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The inflammatory response is a major pathological feature in most kidney diseases and often evokes compensatory mechanisms. Recent evidence suggests that TSG-6 (tumor necrosis factor-α-stimulated gene/protein-6) plays a pivotal role in anti-inflammation in various renal diseases, including immune-mediated and nonimmune-mediated renal diseases. TSG-6 has a diverse repertoire of anti-inflammatory functions: it potentiates antiplasmin activity of IαI (inter-α-inhibitor) by binding to its light chain, crosslinks hyaluronan to promote its binding to cell surface receptor CD44, and thereby regulate the migration and adhesion of lymphocytes, inhibits chemokine-stimulated transendothelial migration of neutrophils by directly interacting with the glycosaminoglycan binding site of CXCL8 (CXC motif chemokine ligand-8), and upregulates COX-2 (cyclooxygenase-2) to produce anti-inflammatory metabolites. Hopefully, further developments can target this anti-inflammatory molecule to the kidney and harness its remedial properties. This review provides an overview of the emerging role of TSG-6 in blunting renal inflammation.

AbstractBackgroundThe growing adoption of magnetic resonance imaging (MRI)‐guided radiation therapy (RT) platforms and a focus on MRI‐only RT workflows have brought the technical challenge of synthetic computed tomography (sCT) reconstruction to the forefront. Unpaired‐data deep learning‐based approaches to the problem offer the attractive characteristic of not requiring paired training data, but the gap between paired‐ and unpaired‐data results can be limiting.PurposeWe present two distinct approaches aimed at improving unpaired‐data sCT reconstruction results: a cascade ensemble that combines multiple models and a personalized training strategy originally designed for the paired‐data setting.MethodsComparisons are made between the following models: (1) the paired‐data fully convolutional DenseNet (FCDN), (2) the FCDN with the Intentional Deep Overfit Learning (IDOL) personalized training strategy, (3) the unpaired‐data CycleGAN, (4) the CycleGAN with the IDOL training strategy, and (5) the CycleGAN as an intermediate model in a cascade ensemble approach. Evaluation of the various models over 25 total patients is carried out using a five‐fold cross‐validation scheme, with the patient‐specific IDOL models being trained for the five patients of fold 3, chosen at random.ResultsIn both the paired‐ and unpaired‐data settings, adopting the IDOL training strategy led to improvements in the mean absolute error (MAE) between true CT images and sCT outputs within the body contour (mean improvement, paired‐ and unpaired‐data approaches, respectively: 38%, 9%) and in regions of bone (52%, 5%), the peak signal‐to‐noise ratio (PSNR; 15%, 7%), and the structural similarity index (SSIM; 6%, <1%). The ensemble approach offered additional benefits over the IDOL approach in all three metrics (mean improvement over unpaired‐data approach in fold 3; MAE: 20%; bone MAE: 16%; PSNR: 10%; SSIM: 2%), and differences in body MAE between the ensemble approach and the paired‐data approach are statistically insignificant.ConclusionsWe have demonstrated that both a cascade ensemble approach and a personalized training strategy designed initially for the paired‐data setting offer significant improvements in image quality metrics for the unpaired‐data sCT reconstruction task. Closing the gap between paired‐ and unpaired‐data approaches is a step toward fully enabling these powerful and attractive unpaired‐data frameworks.

ImportanceCytokine storm due to COVID-19 can cause high morbidity and mortality and may be more common in patients with cancer treated with immunotherapy (IO) due to immune system activation.ObjectiveTo determine the association of baseline immunosuppression and/or IO-based therapies with COVID-19 severity and cytokine storm in patients with cancer.Design, Setting, and ParticipantsThis registry-based retrospective cohort study included 12 046 patients reported to the COVID-19 and Cancer Consortium (CCC19) registry from March 2020 to May 2022. The CCC19 registry is a centralized international multi-institutional registry of patients with COVID-19 with a current or past diagnosis of cancer. Records analyzed included patients with active or previous cancer who had a laboratory-confirmed infection with SARS-CoV-2 by polymerase chain reaction and/or serologic findings.ExposuresImmunosuppression due to therapy; systemic anticancer therapy (IO or non-IO).Main Outcomes and MeasuresThe primary outcome was a 5-level ordinal scale of COVID-19 severity: no complications; hospitalized without requiring oxygen; hospitalized and required oxygen; intensive care unit admission and/or mechanical ventilation; death. The secondary outcome was the occurrence of cytokine storm.ResultsThe median age of the entire cohort was 65 years (interquartile range [IQR], 54-74) years and 6359 patients were female (52.8%) and 6598 (54.8%) were non-Hispanic White. A total of 599 (5.0%) patients received IO, whereas 4327 (35.9%) received non-IO systemic anticancer therapies, and 7120 (59.1%) did not receive any antineoplastic regimen within 3 months prior to COVID-19 diagnosis. Although no difference in COVID-19 severity and cytokine storm was found in the IO group compared with the untreated group in the total cohort (adjusted odds ratio [aOR], 0.80; 95% CI, 0.56-1.13, and aOR, 0.89; 95% CI, 0.41-1.93, respectively), patients with baseline immunosuppression treated with IO (vs untreated) had worse COVID-19 severity and cytokine storm (aOR, 3.33; 95% CI, 1.38-8.01, and aOR, 4.41; 95% CI, 1.71-11.38, respectively). Patients with immunosuppression receiving non-IO therapies (vs untreated) also had worse COVID-19 severity (aOR, 1.79; 95% CI, 1.36-2.35) and cytokine storm (aOR, 2.32; 95% CI, 1.42-3.79).Conclusions and RelevanceThis cohort study found that in patients with cancer and COVID-19, administration of systemic anticancer therapies, especially IO, in the context of baseline immunosuppression was associated with severe clinical outcomes and the development of cytokine storm.Trial RegistrationClinicalTrials.gov Identifier: NCT04354701

Establishing causal links between inherited polymorphisms and cancer risk is challenging. Here, we focus on the single-nucleotide polymorphism rs55705857, which confers a sixfold greater risk of isocitrate dehydrogenase ( IDH) –mutant low-grade glioma (LGG). We reveal that rs55705857 itself is the causal variant and is associated with molecular pathways that drive LGG. Mechanistically, we show that rs55705857 resides within a brain-specific enhancer, where the risk allele disrupts OCT2/4 binding, allowing increased interaction with the Myc promoter and increased Myc expression. Mutating the orthologous mouse rs55705857 locus accelerated tumor development in an Idh1 R132H -driven LGG mouse model from 472 to 172 days and increased penetrance from 30% to 75%. Our work reveals mechanisms of the heritable predisposition to lethal glioma in ~40% of LGG patients.

Abstract Neuromyelitis optica spectrum disorder (NMOSD) is a severe inflammatory autoimmune disease of the central nervous system that is manifested as secondary myelin loss. Oligodendrocyte progenitor cells (OPCs) are the principal source of myelinating oligodendrocytes (OLs) and are abundant in demyelinated regions of NMOSD patients, thus possibly representing a cellular target for pharmacological intervention. To explore the therapeutic compounds that enhance myelination due to endogenous OPCs, we screened the candidate drugs in mouse neural progenitor cell (NPC)‐derived OPCs. We identified drug edaravone, which is approved by the Food and Drug Administration (FDA), as a promoter of OPC differentiation into mature OLs. Edaravone enhanced remyelination in organotypic slice cultures and in mice, even when edaravone was administered following NMO‐IgG‐induced demyelination, and ameliorated motor impairment in a systemic mouse model of NMOSD. The results of mechanistic studies in NMO‐IgG‐treated mice and the biopsy samples of the brain tissues of NMOSD patients indicated that the mTORC1 signaling pathway was significantly inhibited, and edaravone promoted OPC maturation and remyelination by activating mTORC1 signaling. Furthermore, pharmacological activation of mTORC1 signaling significantly enhanced myelin regeneration in NMOSD. Thus, edaravone is a potential therapeutic agent that promotes lesion repair in NMOSD patients by enhancing OPC maturation.

Our study demonstrates a novel pericyte-based therapy for the injured kidney. The beneficial effect of pericyte delivery appears to be mediated by ameliorating oxidative stress, inflammation, cellular apoptosis, and senescence in the stenotic kidney and improved tissue hypoxia, vascular loss, fibrosis, and tubular atrophy. Our data may form the basis for pericyte-based therapy, and additional research studies are needed to gain further insight into their role in improving renal function.