PurposeWe evaluated the prognostic value of total lesion glycolysis (TLG) measured in baseline 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in diffuse large B-cell lymphoma (DLBCL) treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP).MethodsA total of 91 patients with newly diagnosed DLBCL underwent 18F-FDG PET/CT scans before R-CHOP therapy. Metabolic tumor volume (MTV) was measured with the marginal threshold of normal liver mean standard uptake value (SUVmean) plus 3 standard deviations (SD). TLG was the sum of the products of MTV and SUVmean in all measured lesions. The predictive value was estimated by Log-rank test and Cox-regression analysis.ResultsMedian follow-up was 30 months (range, 5-124 months). The 5-year estimated progression-free survival (PFS) of the low and high TLG group were 83% and 34%, respectively (p<0.001). The 5-year overall survival (OS) of the same groups were 92% and 67%, respectively (p<0.001). Patients with high TLG level were more likely to relapse than those with low TLG level even though they had got complete or partial remission in R-CHOP therapy (40% versus 9%, p=0.012). Multivariate analysis revealed TLG was the only independent predictor for PFS (Hazard ratio=5.211, 95% confidence interval=2.210-12.288, p<0.001) and OS (Hazard ratio=9.136, 95% confidence interval=1.829-45.644, p=0.002). Other factors including MTV, National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) and Ann Arbor Stage were not independently predictive for survivals.ConclusionBaseline TLG is the only independent predictor for PFS and OS in DLBCL patients treated with R-CHOP therapy.

Edited by Xiao-Fan WangRET is a transmembrane growth factor receptor. Aberrantly activated RET is found in several types of human cancer and is a target for treating RET aberration-associated cancer. Multiple clinically relevant RET protein-tyrosine kinase inhibitors (TKIs) have been identified, but how TKIs bind to RET is unknown except for vandetanib. Nintedanib is a RET TKI that inhibits the vandetanib-resistant RET(G810A) mutant. Here, we determined the X-ray co-crystal structure of RET kinase domain-nintedanib complex to 1.87 Å resolution and a RET(G810A) kinase domain crystal structure to 1.99 Å resolution. We also identified a vandetanib-resistant RET(L881V) mutation previously found in familial medullary thyroid carcinoma. Drug-sensitivity profiling of RET(L881V) revealed that it remains sensitive to nintedanib. The RET-nintedanib co-crystal structure disclosed that Leu-730 in RET engages in hydrophobic interactions with the piperazine, anilino, and phenyl groups of nintedanib, providing a structural basis for explaining

Nod-like receptor protein 3 (NLRP3)-mediated pyroptosis has a causal role in the pathogenesis of gout. P2Y14 receptor (P2Y14R) distributed in immune cells including macrophages is a Gi-coupled receptor that inhibits the synthesis of cAMP, which has been regarded as a potential regulator of inflammatory response. Nevertheless, the role of P2Y14R in MSU-induced pyroptosis of macrophages involved in acute gouty arthritis is still unclear. In our present study, P2Y14R knockout (P2Y14R-KO) disrupted MSU-induced histopathologic changes in rat synoviums, accompanied with a significant inhibition of pyroptotic cell death characterized by Caspase-1/PI double-positive and blockade of NLRP3 inflammasome activation in synovial tissues, which was consistent with that observed in in vitro studies. Owing to the interaction of NLRP3 inflammasome and cAMP, we then investigated the effect of adenylate cyclase activator (Forskolin) on macrophage pyroptosis and gout flare caused by MSU stimulation. The reversal effect of Forskolin verified the negative regulatory role of cAMP in MSU-induced pyroptosis. More importantly, adenylate cyclase inhibitor (SQ22536) intervention led to a reversal of protection attributed to P2Y14R deficiency. Findings in air pouch animal models also verified aforementioned experimental results. Our study first identified the role of P2Y14R/cAMP/NLRP3 signaling pathway in acute gouty arthritis, which provides a novel insight into the pathological mechanisms of pyroptosis-related diseases.

Background: Acute gouty arthritis is a common inflammatory arthropathy resulting from urate deposition in joints during persistent hyperuricemia. Nevertheless, effective therapeutic strategies are still unavailable. Here, we propose the crucial role of bromodomain-containing protein 4 (BRD4) in acute gouty arthritis. Methods: Therapeutic effect of BRD4 specific inhibitor JQ-1 on acute gouty arthritis was evaluated in vivo and in vitro. Pyroptosis was analyzed by Caspase-1/PI double staining and cleavage of gasdermin D (GSDMD). Expression of key factors involved in BRD4/NF-κB/NLRP3/GSDMD signaling pathway were measured by western blot, and colocalization of NLRP3 and ASC was detected using immunofluorescence. In addition, the role of BRD4 on monosodium uric acid crystals (MSU)-induced pyroptosis was verified in BRD4 siRNA-transfected THP-1 cells. Results: Pretreatment of JQ1 and BRD4 siRNA significantly suppressed pyroptosis and inhibited activation of p65 NF-κB signaling as well as NLRP3 inflammasome in THP-1 cells exposed to MSU. In vivo, JQ-1 administration could effectively attenuate joint swelling and synovial inflammation in rats treated by intra-articular injection of MSU. More importantly, MSU led to macrophage pyroptosis and Brd4/NF-κB/NLRP3/GSDMD signaling induction in rat synoviums, which was improved by JQ-1. Conclusions: Our study identifies the role of BRD4 in MSU-induced pyroptosis through regulating NF-κB/NLRP3/GSDMD signaling pathways, which provides a potential target for treatment of acute gouty arthritis.

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Purpose: The value of 18F-fluorodeoxyglucose positron emission tomography /computed tomography (18F-FDG PET/CT) in assessing bone marrow involvement (BMI) of lymphoma remains controversial. The present study aims to evaluate the prognostic meaning of bone marrow FDG uptake pattern in PET/CT of newly diagnosed diffuse large B-cell lymphoma (DLBCL) patients.Materials and Methods: 193 newly diagnosed DLBCL patients were retrospectively analyzed. All patients received 6-8 cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). The type of BM FDG uptake pattern was recorded by two blinded reviewers independently. The relationship between clinicopathologic features and BM patterns was analyzed. The prognostic value of different BM patterns was evaluated by Log-rank test and Cox-regression analysis.Results: Out of 193 patients, 28 (15%) patients had focal BM FDG uptake higher than liver (fPET+), 18 (9%) patients showed diffuse BM uptake higher than liver (dPET+) and 147 (76%) patients had normal BM uptake (lower than liver) (nPET). BMB positive was found in 35.7% (10/28) of fPET+ patients, in 16.7% (3/18) of dPET+ patients and in 0.7% (1/147) of nPET patients. Diffuse BM pattern was associated with lower hemoglobin level and a trend of higher erythrocyte sedimentation rate (ESR). dPET+ patients had similar 3y-progression-free survival (3y-PFS) and 3y-overall survival (3y-OS) compared with nPET patients (80.5% vs 81.5%, p=0.701; 94.1% vs 90.6%, p=0.809, respectively), while fPET+ patients had worse 3y-PFS and 3y-OS compared with fPET- patients (32.7% vs 81.4%, p<0.001; 69.4% vs 90.9%, p=0.003, respectively). Multivariate analysis showed fPET+ (HR=2.270, p=0.025) and stage III/IV (HR=4.909, p=0.026) were independent predictors for PFS, but no factors were independently predictive for OS.Conclusion: PET/CT-directed BM patterns are meaningful in predicting prognosis of newly diagnosed DLBCL patients. Focal BM pattern is an independent predictor for PFS.

Background: Cone snail venoms are a rich source of novel peptide toxins. Results: Conus imperialis contains two new toxins that define a new cysteine framework and adopt an uncommon all-helical structure. Conclusion: im23a is a novel conotoxin with respect to amino acid sequence, cysteine framework, and three-dimensional structure. Significance: These new toxins extend the repertoire of novel peptides derived from cone snails.

Although the interaction mechanism between shock waves and cells is critical for advancing the medical applications of shock waves, we still have little understanding about it. This work aims to study the response of diseased cells subjected to lipid peroxidation to the nanojet from shock wave-induced bubble collapse by using the coarse-grained molecular dynamics simulation. Factors considered in the simulations include the shock velocity (u p), movement time of piston (τp), bubble size (R), and peroxidation level of membranes. Here, we mainly focus on the role of peroxidation levels, that is, the degree (%) and the distribution of oxidized lipids in membranes. The results indicate that the shock damage threshold (u p at which the pore in membranes is formed) of peroxidation membranes is less than that of normal membranes and decreases with the peroxidation degree. Importantly, the distribution of oxidized lipids has more effect on the damage threshold than the peroxidation degree. The threshold of membrane with 33% localized oxidized lipids is lower than that of membrane with 50% average oxidized lipids. The results can be explained by the stretching modulus (κs) and bending modulus (κb) of cell membranes. For example, the κb value (4.3 × 10–20 J) of 100% peroxidation membrane is about half of that (8.4 × 10–20 J) of a membrane without peroxidation. A lower modulus means high deformation under the same impact. Further analysis shows that peroxidation introduces a polar hydrophobic group to the tail of phospholipids that increases the hydrophilicity of tails and warps the tail of phospholipids toward the membrane–water interface, resulting in looser accumulation. This can be confirmed by the increased average phospholipid area with peroxidation levels. Indeed, most of the pores formed during the shock can heal. However, the permeation of water molecules across the healing membrane still increased. All these membrane-level information obtained from this study will be useful for improving the biomedical applications of shock waves.