NLRX1 suppresses tumorigenesis and attenuates histiocytic sarcoma through the negative regulation of NF-κB signaling

Histiocytic sarcoma is an uncommon malignancy in both humans and veterinary species. Research exploring the pathogenesis of this disease is scarce; thus, diagnostic and therapeutic options for patients are limited. Recent publications have suggested a role for the NLR, NLRX1, in acting as a tumor suppressor. Based on these prior findings, we hypothesized that NLRX1 would function to inhibit tumorigenesis and thus the development of histiocytic sarcoma. To test this, we utilized Nlrx1−/− mice and a model of urethane-induced tumorigenesis. Nlrx1−/− mice exposed to urethane developed splenic histiocytic sarcoma that was associated with significant up-regulation of the NF-λB signaling pathway. Additionally, development of these tumors was also significantly associated with the increased regulation of genes associated with AKT signaling, cell death and autophagy. Together, these data show that NLRX1 suppresses tumorigenesis and reveals new genetic pathways involved in the pathobiology of histiocytic sarcoma

Beyond the inflammasome: regulatory NOD-like receptor modulation of the host immune response following virus exposure

Široko je prihvaćeni koncept da žučovod povećava promjer nakon kolecistektomije. Međutim, postoje prijeporni rezultati u dostupnoj literaturi o ovoj temi. Saznanje može li se kod kolecistektomiranih pacijenata očekivati širi promjer žučnih vodova od opće populacije bilo bi korisno da se izbjegnu nepotrebna i potencijalno invazivna istraživanja žučnih vodova. Cilj rada je prikazati radiološke tehnike u analizi žučnog mjehura i žučnih vodova i prikazati radiološke tehnike u analizi promjena promjera žučnih vodova nakon kolecistektomije. Istražiti relevantnu literaturu i znanstvene baze podataka s prikazom radova na temu dosadašnjih istraživanja promjena promjera žučnih vodova nakon kolecistektomije. Radiološke tehnike u analizi promjena promjera žučnih vodova nakon kolecistektomije su ultrazvuk, endoskopska retrogradna kolangiopankreatografija, endoskopski ultrazvuk, kompjuterizirana tomografija, magnetska rezonancija s magnetskorezonantnom kolangiopankreatografijom. Većina studija na temu promjena promjera žučnih vodova nakon kolecistektomije je ultrazvučna, što je i razumljivo zbog široke dostupnosti i neinvazivnosti pretrage. Veliki broj ultrazvučnih studija su potvrdile ali i opovrgnule tezu o postkolecistektomičnoj dilataciji žučovoda. Prijeporni rezultati mogu se tumačiti i niskom osjetljivošću ultrazvuka u odnosu na druge radiološke tehnike kao što su EUS, MRCP i ERCP. U studijama CT-om koji također ima nisku osjetljivost također su vidljivi prijeporni rezultati. Najmanji broj studija izveden je tehnikama koje imaju veliku osjetljivost, ERCP-om zbog invazivnosti pretrage te EUS-om i MRCP-om zbog manje dostupnosti i cijene pretrage., Rezultati tih studija govore u prilog postkolecistektomične dilatacije. Potrebna su daljnja istraživanja s viskom metodološkom kvalitetom za potvrdu postkolecistektomične dilatacije žučovoda.It is widely accepted that the common bile duct diameter increases after cholecystectomy. However, there are controversial results in available literature on this subject. Knowledge whether cholecystectomy patients are expected to have a wider diameter of bile ducts than the general population would be beneficial to prevent unnecessary and potentially invasive research of the bile ducts. The aim of the research is to present radiological techniques in the analysis of the gallbladder and bile duct and the analysis of bile duct diameter changes after cholecystectomy. Relevant literature and scientific databases on the topic and current research is presented. Radiological techniques in the analysis of the common bile duct diameter after cholecystectomy are: ultrasound, endoscopic retrograde cholangiopankreatography, endoscopic ultrasound, computerized tomography, magnetic resonance imaging with magnetic resonance cholangiopankreatography. Most of the studies of the common bile duct diameter changes after cholecystectomy are performed with ultrasound, due to the wide availability, reproducibily and non-invasiveness of the examination. A large number of ultrasound studies have confirmed but also rejected the thesis on postcholecistectomic dilation of the common bile duct. Controversial results can be interpreted with low sensitivity of ultrasound examination compared to other radiological techniques such as EUS, MRCP and ERCP. Controversial results are also reported for the CT studies. The smallest number of studies have been conducted with high sensitivity techniques. ERCP is a highly invasive examination and EUS and MRCP are not as available due to the high cost. Further research with high methodological quality is required to confirm the postcholecystectomic dilation of the bile ducts

TLR7 Agonism Accelerates Disease and Causes a Fatal Myeloproliferative Disorder in NZM 2410 Lupus Mice

Murine models of lupus, both spontaneous and inducible, are valuable instruments to study SLE pathogenesis. Accelerants such as Type I IFN are often used to trigger earlier disease onset. We used a topical TLR7 agonist, previously reported to induce lupus-like disease in WT mice within weeks, to validate this data in C57BL/6j mice, and to test TLR7 agonism as an accelerant in lupus-prone NZM2410 mice. We found that TLR7-stimulated B6 and NZM2410 mice had significantly reduced survival and exhibited profound splenomegaly with significantly reduced B cells (4 vs. 40%), and T cells (8 vs. 31%). Spleen pathology and IHC revealed massive expansion of F4/80+ cells in TLR7-treated mice consistent with histiocytosis. While resiqimod treatment caused mild autoimmunity in B6 mice and accelerated autoimmunity in NZM2410 mice, it did not cause significant nephritis or proteinuria in either strain (renal function intact at death). Given the macrophage expansion, cytopenias, and disruption of normal splenic lymphoid follicle architecture, histiocytic sarcoma is favored as the cause of death. An alternative etiology is a macrophage activation syndrome (MAS)-like syndrome, since the mice also had a transaminitis and histologic hemophagocytosis in the setting of their rapid mortality. For investigators who are focused on murine models of lupus nephritis, this model is not ideal when utilizing B6 mice, however topical resiqimod may prove useful to accelerate autoimmunity and nephritis in NZM2410 mice, or potentially to investigate secondary complications of lupus such as histiocytic diseases or macrophage activation like syndromes

Retroperitoneal myxosarcoma in a cat

Abstract This report details a retroperitoneal myxosarcoma in a cat that exhibited extremely aggressive biological behavior. An exploratory midline celiotomy revealed a left‐sided retroperitoneal mass firmly adhered to the hypaxial musculature. Histopathological evaluation identified the mass as a myxosarcoma. Following surgical excision, the mass rapidly recurred within 6 weeks after surgery

Differential pathogenesis of Usutu virus isolates in mice.

Usutu virus (USUV; Flavivirus), a close phylogenetic and ecological relative of West Nile virus, is a zoonotic virus that can cause neuroinvasive disease in humans. USUV is maintained in an enzootic cycle between Culex mosquitoes and birds. Since the first isolation in 1959 in South Africa, USUV has spread throughout Africa and Europe. Reported human cases have increased over the last few decades, primarily in Europe, with symptoms ranging from mild febrile illness to severe neurological effects. In this study, we investigated whether USUV has become more pathogenic during emergence in Europe. Interferon α/β receptor knockout (Ifnar1-/-) mice were inoculated with recent USUV isolates from Africa and Europe, as well as the historic 1959 South African strain. The three tested African strains and one European strain from Spain caused 100% mortality in inoculated mice, with similar survival times and histopathology in tissues. Unexpectedly, a European strain from the Netherlands caused only 12% mortality and significantly less histopathology in tissues from mice compared to mice inoculated with the other strains. Viremia was highest in mice inoculated with the recent African strains and lowest in mice inoculated with the Netherlands strain. Based on phylogenetics, the USUV isolates from Spain and the Netherlands were derived from separate introductions into Europe, suggesting that disease outcomes may differ for USUV strains circulating in Europe. These results also suggest that while more human USUV disease cases have been reported in Europe recently, circulating African USUV strains are still a potential major health concern

Correction: Differential pathogenesis of Usutu virus isolates in mice.

[This corrects the article DOI: 10.1371/journal.pntd.0008765.]

Caspase-11 Modulates Inflammation and Attenuates Toxoplasma gondii Pathogenesis

Toxoplasma gondii is an obligate intracellular parasite that is the etiologic agent responsible for toxoplasmosis. Infection with T. gondii results in activation of nucleotide binding domain and leucine rich repeat containing receptors (NLRs). NLR activation leads to inflammasome formation, the activation of caspase-1, and the subsequent cleavage of IL-1β and IL-18. Recently, a noncanonical inflammasome has been characterized which functions through caspase-11 and appears to augment many biological functions previously considered to be dependent upon the canonical inflammasome. To better elucidate the function of this noncanonical inflammasome in toxoplasmosis, we utilized Asc−/− and Casp11−/− mice and infected these animals with T. gondii. Our data indicates that caspase-11 modulates the innate immune response to T. gondii through a mechanism which is distinct from that currently described for the canonical inflammasome. Asc−/− mice demonstrated increased disease pathogenesis during the acute phase of T. gondii infection, whereas Casp11−/− mice demonstrated significantly attenuated disease pathogenesis and reduced inflammation. This attenuated host response was associated with reduced local and systemic cytokine production, including diminished IL-1β. During the chronic phase of infection, caspase-11 deficiency resulted in increased neuroinflammation and tissue cyst burden in the brain. Together, our data suggest that caspase-11 functions to protect the host by enhancing inflammation during the early phase of infection in an effort to minimize disease pathogenesis during later stages of toxoplasmosis