Demonstrating Bioequivalence for Two Dose Strengths of Niraparib and Abiraterone Acetate Dual-Action Tablets Versus Single Agents: Utility of Clinical Study Data Supplemented with Modeling and Simulation.

BACKGROUND AND OBJECTIVE: The combination of niraparib and abiraterone acetate (AA) plus prednisone is under investigation for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) and metastatic castration-sensitive prostate cancer (mCSPC). Regular-strength (RS) and lower-strength (LS) dual-action tablets (DATs), comprising niraparib 100 mg/AA 500 mg and niraparib 50 mg/AA 500 mg, respectively, were developed to reduce pill burden and improve patient experience. A bioequivalence (BE)/bioavailability (BA) study was conducted under modified fasting conditions in patients with mCRPC to support approval of the DATs. METHODS: This open-label randomized BA/BE study (NCT04577833) was conducted at 14 sites in the USA and Europe. The study had a sequential design, including a 21-day screening phase, a pharmacokinetic (PK) assessment phase comprising three periods [namely (1) single-dose with up to 1-week run-in, (2) daily dose on days 1-11, and (3) daily dose on days 12-22], an extension where both niraparib and AA as single-agent combination (SAC; reference) or AA alone was continued from day 23 until discontinuation, and a 30-day follow-up phase. Patients were randomly assigned in a parallel-group design (four-sequence randomization) to receive a single oral dose of niraparib 100 mg/AA 1000 mg as a LS-DAT or SAC in period 1, and patients continued as randomized into a two-way crossover design during periods 2 and 3 where they received niraparib 200 mg/AA 1000 mg once daily as a RS-DAT or SAC. The design was powered on the basis of crossover assessment of RS-DAT versus SAC. During repeated dosing (periods 2 and 3, and extension phase), all patients also received prednisone/prednisolone 5 mg twice daily. Plasma samples were collected for measurement of niraparib and abiraterone plasma concentrations. Statistical assessment of the RS-DAT and LS-DAT versus SAC was performed on log-transformed pharmacokinetic parameters data from periods 2 and 3 (crossover) and from period 1 (parallel), respectively. Additional paired analyses and model-based bioequivalence assessments were conducted to evaluate the similarity between the LS-DAT and SAC. RESULTS: For the RS-DAT versus SAC, the 90% confidence intervals (CI) of geometric mean ratios (GMR) for maximum concentration at a steady state (Cmax,ss) and area under the plasma concentration-time curve from 0-24 h at a steady state (AUC 0-24h,ss) were respectively 99.18-106.12% and 97.91-104.31% for niraparib and 87.59-106.69 and 86.91-100.23% for abiraterone. For the LS-DAT vs SAC, the 90% CI of GMR for AUC0-72h of niraparib was 80.31-101.12% in primary analysis, the 90% CI of GMR for Cmax,ss and AUC 0-24h,ss of abiraterone was 85.41-118.34% and 86.51-121.64% respectively, and 96.4% of simulated LS-DAT versus SAC BE trials met the BE criteria for both niraparib and abiraterone. CONCLUSIONS: The RS-DAT met BE criteria (range 80%-125%) versus SAC based on 90% CI of GMR for Cmax,ss and AUC 0-24h,ss. The LS-DAT was considered BE to SAC on the basis of the niraparib component meeting the BE criteria in the primary analysis for AUC 0-72h; abiraterone meeting the BE criteria in additional paired analyses based on Cmax,ss and AUC 0-24h,ss; and the percentage of simulated LS-DAT versus SAC BE trials meeting the BE criteria for both. GOV IDENTIFIER: NCT04577833.

Bioequivalence of 240 mg Apalutamide Tablets and Preparation in Aqueous Food Vehicles for Alternative Administration.

A 240-mg single tablet has been developed with the focus of reducing the pill burden of the apalutamide daily dose of 240 mg (4 × 60-mg tablets). An open-label, randomized, single-dose phase 1 study with a 2-sequence and 2-period crossover design in healthy men determined the bioequivalence of a 240-mg single tablet versus the currently available 4 × 60-mg tablets (Part 1, N = 74) and assessed effect of a high-fat meal (Part 2, N = 21) on apalutamide maximum plasma concentration (Cmax) and the area under the plasma concentration-time curve (AUC0-72 h). The 90% confidence interval of geometric mean ratios for Cmax and AUC0-72 h fell between 80% and 125% for both Part 1 and Part 2. No new safety concerns with the 240-mg single tablet were observed. To support the use of different food vehicles as well as nasogastric (NG) tubes for alternative administration, we conducted in vitro compatibility studies to evaluate the purity, dose, and stability of 240-mg tablets dispersed in applesauce/yogurt/orange juice/green tea as well as in NG tubes (polyurethane/silicone/polyvinyl chloride). The studies confirmed the alternative administrations do not affect the purity, dose-accuracy, or stability of apalutamide. The apalutamide 240-mg tablet is bioequivalent to 4 × 60-mg tablets and compatible with the tested food vehicles and NG tubes.

Convergent coexpression of autism-associated genes suggests some novel risk genes may not be detectable in large-scale genetic studies.

Autism spectrum disorder (ASD) is a heritable neurodevelopmental disorder characterized by deficits in social interactions and communication. Protein-altering variants in many genes have been shown to contribute to ASD; however, understanding the convergence across many genes remains a challenge. We demonstrate that coexpression patterns from 993 human postmortem brains are significantly correlated with the transcriptional consequences of CRISPR perturbations in human neurons. Across 71 ASD risk genes, there was significant tissue-specific convergence implicating synaptic pathways. Tissue-specific convergence was further demonstrated across schizophrenia and atrial fibrillation risk genes. The degree of ASD convergence was significantly correlated with ASD association from rare variation and differential expression in ASD brains. Positively convergent genes showed intolerance to functional mutations and had shorter coding lengths than known risk genes even after removing association with ASD. These results indicate that convergent coexpression can identify potentially novel genes that are unlikely to be discovered by sequencing studies.

wrk-1 and rig-5 control pioneer and follower axon navigation in the ventral nerve cord of Caenorhabditis elegans in a nid-1 mutant background.

During nervous system development, neurons send out axons, which must navigate large distances to reach synaptic targets. Axons grow out sequentially. The early outgrowing axons, pioneers, must integrate information from various guidance cues in their environment to determine the correct direction of outgrowth. Later outgrowing follower axons can at least in part navigate by adhering to pioneer axons. In Caenorhabditis elegans, the right side of the largest longitudinal axon tract, the ventral nerve cord, is pioneered by the AVG axon. How the AVG axon navigates is only partially understood. In this study, we describe the role of two members of the IgCAM family, wrk-1 and rig-5, in AVG axon navigation. While wrk-1 and rig-5 single mutants do not show AVG navigation defects, both mutants have highly penetrant pioneer and follower navigation defects in a nid-1 mutant background. Both mutations increase the fraction of follower axons following the misguided pioneer axon. We found that wrk-1 and rig-5 act in different genetic pathways, suggesting that we identified two pioneer-independent guidance pathways used by follower axons. We assessed general locomotion, mechanosensory responsiveness, and habituation to determine whether axonal navigation defects impact nervous system function. In rig-5 nid-1 double mutants, we found no significant defects in free movement behavior; however, a subpopulation of animals shows minor changes in response duration habituation after mechanosensory stimulation. These results suggest that guidance defects of axons in the motor circuit do not necessarily lead to major movement or behavioral defects but impact more complex behavioral modulation.

Correction: Hung et al. Anti-Inflammatory Fibronectin-AgNP for Regulation of Biological Performance and Endothelial Differentiation Ability of Mesenchymal Stem Cells. Int. J. Mol. Sci. 2021, 22, 9262.

The authors wish to make the following correction to this paper [...].

Identifying the needs of our older community-based patients in the COVID era: A telephone survey.

Background: Older people's vulnerability during a pandemic may extend to social connectedness, access to healthcare, and information delivery. We sought to identify whether and how older community-based patients are maintaining connections and accessing information during COVID-19. Methods: We administered a telephone questionnaire to all patients (or carer/proxy answering 'on patient's behalf') who previously attended our Geriatric Medicine clinic, May-December 2019. Results: Response rate was 58.8% (151/257), carer respondents comprising 23.8% (36/151). Mean patient age was 81.8 years (SD 8.6); 59.6% were female, 15.2% lived alone. English was the preferred language for 72.9% (110/151). Almost half (46.4%, 70/151) felt COVID-related restrictions had impacted them. Thirty-eight percent (58/151) reported feelings of social isolation, most (38/58) reporting this new since COVID. Nonetheless, 92.1% (139/151) reported maintaining social connections, all with family (139/139), less often with friends (69.8%, 97/139). COVID-related information sources included television 68.9% (104/151), family/friends (54.3%), healthcare providers (24.5%), and written sources (21.2%, 32/151); 12.6% used online resources. Increasing age lowered likelihood of accessing online information, while having smartphone/computer increased. Most (82.6%) believed their healthcare needs were being met, and 76.1% had accessed their GP, 87% (100/115) in-person. Only 33.1% (50/151) agreed telehealth acceptable, more often those with smartphone/computer (OR 2.15, p=0.04). Conclusions: Interventions to reduce isolation and optimize connectedness and healthcare- despite physical distancing- are important during COVID-19. During a rapidly evolving pandemic, healthcare delivery and information provision to our older population is likely best served by a multifaceted approach which acknowledges identified preferences, practices and barriers.

Protein disulfide isomerase a4 promotes lung cancer development via the Stat3 pathway in stromal cells.

BACKGROUND: Protein disulfide isomerases a4 (Pdia4) is known to be involved in cancer development. Our previous publication showed that Pdia4 positively promotes cancer development via its inhibition of procaspase-dependent apoptosis in cancer cells. However, nothing is known about its role in the cancer microenvironment. RESULTS: Here, we first found that Pdia4 expression in lung cancer was negatively correlated with patient survival. Next, we investigated the impact of host Pdia4 in stromal cells during cancer development. We showed that Pdia4 was expressed at a low level in stromal cells, and this expression was up-regulated akin to its expression in cancer cells. This up-regulation was stimulated by tumour cell-derived stimuli. Genetics studies in tumour-bearing wild-type and Pdia4-/- mice showed that host Pdia4 promoted lung cancer development in the mice via cancer stroma. This promotion was abolished in Rag1-/- mice which lacked T and B cells. This promotion could be restored once T and B cells were added back to Rag1-/- mice. In addition, host Pdia4 positively regulated the number and immunosuppressive function of stromal cells. Mechanistic studies showed that host Pdia4 positively controlled the Stat3/Vegf pathway in T and B lymphocytes via its stabilization of activated Stat3 in a Thioredoxin-like domain (CGHC)-dependent manner. CONCLUSIONS: These findings identify Pdia4 as a possible target for intervention in cancer stroma, suggesting that targeting Pdia4 in cancer stroma is a promising anti-cancer approach.

Translating stem cell research into development of cellular drugs-a perspective from manufacture of stem cell products and CMC considerations.

The development of human pluripotent stem cell (PSC)-derived medicinal products has been gathering steam in recent years, but the translation of research protocols into GMP production remains a daunting task. The challenges not only reside with the nature of cellular therapeutics but are also rooted in the general inexperience in industry-scale production of stem cell products. Manufacturers of PSC-derived products should be aware of the technical nuances and take a holistic approach toward early planning and engagement with their academic partners. While not all issues will be readily resolved soon, the collective knowledge and consensus by the manufacturers and key stakeholders will help to guide rapid progression of the field.

ccd-5, a novel cdk-5 binding partner, regulates pioneer axon guidance in the ventral nerve cord of Caenorhabditis elegans.

During nervous system development, axons navigate complex environments to reach synaptic targets. Early extending axons must interact with guidance cues in the surrounding tissue, while later extending axons can interact directly with earlier "pioneering" axons, "following" their path. In Caenorhabditis elegans, the AVG neuron pioneers the right axon tract of the ventral nerve cord. We previously found that aex-3, a rab-3 guanine nucleotide exchange factor, is essential for AVG axon navigation in a nid-1 mutant background and that aex-3 might be involved in trafficking of UNC-5, a receptor for the guidance cue UNC-6/netrin. Here, we describe a new gene in this pathway: ccd-5, a putative cdk-5 binding partner. ccd-5 mutants exhibit increased navigation defects of AVG pioneer as well as interneuron and motor neuron follower axons in a nid-1 mutant background. We show that ccd-5 acts in a pathway with cdk-5, aex-3, and unc-5. Navigation defects of follower interneuron and motoneuron axons correlate with AVG pioneer axon defects. This suggests that ccd-5 mostly affects pioneer axon navigation and that follower axon defects are largely a secondary consequence of pioneer navigation defects. To determine the consequences for nervous system function, we assessed various behavioral and movement parameters. ccd-5 single mutants have no significant movement defects, and nid-1 ccd-5 double mutants are less responsive to mechanosensory stimuli compared with nid-1 single mutants. These surprisingly minor defects indicate either a high tolerance for axon guidance defects within the motor circuit and/or an ability to maintain synaptic connections among commonly misguided axons.

Neurobiology: From genome and connectome to understanding behavior.

Many forms of synaptic plasticity are mediated by changes in the abundance, density, and expression levels of postsynaptic ionotropic receptors. A new study identifies the endogenous ligands of five 'orphan' aminergic ligand-gated ion channels in Caenorhabditis elegans, functionally characterizes these channels, and explores the role of one of them in a simple form of learning.

Anti-Inflammatory Fibronectin-AgNP for Regulation of Biological Performance and Endothelial Differentiation Ability of Mesenchymal Stem Cells.

The engineering of vascular regeneration still involves barriers that need to be conquered. In the current study, a novel nanocomposite comprising of fibronectin (denoted as FN) and a small amount of silver nanoparticles (AgNP, ~15.1, ~30.2 or ~75.5 ppm) was developed and its biological function and biocompatibility in Wharton's jelly-derived mesenchymal stem cells (MSCs) and rat models was investigated. The surface morphology as well as chemical composition for pure FN and the FN-AgNP nanocomposites incorporating various amounts of AgNP were firstly characterized by atomic force microscopy (AFM), UV-Visible spectroscopy (UV-Vis), and Fourier-transform infrared spectroscopy (FTIR). Among the nanocomposites, FN-AgNP with 30.2 ppm silver nanoparticles demonstrated the best biocompatibility as assessed through intracellular ROS production, proliferation of MSCs, and monocytes activation. The expression levels of pro-inflammatory cytokines, TNF-α, IL-1ß, and IL-6, were also examined. FN-AgNP 30.2 ppm significantly inhibited pro-inflammatory cytokine expression compared to other materials, indicating superior performance of anti-immune response. Mechanistically, FN-AgNP 30.2 ppm significantly induced greater expression of vascular endothelial growth factor (VEGF) and stromal-cell derived factor-1 alpha (SDF-1α) and promoted the migration of MSCs through matrix metalloproteinase (MMP) signaling pathway. Besides, in vitro and in vivo studies indicated that FN-AgNP 30.2 ppm stimulated greater protein expressions of CD31 and von Willebrand Factor (vWF) as well as facilitated better endothelialization capacity than other materials. Furthermore, the histological tissue examination revealed the lowest capsule formation and collagen deposition in rat subcutaneous implantation of FN-AgNP 30.2 ppm. In conclusion, FN-AgNP nanocomposites may facilitate the migration and proliferation of MSCs, induce endothelial cell differentiation, and attenuate immune response. These finding also suggests that FN-AgNP may be a potential anti-inflammatory surface modification strategy for vascular biomaterials.

Downregulation of exhausted cytotoxic T cells in gene expression networks of multisystem inflammatory syndrome in children.

Multisystem inflammatory syndrome in children (MIS-C) presents with fever, inflammation and pathology of multiple organs in individuals under 21 years of age in the weeks following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Although an autoimmune pathogenesis has been proposed, the genes, pathways and cell types causal to this new disease remain unknown. Here we perform RNA sequencing of blood from patients with MIS-C and controls to find disease-associated genes clustered in a co-expression module annotated to CD56dimCD57+ natural killer (NK) cells and exhausted CD8+ T cells. A similar transcriptome signature is replicated in an independent cohort of Kawasaki disease (KD), the related condition after which MIS-C was initially named. Probing a probabilistic causal network previously constructed from over 1,000 blood transcriptomes both validates the structure of this module and reveals nine key regulators, including TBX21, a central coordinator of exhausted CD8+ T cell differentiation. Together, this unbiased, transcriptome-wide survey implicates downregulation of NK cells and cytotoxic T cell exhaustion in the pathogenesis of MIS-C.

Pharmacokinetics and Use-Testing of Apalutamide Prepared in Aqueous Food Vehicles for Alternative Administration.

Patients may have difficulty swallowing a whole daily dose of 240 mg (4 × 60-mg tablets) of apalutamide. One of the unique properties of apalutamide tablets is easy disintegration and dispersion when mixed into aqueous vehicles, avoiding the need to crush/split the tablets. To evaluate whether this method of apalutamide tablet administration would be conducive in a patient setting, different variations in preparation were evaluated, and one preparation was tested in humans. In vitro compatibility studies evaluated purity, dose, or stability of different variations of apalutamide in applesauce/yogurt/orange juice/green tea. An open-label, randomized, crossover phase 1 study in healthy men determined the bioavailability of an apalutamide-applesauce mixture versus whole tablets based on maximum plasma analyte concentration (Cmax ), area under the plasma analyte concentration-time curve: AUC0-72h and AUC0-168h . Different amounts of applesauce/yogurt/orange juice/green tea as well as durations (up to 6 hours) did not affect the total apalutamide content available. The phase 1 study (n = 12) showed increased total exposure of 5% and peak exposure of 27.6% when comparing the apalutamide-applesauce mixture with whole-tablet administration. Variations in preparation times and total content for applesauce/yogurt/orange juice/green tea did not affect the purity, dose, or stability of apalutamide. An apalutamide-applesauce mixture is a suitable alternative administration method to whole tablets.

Using the dCas9-KRAB system to repress gene expression in hiPSC-derived NGN2 neurons.

We describe a CRISPR inhibition (CRISPRi) protocol to repress endogenous gene expression (e.g., ATP6V1A) in human induced pluripotent stem cell-derived NGN2-induced glutamatergic neurons. CRISPRi enables efficient and precise gene repression of one or multiple target genes via delivering gRNA(s) to direct a dCas9-KRAB fusion protein to the gene(s) of interest. This protocol can also be adapted for gene activation and high-throughput gene manipulation, allowing assessment of the transcriptomic and phenotypic impact of candidate gene(s) associated with neurodevelopment or brain disease. For complete details on the use and execution of this protocol, please refer to Ho et al. (2017) and Wang et al. (2021).

Niraparib with androgen receptor-axis-targeted therapy in patients with metastatic castration-resistant prostate cancer: safety and pharmacokinetic results from a phase 1b study (BEDIVERE).

PURPOSE: To assess the safety and pharmacokinetics and determine the recommended phase 2 dose (RP2D) of niraparib with apalutamide or abiraterone acetate plus prednisone (AAP) in patients with metastatic castration-resistant prostate cancer (mCRPC). METHODS: BEDIVERE was a multicenter, open-label, phase 1b study of niraparib 200 or 300 mg/day with apalutamide 240 mg or AAP (abiraterone acetate 1000 mg; prednisone 10 mg). Patients with mCRPC were previously treated with ≥ 2 lines of systemic therapy, including ≥ 1 androgen receptor-axis-targeted therapy for prostate cancer. RESULTS: Thirty-three patients were enrolled (niraparib-apalutamide, 6; niraparib-AAP, 27). No dose-limiting toxicities (DLTs) were reported when combinations included niraparib 200 mg; five patients receiving niraparib 300 mg experienced DLTs [niraparib-apalutamide, 2/3 patients (66.7%); niraparib-AAP, 3/8 patients (37.5%)]. Although data are limited, niraparib exposures were lower when given with apalutamide compared with historical niraparib monotherapy exposures in patients with solid tumors. Because of the higher incidence of DLTs, the niraparib-apalutamide combination and niraparib 300 mg combination with AAP were not further evaluated. Niraparib 200 mg was selected as the RP2D with AAP. Of 19 patients receiving niraparib 200 mg with AAP, 12 (63.2%) had grade 3/4 treatment-emergent adverse events, the most common being thrombocytopenia (26.3%) and hypertension (21.1%). Five patients (26.3%) had adverse events leading to treatment discontinuation. CONCLUSIONS: These results support the choice of niraparib 200 mg as the RP2D with AAP. The niraparib-AAP combination was tolerable in patients with mCRPC, with no new safety signals. An ongoing phase 3 study is further assessing this combination in patients with mCRPC. TRIAL REGISTRATION NO: NCT02924766 (ClinicalTrials.gov).

Transformative Network Modeling of Multi-omics Data Reveals Detailed Circuits, Key Regulators, and Potential Therapeutics for Alzheimer's Disease.

To identify the molecular mechanisms and novel therapeutic targets of late-onset Alzheimer's Disease (LOAD), we performed an integrative network analysis of multi-omics profiling of four cortical areas across 364 donors with varying cognitive and neuropathological phenotypes. Our analyses revealed thousands of molecular changes and uncovered neuronal gene subnetworks as the most dysregulated in LOAD. ATP6V1A was identified as a key regulator of a top-ranked neuronal subnetwork, and its role in disease-related processes was evaluated through CRISPR-based manipulation in human induced pluripotent stem cell-derived neurons and RNAi-based knockdown in Drosophila models. Neuronal impairment and neurodegeneration caused by ATP6V1A deficit were improved by a repositioned compound, NCH-51. This study provides not only a global landscape but also detailed signaling circuits of complex molecular interactions in key brain regions affected by LOAD, and the resulting network models will serve as a blueprint for developing next-generation therapeutic agents against LOAD.

Widespread Behavioral Responses by Mammals and Fish to Zoo Visitors Highlight Differences between Individual Animals.

The impact that humans have on zoo animals can vary based on the species of animal, exhibit design, and individual differences in behavioral responses. We independently analyzed data from 10 never-published studies that examined the impact of zoo visitors on zoo animal behavior. Of the 16 species studied, 90.9% of the mammal species and 60.0% of the fish species demonstrated a change in at least one behavior based on zoo visitor abundance or visitor behavior (e.g., noise, solicitation of interactions from zoo animals). In addition, behavioral changes associated with zoo visitors were present in animals housed in exhibits where there was direct contact with zoo visitors, as well as in exhibits where there was indirect contact and no direct contact. Individuals often varied in their behavioral responses, and some individuals appeared to seek out interactions with visitors. Our findings demonstrate that short-term research projects can provide valuable insight into individual animal-level and species-level responses to visitor abundance and visitor behavior in the zoo setting. We recommend that behavioral assessments focus on the analysis of behaviors of individual animals whenever possible, and we recommend that exhibits provide areas that allow for animals to retreat from the public view.

Bidirectional Expandable Technology for Transforaminal or Posterior Lumbar Interbody Fusion: A Retrospective Analysis of Safety and Performance.

BACKGROUND: Expandable devices for transforaminal or posterior lumbar interbody fusion (TLIF and PLIF, respectively) may enable greater restoration of disc height, foraminal height, and stability within the interbody space than static spacers. Medial-lateral expansion may also increase stability and resistance to subsidence. This study evaluates the clinical and radiographic outcomes from early experience with a bidirectional expandable device. METHODS: This was a retrospective analysis of a continuous series of patients across 3 sites who had previously undergone TLIF or PLIF surgery with a bidirectional expandable interbody fusion device (FlareHawk, Integrity Implants, Inc) at 1 or 2 contiguous levels between L2 and S1. Outcomes included the Oswestry Disability Index (ODI), a visual analog scale (VAS) for back pain or leg pain, radiographic fusion by 1 year of follow-up, subsidence, device migration, and adverse events (AE). RESULTS: There were 58 eligible patients with radiographs for 1-year fusion assessments and 45 patients with ODI, VAS back pain, or VAS leg pain data at baseline and a mean follow-up of 4.5 months. The ODI, VAS back pain, and VAS leg pain scores improved significantly from baseline to final follow-up, with mean improvements of 14.6 ± 19.1, 3.4 ± 2.6, and 3.9 ± 3.4 points (P < .001 for each), respectively. In addition, 58% of patients achieved clinically significant improvements in ODI, 76% in VAS back pain, and 71% in VAS leg pain. By 1 year, 96.6% of patients and 97.4% of levels were considered fused. There were zero cases of device subsidence and 1 case of device migration (1.7%). There were zero device-related AEs, 1 intraoperative dural tear, and 3 subsequent surgical interventions. CONCLUSIONS: The fusion rate, improvements in patient-reported outcomes, and the AEs observed are consistent with those of other devices. The bidirectional expansion mechanism may provide other important clinical value, but further studies will be required to elucidate the unique advantages. LEVEL OF EVIDENCE: 4.

Cytotoxic lymphocytes are dysregulated in multisystem inflammatory syndrome in children.

Multisystem inflammatory syndrome in children (MIS-C) presents with fever, inflammation and multiple organ involvement in individuals under 21 years following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. To identify genes, pathways and cell types driving MIS-C, we sequenced the blood transcriptomes of MIS-C cases, pediatric cases of coronavirus disease 2019, and healthy controls. We define a MIS-C transcriptional signature partially shared with the transcriptional response to SARS-CoV-2 infection and with the signature of Kawasaki disease, a clinically similar condition. By projecting the MIS-C signature onto a co-expression network, we identified disease gene modules and found genes downregulated in MIS-C clustered in a module enriched for the transcriptional signatures of exhausted CD8 + T-cells and CD56 dim CD57 + NK cells. Bayesian network analyses revealed nine key regulators of this module, including TBX21 , a central coordinator of exhausted CD8 + T-cell differentiation. Together, these findings suggest dysregulated cytotoxic lymphocyte response to SARS-Cov-2 infection in MIS-C.