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Non-alcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease that can progress to liver fibrosis. Recent clinical advance suggests a reversibility of liver fibrosis, but the cellular and molecular mechanisms underlying NASH resolution remain unclarified. Here, using a murine diet-induced NASH and the subsequent resolution model, we demonstrate direct roles of CD8 + tissue-resident memory CD8 + T (CD8 + Trm) cells in resolving liver fibrosis. Single-cell transcriptome analysis and FACS analysis revealed CD69 + CD103 − CD8 + Trm cell enrichment in NASH resolution livers. The reduction of liver CD8 + Trm cells, maintained by tissue IL-15, significantly delayed fibrosis resolution, while adoptive transfer of these cells protected mice from fibrosis progression. During resolution, CD8 + Trm cells attracted hepatic stellate cells (HSCs) in a CCR5-dependent manner, and predisposed activated HSCs to FasL-Fas-mediated apoptosis. Histological assessment of patients with NASH revealed CD69 + CD8 + Trm abundance in fibrotic areas, further supporting their roles in humans. These results highlight the undefined role of liver CD8 + Trm in fibrosis resolution. The cellular and molecular mechanisms underlying the resolution of non-alcoholic steatohepatitis remain incompletely understood. Here the authors report a single cell-based analysis that identified CD8 + tissue-resident memory T cells, which contribute to resolution of liver fibrosis potentially via elimination of hepatic stellate cells through Fas-mediated cytotoxicity.

Recent clinical and experimental evidence has evoked the concept of the gut–brain axis to explain mutual interactions between the central nervous system and gut microbiota that are closely associated with the bidirectional effects of inflammatory bowel disease and central nervous system disorders 1 – 4 . Despite recent advances in our understanding of neuroimmune interactions, it remains unclear how the gut and brain communicate to maintain gut immune homeostasis, including in the induction and maintenance of peripheral regulatory T cells (pT reg cells), and what environmental cues prompt the host to protect itself from development of inflammatory bowel diseases. Here we report a liver–brain–gut neural arc that ensures the proper differentiation and maintenance of pT reg cells in the gut. The hepatic vagal sensory afferent nerves are responsible for indirectly sensing the gut microenvironment and relaying the sensory inputs to the nucleus tractus solitarius of the brainstem, and ultimately to the vagal parasympathetic nerves and enteric neurons. Surgical and chemical perturbation of the vagal sensory afferents at the hepatic afferent level reduced the abundance of colonic pT reg cells; this was attributed to decreased aldehyde dehydrogenase (ALDH) expression and retinoic acid synthesis by intestinal antigen-presenting cells. Activation of muscarinic acetylcholine receptors directly induced ALDH gene expression in both human and mouse colonic antigen-presenting cells, whereas genetic ablation of these receptors abolished the stimulation of antigen-presenting cells in vitro. Disruption of left vagal sensory afferents from the liver to the brainstem in mouse models of colitis reduced the colonic pT reg cell pool, resulting in increased susceptibility to colitis. These results demonstrate that the novel vago-vagal liver–brain–gut reflex arc controls the number of pT reg cells and maintains gut homeostasis. Intervention in this autonomic feedback feedforward system could help in the development of therapeutic strategies to treat or prevent immunological disorders of the gut. A liver–brain–gut neural circuit responds to the gut microenvironment and regulates the activity of peripheral regulatory T cells in the colon by controlling intestinal antigen-presenting cells in a muscarinic signalling-dependent manner.

To select the most suitable chelate for 225Ac radiolabeling of the anti‐FZD10 antibody OTSA101, we directly compared three chelates: S‐2‐(4‐isothiocyanatobenzyl)‐1,4,7,10‐tetraazacyclododecane tetraacetic acid (p‐SCN‐Bn‐DOTA), 2,2′,2″‐(10‐(1‐carboxy‐4‐((4‐isothiocyanatobenzyl)amino)‐4‐oxobutyl)‐1,4,7,10‐tetraazacyclododecane‐1,4,7‐triyl) triacetic acid (p‐SCN‐Bn‐DOTAGA), and 1,4,7,10‐tetraazacyclododecane‐1,4,7,10‐tetraacetic acid mono‐N‐hydroxysuccinimide ester (DO3A‐NHS‐ester). We evaluated the binding affinity of the chelate‐conjugated OTSA101 antibodies, as well as the labeling efficiency and stability in murine serum of 225Ac‐labeled OTSA101 as in vitro properties. The biodistribution, intratumoral distribution, absorbed doses, and therapeutic effects of the chelate‐conjugated OTSA101 antibodies were assessed in the synovial sarcoma mouse model SYO‐1. Of the three conjugates, DOTAGA conjugation had the smallest impact on the binding affinity (p < 0.01). The labeling efficiencies of DOTAGA‐OTSA101 and DO3A‐OTSA101 were 1.8‐fold higher than that of DOTA‐OTSA101 (p < 0.01). The stabilities were similar between 225Ac‐labeled DOTA‐OTSA101, DOTAGA‐OTSA101, and DO3A‐OTSA101in serum at 37 and 4°C. The dosimetric analysis based on the biodistribution revealed significantly higher tumor‐absorbed doses by 225Ac‐labeled DOTA‐OTSA101 and DOTAGA‐OTSA101 compared with 225Ac‐DO3A‐OTSA101 (p < 0.05). 225Ac‐DOTAGA‐OTSA101 exhibited the highest tumor‐to‐bone marrow ratio, with bone marrow being the dose‐limiting tissue. The therapeutic and adverse effects were not significantly different between the three conjugates. Our findings indicate that among the three evaluated chelates, DOTAGA appears to be the most promising chelate to produce 225Ac‐labeled OTSA101 with high binding affinity and high radiochemical yields while providing high absorbed doses to tumors and limited absorbed doses to bone marrow. A direct comparison of three bifunctional chelates, p‐SCN‐Bn‐DOTA, p‐SCN‐Bn‐DOTAGA, and DO3A‐NHS‐ester demonstrated that DOTAGA would be the most promising chelate to produce 225Ac‐labeled OTSA101 with high binding affinity and high labeling efficiency and to provide high absorbed doses to tumors and limited ones to bone marrow.

Background The PreserFlo MicroShunt is a minimally invasive glaucoma drainage device designed to lower intraocular pressure (IOP) with fewer complications compared with those of traditional filtration surgery. Hypotony and choroidal detachment (CD) are known postoperative risks. However, retinal pigment epithelium (RPE) tears and serous retinal detachment following PreserFlo MicroShunt have not been reported previously. We report a case of retinal detachment with an RPE tear under hypotony following minimally invasive glaucoma surgery using a drainage device that required surgical intervention to elevate the IOP and achieve resolution. Case presentation A 53-year-old man with a history of ocular hypertension and cataract surgery with intraocular lens suturing developed uncontrolled IOP in his right eye. PreserFlo MicroShunt surgery was performed but resulted in hypotony and subsequent CD. Despite initial management with atropine eye drops and oral steroids, retinal detachment with RPE tears developed. Scleral drainage and pars plana vitrectomy with sulfur hexafluoride (SF6) gas tamponade were performed to elevate IOP and stabilize the retinal condition, leading to the successful resolution of the detachment. Postoperatively, the IOP stabilized within the mid-teens without observing recurrence. Conclusions This is the first reported case of RPE tears and serous retinal detachment following Preserflo MicroShunt surgery. These findings highlight that a rapid and significant reduction in IOP, even without reaching absolute hypotony, might disrupt choroidal circulation and RPE integrity, particularly in eyes with predisposing factors, such as atopic dermatitis and long-term steroid use. Early recognition of CD and timely intervention to elevate IOP are crucial for preventing vision-threatening complications.

Purpose To analyze the clinical characteristics and treatment of noninfectious scleritis in Japanese patients, focusing on the efficacy of methotrexate (MTX). Study design Retrospective. Patients and methods A retrospective study of patients with noninfectious scleritis treated at Hiroshima University from February 2016 to May 2020 was performed. The patients’ clinical features, associated systemic diseases, treatments, and visual outcomes were studied. The efficacy of MTX was also analyzed. Results The study comprised 57 patients (88 eyes) with noninfectious scleritis, of whom 31 had bilateral involvement and the majority had anterior diffuse scleritis (n = 45). The commonest ocular complication was anterior chamber cells (38.6%), followed by ocular hypertension (28.1%). Associated systemic diseases were observed in 24.6% of the patients. Systemic immunosuppressive treatment was required in 78.9% of the patients, and 45.6% of the patients needed corticosteroid-sparing immunosuppressive treatment. Treatment success was achieved in 88.2% of the patients. Decreased vision was observed in 9.8% of the patients with ≥ 3-month follow-up. Seventeen patients were treated with MTX; the median maximum dose was 16 mg/week (range 8–16 mg). The scleritis was well controlled in almost 80% of the patients treated with MTX and systemic corticosteroids ≤ 5 mg. MTX adverse effects occurred in 47.1% of the MTX-treated patients; they were either tolerable or improved with dose adjustment in most cases. Conclusion Our study suggests the significance of prompt initiation of corticosteroid-sparing immunosuppressive treatment in treating patients with refractory scleritis or those intolerant of systemic corticosteroids. Moreover, MTX may be used effectively and safely for the treatment of noninfectious scleritis in Japanese patients.

Background and Objectives: Faricimab is the first intravitreal injection of vascular endothelial growth factor-A and angiopoietin-2 bispecific monoclonal antibody. Here, we evaluate the functional and anatomical outcomes of faricimab treatment in patients with diabetic macular edema (DME) that was refractory to ranibizumab or aflibercept. Materials and Methods: We performed a retrospective, observational, consecutive-case study of patients who had DME that was refractory to treatment with ranibizumab or aflibercept and were treated with faricimab between July 2022 and January 2023 under a pro re nata regimen. All the participants were followed for ≥4 months after the initiation of faricimab. The primary outcome was a recurrence interval of ≥12 weeks, and the secondary outcomes were the changes in best-corrected visual acuity (BCVA) and central macular thickness (CMT). Results: We analyzed 18 eyes of 18 patients. The mean recurrence interval of previous anti-VEGF injection was 5.8 ± 2.5 weeks, which was significantly extended to 10.8 ± 4.9 weeks (p = 0.0005) by the switch to faricimab. Eight patients (44.4%) achieved a recurrence interval of ≥12 weeks. A history of subtenon injection of triamcinolone acetonide (p = 0.0034) and the presence of disorganization of the retinal inner layers (p = 0.0326) were found to be significantly associated with a recurrence interval of <12 weeks. The mean BCVAs were 0.23 ± 0.28 logMAR and 0.19 ± 0.23 logMAR, and the mean CMTs were 473.8 ± 222.0 µm and 381.3 ± 219.4 µm at baseline and 4 months, respectively, but these changes were not statistically significant. None of the patients experienced serious adverse events. Conclusions: Faricimab may extend the treatment interval for patients with DME that is refractory to ranibizumab or aflibercept. DME previously treated with the subtenon injection of triamcinolone acetonide or associated with disorganization of the retinal inner layers may be less likely to be associated with a longer recurrence interval after switching to faricimab.

The purpose of this study was to compare the incidence of ciliochoroidal detachment (CCD) after intrascleral lens fixation using the Yamane technique and other vitrectomy procedures. This retrospective study evaluated patients who underwent intrascleral lens fixation using the Yamane technique at Hiroshima University Hospital between March 2023 and February 2024 and who could be followed up for at least one month. Patients who underwent vitrectomy for macular disease without air-fluid exchange comprised the control group. The frequency of CCD was compared using anterior segment optical coherence tomography imaging. Forty-five eyes of 45 patients (26 men and 19 women, mean age 70.8 years) were included. There were no significant differences in the population means or proportions between the intrascleral fixation and control groups for age, sex ratio, right-to-left eye ratio, preoperative visual acuity, preoperative intraocular pressure (IOP), ocular axis, and corneal thickness. The population mean of IOP on the day after surgery was significantly lower in the Yamane intrascleral fixation group (8.4 mmHg) than in the control group (11.5 mmHg) (P < 0.05). There was no significant difference in the population proportions of CCD on the day after surgery between the Yamane intrascleral fixation group and the control group. However, the CCD incidence was 20 eyes (80%) for the Yamane intrascleral fixation group and 12 eyes (60%) for the control group, which was higher in the intrascleral fixation group. There was no significant difference in population means of IOP or population proportions of CCD at one week and one month. There was no significant difference in population proportions of CCD on the day after surgery, although the CCD rate for the Yamane intrascleral fixation group was higher, and the population mean of the IOP was significantly lower. The Yamane technique assumedly lowered IOP because of the stress placed on the ciliary body. One week after the procedure, the IOP in the intrascleral fixation group normalized.

Synovial sarcomas are rare tumors arising in adolescents and young adults. The prognosis for advanced disease is poor, with an overall survival of 12‐18 months. Frizzled homolog 10 (FZD10) is overexpressed in most synovial sarcomas, making it a promising therapeutic target. The results of a phase 1 trial of β‐radioimmunotherapy (RIT) with the 90Y‐labeled anti‐FZD10 antibody OTSA101 revealed a need for improved efficacy. The present study evaluated the potential of α‐RIT with OTSA101 labeled with the α‐emitter 225Ac. Competitive inhibition and cell binding assays showed that specific binding of 225Ac‐labeled OTSA101 to SYO‐1 synovial sarcoma cells was comparable to that of the imaging agent 111In‐labeled OTSA101. Biodistribution studies showed high uptake in SYO‐1 tumors and low uptake in normal organs, except for blood. Dosimetric studies showed that the biologically effective dose (BED) of 225Ac‐labeled OTSA101 for tumors was 7.8 Bd higher than that of 90Y‐labeled OTSA101. 90Y‐ and 225Ac‐labeled OTSA101 decreased tumor volume and prolonged survival. 225Ac‐labeled OTSA101 achieved a complete response in 60% of mice, and no recurrence was observed. 225Ac‐labeled OTSA101 induced a larger amount of necrosis and apoptosis than 90Y‐labeled OTSA101, although the cell proliferation decrease was comparable. The BED for normal organs and tissues was tolerable; no treatment‐related mortality or obvious toxicity, except for temporary body weight loss, was observed. 225Ac‐labeled OTSA101 provided a high BED for tumors and achieved a 60% complete response in the synovial sarcoma mouse model SYO‐1. RIT with 225Ac‐labeled OTSA101 is a promising therapeutic option for synovial sarcoma. FZD10‐targeted alpha‐radioimmunotherapy with 225Ac‐labeled OTSA101 provided a high radiation dose to tumors and achieved 60% complete response in the synovial sarcoma mouse model SYO‐1. This is the best outcome among FZD10‐targeted therapy to date. Our alpha‐radioimmunotherapy would provide an additional therapeutic option to synovial sarcoma patients that do not show a good response to conventional therapy.

We report four cases of syphilitic uveitis with diverse clinical presentations. All patients were men who have sex with women, and were aged 19-68 years, and none were HIV-positive. All cases were bilateral. One case presented with anterior uveitis, while three exhibited panuveitis. One patient had acute syphilitic posterior placoid chorioretinitis and two had retinal vasculitis resulting in damage to the outer retinal and retinal pigment epithelium. The rapid plasma reagin (RPR) test and (TP) hemagglutination test were both positive in all cases. Six of eight eyes had improved vision and best-corrected visual acuity better than 20/20 after antibiotic treatment. Serological testing is mandatory for the diagnosis of syphilitic uveitis. Additionally, multimodal imaging, including optical coherence tomography (OCT), fundus autofluorescence (FAF), and fluorescein angiography (FA), can provide useful adjunctive information for early diagnosis and assessment of treatment response.