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1.
Alzheimers Res Ther ; 16(1): 205, 2024 Oct 03.
Artículo en Inglés | MEDLINE | ID: mdl-39358780

RESUMEN

BACKGROUND: The approval of lecanemab, an anti-amyloid therapy for Alzheimer's disease (AD), necessitates addressing healthcare preparedness for disease-modifying treatment (DMT) to ensure appropriate, safe, and sustainable drug administration. Understanding public perceptions on this matter is crucial. We aimed to assess discrepancies and similarities in the perceptions of Japanese trial-ready cohort study ('J-TRC webstudy') participants and clinical specialists in the fields of dementia treatment and radiology, concerning affairs related to challenges in DMT preparedness. METHODS: This was a cross-sectional prospective observational study conducted in November-December 2023. The J-TRC webstudy participants were invited to participate in an online survey using Google Forms, and clinical specialists were invited to complete a mail-based survey. Main questionnaire items had been designed to be common in both surveys, and their responses were analyzed for participant attributes, interests, attitudes, expectations, and concerns about DMTs without specifying lecanemab. RESULTS: Responses were obtained from n = 2,050 J-TRC webstudy participants and n = 1,518 clinical specialists. Compared to specialists, more J-TRC respondents perceived the eligible proportion for DMT as smaller (59.1% versus 30.7%), perceived the eligible severity for DMT as more limited (58.0% versus 24.5%), and perceived the efficacy of DMT as slightly more encouraging (29.3% versus 34.8%). In terms of treatment prioritization, both J-TRC respondents and specialist respondents exhibited similar levels of acceptance for prioritizing patients to treat: e.g., approximately two-thirds endorsed patient prioritization under hypothetical resource constraints or other reasons. A medical rationale emerged as the most compelling reason for acceptance of patient prioritization across the surveys. In contrast, the need to address vulnerable populations was the reason that led to the least acceptance of prioritization, followed by economic considerations. CONCLUSIONS: Our findings offer valuable insights into the discrepancies in knowledge and perception between patients and healthcare providers. This could enhance the delivery of patient information in clinical settings and inform the discussion surrounding patient prioritization strategies.


Asunto(s)
Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/terapia , Enfermedad de Alzheimer/psicología , Japón , Masculino , Femenino , Estudios Transversales , Estudios Prospectivos , Persona de Mediana Edad , Encuestas y Cuestionarios , Opinión Pública , Anciano , Adulto , Conocimientos, Actitudes y Práctica en Salud , Percepción , Anticuerpos Monoclonales Humanizados/uso terapéutico
2.
J Clin Exp Hematop ; 64(3): 223-231, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39343610

RESUMEN

IgG4-related sialadenitis (IgG4-SA) is one of the IgG4-related disease. The histological features of IgG4-SA include dense lymphoplasmacytic infiltrates and fibrosis. This study aimed to reveal the involvement of plasma cells in the development of fibrosis and the mechanism underlying fibrosis in IgG4-SA. Hematoxylin-eosin staining, Azan staining, silver staining, and immunohistochemistry (IHC) were performed on IgG4-SA and chronic sialadenitis specimens, and theses samples were analyzed by image analysis software. Histological spatial analysis was used to analyze the localization of IHC-positive cells and the distances between these cells. In the IgG4-SA group, many secondary lymphoid follicles with germinal centers were found, and many collagen fibers developed around these germinal centers. Collagen fibers composed mainly of type I collagen was abundant at sites away from secondary lymphoid follicles, and reticular fibers composed of type III collagen was abundant near secondary lymphoid follicles. Many FAP+ fibroblasts and MUM1+ plasma cells were localized near secondary lymphoid follicles. Histological spatial analysis demonstrated that 90.4% of MUM1+ plasma cells accumulated within 20 µm of FAP+ fibroblasts. Multiple immunofluorescence assays revealed that MUM1+ plasma cells expressed platelet-derived growth factor (PDGF) ß, and FAP+ fibroblasts expressed PDGF receptor (PDGFR) ß and pSTAT3 in IgG4-SA. We have shown that fibrosis is localized around secondary lymphoid follicles and that fibroblasts are activated by plasma cells via PDGF/PDGFR signaling in IgG4-SA.


Asunto(s)
Fibroblastos , Inmunoglobulina G , Células Plasmáticas , Sialadenitis , Transducción de Señal , Sialadenitis/patología , Sialadenitis/metabolismo , Sialadenitis/inmunología , Humanos , Células Plasmáticas/metabolismo , Células Plasmáticas/patología , Células Plasmáticas/inmunología , Fibroblastos/metabolismo , Fibroblastos/patología , Inmunoglobulina G/metabolismo , Inmunoglobulina G/inmunología , Enfermedad Relacionada con Inmunoglobulina G4/patología , Enfermedad Relacionada con Inmunoglobulina G4/metabolismo , Factor de Crecimiento Derivado de Plaquetas/metabolismo , Fibrosis , Masculino , Femenino , Receptores del Factor de Crecimiento Derivado de Plaquetas/metabolismo , Persona de Mediana Edad
3.
Radiol Case Rep ; 19(9): 3618-3621, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38983292

RESUMEN

A 75-year-old male, weighing 71 kg, was admitted to our institution with anemia related to a subcapsular hematoma after accidental extraction of a nephrostomy catheter. While the patient exhibited the progression of chronic kidney disease, he was not yet on dialysis. His serum creatinine level increased to 6.8 mg/dL, with an estimated glomerular filtration rate of 7.4 mL/min/1.73 m2. Radiologists planned contrast-enhanced photon-counting detector CT (PCD-CT) with an ultra-low-dose contrast media to mitigate the impact on renal function. The contrast media dosage was set at 7.4 gI, which was 82.6% lower that used in the standard protocol for a male weighing 71 kg. Non-contrast-enhanced PCD-CT identified a low-density nodular area within the renal subcapsular hematoma. Contrast-enhanced PCD-CT revealed contrast enhancement in both the early and late phases corresponding to the nodular area. On virtual monoenergetic images, the renal pseudoaneurysm was most clearly delineated at 40 keV. Following the diagnosis of a pseudoaneurysm, transcatheter arterial coil embolization was performed. No subsequent progression of anemia or the deterioration of renal function was observed, showcasing the potential of ultra-low-dose contrast-enhanced PCD-CT for the detection of small vascular abnormalities while minimizing adverse effects on renal function.

4.
J Alzheimers Dis ; 99(3): 953-963, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38759009

RESUMEN

Background: Primary outcome measure in the clinical trials of disease modifying therapy (DMT) drugs for Alzheimer's disease (AD) has often been evaluated by Clinical Dementia Rating sum of boxes (CDRSB). However, CDR testing requires specialized training and 30-50 minutes to complete, not being suitable for daily clinical practice. Objective: Herein, we proposed a machine-learning method to estimate CDRSB changes using simpler cognitive/functional batteries (Mini-Mental State Examination [MMSE] and Functional Activities Questionnaire [FAQ]), to replace CDR testing. Methods: Baseline data from 944 ADNI and 171 J-ADNI amyloid-positive participants were used to build machine-learning models predicting annualized CDRSB changes between visits, based on MMSE and FAQ scores. Prediction performance was evaluated with mean absolute error (MAE) and R2 comparing predicted to actual rmDeltaCDRSB/rmDeltayear. We further assessed whether decline in cognitive function surpassing particular thresholds could be identified using the predicted rmDeltaCDRSB/rmDeltayear. RESULTS: The models achieved the minimum required prediction errors (MAE < 1.0) and satisfactory prediction accuracy (R2>0.5) for mild cognitive impairment (MCI) patients for changes in CDRSB over periods of 18 months or longer. Predictions of annualized CDRSB progression>0.5, >1.0, or >1.5 demonstrated a consistent performance (i.e., Matthews correlation coefficient>0.5). These results were largely replicated in the J-ADNI case predictions. CONCLUSIONS: Our method effectively predicted MCI patient deterioration in the CDRSB based solely on MMSE and FAQ scores. It may aid routine practice for disease-modifying therapy drug efficacy evaluation, without necessitating CDR testing at every visit.


Asunto(s)
Enfermedad de Alzheimer , Aprendizaje Automático , Pruebas de Estado Mental y Demencia , Humanos , Enfermedad de Alzheimer/diagnóstico , Enfermedad de Alzheimer/tratamiento farmacológico , Femenino , Masculino , Anciano , Pruebas de Estado Mental y Demencia/estadística & datos numéricos , Anciano de 80 o más Años , Encuestas y Cuestionarios , Progresión de la Enfermedad , Pruebas Neuropsicológicas/estadística & datos numéricos , Disfunción Cognitiva/diagnóstico
5.
Alzheimers Res Ther ; 16(1): 115, 2024 05 23.
Artículo en Inglés | MEDLINE | ID: mdl-38778353

RESUMEN

BACKGROUND: Maximizing the efficiency to screen amyloid-positive individuals in asymptomatic and non-demented aged population using blood-based biomarkers is essential for future success of clinical trials in the early stage of Alzheimer's disease (AD). In this study, we elucidate the utility of combination of plasma amyloid-ß (Aß)-related biomarkers and tau phosphorylated at threonine 217 (p-tau217) to predict abnormal Aß-positron emission tomography (PET) in the preclinical and prodromal AD. METHODS: We designed the cross-sectional study including two ethnically distinct cohorts, the Japanese trial-ready cohort for preclinica and prodromal AD (J-TRC) and the Swedish BioFINDER study. J-TRC included 474 non-demented individuals (CDR 0: 331, CDR 0.5: 143). Participants underwent plasma Aß and p-tau217 assessments, and Aß-PET imaging. Findings in J-TRC were replicated in the BioFINDER cohort including 177 participants (cognitively unimpaired: 114, mild cognitive impairment: 63). In both cohorts, plasma Aß(1-42) (Aß42) and Aß(1-40) (Aß40) were measured using immunoprecipitation-MALDI TOF mass spectrometry (Shimadzu), and p-tau217 was measured with an immunoassay on the Meso Scale Discovery platform (Eli Lilly). RESULTS: Aß-PET was abnormal in 81 participants from J-TRC and 71 participants from BioFINDER. Plasma Aß42/Aß40 ratio and p-tau217 individually showed moderate to high accuracies when detecting abnormal Aß-PET scans, which were improved by combining plasma biomarkers and by including age, sex and APOE genotype in the models. In J-TRC, the highest AUCs were observed for the models combining p-tau217/Aß42 ratio, APOE, age, sex in the whole cohort (AUC = 0.936), combining p-tau217, Aß42/Aß40 ratio, APOE, age, sex in the CDR 0 group (AUC = 0.948), and combining p-tau217/Aß42 ratio, APOE, age, sex in the CDR 0.5 group (AUC = 0.955), respectively. Each subgroup results were replicated in BioFINDER, where the highest AUCs were seen for models combining p-tau217, Aß42/40 ratio, APOE, age, sex in cognitively unimpaired (AUC = 0.938), and p-tau217/Aß42 ratio, APOE, age, sex in mild cognitive impairment (AUC = 0.914). CONCLUSIONS: Combination of plasma Aß-related biomarkers and p-tau217 exhibits high performance when predicting Aß-PET positivity. Adding basic clinical information (i.e., age, sex, APOE Îµ genotype) improved the prediction in preclinical AD, but not in prodromal AD. Combination of Aß-related biomarkers and p-tau217 could be highly useful for pre-screening of participants in clinical trials of preclinical and prodromal AD.


Asunto(s)
Péptidos beta-Amiloides , Biomarcadores , Encéfalo , Tomografía de Emisión de Positrones , Proteínas tau , Humanos , Péptidos beta-Amiloides/sangre , Péptidos beta-Amiloides/metabolismo , Femenino , Masculino , Proteínas tau/sangre , Anciano , Tomografía de Emisión de Positrones/métodos , Biomarcadores/sangre , Estudios Transversales , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Anciano de 80 o más Años , Estudios de Cohortes , Fosforilación , Persona de Mediana Edad , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/diagnóstico , Fragmentos de Péptidos/sangre , Disfunción Cognitiva/sangre , Disfunción Cognitiva/diagnóstico por imagen , Disfunción Cognitiva/diagnóstico
6.
JAMA Neurol ; 81(6): 582-593, 2024 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-38683602

RESUMEN

Importance: Effects of antiamyloid agents, targeting either fibrillar or soluble monomeric amyloid peptides, on downstream biomarkers in cerebrospinal fluid (CSF) and plasma are largely unknown in dominantly inherited Alzheimer disease (DIAD). Objective: To investigate longitudinal biomarker changes of synaptic dysfunction, neuroinflammation, and neurodegeneration in individuals with DIAD who are receiving antiamyloid treatment. Design, Setting, and Participants: From 2012 to 2019, the Dominantly Inherited Alzheimer Network Trial Unit (DIAN-TU-001) study, a double-blind, placebo-controlled, randomized clinical trial, investigated gantenerumab and solanezumab in DIAD. Carriers of gene variants were assigned 3:1 to either drug or placebo. The present analysis was conducted from April to June 2023. DIAN-TU-001 spans 25 study sites in 7 countries. Biofluids and neuroimaging from carriers of DIAD gene variants in the gantenerumab, solanezumab, and placebo groups were analyzed. Interventions: In 2016, initial dosing of gantenerumab, 225 mg (subcutaneously every 4 weeks) was increased every 8 weeks up to 1200 mg. In 2017, initial dosing of solanezumab, 400 mg (intravenously every 4 weeks) was increased up to 1600 mg every 4 weeks. Main Outcomes and Measures: Longitudinal changes in CSF levels of neurogranin, soluble triggering receptor expressed on myeloid cells 2 (sTREM2), chitinase 3-like 1 protein (YKL-40), glial fibrillary acidic protein (GFAP), neurofilament light protein (NfL), and plasma levels of GFAP and NfL. Results: Of 236 eligible participants screened, 43 were excluded. A total of 142 participants (mean [SD] age, 44 [10] years; 72 female [51%]) were included in the study (gantenerumab, 52 [37%]; solanezumab, 50 [35%]; placebo, 40 [28%]). Relative to placebo, gantenerumab significantly reduced CSF neurogranin level at year 4 (mean [SD] ß = -242.43 [48.04] pg/mL; P < .001); reduced plasma GFAP level at year 1 (mean [SD] ß = -0.02 [0.01] ng/mL; P = .02), year 2 (mean [SD] ß = -0.03 [0.01] ng/mL; P = .002), and year 4 (mean [SD] ß = -0.06 [0.02] ng/mL; P < .001); and increased CSF sTREM2 level at year 2 (mean [SD] ß = 1.12 [0.43] ng/mL; P = .01) and year 4 (mean [SD] ß = 1.06 [0.52] ng/mL; P = .04). Solanezumab significantly increased CSF NfL (log) at year 4 (mean [SD] ß = 0.14 [0.06]; P = .02). Correlation analysis for rates of change found stronger correlations between CSF markers and fluid markers with Pittsburgh compound B positron emission tomography for solanezumab and placebo. Conclusions and Relevance: This randomized clinical trial supports the importance of fibrillar amyloid reduction in multiple AD-related processes of neuroinflammation and neurodegeneration in CSF and plasma in DIAD. Additional studies of antiaggregated amyloid therapies in sporadic AD and DIAD are needed to determine the utility of nonamyloid biomarkers in determining disease modification. Trial Registration: ClinicalTrials.gov Identifier: NCT04623242.


Asunto(s)
Enfermedad de Alzheimer , Anticuerpos Monoclonales Humanizados , Biomarcadores , Humanos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Femenino , Masculino , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/líquido cefalorraquídeo , Enfermedad de Alzheimer/sangre , Método Doble Ciego , Persona de Mediana Edad , Biomarcadores/líquido cefalorraquídeo , Biomarcadores/sangre , Adulto , Péptidos beta-Amiloides/líquido cefalorraquídeo , Proteína 1 Similar a Quitinasa-3/sangre , Proteína 1 Similar a Quitinasa-3/líquido cefalorraquídeo , Anciano , Proteínas de Neurofilamentos/líquido cefalorraquídeo , Proteínas de Neurofilamentos/sangre
7.
Cancer Cell Int ; 24(1): 107, 2024 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-38486225

RESUMEN

BACKGROUND: A higher number of tumor buds in the invasive front of colorectal cancer (CRC) specimens has been shown to contribute to a poor prognosis in CRC patients. Because macrophages (Mφs) have been demonstrated to alter the phenotype of cancer cells, we hypothesized that the phenotype of CRC cells in the tumor budding (TB) area might be changed by the interaction between CRC cells and Mφs. METHODS: We assessed the expression of topoisomerase 1 in CRC cells to estimate the acquisition of chemoresistance in CRC. To demonstrate the tumor-stromal interaction between CRC cells and Mφs, we assessed two histological findings, the number of Mφs per single CRC cell and the proximity between CRC cells and Mφs by histological spatial analysis using HALO software. RESULTS: The expression levels of topoisomerase 1 in CRC cells were decreased in deeper areas, especially in the TB area, compared to the surface area. Our histological spatial analysis revealed that 2.6 Mφs located within 60 µm of a single CRC cell were required to alter the phenotype of the CRC cell. Double-immunofluorescence staining revealed that higher Mφs were positive for interleukin-6 (IL-6) in the TB area and that AE1/AE3-positive CRC cells were also positive for phospho-STAT3 (pSTAT3) in the TB area; thus, the IL-6 receptor (IL-6R)/STAT3 signaling pathway in CRC cells was upregulated by IL-6 derived from neighboring Mφs. CONCLUSION: IL-6 secreted from the neighboring Mφs would alter the phenotype of CRC cells via IL-6R/STAT3 signaling pathway.

8.
Alzheimers Dement ; 20(4): 2698-2706, 2024 04.
Artículo en Inglés | MEDLINE | ID: mdl-38400532

RESUMEN

INTRODUCTION: Increasing evidence suggests that amyloid reduction could serve as a plausible surrogate endpoint for clinical and cognitive efficacy. The double-blind phase 3 DIAN-TU-001 trial tested clinical and cognitive declines with increasing doses of solanezumab or gantenerumab. METHODS: We used latent class (LC) analysis on data from the Dominantly Inherited Alzheimer Network Trials Unit 001 trial to test amyloid positron emission tomography (PET) reduction as a potential surrogate biomarker. RESULTS: LC analysis categorized participants into three classes: amyloid no change, amyloid reduction, and amyloid growth, based on longitudinal amyloid Pittsburgh compound B PET standardized uptake value ratio data. The amyloid-no-change class was at an earlier disease stage for amyloid amounts and dementia. Despite similar baseline characteristics, the amyloid-reduction class exhibited reductions in the annual decline rates compared to the amyloid-growth class across multiple biomarker, clinical, and cognitive outcomes. DISCUSSION: LC analysis indicates that amyloid reduction is associated with improved clinical outcomes and supports its use as a surrogate biomarker in clinical trials. HIGHLIGHTS: We used latent class (LC) analysis to test amyloid reduction as a surrogate biomarker. Despite similar baseline characteristics, the amyloid-reduction class exhibited remarkably better outcomes compared to the amyloid-growth class across multiple measures. LC analysis proves valuable in testing amyloid reduction as a surrogate biomarker in clinical trials lacking significant treatment effects.


Asunto(s)
Enfermedad de Alzheimer , Humanos , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/tratamiento farmacológico , Enfermedad de Alzheimer/genética , Amiloide , Péptidos beta-Amiloides , Proteínas Amiloidogénicas , Biomarcadores , Método Doble Ciego , Análisis de Clases Latentes , Tomografía de Emisión de Positrones/métodos
9.
J Gen Appl Microbiol ; 70(1)2024 Jul 20.
Artículo en Inglés | MEDLINE | ID: mdl-38233172

RESUMEN

We investigated the presence and functionality of the carbon storage regulator (Csr) system in Aeromonas salmonicida SWSY-1.411. CsrA, an RNA-binding protein, shared 89% amino acid sequence identity with Escherichia coli CsrA. CsrB/C sRNAs exhibited a typical stem-loop structure, with more GGA motifs, which bind CsrA, than E. coli. CsrD had limited sequence identity with E. coli CsrD; however, it contained the conserved GGDEF and EAL domains. Functional analysis in E. coli demonstrated that the Csr system of A. salmonicida influences glycogen biosynthesis, biofilm formation, motility, and stability of both CsrB and CsrC sRNAs. These findings suggest that in A. salmonicida, the Csr system affects phenotypes like its E. coli counterpart. In A. salmonicida, defects in csr homologs affected biofilm formation, motility, and chitinase production. However, glycogen accumulation and protease production were unaffected. The expression of flagellar-related genes and chitinase genes was suppressed in the csrA-deficient A. salmonicida. Northern blot analysis indicated the stabilization of CsrB and CsrC in the csrD-deficient A. salmonicida. Similar to that in E. coli, the Csr system in A. salmonicida comprises the RNA-binding protein CsrA, the sRNAs CsrB and CsrC, and the sRNA decay factor CsrD. This study underscores the conservation and functionality of the Csr system and raises questions about its regulatory targets and mechanisms in A. salmonicida.


Asunto(s)
Aeromonas salmonicida , Proteínas Bacterianas , Biopelículas , Escherichia coli , Regulación Bacteriana de la Expresión Génica , Estabilidad del ARN , ARN Bacteriano , Proteínas de Unión al ARN , Aeromonas salmonicida/genética , Aeromonas salmonicida/metabolismo , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Biopelículas/crecimiento & desarrollo , Escherichia coli/genética , Escherichia coli/metabolismo , Proteínas Bacterianas/genética , Proteínas Bacterianas/metabolismo , ARN Bacteriano/genética , Glucógeno/metabolismo , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Secuencia de Aminoácidos , Proteínas Represoras
10.
Nat Biomed Eng ; 8(2): 132-148, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37430157

RESUMEN

Engineering cells for adoptive therapy requires overcoming limitations in cell viability and, in the efficiency of transgene delivery, the duration of transgene expression and the stability of genomic integration. Here we report a gene-delivery system consisting of a Sleeping Beauty (SB) transposase encoded into a messenger RNA delivered by an adeno-associated virus (AAV) encoding an SB transposon that includes the desired transgene, for mediating the permanent integration of the transgene. Compared with lentiviral vectors and with the electroporation of plasmids of transposon DNA or minicircle DNA, the gene-delivery system, which we named MAJESTIC (for 'mRNA AAV-SB joint engineering of stable therapeutic immune cells'), offers prolonged transgene expression, as well as higher transgene expression, therapeutic-cell yield and cell viability. MAJESTIC can deliver chimeric antigen receptors (CARs) into T cells (which we show lead to strong anti-tumour activity in vivo) and also transduce natural killer cells, myeloid cells and induced pluripotent stem cells with bi-specific CARs, kill-switch CARs and synthetic T-cell receptors.


Asunto(s)
Dependovirus , Transposasas , Transposasas/genética , Transposasas/metabolismo , Dependovirus/genética , Elementos Transponibles de ADN/genética , ARN Mensajero/genética , Técnicas de Transferencia de Gen
11.
Rinsho Shinkeigaku ; 63(10): 661-664, 2023 Oct 25.
Artículo en Japonés | MEDLINE | ID: mdl-37779022

RESUMEN

Tuberculous meningitis (TBM) is a central nervous system infection with a high mortality rate and requires early diagnosis and treatment. Identification of Mycobacterium tuberculosis in the cerebrospinal fluid is of primary importance in the diagnosis of TBM, however, conventional methods have some disadvantages: Rapid results tests such as smear and regular PCR method do not have sufficient diagnostic sensitivity; Nested PCR, which is one of the most sensitive tests, is not available in all facilities; Culture tests require a long period of 4-8 weeks for results. Here we report a case of TBM, diagnosed 14 days earlier than culture test by direct Loop-Mediated Isothermal Amplification (LAMP) method using centrifuged medium of cerebrospinal fluid (day 18) culture. The method we used here is simple, widely available, and considered to be useful for early detection of TBM.


Asunto(s)
Mycobacterium tuberculosis , Tuberculosis Meníngea , Humanos , Tuberculosis Meníngea/diagnóstico , Sensibilidad y Especificidad , Mycobacterium tuberculosis/genética , Técnicas de Amplificación de Ácido Nucleico/métodos , Líquido Cefalorraquídeo/microbiología
12.
Breast Cancer ; 30(6): 1094-1104, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37792212

RESUMEN

BACKGROUND: Programmed death-ligand 1 (PD-L1) plays important roles in the evasion of antitumor immunity. Because we observed the localization of PD-L1-positive (PD-L1+) cells in the marginal region of triple-negative breast cancer (TNBC) specimens, we hypothesized that the marginal microenvironment of TNBC would involve the induction of PD-L1+ cells. METHODS: One hundred and one TNBC surgical specimens were examined. We performed immunohistochemical (IHC) studies of PD-L1, CD68, CD8, and pan-cytokeratin in these specimens. We analyzed the localization of IHC-positive cells and the distance between these cells by histological spatial analysis. RESULTS: In 30.7% of TNBC specimens, PD-L1+ cells were located in the marginal region. Approximately three PD-L1+ cells accumulated around a single TNBC cell. Most PD-L1+ cells were located within 50 µm of TNBC cells. PD-L1+ cells were indicated to interact with TNBC cells in the marginal region. PD-L1+CD68+ cells were located in the marginal region, while CD68+ macrophages (MΦs) were observed either in the marginal region or the core region. PD-L1 expression in MΦs was induced in the marginal region. The colocalization of CD8+ T cells in the marginal region indicates that PD-L1 expression in MΦs would be induced by interaction with CD8+ T cells. Because CD8+ T cells are positive for CCL2, CCL2 may induce PD-L1 expression in MΦs. CONCLUSION: At the marginal microenvironment of TNBC, PD-L1 expression would be induced in MΦs by interaction with CD8+ T cells through CCL2. The interaction between PD-L1+ MΦs and TNBC cells would facilitate the growth of TNBC under antitumor immunity. These interactions would be potential targets for restoring antitumor immunity and suppressing TNBC progression.


Asunto(s)
Antígeno B7-H1 , Neoplasias de la Mama Triple Negativas , Humanos , Pronóstico , Antígeno B7-H1/metabolismo , Neoplasias de la Mama Triple Negativas/patología , Linfocitos T CD8-positivos/metabolismo , Macrófagos/metabolismo , Macrófagos/patología , Microambiente Tumoral
13.
Nat Immunol ; 24(9): 1499-1510, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37500885

RESUMEN

Chimeric antigen receptor (CAR)-T cells are powerful therapeutics; however, their efficacy is often hindered by critical hurdles. Here utilizing the endocytic feature of the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) cytoplasmic tail, we reprogram CAR function and substantially enhance CAR-T efficacy in vivo. CAR-T cells with monomeric, duplex or triplex CTLA-4 cytoplasmic tails (CCTs) fused to the C terminus of CAR exhibit a progressive increase in cytotoxicity under repeated stimulation, accompanied by reduced activation and production of proinflammatory cytokines. Further characterization reveals that CARs with increasing CCT fusion show a progressively lower surface expression, regulated by their constant endocytosis, recycling and degradation under steady state. The molecular dynamics of reengineered CAR with CCT fusion results in reduced CAR-mediated trogocytosis, loss of tumor antigen and improved CAR-T survival. CARs with either monomeric (CAR-1CCT) or duplex CCTs (CAR-2CCT) have superior antitumor efficacy in a relapsed leukemia model. Single-cell RNA sequencing and flow cytometry analysis reveal that CAR-2CCT cells retain a stronger central memory phenotype and exhibit increased persistence. These findings illuminate a unique strategy for engineering therapeutic T cells and improving CAR-T function through synthetic CCT fusion, which is orthogonal to other cell engineering techniques.


Asunto(s)
Receptores Quiméricos de Antígenos , Receptores Quiméricos de Antígenos/genética , Receptores Quiméricos de Antígenos/metabolismo , Antígeno CTLA-4/genética , Inmunoterapia Adoptiva/métodos , Linfocitos T , Citocinas/metabolismo , Abatacept , Receptores de Antígenos de Linfocitos T/genética , Línea Celular Tumoral
15.
bioRxiv ; 2023 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-36993364

RESUMEN

Chimeric antigen receptor (CAR) T cells are powerful therapeutics; however, their efficacy is often hindered by critical hurdles. Here, utilizing the endocytic feature of the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) cytoplasmic tail (CT), we reprogram CAR function and substantially enhance CAR-T efficacy in vivo . CAR-T cells with monomeric, duplex, or triplex CTLA-4 CTs (CCTs) fused to the C-terminus of CAR exhibit a progressive increase in cytotoxicity under repeated stimulation, accompanied by reduced activation and production of pro-inflammatory cytokines. Further characterization reveals that CARs with increasing CCT fusion show a progressively lower surface expression, regulated by their constant endocytosis, recycling and degradation under steady state. The molecular dynamics of reengineered CAR with CCT fusion results in reduced CAR-mediated trogocytosis, loss of tumor antigen, and improved CAR-T survival. CARs with either monomeric (CAR-1CCT) or duplex CCTs (CAR-2CCT) have superior anti-tumor efficacy in a relapsed leukemia model. Single-cell RNA sequencing and flow cytometry analysis reveal that CAR-2CCT cells retain a stronger central memory phenotype and exhibit increased persistence. These findings illuminate a unique strategy for engineering therapeutic T cells and improving CAR-T function through synthetic CCT fusion, which is orthogonal to other cell engineering techniques.

16.
bioRxiv ; 2023 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-36993594

RESUMEN

Adoptive cell therapy has shown clinical success in patients with hematological malignancies. Immune cell engineering is critical for production, research, and development of cell therapy; however, current approaches for generation of therapeutic immune cells face various limitations. Here, we establish a composite gene delivery system for the highly efficient engineering of therapeutic immune cells. This system, termed MAJESTIC ( m RNA A AV-Sleeping-Beauty J oint E ngineering of S table T herapeutic I mmune C ells), combines the merits of mRNA, AAV vector, and transposon into one composite system. In MAJESTIC, the transient mRNA component encodes a transposase that mediates permanent genomic integration of the Sleeping Beauty (SB) transposon, which carries the gene-of-interest and is embedded within the AAV vector. This system can transduce diverse immune cell types with low cellular toxicity and achieve highly efficient and stable therapeutic cargo delivery. Compared with conventional gene delivery systems, such as lentiviral vector, DNA transposon plasmid, or minicircle electroporation, MAJESTIC shows higher cell viability, chimeric antigen receptor (CAR) transgene expression, therapeutic cell yield, as well as prolonged transgene expression. CAR-T cells generated by MAJESTIC are functional and have strong anti-tumor activity in vivo . This system also demonstrates versatility for engineering different cell therapy constructs such as canonical CAR, bi-specific CAR, kill switch CAR, and synthetic TCR; and for CAR delivery into various immune cells, including T cells, natural killer cells, myeloid cells, and induced pluripotent stem cells.

17.
bioRxiv ; 2023 Mar 14.
Artículo en Inglés | MEDLINE | ID: mdl-36993642

RESUMEN

Cas9 transgenic animals have drastically accelerated the discovery of novel immune modulators. But due to its inability to process its own CRISPR RNAs (crRNAs), simultaneous multiplexed gene perturbations using Cas9 remains limited, especially by pseudoviral vectors. Cas12a/Cpf1, however, can process concatenated crRNA arrays for this purpose. Here, we created conditional and constitutive LbCas12a knock-in transgenic mice. With these mice, we demonstrated efficient multiplexed gene editing and surface protein knockdown within individual primary immune cells. We showed genome editing across multiple types of primary immune cells including CD4 and CD8 T cells, B cells, and bone-marrow derived dendritic cells. These transgenic animals, along with the accompanying viral vectors, together provide a versatile toolkit for a broad range of ex vivo and in vivo gene editing applications, including fundamental immunological discovery and immune gene engineering.

19.
Cell Chem Biol ; 30(1): 85-96.e6, 2023 01 19.
Artículo en Inglés | MEDLINE | ID: mdl-36640761

RESUMEN

As a clinical vaccine, lipid nanoparticle (LNP) mRNA has demonstrated potent and broad antibody responses, leading to speculation about its potential for antibody discovery. Here, we developed RAMIHM, a highly efficient strategy for developing fully human monoclonal antibodies that employs rapid mRNA immunization of humanized mice followed by single B cell sequencing (scBCR-seq). We immunized humanized transgenic mice with RAMIHM and generated 15 top-ranked clones from peripheral blood, plasma B, and memory B cell populations, demonstrating a high rate of antigen-specificity (93.3%). Two Omicron-specific neutralizing antibodies with high potency and one broad-spectrum neutralizing antibody were discovered. Furthermore, we extended the application of RAMIHM to cancer immunotherapy targets, including a single transmembrane protein CD22 and a multi-transmembrane G protein-coupled receptor target, GPRC5D, which is difficult for traditional protein immunization methods. RAMIHM-scBCR-seq is a broadly applicable platform for the rapid and efficient development of fully human monoclonal antibodies against an assortment of targets.


Asunto(s)
Anticuerpos Monoclonales , Inmunización , Ratones , Humanos , Animales , Anticuerpos Monoclonales/genética , ARN Mensajero/genética , Vacunación , Anticuerpos Neutralizantes/genética , Ratones Transgénicos
20.
Alzheimers Dement ; 19(7): 2923-2932, 2023 07.
Artículo en Inglés | MEDLINE | ID: mdl-36640138

RESUMEN

BACKGROUND: Comparisons of late-onset Alzheimer's disease (LOAD) and autosomal dominant AD (ADAD) are confounded by age. METHODS: We compared biomarkers from cerebrospinal fluid (CSF), magnetic resonance imaging, and amyloid imaging with Pittsburgh Compound-B (PiB) across four groups of 387 cognitively normal participants, 42 to 65 years of age, in the Dominantly Inherited Alzheimer Network (DIAN) and the Adult Children Study (ACS) of LOAD: DIAN mutation carriers (MCs) and non-carriers (NON-MCs), and ACS participants with a positive (FH+) and negative (FH-) family history of LOAD. RESULTS: At baseline, MCs had the lowest age-adjusted level of CSF Aß42 and the highest levels of total and phosphorylated tau-181, and PiB uptake. Longitudinally, MC had similar increase in PiB uptake to FH+, but drastically faster decline in hippocampal volume than others, and was the only group showing cognitive decline. DISCUSSION: Preclinical ADAD and LOAD share many biomarker signatures, but cross-sectional and longitudinal differences may exist.


Asunto(s)
Enfermedad de Alzheimer , Adulto , Humanos , Persona de Mediana Edad , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/líquido cefalorraquídeo , Péptidos beta-Amiloides/líquido cefalorraquídeo , Biomarcadores/líquido cefalorraquídeo , Cognición , Estudios Transversales , Padres , Tomografía de Emisión de Positrones
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