Glutamyl-prolyl-tRNA synthetase (EPRS1) drives tubulointerstitial nephritis-induced fibrosis by enhancing T cell proliferation and activity.

Toxin- and drug-induced tubulointerstitial nephritis (TIN), characterized by interstitial infiltration of immune cells, frequently necessitates dialysis for patients due to irreversible fibrosis. However, agents modulating interstitial immune cells are lacking. Here, we addressed whether the housekeeping enzyme glutamyl-prolyl-transfer RNA synthetase 1 (EPRS1), responsible for attaching glutamic acid and proline to transfer RNA, modulates immune cell activity during TIN and whether its pharmacological inhibition abrogates fibrotic transformation. The immunological feature following TIN induction by means of an adenine-mixed diet was infiltration of EPRS1high T cells, particularly proliferating T and γδ T cells. The proliferation capacity of both CD4+ and CD8+ T cells, along with interleukin-17 production of γδ T cells, was higher in the kidneys of TIN-induced Eprs1+/+ mice than in the kidneys of TIN-induced Eprs1+/- mice. This discrepancy contributed to the fibrotic amelioration observed in kidneys of Eprs1+/- mice. TIN-induced fibrosis was also reduced in Rag1-/- mice adoptively transferred with Eprs1+/- T cells compared to the Rag1-/- mice transferred with Eprs1+/+ T cells. The use of an EPRS1-targeting small molecule inhibitor (bersiporocin) under clinical trials to evaluate its therapeutic potential against idiopathic pulmonary fibrosis alleviated immunofibrotic aggravation in TIN. EPRS1 expression was also observed in human kidney tissues and blood-derived T cells, and high expression was associated with worse patient outcomes. Thus, EPRS1 may emerge as a therapeutic target in toxin- and drug-induced TIN, modulating the proliferation and activity of infiltrated T cells.

IDO1 scavenges reactive oxygen species in myeloid-derived suppressor cells to prevent graft-versus-host disease.

Tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) also has an immunological function to suppress T cell activation in inflammatory circumstances, including graft-versus-host disease (GVHD), a fatal complication after allogeneic bone marrow transplantation (allo-BMT). Although the mononuclear cell expression of IDO1 has been associated with improved outcomes in GVHD, the underlying mechanisms remain unclear. Herein, we used IDO-deficient (Ido1-/-) BMT to understand why myeloid IDO limits the severity of GVHD. Hosts with Ido1-/- BM exhibited increased lethality, with enhanced proinflammatory and reduced regulatory T cell responses compared with wild type (WT) allo-BMT controls. Despite the comparable expression of the myeloid-derived suppressor cell (MDSC) mediators, arginase-1, inducible nitric oxide synthase, and interleukin 10, Ido1-/- Gr-1+CD11b+ cells from allo-BMT or in vitro BM culture showed compromised immune-suppressive functions and were skewed toward the Ly6ClowLy6Ghi subset, compared with the WT counterparts. Importantly, Ido1-/-Gr-1+CD11b+ cells exhibited elevated levels of reactive oxygen species (ROS) and neutrophil numbers. These characteristics were rescued by human IDO1 with intact heme-binding and catalytic activities and were recapitulated by the treatment of WT cells with the IDO1 inhibitor L1-methyl tryptophan. ROS scavenging by N-acetylcysteine reverted the Ido1-/-Gr-1+CD11b+ composition and function to an MDSC state, as well as improved the survival of GVHD hosts with Ido1-/- BM. In summary, myeloid-derived IDO1 enhances GVHD survival by regulating ROS levels and limiting the ability of Gr-1+CD11b+ MDSCs to differentiate into proinflammatory neutrophils. Our findings provide a mechanistic insight into the immune-regulatory roles of the metabolic enzyme IDO1.

Efficacy of fosfomycin compared to second generation cephalosporin flumarin as antimicrobial prophylaxis for transrectal ultrasound-guided prostate biopsy: a single center retrospective study.

BACKGROUND: Fluoroquinolone has been the historic choice of antimicrobial prophylaxis for transrectal ultrasound (TRUS) guided prostate biopsy. However, increased fluoroquinolone resistance and recent restrictions of its use for antimicrobial prophylaxis has led to the emergence of alternative agents for antimicrobial prophylaxis for TRUS guided prostate biopsy including fosfomycin and cephalosporins. This study aimed to compare the efficacy of fosfomycin and a second-generation cephalosporin flumarin as alternative antimicrobials for TRUS-guided prostate biopsy in terms of the incidence of infectious complications after TRUS-guided prostate biopsy. METHODS: A retrospective chart review of all patients who underwent TRUS-guided prostate biopsy between November 2009 to January 2023 was undertaken. Comparison of baseline characteristics and the incidence of infectious complications was done between those who received fosfomycin as antimicrobial prophylaxis for TRUS-guided prostate biopsy and those who received flumarin. Multivariate logistic regression analysis was conducted to identify risk factors for infectious complications after TRUS-guided prostate biopsy. RESULTS: Of 2,900 patients identified as eligible candidates for analysis, 333 (11.5%) received fosfomycin and 2,567 (88.5%) received flumarin. The overall rate of infectious complications was approximately 3% lower in patients who received fosfomycin, although such difference did not reach statistical significance (5.7% vs. 8.6%, p = 0.074). Multivariate logistic regression analysis showed that history of operation done under general anaesthesia within six months of the biopsy (odds ratio [OR]: 2.216; 95% confidence interval [CI]: 1.042-4.713; p = 0.039) and history of prior antimicrobial use within six months (OR: 1.457; 95% CI: 1.049-2.024; p = 0.025) were significant risk factors for infectious complications after TRUS-guided prostate biopsy. CONCLUSION: Fosfomycin was comparable to second-generation cephalosporin flumarin in preventing infectious complications after TRUS-guided prostate biopsy. Coupled with its properties such as ease of administration, low adverse effects, low resistance rate, and low collateral damage, fosfomycin might be an attractive alternative antimicrobial prophylaxis for TRUS-guided prostate biopsy.

The natural course of incidental ureteral polyp during ureteroscopic surgery: KSER research.

BACKGROUND: The natural course of polypoid lesions in the ureter during ureteroscopic stone surgery was not yet clarified. METHODS: Patient data were collected prospectively from six teaching hospitals between 2019 and 2021. Patients with polypoid lesions in the ureter distal to ureteral stones were included during ureteroscopy. Computed tomography was performed on all enrolled patients three months after the procedure. Follow-up ureteroscopy was performed only if the patient consented, due to the need for general anesthesia and ethical considerations. RESULTS: Among the 35 patients who were followed up, 14 had fibroepithelial polyps and 21 had inflammatory polyps. Twenty of the followed-up patients underwent ureteroscopy, and nine of them had fibroepithelial polyps. Although fibroepithelial polyps did not disappear in the follow-up ureteroscopy (p = 0.002), the rate of postoperative hydronephrosis was not higher in the fibroepithelial group than in the inflammatory group. Postoperative ureteral stricture and moderate-to-severe hydronephrosis were found to be closely related to the number of resected polyps, regardless of the type of polyp (p = 0.014 and 0.006, respectively). CONCLUSION: Fibroepithelial polyps in the ureter may persist after treatment of adjacent ureter stones. However, conservative management may be preferable to active removal of ureteral polyps because fibroepithelial polyps may not contribute to clinically significant hydronephrosis after surgery, and inflammatory polyps disappear spontaneously. Hasty resections of polyps may increase the risk of ureteral stricture.

Targeted Protein Upregulation of STING for Boosting the Efficacy of Immunotherapy.

Modulating target proteins via the ubiquitin-proteasome system has recently expanded the scope of pharmacological inventions. Stimulator of interferon genes (STING) is an auspicious target for immunotherapy. Seminal studies envisioned the importance of STING as well as the utility of its agonists in immunotherapy outcomes. Herein, we suggest UPPRIS (upregulation of target proteins by protein-protein interaction strategy) to pharmacologically increase cellular STING levels for improved immunotherapy. We discovered the small molecule SB24011 that inhibits STING-TRIM29 E3 ligase interaction, thus blocking TRIM29-induced degradation of STING. SB24011 enhanced STING immunity by upregulating STING protein levels, which robustly potentiated the immunotherapy efficacy of STING agonist and anti-PD-1 antibody via systemic anticancer immunity. Overall, we demonstrated that targeted protein upregulation of STING can be a promising approach for immuno-oncology.

IL-7Rαlow CD8+ T Cells from Healthy Individuals Are Anergic with Defective Glycolysis.

Effector memory (EM) CD8+ T cells expressing lower levels of IL-7R α (IL-7Rαlow) from healthy individuals are partly compromised in vitro, but the identity of these cells has remained unclear. In this study, we demonstrate that human IL-7Rαlow EM CD8+ T cells are naturally occurring anergic cells in vivo and impaired in proliferation and IL-2 production but competent in IFN-γ and TNF-α production, a state that can be restored by IL-2 stimulation. IL-7Rαlow EM CD8+ T cells show decreased expression of GATA3 and c-MYC and are defective in metabolic reprogramming toward glycolysis, a process required for the proliferation of T cells. However, IL-7Rαlow EM CD8+ T cells can proliferate with TCR stimulation in the presence of IL-2 and IL-15, suggesting that these cells can be restored to normality or increased activity by inflammatory conditions and may serve as a reservoir for functional immunity.

Longitudinal Analysis of Human Memory T-Cell Response According to the Severity of Illness up to 8 Months After Severe Acute Respiratory Syndrome Coronavirus 2 Infection.

BACKGROUND: Understanding the memory T-cell response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is crucial for assessing the longevity of protective immunity after SARS-CoV-2 infection or coronavirus disease 2019 (COVID-19) vaccination. However, the longitudinal memory T-cell response up to 8 months post-symptom onset (PSO) according to the severity of illness is unknown. METHODS: We analyzed peripheral blood mononuclear cells (PBMCs) from healthy volunteers or patients with COVID-19 who experienced asymptomatic, mild, or severe illness at 2, 5, and 8 months PSO. SARS-CoV-2 spike, nucleocapsid, and membrane protein-stimulated PBMCs were subjected to flow cytometry analysis. RESULTS: A total of 24 patients (7 asymptomatic, 9 with mild disease, and 8 with severe disease) and 6 healthy volunteers were analyzed. SARS-CoV-2-specific OX40+CD137+CD4+ T cells and CD69+CD137+CD8+ T cells persisted at 8 months PSO. Also, antigen-specific cytokine-producing or polyfunctional CD4+ T cells were maintained for up to 8 months PSO. Memory CD4+ T-cell responses tended to be greater in patients who had severe illness than in those with mild or asymptomatic disease. CONCLUSIONS: Memory response to SARS-CoV-2, based on the frequency and functionality, persists for 8 months PSO. Further investigations involving its longevity and protective effect from reinfection are warranted.

Effects of an alpha-1d adrenoreceptor antagonist (naftopidil) on bladder dysfunction after radiotherapy in female rats.

PURPOSE: Storage-phase bladder dysfunction can develop after pelvic radiotherapy. As the alpha-1d adrenoreceptor (a1d-AR) is dominant in the human detrusor, we aimed to investigate the effect of an a1d-AR antagonist on bladder dysfunction after pelvic radiotherapy in a rat model. MATERIALS AND METHODS: Twenty-four female Wistar rats were used. Eight rats (14-15 weeks, 250-300 g) were randomized to three groups (normal reference group, radiation alone group and radiation plus naftopidil group). An 18-Gy dose of radiotherapy was applied to the radiation alone and radiation plus naftopidil groups. Naftopidil (20 mg/kg) was administered daily to the radiation plus naftopidil group. Four weeks after radiation, all rats underwent cystometry and were killed for reverse transcription polymerase chain reaction to detect mRNAs [a1d-AR, brain-derived neurotrophic factor (BDNF) and vascular endothelial growth factor (VEGF)], Western blot to detect proteins (a1d-AR, extracellular-signal-regulated kinase, BDNF and VEGF) and immunohistochemistry. RESULTS: Compared to the radiation alone group, (1) the decrease in the mRNA and protein expression of a1d-AR and VEGF was ameliorated, (2) the increase in the expression of BDNF mRNA and proteins such as extracellular-signal-regulated kinase and BDNF was suppressed, (3) submucosal thickness and vascularity on immunohistochemistry were improved, and (4) the baseline intravesical pressure and intercontraction interval in cystometry were ameliorated in the radiation plus naftopidil group. CONCLUSION: Administration of an a1d-AR antagonist could improve storage-phase bladder dysfunction after radiotherapy not only by upregulating a1d-AR, which might decrease bladder compliance, but also by enhancing vascularity, which might protect the urinary bladder from chronic ischemic inflammation.

Cancer Stem Cells in the Immune Microenvironment.

Cancer stem cells are a subpopulation of cancer cells responsible for the most demanding and aggressive cancer cell phenotypes: therapy resistance, a self-protective feature of stem cells; distant metastasis, requiring anchorage independence for survival in the circulation; and recurrence, which is related to the dormant-active cycling of stem cells. Normal tissues are composed of parenchymal cells, supportive connective components, and cellular disposal systems for removing the products of physiological wear and tear. Cancer stem cells develop from normal counterparts and progressively interact with their microenvironments, modifying and conditioning the cancer microenvironment. Cancer-associated myeloid cells constitute a major element of the cancer microenvironment. During the process of carcinogenesis, cancer stem cells and their intimately associated myeloid cells mutually interact and evolve, such that the cancer cells potentiate the activity of the myeloid cells and, in return, the myeloid cells increase cancer stem cell characteristics. Normal myeloid cells function as key accessory cells to maintain homeostasis in normal tissues and organs; in cancers, these cells co-evolve with the malignant parenchymal cells and are involved in every aspect of cancer cell biology, including proliferation, invasion, distant metastasis, and the development of resistance to therapy. In this way, cancer-associated myeloid cells provide two of the key hallmarks of cancer: evasion of immune destruction and cancer-promoting inflammation.

Wireless, intraoral hybrid electronics for real-time quantification of sodium intake toward hypertension management.

Recent wearable devices offer portable monitoring of biopotentials, heart rate, or physical activity, allowing for active management of human health and wellness. Such systems can be inserted in the oral cavity for measuring food intake in regard to controlling eating behavior, directly related to diseases such as hypertension, diabetes, and obesity. However, existing devices using plastic circuit boards and rigid sensors are not ideal for oral insertion. A user-comfortable system for the oral cavity requires an ultrathin, low-profile, and soft electronic platform along with miniaturized sensors. Here, we introduce a stretchable hybrid electronic system that has an exceptionally small form factor, enabling a long-range wireless monitoring of sodium intake. Computational study of flexible mechanics and soft materials provides fundamental aspects of key design factors for a tissue-friendly configuration, incorporating a stretchable circuit and sensor. Analytical calculation and experimental study enables reliable wireless circuitry that accommodates dynamic mechanical stress. Systematic in vitro modeling characterizes the functionality of a sodium sensor in the electronics. In vivo demonstration with human subjects captures the device feasibility for real-time quantification of sodium intake, which can be used to manage hypertension.