Asociación obesidad e hiperplasia nodular focal (HNF) telangiectásica. Reevaluación de 24 casos.

La hiperplasia nodular focal no es una verdadera neo plasia. Es una respuesta regenerativa de los hepatocitos a una anomalía vascular. Se reevaluaron 24 casos diagnosticados y confirmados en el estudio anatomopatológico como hiperplasia nodular focal. Tres de los 24 casos fueron reclasificados como adenomas inflamatorios telangiectásico, vinculado con antecedentes de síndromes metabolicos y con imnumorreactividad frente a la Amiloide A. La presencia de ectasia vascular, dilatación sinusoidal, áreas de peliosis con signos inflamatorios focales o difusos asociados a inmunorreactividad frente al Amiloide A son signos histológicos que nos indican la presencia de adenomas hepatocelulares inflamatorios telangiectásicos antiguamente clasificados como hiperplasia nodular focal atípica. El antecedentes de obesidad u hígado graso, unido al incremento en la reactividad frente al Amiloide A caracteriza a los adenomas inflamatorios telan giec - tásicos

Pathogenic FAM83g palmoplantar keratoderma mutations inhibit the PAWS1::Ck1α association and attenuate wnt signalling

Background: Two recessive mutations in the FAM83G gene, causing A34E and R52P amino acid substitutions in the DUF1669 domain of the PAWS1 protein, are associated with palmoplantar keratoderma (PPK) in humans and dogs respectively. We have previously reported that PAWS1 associates with the Ser/Thr protein kinase CK1α through the DUF1669 domain to mediate canonical Wnt signalling. Methods: Co-immunoprecipitation was used to investigate possible changes to PAWS1 interactors caused by the mutations. We also compared the stability of wild-type and mutant PAWS1 in cycloheximide-treated cells. Effects on Wnt signalling were determined using the TOPflash luciferase reporter assay in U2OS cells expressing PAWS1 mutant proteins. The ability of PAWS1 to induce axis duplication in Xenopus embryos was also tested. Finally, we knocked-in the A34E mutation at the native gene locus and measured Wnt-induced AXIN2 gene expression by RT-qPCR. Results: We show that these PAWS1 A34E and PAWS1 R52P mutants fail to interact with CK1α but, like the wild-type protein, do interact with CD2AP and SMAD1. Like cells carrying a PAWS1 F296A mutation, which also abolishes CK1α binding, cells carrying the A34E and R52P mutants respond poorly to Wnt signalling to an extent resembling that observed in FAM83G gene knockout cells. Consistent with this observation, these mutants, in contrast to the wild-type protein, fail to induce axis duplication in Xenopus embryos. We also found that the A34E and R52P mutant proteins are less abundant than the native protein and appear to be less stable, both when overexpressed in FAM83G-knockout cells and when knocked-in at the native FAM83G locus. Ala 34 of PAWS1 is conserved in all FAM83 proteins and mutating the equivalent residue in FAM83H (A31E) also abolishes interaction with CK1 isoforms. Conclusions: We propose that mutations in PAWS1 cause PPK pathogenesis through disruption of the CK1α interaction and attenuation of Wnt signalling. </p

Csnk1a1 inhibition has p53-dependent therapeutic efficacy in acute myeloid leukemia

Despite extensive insights into the underlying genetics and biology of acute myeloid leukemia (AML), overall survival remains poor and new therapies are needed. We found that casein kinase 1 α (Csnk1a1), a serine-threonine kinase, is essential for AML cell survival in vivo. Normal hematopoietic stem and progenitor cells (HSPCs) were relatively less affected by shRNA-mediated knockdown of Csnk1a1. To identify downstream mediators of Csnk1a1 critical for leukemia cells, we performed an in vivo pooled shRNA screen and gene expression profiling. We found that Csnk1a1 knockdown results in decreased Rps6 phosphorylation, increased p53 activity, and myeloid differentiation. Consistent with these observations, p53-null leukemias were insensitive to Csnk1a1 knockdown. We further evaluated whether D4476, a casein kinase 1 inhibitor, would exhibit selective antileukemic effects. Treatment of leukemia stem cells (LSCs) with D4476 showed highly selective killing of LSCs over normal HSPCs. In summary, these findings demonstrate that Csnk1a1 inhibition causes reduced Rps6 phosphorylation and activation of p53, resulting in selective elimination of leukemia cells, revealing Csnk1a1 as a potential therapeutic target for the treatment of AML

Olfactory Nomenclature: An Orchestrated Effort to Clarify Terms and Definitions of Dysosmia, Anosmia, Hyposmia, Normosmia, Hyperosmia, Olfactory Intolerance, Parosmia, and Phantosmia/Olfactory Hallucination

BACKGROUND: Definitions are essential for effective communication and discourse, particularly in science. They allow the shared understanding of a thought or idea, generalization of knowledge, and comparison across scientific investigation. The current terms describing olfactory dysfunction are vague and overlapping. SUMMARY: As a group of clinical olfactory researchers, we propose the standardization of the terms "dysosmia," "anosmia," "hyposmia," "normosmia," "hyperosmia," "olfactory intolerance," "parosmia," and "phantosmia" (or "olfactory hallucination") in olfaction-related communication, with specific definitions in this text. KEY MESSAGES: The words included in this paper were determined as those which are most frequently used in the context of olfactory function and dysfunction, in both clinical and research settings. Despite widespread use in publications, however, there still exists some disagreement in the literature regarding the definitions of terms related to olfaction. Multiple overlapping and imprecise terms that are currently in use are confusing and hinder clarity and universal understanding of these concepts. There is a pressing need to have a unified agreement on the definitions of these olfactory terms by researchers working in the field of chemosensory sciences. With the increased interest in olfaction, precise use of these terms will improve the ability to integrate and advance knowledge in this field

Hypercalcemia after transplant nephrectomy in a hemodialysis patient: a case report

<p>Abstract</p> <p>Introduction</p> <p>Hypercalcemia is a complication often seen in chronic hemodialysis patients. A rare cause of this condition is sarcoidosis. Its highly variable clinical presentation is challenging. Especially in patients suffering chronic kidney graft failure the nonspecific constitutional symptoms of sarcoidosis like fever, weight loss, arthralgia and fatigue may be easily misleading.</p> <p>Case presentation</p> <p>A 51 year old male developed hypercalcemia, arthralgia and B-symptoms after explantation of his kidney graft because of suspected acute rejection. The removed kidney showed vasculopathy and tubulointerstitial nephritis, which had not been overt in the biopsy taken half a year earlier. Despite explantation and withdrawal of the immunosuppression the patient's general condition deteriorated progressively. A rapid rise in serum calcium finally provoked us to check for sarcoidosis. CT scans of the lungs, broncho-alveolar-lavage and further lab tests confirmed the diagnosis.</p> <p>Conclusion</p> <p>This case demonstrates that withdrawal of immunosuppressive drugs sometimes unmasks sarcoidosis. It should be considered as differential diagnosis even in hemodialysis patients, in whom other reasons for hypercalcemia are much more common.</p