Lupus anticoagulant in patients without thrombotic or obstetric complications

El inhibidor lúpico (IL) es un criterio de laboratorio para síndrome antifosfolipídico (SAF); sin embargo, puede detectarse en individuos asintomáticos o estar asociado a otras situaciones clínicas. Presentamos un análisis retrospectivo de 2000 exámenes consecutivos para IL (TTPA, DRVVT), de los cuales 499 casos no presentaban criterios clínicos de SAF (trombosis o complicaciones obstétricas). Aplicando los criterios SSC-ISTH, hallamos IL+ en 27,3% (410/1501) y 43,3% (216/499) de los casos con y sin clínica de SAF respectivamente, analizándose en los casos no-SAF las características clínicas y de laboratorio. Contexto clínico de casos IL+ no-SAF: 18,0% asintomáticos, 34,3% sangrado (epistaxis, gingivorragia, equimosis, hematomas espontáneos) y 47,7% otras manifestaciones (infertilidad, insuficiencia renal crónica, desórdenes autoinmunes, cardiopatía isquémica, trombocitopenia inmune, entre otras). Otras alteraciones de laboratorio en casos IL+ no- SAF, con síntomas de sangrado: alteraciones plaquetarias, descenso de VWF:RCo y/o VWF:Ag, disthrombocytopeminución de FVIII, FII, FV, FVII, FXI o fibrinógeno (sólo o sumado a disminución de plaquetas o FX), inhibidor a-FV o hiperfibrinolisis fueron detectadas en el 55,4% de los casos. El análisis mostró IL+ en un número importante de estudios (216/2000) sin criterios de SAF (1,95% en individuos asintomáticos, 3,70% en pacientes con síntomas de sangrado y 5,15% en casos con otro contexto clínico). Los casos con IL+ y sangrado representan un desafío particular, al requerir evaluar otros posibles defectos subyacentes, que pudiesen justificar el comportamiento clínico. La detección e identificación de defectos combinados requiere de un análisis minucioso, a fin de alcanzar un diagnóstico correcto, esencial para tomar decisiones terapéuticas adecuadas.Despite lupus anticoagulant (LA) is a laboratory criterion for antiphospholipid syndrome (APS), it can be present in asymptomatic subjects or it can be associated with other clinical settings. We present a retrospective analysis of 2000 consecutive LA assays (APTT, DRVVT), 499 of them were performed in patients without APS clinical criteria (thrombosis or obstetric complications). According to SSC-ISTH criteria, LA+ was found in 27.3% (410/1501) and 43.3% (216/499) of cases with or without APS criteria respectively; in no-APS group, the analysis of clinical background and laboratory features was done. Clinical background of LA+ cases no-APS: 18.0% asymptomatic, 34.3% bleeding symptoms (epistaxis, gingivorrhagia, bruising, spontaneous hematomas) and 47.7% other clinical settings (infertility, chronic kidney disease, autoimmune disorders, ischemic heart disease, idiopathic thrombocytopenic purpura, among others). Other abnormal laboratory tests in LA+ cases no- APS with bleeding symptoms: platelet dysfunction; low VWF:RCo and/or VWF:Ag; decrease of FVIII, FII, FV, FVII, FXI or fibrinogen (alone or with low platelet count or low FX), a-FV inhibitor and hyperfibrinolysis were found in the 55.4% of the cases. The analysis showed LA+ in an important number of cases (216/2000) without APS criteria (1.95% in asymptomatic cases, 3.70% in patients with bleeding symptoms and 5.15% in cases with other clinical settings). Those LA+ cases with bleeding symptoms represent a particular challenge because other possible underlying defects have to be analysed in order to explain the clinical behaviour. The detection and identifications of combined defects required a careful analysis in order to achieve an accurate diagnosis, essential for therapeutic decisions.Fil: Remotti, L.. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas ; ArgentinaFil: Grosso, S. H.. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas ; ArgentinaFil: Ingratti, M. F.. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas ; ArgentinaFil: Vera Morandini, Maria Paula. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas ; ArgentinaFil: Woods, Adriana Inés. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Bermejo, E. I.. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas ; ArgentinaFil: Sánchez Luceros, Analía Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas ; ArgentinaFil: Meschengieser, S. S.. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas ; ArgentinaFil: Lazzari, María Ángela. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Blanco, A. N.. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas ; Argentin

Smad4 Loss Synergizes with TGFα Overexpression in Promoting Pancreatic Metaplasia, PanIN Development, and Fibrosis

Aims: While overexpression of TGFα has been reported in human pancreatic ductal adenocarcinoma (PDAC), mice with overexpressed TGFα develop premalignant pancreatic acinar-toductal metaplasia (ADM) but not PDAC. TGF-β signaling pathway is pivotal to the development of PDAC and tissue fibrosis. Here we sought to investigate the interplay between TGFα and TGF-β signaling in pancreatic tumorigenesis and fibrosis, namely via Smad4 inactivation. Methods: The MT-TGFα mouse was crossed with a new Smad4 conditional knock-out mouse (Smad4flox/flox;p48-Cre or S4) to generate Smad4flox/flox;MT-TGFα;p48-Cre (STP). After TGFα overexpression was induced with zinc sulfate water for eight months, the pancreata of the STP, MT-TGFα, and S4 mice were examined for tumor development and fibrotic responses. PanIN lesions and number of ducts were counted, and proliferation was measured by Ki67 immunohistochemistry (IHC). Qualitative analysis of fibrosis was analyzed by Trichrome Masson and Sirius Red staining, while vimentin was used for quantification. Expression analyses of fibrosis, pancreatitis, or desmoplasia associated markers (α-SMA, Shh, COX-2, Muc6, Col1a1, and Ctgf) were performed by IHC and/or qRT-PCR. Results: Our STP mice exhibited advanced ADM, increased fibrosis, increased numbers of PanIN lesions, overexpression of chronic pancreatitis-related marker Muc6, and elevated expression of desmoplasia-associated marker Col1A1, compared to the MT-TGFα mice. The inactivation of Smad4 in the exocrine compartment was responsible for both the enhanced PanIN formation and fibrosis in the pancreas. The phenotype of the STP mice represents a transient state from ADMs to PanINs, closely mimicking the interface area seen in human chronic pancreatitis associated with PDAC. Conclusion: We have documented a novel mouse model, the STP mice, which displayed histologic presentations reminiscent to those of human chronic pancreatitis with signs of early tumorigenesis. The STP mice could be a suitable animal model for interrogating the transition of chronic pancreatitis to pancreatic cancer

Long-lived intestinal tuft cells serve as colon cancer-initiating cells

Doublecortin-like kinase 1 protein (DCLK1) is a gastrointestinal tuft cell marker that has been proposed to identify quiescent and tumor growth-sustaining stem cells. DCLK1+ tuft cells are increased in inflammation-induced carcinogenesis; however, the role of these cells within the gastrointestinal epithelium and their potential as cancer-initiating cells are poorly understood. Here, using a BAC-CreERT-dependent genetic lineage-tracing strategy, we determined that a subpopulation of DCLK1+ cells is extremely long lived and possesses rare stem cell abilities. Moreover, genetic ablation of Dclk1 revealed that DCLK1+ tuft cells contribute to recovery following intestinal and colonic injury. Surprisingly, conditional knockdown of the Wnt regulator APC in DCLK1+ cells was not sufficient to drive colonic carcinogenesis under normal conditions; however, dextran sodium sulfate-induced (DSS-induced) colitis promoted the development of poorly differentiated colonic adenocarcinoma in mice lacking APC in DCLK1+ cells. Importantly, colonic tumor formation occurred even when colitis onset was delayed for up to 3 months after induced APC loss in DCLK1+ cells. Thus, our data define an intestinal DCLK1+ tuft cell population that is long lived, quiescent, and important for intestinal homeostasis and regeneration. Long-lived DCLK1+ cells maintain quiescence even following oncogenic mutation, but are activated by tissue injury and can serve to initiate colon cancer

Dclk1 Defines Quiescent Pancreatic Progenitors that Promote Injury-Induced Regeneration and Tumorigenesis

The existence of adult pancreatic progenitor cells has been debated. While some favor the concept of facultative progenitors involved in homeostasis and repair, neither a location nor markers for such cells have been defined. Using genetic lineage tracing, we show that Doublecortin-like kinase-1 (Dclk1) labels a rare population of long-lived, quiescent pancreatic cells. In vitro, Dclk1+ cells proliferate readily and sustain pancreatic organoid growth. In vivo, Dclk1+ cells are necessary for pancreatic regeneration following injury and chronic inflammation. Accordingly, their loss has detrimental effects after cerulein-induced pancreatitis. Expression of mutant Kras in Dclk1+ cells does not affect their quiescence or longevity. However, experimental pancreatitis converts Kras mutant Dclk1+ cells into potent cancer-initiating cells. As a potential effector of Kras, Dclk1 contributes functionally to the pathogenesis of pancreatic cancer. Taken together, these observations indicate that Dclk1 marks quiescent pancreatic progenitors that are candidates for the origin of pancreatic cancer

Acidic fibroblast growth factor is expressed sequentially in the progression from Barrett\u27s esophagus to esophageal adenocarcinoma.

Acidic fibroblast growth factor 1 (FGF-1) is sequentially accumulated in Barrett\u27s esophagus and its expression in glandular dysplasias is independent of esophageal adenocarcinoma. This suggests that FGF-1 immunohistochemistry could be used as an adjunct to the routine histopathologic diagnosis of dysplasia in Barrett\u27s esophagus. The data also underscore the important role of fibroblast growth factors in tumorigenesis