J Med Chem ; 278: 116801, 2024 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-39241481

RESUMO

The rational installation of pharmacophores targeting HSP90 and LSD1 axes has achieved significant anti-cancer capacity in prostate and colorectal cancer. Among the series of hybrids, inhibitor 6 exhibited remarkable anti-proliferative activity against prostate cancer cell lines PC-3 and DU145, with GI50 values of 0.24 and 0.30 µM, respectively. It demonstrated notable efficacy in combinatorial attack and cell death initiation towards apoptosis. The cell death process was mediated by PARP induction and γH2AX signaling, and was also characterized as caspase-dependent and Bcl-xL/Bax-independent. Notably, no difference in eye size or morphology was observed in the zebrafish treated with compound 6 compared to the reference group (AUY922). The profound treatment response in docetaxel-resistant PC-3 cells highlighted the dual inhibitory ability in improving docetaxel sensitivity. Additionally, at a minimum concentration of 1.25 µM, compound 6 effectively inhibited the growth of patient-derived colorectal cancer (CRC) organoids for up to 10 days in vitro. Together, the designed HSP90/LSD1 inhibitors present a novel route and significant clinical value for anti-cancer drug therapy.


Assuntos
Antineoplásicos , Proliferação de Células , Neoplasias Colorretais , Ensaios de Seleção de Medicamentos Antitumorais , Proteínas de Choque Térmico HSP90 , Histona Desmetilases , Organoides , Neoplasias da Próstata , Proteínas de Choque Térmico HSP90/antagonistas & inibidores , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Masculino , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Proliferação de Células/efeitos dos fármacos , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Animais , Organoides/efeitos dos fármacos , Organoides/patologia , Histona Desmetilases/antagonistas & inibidores , Histona Desmetilases/metabolismo , Relação Estrutura-Atividade , Estrutura Molecular , Relação Dose-Resposta a Droga , Peixe-Zebra , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral
3.
Biochim Biophys Acta Rev Cancer ; 1879(5): 189174, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39218402

RESUMO

The therapeutic landscape for hormone receptor-positive (HR+) breast carcinoma has undergone a significant transformation with the advent of cyclin-dependent kinase (CDK)4/6 inhibitors, particularly in combination with endocrine therapy as the primary regimen. However, the evolution of resistance mechanisms in response to CDK4/6 inhibitors in HR+ metastatic breast cancer presents substantial challenges in managing the disease. This review explores the diverse genomic landscape underlying resistance, including disturbances in the cell cycle, deviations in oncogenic signaling pathways, deficiencies in DNA damage response (DDR) mechanisms, and changes in the tumor microenvironment (TME). Additionally, it discusses potential strategies to surmount resistance, including advancements in endocrine therapy, targeted inhibition of cell cycle components, suppression of AKT/mTOR activation, exploration of the FGFR pathway, utilization of antibody-drug conjugates (ADCs), and integration of immune checkpoint inhibitors (ICIs) with endocrine therapy and CDK4/6 inhibitors, providing pathways for enhancing patient outcomes amidst treatment challenges.


Assuntos
Neoplasias da Mama , Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de Ciclina , Resistencia a Medicamentos Antineoplásicos , Inibidores de Proteínas Quinases , Microambiente Tumoral , Humanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/genética , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Feminino , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Receptores de Estrogênio/metabolismo
4.
Artigo em Inglês | MEDLINE | ID: mdl-39311687

RESUMO

Background: To investigate the association of demographic, clinical, and metabolic factors with nonalcoholic fatty liver disease (NAFLD) in a non-overweight/obese and overweight/obese Chinese population at risk for metabolic syndrome. Patients and Method: A cross-sectional multicenter study was conducted using convenience sampling from eight selected counties/cities in Zhejiang, China, between May 2021 and September 2022. Demographics, epidemiological, anthropometric, and clinical characteristics were obtained from a questionnaire. Least absolute shrinkage and selection operator (LASSO)-logistic regression analysis was used to identify the variables associated with NAFLD. Receiver operating characteristic (ROC) curve analysis and decision curve analysis (DCA) were performed to evaluate the diagnostic value and clinical utility of the variables and models. Results: A total of 1739 patients were enrolled in the final analysis, 345 (19.8%) were non-overweight/obese and 1394 (80.2%) were overweight/obese participants. There were 114 (33.0%) and 1094 (78.5%) patients who met the criteria for NAFLD in the non-overweight/obese participants and the overweight/obese participants respectively. Older age, current smoking, higher triglyceride (TG) levels, higher AST levels, higher albumin levels, lower insulin levels, and higher controlled attenuation parameter (CAP) scores were associated with NAFLD in both non-overweight/obese and overweight/obese participants. The combination of TG+CAP scores had strong predictive values for NAFLD, especially in non-overweight/obese (Area Under Curve = 0.812, 95% confidence interval: 0.764-0.863). DCA showed a superior net benefit of the TG+CAP score over other variables or models, suggesting a better clinical utility in identifying NAFLD. Conclusions: More stringent lipid management strategies remain essential, and the convenience and efficacy of transient elastography for liver steatosis should be recognized, especially in the non-overweight/obese population.

5.
Int Breastfeed J ; 19(1): 65, 2024 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-39285438

RESUMO

BACKGROUND: Mammographic density has been associated with breast cancer risk, and is modulated by established breast cancer risk factors, such as reproductive and hormonal history, as well as lifestyle. Recent epidemiological and biological findings underscore the recognized benefits of breastfeeding in reducing breast cancer risk, especially for aggressive subtypes. Current research exploring the association among mammographic density, breastfeeding, and breast cancer is sparse. MAIN FINDINGS: Changes occur in the breasts during pregnancy in preparation for lactation, characterized by the proliferation of mammary gland tissues and the development of mammary alveoli. During lactation, the alveoli fill with milk, and subsequent weaning triggers the involution and remodeling of these tissues. Breastfeeding influences the breast microenvironment, potentially altering mammographic density. When breastfeeding is not initiated after birth, or is abruptly discontinued shortly after, the breast tissue undergoes forced and abrupt involution. Conversely, when breastfeeding is sustained over an extended period and concludes gradually, the breast tissue undergoes slow remodeling process known as gradual involution. Breast tissue undergoing abrupt involution displays denser stroma, altered collagen composition, heightened inflammation and proliferation, along with increased expression of estrogen receptor α (ERα) and progesterone receptor. Furthermore, elevated levels of pregnancy-associated plasma protein-A (PAPP-A) surpass those of its inhibitors during abrupt involution, enhancing insulin-like growth factor (IGF) signaling and collagen deposition. Prolactin and small molecules in breast milk may also modulate DNA methylation levels. Drawing insights from contemporary epidemiological and molecular biology studies, our review sheds light on how breastfeeding impacts mammographic density and explores its role in influencing breast cancer. CONCLUSION: This review highlights a clear protective link between breastfeeding and reduced breast cancer risk via changes in mammographic density. Future research should investigate the effects of breastfeeding on mammographic density and breast cancer risk among various ethnic groups and elucidate the molecular mechanisms underlying these associations. Such comprehensive research will enhance our understanding and facilitate the development of targeted breast cancer prevention and treatment strategies.


Assuntos
Densidade da Mama , Aleitamento Materno , Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/patologia , Mamografia , Fatores de Risco , Gravidez , Lactação , Mama/diagnóstico por imagem , Mama/patologia
6.
Front Pediatr ; 12: 1416189, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39296668

RESUMO

Mycoplasma pneumoniae is the primary pathogen causing community-acquired pneumonia in children, accounting for approximately 10%-40% of cases. It can lead to various extrapulmonary complications, including acute pancreatitis, which has been reported in approximately 30 cases to date. Here, we report a 4-year-old girl who presented with fever, cough, and elevated levels of M. pneumoniae IgM antibodies, followed by the onset of abdominal pain, elevated lipase, and elevated blood and urine amylase. Abdominal CT implied diffuse inflammation of the pancreas. Serum inflammatory cytokines, such as interleukin (IL)-2, IL-6, IL-17A, tumor necrosis factor, and interferon-gamma, were elevated. After excluding other causes, it was determined that M. pneumoniae infection was the cause of her acute pancreatitis. She was treated with macrolides and glucocorticoids and ultimately made a full recovery. Therefore, acute pancreatitis should be included in the differential diagnosis for patients with M. pneumoniae infection who present with abdominal pain. Inflammatory cytokines may play a role in mediating pancreatic damage.

8.
Int Immunopharmacol ; 140: 112769, 2024 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-39098228

RESUMO

B cells are crucial to the humoral immune response, originating in the bone marrow and maturing in the spleen and lymph nodes. They primarily function to protect against a wide range of infections through the secretion of antibodies. The role of B cells in primary membranous nephropathy (PMN) has gained significant attention, especially following the discovery of various autoantibodies that target podocyte antigens and the observed positive outcomes from B cell depletion therapy. Increasing evidence points to the presence of abnormal B cell subsets and functions in MN. B cells have varied roles during the different stages of disease onset, progression, and relapse. Initially, B cells facilitate self-antigen presentation, activate effector T cells, and initiate cellular immunity. Subsequently, the disruption of both central and peripheral immune tolerance results in the emergence of autoreactive B cells, with strong germinal center responses as a major source of MN autoantibodies. Additionally, critical B cell subsets, including Bregs, memory B cells, and plasma cells, play roles in the immune dysregulation observed in MN, assisting in predicting disease recurrence and guiding management strategies for MN. This review offers a detailed overview of research advancements on B cells and elucidates their pathological roles in MN.


Assuntos
Linfócitos B , Glomerulonefrite Membranosa , Depleção Linfocítica , Humanos , Glomerulonefrite Membranosa/imunologia , Glomerulonefrite Membranosa/terapia , Animais , Linfócitos B/imunologia , Autoanticorpos/imunologia , Subpopulações de Linfócitos B/imunologia
9.
Front Pharmacol ; 15: 1381830, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39144619

RESUMO

Objective: This study aimed to assess the chemopreventive effect of ursodeoxycholic acid (UDCA) against COVID-19 and to analyze infection risk factors, symptoms, and recovery in outpatients with UDCA exposure. Methods: The study enrolled outpatients prescribed UDCA from the Second Affiliated Hospital of Chongqing Medical University, China, between 01 July 2022, and 31 December 2022. Data on demographics, comorbidities, and drug combinations were collected using electronic medical records. COVID-19 infection, symptoms, severity, prognosis, vaccinations, and UDCA administration were surveyed by telephone interviews. UDCA non-users served as controls and were matched in a 1:2 ratio with UDCA users using propensity score matching with the nearest neighbor algorithm. Infection rates, symptomatology, severity, and prognosis were compared between matched and control cohorts, and risk factors and infection and recovery symptoms were analyzed in UDCA-exposed outpatients. Results: UDCA-exposed outpatients (n = 778, 74.8%) and matched UDCA users (n = 95, 74.2%) showed significantly lower SARS-CoV-2 infection rates than control patients (n = 59, 92.2%) (p < 0.05). The matched UDCA group exhibited substantially lower fever, cough, sore throat, and fatigue rates than controls (p < 0.05). Participants with UDCA exposure generally experienced mild symptoms, while those without UDCA had moderate symptoms. The matched UDCA group also had significantly shorter durations of fever and cough (p < 0.05). Risk factors such as age over 60, less than 1 month of UDCA administration, diabetes mellitus, and coronary artery disease significantly increased SARS-CoV-2 infection rates (p < 0.05), while smoking led to a decrease (p < 0.05). Hypertension was associated with a prolonged COVID-19 recovery (p < 0.05), while smoking, vaccination, and fatty liver disease were associated with shorter recovery periods (p < 0.05). The main symptoms in the full UDCA cohort were fever, cough, and sore throat, with fatigue, cough, and hyposthenia being the most persistent. Conclusion: UDCA demonstrated chemopreventive effect against SARS-CoV-2 in outpatients by significantly reducing infection incidence and mitigating COVID-19 symptoms, severity, and recovery duration. Old age, short UDCA course, and comorbidities such as diabetes mellitus and CAD increased infection rates, while hypertension prolonged recovery. Smoking, vaccination, and fatty liver disease reduced infection rates and shortened recovery. UDCA had minimal impact on symptom types. Larger and longer-term clinical studies are needed further to assess UDCA's effectiveness in COVID-19 prevention or treatment.

10.
Front Pharmacol ; 15: 1401428, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39144623

RESUMO

Inflammatory myofibroblastic tumor (IMT) is a rare tumor originating from mesenchymal tissue. Epithelioid inflammatory myofibroblastic sarcoma (EIMS) represents a rare and particularly aggressive variant, associated with a worse prognosis. Almost all EIMS cases exhibits activating anaplastic lymphoma kinase (ALK) gene rearrangements, which suggests that EIMS patients may potentially benefit from treatment with ALK tyrosine kinase inhibitors (TKIs). We presented a case involving a 34-year-old woman who was diagnosed with mediastinal EIMS and had a rare echinoderm microtubule-associated protein-like 4 (EML4) -ALK fusion. Following 15 months of neoadjuvant lorlatinib treatment, the patient underwent a complete surgical resection, resulting in a pathological complete response. Given the heightened risk of postoperative recurrence associated with EIMS, the patient's treatment plan included ongoing adjuvant therapy with lorlatinib. As of the present moment, the patient has achieved an overall survival of over 2 years with no observed tumor recurrence. Consequently, the case offers valuable clinical evidence supporting the potential benefits of neoadjuvant lorlatinib treatment for ALK-positive locally mediastinal EIMS patients, with a demonstrated tolerable safety profile.

11.
Theranostics ; 14(11): 4256-4277, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-39113793

RESUMO

Rationale: Posttranslational modifications of proteins have not been addressed in studies aimed at elucidating the cardioprotective effect of exercise in atherosclerotic cardiovascular disease (ASCVD). In this study, we reveal a novel mechanism by which exercise ameliorates atherosclerosis via lactylation. Methods: Using ApoE-/- mice in an exercise model, proteomics analysis was used to identify exercise-induced specific lactylation of MeCP2 at lysine 271 (K271). Mutation of the MeCP2 K271 lactylation site in aortic plaque macrophages was achieved by recombinant adenoviral transfection. Explore the molecular mechanisms by which motility drives MeCP2 K271 lactylation to improve plaque stability using ATAC-Seq, CUT &Tag and molecular biology. Validation of the potential target RUNX1 for exercise therapy using Ro5-3335 pharmacological inhibition. Results: we showed that in ApoE-/- mice, methyl-CpG-binding protein 2 (MeCP2) K271 lactylation was observed in aortic root plaque macrophages, promoting pro-repair M2 macrophage polarization, reducing the plaque area, shrinking necrotic cores, reducing plaque lipid deposition, and increasing collagen content. Adenoviral transfection, by introducing a mutant at lysine 271, overexpressed MeCP2 K271 lactylation, which enhanced exercise-induced M2 macrophage polarization and increased plaque stability. Mechanistically, the exercise-induced atheroprotective effect requires an interaction between MeCP2 K271 lactylation and H3K36me3, leading to increased chromatin accessibility and transcriptional repression of RUNX1. In addition, the pharmacological inhibition of the transcription factor RUNX1 exerts atheroprotective effects by promoting the polarization of plaque macrophages towards the pro-repair M2 phenotype. Conclusions: These findings reveal a novel mechanism by which exercise ameliorates atherosclerosis via MeCP2 K271 lactylation-H3K36me3/RUNX1. Interventions that enhance MeCP2 K271 lactylation have been shown to increase pro-repair M2 macrophage infiltration, thereby promoting plaque stabilization and reducing the risk of atherosclerotic cardiovascular disease. We also established RUNX1 as a potential drug target for exercise therapy, thereby providing guidance for the discovery of new targets.


Assuntos
Apolipoproteínas E , Aterosclerose , Macrófagos , Proteína 2 de Ligação a Metil-CpG , Animais , Humanos , Masculino , Camundongos , Apolipoproteínas E/metabolismo , Apolipoproteínas E/genética , Aterosclerose/metabolismo , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Subunidade alfa 2 de Fator de Ligação ao Core/genética , Modelos Animais de Doenças , Macrófagos/metabolismo , Proteína 2 de Ligação a Metil-CpG/metabolismo , Proteína 2 de Ligação a Metil-CpG/genética , Camundongos Endogâmicos C57BL , Condicionamento Físico Animal , Placa Aterosclerótica/metabolismo , Processamento de Proteína Pós-Traducional
12.
J Orthop Surg Res ; 19(1): 486, 2024 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-39152470

RESUMO

BACKGROUND: There is a corresponding increase in the prevalence of osteoporosis and related fractures with the aging population on the rise. Furthermore, osteoporotic vertebral compression fractures (OVCF) may contribute to higher patient mortality rates. It is essential to conduct research on risk factors for OVCF and provide a theoretical basis for preventing such fractures. METHODS: We retrospectively recruited patients who had spine CT for OVCF or back pain. Demographic and CT data were collected. Quantitative computed tomography (QCT) software analyzed the CT data, using subcutaneous fat and paraspinal muscles as reference standards for BMD processing. BMD of cortical and cancellous bones in each patient's vertebral body was determined. RESULTS: In this study, 144 patients were divided into non-OVCF (96) and OVCF (48) groups. Non-OVCF patients had higher cortical BMD of 382.5 ± 52.4 to 444.6 ± 70.1 mg/cm3, with T12 having the lowest BMD (p < 0.001, T12 vs. L2). Cancellous BMD ranged from 128.5 ± 58.4 to 140.9 ± 58.9 mg/cm3, with L3 having the lowest BMD. OVCF patients had lower cortical BMD of 365.0 ± 78.9 to 429.3 ± 156.7 mg/cm3, with a further decrease in T12 BMD. Cancellous BMD ranged from 71.68 ± 52.07 to 123.9 ± 126.2 mg/cm3, with L3 still having the lowest BMD. Fractured vertebrae in OVCF patients (T12, L1, and L2) had lower cortical bone density compared to their corresponding vertebrae without fractures (p < 0.05). CONCLUSIONS: T12 had the lowest cortical BMD and L3 had the lowest cancellous BMD in OVCF patients, with T12 also having the highest incidence of osteoporotic fractures. These findings suggest that reduction in cortical BMD has a greater impact on OVCF than reduction in cancellous BMD, along with biomechanical factors.


Assuntos
Densidade Óssea , Osso Cortical , Fraturas por Osteoporose , Fraturas da Coluna Vertebral , Tomografia Computadorizada por Raios X , Humanos , Feminino , Idoso , Masculino , Fraturas por Osteoporose/diagnóstico por imagem , Fraturas por Osteoporose/etiologia , Estudos Retrospectivos , Fraturas da Coluna Vertebral/diagnóstico por imagem , Fraturas da Coluna Vertebral/etiologia , Fraturas da Coluna Vertebral/fisiopatologia , Tomografia Computadorizada por Raios X/métodos , Pessoa de Meia-Idade , Osso Cortical/diagnóstico por imagem , Fatores de Risco , Idoso de 80 Anos ou mais , Corpo Vertebral/diagnóstico por imagem , Fraturas por Compressão/diagnóstico por imagem , Fraturas por Compressão/etiologia , Osteoporose/diagnóstico por imagem
13.
J Transl Med ; 22(1): 752, 2024 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-39127679

RESUMO

Circular RNAs (circRNAs) are a class of endogenous noncoding RNAs characterized by their lack of 5' caps and 3' poly(A) tails. These molecules have garnered substantial attention from the scientific community. A wide range of circRNA types has been found to be expressed in various tissues of the human body, exhibiting unique characteristics such as high abundance, remarkable stability, and tissue-specific expression patterns. These attributes, along with their detectability in liquid biopsy samples such as plasma, position circRNAs an ideal choice as cancer diagnostic and prognostic biomarkers. Additionally, several studies have reported that the functions of circRNAs are associated with tumor proliferation, metastasis, and drug resistance. They achieve this through various mechanisms, including modulation of parental gene expression, regulation of gene transcription, acting as microRNA (miRNA) sponges, and encoding functional proteins. In recent years, a large number of studies have focused on synthesizing circRNAs in vitro and delivering them to tumor tissue to exert its effects in inhibit tumor progression. Herein, we briefly discuss the biogenesis, characteristics, functions, and detection of circRNAs, emphasizing their clinical potential as biomarkers for cancer diagnosis and prognosis. We also provide an overview the recent techniques for synthesizing circRNAs and delivery strategies, and outline the application of engineered circRNAs in clinical cancer therapy.


Assuntos
Biomarcadores Tumorais , Neoplasias , RNA Circular , Humanos , RNA Circular/genética , RNA Circular/metabolismo , Neoplasias/genética , Neoplasias/terapia , Neoplasias/diagnóstico , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Animais , Regulação Neoplásica da Expressão Gênica
14.
Cancer Cell ; 42(8): 1336-1351.e9, 2024 Aug 12.
Artigo em Inglês | MEDLINE | ID: mdl-39029462

RESUMO

The POU2F3-POU2AF2/3 transcription factor complex is the master regulator of the tuft cell lineage and tuft cell-like small cell lung cancer (SCLC). Here, we identify a specific dependence of the POU2F3 molecular subtype of SCLC (SCLC-P) on the activity of the mammalian switch/sucrose non-fermentable (mSWI/SNF) chromatin remodeling complex. Treatment of SCLC-P cells with a proteolysis targeting chimera (PROTAC) degrader of mSWI/SNF ATPases evicts POU2F3 and its coactivators from chromatin and attenuates downstream signaling. B cell malignancies which are dependent on the POU2F1/2 cofactor, POU2AF1, are also sensitive to mSWI/SNF ATPase degraders, with treatment leading to chromatin eviction of POU2AF1 and IRF4 and decreased IRF4 signaling in multiple myeloma cells. An orally bioavailable mSWI/SNF ATPase degrader significantly inhibits tumor growth in preclinical models of SCLC-P and multiple myeloma without signs of toxicity. This study suggests that POU2F-POU2AF-driven malignancies have an intrinsic dependence on the mSWI/SNF complex, representing a therapeutic vulnerability.


Assuntos
Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Fatores de Transcrição , Humanos , Animais , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Carcinoma de Pequenas Células do Pulmão/genética , Carcinoma de Pequenas Células do Pulmão/metabolismo , Carcinoma de Pequenas Células do Pulmão/patologia , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Linhagem Celular Tumoral , Fator 3 de Transcrição de Octâmero/metabolismo , Fator 3 de Transcrição de Octâmero/genética , Ensaios Antitumorais Modelo de Xenoenxerto , Transdução de Sinais , Regulação Neoplásica da Expressão Gênica , Fator 2 de Transcrição de Octâmero
15.
J Gene Med ; 26(7): e3715, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38962887

RESUMO

BACKGROUND: The present study aimed to dissect the cellular complexity of Crohn's disease (CD) using single-cell RNA sequencing, focusing on identifying key cell populations and their transcriptional profiles in inflamed tissue. METHODS: We applied scRNA-sequencing to compare the cellular composition of CD patients with healthy controls, utilizing Seurat for clustering and annotation. Differential gene expression analysis and protein-protein interaction networks were constructed to identify crucial genes and pathways. RESULTS: Our study identified eight distinct cell types in CD, highlighting crucial fibroblast and T cell interactions. The analysis revealed key cellular communications and identified significant genes and pathways involved in the disease's pathology. The role of fibroblasts was underscored by elevated expression in diseased samples, offering insights into disease mechanisms and potential therapeutic targets, including responses to ustekinumab treatment, thus enriching our understanding of CD at a molecular level. CONCLUSIONS: Our findings highlight the complex cellular and molecular interplay in CD, suggesting new biomarkers and therapeutic targets, offering insights into disease mechanisms and treatment implications.


Assuntos
Doença de Crohn , Análise de Célula Única , Ustekinumab , Doença de Crohn/genética , Doença de Crohn/tratamento farmacológico , Humanos , Ustekinumab/uso terapêutico , Análise de Célula Única/métodos , Perfilação da Expressão Gênica/métodos , Mapas de Interação de Proteínas , Fibroblastos/metabolismo , Biomarcadores , Feminino , Transcriptoma , Adulto , Masculino , Linfócitos T/metabolismo , Linfócitos T/imunologia , Resultado do Tratamento , Análise de Sequência de RNA/métodos , Redes Reguladoras de Genes
16.
BMC Surg ; 24(1): 208, 2024 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-39010005

RESUMO

BACKGROUND: SII, PNI, SIRI, AAPR, and LIPI are prognostic scores based on inflammation, nutrition, and immunity. The purpose of this study was to examine the prognostic value of the SII, PNI, SIRI, AAPR, and LIPI in patients with UTUC who underwent radical nephroureterectomy with bladder cuff excision. MATERIALS AND METHODS: Data of UTUC patients in Sichuan Provincial People's Hospital from January 2017 to December 2021 were collected. The optimal critical values of SII, PNI, SIRI, and AAPR were determined by ROC curve, and LIPI was stratified according to the dNLR and LDH. The Kaplan-Meier method was used to draw the survival curve, and Cox proportional hazard model was used to analyze the factors affecting the prognosis of UTUC patients. RESULTS: A total of 81 patients with UTUC were included in this study. The optimal truncation value of PNI, SII, SIRI and AAPR were determined to be 48.15, 596.4, 1.45 and 0.50, respectively. Univariate Cox proportional hazard regression showed that low PNI, high SII, high SIRI, low AAPR and poor LIPI group were effective predictors of postoperative prognosis of UTUC patients. Multivariate Cox proportional hazard regression showed that high SII was an independent risk factor for postoperative prognosis of UTUC patients. According to ROC curve, the prediction efficiency of fitting indexes of PNI, SII, SIRI, AAPR and LIPI is better than that of using them alone. CONCLUSIONS: The SII, PNI, SIRI, AAPR, and LIPI was a potential prognostic predictor in UTUC patients who underwent radical nephroureterectomy with bladder cuff excision.


Assuntos
Inflamação , Nefroureterectomia , Humanos , Estudos Retrospectivos , Masculino , Feminino , Prognóstico , Pessoa de Meia-Idade , Inflamação/imunologia , Idoso , Carcinoma de Células de Transição/cirurgia , Carcinoma de Células de Transição/mortalidade , Estado Nutricional , Avaliação Nutricional , Período Pré-Operatório , Imunidade , Neoplasias Renais/cirurgia , Neoplasias Renais/imunologia , Neoplasias Renais/mortalidade
17.
Front Pharmacol ; 15: 1409022, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38989147

RESUMO

Introduction: To clarify the prevalence of adverse renal outcomes following targeted therapies in renal cell carcinoma (RCC). Methods: A systematic search was performed in MEDLINE, EMBASE, and Cochrane Central Library. Studies that had reported adverse renal outcomes following targeted therapies in RCC were eligible. Outcomes included adverse renal outcomes defined as either renal dysfunction as evidenced by elevated serum creatinine levels or the diagnosis of acute kidney injury, or proteinuria as indicated by abnormal urine findings. The risk of bias was assessed according to Cochrane handbook guidelines. Publication bias was assessed using Funnel plot analysis and Egger Test. Results: The occurrences of the examined outcomes, along with their corresponding 95% confidence intervals (CIs), were combined using a random-effects model. In all, 23 studies including 10 RCTs and 13 observational cohort studies were included. The pooled incidence of renal dysfunction and proteinuria following targeted therapies in RCC were 17% (95% CI: 12%-22%; I2 = 88.5%, p < 0.01) and 29% (95% CI: 21%-38%; I2 = 93.2%, p < 0.01), respectively. The pooled incidence of both types of adverse events varied substantially across different regimens. Occurrence is more often in polytherapy compared to monotherapy. The majority of adverse events were rated as CTCAE grades 1 or 2 events. Four studies were assessed as having low risk of bias. Conclusion: Adverse renal outcomes reflected by renal dysfunction and proteinuria following targeted therapies in RCC are not uncommon and are more often observed in polytherapy compared to monotherapy. The majority of the adverse events were of mild severity. Systematic Review Registration: Identifier CRD42023441979.

18.
Int Heart J ; 65(4): 612-620, 2024 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-39010223

RESUMO

Currently, providing patients, particularly those with acute myocardial infarction (AMI), with comprehensive cardiac rehabilitation (CR) has been challenging because of the inadequate availability of medical resources in developing countries. To ensure balance between disease instability and early rehabilitation, strategies for facilitating professional and comprehensive CR opportunities for patients with AMI must be explored.A prospective cohort study was carried out on 1,533 patients with AMI who were admitted to a tertiary hospital between July 2018 and October 2019. Following the principle of voluntarism, 286 patients with AMI participated in home-center-based CR (HCB group), whereas 1,247 patients received usual care (UC group). The primary endpoint of this study was the occurrence of cardiovascular events at 30 months after AMI. Moreover, the study analyzed factors that influence participation rate and effectiveness of the CR model.After analysis, a significant difference in the occurrence of cardiovascular endpoints between the HCB group and the UC group was observed (harzard ratio, 0.68 [95%CI, 0.51-0.91], P = 0.008), with participation in home-center-based CR being an independent influencing factor. Multivariate regression analysis revealed age, gender, smoking history, triglyceride levels, and ejection fraction as independent factors that influence participation rate. Female gender, peak oxygen uptake per kilogram body weight, and ventilation/carbon dioxide production slope were identified as factors that affect the effectiveness of the CR model.In the context of developing countries, this study demonstrates that the home-center-based CR model is efficient and analyzes factors that influence participation rate and effectiveness of the model. These findings provide practical insights for further development of CR programs.


Assuntos
Reabilitação Cardíaca , Infarto do Miocárdio , Humanos , Masculino , Feminino , Reabilitação Cardíaca/métodos , Infarto do Miocárdio/reabilitação , Pessoa de Meia-Idade , Estudos Prospectivos , Idoso , Resultado do Tratamento , Serviços de Assistência Domiciliar
19.
Huan Jing Ke Xue ; 45(6): 3649-3660, 2024 Jun 08.
Artigo em Chinês | MEDLINE | ID: mdl-38897784

RESUMO

This research aimed to clarify the effects of exogenously applied chitosan on the physiological characteristics, antioxidant activities, and Cd accumulation of wheat (Triticum aestivum L.) seedlings under cadmium (Cd) stress and to identify the key indicators based on the partial least squares model. The wheat variety studied was Bainong207 (BN207), and Cd-stress was achieved by growing seedlings in a hydroponic culture experiment with 10 and 25 µmol·L-1 Cd2+ added to the culture solution. It was found that both Cd-stress at 10 and 25 µmol·L-1 significantly inhibited the chlorophyll content, photosynthesis, and biomass accumulation of wheat seedlings. Seedling roots became shorter and thicker, and the lateral roots decreased under Cd-stress. The Cd-stress also increased H2O2 and MDA accumulation and the degree of cell membrane lipid peroxidation and affected the activities of antioxidant enzymes such as superoxide dismutase (SOD) and peroxidase (POD). Under Cd stress, exogenous chitosan decreased the Cd content in the aboveground and underground parts of wheat by 13.22 %-21.63 % and 7.92 %-28.32 % and reduced Cd accumulation in the aboveground and underground parts by 5.37 %-6.71 % and 1.91 %-4.09 %, respectively. Whereas exogenous chitosan application significantly reduced the content of H2O2 in roots and aboveground parts of wheat by 38.21 %-47.46 % and 45.81 %-55.73 % and MDA content by 37.65 %-48.12 % and 29.87 %-32.51 %, it increased the activities of SOD and POD in roots by 2.78 %-5.61 % and 13.81 %-18.33 %, respectively. In summary, exogenous chitosan can improve the photosynthetic characteristics and antioxidant enzyme activities of wheat seedlings under Cd stress, reduce the content and accumulation of Cd in the root and aboveground parts of wheat, and alleviate the damage of lipid peroxidation to the cell membrane. All of these results provide the basal data for the application of exogenous chitosan to alleviate Cd toxicity to wheat seedlings.


Assuntos
Antioxidantes , Cádmio , Quitosana , Plântula , Triticum , Triticum/metabolismo , Triticum/efeitos dos fármacos , Triticum/crescimento & desenvolvimento , Cádmio/toxicidade , Cádmio/metabolismo , Quitosana/metabolismo , Quitosana/farmacologia , Plântula/efeitos dos fármacos , Plântula/metabolismo , Antioxidantes/metabolismo , Estresse Fisiológico/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Poluentes do Solo/toxicidade , Poluentes do Solo/metabolismo
20.
Front Genet ; 15: 1296533, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38919951

RESUMO

Small RNAs (sRNAs) are important non-coding RNA regulators that play key roles in the development and pathogenesis of plant pathogens, as well as in other biological processes. However, whether these abundant and varying sRNAs are involved in Phytophthora development or infection remains enigmatic. In this study, sRNA sequencing of 4 asexual stages of Phytophthora capsici (P. capsici), namely, as mycelia (HY), sporangia (SP), zoospores (ZO), cysts (CY), and pepper infected with P. capsici (IN), were performed, followed by sRNA analysis, microRNA (miRNA) identification, and miRNA target prediction. sRNAs were mainly distributed at 25-26 nt in HY, SP, and ZO but distributed at 18-34 nt in CY and IN. 92, 42, 176, 39, and 148 known miRNAs and 15, 19, 54, 13, and 1 novel miRNA were identified in HY, SP, ZO, CY, and IN, respectively. It was found that the expression profiles of known miRNAs vary greatly at different stages and could be divided into 4 categories. Novel miRNAs mostly belong to part I. Gene ontology (GO) analysis of known miRNA-targeting genes showed that they are involved in the catalytic activity pathway, binding function, and other biological processes. Kyoto Encyclopedia of Gene and Genome (KEGG) analysis of novel miRNA-targeting genes showed that they are involved in the lysine degradation pathway. The expression of candidate miRNAs was validated using quantitative reverse transcription-polymerase chain reaction (qRT-PCR), and miRNAs were downregulated in PcDCL1 or PcAGO1 mutants. To further explore the function of the detected miRNAs, the precursor of a novel miRNA, miR91, was knockout by CRISPR-Cas9, the mutants displayed decreased mycelial growth, sporangia production, and zoospore production. It was found that 503142 (Inositol polyphosphate 5-phosphatase and related proteins) can be predicted as a target of miR91, and the interaction between miR91 and 503142 was verified using the tobacco transient expression system. Overall, our results indicate that the diverse and differentially expressed sRNAs are involved in the development and pathogenesis of P. capsici.

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