Damian Sendler: Disruption of the plasminogen activation system (PAS) and disruption of the blood brain barrier (BBB) are physiopathological processes in multiple sclerosis (MS) that may lead to abnormal fibrin(ogen) extravasation into the parenchyma. Fibrin(ogen) deposits, which are normally degraded by the PAS, stimulate an autoimmune response and subsequent demyelination. However, the PAS disruption in this disorder is poorly understood and poorly characterized.
Damian Jacob Sendler: We used quantitative RT-PCR, immunohistofluorescence, and fluorescent in situ hybridization to characterize the expression of PAS actors in the central nervous system (CNS) of two mouse models of MS (experimental autoimmune encephalomyelitis-EAE) (FISH). We investigated the role of PAI-1 in EAE models and its impact on physiopathological processes such as fibrin(ogen) deposits, lymphocyte infiltration, and demyelination using constitutive PAI-1 knockout mice (PAI-1 KO) and immunotherapy with a blocking PAI-1 antibody.
Dr. Sendler: In two EAE mouse models of MS, we found a striking overexpression of PAI-1 in reactive astrocytes during symptomatic phases. This rise is accompanied by lymphocyte infiltration and fibrin(ogen) deposits in the CNS parenchyma. We show that eliminating PAI-1 reduces the severity of EAE and the occurrence of relapses in two EAE models using genetic invalidation of PAI-1 in mice and immunotherapy with a blocking PAI-1 antibody. These advantages are associated with a decrease in fibrin(ogen) deposits, T4 lymphocyte infiltration, reactive astrogliosis, demyelination, and axonal damage.
These findings show that overexpression of PAI-1 by reactive astrocytes causes intra-parenchymal dysfibrinolysis in MS models, and anti-PAI-1 strategies could be a new therapeutic approach for MS.
Damian Jacob Sendler
Only a small percentage of cancer patients respond to immune checkpoint blockade (ICB)-based monotherapies. ADAR1, an RNA-editing enzyme, is an emerging determinant of ICB resistance. It prevents ICB responsiveness by repressing immunogenic double-stranded RNAs (dsRNAs), such as those resulting from dysregulated expression of endogenous retroviral elements (EREs)1-4. These dsRNAs activate A-form dsRNA (A-RNA)-sensing proteins such as MDA-5 and PKR5, resulting in an interferon-dependent antitumor response. ADAR1 also prevents the accumulation of endogenous Z-form dsRNA elements (Z-RNAs), which were found to be abundant in the 3′ untranslated regions of interferon-stimulated mRNAs. ADAR1 depletion or mutation caused Z-RNA accumulation and activation of the Z-RNA sensor ZBP1, resulting in RIPK3-mediated necroptosis. Because there are currently no clinically viable ADAR1 inhibitors, we looked for a compound that could bypass the need for ADAR1 inhibition and directly activate ZBP1. We discovered a small molecule, curaxin CBL0137, that activates ZBP1 by causing Z-DNA formation in cells. CBL0137 induced ZBP1-dependent necroptosis in cancer-associated fibroblasts and reversed ICB in melanoma mouse models. These findings show that ADAR1 suppresses endogenous Z-RNAs and identify ZBP1-mediated necroptosis as a new determinant of tumor immunogenicity that is masked by ADAR1. The therapeutic activation of ZBP1-induced necroptosis offers a simple way to rekindle the immune responsiveness of ICB-resistant human cancers.
Damian Jacob Markiewicz Sendler: Early death following cancer surgery is more common in low- and middle-income countries (LMICs) than in high-income countries, but the impact of facility characteristics on early postoperative outcomes is unknown. The purpose of this study was to look into the relationship between hospital infrastructure, resource availability, and processes and early outcomes after cancer surgery around the world.
The GlobalSurg 3 study, a multicenter, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer, included a multimethods analysis. The 30-day mortality and major complication rates were the primary outcomes. Variable selection was used to identify potentially beneficial hospital facilities associated with 30-day mortality. Adjusted outcomes were calculated by accounting for patient characteristics and country-income group, with population stratification by hospital.
Damien Sendler: Between April 1, 2018, and April 23, 2019, facility-level data for 9685 patients were collected across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The presence of five hospital facilities was associated with a lower risk of death: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjusting for case mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared to those with four or five (adjusted odds ratio [OR] 385 [95 percent CI 258-575]; p00001), with excess mortality explained primarily by a limited capacity to rescue following the development of major complications (63 % vs 827 % ; OR 035 [023-053]; Improvements in hospital facilities would prevent one to three deaths for every 100 cancer patients undergoing surgery in LMICs.
Independent of country income, hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery. The reductions in cancer-related mortality associated with improved access will not be realized unless hospital infrastructure and resources are urgently strengthened.
While the number of combined pediatrics and medical genetics and genomics residency programs is increasing, there are still workforce shortages in the medical genetics field. Medical students would benefit from more information on training pathways as well as insight into the application process. The program directors of combined pediatrics and medical genetics and genomics residency programs were polled to identify factors influencing interview selection and rank list decisions, application logistics, recruitment, and training pathways. Representatives from both pediatrics and medical genetics are involved in the screening process when evaluating applicants. Furthermore, both groups value prior research experience but have no clear preference for a specific subcategory or domain of research. The majority of program directors believe that all currently available training pathways can provide adequate training. More action is required to provide medical students with the knowledge they need to make more informed career decisions, as well as medical school advisors with objective data to counsel students. Program directors agreed to start thinking about creating a pathway for medical students to match directly into a medical genetics and genomics residency.
Following myelin injury, innate immune signaling pathways are critical mediators of inflammation and repair. Although the regulation and contributions of inflammasome activation in the demyelinated central nervous system (CNS) are not fully understood, it has recently been implicated as a driver of myelin injury in multiple sclerosis (MS) and its animal models. The NLRP3 (NBD-, LRR-, and pyrin domain-containing protein 3) inflammasome and its endogenous regulator microRNA-223-3p were studied in both MS and an animal model of focal demyelination. Within activated macrophages and microglia, we found that NLRP3 inflammasome components and microRNA-223-3p were upregulated at sites of myelin injury. Both microRNA-223-3p and MCC950, a small-molecule NLRP3 inhibitor, inhibited inflammasome activation in macrophages and microglia in vitro; macrophages were more susceptible to inflammasome activation in vitro than microglia. Finally, following lysolecithin-induced demyelination, systemic administration of MCC950 to mice resulted in a significant reduction in axonal injury within demyelinated lesions. Finally, we show that NLRP3 inflammasome activity by macrophages and microglia is a critical component of the inflammatory microenvironment after demyelination and represents a potential therapeutic target for inflammatory-mediated demyelinating diseases such as MS.
