RESUMEN
Whether cancer is maintained by a small number of stem cells or is composed of proliferating cells with approximate phenotypic equivalency is a central question in cancer biology. In the stem cell hypothesis, relapse after treatment may occur by failure to eradicate cancer stem cells. Chronic myeloid leukaemia (CML) is quintessential to this hypothesis. CML is a myeloproliferative disorder that results from dysregulated tyrosine kinase activity of the fusion oncoprotein BCR-ABL. During the chronic phase, this sole genetic abnormality (chromosomal translocation Ph(+): t(9;22)(q34;q11)) at the stem cell level causes increased proliferation of myeloid cells without loss of their capacity to differentiate. Without treatment, most patients progress to the blast phase when additional oncogenic mutations result in a fatal acute leukaemia made of proliferating immature cells. Imatinib mesylate and other tyrosine kinase inhibitors (TKIs) that target the kinase activity of BCR-ABL have improved patient survival markedly. However, fewer than 10% of patients reach the stage of complete molecular response (CMR), defined as the point when BCR-ABL transcripts become undetectable in blood cells. Failure to reach CMR results from the inability of TKIs to eradicate quiescent CML leukaemia stem cells (LSCs). Here we show that the residual CML LSC pool can be gradually purged by the glitazones, antidiabetic drugs that are agonists of peroxisome proliferator-activated receptor-γ (PPARγ). We found that activation of PPARγ by the glitazones decreases expression of STAT5 and its downstream targets HIF2α and CITED2, which are key guardians of the quiescence and stemness of CML LSCs. When pioglitazone was given temporarily to three CML patients in chronic residual disease in spite of continuous treatment with imatinib, all of them achieved sustained CMR, up to 4.7 years after withdrawal of pioglitazone. This suggests that clinically relevant cancer eradication may become a generally attainable goal by combination therapy that erodes the cancer stem cell pool.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Benzamidas/administración & dosificación , Leucemia Mielógena Crónica BCR-ABL Positiva/tratamiento farmacológico , Leucemia Mielógena Crónica BCR-ABL Positiva/patología , Células Madre Neoplásicas/efectos de los fármacos , PPAR gamma/agonistas , Piperazinas/administración & dosificación , Pirimidinas/administración & dosificación , Tiazolidinedionas/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Benzamidas/farmacología , Benzamidas/uso terapéutico , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Humanos , Mesilato de Imatinib , Leucemia Mielógena Crónica BCR-ABL Positiva/genética , Leucemia Mielógena Crónica BCR-ABL Positiva/metabolismo , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , PPAR gamma/metabolismo , Pioglitazona , Piperazinas/farmacología , Piperazinas/uso terapéutico , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Proteínas Represoras/metabolismo , Factor de Transcripción STAT5/metabolismo , Tiazolidinedionas/farmacología , Tiazolidinedionas/uso terapéutico , Transactivadores/metabolismoRESUMEN
BACKGROUND: Angiotensin-converting enzyme 2 is the receptor that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses for entry into lung cells. Because ACE-2 may be modulated by angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs), there is concern that patients treated with ACEIs and ARBs are at higher risk of coronavirus disease 2019 (COVID-19) pneumonia. AIM: This study sought to analyze the association of COVID-19 pneumonia with previous treatment with ACEIs and ARBs. MATERIALS AND METHODS: We retrospectively reviewed 684 consecutive patients hospitalized for suspected COVID-19 pneumonia and tested by polymerase chain reaction assay. Patients were split into two groups, according to whether (group 1, n = 484) or not (group 2, n = 250) COVID-19 was confirmed. Multivariable adjusted comparisons included a propensity score analysis. RESULTS: The mean age was 63.6 ± 18.7 years, and 302 patients (44%) were female. Hypertension was present in 42.6% and 38.4% of patients in groups 1 and 2, respectively (P = 0.28). Treatment with ARBs was more frequent in group 1 than group 2 (20.7% vs. 12.0%, respectively; odds ratio [OR] 1.92, 95% confidence interval [CI] 1.23-2.98; P = 0.004). No difference was found for treatment with ACEIs (12.7% vs. 15.7%, respectively; OR 0.81, 95% CI 0.52-1.26; P = 0.35). Propensity score-matched multivariable logistic regression confirmed a significant association between COVID-19 and previous treatment with ARBs (adjusted OR 2.36, 95% CI 1.38-4.04; P = 0.002). Significant interaction between ARBs and ACEIs for the risk of COVID-19 was observed in patients aged > 60 years, women, and hypertensive patients. CONCLUSIONS: This study suggests that ACEIs and ARBs are not similarly associated with COVID-19. In this retrospective series, patients with COVID-19 pneumonia more frequently had previous treatment with ARBs compared with patients without COVID-19.
Asunto(s)
Bloqueadores del Receptor Tipo 2 de Angiotensina II/efectos adversos , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , COVID-19/complicaciones , Neumonía/complicaciones , Adulto , Anciano , Anciano de 80 o más Años , Bloqueadores del Receptor Tipo 2 de Angiotensina II/uso terapéutico , COVID-19/diagnóstico , Femenino , Humanos , Hipertensión/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Neumonía/diagnóstico , Estudios Retrospectivos , Factores de RiesgoRESUMEN
The antigenic peptides processed by ß-cells and presented through surface HLA class I molecules are poorly characterized. Each HLA variant (e.g., the most common being HLA-A2 and HLA-A3) carries some peptide-binding specificity. Hence, features that, despite these specificities, remain shared across variants may reveal factors favoring ß-cell immunogenicity. Building on our previous description of the HLA-A2/A3 peptidome of ß-cells, we analyzed the HLA-A3-restricted peptides targeted by circulating CD8+ T cells. Several peptides were recognized by CD8+ T cells within a narrow frequency (1-50/106), which was similar in donors with and without type 1 diabetes and harbored variable effector/memory fractions. These epitopes could be classified as conventional peptides or neoepitopes, generated either via peptide cis-splicing or mRNA splicing (e.g., secretogranin-5 [SCG5]-009). As reported for HLA-A2-restricted peptides, several epitopes originated from ß-cell granule proteins (e.g., SCG3, SCG5, and urocortin-3). Similarly, H-2Kd-restricted CD8+ T cells recognizing the murine orthologs of SCG5, urocortin-3, and proconvertase-2 infiltrated the islets of NOD mice and transferred diabetes into NOD/scid recipients. The finding of granule proteins targeted in both humans and NOD mice supports their disease relevance and identifies the insulin granule as a rich source of epitopes, possibly reflecting its impaired processing in type 1 diabetes.
Asunto(s)
Cromograninas/metabolismo , Diabetes Mellitus Tipo 1/metabolismo , Adulto , Empalme Alternativo , Animales , Linfocitos T CD8-positivos , Estudios de Casos y Controles , Cromograninas/genética , Simulación por Computador , Minería de Datos , Diabetes Mellitus Tipo 1/genética , Epítopos , Femenino , Regulación de la Expresión Génica , Antígeno HLA-A3 , Humanos , Insulina , Masculino , Ratones , Ratones Endogámicos NOD , Proteína 7B2 Secretora Neuroendocrina/genética , Proteína 7B2 Secretora Neuroendocrina/metabolismo , Unión Proteica , ARN Mensajero/genética , Urocortinas/genética , Urocortinas/metabolismo , Adulto JovenRESUMEN
Although CD8+ T-cell-mediated autoimmune ß cell destruction occurs in type 1 diabetes (T1D), the target epitopes processed and presented by ß cells are unknown. To identify them, we combined peptidomics and transcriptomics strategies. Inflammatory cytokines increased peptide presentation in vitro, paralleling upregulation of human leukocyte antigen (HLA) class I expression. Peptide sources featured several insulin granule proteins and all known ß cell antigens, barring islet-specific glucose-6-phosphatase catalytic subunit-related protein. Preproinsulin yielded HLA-A2-restricted epitopes previously described. Secretogranin V and its mRNA splice isoform SCG5-009, proconvertase-2, urocortin-3, the insulin gene enhancer protein ISL-1, and an islet amyloid polypeptide transpeptidation product emerged as antigens processed into HLA-A2-restricted epitopes, which, as those already described, were recognized by circulating naive CD8+ T cells in T1D and healthy donors and by pancreas-infiltrating cells in T1D donors. This peptidome opens new avenues to understand antigen processing by ß cells and for the development of T cell biomarkers and tolerogenic vaccination strategies.
Asunto(s)
Presentación de Antígeno , Linfocitos T CD8-positivos/inmunología , Diabetes Mellitus Tipo 1/inmunología , Epítopos de Linfocito T/inmunología , Transcriptoma/inmunología , Animales , Biomarcadores/metabolismo , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/metabolismo , Estudios de Casos y Controles , Línea Celular , Hormona Liberadora de Corticotropina/metabolismo , Citocinas/metabolismo , Antígenos HLA/metabolismo , Humanos , Insulina/metabolismo , Polipéptido Amiloide de los Islotes Pancreáticos/metabolismo , Ratones , Proteína 7B2 Secretora Neuroendocrina/metabolismo , Proproteína Convertasa 2/metabolismo , Precursores de Proteínas/metabolismo , Proteómica/métodos , Urocortinas/metabolismoRESUMEN
The human leukocyte antigen-A2 (HLA-A2)-restricted zinc transporter 8186-194 (ZnT8186-194) and other islet epitopes elicit interferon-γ secretion by CD8+ T cells preferentially in type 1 diabetes (T1D) patients compared with controls. We show that clonal ZnT8186-194-reactive CD8+ T cells express private T cell receptors and display equivalent functional properties in T1D and healthy individuals. Ex vivo analyses further revealed that CD8+ T cells reactive to ZnT8186-194 and other islet epitopes circulate at similar frequencies and exhibit a predominantly naïve phenotype in age-matched T1D and healthy donors. Higher frequencies of ZnT8186-194-reactive CD8+ T cells with a more antigen-experienced phenotype were detected in children versus adults, irrespective of disease status. Moreover, some ZnT8186-194-reactive CD8+ T cell clonotypes were found to cross-recognize a Bacteroides stercoris mimotope. Whereas ZnT8 was poorly expressed in thymic medullary epithelial cells, variable thymic expression levels of islet antigens did not modulate the peripheral frequency of their cognate CD8+ T cells. In contrast, ZnT8186-194-reactive cells were enriched in the pancreata of T1D patients versus nondiabetic and type 2 diabetic individuals. Thus, islet-reactive CD8+ T cells circulate in most individuals but home to the pancreas preferentially in T1D patients. We conclude that the activation of this common islet-reactive T cell repertoire and progression to T1D likely require defective peripheral immunoregulation and/or a proinflammatory islet microenvironment.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Diabetes Mellitus Tipo 1/inmunología , Islotes Pancreáticos/inmunología , Páncreas/citología , Páncreas/inmunología , Adulto , Línea Celular , Niño , Femenino , Antígeno HLA-A2/inmunología , Voluntarios Sanos , Humanos , MasculinoRESUMEN
The rare association of Cushing's syndrome and pregnancy is explained by the amenorrhea and sterility inherent to the syndrome. In the literature, 125 cases have been reported: 30 cases of early diagnosis and 95 others diagnosed in the second half of pregnancy. AT THE START OF PREGNANCY: When hypercorticism exists before pregnancy it is hardly secretory. Its diagnosis, at an early stage, is not hindered by the hormone modifications of pregnancy. Its aetiological treatment raises the problem of the compatibility in pursuing the latter. IN THE SECOND HALF OF PREGNANCY: The positive and aetiological diagnoses of Cushing's syndrome are difficult and its prevalence may therefore be underestimated. The evocative clinical signs are unspecific: excessive weight gain, hypertension of pregnancy and gestational diabetes. The 24-hour free hypercortisoluria and the absence of dexamethasone inhibition are of little diagnostic value after the 14th week of amenorrhea. The positive diagnosis therefore relies essentially on the abolition of the circadian rhythm of cortisol. The biological hyperandrogenia commonly observed is not discriminating. Adrenal aetiologies are frequent. Imaging must be performed to eliminate an adrenocortical tumor. PROGNOSIS: The maternal prognosis depends on the hypertension, preeclampsia, diabetes and the complications of Cushing's syndrome. It depends on the activity of the hypercorticism and its early aetiological treatment, which must not be delayed after pregnancy. The foetal prognosis depends on the maternal prognosis. It is represented by preterm delivery, hypotrophy and death of the foetus in utero. The therapeutic management must be symptomatic and aetiologic, maternal and obstetrical.
Asunto(s)
Síndrome de Cushing , Complicaciones del Embarazo , Neoplasias de la Corteza Suprarrenal/sangre , Neoplasias de la Corteza Suprarrenal/diagnóstico , Adulto , Antiinflamatorios/uso terapéutico , Antimetabolitos/uso terapéutico , Síndrome de Cushing/sangre , Síndrome de Cushing/diagnóstico , Síndrome de Cushing/tratamiento farmacológico , Dexametasona/uso terapéutico , Femenino , Enfermedades Fetales/etiología , Humanos , Hidrocortisona/sangre , Recién Nacido , Luteoma/sangre , Luteoma/diagnóstico , Metirapona/uso terapéutico , Trabajo de Parto Prematuro/etiología , Neoplasias Ováricas/sangre , Neoplasias Ováricas/diagnóstico , Embarazo , Complicaciones del Embarazo/sangre , Complicaciones del Embarazo/diagnóstico , Complicaciones del Embarazo/tratamiento farmacológico , Pronóstico , Factores de Riesgo , Testosterona/sangreRESUMEN
There are many similarities between mycobacteriosis, in particular, tuberculosis, and sarcoidosis such as predominant intrathoracic localisation (even if all organs and tissues may be concerned), great variability of phenotypic expression, and granulomatous inflammatory reaction, caseous necrosis not being an absolute criterion of tuberculosis. Moreover, microbial (or mycobacterial?) agents may play a role in the pathogenesis of sarcoidosis which remains a diagnosis of exclusion particularly in atypical cases. The authors report a case of a non-immunocompromised female patient who presented, simultaneously, isolated axillary tubercular adenitis and neuro-sarcoidosis without any other localisation. This case illustrates the difficulty to distinguish between both of these two diseases and thus to choose an adequate treatment when diagnosis is not proven. Moreover, our patient (human leucocyte antigen B27 positive) presented symptoms of spondylarthritis which also may have a nosological link with tuberculosis or sarcoidosis.