Thyroglossal Duct Lipoma: A Case Report and a Systematic Review of the Literature for Its Management

Thyroglossal duct (TGD) remnants in the form of cysts or fistulas usually present as midline neck masses and they are removed along with the central body of the hyoid bone (Sistrunk’s procedure). For other pathologies associated with the TGD tract, the latter operation might be not necessary. In the present report, a case of a TGD lipoma is presented and a systematic review of the pertinent literature was performed. We present the case of a 57-year-old woman with a pathologically confirmed TGD lipoma who underwent transcervical excision without resecting the hyoid bone. Recurrence was not observed after six months of follow-up. The literature search revealed only one other case of TGD lipoma and controversies are addressed. TGD lipoma is an exceedingly rare entity whose management might avoid hyoid bone excision

Hematopoietic Stem Cell (HSC)-Independent Progenitors Are Susceptible to Mll-Af9-Induced Leukemic Transformation.

Infant acute myeloid leukemia (AML) is a heterogeneous disease, genetically distinct from its adult counterpart. Chromosomal translocations involving the KMT2A gene (MLL) are especially common in affected infants of less than 1 year of age, and are associated with a dismal prognosis. While these rearrangements are likely to arise in utero, the cell of origin has not been conclusively identified. This knowledge could lead to a better understanding of the biology of the disease and support the identification of new therapeutic vulnerabilities. Over the last few years, important progress in understanding the dynamics of fetal hematopoiesis has been made. Several reports have highlighted how hematopoietic stem cells (HSC) provide little contribution to fetal hematopoiesis, which is instead largely sustained by HSC-independent progenitors. Here, we used conditional Cre-Lox transgenic mouse models to engineer the Mll-Af9 translocation in defined subsets of embryonic hematopoietic progenitors. We show that embryonic hematopoiesis is generally permissive for Mll-Af9-induced leukemic transformation. Surprisingly, the selective introduction of Mll-Af9 in HSC-independent progenitors generated a transplantable myeloid leukemia, whereas it did not when introduced in embryonic HSC-derived cells. Ex vivo engineering of the Mll-Af9 rearrangement in HSC-independent progenitors using a CRISPR/Cas9-based approach resulted in the activation of an aberrant myeloid-biased self-renewal program. Overall, our results demonstrate that HSC-independent hematopoietic progenitors represent a permissive environment for Mll-Af9-induced leukemic transformation, and can likely act as cells of origin of infant AML

Analysis of Familial Hemophagocytic Lymphohistiocytosis type 4 (FHL-4) mutant proteins reveals that S-acylation is required for the function of syntaxin 11 in natural killer cells

Natural killer (NK) cell secretory lysosome exocytosis and cytotoxicity are impaired in familial hemophagocytic lymphohistiocytosis type 4 (FHL-4), a disorder caused by mutations in the gene encoding the SNARE protein syntaxin 11. We show that syntaxin 11 binds to SNAP23 in NK cells and that this interaction is reduced by FHL-4 truncation and frameshift mutation proteins that delete all or part of the SNARE domain of syntaxin 11. In contrast the FHL-4 mutant proteins bound to the Sec-1/Munc18-like (SM) protein Munc18-2. We demonstrate that the C-terminal cysteine rich region of syntaxin 11, which is deleted in the FHL-4 mutants, is S-acylated. This posttranslational modification is required for the membrane association of syntaxin 11 and for its polarization to the immunological synapse in NK cells conjugated to target cells. Moreover, we show that Munc18-2 is recruited by syntaxin 11 to intracellular membranes in resting NK cells and to the immunological synapse in activated NK cells. This recruitment of Munc18-2 is abolished by deletion of the C-terminal cysteine rich region of syntaxin 11. These results suggest a pivotal role for S-acylation in the function of syntaxin 11 in NK cells

Clinical classification of cancer cachexia:phenotypic correlates in human skeletal muscle

Aim – To relate muscle phenotype to a range of current diagnostic criteria for cancer cachexia Methods – 41 patients with resectable upper gastrointestinal (GI) or pancreatic cancer underwent characterisation for cachexia based on weight-loss (WL) and / or low muscularity (LM). Four diagnostic criteria were used >5%WL, >10% WL, LM, and LM + >2%WL. Patients underwent biopsy of the rectus muscle. Analysis included immunohistochemistry for fibre size and type, protein and nucleic acid concentration, and Western blots for markers of autophagy, SMAD signalling, and inflammation. Results – Compared with non-cachectic cancer patients, if patients were classified by LM or LM + >2%WL, mean muscle fibre diameter was significantly reduced (p = 0.02 and p = 0.001) repectively. No difference in fibre diameter was observed if patients were classified with WL alone. Regardless of classification, there was no difference in fibre number or proportion of fibre type across all myosin heavy chain isoforms. Mean muscle protein content was reduced and the ratio of RNA/DNA decreased if patients were classified by either >5% WL or LM + >2%WL. Compared with non-cachectic patients, when patients were classified according to >5% WL, SMAD3 protein levels were increased (p=0.022) and with >10% WL, beclin (p = 0.05) and ATG5 (p = 0.01) protein levels were also increased. There were no differences in pNFkB or pSTAT3 levels across any of the groups. Conclusions – Whereas fibre type is not targeted selectively, muscle fibre size, biochemical composition and pathway phenotype can vary according to whether the criteria for cachexia include both a measure of low muscularity and weight loss

TRAF2 and p38 are involved in B cells CD40-mediated APE/Ref-1 nuclear translocation: a novel pathway in B cell activation

The interaction between CD40 and its ligand CD40L plays a key role in the regulation of B cell proliferation, activation, isotype switching and the humoral memory response. APE/Ref-1 plays a key role in transcriptional responses during CD40-mediated B cell activation. It is demonstrated that CD40 signaling is mediated principally through TRAF adapter proteins. Different TRAFs exhibit specific biological functions and the role of individual TRAFs in the activation of different CD40-dependent signaling pathways has not yet been defined. To better understand the role of these factors in CD40-mediated B cell activation and how they contribute to APE/Ref-1 activity, we investigated the TRAF molecules and the downstream protein kinases directly activated in the pathways triggered by CD40. Here we show that TRAF2 is involved in CD40-mediated induction of APE/Ref-1 nuclear translocation and that the two proteins physically interact in vitro and in vivo. Moreover, treatment with the p38 inhibitor, SB203580 or site directed mutagenesis of the serine 54 (Ser(54)) in the MAP kinase consensus site present in APE/Ref-1 blocks its nuclear translocation caused by CD40-mediated B cell activation and reveals a potential role of p38 in this pathway. These data together uncovers a new signaling pathway regulating APE/Ref-1 nuclear translocation involving CD40-crosslinking, TRAF2 and p38