Treatment of Morganella morganii-Associated Non-healing Diabetic Foot Ulcer With Vaporous Hyperoxia Therapy: A Case Report.

Diabetic foot ulcers represent a significant complication of diabetes mellitus, characterized by mechanical changes of bony architecture often leading to chronic wounds with increased risk of infection and impaired healing. Morganella morganii, a Gram-negative bacterium, is one of the pathogens found in infected diabetic foot ulcers. It is a human gastrointestinal commensal organism that may cause widespread deadly infections. This report discusses the case of a 76-year-old male with diabetes mellitus who presented with M. morganii diabetic foot ulcer to an in-patient rehabilitation facility. Despite conventional wound care and antibiotic therapy, the ulcer failed to improve. The management approach for this patient consisted of a rehabilitation modality called Vaporox, a machine that utilizes vaporous hyperoxia therapy (VHT), as it combines ultrasonic mist and high concentration of oxygen to fasten revascularization and healing. This case highlights the potential efficacy of VHT as an adjunctive therapy for the management of diabetic foot ulcers, particularly those complicated by pathogens, such as M. morganii.

[The preliminary application of mNGS in the diagnosis of invasive fungal sinusitis].

Objective: By conducting a retrospective analysis of the clinical data of 14 patients diagnosed with invasive fungal rhinosinusitis (IFRS) confirmed by metagenomics next generation sequencing (mNGS) technology, we aim to explore the rapid diagnosis value of mNGS in IFRS. Methods: The clinical data of 14 IFRS patients admitted to TianJin First Central Hospital were retrospectively analyzed from February 2021 to October 2023. The study cohort comprised 8 males and 6 females, with ages ranging from 14 to 77 years. All patients were diagnosed as IFRS by performing mNGS sequencing technology of nasal sinus lesion biopsy specimens. Clinical data such as laboratory examination, imaging examination, histopathological examination results, treatment plan and prognosis were summarized and analyzed. Results: All 14 patients were diagnosed as IFRS, with mNGS detecting pathogens such as Rhizopus (7 cases), Aspergillus (5 cases), Trichoderma (1 case), and Scedosporium apiospermum (1 case). Follow-up evaluations were conducted for a period ranging from 2 months to 2 years post-treatment. At the end of follow-up, 11 out of 14 IFRS patients achieved a complete cure with no signs of recurrence, while the symptoms of the remaining 3 patients significantly improved with comprehensive treatment. Conclusion: mNGS emerges as a highly effective diagnostic tool for IFRS, providing valuable microbiological evidence for clinical diagnosis and demonstrating promising clinical utility.

[Efficacy of high-dose dual therapy for Helicobacter pylori infection eradication in servicemen: a randomized controlled trial].

Objective: To assess the efficacy and cost-effectiveness of high-dose dual therapy compared with bismuth-containing quadruple therapy for treating Helicobacter pylori(H.pylori) infection in servicemen patients. Methods: A total of 160 H. pylori-infected, treatment-naive servicemen, including 74 men and 86 women, aged from 20 years to 74 years, with a mean (SD) age of 43 (13) years, tested in the First Center of Chinese PLA General Hospital from March 2022 to May 2022 were enrolled in this open-label, randomized controlled clinical trial. Patients were randomly allocated into 2 groups: the 14-day high-dose dual therapy group and the bismuth-containing quadruple therapy group. Eradication rates, adverse events, patient compliance, and drug costs were compared between the two groups. The t-test was used for continuous variables, and the Chi-square test for categorical variables. Results: No significant difference in H. pylori eradication rates were found between high-dose dual therapy and bismuth-containing quadruple therapy by ITT, mITT and PP analysis[ITT:90.0% (95%CI 81.2%-95.6%) vs. 87.5% (95%CI 78.2%-93.8%), χ2=0.25, P=0.617;mITT:93.5% (95%CI 85.5%-97.9%) vs. 93.3% (95%CI 85.1%-97.8%), χ2<0.01, P=1.000; PP: 93.5% (95%CI 85.5%-97.9%) vs. 94.5% (95%CI 86.6%-98.5%), χ2<0.01, P=1.000 ]. The dual therapy group exhibited significantly less overall side effects compared with the quadruple therapy group [21.8% (17/78) vs. 38.5% (30/78), χ2=5.15,P=0.023]. There were no significant differences in the compliance rates between the two groups [98.7%(77/78) vs. 94.9%(74/78), χ2=0.83,P=0.363]. The cost of medications in the dual therapy was 32.0% lower compared with that in the quadruple therapy (472.10 RMB vs. 693.94 RMB). Conclusions: The dual regimen has a favorable effect on the eradication of H. pylori infection in servicemen patients. Based on the ITT analysis, the eradication rate of the dual regimen is grade B (90%, good). Additionally, it exhibited a lower incidence of adverse events, better compliance and significantly reduced cost. The dual regimen is expected to be a new choice for the first-line treatment of H. pylori infection in servicemen but needs further evaluation.

Widespread autogenous mRNA-protein interactions detected by CLIP-seq.

Autogenous interactions between mRNAs and the proteins they encode are implicated in cellular feedback-loop regulation, but their extent and mechanistic foundation are unclear. It was recently hypothesized that such interactions may be common, reflecting the role of intrinsic nucleobase-amino acid affinities in shaping the genetic code's structure. Here we analyze a comprehensive set of CLIP-seq experiments involving multiple protocols and report on widespread autogenous interactions across different organisms. Specifically, 230 of 341 (67%) studied RNA-binding proteins (RBPs) interact with their own mRNAs, with a heavy enrichment among high-confidence hits and a preference for coding sequence binding. We account for different confounding variables, including physical (overexpression and proximity during translation), methodological (difference in CLIP protocols, peak callers and cell types) and statistical (treatment of null backgrounds). In particular, we demonstrate a high statistical significance of autogenous interactions by sampling null distributions of fixed-margin interaction matrices. Furthermore, we study the dependence of autogenous binding on the presence of RNA-binding motifs and structured domains in RBPs. Finally, we show that intrinsic nucleobase-amino acid affinities favor co-aligned binding between mRNA coding regions and the proteins they encode. Our results suggest a central role for autogenous interactions in RBP regulation and support the possibility of a fundamental connection between coding and binding.

[Berberine alleviates programmed necrosis of metabolic-associated fatty liver disease via activating Nrf2 pathway in mice].

Objective: To investigate the effect of berberine on programmed necrosis of hepatocytes induced by metabolic-associated fatty liver disease (MAFLD) in mice and its related molecular mechanism. Methods: Twenty male C57BL/6N mice were randomly divided into four groups (n=5 in each group): control group (S), fatty liver group (H), berberine group(B), nuclear factor erythroid 2-related factor 2 inhibitor group (Nrf2), and all-trans-retinoic acid (ATRA) group (A). Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), triglycerides (TG), total cholesterol (TC), tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß) concentrations were detected at the end of week 12 to calculate fatty liver index (liver mass/body mass ratio). Liver tissue was stained with HE, Masson and Oil Red O, and SAF score was used to evaluate the degree of liver injury. The expression levels of hepatic programmed necrosis-related proteins, namely receptor-interacting protein kinase 3 (RIPK3), phosphorylated mixed series protease-like domain (p-MLKL) and Nrf2 were detected by Western blot method. One-way ANOVA was used for intragroup comparisons and LSD-t tests were used for intergroup comparisons. Results: Compared with S group, H group serum ALT, AST, LDH, TG, TC, TNF-α, IL-1ß levels and fatty liver index were significantly increased. The liver tissue was filled with vacuolar-like changes and inflammatory cell infiltration. Numerous red lipid droplets were observed with oil red O staining. Collagen fiber hyperplasia was evident with Masson staining. SAF scores (6.60 ± 0.55 and 0.80 ± 0.45) were significantly increased. The expressions of RIPK3 and p-MLKL were up-regulated. Nrf2 level was relatively increased, and the differences were statistically significant (P < 0.05). Compared with H group, berberine intervention group liver biochemical indexes, lipid levels, pro-inflammatory mediator expression, fatty liver index, and SAF score were significantly reduced, and the expression of RIPK3 and p-MLKL were down-regulated, while Nrf2 levels were further increased, and the differences were statistically significant (P<0.05). Compared with B group, treatment with Nrf2 inhibitor had antagonized the protective effect of berberine on fatty liver. Serum ALT, AST, LDH, TG, TC and TNF-α, IL-1ß levels, fatty liver index, and SAF scores were significantly increased and the expressions of RIPK3 and p-MLKL were relatively increased, and the differences were statistically significant (P < 0.05). Conclusion: Berberine can significantly improve the metabolic-associated fatty liver disease injury in mice, and its mechanism is related to activation of Nrf2 and inhibition of programmed necrosis of hepatocytes.

V-CARMA: A tool for the detection and modification of antigen-specific T cells.

T cells promote our body's ability to battle cancers and infectious diseases but can act pathologically in autoimmunity. The recognition of peptides presented by major histocompatibility complex (pMHC) molecules by T cell receptors (TCRs) enables T cell-mediated responses. To modify disease-relevant T cells, new tools to genetically modify T cells and decode their antigen recognition are needed. Here, we present an approach using viruses pseudotyped with peptides loaded on MHC called V-CARMA (Viral ChimAeric Receptor MHC-Antigen) to specifically target T cells expressing cognate TCRs for antigen discovery and T cell engineering. We show that lentiviruses displaying antigens on human leukocyte antigen (HLA) class I and class II molecules can robustly infect CD8+ and CD4+ T cells expressing cognate TCRs, respectively. The infection rates of the pseudotyped lentiviruses (PLVs) are correlated with the binding affinity of the TCR to its cognate antigen. Furthermore, peptide-HLA pseudotyped lentivirus V-CARMA constructs can identify target cells from a mixed T cell population, suppress PD-1 expression on CD8+ T cells via PDCD1 shRNA delivery, and induce apoptosis in autoreactive CD4+ T cells. Thus, V-CARMA is a versatile tool for TCR ligand identification and selective T cell manipulation.

ILF3-AS1 promotes the aerobic glycolysis and proliferation of melanoma cells by regulating miR-493-5p/PDK1 pathway.

BACKGROUND: The aim of this study was to investigate the role of ILF3-AS1 in regulating the survival of melanoma and its molecular mechanism. METHODS: The relative expression level of ILF3-AS1 in melanoma was assessed by qPCR. The effect of ILF3-AS1 and PDK1 on the cell viability was tested by MTT assay. Glucose uptake colorimetric assay, lactate assay, the measurements of extracellular acidification rate (ECAR) and Oxygen consumption rate (OCR) were performed to test the effect of ILF3-AS1 and PDK1 on the cellular glycolysis. Luciferase assay was conducted to detect the interactions of ILF3-AS1, miR-493-5p and PDK1. RNA immunoprecipitation chip (RIP) assay was used to detect the enrichments of ILF3-AS1 and miR-493-5p in the complex. Protein level of PDK1 was detected by western blot analysis. RESULTS: qPCR revealed that ILF3-AS1 was upregulated in human melanoma cell lines. MTT assay showed that ILF3-AS1 knockdown blunted cell proliferation, which was rescued by the overexpression of PDK1. Glucose uptake colorimetric assay, lactate assay, the measurements of ECAR and OCR indicated that ILF3-AS1 promoted glycolysis through PDK1. Western blotting results showed that ILF3-AS1 overexpression promoted PDK1 expression, which was prevented by miR-493-5p overexpression in SK-MEL-1 cells. CONCLUSIONS: ILF3-AS1 promotes the aerobic glycolysis and survival of melanoma cells involving miR-493-5p/PDK1 pathway.

[Correlations of serum TgAb and TPOAb and clinicopathological features of PTC in children and adolescents].

Objective: To analyze the correlations between serum thyroglobulin antibody (TgAb) and thyroid peroxidase antibody (TPOAb) and clinicopathological features in children and adolescents with papillary thyroid carcinoma (PTC). Methods: A retrospective analysis was conduced on the clinicopathological data of children and adolescents (age≤21 years old) with PTC admitted to Tianjin Medical University Cancer Hospital from 2011 to 2019, and then, we used χ2 test or Fisher's exact probability test to compare the differences in clinicopathological characteristics between groups with different TgAb and TPOAb status and multivariate logistic regression model analysis to evaluate independent predictors of cervical lymph node metastasis. Results: A total of 304 patients, including 89 males and 215 females, aged 5-21 years (median age 19 years), were enrolled in this study. The comparison between groups with different TgAb and TPOAb status showed that there were significant differences in gender, preoperative thyroglobulin (Tg) level, primary tumor location, number of primary tumors and maximum tumor diameter (all P<0.05), which suggested that TgAb+group (n=81) and TPOAb+group (n=84) had relatively better primary tumor characteristics. Patitents with TgAb+and TPOAb+were more common in females and their preoperative Tg level was mostly within the normal range, and there were significant differences in primary tumor location, number of primary tumors and maximum tumor diameter between TgAb+and TgAb-(223 cases) groups (all P<0.05). There was significant difference in the maximum tumor diameter between TPOAb+and TPOAb-(220 cases) groups (P<0.05). Analysis of risk factors for cervical lymph node metastasis showed that independent risk factors for central lymph node metastasis were maximum tumor diameter>2 cm (OR=2.84, 95%CI: 1.59-5.07, P<0.001) and extra-thyroid extension (OR=0.32, 95%CI: 0.17-0.60, P<0.001), and independent risk factors for lateral neck lymph node metastasis included age≤14 years old (OR=0.34, 95%CI: 0.18-0.67, P=0.002), preoperative Tg+(OR=2.16, 95%CI: 1.10-4.24, P=0.026) and maximum tumor diameter>2 cm (OR=3.99, 95%CI: 2.33-6.82, P<0.001). Conclusion: It is recommended to test routinely serum TgAb and TPOAb before surgery in children and adolescents with PTC. Preoperative Tg+, age≤14 years, maximum tumor diameter>2 cm, and extra-thyroid extension are risk factors for cervical lymph node metastasis.

Prognostic value and immunological characteristics of a novel autophagy-related signature in pancreatic cancer.

Autophagy affects the development, progression, and prognosis of various cancers including pancreatic cancer. To develop an autophagy-related prognostic model of pancreatic cancer, we systematically analyzed gene expression profile from The Cancer Genome Atlas and Genotype-Tissue Expression. Ten autophagy-relevant genes with potential prognostic values were identified, based on which a prognostic model was constructed. We divided patients into a high- and a low-risk group with this model. Time-dependent receiver operating characteristic and Kaplan-Meier curves were conducted to evaluate the accuracy of the model. The Area Under Curvevalues of this model at 12, 18, and 24 months were 0.76, 0.73, and 0.78, respectively. The model was further validated in two Gene Expression Omnibus datasets. Gene set enrichment analysis and Cibersort were applied to analyze immune infiltration patterns and immune checkpoint blockade (ICB) molecules. The expression of ICB molecules, such as PD-L1 and PD1, presented significant correlation with the risk score. In conclusion, the risk score model established herein has been proved to be robust for evaluating the prognosis of pancreatic cancer and facilitate to improve the efficacy of ICB.

Activated CD4+ T cells and CD14hiCD16+ monocytes correlate with antibody response following influenza virus infection in humans.

The failure to mount an antibody response following viral infection or seroconversion failure is a largely underappreciated and poorly understood phenomenon. Here, we identified immunologic markers associated with robust antibody responses after influenza virus infection in two independent human cohorts, SHIVERS and FLU09, based in Auckland, New Zealand and Memphis, Tennessee, USA, respectively. In the SHIVERS cohort, seroconversion significantly associates with (1) hospitalization, (2) greater numbers of proliferating, activated CD4+ T cells, but not CD8+ T cells, in the periphery during the acute phase of illness, and (3) fewer inflammatory monocytes (CD14hiCD16+) by convalescence. In the FLU09 cohort, fewer CD14hiCD16+ monocytes during early illness in the nasal mucosa were also associated with the generation of influenza-specific mucosal immunoglobulin A (IgA) and IgG antibodies. Our study demonstrates that seroconversion failure after infection is a definable immunological phenomenon, associated with quantifiable cellular markers that can be used to improve diagnostics, vaccine efficacy, and epidemiologic efforts.

Changes in weight and BMI with first-line doravirine-based therapy.

OBJECTIVE: To evaluate changes in weight and BMI in adults with HIV-1 at 1 and 2 years after starting an antiretroviral regimen that included doravirine, ritonavir-boosted darunavir, or efavirenz. DESIGN: Post-hoc analysis of pooled data from three randomized controlled trials. METHODS: We evaluated weight change from baseline, weight gain at least 10%, and increase in BMI after 48 and 96 weeks of treatment with doravirine, ritonavir-boosted darunavir, or efavirenz-based regimens. Risk factors for weight gain and metabolic outcomes associated with weight gain were also examined. RESULTS: Mean (and median) weight changes were similar for doravirine [1.7 (1.0) kg] and ritonavir-boosted darunavir [1.4 (0.6) kg] and were lower for efavirenz [0.6 (0.0) kg] at week 48 but were similar across all treatment groups at week 96 [2.4 (1.5), 1.8 (0.7), and 1.6 (1.0) kg, respectively]. No significant differences between treatment groups were found in the proportion of participants with at least 10% weight gain or the proportion with BMI class increase at either time point. Low CD4 T-cell count and high HIV-1 RNA at baseline were associated with at least 10% weight gain and BMI class increase at both timepoints, but treatment group, age, sex, and race were not. CONCLUSION: Weight gains over 96 weeks were low in all treatment groups and were similar to the average yearly change in adults without HIV-1. Significant weight gain and BMI class increase were similar across the treatment groups and were predicted by low baseline CD4 T-cell count and high baseline HIV-1 RNA.

Publisher Correction: Exuberant fibroblast activity compromises lung function via ADAMTS4.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Dynamic change of the gastrointestinal bacterial ecology in cows from birth to adulthood.

The gut microbiota plays multiple critical roles in maintaining the health of the host, especially in ruminants. However, our understanding of the establishment of gut microbiota from birth to adulthood is still limited. To address this, the bacterial ecology of the rumen, abomasum, duodenum, and rectum in Holstein cows ranging in age from 1 week to 5 years old was investigated using 16S rRNA gene sequencing in this study. A major change in the composition, diversity, and abundance of bacteria was observed with increased age (p < 0.05). Microbiota gradually matured in each gut segment and followed the Gompertz model when the Chao1, Shannon, and maturity indexes (p < 0.05, r > 0.94) were applied. Importantly, the Gompertz model parameter differed between the gut segments, with the highest microbiota growth rate found in the rectum, followed by the rumen, abomasum, and duodenum. Compared to older animals, greater microbiota similarities were found in the adjacent gut segments of younger animals (p < 0.05). Our findings indicate that gut microbiotas are established quickly when cows are young and then slow with age and that early in life, hindgut microbiota may be more easily affected by the foregut microbiota.

Exuberant fibroblast activity compromises lung function via ADAMTS4.

Severe respiratory infections can result in acute respiratory distress syndrome (ARDS)1. There are no effective pharmacological therapies that have been shown to improve outcomes for patients with ARDS. Although the host inflammatory response limits spread of and eventually clears the pathogen, immunopathology is a major contributor to tissue damage and ARDS1,2. Here we demonstrate that respiratory viral infection induces distinct fibroblast activation states, which we term extracellular matrix (ECM)-synthesizing, damage-responsive and interferon-responsive states. We provide evidence that excess activity of damage-responsive lung fibroblasts drives lethal immunopathology during severe influenza virus infection. By producing ECM-remodelling enzymes-in particular the ECM protease ADAMTS4-and inflammatory cytokines, damage-responsive fibroblasts modify the lung microenvironment to promote robust immune cell infiltration at the expense of lung function. In three cohorts of human participants, the levels of ADAMTS4 in the lower respiratory tract were associated with the severity of infection with seasonal or avian influenza virus. A therapeutic agent that targets the ECM protease activity of damage-responsive lung fibroblasts could provide a promising approach to preserving lung function and improving clinical outcomes following severe respiratory infections.

Necroptosis restricts influenza A virus as a stand-alone cell death mechanism.

Influenza A virus (IAV) activates ZBP1-initiated RIPK3-dependent parallel pathways of necroptosis and apoptosis in infected cells. Although mice deficient in both pathways fail to control IAV and succumb to lethal respiratory infection, RIPK3-mediated apoptosis by itself can limit IAV, without need for necroptosis. However, whether necroptosis, conventionally considered a fail-safe cell death mechanism to apoptosis, can restrict IAV-or indeed any virus-in the absence of apoptosis is not known. Here, we use mice selectively deficient in IAV-activated apoptosis to show that necroptosis drives robust antiviral immune responses and promotes effective virus clearance from infected lungs when apoptosis is absent. We also demonstrate that apoptosis and necroptosis are mutually exclusive fates in IAV-infected cells. Thus, necroptosis is an independent, "stand-alone" cell death mechanism that fully compensates for the absence of apoptosis in antiviral host defense.

Effects of ertugliflozin on renal function over 104 weeks of treatment: a post hoc analysis of two randomised controlled trials.

AIMS/HYPOTHESIS: This study aimed to evaluate the effect of ertugliflozin, a sodium-glucose cotransporter 2 (SGLT2) inhibitor, on eGFR and albuminuria (urine albumin/creatinine ratio [UACR]) vs glimepiride or placebo/glimepiride (non-ertugliflozin) over 104 weeks of treatment in participants with type 2 diabetes mellitus, using pooled data from two randomised controlled, active comparator studies from the eValuation of ERTugliflozin effIcacy and Safety (VERTIS) programme (Clinicaltrials.gov NCT01999218 [VERTIS SU] and NCT02033889 [VERTIS MET]). In the VERTIS SU study, ertugliflozin was evaluated vs glimepiride over 104 weeks. In the VERTIS MET study, ertugliflozin was evaluated vs placebo over 26 weeks; eligible participants were switched from placebo to blinded glimepiride from week 26 to week 104. The glycaemic efficacy of ertugliflozin vs non-ertugliflozin was also assessed in the pooled population. METHODS: Post hoc, exploratory analysis was used to investigate mean changes from baseline in eGFR and UACR over 104 weeks. RESULTS: Overall, mean (SD) baseline eGFR was 88.2 (18.8) ml min-1 (1.73 m)-2 and geometric mean (95% CI) of baseline UACR was 1.31 mg/mmol (1.23, 1.38). At week 6, the changes in eGFR from baseline were -2.3, -2.7 and -0.7 ml min-1 (1.73 m)-2 for the ertugliflozin 5 mg, ertugliflozin 15 mg and non-ertugliflozin groups, respectively. Mean eGFR in the ertugliflozin groups increased over time thereafter, while it decreased in the non-ertugliflozin group. Week 104 changes in eGFR from baseline were -0.2, 0.1 and -2.0 ml min-1 (1.73 m)-2 for the ertugliflozin 5 mg, ertugliflozin 15 mg and non-ertugliflozin groups, respectively. Among 415 patients (21.4% of the cohort) with albuminuria at baseline, the ertugliflozin groups had greater reductions in UACR at all measured time points up to week 104. At week 104, the non-ertugliflozin-corrected difference in UACR (95% CI) was -29.5% (-44.8, -9.8; p < 0.01) for ertugliflozin 5 mg and -37.6% (-51.8, -19.2; p < 0.001) for ertugliflozin 15 mg. Least squares mean changes from baseline in HbA1c (mmol/mol [95% CI]) at week 104 were similar between treatment groups: -6.84 (-7.64, -6.03), -7.74 (-8.54, -6.94) and -6.84 (-7.65, -6.03) in the ertugliflozin 5 mg, ertugliflozin 15 mg and non-ertugliflozin groups, respectively. Least squares mean changes from baseline in HbA1c (% [95% CI]) at week 104 were: -0.63 (-0.70, -0.55), -0.71 (-0.78, -0.64) and -0.63 (-0.70, -0.55) in the ertugliflozin 5 mg, ertugliflozin 15 mg and non-ertugliflozin groups, respectively. CONCLUSIONS/INTERPRETATION: Ertugliflozin reduced eGFR at week 6, consistent with the known pharmacodynamic effects of SGLT2 inhibitors on renal function. Over 104 weeks, eGFR values returned to baseline and were higher with ertugliflozin compared with non-ertugliflozin treatment, even though changes in HbA1c did not differ between the groups. Ertugliflozin reduced UACR in patients with baseline albuminuria. TRIAL REGISTRATION: clinicaltrials.gov NCT01999218 and NCT02033889.

Pediatric patients with acute lymphoblastic leukemia generate abundant and functional neoantigen-specific CD8+ T cell responses.

Cancer arises from the accumulation of genetic alterations, which can lead to the production of mutant proteins not expressed by normal cells. These mutant proteins can be processed and presented on the cell surface by major histocompatibility complex molecules as neoepitopes, allowing CD8+ T cells to mount responses against them. For solid tumors, only an average 2% of neoepitopes predicted by algorithms have detectable endogenous antitumor T cell responses. This suggests that low mutation burden tumors, which include many pediatric tumors, are poorly immunogenic. Here, we report that pediatric patients with acute lymphoblastic leukemia (ALL) have tumor-associated neoepitope-specific CD8+ T cells, responding to 86% of tested neoantigens and recognizing 68% of the tested neoepitopes. These responses include a public neoantigen from the ETV6-RUNX1 fusion that is targeted in seven of nine tested patients. We characterized phenotypic and transcriptional profiles of CD8+ tumor-infiltrating lymphocytes (TILs) at the single-cell level and found a heterogeneous population that included highly functional effectors. Moreover, we observed immunodominance hierarchies among the CD8+ TILs restricted to one or two putative neoepitopes. Our results indicate that robust antitumor immune responses are induced in pediatric ALL despite their low mutation burdens and emphasize the importance of immunodominance in shaping cellular immune responses. Furthermore, these data suggest that pediatric cancers may be amenable to immunotherapies aimed at enhancing immune recognition of tumor-specific neoantigens.

Macrophage migration inhibitory factor promotes renal injury induced by ischemic reperfusion.

Macrophage migration inhibitory factor (MIF) is pleiotropic cytokine that has multiple effects in many inflammatory and immune diseases. This study reveals a potential role of MIF in acute kidney injury (AKI) in patients and in kidney ischemic reperfusion injury (IRI) mouse model in MIF wild-type (WT) and MIF knockout (KO) mice. Clinically, plasma and urinary MIF levels were largely elevated at the onset of AKI, declined to normal levels when AKI was resolved and correlated tightly with serum creatinine independent of disease causes. Experimentally, MIF levels in plasma and urine were rapidly elevated after IRI-AKI and associated with the elevation of serum creatinine and the severity of tubular necrosis, which were suppressed in MIF KO mice. It was possible that MIF may mediate AKI via CD74/TLR4-NF-κB signalling as mice lacking MIF were protected from AKI by largely suppressing CD74/TLR-4-NF-κB associated renal inflammation, including the expression of MCP-1, TNF-α, IL-1ß, IL-6, iNOS, CXCL15(IL-8 in human) and infiltration of macrophages, neutrophil, and T cells. In conclusion, our study suggests that MIF may be pathogenic in AKI and levels of plasma and urinary MIF may correlate with the progression and regression of AKI.