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1.
Front Immunol ; 14: 1332733, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38385142

RESUMEN

Tuberculosis (TB) and sarcoidosis are both granulomatous diseases. Here, we compared the immunological microenvironments of granulomas from TB and sarcoidosis patients using in situ sequencing (ISS) transcriptomic analysis and multiplexed immunolabeling of tissue sections. TB lesions consisted of large necrotic and cellular granulomas, whereas "multifocal" granulomas with macrophages or epitheloid cell core and a T-cell rim were observed in sarcoidosis samples. The necrotic core in TB lesions was surrounded by macrophages and encircled by a dense T-cell layer. Within the T-cell layer, compact B-cell aggregates were observed in most TB samples. These B-cell clusters were vascularized and could contain defined B-/T-cell and macrophage-rich areas. The ISS of 40-60 immune transcripts revealed the enriched expression of transcripts involved in homing or migration to lymph nodes, which formed networks at single-cell distances in lymphoid areas of the TB lesions. Instead, myeloid-annotated regions were enriched in CD68, CD14, ITGAM, ITGAX, and CD4 mRNA. CXCL8 and IL1B mRNA were observed in granulocytic areas in which M. tuberculosis was also detected. In line with ISS data indicating tertiary lymphoid structures, immune labeling of TB sections expressed markers of high endothelial venules, follicular dendritic cells, follicular helper T cells, and lymph-node homing receptors on T cells. Neither ISS nor immunolabeling showed evidence of tertiary lymphoid aggregates in sarcoidosis samples. Together, our finding suggests that despite their heterogeneity, the formation of tertiary immune structures is a common feature in granulomas from TB patients.


Asunto(s)
Mycobacterium tuberculosis , Sarcoidosis Pulmonar , Sarcoidosis , Tuberculosis , Humanos , Granuloma , Sarcoidosis Pulmonar/genética , Sarcoidosis Pulmonar/patología , Pulmón/patología , ARN Mensajero
2.
Eur Respir Rev ; 30(160)2021 Jun 30.
Artículo en Inglés | MEDLINE | ID: mdl-34039674

RESUMEN

Standardised management of tuberculosis may soon be replaced by individualised, precision medicine-guided therapies informed with knowledge provided by the field of systems biology. Systems biology is a rapidly expanding field of computational and mathematical analysis and modelling of complex biological systems that can provide insights into mechanisms underlying tuberculosis, identify novel biomarkers, and help to optimise prevention, diagnosis and treatment of disease. These advances are critically important in the context of the evolving epidemic of drug-resistant tuberculosis. Here, we review the available evidence on the role of systems biology approaches - human and mycobacterial genomics and transcriptomics, proteomics, lipidomics/metabolomics, immunophenotyping, systems pharmacology and gut microbiomes - in the management of tuberculosis including prediction of risk for disease progression, severity of mycobacterial virulence and drug resistance, adverse events, comorbidities, response to therapy and treatment outcomes. Application of the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach demonstrated that at present most of the studies provide "very low" certainty of evidence for answering clinically relevant questions. Further studies in large prospective cohorts of patients, including randomised clinical trials, are necessary to assess the applicability of the findings in tuberculosis prevention and more efficient clinical management of patients.


Asunto(s)
Biología de Sistemas , Tuberculosis , Genómica , Humanos , Metabolómica , Estudios Prospectivos , Tuberculosis/diagnóstico , Tuberculosis/tratamiento farmacológico
3.
Radiat Oncol ; 15(1): 7, 2020 Jan 06.
Artículo en Inglés | MEDLINE | ID: mdl-31906998

RESUMEN

BACKGROUND: Definitive chemoradiotherapy (dCRT) is a standard treatment for patients with locally advanced head and neck cancer. There is a clinical need for a stratification of this prognostically heterogeneous group of tumors in order to optimize treatment of individual patients. We retrospectively reviewed all patients with head and neck squamous cell carcinoma (HNSCC) of the oral cavity, oropharynx, hypopharynx, or larynx, treated with dCRT from 09/2008 until 03/2016 at the Department of Radiation Oncology, LMU Munich. Here we report the clinical results of the cohort which represent the basis for biomarker discovery and molecular genetic research within the framework of a clinical cooperation group. METHODS: Patient data were collected and analyzed for outcome and treatment failures with regard to previously described and established risk factors. RESULTS: We identified 184 patients with a median follow-up of 65 months and a median age of 64 years. Patients received dCRT with a median dose of 70 Gy and simultaneous chemotherapy in 90.2% of cases, mostly mitomycin C / 5-FU in concordance with the ARO 95-06 trial. The actuarial 3-year overall survival (OS), local, locoregional and distant failure rates were 42.7, 29.8, 34.0 and 23.4%, respectively. Human papillomavirus-associated oropharynx cancer (HPVOPC) and smaller gross tumor volume were associated with significantly improved locoregional tumor control rate, disease-free survival (DFS) and OS in multivariate analysis. Additionally, lower hemoglobin levels were significantly associated with impaired DFS und OS in univariate analysis. The extent of lymph node involvement was associated with distant failure, DFS and OS. Moreover, 92 patients (50%) of our cohort have been treated in concordance with the ARO 95-06 study, corroborating the results of this study. CONCLUSION: Our cohort is a large unselected monocentric cohort of HNSCC patients treated with dCRT. Tumor control rates and survival rates compare favorably with the results of previously published reports. The clinical data, together with the available tumor samples from biopsies, will allow translational research based on molecular genetic analyses.


Asunto(s)
Quimioradioterapia , Neoplasias de Cabeza y Cuello/terapia , Carcinoma de Células Escamosas de Cabeza y Cuello/terapia , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Femenino , Neoplasias de Cabeza y Cuello/mortalidad , Neoplasias de Cabeza y Cuello/patología , Humanos , Masculino , Persona de Mediana Edad , Medicina de Precisión , Carcinoma de Células Escamosas de Cabeza y Cuello/mortalidad , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Carga Tumoral
4.
Sci Rep ; 9(1): 18134, 2019 12 02.
Artículo en Inglés | MEDLINE | ID: mdl-31792345

RESUMEN

The pathophysiology of malarial anemia is multifactorial and incompletely understood. We assessed mechanistic and risk factors for post-malarial anemia in Ghanaian and Gabonese children with severe P. falciparum malaria treated with parenteral artesunate followed by an oral artemisinin-combination therapy. We analyzed data from two independent studies in which children were followed on Days 7,14, and 28 after treatment with artesunate. Specific hematological parameters included the presence of hemoglobinopathies and erythropoietin. Presence of once-infected erythrocytes was assessed by flow cytometry in a sub-population. Of 143 children with a geometric mean parasitemia of 116,294/µL (95% CI: 95,574-141,505), 91 (88%) had anemia (Hb < 10 g/dL) at presentation. Hemoglobin increased after Day 7 correlating with increased erythropoiesis through adequate erythropoietin stimulation. 22 children (24%) remained anemic until Day 28. Post-artesunate delayed hemolysis was detected in 7 children (5%) with only minor differences in the dynamics of once-infected erythrocytes. Hyperparasitemia and hemoglobin at presentation were associated with anemia on Day 14. On Day 28 only lower hemoglobin at presentation was associated with anemia. Most children showed an adequate erythropoiesis and recovered from anemia within one month. Post-artesunate delayed hemolysis (PADH) and hyperparasitemia are associated with early malarial anemia and pre-existing anemia is the main determinant for prolonged anemia.


Asunto(s)
Anemia/inducido químicamente , Antimaláricos/efectos adversos , Artesunato/efectos adversos , Malaria/complicaciones , Malaria/tratamiento farmacológico , Anemia/terapia , Antimaláricos/administración & dosificación , Antimaláricos/uso terapéutico , Artesunato/administración & dosificación , Artesunato/uso terapéutico , Transfusión Sanguínea , Niño , Preescolar , Eritropoyetina/sangre , Femenino , Humanos , Lactante , Infusiones Parenterales , Masculino , Parasitemia/tratamiento farmacológico
5.
Am J Respir Cell Mol Biol ; 51(1): 155-62, 2014 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-24521348

RESUMEN

Pulmonary arterial hypertension (PAH) is characterized by adverse remodeling of pulmonary arteries. Although the origin of the disease and its underlying pathophysiology remain incompletely understood, inflammation has been identified as a central mediator of disease progression. Oxidative inflammatory conditions support the formation of electrophilic fatty acid nitroalkene derivatives, which exert potent anti-inflammatory effects. The current study investigated the role of 10-nitro-oleic acid (OA-NO2) in modulating the pathophysiology of PAH in mice. Mice were kept for 28 days under normoxic or hypoxic conditions, and OA-NO2 was infused subcutaneously. Right ventricular systolic pressure (RVPsys) was determined, and right ventricular and lung tissue was analyzed. The effect of OA-NO2 on cultured pulmonary artery smooth muscle cells (PASMCs) and macrophages was also investigated. Changes in RVPsys revealed increased pulmonary hypertension in mice on hypoxia, which was significantly decreased by OA-NO2 administration. Right ventricular hypertrophy and fibrosis were also attenuated by OA-NO2 treatment. The infiltration of macrophages and the generation of reactive oxygen species were elevated in lung tissue of mice on hypoxia and were diminished by OA-NO2 treatment. Moreover, OA-NO2 decreased superoxide production of activated macrophages and PASMCs in vitro. Vascular structural remodeling was also limited by OA-NO2. In support of these findings, proliferation and activation of extracellular signal-regulated kinases 1/2 in cultured PASMCs was less pronounced on application of OA-NO2.Our results show that the oleic acid nitroalkene derivative OA-NO2 attenuates hypoxia-induced pulmonary hypertension in mice. Thus, OA-NO2 represents a potential therapeutic agent for the treatment of PAH.


Asunto(s)
Modelos Animales de Enfermedad , Hipertensión Pulmonar/prevención & control , Hipertrofia Ventricular Derecha/prevención & control , Hipoxia/fisiopatología , Inflamación/prevención & control , Ácidos Oléicos/uso terapéutico , Animales , Western Blotting , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Cromatografía Líquida de Alta Presión , Quinasas MAP Reguladas por Señal Extracelular/genética , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Hipertensión Pulmonar Primaria Familiar , Hipertensión Pulmonar/etiología , Hipertensión Pulmonar/patología , Hipertrofia Ventricular Derecha/etiología , Hipertrofia Ventricular Derecha/patología , Inflamación/etiología , Inflamación/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Miocitos del Músculo Liso/patología , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Superóxidos/metabolismo
6.
Nucleic Acid Ther ; 23(1): 62-70, 2013 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-23308381

RESUMEN

To treat urethral strictures of the lower urinary tract, urethrotomy is the method of choice. But this minimally invasive method suffers from poor outcome rates and leads often to restenosis of the urinary tract because of hyper-proliferating fibroblasts. Our aim is to minimize the proliferation of excessive tissue due to a new minimal invasive therapeutic approach. As an appropriate model, we isolated fibroblasts from different benign prostatic hyperplasia patients and transfected them with small interfering RNA (siRNA) against the transcription factor serum response factor (SRF), a key factor for cell cycle regulation and apoptosis. The resulting knockdown of SRF was examined on the messenger RNA level by quantitative real-time polymerase chain reaction and on the protein level by western blot. The correlation of SRF silencing and impact on cell proliferation was examined by xCELLigence, 5-bromo-2'-deoxiuridine proliferation assay, total cell counts, and senescence assay. The transfection of primary prostatic fibroblasts with SRFsiRNA revealed specific and significant knockdown of SRF, leading to significant inhibition of proliferation after the second transfection, which was revealed by proliferation assay and total cell number. The results of this study indicate a substantial role of SRF in prostatic fibroblasts and we suggest that SRF silencing might be used for the treatment of urethral strictures to achieve a durably patent urethra.


Asunto(s)
Hiperplasia Prostática/terapia , ARN Interferente Pequeño/genética , ARN Interferente Pequeño/uso terapéutico , Factor de Respuesta Sérica/antagonistas & inhibidores , Proliferación Celular , Células Cultivadas , Fibroblastos/metabolismo , Fibroblastos/patología , Humanos , Masculino , Hiperplasia Prostática/genética , Hiperplasia Prostática/patología , ARN Mensajero/genética , ARN Mensajero/metabolismo , Factor de Respuesta Sérica/genética , Transfección
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