Design principles for inflammasome inhibition by pyrin-only-proteins.

Inflammasomes are filamentous signaling platforms essential for host defense against various intracellular calamities such as pathogen invasion and genotoxic stresses. However, dysregulated inflammasomes cause an array of human diseases including autoinflammatory disorders and cancer. It was recently identified that endogenous pyrin-only-proteins (POPs) regulate inflammasomes by directly inhibiting their filament assembly. Here, by combining Rosetta in silico, in vitro, and in cellulo methods, we investigate the target specificity and inhibition mechanisms of POPs. We find here that POP1 is ineffective in directly inhibiting the central inflammasome adaptor ASC. Instead, POP1 acts as a decoy and targets the assembly of upstream receptor pyrin-domain (PYD) filaments such as those of AIM2, IFI16, NLRP3, and NLRP6. Moreover, not only does POP2 directly suppress the nucleation of ASC, but it can also inhibit the elongation of receptor filaments. In addition to inhibiting the elongation of AIM2 and NLRP6 filaments, POP3 potently suppresses the nucleation of ASC. Our Rosetta analyses and biochemical experiments consistently suggest that a combination of favorable and unfavorable interactions between POPs and PYDs is necessary for effective recognition and inhibition. Together, we reveal the intrinsic target redundancy of POPs and their inhibitory mechanisms.

Endovascular Management of Life-Threatening Hemoptysis in Primary Lung Cancer: A Retrospective Study.

OBJECTIVE: The aim of this study was to evaluate the efficacy and safety of endovascular treatment of hemoptysis caused by primary lung cancer. METHODS: We conducted a single-center retrospective study (2005-2021), including patients who underwent thoracic embolization for life-threatening hemoptysis complication of lung cancer. Exclusion criteria were hemoptysis caused by a benign lung tumor or by a lung metastasis of a primary non-lung tumor. Depending on the origin of the bleeding, determined by CT-angiography, systemic arteries were treated with microspheres or coils, and pulmonary arteries with coils, plugs or covered stents. Outcomes were assessed from patients' medical records in April 2022. Primary endpoints were clinical success at one month and at one year. Secondary endpoints were incidence of complications, 1 year overall survival, and relative risk of recurrence of hemoptysis. Survival was compared with a log-rank test. RESULTS: Sixty-two patients underwent 68 systemic artery embolizations and 14 pulmonary artery procedures. Clinical success defined as cessation of hemoptysis without any recurrence was 81% at one month and 74% at one year. Three major complications occurred: spinal cord ischemia, stroke, and acute pancreatitis. 5% of patient died from hemoptysis. One-year overall survival was 29% and was significantly higher in patients without hemoptysis recurrence when compared to patients with recurring hemoptysis (p = 0.021). In univariate analysis, recurrence of hemoptysis at one year was associated with massive hemoptysis (RR = 2.50; p = 0.044) and with tumor cavitation (RR = 2.51; p = 0.033). CONCLUSION: Endovascular treatment for primary lung cancer-related hemoptysis is effective but not uneventful.

Endovascular treatment of haemorrhagic pancreatic serous cystadenoma.

BACKGROUND: Pancreatic microcystic serous cystadenoma are rare benign pancreatic tumors. No treatment is needed in most cases as this lesion is often discovered incidentally. Surgery is not required except in symptomatic cases. CASE PRESENTATION: We report herein a rare case of pancreatic serous cystadenoma complicated with a hemorrhage in a 95 years old patient treated with arterial embolization since surgery was not possible. The patient recovered without any adverse events or bleed recurrence in the 6 months following the procedure. CONCLUSION: Hemorrhage secondary to a pancreatic serous cystadenoma was successfully treated with arterial embolization, which may represent an alternative therapeutic option to surgery.

Synchronous global assessment of gene and protein expression in colorectal cancer progression.

Well-established models of colorectal cancer progression are based on the idea that the disease evolves through a multistep process involving sequential genetic mutations, suggesting that progression through clinically defined stages should correlate with well-defined patterns of gene expression. The majority of studies to date, however, have assessed these processes one gene and one protein at a time. We report the first comprehensive assessment of both gene and protein expression performed in parallel across progressive stages of human colorectal neoplasia. Remarkably, despite the global nature of the gene expression assessment, very few genes could be linked with certainty to specific proteins through currently available annotations. Furthermore, the correlation of expression between identified genes and proteins was poor. Nevertheless, both produced expression signatures that differentiated normal mucosa and nonmalignant adenomas from each other and from the malignant carcinomas and both produced fairly consistent subclasses of the malignancies, suggesting that a molecular staging might be more appropriate provided that these profiles can be tied to clinical outcome. This is potentially important as clinical staging is widely used as a prognostic indicator and used in the decision to pursue adjuvant therapies.