MR Molecular Imaging of Extradomain-B Fibronectin for Assessing Progression and Therapy Resistance of Prostate Cancer.

Accurate assessment and characterization of the progression and therapy response of prostate cancer are essential for precision healthcare of patients diagnosed with the disease. MRI is a clinical imaging modality routinely used for diagnostic imaging and treatment planning of prostate cancer. Extradomain B fibronectin (EDB-FN) is an oncofetal subtype of fibronectin highly expressed in the extracellular matrix of aggressive cancers, including prostate cancer. It is a promising molecular target for the detection and risk-stratification of prostate cancer with high-resolution MR molecular imaging (MRMI). In this study, we investigated the effectiveness of MRMI with an EDB-FN specific contrast agent MT218 for assessing the progression and therapy resistance of prostate cancer. Low grade LNCaP prostate cancer cells became an invasive phenotype LNCaP-CXCR2 with elevated EDB-FN expression after acquisition of the C-X-C motif chemokine receptor 2 (CXCR2). MT218-MRMI showed brighter signal enhancement in LNCaP-CXCR2 tumor xenografts with a ∼2-fold contrast-to-noise (CNR) increase than in LNCaP tumors in mice. Enzalutamide-resistant C4-2-DR prostate cancer cells were more invasive, with higher EDB-FN expression than parental C4-2 cells. Brighter signal enhancement with a ∼2-fold CNR increase was observed in the C4-2-DR xenografts compared to that of C4-2 tumors in mice with MT218-MRMI. Interestingly, when invasive PC3 prostate cancer cells developed resistance to paclitaxel, the drug-resistant PC3-DR cells became less invasive with reduced EDB-FN expression than the parental PC3 cells. MT218-MRMI detected reduced brightness in the PC3-DR xenografts with more than 2-fold reduction of CNR compared to PC3 tumors in mice. The signal enhancement in all tumors was supported by the immunohistochemical staining of EDB-FN with the G4 monoclonal antibody. The results indicate that MRMI of EDB-FN with MT218 has promise for detection, risk stratification, and monitoring the progression and therapy response of invasive prostate cancer.

Prediction of extracapsular extension of prostate cancer by MRI radiomic signature: a systematic review.

The objective of this review is to survey radiomics signatures for detecting pathological extracapsular extension (pECE) on magnetic resonance imaging (MRI) in patients with prostate cancer (PCa) who underwent prostatectomy. Scientific Literature databases were used to search studies published from January 2007 to October 2023. All studies related to PCa MRI staging and using radiomics signatures to detect pECE after prostatectomy were included. Systematic review was performed according to Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA). The risk of bias and certainty of the evidence was assessed using QUADAS-2 and the radiomics quality score. From 1247 article titles screened, 16 reports were assessed for eligibility, and 11 studies were included in this systematic review. All used a retrospective study design and most of them used 3 T MRI. Only two studies were performed in more than one institution. The highest AUC of a model using only radiomics features was 0.85, for the test validation. The AUC for best model performance (radiomics associated with clinical/semantic features) varied from 0.72-0.92 and 0.69-0.89 for the training and validation group, respectively. Combined models performed better than radiomics signatures alone for detecting ECE. Most of the studies showed a low to medium risk of bias. After thorough analysis, we found no strong evidence supporting the clinical use of radiomics signatures for identifying extracapsular extension (ECE) in pre-surgery PCa patients. Future studies should adopt prospective multicentre approaches using large public datasets and combined models for detecting ECE. CRITICAL RELEVANT STATEMENT: The use of radiomics algorithms, with clinical and AI integration, in predicting extracapsular extension, could lead to the development of more accurate predictive models, which could help improve surgical planning and lead to better outcomes for prostate cancer patients. PROTOCOL OF SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42021272088. Published: https://doi.org/10.1136/bmjopen-2021-052342 . KEY POINTS: Radiomics can extract diagnostic features from MRI to enhance prostate cancer diagnosis performance. The combined models performed better than radiomics signatures alone for detecting extracapsular extension. Radiomics are not yet reliable for extracapsular detection in PCa patients.

Kmt2c restricts G-CSF-driven HSC mobilization and granulocyte production in a methyltransferase-independent manner.

Granulocyte colony-stimulating factor (G-CSF) is widely used to enhance myeloid recovery after chemotherapy and to mobilize hematopoietic stem cells (HSCs) for transplantation. Unfortunately, through the course of chemotherapy, cancer patients can acquire leukemogenic mutations that cause therapy-related myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). This raises the question of whether therapeutic G-CSF might potentiate therapy-related MDS/AML by disproportionately stimulating mutant HSCs and other myeloid progenitors. A common mutation in therapy-related MDS/AML involves chromosome 7 deletions that inactivate many tumor suppressor genes, including KMT2C. Here, we show that Kmt2c deletions hypersensitize murine HSCs and myeloid progenitors to G-CSF, as evidenced by increased HSC mobilization and enhanced granulocyte production from granulocyte-monocyte progenitors (GMPs). Furthermore, Kmt2c attenuates the G-CSF response independently from its SET methyltransferase function. Altogether, the data raise concerns that monosomy 7 can hypersensitize progenitors to G-CSF, such that clinical use of G-CSF may amplify the risk of therapy-related MDS/AML.

Reproducibility in Radiomics: A Comparison of Feature Extraction Methods and Two Independent Datasets.

Radiomics involves the extraction of information from medical images that are not visible to the human eye. There is evidence that these features can be used for treatment stratification and outcome prediction. However, there is much discussion about the reproducibility of results between different studies. This paper studies the reproducibility of CT texture features used in radiomics, comparing two feature extraction implementations, namely the MATLAB toolkit and Pyradiomics, when applied to independent datasets of CT scans of patients: (i) the open access RIDER dataset containing a set of repeat CT scans taken 15 min apart for 31 patients (RIDER Scan 1 and Scan 2, respectively) treated for lung cancer; and (ii) the open access HN1 dataset containing 137 patients treated for head and neck cancer. Gross tumor volume (GTV), manually outlined by an experienced observer available on both datasets, was used. The 43 common radiomics features available in MATLAB and Pyradiomics were calculated using two intensity-level quantization methods with and without an intensity threshold. Cases were ranked for each feature for all combinations of quantization parameters, and the Spearman's rank coefficient, rs, calculated. Reproducibility was defined when a highly correlated feature in the RIDER dataset also correlated highly in the HN1 dataset, and vice versa. A total of 29 out of the 43 reported stable features were found to be highly reproducible between MATLAB and Pyradiomics implementations, having a consistently high correlation in rank ordering for RIDER Scan 1 and RIDER Scan 2 (rs > 0.8). 18/43 reported features were common in the RIDER and HN1 datasets, suggesting they may be agnostic to disease site. Useful radiomics features should be selected based on reproducibility. This study identified a set of features that meet this requirement and validated the methodology for evaluating reproducibility between datasets.

T-bet Regulates Ion Channels and Transporters and Induces Apoptosis in Intestinal Epithelial Cells.

T-bet, encoded by TBX21, is extensively expressed across various immune cell types, and orchestrates critical functions in their development, survival, and physiological activities. However, the role of T-bet in non-immune compartments, notably the epithelial cells, remains obscure. Herein, a Tet-O-T-bet transgenic mouse strain is generated for doxycycline-inducible T-bet expression in adult animals. Unexpectedly, ubiquitous T-bet overexpression causes acute diarrhea, intestinal damage, and rapid mortality. Cell-type-specific analyses reveal that T-bet-driven pathology is not attributable to its overexpression in CD4+ T cells or myeloid lineages. Instead, inducible T-bet overexpression in the intestinal epithelial cells is the critical determinant of the observed lethal phenotype. Mechanistically, T-bet overexpression modulates ion channel and transporter profiles in gut epithelial cells, triggering profound fluid secretion and subsequent lethal dehydration. Furthermore, ectopic T-bet expression enhances gut epithelial cell apoptosis and markedly suppresses colon cancer development in xenograft models. Collectively, the findings unveil a previously unrecognized role of T-bet in intestinal epithelial cells for inducing apoptosis, diarrhea, and local inflammation, thus implicating its potential as a therapeutic target for the treatment of cancer and inflammatory diseases.

Clinical application of machine learning models in patients with prostate cancer before prostatectomy.

BACKGROUND: To build machine learning predictive models for surgical risk assessment of extracapsular extension (ECE) in patients with prostate cancer (PCa) before radical prostatectomy; and to compare the use of decision curve analysis (DCA) and receiver operating characteristic (ROC) metrics for selecting input feature combinations in models. METHODS: This retrospective observational study included two independent data sets: 139 participants from a single institution (training), and 55 from 15 other institutions (external validation), both treated with Robotic Assisted Radical Prostatectomy (RARP). Five ML models, based on different combinations of clinical, semantic (interpreted by a radiologist) and radiomics features computed from T2W-MRI images, were built to predict extracapsular extension in the prostatectomy specimen (pECE+). DCA plots were used to rank the models' net benefit when assigning patients to prostatectomy with non-nerve-sparing surgery (NNSS) or nerve-sparing surgery (NSS), depending on the predicted ECE status. DCA model rankings were compared with those drived from ROC area under the curve (AUC). RESULTS: In the training data, the model using clinical, semantic, and radiomics features gave the highest net benefit values across relevant threshold probabilities, and similar decision curve was observed in the external validation data. The model ranking using the AUC was different in the discovery group and favoured the model using clinical + semantic features only. CONCLUSIONS: The combined model based on clinical, semantic and radiomic features may be used to predict pECE + in patients with PCa and results in a positive net benefit when used to choose between prostatectomy with NNS or NNSS.

Absence of functional deficits in rats following systemic administration of an AAV9 vector despite moderate peripheral nerve and dorsal root ganglia findings: A clinically silent peripheral neuropathy.

Adeno-associated virus (AAV)-based vectors are commonly used for delivering transgenes in gene therapy studies, but they are also known to cause dorsal root ganglia (DRG) and peripheral nerve toxicities in animals. However, the functional implications of these pathologic findings and their time course remain unclear. At 2, 4, 6, and 8 weeks following a single dose of an AAV9 vector carrying human frataxin transgene in rats, non-standard functional assessments, including von Frey filament, electrophysiology, and Rotarod tests, were conducted longitudinally to measure allodynia, nerve conduction velocity, and coordination, respectively. Additionally, DRGs, peripheral nerves, brain and spinal cord were evaluated histologically and circulating neurofilament light chain (NfL) was quantified at 1, 2, 4, and 8 weeks, respectively. At 2 and 4 weeks after dosing, minimal-to-moderate nerve fiber degeneration and neuronal degeneration were observed in the DRGs in some of the AAV9 vector-dosed animals. At 8 weeks, nerve fiber degeneration was observed in DRGs, with or without neuronal degeneration, and in sciatic nerves of all AAV9 vector-dosed animals. NfL values were higher in AAV9 vector-treated animals at weeks 4 and 8 compared with controls. However, there were no significant differences in the three functional endpoints evaluated between the AAV9 vector- and vehicle-dosed animals, or in a longitudinal comparison between baseline (predose), 4, and 8 week values in the AAV9 vector-dose animals. These findings demonstrate that there is no detectable functional consequence to the minimal-to-moderate neurodegeneration observed with our AAV9 vector treatment in rats, suggesting a functional tolerance or reserve for loss of DRG neurons after systemic administration of AAV9 vector.

Significance of Crypt Atypia in Barrett's Esophagus: A Clinical, Molecular, and Outcome Study.

BACKGROUND & AIMS: The aim of this study was to characterize baseline morphologic features of crypts in nondysplastic Barrett's esophagus and correlate them with DNA content abnormalities and risk of progression to high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC). METHODS: The morphologic features of nondysplastic crypts in baseline biopsy specimens from 212 BE patients (2956 biopsy specimens) were graded histologically using a 4-point scale (crypt atypia levels, 0-3). DNA content abnormalities were detected using flow cytometry. RESULTS: In patients who had dysplasia in their baseline biopsy specimens, dysplasia was associated significantly with increasing grades of crypt atypia in the background nondysplastic Barrett's esophagus (P < .001). In a subset of patients without dysplasia at baseline (N = 149), a higher grade of crypt atypia was associated with longer Barrett's esophagus segment length (5.5 vs 3.3 cm; P = .0095), and a higher percentage of cells with 4N DNA content (3.67 ± 1.27 vs 2.93 ± 1.22; P = .018). Crypt atypia was associated with the development of any neoplasia (low-grade dysplasia and HGD/EAC). Although no significant association was noted between the grade of crypt atypia and increased 4N, aneuploidy, or progression to HGD/EAC, only patients with grade 2 or 3 crypt atypia showed increased 4N, aneuploidy, or progression to HGD/EAC. CONCLUSIONS: Patients with Barrett's esophagus likely develop dysplasia via a progressive increase in the level of crypt atypia before the onset of dysplasia, and these changes may reflect some alteration of DNA content.

The Interplay between T Cells and Cancer: The Basis of Immunotherapy.

Over the past decade, immunotherapy has emerged as one of the most promising approaches to cancer treatment. The use of immune checkpoint inhibitors has resulted in impressive and durable clinical responses in the treatment of various cancers. Additionally, immunotherapy utilizing chimeric antigen receptor (CAR)-engineered T cells has produced robust responses in blood cancers, and T cell receptor (TCR)-engineered T cells are showing promising results in the treatment of solid cancers. Despite these noteworthy advancements in cancer immunotherapy, numerous challenges remain. Some patient populations are unresponsive to immune checkpoint inhibitor therapy, and CAR T cell therapy has yet to show efficacy against solid cancers. In this review, we first discuss the significant role that T cells play in the body's defense against cancer. We then delve into the mechanisms behind the current challenges facing immunotherapy, starting with T cell exhaustion due to immune checkpoint upregulation and changes in the transcriptional and epigenetic landscapes of dysfunctional T cells. We then discuss cancer-cell-intrinsic characteristics, including molecular alterations in cancer cells and the immunosuppressive nature of the tumor microenvironment (TME), which collectively facilitate tumor cell proliferation, survival, metastasis, and immune evasion. Finally, we examine recent advancements in cancer immunotherapy, with a specific emphasis on T-cell-based treatments.

Colorectal dysplasia in chronic inflammatory bowel disease: a contemporary consensus classification and interobserver study.

The clinical management of patients with dysplasia in chronic inflammatory bowel disease (IBD) is currently guided by Riddell et al.'s grading system (negative, indefinite, low grade, high grade) from 1983 which was based primarily on nuclear cytoarchitectural characteristics. Although most dysplasia in IBD resembles sporadic adenomas morphologically, other distinctive potential cancer precursors in IBD have been described over time. Recognizing the need for a updated comprehensive classification for IBD-associated dysplasia, an international working group of pathologists with extensive clinical and research experience in IBD devised a new classification system and assessed its reproducibility by having each participant assess test cases selected randomly from a repository of electronic images of potential cancer precursor lesions. The new classification system now encompasses three broad categories and nine sub-categories: 1) intestinal dysplasia (tubular/villous adenoma-like, goblet cell deficient, crypt cell, traditional serrated adenoma-like, sessile serrated lesion-like and serrated NOS), 2) gastric dysplasia (tubular/villous and serrated), and 3) mixed intestinal-gastric dysplasia. In the interobserver analysis, 67% of the diagnoses were considered definitive and achieved substantial inter-rater agreement. The key distinctions between intestinal and gastric lesions and between serrated and non-serrated lesions achieved substantial and moderate inter-rater agreement overall, respectively, however, the distinctions among certain serrated sub-categories achieved only fair agreement. Based on the Riddell grading system, definite dysplasia accounted for 86% of the collective responses (75% low grade, 11% high grade). Based on these results, this new classification of dysplasia in IBD can provide a sound foundation for future clinical and basic IBD research.

Transcription factor induction of vascular blood stem cell niches in vivo.

The hematopoietic niche is a supportive microenvironment composed of distinct cell types, including specialized vascular endothelial cells that directly interact with hematopoietic stem and progenitor cells (HSPCs). The molecular factors that specify niche endothelial cells and orchestrate HSPC homeostasis remain largely unknown. Using multi-dimensional gene expression and chromatin accessibility analyses in zebrafish, we define a conserved gene expression signature and cis-regulatory landscape that are unique to sinusoidal endothelial cells in the HSPC niche. Using enhancer mutagenesis and transcription factor overexpression, we elucidate a transcriptional code that involves members of the Ets, Sox, and nuclear hormone receptor families and is sufficient to induce ectopic niche endothelial cells that associate with mesenchymal stromal cells and support the recruitment, maintenance, and division of HSPCs in vivo. These studies set forth an approach for generating synthetic HSPC niches, in vitro or in vivo, and for effective therapies to modulate the endogenous niche.

Corrigendum: PHF20 promotes glioblastoma cell malignancies through a WISP1/BGN-dependent pathway.

[This corrects the article DOI: 10.3389/fonc.2020.573318.].

Phenotypic Switch and Growth of Melanoma Spheroids in the Presence of Mast Cells: Potential Impact of Nutrient-starvation Effects.

BACKGROUND/AIM: Mast cells are abundant in melanoma tumors, and studies suggest that they can be either detrimental or protective for melanoma growth. However, the underlying mechanisms are not fully understood. MATERIALS AND METHODS: Here, we adopted an established hanging-drop spheroid system to investigate how mast cells influence melanoma growth and phenotype in a 3-D context. To address the underlying mechanism, we conducted transcriptomic and pathway analyses. RESULTS: In the presence of mast cells or mast cell-conditioned medium, growth of melanoma spheroids was profoundly reduced. Transcriptomic analysis revealed that mast cell-conditioned medium had extensive effects on the gene-expression patterns of melanoma. Pathway analyses revealed profound effects on the expression of genes related to amino acid and protein metabolism. The conditioned medium also induced up-regulation of cancer-related genes, including adhesion molecules implicated in metastatic spreading. In line with this, after transfer to a Matrigel extracellular matrix milieu, spheroids that had been developed in the presence of mast cell-conditioned medium displayed enhanced growth and adhesive properties. However, when assessing the possible impact of nutrient starvation, i.e., reduced nutrient content in mast cell-conditioned medium, we found that the observed effects on growth of melanoma spheroids could potentially be explained by such a scenario. CONCLUSION: Our findings suggest that the phenotypic alterations of melanoma spheroids grown in the presence of mast cells or mast cell-conditioned media are, at least partly, due to nutrient starvation rather than to the action of factors secreted by mast cells. Our findings may provide insight into the effects on gene-expression events that occur in melanoma tumors under nutrient stress.

Heparanase Modulates Chromatin Accessibility.

Heparanase is the sole endoglucuronidase that degrades heparan sulfate in the cell surface and extracellular matrix (ECM). Several studies have reported the localization of heparanase in the cell nucleus, but the functional role of the nuclear enzyme is still obscure. Subjecting mouse embryonic fibroblasts (MEFs) derived from heparanase knockout (Hpse-KO) mice and applying transposase-accessible chromatin with sequencing (ATAC-seq), we revealed that heparanase is involved in the regulation of chromatin accessibility. Integrating with genome-wide analysis of chromatin states revealed an overall low activity in the enhancer and promoter regions of Hpse-KO MEFs compared with wild-type (WT) MEFs. Western blot analysis of MEFs and tissues derived from Hpse-KO vs. WT mice confirmed reduced expression of H3K27ac (acetylated lysine at N-terminal position 27 of the histone H3 protein). Our results offer a mechanistic explanation for the well-documented attenuation of inflammatory responses and tumor growth in Hpse-KO mice.

Basal type I interferon signaling has only modest effects on neonatal and juvenile hematopoiesis.

Type I interferon (IFN-1) regulates gene expression and hematopoiesis both during development and in response to inflammatory stress. We previously showed that during development in mice, hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs) induce IFN-1 target genes shortly before birth. This coincides with the onset of a transition to adult hematopoiesis, and it drives the expression of genes associated with antigen presentation. However, it is not clear whether perinatal IFN-1 modulates hematopoietic output, as has been observed in contexts of inflammation. We have characterized hematopoiesis at several different stages of blood formation, from HSCs to mature blood cells, and found that loss of the IFN-1 receptor (IFNAR1) leads to depletion of several phenotypic HSC and MPP subpopulations in neonatal and juvenile mice. Committed lymphoid and myeloid progenitor populations expand simultaneously. These changes had a surprisingly little effect on the production of more differentiated blood cells. Cellular indexing of transcriptomes and epitopes by sequencing resolved the discrepancy between the extensive changes in progenitor numbers and modest changes in hematopoiesis, revealing stability in most MPP populations in Ifnar1-deficient neonates when the populations were identified based on gene expression rather than surface marker phenotype. Thus, basal IFN-1 signaling has only modest effects on hematopoiesis. Discordance between transcriptionally and phenotypically defined MPP populations may affect interpretations of how IFN-1 shapes hematopoiesis in other contexts, such as aging or inflammation.

Recent Advances in the Digestive, Metabolic and Therapeutic Effects of Farnesoid X Receptor and Fibroblast Growth Factor 19: From Cholesterol to Bile Acid Signaling.

Bile acids (BA) are amphiphilic molecules synthesized in the liver (primary BA) starting from cholesterol. In the small intestine, BA act as strong detergents for emulsification, solubilization and absorption of dietary fat, cholesterol, and lipid-soluble vitamins. Primary BA escaping the active ileal re-absorption undergo the microbiota-dependent biotransformation to secondary BA in the colon, and passive diffusion into the portal vein towards the liver. BA also act as signaling molecules able to play a systemic role in a variety of metabolic functions, mainly through the activation of nuclear and membrane-associated receptors in the intestine, gallbladder, and liver. BA homeostasis is tightly controlled by a complex interplay with the nuclear receptor farnesoid X receptor (FXR), the enterokine hormone fibroblast growth factor 15 (FGF15) or the human ortholog FGF19 (FGF19). Circulating FGF19 to the FGFR4/ß-Klotho receptor causes smooth muscle relaxation and refilling of the gallbladder. In the liver the binding activates the FXR-small heterodimer partner (SHP) pathway. This step suppresses the unnecessary BA synthesis and promotes the continuous enterohepatic circulation of BAs. Besides BA homeostasis, the BA-FXR-FGF19 axis governs several metabolic processes, hepatic protein, and glycogen synthesis, without inducing lipogenesis. These pathways can be disrupted in cholestasis, nonalcoholic fatty liver disease, and hepatocellular carcinoma. Thus, targeting FXR activity can represent a novel therapeutic approach for the prevention and the treatment of liver and metabolic diseases.

The Assessment on Synergistic Activity of Ebselen and Silver Ion Against Yersinia pseudotuberculosis.

Yersinia pseudotuberculosis is a foodborne zoonotic bacterium that is pathogenic to guinea pigs, rabbits, and mice. It also causes pseudotuberculosis in humans. However, it still lacked the scientific basis for control. Here, we found out that Ebselen (EbSe) exhibited synergistic antibacterial activity with silver nitrate (Ag+) against Y. pseudotuberculosis YpIII strain with high efficacy in vitro using UV-visible light absorption spectrum, 5,5'-dithiobis-(2-nitrobenzoic acid), laser scanning confocal microscope, flow cytometry, transmission electron microscopy and Western blotting assays. The depletion of total glutathione (GSH) amount and inhibition of thioredoxin reductase (TrxR) activity in thiol-dependent redox system revealed the destructiveness of EbSe-Ag+-caused intracellular oxidative stress. Furthermore, a YpIII-caused mice gastroenteritis model was constructed. EbSe-Ag+ significantly reduced bacterial loads with low toxicity. It also down-regulated the expression levels of interferon (IL)-1ß and tumor necrosis factor-α, up-regulated the expression level of IL-10 on-site. All the in vivo results demonstrated the antibacterial activity and immune-modulatory property of EbSe-Ag+. Collectively, these results provided academic fundament for further analysis and development of EbSe-Ag+ as the antibacterial agents for pseudotuberculosis control.

Interaction between microbiota and immunity and its implication in colorectal cancer.

Colorectal cancer (CRC) is one of the leading causes of cancer-related death in the world. Besides genetic causes, colonic inflammation is one of the major risk factors for CRC development, which is synergistically regulated by multiple components, including innate and adaptive immune cells, cytokine signaling, and microbiota. The complex interaction between CRC and the gut microbiome has emerged as an important area of current CRC research. Metagenomic profiling has identified a number of prominent CRC-associated bacteria that are enriched in CRC patients, linking the microbiota composition to colitis and cancer development. Some microbiota species have been reported to promote colitis and CRC development in preclinical models, while a few others are identified as immune modulators to induce potent protective immunity against colitis and CRC. Mechanistically, microbiota regulates the activation of different immune cell populations, inflammation, and CRC via crosstalk between innate and adaptive immune signaling pathways, including nuclear factor kappa B (NF-κB), type I interferon, and inflammasome. In this review, we provide an overview of the potential interactions between gut microbiota and host immunity and how their crosstalk could synergistically regulate inflammation and CRC, thus highlighting the potential roles and mechanisms of gut microbiota in the development of microbiota-based therapies to prevent or alleviate colitis and CRC.

Circulating neurofilament light chain as a promising biomarker of AAV-induced dorsal root ganglia toxicity in nonclinical toxicology species.

Adeno-associated virus (AAV)-induced dorsal root ganglia (DRG) toxicity has been observed in several nonclinical species, where lesions are characterized by neuronal degeneration/necrosis, nerve fiber degeneration, and mononuclear cell infiltration. As AAV vectors become an increasingly common platform for novel therapeutics, non-invasive biomarkers are needed to better characterize and manage the risk of DRG neurotoxicity in both nonclinical and clinical studies. Based on biological relevance, reagent availability, antibody cross-reactivity, DRG protein expression, and assay performance, neurofilament light chain (NF-L) emerged as a promising biomarker candidate. Dose- and time-dependent changes in NF-L were evaluated in male Wistar Han rats and cynomolgus monkeys following intravenous or intrathecal AAV injection, respectively. NF-L profiles were then compared against microscopic DRG lesions on day 29 post-dosing. In animals exhibiting DRG toxicity, plasma/serum NF-L was strongly associated with the severity of neuronal degeneration/necrosis and nerve fiber degeneration, with elevations beginning as early as day 8 in rats (≥5 × 1013 vg/kg) and day 14 in monkeys (≥3.3 × 1013 vg/dose). Consistent with the unique positioning of DRGs outside the blood-brain barrier, NF-L in cerebrospinal fluid was only weakly associated with DRG findings. In summary, circulating NF-L is a promising biomarker of AAV-induced DRG toxicity in nonclinical species.

Activation of cGAS-STING by Lethal Malaria N67C Dictates Immunity and Mortality through Induction of CD11b+ Ly6Chi Proinflammatory Monocytes.

Cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) play critical roles in the innate immunity against infectious diseases and are required to link pathogen DNA sensing to immune responses. However, the mechanisms by which cGAS-STING-induced cytokines suppress the adaptive immune response against malaria infections remain poorly understood. Here, cGAS-STING signaling is identified to play a detrimental role in regulating anti-malaria immunity. cGAS or STING deficiency in mice markedly prolongs mouse survival during lethal malaria Plasmodium yoelii nigeriensis N67C infections by reducing late interleukin (IL)-6 production. Mechanistically, cGAS/STING recruits myeloid differentiation factor 88 (MyD88) and specifically induces the p38-dependent signaling pathway for late IL-6 production, which, in turn, expands CD11b+ Ly6Chi proinflammatory monocytes to inhibit immunity. Moreover, the blockage or ablation of the cGAS-STING-MyD88-p38-IL-6 signaling axis or the depletion of CD11b+ Ly6Chi proinflammatory monocytes provides mice a significant survival benefit during N67C and other lethal malaria-strain infections. Taken together, these findings identify a previously unrecognized detrimental role of cGAS-STING-MyD88-p38 axis in infectious diseases through triggering the late IL-6 production and proinflammatory monocyte expansion and provide insight into how targeting the DNA sensing pathway, dysregulated cytokines, and proinflammatory monocytes enhances immunity against infection.