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BackgroundActivation and coagulation biomarkers were measured within the Strategies for Management of Antiretroviral Therapy (SMART) trial. Their associations with opportunistic disease (OD) in human immunodeficiency virus (HIV)–positive patients were examined MethodsInflammatory (high-sensitivity C-reactive protein [hsCRP], interleukin-6 [IL–6], amyloid-A, and amyloid-P) and coagulation (D-dimer and prothrombin-fragment 1+2) markers were determined. Conditional logistic regression analyses were used to assess associations between these biomarkers and risk of OD ResultsThe 91 patients who developed an OD were matched to 182 control subjects. Patients with an hsCRP level ⩾5 μg/mL at baseline had a 3.5 higher odds of OD (95% confidence interval [CI], 1.5–8.1) than did those with an hsCRP level <1 μg/mL (P=.003, by test for trend) and patients with an IL-6 level ⩾3 pg/mL at baseline had a 2.4 higher odds of OD (95% CI, 1.0–5.4) than did those with an IL-6 level <1.5 pg/mL (P=.02, by test for trend). No other baseline biomarkers predicted development of an OD. Latest follow-up hsCRP level for those with an hsCRP level ⩾5 μg/mL (compared with a level <1 μg/mL; odds ratio [OR], 7.6; 95% CI, 2.0–28.5; P=.002, by test for trend), latest amyloid-A level for those with an amyloid-A level ⩾6 mg/L (compared with a level <2 mg/L; OR, 3.8; 95% CI, 1.1–13.4; P=.03, by test for trend), and latest IL-6 level for those with an IL-6 level ⩾3 pg/mL (compared with a level <1.5 pg/mL; OR 2.4; 95% CI, 0.7–8.8; P=.04, by test for trend) were also associated with development of an OD ConclusionsHigher IL-6 and hsCRP levels independently predicted development of OD. These biomarkers could provide additional prognostic information for predicting the risk of OD Clinical trials registrationClinical Trials.gov number NCT00027352

Secondary, or amyloid protein A (AA), amyloidosis is a complication of chronic inflammatory diseases, both infectious and noninfectious. AA constitutes the insoluble fibrils, which are deposited in different organs, and is a major N-terminal part of the acute phase protein serum AA. It is not known why only some patients with chronic inflammation develop AA amyloidosis. Nucleation is a widely accepted mechanism in amyloidogenesis. Preformed amyloid-like fibrils act as nuclei in amyloid fibril formation in vitro, and AA amyloid fibrils and synthetic amyloid-like fibrils also may serve as seed for fibril formation in vivo. In addition to amyloid fibrils, there is a variety of similar nonmammalian protein fibrils with β-pleated structure in nature. We studied three such naturally occurring protein fibrils: silk from Bombyx mori, Sup35 from Saccharomyces cerevisiae, and curli from Escherichia coli. Our results show that these protein fibrils exert amyloid-accelerating properties in the murine experimental AA amyloidosis, suggesting that such environment factors may be important risk factors in amyloidogenesis.

Systemic AA amyloidosis is a worldwide occurring protein misfolding disease of humans and animals. It arises from the formation of amyloid fibrils from the acute phase protein serum amyloid A. Here, we report the purification and electron cryo-microscopy analysis of amyloid fibrils from a mouse and a human patient with systemic AA amyloidosis. The obtained resolutions are 3.0 Å and 2.7 Å for the murine and human fibril, respectively. The two fibrils differ in fundamental properties, such as presence of right-hand or left-hand twisted cross-β sheets and overall fold of the fibril proteins. Yet, both proteins adopt highly similar β-arch conformations within the N-terminal ~21 residues. Our data demonstrate the importance of the fibril protein N-terminus for the stability of the analyzed amyloid fibril morphologies and suggest strategies of combating this disease by interfering with specific fibril polymorphs. Systemic AA amyloidosis is caused by misfolding of the acute phase protein serum amyloid A1. Here the authors present the cryo-EM structures of murine and human AA amyloid fibrils that were isolated from tissue samples and describe how the fibrils differ in their fundamental structural properties.

Systemic AA amyloidosis is a world-wide occurring protein misfolding disease of humans and animals. It arises from the formation of amyloid fibrils from serum amyloid A (SAA) protein. Using cryo electron microscopy we here show that amyloid fibrils which were purified from AA amyloidotic mice are structurally different from fibrils formed from recombinant SAA protein in vitro. Ex vivo amyloid fibrils consist of fibril proteins that contain more residues within their ordered parts and possess a higher β-sheet content than in vitro fibril proteins. They are also more resistant to proteolysis than their in vitro formed counterparts. These data suggest that pathogenic amyloid fibrils may originate from proteolytic selection, allowing specific fibril morphologies to proliferate and to cause damage to the surrounding tissue. Systemic AA amyloidosis is a protein misfolding disease caused by the formation of amyloid fibrils from serum amyloid A (SAA) protein. Here, the authors present the cryo-EM structures of AA amyloid fibrils isolated from mouse tissue and in vitro formed fibrils, which differ in their structures and they also show that the ex vivo fibrils are more resistant to proteolysis than the in vitro fibrils and propose that pathogenic amyloid fibrils might originate from proteolytic selection.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by the presence of abundant desmoplastic stroma primarily composed of cancer-associated fibroblasts (CAFs). It is generally accepted that CAFs stimulate tumor progression and might be implicated in drug resistance and immunosuppression. Here, we have compared the transcriptional profile of PDGFRα⁺ CAFs isolated from genetically engineered mouse PDAC tumors with that of normal pancreatic fibroblasts to identify genes potentially implicated in their protumorigenic properties. We report that the most differentially expressed gene, Saa3, a member of the serum amyloid A (SAA) apolipoprotein family, is a key mediator of the protumorigenic activity of PDGFRα⁺ CAFs. Whereas Saa3-competent CAFs stimulate the growth of tumor cells in an orthotopic model, Saa3-null CAFs inhibit tumor growth. Saa3 also plays a role in the cross talk between CAFs and tumor cells. Ablation of Saa3 in pancreatic tumor cells makes them insensitive to the inhibitory effect of Saa3-null CAFs. As a consequence, germline ablation of Saa3 does not prevent PDAC development in mice. The protumorigenic activity of Saa3 in CAFs is mediated by Mpp6, a member of the palmitoylated membrane protein subfamily of the peripheral membrane-associated guanylate kinases (MAGUK). Finally, we interrogated whether these observations could be translated to a human scenario. Indeed, SAA1, the ortholog of murine Saa3, is overexpressed in human CAFs. Moreover, high levels of SAA1 in the stromal component correlate with worse survival. These findings support the concept that selective inhibition of SAA1 in CAFs may provide potential therapeutic benefit to PDAC patients.

The molecular basis for the propensity of a small number of environmental proteins to provoke allergic responses is largely unknown. Herein, we report that mite group 13 allergens of the fatty acid-binding protein (FABP) family are sensed by an evolutionarily conserved acute-phase protein, serum amyloid A1 (SAA1), that promotes pulmonary type 2 immunity. Mechanistically, SAA1 interacted directly with allergenic mite FABPs (Der p 13 and Blo t 13). The interaction between mite FABPs and SAA1 activated the SAA1-binding receptor, formyl peptide receptor 2 (FPR2), which drove the epithelial release of the type-2-promoting cytokine interleukin (IL)-33 in a SAA1-dependent manner. Importantly, the SAA1–FPR2–IL-33 axis was upregulated in nasal epithelial cells from patients with chronic rhinosinusitis. These findings identify an unrecognized role for SAA1 as a soluble pattern recognition receptor for conserved FABPs found in common mite allergens that initiate type 2 immunity at mucosal surfaces. Smole and colleagues show that the soluble pattern recognition receptor serum amyloid A (SAA) recognizes several mite allergenic proteins, including Der p 13 and Blo t 13, which are conserved fatty acid-binding proteins. Such FABP–SAA1 binding triggers epithelial cell release of the type-2-promoting cytokine IL-33, which in turn drives IL-13 production and allergic syptoms.

To examine whether the long non‐coding RNA (lncRNA) metastasis associated lung adenocarcinoma transcript 1 (MALAT1) is altered in the endothelial cells in response to glucose and the significance of such alteration. We incubated human umbilical vein endothelial cells with media containing various glucose levels. We found an increase in MALAT1 expression peaking after 12 hrs of incubation in high glucose. This increase was associated with parallel increase in serum amyloid antigen 3 (SAA3), an inflammatory ligand and target of MALAT1 and was further accompanied by increase in mRNAs and proteins of inflammatory mediators, tumour necrosis factor alpha (TNF‐α) and interleukin 6 (IL‐6). Renal tissue from the diabetic animals showed similar changes. Such cellular alterations were prevented following MALAT1 specific siRNA transfection. Results of this study indicate that LncRNA MALAT1 regulates glucose‐induced up‐regulation of inflammatory mediators IL‐6 and TNF‐α through activation of SAA3. Identification of such novel mechanism may lead to the development of RNA‐based therapeutics targeting MALAT1 for diabetes‐induced micro and macro vascular complications.

The liver is the most common site of metastatic disease 1 . Although this metastatic tropism may reflect the mechanical trapping of circulating tumour cells, liver metastasis is also dependent, at least in part, on the formation of a ‘pro-metastatic’ niche that supports the spread of tumour cells to the liver 2 , 3 . The mechanisms that direct the formation of this niche are poorly understood. Here we show that hepatocytes coordinate myeloid cell accumulation and fibrosis within the liver and, in doing so, increase the susceptibility of the liver to metastatic seeding and outgrowth. During early pancreatic tumorigenesis in mice, hepatocytes show activation of signal transducer and activator of transcription 3 (STAT3) signalling and increased production of serum amyloid A1 and A2 (referred to collectively as SAA). Overexpression of SAA by hepatocytes also occurs in patients with pancreatic and colorectal cancers that have metastasized to the liver, and many patients with locally advanced and metastatic disease show increases in circulating SAA. Activation of STAT3 in hepatocytes and the subsequent production of SAA depend on the release of interleukin 6 (IL-6) into the circulation by non-malignant cells. Genetic ablation or blockade of components of IL-6–STAT3–SAA signalling prevents the establishment of a pro-metastatic niche and inhibits liver metastasis. Our data identify an intercellular network underpinned by hepatocytes that forms the basis of a pro-metastatic niche in the liver, and identify new therapeutic targets. Pancreatic cancer activates IL-6–STAT3 signalling in hepatocytes to induce the formation of a pro-metastatic niche in the liver.

T cell infiltration into tumors is a favorable prognostic feature, but most solid tumors lack productive T cell responses. Mechanisms that coordinate T cell exclusion are incompletely understood. Here we identify hepatocyte activation via interleukin-6/STAT3 and secretion of serum amyloid A (SAA) proteins 1 and 2 as important regulators of T cell surveillance of extrahepatic tumors. Loss of STAT3 in hepatocytes or SAA remodeled the tumor microenvironment with infiltration by CD8 + T cells, while interleukin-6 overexpression in hepatocytes and SAA signaling via Toll-like receptor 2 reduced the number of intratumoral dendritic cells and, in doing so, inhibited T cell tumor infiltration. Genetic ablation of SAA enhanced survival after tumor resection in a T cell-dependent manner. Likewise, in individuals with pancreatic ductal adenocarcinoma, long-term survivors after surgery demonstrated lower serum SAA levels than short-term survivors. Taken together, these data define a fundamental link between liver and tumor immunobiology wherein hepatocytes govern productive T cell surveillance in cancer. Here the authors show how the liver affects the immune response to pancreatic ductal adenocarcinoma and that cancer immunity and survival outcomes after surgery might be bolstered by therapeutic intervention on hepatocyte release of serum amyloid A proteins.

Although pancreatic cancer often invades peripancreatic adipose tissue, little information is known about cancer‐adipocyte interaction. We first investigated the ability of adipocytes to de‐differentiate to cancer‐associated adipocytes (CAAs) by co‐culturing with pancreatic cancer cells. We then examined the effects of CAA‐conditioned medium (CAA‐CM) on the malignant characteristics of cancer cells, the mechanism underlying those effects, and their clinical relevance in pancreatic cancer. When 3T3‐L1 adipocytes were co‐cultured with pancreatic cancer cells (PANC‐1) using the Transwell system, adipocytes lost their lipid droplets and changed morphologically to fibroblast‐like cells (CAA). Adipocyte‐specific marker mRNA levels significantly decreased but those of fibroblast‐specific markers appeared, characteristic findings of CAA, as revealed by real‐time PCR. When PANC‐1 cells were cultured with CAA‐CM, significantly higher migration/invasion capability, chemoresistance, and epithelial‐mesenchymal transition (EMT) properties were observed compared with control cells. To investigate the mechanism underlying these effects, we performed microarray analysis of PANC‐1 cells cultured with CAA‐CM and found a 78.5‐fold higher expression of SAA1 compared with control cells. When the SAA1 gene in PANC‐1 cells was knocked down with SAA1 siRNA, migration/invasion capability, chemoresistance, and EMT properties were significantly attenuated compared with control cells. Immunohistochemical analysis on human pancreatic cancer tissues revealed positive SAA1 expression in 46/61 (75.4%). Overall survival in the SAA1‐positive group was significantly shorter than in the SAA1‐negative group (P = .013). In conclusion, we demonstrated that pancreatic cancer cells induced de‐differentiation in adipocytes toward CAA, and that CAA promoted malignant characteristics of pancreatic cancer via SAA1 expression, suggesting that SAA1 is a novel therapeutic target in pancreatic cancer. Cancer‐associated adipocyte (CAA) promotes migration/invasion of pancreatic cancer cells. CAA also induced pancreatic cancer cells drug resistance, epithelial‐mesenchymal transition.