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The underlying mechanisms of diseases affecting the central nervous system (CNS) remain unclear, limiting the development of effective therapeutic strategies. Remarkably, cellular senescence, a biological phenomenon observed in cultured fibroblasts in vitro, is a crucial intrinsic mechanism that influences homeostasis of the brain microenvironment and contributes to the onset and progression of CNS diseases. Cellular senescence has been observed in disease models established in vitro and in vivo and in bodily fluids or tissue components from patients with CNS diseases. These findings highlight cellular senescence as a promising target for preventing and treating CNS diseases. Consequently, emerging novel therapies targeting senescent cells have exhibited promising therapeutic effects in preclinical and clinical studies on aging-related diseases. These innovative therapies can potentially delay brain cell loss and functional changes, improve the prognosis of CNS diseases, and provide alternative treatments for patients. In this study, we examined the relevant advancements in this field, particularly focusing on the targeting of senescent cells in the brain for the treatment of chronic neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, and multiple sclerosis) and acute neurotraumatic insults (e.g., ischemic stroke, spinal cord injury, and traumatic brain injury).
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In order to guide the formulation of post-stroke treatment strategy in time, it is necessary to have real-time feedback on collateral circulation and revascularization. Currently used near-infrared II (NIR-II) probes have inherent binding with endogenous albumin, resulting in significant background signals and uncontrollable pharmacokinetics. Therefore, the albumin-escaping properties of the new probe, IR-808AC, was designed, which achieved timely excretion and low background signal, enabling the short-term repeatable injection for visualization of cerebral vessels and perfusion. We further achieved continuous observation of changes in collateral vessels and perfusion during the 7-d period in middle cerebral artery occlusion mice using IR-808AC in vivo. Furthermore, using IR-808AC, we confirmed that remote ischemic conditioning could promote collateral vessels and perfusion. Finally, we evaluated the revascularization after thrombolysis on time in embolic stroke mice using IR-808AC. Overall, our study introduces a novel methodology for safe, non-invasive, and repeatable assessment of collateral circulation and revascularization in real-time that is crucial for the optimization of treatment strategies.
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Modelos Animales de Enfermedad , Accidente Cerebrovascular , Animales , Accidente Cerebrovascular/diagnóstico por imagen , Ratones , Masculino , Imagen de Perfusión/métodos , Arterias Cerebrales/diagnóstico por imagen , Ratones Endogámicos C57BL , Albúminas/química , Infarto de la Arteria Cerebral Media/diagnóstico por imagen , Espectroscopía Infrarroja Corta/métodos , Circulación ColateralRESUMEN
BACKGROUND: The clinical and genetic characteristics, as well as treatment outcomes, of diffuse large B-cell lymphoma (DLBCL) patients with different MYD88 and CD79B mutation status merit further investigation. OBJECTIVE: This study aims to investigate the distinctions in clinical manifestations, genetic characteristics, and treatment outcomes among MYD88-CD79Bco-mut, MYD88/CD79Bsingle-mut, and MYD88-CD79Bco-wt DLBCL patients. PATIENTS AND METHODS: Clinical and genetic characteristics, along with treatment outcomes among 2696 DLBCL patients bearing MYD88-CD79Bco-mut, MYD88/CD79Bsingle-mut, and MYD88-CD79Bco-wt treated with R-CHOP/R-CHOP-like regimens from the Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College and six external cohorts were analyzed. Potential molecular mechanisms were investigated through Gene Set Enrichment Analysis and xCell methodology. RESULTS: In the MCD subtype, patients with MYD88-CD79Bco-mut showed comparable progression-free survival (PFS) and overall survival (OS) compared to MYD88/CD79Bsingle-mut or MYD88-CD79Bco-wt. However, in the non-MCD subtype, patients with MYD88-CD79Bco-mut exhibited significantly inferior OS than MYD88/CD79Bsingle-mut or MYD88-CD79Bco-wt, while there was no significant OS difference between MYD88/CD79Bsingle-mut and MYD88-CD79Bco-wt (median OS: 68.8 [95% CI 22-NA] vs NA [95% CI 112-NA] vs 177.7 [95% CI 159-NA] months; MYD88-CD79Bco-mut vs MYD88/CD79Bsingle-mut: p = 0.02; MYD88-CD79Bco-mut vs MYD88-CD79Bco-wt: p = 0.03; MYD88/CD79Bsingle-mut vs MYD88-CD79Bco-wt: p = 0.33). Regarding patients with MYD88-CD79Bco-mut, there was no significant difference in PFS and OS between the MCD and non-MCD subtypes. Within the MYD88-CD79Bco-mut group, patients with PIM1mut had better PFS than PIM1wt (median PFS: 8.34 [95% CI 5.56-NA] vs 43.8 [95% CI 26.4-NA] months; p = 0.02). Possible mechanisms contributing to the superior PFS of PIM1mut patients may include activated lymphocyte-mediated immunity and interferon response, a higher proportion of natural killer T cells and plasmacytoid dendritic cells, as well as suppressed angiogenesis and epithelial-mesenchymal transition, along with lower fibroblast and stromal score. CONCLUSIONS: In the MCD subtype, patients with MYD88-CD79Bco-mut showed comparable PFS and OS compared to MYD88/CD79Bsingle-mut or MYD88-CD79Bco-wt, while in the non-MCD subtype, they exhibited significantly inferior OS. There was no significant disparity in PFS and OS of MYD88-CD79Bco-mut between the MCD and non-MCD subtypes. The presence of PIM1mut within the MYD88-CD79Bco-mut group correlated with better PFS, which may result from an intricate interplay of immune processes and tumor microenvironment alterations.
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Antígenos CD79 , Linfoma de Células B Grandes Difuso , Mutación , Factor 88 de Diferenciación Mieloide , Humanos , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/mortalidad , Factor 88 de Diferenciación Mieloide/genética , Antígenos CD79/genética , Pronóstico , Masculino , Femenino , Resultado del Tratamiento , Persona de Mediana Edad , Anciano , AdultoRESUMEN
Sulfide-releasing compounds reduce reperfusion injury by decreasing mitochondria-derived reactive oxygen species production. We previously characterised ammonium tetrathiomolybdate (ATTM), a clinically used copper chelator, as a sulfide donor in rodents. Here we assessed translation to large mammals prior to clinical testing. In healthy pigs an intravenous ATTM dose escalation revealed a reproducible pharmacokinetic/pharmacodynamic (PK/PD) relationship with minimal adverse clinical or biochemical events. In a myocardial infarction (1-h occlusion of the left anterior descending coronary artery)-reperfusion model, intravenous ATTM or saline was commenced just prior to reperfusion. ATTM protected the heart (24-h histological examination) in a drug-exposure-dependent manner (r2 = 0.58, p < 0.05). Blood troponin T levels were significantly (p < 0.05) lower in ATTM-treated animals while myocardial glutathione peroxidase activity, an antioxidant selenoprotein, was elevated (p < 0.05). Overall, our study represents a significant advance in the development of sulfides as therapeutics and underlines the potential of ATTM as a novel adjunct therapy for reperfusion injury. Mechanistically, our study suggests that modulating selenoprotein activity could represent an additional mode of action of sulfide-releasing drugs.
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Modelos Animales de Enfermedad , Daño por Reperfusión Miocárdica , Sulfuros , Animales , Porcinos , Sulfuros/farmacología , Sulfuros/administración & dosificación , Sulfuros/uso terapéutico , Daño por Reperfusión Miocárdica/metabolismo , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/patología , Oclusión Coronaria/tratamiento farmacológico , Oclusión Coronaria/metabolismo , Infarto del Miocardio/metabolismo , Infarto del Miocardio/tratamiento farmacológico , Infarto del Miocardio/patología , Glutatión Peroxidasa/metabolismo , Miocardio/metabolismo , Miocardio/patología , Masculino , MolibdenoRESUMEN
The incidence of ischemic stroke (IS) is rising in tandem with the global aging population. There is an urgent need to delve deeper into the pathological mechanisms and develop new neuroprotective strategies. In the present review, we discuss the latest advancements and research on various nanodrug delivery systems (NDDSs) for targeting microglial polarization in IS treatment. Furthermore, we critically discuss the different strategies. NDDSs have demonstrated exceptional qualities to effectively permeate the blood-brain barrier, aggregate at the site of ischemic injury, and target specific cell types within the brain when appropriately modified. Consequently, NDDSs have considerable potential for reshaping the polarization phenotype of microglia and could be a prospective therapeutic strategy for IS. The treatment of IS remains a challenge. However, this review provides a new perspective on neuro-nanomedicine for IS therapies centered on microglial polarization, thereby inspiring new research ideas and directions.
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This study evaluated the welfare and behaviors of Cobb 700 broilers as affected by growth rate (GR) and stocking density (SD). Slower-growth (weight gain < 50 g/d) and medium-growth (weight gain = 50-60 g/d) broilers were produced by providing 57.1% and 78.6% of the feed intake listed in the Cobb 700 production manual for standard (fed ad libitum) broilers (weight gain > 60 g/d). Broilers at all 3 GRs were reared at 2 SDs of 30 and 40 kg/m2. Broiler welfare indicators, including gait score, tibia strength, feather coverage, and footpad condition were evaluated when birds reached 1, 2, and 3 kg of body weight. The activity index was determined by overhead cameras and image processing, and the time spent at feeders was recorded using the radio-frequency identification (RFID) systems. The results show that it took 45 d for standard, 52 d for medium-growth, and 62 d for slower-growth broilers to reach a 3 kg market body weight. Feed conversion ratios (FCR, kg/kg) were 1.57 for standard, 1.67 for medium-growth, and 1.80 for slower-growth broilers. Growth rate and SD had an interaction effect on feather cleanliness (P = 0.03), and belly feather coverage (P = 0.02). Slower-growth broilers were more active and had better feather coverage and gait scores than medium-growth and standard broilers (all P < 0.01) but may feel hungry and depressed, medium-growth broilers spent the most time at the feeder among the 3 growth groups (P = 0.02), and standard broilers showed the best production performance. Broilers at 30 kg/m2 showed better bone strength (P = 0.04), and footpad condition (P < 0.01) compared to those at 40 kg/m2. In conclusion, reducing GR and SD may slightly improve broiler leg health at the high expense of compromised production performance and prolonged production cycles.
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Crianza de Animales Domésticos , Pollos , Animales , Crianza de Animales Domésticos/métodos , Peso Corporal , Aumento de Peso , Ingestión de AlimentosRESUMEN
Background: Radiotherapy is an effective treatment for indolent non-Hodgkin lymphoma (iNHL); however, the optimal radiotherapy dose remains to be determined. We hypothesize that a suitable dose may exist between 4 and 24 Gy. Methods: This prospective multicenter phase II trial intends to recruit 73 sites of iNHL patients, who will receive involved-site radiotherapy of 12 Gy in four fractions. The primary objective is the 6-month clinical complete response rate. Tumor tissue, blood and conjunctival specimens will be collected to identify potential predictive biomarkers. Discussion: The CLCG-iNHL-01 trial will evaluate the efficacy and toxicity of 12 Gy in patients with iNHL and provide information on a novel hypofractionation regimen of low-dose radiotherapy. Clinical Trial Registration: NCT05543070 (ClinicalTrials.gov).
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Linfoma no Hodgkin , Humanos , Estudios Prospectivos , Linfoma no Hodgkin/tratamiento farmacológico , Resultado del Tratamiento , Ensayos Clínicos Fase II como Asunto , Estudios Multicéntricos como AsuntoRESUMEN
BACKGROUND: The number of migrant older adults with children (MOAC) in China has been increasing in recent years, and most of them are women. This study aimed to explore the mediating effect of social support between social integration and loneliness among the female MOAC in Jinan, China. METHODS: In this study, 418 female MOAC were selected using multi-stage cluster random sampling in Jinan, Shandong Province, China. Loneliness was measured by the eight-item version of the University of California Los Angeles Loneliness Scale (ULS-8), and social support was measured by The Social Support Rating Scale (SSRS). Descriptive analyses, t-tests, ANOVA, and structural equation modeling (SEM) were used to illustrate the relationship between social integration, social support, and loneliness. RESULTS: The average scores of ULS-8 and SSRS were 12.9 ± 4.0 and 39.4 ± 5.9 among female MOAC in this study. Social integration and social support were found to be negatively related to loneliness, and the standardized direct effect was -0.20 [95% CI: -0.343 to -0.068] and -0.39 [95% CI: -0.230 to -0.033], respectively. Social support mediated the relationship between social integration and loneliness, and the indirect effect was -0.16 [95% CI: -0.252 to -0.100]. CONCLUSION: The female MOAC's loneliness was at a relatively lower level in this study. It was found that social integration was negatively associated with loneliness, and social support mediated the relationship between them. Helping female MOAC integrate into the inflow city and improving their social support could be beneficial for alleviating their loneliness.
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Migrantes , Humanos , Femenino , Anciano , Masculino , Soledad , Apoyo Social , Proyectos de Investigación , Integración Social , China/epidemiologíaRESUMEN
BACKGROUND: This study aimed to develop and validate a novel risk stratification model and a web-based survival rate calculator to improve discriminative and predictive accuracy for diffuse large B-cell lymphoma (DLBCL) in the rituximab era. METHODS: We retrospectively collected pre-treatment data from 873 primary DLBCL patients who received R-CHOP-based immunochemotherapy regimens at the Cancer Hospital, Chinese Academy of Medical Sciences, from January 1, 2005, to December 31, 2018. An independent cohort of 175 DLBCL patients from Fujian Cancer Hospital was used for external validation. FINDINGS: Age, ECOG PS, number of extranodal sites, Ann Arbor stage, bulky disease, and LDH levels were screened to develop the nomogram and web-based survival rate calculator. The C-index of the nomogram in the training, internal validation, and external validation cohorts was 0.761, 0.758, and 0.768, respectively. The risk stratification model generated based on the nomogram effectively stratified patients into three distinct risk groups. K-M survival curves demonstrated that the novel risk stratification model exhibited a superior level of predictive accuracy compared to IPI, R-IPI, and NCCN-IPI both in training and two validation cohorts. Additionally, the area under the curve (AUC) value of the novel model (0.763) for predicting 5-year overall survival rates was higher than those of IPI (0.749), R-IPI (0.725), and NCCN-IPI (0.727) in the training cohort. Similar results were observed in both internal and external validation cohort. CONCLUSIONS: In conclusion, we have successfully developed and validated a novel risk stratification model and a web-based survival rate calculator that demonstrated superior discriminative and predictive accuracy compared to IPI, R-IPI, and NCCN-IPI in the rituximab era.
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Protocolos de Quimioterapia Combinada Antineoplásica , Linfoma de Células B Grandes Difuso , Humanos , Rituximab/uso terapéutico , Tasa de Supervivencia , Estudios Retrospectivos , Pronóstico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Estudios de Cohortes , Linfoma de Células B Grandes Difuso/patología , Ciclofosfamida/uso terapéutico , Prednisona/uso terapéutico , Vincristina/uso terapéutico , Doxorrubicina/uso terapéutico , Medición de RiesgoRESUMEN
Low-risk early-stage extranodal natural killer/T-cell lymphoma, nasal type has a favorable outcome with radiation therapy alone, and the addition of chemotherapy shows no survival benefit. Nonetheless, a proportion of patients will relapse or progress, with a dismal outcome, highlighting the need for a novel therapeutic strategy. Promising preliminary findings indicate the efficacy of PD-1/PD-L1 inhibitors in extranodal natural killer/T-cell lymphoma, nasal type, with good toxicity profiles. Here we describe the design of a phase II study (CLCG-NKT-2101), which is evaluating the safety and efficacy of adding anti-PD-1 antibody to the current radiation therapy regimen in low-risk early-stage extranodal natural killer/T-cell lymphoma, nasal type patients. Tislelizumab will be added in an inductive and concurrent way to radiation therapy. The primary end point will be the complete response rate after induction immunotherapy. Clinical trial registration: ClinicalTrials.gov (NCT05149170).
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Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Linfoma de Células T , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Estadificación de Neoplasias , Linfoma de Células T/etiología , Células Asesinas Naturales , Ensayos Clínicos Fase II como AsuntoRESUMEN
Anode materials with excellent properties have become the key to develop sodium-ion hybrid capacitors (SIHCs) that combine the advantages of both batteries and capacitors. Amorphous modulation is an effective strategy to realize high energy/power density in SIHCs. Herein, atomically amorphous Nb-O/N clusters with asymmetric coordination are in situ created in N-doped hollow carbon shells (Nb-O/N@C). The amorphous clusters with asymmetric Nb-O3/N1 configurations have abundant charge density and low diffusion energy barriers, which effectively modulate the charge transport paths and improve the reaction kinetics. The clusters are also enriched with unsaturated vacancy defects and isotropic ion-transport channels, and their atomic disordering exhibits high structural stress buffering, which are strong impetuses for realizing bulk-phase-indifferent ion storage and enhancing the storage properties of the composite. Based on these features, Nb-O/N@C achieves notably improved sodium-ion storage properties (reversible capacity of 240.1 mAh g-1 at 10.0 A g-1 after 8000 cycles), and has great potential for SIHCs (230 Wh Kg-1 at 4001.5 W Kg-1). This study sheds new light on developing high-performance electrodes for sodium-ion batteries and SIHCs by designing amorphous clusters and asymmetric coordination.
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Inflammatory bowel disease (IBD) is a complex group of chronic intestinal diseases, the cause of which has not yet been clarified, but it is widely believed that the disorder of the intestinal microenvironment and its related functional changes are key factors in the development of the disease. Houttuynia cordata thunb. is a traditional plant with abundant resources and long history of utilization in China, which has attracted widespread attention in recent years due to its potential in the treatment of IBD. However, its development and utilization are limited owing to the aristolochic acid alkaloids contained in it. Therefore, based on the relationship between the intestinal microenvironment and IBD, this article summarizes the potential mechanisms by which the main active ingredients of Houttuynia cordata thunb., such as volatile oils, polysaccharides, and flavonoids, and related traditional Chinese medicine preparations, such as Xiezhuo Jiedu Formula, alleviate IBD by regulating the intestinal microenvironment. At the same time, combined with current reports, the medicinal and edible safety of Houttuynia cordata thunb. is explained for providing ideas for further research and development of Houttuynia chordate thunb. in IBD disease, more treatment options for IBD patients, and more insights into the therapeutic potential of plants with homology of medicine and food in intestinal diseases, and even more diseases.
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Alcaloides , Medicamentos Herbarios Chinos , Houttuynia , Enfermedades Inflamatorias del Intestino , Humanos , Extractos Vegetales , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/uso terapéutico , Enfermedades Inflamatorias del Intestino/tratamiento farmacológicoRESUMEN
ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) rearrangements are a crucial therapeutic target in non-small cell lung cancer (NSCLC). However, there is limited comprehensive analysis of the molecular patterns of ROS1 fusions. This study aimed to address this gap by analysing 135 ROS1 fusions from 134 Chinese NSCLC patients using next-generation sequencing (NGS). The fusions were categorized into common and uncommon based on their incidence. Our study revealed, for the first time, a unique distribution preference of breakpoints within ROS1, with common fusions occurring in introns 31-33 and uncommon fusions occurring in introns 34 and 35. Additionally, we identified previously unknown breakpoints within intron 28 of ROS1. Furthermore, we identified a close association between the distribution patterns of fusion partners and breakpoints on ROS1, providing important insights into the molecular landscape of ROS1 fusions. We also confirmed the presence of inconsistent breakpoints in ROS1 fusions between DNA-based NGS and RNA-based NGS through rigorous validation methods. These inconsistencies were attributed to alternative splicing resulting in out-of-frame or exonic ROS1 fusions. These findings significantly contribute to our understanding of the molecular characteristics of ROS1 fusions, which have implications for panel design and the treatment of NSCLC patients with ROS1 rearrangements.
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The protective effects of remote ischemic conditioning (RIC) on acute ischemic stroke have been reported. However, the protective mechanisms of RIC have not been fully elucidated. This study aimed to investigate whether RIC could reduce oxidative stress and inflammatory responses in middle cerebral artery occlusion (MCAO)-reperfusion mice via the nuclear factor-E2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway. C57BL/6 mice were subjected to MCAO and underwent RIC twice daily at 1, 3, and 7 days after MCAO. ML385 was used to specifically inhibit Nrf2 in MCAO mice. Neurological deficit scores, infarct volume, and hematoxylin-eosin (HE) staining were assessed. Oxidative stress levels were assessed based on total antioxidant capacity (TAC), malonaldehyde (MDA), superoxide dismutase (SOD), and glutathione/glutathione disulfide (GSH/GSSG). mRNA levels were detected using real-time polymerase chain reaction (PCR), and protein levels were detected using western blotting and enzyme-linked immunosorbent assay (ELISA). Protein localization was investigated using immunofluorescence staining. RIC significantly reduced infarct volume and improved neurological function and histological changes after MCAO. RIC significantly increased TAC, SOD, and GSH/GSSG levels and decreased MDA levels. RIC significantly increased Nrf2 and HO-1 mRNA levels and decreased Keap1, NLRP3, and Cleaved Caspase-1 mRNA levels. RIC significantly increased Nrf2, HO-1, and NQO1 protein expression and decreased Keap1, NLRP3, Cleaved Caspase-1, Cleaved IL-1ß, IL-6, and TNF-α protein expression. RIC promoted the activation and translocation of Nrf2 into the nucleus. The protective effects of RIC were abolished by ML385 treatment. In conclusion, our findings suggest that RIC alleviates oxidative stress and inflammatory responses via the Nrf2/HO-1 pathway, which in turn improves neurobehavioral function. RIC may provide novel therapeutic options for acute ischemic stroke.
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Accidente Cerebrovascular Isquémico , Factor 2 Relacionado con NF-E2 , Animales , Ratones , Ratones Endogámicos C57BL , Proteína 1 Asociada A ECH Tipo Kelch , Factor 2 Relacionado con NF-E2/genética , Infarto de la Arteria Cerebral Media , Hemo-Oxigenasa 1/genética , Disulfuro de Glutatión , Proteína con Dominio Pirina 3 de la Familia NLR , Estrés Oxidativo , Antioxidantes , Inflamación , Caspasa 1RESUMEN
Background: Little is known about the association between frailty level and medical financial hardship among older adults with cancer. This study aims to describe the prevalence of frailty and to identify its association with medical financial hardship among older cancer survivors in the United States. Methods: The National Health Interview Survey (NHIS; 2019-2020) was used to identify older cancer survivors (n = 3,919). Both the five-item (Fatigue, Resistance, Ambulation, Illnesses, and Low weight-for-height) FRAIL and the three-domain (Material, Psychological, and Behavioral) medical financial hardship questions were constructed based on the NHIS questionnaire. Multivariable logistic models were used to identify the frailty level associated with financial hardship and its intensity. Results: A total of 1,583 (40.3%) older individuals with cancer were robust, 1,421 (35.9%) were pre-frail, and 915 (23.8%) were frail. Compared with robust cancer survivors in adjusted analyses, frail cancer survivors were more likely to report issues with material domain (odds ratio (OR) = 3.19, 95%CI: 2.16-4.69; p < 0.001), psychological domain (OR = 1.47, 95%CI: 1.15-1.88; p < 0.001), or behavioral domain (ORs ranged from 2.19 to 2.90, all with p < 0.050), and greater intensities of financial hardship. Conclusion: Both pre-frail and frailty statuses are common in the elderly cancer survivor population, and frail cancer survivors are vulnerable to three-domain financial hardships as compared with robust cancer survivors. Ongoing attention to frailty highlights the healthy aging of older survivors, and efforts to targeted interventions should address geriatric vulnerabilities during cancer survivorship.
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BACKGROUND: Patients with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL) have poor outcomes and few treatment options. We report the preliminary results of the efficacy and safety of PD-1 monoclonal antibody (mab) plus Rituximab for r/r DLBCL. METHODS: In this single-center, single-arm phase 2 and retrospective study, r/r DLBCL patients received PD-1 mab and Rituximab every 3 weeks. Immunohistochemistry, fluorescence in situ hybridization, and probe capture-based high-resolution sequencing were performed. Efficacy, safety and prognostic factors were analyzed. RESULTS: Between October 16th, 2018, and July 10th, 2022, 36 patients (10 patients in retrospective study and 26 patients in phase 2 study) were enrolled and received at least one dose of PD-1 mab combined with Rituximab. The objective response rate was 52.8%. The median progression free survival (PFS) and overall survival was 2.8 and 19.6 months, respectively. The median duration of response was 18.7 months. Rare grade 3 or 4 treatment related adverse events were observed. B2M mutations correlated with a significantly poor PFS (p = .013) and OS (p = .009) in DLBCL patients treated with this regimen. CONCLUSION: PD-1 mab combined with Rituximab could be a potential treatment option for r/r DLBCL with manageable safety profile.
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Linfoma de Células B Grandes Difuso , Linfoma no Hodgkin , Humanos , Rituximab/efectos adversos , Anticuerpos Monoclonales/efectos adversos , Receptor de Muerte Celular Programada 1 , Estudios Retrospectivos , Hibridación Fluorescente in Situ , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Linfoma no Hodgkin/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/diagnóstico , Linfoma de Células B Grandes Difuso/tratamiento farmacológicoRESUMEN
PURPOSE: This study aims to investigate the clinical and molecular differences between diffuse large B-cell lymphoma (DLBCL) patients with MYD88L265P and MYD88other. METHODS: DLBCL patients with MYD88 variations were collected from the Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College (CHCAMS), and Suzhou Municipal Hospital from February 6th, 2007 to May 20th, 2022. Clinicopathological parameters and treatment outcomes between MYD88L265P and MYD88other were investigated. RESULTS: A total of 132 patients with MYD88 variations from a cohort of 475 DLBCL patients were included, among which, 78 were MYD88L265P, while 54 were MYD88other. MYD88L265P was more common in non-GCB subtype than MYD88other (83% vs. 60%, P = 0.004). Besides, MYD88L265P was significantly related to higher proportion of testicle/ central nervous system involvement (31% vs. 6%, P < 0.001), PIM1 mutation (71% vs. 39%, P < 0.001), and PIM1 hypermutation (28% vs. 11%, P = 0.018), compared with MYD88other. Compared with MYD88L265P, MYD88other were more likely to have higher percentage of advanced stage (60% vs. 42%, P = 0.044), extranodal site ≥ 2 (45% vs. 28%, P = 0.044), elevated LDH (55% vs. 35%, P = 0.033), positive CD10 expression (36% vs. 16%, P = 0.009), BCL-6 translocation (20% vs. 8%, P = 0.033), and NOTCH pathway gene alteration (24% vs. 13%, P = 0.040). In non-GCB DLBCL subtype, patients with MYD88other were significantly associated with worse progression free survival (PFS) than those with MYD88L265P when treated initially with R-CHOP/R-CHOP-like regimen (P = 0.010). CONCLUSION: The findings of this study indicate that DLBCL patients with MYD88L265P and MYD88other are likely to be two subgroups with different clinical and molecular characteristics. The survival of patients with MYD88other is not superior than those with MYD88L265P, even poorer when focusing on the non-GCB subtype.
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Linfoma de Células B Grandes Difuso , Factor 88 de Diferenciación Mieloide , Humanos , Pronóstico , Factor 88 de Diferenciación Mieloide/genética , Mutación , Linfoma de Células B Grandes Difuso/tratamiento farmacológico , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Resultado del TratamientoRESUMEN
Advances in spatial transcriptomics enlarge the use of single cell technologies to unveil the expression landscape of the tissues with valuable spatial context. Here, we propose an unsupervised and manifold learning-based algorithm, Spatial Transcriptome based cEll typE cLustering (STEEL), which identifies domains from spatial transcriptome by clustering beads exhibiting both highly similar gene expression profiles and close spatial distance in the manner of graphs. Comprehensive evaluation of STEEL on spatial transcriptomic datasets from 10X Visium platform demonstrates that it not only achieves a high resolution to characterize fine structures of mouse brain but also enables the integration of multiple tissue slides individually analyzed into a larger one. STEEL outperforms previous methods to effectively distinguish different cell types/domains of various tissues on Slide-seq datasets, featuring in higher bead density but lower transcript detection efficiency. Application of STEEL on spatial transcriptomes of early-stage mouse embryos (E9.5-E12.5) successfully delineates a progressive development landscape of tissues from ectoderm, mesoderm and endoderm layers, and further profiles dynamic changes on cell differentiation in heart and other organs. With the advancement of spatial transcriptome technologies, our method will have great applicability on domain identification and gene expression atlas reconstruction.
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Acero , Transcriptoma , Animales , Ratones , Perfilación de la Expresión Génica/métodos , Diferenciación Celular , AlgoritmosRESUMEN
After an ischemic stroke (IS) occurs, immune cells begin traveling to the brain and immune system from the gut and gastrointestinal tract, where most of them typically reside. Because the majority of the body's macrophages and more than 70% of the total immune cell pool are typically found within the gut and gastrointestinal tract, inflammation and immune responses in the brain and immune organs require the mobilization of a large number of immune cells. The bidirectional communication pathway between the brain and gut is often referred to as the gut-brain axis. IS usually leads to intestinal motility disorders, dysbiosis of intestinal microbiota, and a leaky gut, which are often associated with poor prognosis in patients with IS. In recent years, several studies have suggested that intestinal inflammation and immune responses play key roles in the development of IS, and thus may become potential therapeutic targets that can drive new therapeutic strategies. However, research on gut inflammation and immune responses after stroke remains in its infancy. A better understanding of gut inflammation and immune responses after stroke may be important for developing effective therapies. This review discusses the immune-related mechanisms of the gut-brain axis after IS and compiles potential therapeutic targets to provide new ideas and strategies for the future effective treatment of IS.