RESUMEN
Emerging evidence shows the crucial role of inflammation (particularly NF-κB pathway) in the development and progression of myelofibrosis (MF), becoming a promising therapeutic target. Furthermore, tailoring treatment with currently available JAK inhibitors (such as ruxolitinib or fedratinib) does not modify the natural history of the disease and has important limitations, including cytopenias. Since recent studies have highlighted the role of miR-146a, a negative regulator of the NF-κB pathway, in the pathogenesis of MF; here we used miR-146a-/- (KO) mice, a MF-like model lacking driver mutations, to investigate whether pharmacological inhibition of JAK/STAT and/or NF-κB pathways may reverse the myelofibrotic phenotype of these mice. Specifically, we tested the JAK1/2 inhibitor, ruxolitinib; the NF-κB inhibitor via IKKα/ß, BMS-345541; both inhibitors in combination; or a dual inhibitor of both pathways (JAK2/IRAK1), pacritinib. Although all treatments decreased spleen size and partially recovered its architecture, only NF-κB inhibition, either using BMS-345541 (alone or in combination) or pacritinib, resulted in a reduction of extramedullary hematopoiesis, bone marrow (BM) fibrosis and osteosclerosis, along with an attenuation of the exacerbated inflammatory state (via IL-1ß and TNFα). However, although dual inhibitor improved anemia and reversed thrombocytopenia, the combined therapy worsened anemia by inducing BM hypoplasia. Both therapeutic options reduced NF-κB and JAK/STAT signaling in a context of JAK2V617F-driven clonal hematopoiesis. Additionally, combined treatment reduced both COL1A1 and IL-6 production in an in vitro model mimicking JAK2-driven fibrosis. In conclusion, NF-κB inhibition reduces, in vitro and in vivo, disease burden and BM fibrosis, which could provide benefits in myelofibrosis patients.
Asunto(s)
Ratones Noqueados , MicroARNs , FN-kappa B , Nitrilos , Mielofibrosis Primaria , Pirazoles , Pirimidinas , Animales , Mielofibrosis Primaria/tratamiento farmacológico , Mielofibrosis Primaria/genética , MicroARNs/genética , Ratones , FN-kappa B/metabolismo , Nitrilos/uso terapéutico , Nitrilos/farmacología , Pirimidinas/uso terapéutico , Pirimidinas/farmacología , Pirazoles/uso terapéutico , Pirazoles/farmacología , Transducción de Señal/efectos de los fármacos , Modelos Animales de Enfermedad , Hematopoyesis Extramedular/efectos de los fármacosRESUMEN
Studies prior to next-generation sequencing (NGS) showed that the frequent indolent course of chronic lymphocytic leukaemia (CLL) is related to most cells remaining quiescent in the G0 -G1 cell cycle phase, due to the expression of dysregulated cyclin genes. Of note, the activating nature of the NOTCH1 mutation in T lymphoblastic leukaemia also drives the dysregulation of cell cycle genes. Our goal was to comprehensively revisit the cell cycle in NOTCH1-mutated CLL (NOTCH1MUT ) to test for potential therapeutic targets. Among 378 NGS-annotated CLL cases, NOTCH1MUT cells displayed a unique transcriptome profile of G0 -G1 cell cycle components, with an overexpression of early-phase effectors, reaching a 38-, 27- and ninefold change increase for the complex elements CCND3, CDK4 and CDK6, respectively. This NOTCH1MUT cells' profile was related to more cells traversing through the cell cycle. In-vitro targeted inhibition of NOTCH1 gamma-secretase and CDK4/6 reversed the distribution of cells through the cycle phases and enhanced the killing of NOTCH1MUT CLL cells, suggesting new therapeutic approaches.
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Leucemia Linfocítica Crónica de Células B , Humanos , Leucemia Linfocítica Crónica de Células B/genética , Leucemia Linfocítica Crónica de Células B/metabolismo , Ciclinas/genética , Ciclo Celular/genética , División Celular , Mutación , Receptor Notch1/genética , Receptor Notch1/metabolismoRESUMEN
Thrombosis is a major cause of morbimortality in patients with chronic Philadelphia chromosome-negative myeloproliferative neoplasms (MPN). In the last decade, multiple lines of evidence support the role of leukocytes in thrombosis of MPN patients. Besides the increase in the number of cells, neutrophils and monocytes of MPN patients show a pro-coagulant activated phenotype. Once activated, neutrophils release structures composed of DNA, histones, and granular proteins, called extracellular neutrophil traps (NETs), which in addition to killing pathogens, provide an ideal matrix for platelet activation and coagulation mechanisms. Herein, we review the published literature related to the involvement of NETs in the pathogenesis of thrombosis in the setting of MPN; the effect that cytoreductive therapies and JAK inhibitors can have on markers of NETosis, and, finally, the novel therapeutic strategies targeting NETs to reduce the thrombotic complications in these patients.
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Leucemia/complicaciones , Trastornos Mieloproliferativos/complicaciones , Neutrófilos , Trombosis/etiología , Animales , Humanos , Leucemia/inmunología , Trastornos Mieloproliferativos/inmunología , Trombosis/inmunologíaRESUMEN
Exosomes are extracellular vesicles that contain nucleic acids, lipids and metabolites, and play a critical role in health and disease as mediators of intercellular communication. The majority of extracellular vesicles in the blood are platelet-derived. Compared to adults, neonatal platelets are hyporeactive and show impaired granule release, associated with defects in Soluble N-ethylmaleimide-sensitive fusion Attachment protein REceptor (SNARE) proteins. Since these proteins participate in biogenesis of exosomes, we investigated the potential differences between newborn and adult plasma-derived exosomes. Plasma-derived exosomes were isolated by ultracentrifugation of umbilical cord blood from full-term neonates or peripheral blood from adults. Exosome characterization included size determination by transmission electron microscopy and quantitative proteomic analysis. Plasma-derived exosomes from neonates were significantly smaller and contained 65% less protein than those from adults. Remarkably, 131 proteins were found to be differentially expressed, 83 overexpressed and 48 underexpressed in neonatal (vs. adult) exosomes. Whereas the upregulated proteins in plasma exosomes from neonates are associated with platelet activation, coagulation and granule secretion, most of the underexpressed proteins are immunoglobulins. This is the first study showing that exosome size and content change with age. Our findings may contribute to elucidating the potential "developmental hemostatic mismatch risk" associated with transfusions containing plasma exosomes from adults.
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Plaquetas/citología , Exosomas/metabolismo , Exosomas/ultraestructura , Sangre Fetal/citología , Plasma/citología , Adulto , Coagulación Sanguínea , Gránulos Citoplasmáticos/metabolismo , Humanos , Inmunoglobulinas/sangre , Recién Nacido , Microscopía Electrónica de Transmisión/métodos , Activación Plaquetaria , Proteína S/análisis , Proteína S/metabolismo , Proteoma , Proteómica/métodos , Investigación Cualitativa , Ultracentrifugación , Factor de von Willebrand/análisis , Factor de von Willebrand/metabolismoRESUMEN
The authors wish to make the following corrections to this paper [...].
RESUMEN
Platelets are anuclear cells with a short lifespan that play an essential role in many pathophysiological processes, including haemostasis, inflammation, infection, vascular integrity, and metastasis. Billions of platelets are produced daily from megakaryocytes (platelet precursors). Despite this high production, the number of circulating platelets is stable and, under resting conditions, they maintain their typical discoid shape thanks to cytoskeleton proteins. The activation of platelets is associated with dynamic and rapid changes in the cytoskeleton. Two cytoskeletal polymer systems exist in megakaryocytes and platelets: actin filaments and microtubules, based on actin, and α- and ß-tubulin heterodimers, respectively. Herein, we will focus on platelet-specific tubulins and their alterations and role of the microtubules skeleton in platelet formation (thrombopoiesis). During this process, microtubules mediate elongation of the megakaryocyte extensions (proplatelet) and granule trafficking from megakaryocytes to nascent platelets. In platelets, microtubules form a subcortical ring, the so-called marginal band, which confers the typical platelet discoid shape and is also responsible for changes in platelet morphology upon activation. Molecular alterations in the gene encoding ß1 tubulin and microtubules post-translational modifications may result in quantitative or qualitative changes in tubulin, leading to altered cytoskeleton reorganization that may induce changes in the platelet number (thrombocytopenia), morphology or function. Consequently, ß1-tubulin modifications may participate in pathological and physiological processes, such as development.
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Plaquetas/metabolismo , Tubulina (Proteína)/metabolismo , Animales , Variación Genética , Humanos , Procesamiento Proteico-Postraduccional , Tubulina (Proteína)/química , Tubulina (Proteína)/genéticaRESUMEN
Hiccups are a minor nuisance for most people and usually resolve within minutes. However, for some, they can persist for years and result in severe symptoms and even death. This case report describes a patient found to have a mediastinal lipoma resulting in intractable hiccups. The discussion highlights the pathophysiology, etiologies, and treatments of hiccups.
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Acute hepatitis A virus infection is routinely identified through a thorough patient history in conjunction with liver chemistries and viral serologies. The diagnosis has the potential to be delayed when the clinical picture is obscured with another, seemingly more urgent presenting pathology with overlapping features. Here, we describe the case of a young female who presented with acute calculous cholecystitis with concurrent acute hepatitis A virus infection.
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Chronic myelomonocytic leukemia (CMML) is frequently associated with mutations in the rat sarcoma gene (RAS), leading to worse prognosis. RAS mutations result in active RAS-GTP proteins, favoring myeloid cell proliferation and survival and inducing the NLRP3 inflammasome together with the apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), which promote caspase-1 activation and interleukin (IL)-1ß release. Here, we report, in a cohort of CMML patients with mutations in KRAS, a constitutive activation of the NLRP3 inflammasome in monocytes, evidenced by ASC oligomerization and IL-1ß release, as well as a specific inflammatory cytokine signature. Treatment of a CMML patient with a KRASG12D mutation using the IL-1 receptor blocker anakinra inhibits NLRP3 inflammasome activation, reduces monocyte count, and improves the patient's clinical status, enabling a stem cell transplant. This reveals a basal inflammasome activation in RAS-mutated CMML patients and suggests potential therapeutic applications of NLRP3 and IL-1 blockers.
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Inflamasomas , Leucemia Mielomonocítica Crónica , Humanos , Inflamasomas/genética , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismo , Leucemia Mielomonocítica Crónica/tratamiento farmacológico , Leucemia Mielomonocítica Crónica/genética , Carga Sintomática , Interleucina-1/metabolismoRESUMEN
Most low-grade gastric lymphomas arising from the mucosa-associated lymphoid tissue (MALT) are directly related to Helicobacter pylori infection. Most cases of MALT lymphoma limited to the stomach can be cured with H. pylori eradication and remain in remission for years. In contrast, high-grade lymphomas of the stomach, although potentially related to H. pylori, do not usually respond to H. pylori eradication. Here, we present the case of a woman with high-grade diffuse large B-cell lymphoma who achieved complete remission following H. pylori eradication.
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Small intestinal bacterial overgrowth (SIBO) is a commonly diagnosed gastrointestinal disorder affecting millions of individuals throughout the United States. It refers to a condition in which there is an excess and imbalance of small intestinal bacteria. Despite its prevalence, it remains underdiagnosed due to the invasive nature of diagnostic testing. Symptoms observed in SIBO, including abdominal distension, bloating, diarrhea, and gas formation, are nonspecific and can overlap with other gastrointestinal disorders. Frequently cited predisposing factors include gastric acid suppression, dysmotility, gastric bypass, and opioids. The diagnostic gold standard remains small bowel aspirate and culture. However, due to its invasive nature, it remains an unpopular method among patients and clinicians alike. Glucose and lactulose breath testing have become the go-to diagnostic method in clinical practice due to its noninvasive nature and low cost. Treatment is guided towards the eradication of bacteria in the small bowel and usually consists of a prolonged course of oral antibiotics. Due to recent advances in our understanding of the human microbiome, we are surely poised for a transformation in our approach to diagnosing and treating this condition.
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Primitive neuroectodermal tumors (PNETs) are rare small round cell malignancies closely related to Ewing's sarcoma. Involvement of the abdominal cavity, specifically the pancreas, is extremely rare. PNETs affect predominantly children and young adults. The clinical presentation is mostly vague, with a short history of symptoms even in metastatic disease. Findings on imaging studies are nonspecific. The diagnosis can be suggested by the microscopic appearance of the tumor cells, but should be confirmed by histology, immunohistochemistry, fluorescence in situ hybridization, immunoreactivity evaluation of MIC2-protein (CD99) expression, and when possible testing for the chromosome translocation t(11;22) (q24,q12). In adults, the prognosis is poor with no standard treatment. Here, we present a case of pancreatic PNET in a 61-year-old man who presented with persistent abdominal pain and weight loss.