Transcription factor EGR2 controls homing and pathogenicity of TH17 cells in the central nervous system.

CD4+ T helper 17 (TH17) cells protect barrier tissues but also trigger autoimmunity. The mechanisms behind these opposing processes remain unclear. Here, we found that the transcription factor EGR2 controlled the transcriptional program of pathogenic TH17 cells in the central nervous system (CNS) but not that of protective TH17 cells at barrier sites. EGR2 was significantly elevated in myelin-reactive CD4+ T cells from patients with multiple sclerosis and mice with autoimmune neuroinflammation. The EGR2 transcriptional program was intricately woven within the TH17 cell transcriptional regulatory network and showed high interconnectivity with core TH17 cell-specific transcription factors. Mechanistically, EGR2 enhanced TH17 cell differentiation and myeloid cell recruitment to the CNS by upregulating pathogenesis-associated genes and myelomonocytic chemokines. T cell-specific deletion of Egr2 attenuated neuroinflammation without compromising the host's ability to control infections. Our study shows that EGR2 regulates tissue-specific and disease-specific functions in pathogenic TH17 cells in the CNS.

Pathways and mechanisms of CD4+CD8αα+ intraepithelial T cell development.

The mammalian small intestine epithelium harbors a peculiar population of CD4+CD8αα+ T cells that are derived from mature CD4+ T cells through reprogramming of lineage-specific transcription factors. CD4+CD8αα+ T cells occupy a unique niche in T cell biology because they exhibit mixed phenotypes and functional characteristics of both CD4+ helper and CD8+ cytotoxic T cells. The molecular pathways driving their generation are not fully mapped. However, recent studies demonstrate the unique role of the commensal gut microbiota as well as distinct cytokine and chemokine requirements in the differentiation and survival of these cells. We review the established and newly identified factors involved in the generation of CD4+CD8αα+ intraepithelial lymphocytes (IELs) and place them in the context of the molecular machinery that drives their phenotypic and functional differentiation.

The transcription factor ThPOK suppresses Runx3 and imposes CD4(+) lineage fate by inducing the SOCS suppressors of cytokine signaling.

Lineage fate in the thymus is determined by mutually exclusive expression of the transcription factors ThPOK and Runx3, with ThPOK imposing the CD4(+) lineage fate and Runx3 promoting the CD8(+) lineage fate. While it is known that cytokine signals induce thymocytes to express Runx3, it is not known how ThPOK prevents thymocytes from expressing Runx3 and adopting the CD8(+) lineage fate, nor is it understood why ThPOK itself imposes the CD4(+) lineage fate on thymocytes. We now report that genes encoding members of the SOCS (suppressor of cytokine signaling) family are critical targets of ThPOK and that their induction by ThPOK represses Runx3 expression and promotes the CD4(+) lineage fate. Thus, induction of SOCS-encoding genes is the main mechanism by which ThPOK imposes the CD4(+) lineage fate in the thymus.

IL-7 signaling must be intermittent, not continuous, during CD8⁺ T cell homeostasis to promote cell survival instead of cell death.

The maintenance of naive CD8(+) T cells is necessary for lifelong immunocompetence but for unknown reasons requires signaling via both interleukin 7 (IL-7) and the T cell antigen receptor (TCR). We now report that naive CD8(+) T cells required IL-7 signaling to be intermittent, not continuous, because prolonged IL-7 signaling induced naive CD8(+) T cells to proliferate, produce interferon-γ (IFN-γ) and undergo IFN-γ-triggered cell death. Homeostatic engagement of the TCR interrupted IL-7 signaling and thereby supported the survival and quiescence of CD8(+) T cells. However, CD8(+) T cells with insufficient TCR affinity for self ligands received prolonged IL-7 signaling and died during homeostasis. In this study we identified regulation of the duration of IL-7 signaling by homeostatic engagement of the TCR as the basis for in vivo CD8(+) T cell homeostasis.

Comparative analysis of glymphatic system alterations in multiple sclerosis and neuromyelitis optica spectrum disorder using MRI indices from diffusion tensor imaging.

OBJECTIVE: The glymphatic system is a glial-based perivascular network that promotes brain metabolic waste clearance. Glymphatic system dysfunction has been observed in both multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD), indicating the role of neuroinflammation in the glymphatic system. However, little is known about how the two diseases differently affect the human glymphatic system. The present study aims to evaluate the diffusion MRI-based measures of the glymphatic system by contrasting MS and NMOSD. METHODS: This prospective study included 63 patients with NMOSD (n = 21) and MS (n = 42) who underwent DTI. The fractional volume of extracellular-free water (FW) and an index of diffusion tensor imaging (DTI) along the perivascular space (DTI-ALPS) were used as indirect indicators of water diffusivity in the interstitial extracellular and perivenous spaces of white matter, respectively. Age and EDSS scores were adjusted. RESULTS: Using Bayesian hypothesis testing, we show that the present data substantially favor the null model of no differences between MS and NMOSD for the diffusion MRI-based measures of the glymphatic system. The inclusion Bayes factor (BF10) of model-averaged probabilities of the group (MS, NMOSD) was 0.280 for FW and 0.236 for the ALPS index. CONCLUSION: Together, these findings suggest that glymphatic alteration associated with MS and NMOSD might be similar and common as an eventual result, albeit the disease etiologies differ. PRACTITIONER POINTS: Previous literature indicates important glymphatic system alteration in MS and NMOSD. We explore the difference between MS and NMOSD using diffusion MRI-based measures of the glymphatic system. We show support for the null hypothesis of no difference between MS and NMOSD. This suggests that glymphatic alteration associated with MS and NMOSD might be similar and common etiology.

Clonal deletion and the fate of autoreactive thymocytes that survive negative selection.

Clonal deletion of autoreactive thymocytes is important for self-tolerance, but the intrathymic signals that induce clonal deletion have not been clearly identified. We now report that clonal deletion during negative selection required CD28-mediated costimulation of autoreactive thymocytes at the CD4(+)CD8(lo) intermediate stage of differentiation. Autoreactive thymocytes were prevented from undergoing clonal deletion by either a lack of CD28 costimulation or transgenic overexpression of the antiapoptotic factors Bcl-2 or Mcl-1, with surviving thymocytes differentiating into anergic CD4(-)CD8(-) double-negative thymocytes positive for the T cell antigen receptor αß subtype (TCRαß) that 'preferentially' migrated to the intestine, where they re-expressed CD8α and were sequestered as CD8αα(+) intraepithelial lymphocytes (IELs). Our study identifies costimulation by CD28 as the intrathymic signal required for clonal deletion and identifies CD8αα(+) IELs as the developmental fate of autoreactive thymocytes that survive negative selection.

The ever-expanding role of cytokine receptor DR3 in T cells.

Death Receptor 3 (DR3) is a cytokine receptor of the Tumor Necrosis Factor receptor superfamily that plays a multifaceted role in both innate and adaptive immunity. Based on the death domain motif in its cytosolic tail, DR3 had been proposed and functionally affirmed as a trigger of apoptosis. Further studies, however, also revealed roles of DR3 in other cellular pathways, including inflammation, survival, and proliferation. DR3 is expressed in various cell types, including T cells, B cells, innate lymphocytes, myeloid cells, fibroblasts, and even outside the immune system. Because DR3 is mainly expressed on T cells, DR3-mediated immune perturbations leading to autoimmunity and other diseases were mostly attributed to DR3 activation of T cells. However, which T cell subset and what T effector functions are controlled by DR3 to drive these processes remain incompletely understood. DR3 engagement was previously found to alter CD4 T helper subset differentiation, expand the Foxp3+ Treg cell pool, and maintain intraepithelial γδ T cells in the gut. Recent studies further unveiled a previously unacknowledged aspect of DR3 in regulating innate-like invariant NKT (iNKT) cell activation, expanding the scope of DR3-mediated immunity in T lineage cells. Importantly, in the context of iNKT cells, DR3 ligation exerted costimulatory effects in agonistic TCR signaling, unveiling a new regulatory framework in T cell activation and proliferation. The current review is aimed at summarizing such recent findings on the role of DR3 on conventional T cells and innate-like T cells and discussing them in the context of immunopathogenesis.

Predicting hematoma expansion in acute spontaneous intracerebral hemorrhage: integrating clinical factors with a multitask deep learning model for non-contrast head CT.

PURPOSE: To predict hematoma growth in intracerebral hemorrhage patients by combining clinical findings with non-contrast CT imaging features analyzed through deep learning. METHODS: Three models were developed to predict hematoma expansion (HE) in 572 patients. We utilized multi-task learning for both hematoma segmentation and prediction of expansion: the Image-to-HE model processed hematoma slices, extracting features and computing a normalized DL score for HE prediction. The Clinical-to-HE model utilized multivariate logistic regression on clinical variables. The Integrated-to-HE model combined image-derived and clinical data. Significant clinical variables were selected using forward selection in logistic regression. The two models incorporating clinical variables were statistically validated. RESULTS: For hematoma detection, the diagnostic performance of the developed multi-task model was excellent (AUC, 0.99). For expansion prediction, three models were evaluated for predicting HE. The Image-to-HE model achieved an accuracy of 67.3%, sensitivity of 81.0%, specificity of 64.0%, and an AUC of 0.76. The Clinical-to-HE model registered an accuracy of 74.8%, sensitivity of 81.0%, specificity of 73.3%, and an AUC of 0.81. The Integrated-to-HE model, merging both image and clinical data, excelled with an accuracy of 81.3%, sensitivity of 76.2%, specificity of 82.6%, and an AUC of 0.83. The Integrated-to-HE model, aligning closest to the diagonal line and indicating the highest level of calibration, showcases superior performance in predicting HE outcomes among the three models. CONCLUSION: The integration of clinical findings with non-contrast CT imaging features analyzed through deep learning showed the potential for improving the prediction of HE in acute spontaneous intracerebral hemorrhage patients.

The cytokine receptor DR3 identifies and promotes the activation of thymic NKT17 cells.

Invariant natural killer T (iNKT) cells correspond to a population of thymus-generated T cells with innate-like characteristics and effector functions. Among the various iNKT subsets, NKT17 is the only subset that produces the proinflammatory cytokine IL-17. But, how NKT17 cells acquire this ability and what would selectively trigger their activation remain incompletely understood. Here, we identified the cytokine receptor DR3 being specifically expressed on thymic NKT17 cells and mostly absent on other thymic iNKT subsets. Moreover, DR3 ligation promoted the in vivo activation of thymic NKT17 cells and provided costimulatory effects upon agonistic α-GalCer stimulation. Thus, we identified a specific surface marker for thymic NKT17 cells that triggers their activation and augments their effector functions both in vivo and in vitro. These findings provide new insights for deciphering the role and function of murine NKT17 cells and for understanding the development and activation mechanisms of iNKT cells in general.

Effectiveness of Mechanical Bowel Preparation Before Robot-assisted Laparoscopic Gynecologic Surgery: a Randomized, Single-Blind, Controlled Trial.

OBJECTIVE: The objective of this randomized controlled trial is to compare the effect of bowel preparation using only oral polyethylene glycol electrolyte (PEG) solution vs. oral polyethylene glycol electrolyte solution (PEG) combined with mechanical sodium phosphate (NaP) enema on the surgical field visualization in patients undergoing robot-assisted laparoscopic gynecologic procedures. METHODS: Participants were randomized to either a single oral PEG solution or an oral PEG solution combined by mechanical NaP enema. The intraoperative visualization of the surgical field, the ease of manipulation of the bowels and overall difficulty level of the surgery were evaluated by the surgeon using a self-administered questionnaire. After the surgery, the patients completed a survey assessing postoperative gastrointestinal discomfort. RESULTS: 114 women were enrolled and randomized to oral PEG solution only group (n=48), and oral PEG plus mechanical NaP enema group (n=66). 42 women in oral PEG only group and 59 oral PEG plus NaP enema group completed the study. There was no difference in intraoperative visualization, or overall difficulty of the operation between the two groups, and bowel manipulation was easier in the oral PEG only group. Also, there was no difference in operating time between the groups. The patients' level of gastrointestinal discomfort after the surgery was not significantly different between the two groups. CONCLUSION: Routine use of mechanical NaP enema before robot-assisted laparoscopic gynecologic surgery is not recommended, because it has no additional benefit regarding intraoperative visualization or the surgical level of difficulty over oral bowel preparation methods.

No increased risk of osteonecrosis of the jaw in osteoporotic patients with dental implants: a nationwide cohort study.

OBJECTIVES: The occurrence of implant-associated osteonecrosis of the jaw (ONJ) has been reported in osteoporotic patients, particularly in association with bisphosphonate therapy. This study aimed to investigate the risk of implant surgery and implant presence for ONJ occurrence in osteoporotic patients longitudinally. METHODS: Based on Korean National Health Information Database, subjects over the age of 65 who were diagnosed with osteoporosis between July 2014 and December 2016 were included. The implant group included subjects who had undergone dental implant surgery between January 2017 and December 2017, while the control group included those who had no history of dental implants. The primary outcome was the occurrence of ONJ, and the date of final follow-up was December 2020. RESULTS: A total of 332,728 subjects with osteoporosis were included in the analysis: 83,182 in the implant group and 249,546 in the control group. The risk of ONJ among those who had undergone implant surgery (risk of implant surgery-associated ONJ) was not higher than that among those without implant surgery. The risk of ONJ among those with implants (risk of implant presence-associated ONJ) was lower than that among those without implants. Even in subjects with a history of bisphosphonates, steroids, periodontitis, or tooth extraction, those who had undergone implant surgery or had implants did not have a higher ONJ risk than those who had not undergone surgery or did not have implants; rather, they showed a lower risk. CONCLUSIONS: The results may suggest that dental implants are not associated with an increased risk of ONJ. A further study on whether dental implants are associated with lower ONJ risk is needed. CLINICAL RELEVANCE: Dental implants did not increase the risk of ONJ development in osteoporotic patients, even with a history of bisphosphonates. This may suggest that the risk profiles for ONJ occurrence between selective insertion of dental implants and other dentoalveolar surgery associated with infectious conditions are different.

Enhanced Efficacy of Gastric Cancer Treatment through Targeted Exosome Delivery of 17-DMAG Anticancer Agent.

In this study, we explored the potential of genetically engineered exosomes as vehicles for precise drug delivery in gastric cancer therapy. A novel antitumor strategy using biocompatible exosomes (Ex) was devised by genetically engineering adipose-derived stem cells to express an MKN45-binding peptide (DE532) on their surfaces. 17-(Dimethylaminoethylamino)-17-demethoxygeldanamycin (17-DMAG) was encapsulated in engineered exosomes, resulting in 17-DMAG-loaded DE532 exosomes. In both in vitro and in vivo experiments using mouse gastric cancer xenograft models, we demonstrated that 17-DMAG-loaded DE532 Ex exhibited superior targetability over DE532 Ex, 17-DMAG-loaded Ex, and Ex. Administration of the 17-DMAG-loaded DE532 Ex yielded remarkable antitumor effects, as evidenced by the smallest tumor size, lowest tumor growth rate, and lowest excised tumor weight. Further mechanistic examinations revealed that the 17-DMAG-loaded DE532 Ex induced the highest upregulation of the pro-apoptotic marker B-cell lymphoma-2-like protein 11 and the lowest downregulation of the anti-apoptotic marker B-cell lymphoma-extra large. Concurrently, the 17-DMAG-loaded DE532 Ex demonstrated the lowest suppression of antioxidant enzymes, such as superoxide dismutase 2 and catalase, within tumor tissues. These findings underscore the potential of 17-DMAG-loaded DE532 exosomes as a potent therapeutic strategy for gastric cancer, characterized by precise targetability and the potential to minimize adverse effects.

Cutting-Edge HEK293T Protein-Integrated Lipid Nanostructures: Boosting Biocompatibility and Efficacy.

Recently, artificial exosomes have been developed to overcome the challenges of natural exosomes, such as production scalability and stability. In the production of artificial exosomes, the incorporation of membrane proteins into lipid nanostructures is emerging as a notable approach for enhancing biocompatibility and treatment efficacy. This study focuses on incorporating HEK293T cell-derived membrane proteins into liposomes to create membrane-protein-bound liposomes (MPLCs), with the goal of improving their effectiveness as anticancer therapeutics. MPLCs were generated by combining two key elements: lipid components that are identical to those in conventional liposomes (CLs) and membrane protein components uniquely derived from HEK293T cells. An extensive comparison of CLs and MPLCs was conducted across multiple in vitro and in vivo cancer models, employing advanced techniques such as cryo-TEM (tramsmission electron microscopy) imaging and FT-IR (fourier transform infrared spectroscopy). MPLCs displayed superior membrane fusion capabilities in cancer cell lines, with significantly higher cellular uptake. Additionally, MPLCs maintained their morphology and size better than CLs when exposed to FBS (fetal bovine serum), suggesting enhanced serum stability. In a xenograft mouse model using HeLa and ASPC cancer cells, intravenous administration of MPLCs MPLCs accumulated more in tumor tissues, highlighting their potential for targeted cancer therapy. Overall, these results indicate that MPLCs have superior tumor-targeting properties, possibly attributable to their membrane protein composition, offering promising prospects for enhancing drug delivery efficiency in cancer treatments. This research could offer new clinical application opportunities, as it uses MPLCs with membrane proteins from HEK293T cells, which are known for their efficient production and compatibility with GMP (good manufacturing practice) standards.

Enhanced Expression of Glycolytic Enzymes and Succinate Dehydrogenase Complex Flavoprotein Subunit A by Mesothelin Promotes Glycolysis and Mitochondrial Respiration in Myeloblasts of Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is an aggressive malignancy characterized by rapid growth and uncontrolled proliferation of undifferentiated myeloid cells. Metabolic reprogramming is commonly observed in the bone marrow of AML patients, as leukemia cells require increased ATP supply to support disease progression. In this study, we examined the potential role of mesothelin as a metabolic modulator in myeloid cells in AML. Mesothelin is a well-known marker of solid tumors that promotes cancer cell proliferation and survival. We initially analyzed alterations in mesothelin expression in the myeloblast subpopulations, defined as SSC-Alow/CD45dim, obtained from the bone marrow of AML patients using flow cytometry. Our results showed overexpression of mesothelin in 34.8% of AML patients. Subsequently, metabolic changes in leukemia cells were evaluated by comparing the oxygen consumption rates (OCR) of bone marrow samples derived from adult AML patients. Notably, a higher OCR was observed in the mesothelin-positive compared to the mesothelin-low and non-expressing groups. Treatment with recombinant human mesothelin protein enhanced OCR and increased the mRNA expression of glycolytic enzymes and mitochondrial complex II in KG1α AML cells. Notably, siRNA targeting mesothelin in KG1α cells led to the reduction of glycolysis-related gene expression but had no effect on the mitochondrial complex gene. The collective results demonstrate that mesothelin induces metabolic changes in leukemia cells, facilitating the acquisition of a rapid supply of ATP for proliferation in AML. Therefore, the targeting of mesothelin presents a potentially promising approach to mitigating the progression of AML through the inhibition of glycolysis and mitochondrial respiration in myeloid cells.

Coccygodynia in a Long-Term Cancer Survivor Diagnosed with Metastatic Cancer: A Case Report.

Background and Objectives: Rectal cancer is considered cured if no recurrence is found during the 5-year follow-up period after treatment. After this period, patients often believe that the cancer is completely eradicated. However, in modern society, where lifespans have become longer, it is important to recognize that metastatic cancer may occur long after the initial treatment has concluded. This highlights the necessity of continued vigilance and the long-term follow-up of cancer survivors. Case report: We present a case of metastatic cancer of the coccyx in an 87-year-old female patient. This patient had undergone successful surgery and treatment for rectal cancer 10 years prior. She was considered cured after the standard 5-year follow-up period as she showed no signs of recurrence. The patient presented with simple coccygeal pain as the main complaint, without any other accompanying symptoms such as weight loss, fever, or changes in bowel habits, typically associated with cancer recurrence. During the clinical evaluation, irregularities in the bone cortex were detected while performing a nerve block using ultrasound. Given these findings, further diagnostic evaluations were performed. Advanced imaging techniques including MRI and CT scans led to a diagnosis of coccygeal metastasis. Conclusions: While the 5-year mark post-treatment is a significant milestone for rectal cancer patients, it does not guarantee the absolute eradication of the disease. Long-term monitoring and a thorough evaluation of new symptoms are essential for the early detection and management of late metastatic recurrences. This approach ensures that patients receive timely and appropriate care, potentially improving outcomes and quality of life.

Impact of Intraoperative Nefopam on Postoperative Pain, Opioid Use, and Recovery Quality with Parietal Pain Block in Single-Port Robotic Cholecystectomy: A Prospective Randomized Controlled Trial.

Background and Objectives: This study explored how nefopam, a non-opioid analgesic in a multimodal regimen, impacts postoperative pain, opioid use, and recovery quality in single-port robot-assisted laparoscopic cholecystectomy (RALC) patients with a parietal pain block, addressing challenges in postoperative pain management. Materials and Methods: Forty patients scheduled for elective single-port RALC were enrolled and randomized to receive either nefopam or normal saline intravenously. Parietal pain relief was provided through a rectus sheath block (RSB). Postoperative pain was assessed using a numeric rating scale (NRS) in the right upper quadrant (RUQ) of the abdomen, at the umbilicus, and at the shoulder. Opioid consumption and recovery quality, measured using the QoR-15K questionnaire, were also recorded. Results: The 40 patients had a mean age of 48.3 years and an average body mass index (BMI) of 26.2 kg/m2. There were no significant differences in the pre- or intraoperative variables between groups. Patients receiving nefopam reported significantly lower RUQ pain scores compared to the controls, while the umbilicus and shoulder pain scores were similar. Rescue fentanyl requirements were lower in the nefopam group in both the PACU and ward. The QoR-15K questionnaire scores for nausea and vomiting were better in the nefopam group, but the overall recovery quality scores were comparable between the groups. Conclusions: Nefopam reduces RUQ pain and opioid use post-single-port RALC with a parietal pain block without markedly boosting RSB's effect on umbilicus or shoulder pain. It may also better manage postoperative nausea and vomiting, underscoring its role in analgesia strategies for this surgery.

Postural Orthostatic Tachycardia Syndrome Associated with COVID-19: A Narrative Review.

Postural orthostatic tachycardia syndrome (POTS) is a complex condition marked by an atypical autonomic response to standing, leading to orthostatic intolerance and significant tachycardia without accompanying hypotension. In recent studies, a considerable number of individuals recovering from COVID-19 have been reported to experience POTS within 6 to 8 months post-infection. Key symptoms of POTS include fatigue, difficulty with orthostatic tolerance, tachycardia, and cognitive challenges. The underlying causes of POTS following COVID-19 remain unknown, with various theories proposed such as renin-angiotensin-aldosterone system (RAAS) dysregulation, hyperadrenergic reaction, and direct viral infection. Healthcare professionals should be vigilant for POTS in patients who have recovered from COVID-19 and are experiencing signs of autonomic dysfunction and use diagnostic procedures such as the tilt-up table test for confirmation. COVID-19-related POTS should be approached with a holistic strategy. Although many patients show improvement with initial non-drug treatments, for subjects who do not respond and exhibit more severe symptoms, medication-based therapies may be necessary. The current understanding of COVID-19-related POTS is limited, underscoring the need for more research to increase knowledge and enhance treatment approaches.