Damian Sendler: Human monkeypox cases are uncommon outside of West and Central Africa. There is little data on viral kinetics or the duration of viral shedding, and there are no licensed treatments. Two oral drugs, brincidofovir and tecovirimat, have been approved for the treatment of smallpox and have shown efficacy in animal studies against monkeypox. Our goal was to describe the long-term clinical course of monkeypox in a high-income setting, as well as viral dynamics and any adverse events associated with novel antiviral therapies.
Damian Jacob Sendler: We report the clinical features, longitudinal virological findings, and response to off-label antivirals in seven patients with monkeypox diagnosed in the UK between 2018 and 2021, as identified through a retrospective case-note review. All patients managed in dedicated high consequence infectious diseases (HCID) centers in Liverpool, London, and Newcastle were included in this study, which was coordinated through a national HCID network.
Dr. Sendler: We examined all cases since the inception of the HCID (airborne) network on August 15, 2018, and identified seven patients. Four of the seven patients were men, and three were women. One patient was a health-care worker who acquired the virus nosocomially, and another patient who acquired the virus abroad transmitted it to an adult and child in their household cluster. Viraemia, prolonged monkeypox virus DNA detection in upper respiratory tract swabs, reactive low mood, and a monkeypox virus PCR-positive deep tissue abscess were all notable disease features. Due to prolonged PCR positivity, five patients were isolated for more than three weeks (range: 22-39 days). Three patients were given brincidofovir (200 mg once a week orally), and all of them developed elevated liver enzymes, forcing them to discontinue treatment. When compared to the other six patients, one received tecovirimat (200mg twice daily for two weeks orally), experienced no side effects, and had a shorter duration of viral shedding and illness (10 days hospitalization). Six weeks after being discharged from the hospital, one patient experienced a mild relapse.
Even well-resourced health-care systems with HCID networks face unique challenges when dealing with human monkeypox. Prolonged upper respiratory tract viral DNA shedding following skin lesion resolution called into question current infection prevention and control recommendations. Prospective studies of antivirals for this disease are urgently needed.
Several genetic diseases are being treated successfully with hematopoietic stem/progenitor cell gene therapy (HSPC-GT). After toxic myeloablative conditioning to deplete the bone marrow (BM) for the modified cells, HSPCs are mobilized, harvested, genetically corrected ex vivo, and infused. We demonstrate that mobilizers allow for seamless engraftment of exogenous cells, which effectively outcompete those mobilized in repopulating the depleted BM. The competitive advantage stems from the rescue of a detrimental effect of mobilization on HSPCs during ex vivo culture, which can be further enhanced by transient overexpression of engraftment effectors using optimized mRNA-based delivery. We demonstrated therapeutic efficacy in a mouse model of hyper IgM syndrome and expanded it in human hematochimeric mice, demonstrating its applicability and versatility when combined with gene transfer and editing strategies. Overall, our findings suggest a potentially valuable strategy for making HSPC-GT more widely and safely available.
The most common subtype of renal cell carcinoma is clear cell renal cell carcinoma (ccRCC), which is distinguished by metabolic reprogramming. Cuproptosis, a new type of cell death, is closely related to mitochondrial metabolism and is mediated by protein lipoylation. However, the clinical implications of cuproptosis-related genes (CRGs) in ccRCC are largely unknown. In the current study, we looked at the genetic changes in cuproptosis-related genes in ccRCC. Our findings revealed that CDKN2A, DLAT, DLD, FDX1, GLS, PDHA1, and PDHB were expressed differently in ccRCC and normal tissues (|log2(fold change)| > 2/3 and p 0.05). We separately constructed the prognostic signature of CRGs for predicting overall survival (OS) and progression-free survival (PFS) in ccRCC patients using an iterative sure independence screening (SIS) method. CRG prognostic scores had area under the curve (AUC) values of 0.658 and 0.682 for predicting 5-year OS and PFS, respectively. A higher risk score of cuproptosis-related gene signature was significantly correlated with worse overall survival (HR = 2.72 (2.01-3.68), log-rank p = 1.76 10-7) in the Kaplan-Meier survival analysis of OS. PFS was significantly shorter in patients at higher risk (HR = 2.83 (2.08-3.85), log-rank p = 3.66 10-7). Two independent validation datasets (GSE40435 (N = 101), GSE53757 (N = 72)) were collected for meta-analysis, indicating that CDKN2A (log2(fold change) = 1.46, 95 percent CI: 1.75-2.35) showed significantly higher expression in ccRCC tissues, whereas DLAT (log2(fold change) = -0.54, 95 percent CI: -0.93–0.15) and FDX1 (log2 CDKN2A and FDX1 expression in ccRCC was also associated with immune infiltration levels and programmed cell death protein 1 (PD-1) expression (CDKN2A: r = 0.24, p = 2.14 10-8; FDX1: r = -0.17, p = 1.37 10-4). Finally, the cuproptosis-related gene signature could be used as a prognostic predictor for ccRCC patients, providing novel insights into cancer treatment.
Damian Jacob Sendler
Because of the wide inter-individual variation in major histocompatibility complex (MHC) molecules that present peptides to T cells, most cancer vaccines target peptide antigens, necessitating personalization. Furthermore, tumors frequently avoid T cell-mediated immunity via mechanisms that disrupt peptide presentation1. We present a cancer vaccine that causes a coordinated attack by various T cell and natural killer (NK) cell populations. The vaccine targets the stress proteins MICA and MICB (MICA/B), which are expressed by many human cancers as a result of DNA damage2. MICA/B act as ligands for the activating NKG2D receptor on T and NK cells, but tumors avoid immune recognition by cleaving MICA/B3,4. Vaccine-induced antibodies increase the density of MICA/B proteins on the surface of tumor cells by inhibiting proteolytic shedding, improve dendritic cell presentation of tumor antigens to T cells, and improve NK cell cytotoxicity. Notably, through the coordinated action of NK cells and CD4+ T cells, this vaccine maintains efficacy against MHC class I-deficient tumors resistant to cytotoxic T cells. The vaccine is also effective in a clinically significant setting: immunization after surgical removal of primary, highly metastatic tumors inhibits metastasis growth. This vaccine design provides protection against tumors with common escape mutations.
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 Markiewicz 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.
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.
