Xanthoma Disseminatum: Case Report and Mini-Review of the Literature

 Xanthoma disseminatum is a non-familial disorder of non-Langerhans cell origin or a class II histiocytosis with unknown etiology, with just over 100 cases reported in the literature. Because of the rarity of this disease, there is no established treatment. We studied clinical manifestations and different treatments of xanthoma disseminatum from a series of cases, including our own patient. We studied 15 articles on treatment of xanthoma disseminatum. Local treatment with cryotherapy, radiotherapy, surgery, and carbon dioxide lasers have been attempted with various results. Systemic medication with peroxisome proliferator-activated gamma receptors, statins, fenofibrate, chlorodeoxyadenosine, cyclophosphamide, doxycycline, and cyclosporine have also been reported, but none have proven particularly successful.Xanthoma disseminatum is usually benign and is often self-limiting.If the lesions are accessible to surgery, that is likely to give the best results. However, if the lesions are not accessible for surgical removal then carbon dioxide laser treatment may be considered. The choice of oral treatment should be made on the basis of the patient’s condition, since none of them have proven particularly effective. Expectant management is justifiable as long as the lesions are limited to the skin.</p

IDO expression in cancer : different compartment, different functionality?

Indoleamine 2,3-dioxygenase 1 (IDO1) is a cytosolic haem-containing enzyme involved in the degradation of tryptophan to kynurenine. Although initially thought to be solely implicated in the modulation of innate immune responses during infection, subsequent discoveries demonstrated IDO1 as a mechanism of acquired immune tolerance. In cancer, IDO1 expression/activity has been observed in tumor cells as well as in the tumor-surrounding stroma, which is composed of endothelial cells, immune cells, fibroblasts, and mesenchymal cells. IDO1 expression/activity has also been reported in the peripheral blood. This manuscript reviews available data on IDO1 expression, mechanisms of its induction, and its function in cancer for each of these compartments. In-depth study of the biological function of IDO1 according to the expressing (tumor) cell can help to understand if and when IDO1 inhibition can play a role in cancer therapy

Sensing of endogenous nucleic acids by ZBP1 induces keratinocyte necroptosis and skin inflammation

Aberrant detection of endogenous nucleic acids by the immune system can cause inflammatory disease. The scaffold function of the signaling kinase RIPK1 limits spontaneous activation of the nucleic acid sensor ZBP1. Consequently, loss of RIPK1 in keratinocytes induces ZBP1-dependent necroptosis and skin inflammation. Whether nucleic acid sensing is required to activate ZBP1 in RIPK1-deficient conditions and which immune pathways are associated with skin disease remained open questions. Using knock-in mice with disrupted ZBP1 nucleic acid–binding activity, we report that sensing of endogenous nucleic acids by ZBP1 is critical in driving skin pathology characterized by antiviral and IL-17 immune responses. Inducing ZBP1 expression by interferons triggers necroptosis in RIPK1-deficient keratinocytes, and epidermis-specific deletion of MLKL prevents disease, demonstrating that cell-intrinsic events cause inflammation. These findings indicate that dysregulated sensing of endogenous nucleic acid by ZBP1 can drive inflammation and may contribute to the pathogenesis of IL-17–driven inflammatory skin conditions such as psoriasis

Validated UPLC-MS/MS methods to quantitate free and conjugated Alternaria toxins in commercially available tomato products and fruit and vegetable juices in Belgium

Ultraperformance liquid chromatography tandem mass spectrometry and Quick, Easy, Cheap, Effective, Rugged, and Safe based analytical methodologies to quantitate both free (alternariol (1), alternariol monomethyl ether (2), tenuazonic acid (3), tentoxin (4), altenuene (5), altertoxin-I (6)) and conjugated (sulfates and glucosides of 1 and 2) Alternaria toxins in fruit and vegetable juices and tomato products were developed and validated. Acceptable limits of quantitation (0.7-5.7 mu g/kg), repeatability (RSDr < 15.7%), reproducibility (RSDR < 17.9%), and apparent recovery (87.0-110.6%) were obtained for all analytes in all matrices investigated. 129 commercial foodstuffs were analyzed, and 3 was detected in 100% of tomato product samples (<LOQ to 333 mu g/kg), while 1, 2, 4, and 5 were also frequently detected (21-86%, <LOQ to 62 mu g/kg). Moreover, low levels (<LOQ to 9.9 mu g/kg) of modified Alternaria toxins (sulfates of 1 and 2) were repeatedly detected. A deterministic dietary exposure assessment revealed the possible risk for human health related to the presence of 1 and 2 in tomato based foodstuffs, whereas 3 is unlikely to be of human health concern

Xanthoma Disseminatum: Case Report and Mini-Review of the Literature

 Xanthoma disseminatum is a non-familial disorder of non-Langerhans cell origin or a class II histiocytosis with unknown etiology, with just over 100 cases reported in the literature. Because of the rarity of this disease, there is no established treatment. We studied clinical manifestations and different treatments of xanthoma disseminatum from a series of cases, including our own patient. We studied 15 articles on treatment of xanthoma disseminatum. Local treatment with cryotherapy, radiotherapy, surgery, and carbon dioxide lasers have been attempted with various results. Systemic medication with peroxisome proliferator-activated gamma receptors, statins, fenofibrate, chlorodeoxyadenosine, cyclophosphamide, doxycycline, and cyclosporine have also been reported, but none have proven particularly successful.Xanthoma disseminatum is usually benign and is often self-limiting.If the lesions are accessible to surgery, that is likely to give the best results. However, if the lesions are not accessible for surgical removal then carbon dioxide laser treatment may be considered. The choice of oral treatment should be made on the basis of the patient’s condition, since none of them have proven particularly effective. Expectant management is justifiable as long as the lesions are limited to the skin.</p

Are ladybird beetles (Coleoptera: Coccinellidae) affected by Bt proteins expressed in genetically modified insect-resistant crops? A systematic review protocol

Abstract Background Ladybird beetles (Coleoptera: Coccinellidae) are abundant predatory species in many agroecosystems, are valued for their biological pest control functions, and have been recommended as test species for studies supporting the assessment of non-target effects of insect-resistant Bt crops. Although insecticidal Bt proteins are known to be highly specific against target pests, some recent laboratory studies reported putative toxic effects of Bt proteins on ladybird species. While such studies have been criticised because of methodological shortcomings or inconsistencies, they cast doubt on the insecticidal spectrum of activity of some Bt proteins. Performing a systematic review that synthesises all existing evidence on this controversial topic may help to resolve the remaining scientific uncertainties. The review question to be addressed by the systematic review is the following: Are ladybird beetles (Coleoptera: Coccinellidae) affected by Bt proteins expressed in genetically modified insect-resistant crops? The systematic review will focus on studies performed under controlled environmental conditions. Methods An extensive literature search will be conducted to identify the articles relevant to the review question. A wide range of electronic bibliographic databases, the internet search engine Google Scholar, and websites of specialized organizations will be searched. Citation searching, reference list-checking and searching of key journals will also be performed. The relevance of the identified articles will be assessed against a set of pre-defined eligibility criteria, following a two-step approach. In the first step, title and abstract (or summary) will be screened, whilst in the second step the full text of all remaining articles will be assessed by two members of the review team. All relevant studies will be subjected to an appraisal of external (generalisability) and internal (risk of bias) validity. Data from the selected studies will be extracted and synthesised in a narrative report. If a sufficient number of datasets generated with comparable experimental setup is available, statistical meta-analyses will be conducted on a range of comparisons and including sensitivity analyses

Structures of a deAMPylation complex rationalise the switch between antagonistic catalytic activities of FICD.

The endoplasmic reticulum (ER) Hsp70 chaperone BiP is regulated by AMPylation, a reversible inactivating post-translational modification. Both BiP AMPylation and deAMPylation are catalysed by a single ER-localised enzyme, FICD. Here we present crystallographic and solution structures of a deAMPylation Michaelis complex formed between mammalian AMPylated BiP and FICD. The latter, via its tetratricopeptide repeat domain, binds a surface that is specific to ATP-state Hsp70 chaperones, explaining the exquisite selectivity of FICD for BiP's ATP-bound conformation both when AMPylating and deAMPylating Thr518. The eukaryotic deAMPylation mechanism thus revealed, rationalises the role of the conserved Fic domain Glu234 as a gatekeeper residue that both inhibits AMPylation and facilitates hydrolytic deAMPylation catalysed by dimeric FICD. These findings point to a monomerisation-induced increase in Glu234 flexibility as the basis of an oligomeric state-dependent switch between FICD's antagonistic activities, despite a similar mode of engagement of its two substrates - unmodified and AMPylated BiP

The role of the medial geniculate body of the thalamus in the pathophysiology of tinnitus and implications for treatment

Tinnitus is an auditory sensation in the absence of actual external stimulation. Different clinical interventions are used in tinnitus treatment, but only few patients respond to available options. The lack of successful tinnitus treatment is partly due to the limited knowledge about the mechanisms underlying tinnitus. Recently, the auditory part of the thalamus has gained attention as a central structure in the neuropathophysiology of tinnitus. Increased thalamic spontaneous firing rate, bursting activity and oscillations, alongside an increase of GABAergic tonic inhibition have been shown in the auditory thalamus in animal models of tinnitus. In addition, clinical neuroimaging studies have shown structural and functional thalamic changes with tinnitus. This review provides a systematic overview and discussion of these observations that support a central role of the auditory thalamus in tinnitus. Based on this approach, a neuromodulative treatment option for tinnitus is proposed

Romiplostim for temozolomide-induced thrombocytopenia in glioblastoma: The PLATUM trial

OBJECTIVE To determine the efficacy of the thrombopoietin receptor agonist romiplostim for the prevention of temozolomide-induced thrombocytopenia in newly diagnosed glioblastoma. METHODS In the PLATUM phase II open-label, multicenter, single-arm trial, patients diagnosed with Common Terminology Criteria for Adverse Events grade 3 or 4 thrombocytopenia during chemoradiotherapy received weekly subcutaneous romiplostim injections. PLATUM aimed at demonstrating that the percentage of thrombocytopenic patients treated with romiplostim able to complete 6 cycles of maintenance temozolomide chemotherapy exceeded 10% (0 = 0.10; A = 0.35). Using type I error equal to 0.05% and 95% power, 31 patients had to be recruited. According to a Fleming 2-step design with a preplanned interim analysis after recruitment of 20 patients (step 1), the trial was terminated early for success. RESULTS Twenty patients were enrolled in step 1. Median age was 61 years (range 33-73). Twelve patients received 6 temozolomide cycles, corresponding to a success rate of 60% (95% confidence interval 36%-81%). Four patients discontinued temozolomide because they did not respond to romiplostim, 2 for progression, and 2 for adverse events unrelated to romiplostim. CONCLUSION The thrombopoietin receptor agonist romiplostim improves exposure to chemotherapy in patients with glioblastoma experiencing temozolomide-induced thrombocytopenia. CLINICALTRIALSGOV IDENTIFIER NCT02227576. CLASSIFICATION OF EVIDENCE This study provides Class IV evidence that for patients with glioblastoma and thrombocytopenia, romiplostim is effective for the secondary prophylaxis of temozolomide-induced thrombocytopenia

A20 protects cells from TNF-induced apoptosis through linear ubiquitin-dependent and -independent mechanisms

The cytokine TNF promotes inflammation either directly by activating the MAPK and NF-kappa B signaling pathways, or indirectly by triggering cell death. A20 is a potent anti-inflammatory molecule, and mutations in the gene encoding A20 are associated with a wide panel of inflammatory pathologies, both in human and in the mouse. Binding of TNF to TNFR1 triggers the NF-kappa B-dependent expression of A20 as part of a negative feedback mechanism preventing sustained NF-kappa B activation. Apart from acting as an NF-kappa B inhibitor, A20 is also well-known for its ability to counteract the cytotoxic potential of TNF. However, the mechanism by which A20 mediates this function and the exact cell death modality that it represses have remained incompletely understood. In the present study, we provide in vitro and in vivo evidences that deletion of A20 induces RIPK1 kinase-dependent and -independent apoptosis upon single TNF stimulation. We show that constitutively expressed A20 is recruited to TNFR1 signaling complex (Complex I) via its seventh zinc finger (ZF7) domain, in a cIAP1/2-dependent manner, within minutes after TNF sensing. We demonstrate that Complex I-recruited A20 protects cells from apoptosis by stabilizing the linear (M1) ubiquitin network associated to Complex I, a process independent of its E3 ubiquitin ligase and deubiquitylase (DUB) activities and which is counteracted by the DUB CYLD, both in vitro and in vivo. In absence of linear ubiquitylation, A20 is still recruited to Complex I via its ZF4 and ZF7 domains, but this time protects the cells from death by deploying its DUB activity. Together, our results therefore demonstrate two distinct molecular mechanisms by which constitutively expressed A20 protect cells from TNF-induced apoptosis