Lactylated Apolipoprotein C-II Induces Immunotherapy Resistance by Promoting Extracellular Lipolysis.

Mortality rates due to lung cancer are high worldwide. Although PD-1 and PD-L1 immune checkpoint inhibitors boost the survival of patients with non-small-cell lung cancer (NSCLC), resistance often arises. The Warburg Effect, which causes lactate build-up and potential lysine-lactylation (Kla), links immune dysfunction to tumor metabolism. The role of non-histone Kla in tumor immune microenvironment and immunotherapy remains to be clarified. Here, global lactylome profiling and metabolomic analyses of samples from patients with NSCLC is conducted. By combining multi-omics analysis with in vitro and in vivo validation, that intracellular lactate promotes extracellular lipolysis through lactyl-APOC2 is revealed. Mechanistically, lactate enhances APOC2 lactylation at K70, stabilizing it and resulting in FFA release, regulatory T cell accumulation, immunotherapy resistance, and metastasis. Moreover, the anti-APOC2K70-lac antibody that sensitized anti-PD-1 therapy in vivo is developed. This findings highlight the potential of anti lactyl-APOC2-K70 approach as a new combination therapy for sensitizing immunotherapeutic responses.

Analysis of the therapeutic efficacy of robot-assisted percutaneous screw fixation in the minimally invasive treatment of pelvic fractures.

Objective: To compare the therapeutic efficacy of robot-assisted and manual screw placement techniques for the treatment of pelvic fractures. Methods: This study included patients with pelvic fractures admitted to our orthopedic department between January 2020 and January 2022. They were randomly assigned to either the robot-assisted group or the control group. Various parameters, including surgical duration, intraoperative bleeding, fluoroscopy frequency, postoperative pain, length of hospitalization, postoperative hematological indices, postoperative functional scores, and postoperative complications, were compared between the two groups. Results: There were no significant differences in age, sex, body mass index, and preoperative hematological parameters between the two groups. The robot-assisted group exhibited significantly shorter surgical duration, lower fluoroscopy frequencies, lower postoperative pain scores, and shorter length of hospitalization compared to the control group. At 3 and 6 months postoperatively, patients in the robot-assisted group demonstrated significantly higher Majeed functional scores in comparison to the control group. However, there were no significant differences in Majeed scores at 12 months postoperatively. Moreover, there were no significant differences in postoperative complications between the two groups. Conclusion: Robot-assisted minimally invasive treatment of pelvic fractures using hollow screws effectively reduced surgical duration, mitigated intraoperative bleeding and postoperative pain, shortened hospital stays, and promoted faster functional recovery.

[Intraspinal Metastasis of Thymic Carcinoma:Report of One Case].

Intraspinal metastasis from malignant carcinomas in other body parts is rarely reported.Intraspinal metastases are often epidural,with primary tumors mostly from the lung and prostate.The extramedullary subdural metastasis of thymic carcinoma is particularly rare and prone to misdiagnosis due to overlapping imaging features with primary intraspinal tumors.This article reports one case of intraspinal metastasis of thymic carcinoma,with the main diagnostic clues including a history of thymic carcinoma,fast growth rate,and irregular shape.

WTAP/YTHDF1-mediated m6A modification amplifies IFN-γ-induced immunosuppressive properties of human MSCs.

INTRODUCTION: The immunosuppressive capacity of mesenchymal stem cells (MSCs) is dependent on the "license" of several pro-inflammatory factors to express immunosuppressive molecular profiles, which determines the therapeutic efficacy of MSCs in immune-mediated inflammatory diseases. Of those, interferon-γ (IFN-γ) is a key inducer for the expression of immunosuppressive molecular profiles; however, the mechanism underlying this effect is unknown. OBJECTIVES: To elucidate the regulation mechanism and biological functions of N6-methyladenosine (m6A) modification in the immunosuppressive functions by the IFN-γ-licensing MSCs. METHODS: Epitranscriptomic microarray analysis and MeRIP-qPCR assay were performed to identify the regulatory effect of WTAP in the IFN-γ-licensing MSCs. RIP-qPCR, western blot, qRT-PCR and RNA stability assays were used to determine the regulation of WTAP/m6A/YTHDF1 signaling axis in the expression of immunosuppressive molecules. Further, functional capacity of T cells was tested using flow cytometry, and both DSS-induced colitis mice and CIA mice were constructed to clarify the effect of WTAP and YTHDF1 in MSC-mediated immunosuppression. RESULTS: We identified that IFN-γ increased the m6A methylation levels of immunosuppressive molecules, while WTAP deficiency abolished the IFN-γ-induced promotion of m6A modification. IFN-γ activated ERK signaling, which induced WTAP phosphorylation. Additionally, the stabilization of WTAP post-transcriptionally increased the mRNA expression of immunosuppressive molecules (IDO1, PD-L1, ICAM1, and VCAM1) in an m6A-YTHDF1-dependent manner; this effect further impacted the immunosuppressive capacity of IFN-γ licensing MSCs on activated T cells. Notably, WTAP/YTHDF1 overexpression enhanced the therapeutic efficacy of IFN-γ licensing MSCs and restructures the ecology of inflammation in both colitis and arthritis models. CONCLUSION: Our results showed that m6A modification of IDO1, PD-L1, ICAM1, and VCAM1 mRNA mediated by WTAP-YTHDF1 is involved in the regulation of IFN-γ licensing MSCs immunosuppressive abilities, and shed a light to enhance the clinical therapeutic potential of IFN-γ-licensing MSCs.

The natural course, treatment outcomes, and long-term prognosis of cervical spinal cord arteriovenous shunts.

OBJECTIVE: The highly intricate nature of the cervical spinal cord can cause arteriovenous shunts in these segments that may be associated with heightened clinical risks and treatment complexities. In this article, the authors aimed to provide a comprehensive analysis of the detailed natural course, treatment, and clinical outcomes of cervical spinal cord arteriovenous shunts (SCAVSs) based on the largest cohort to date. METHODS: Two hundred forty consecutive patients were included. Data on clinical presentation, angioarchitecture, treatment, and follow-up were retrospectively reviewed. RESULTS: The cohort demonstrated a greater prevalence of acute onset (63.3% vs 36.7%). Spontaneous recovery was observed in 63.7% of patients after onset, with a significantly elevated recovery rate observed among patients experiencing acute onset (72.4% vs 48.9%, p < 0.001). The risks of acute and gradual clinical deterioration after onset was 11.9%/year and 13.4%/year, respectively. Microsurgery was performed in 39.6% of patients, while the remaining 60.4% exclusively underwent embolization. The complete obliteration rate was 65.3% after microsurgery and 21.4% after embolization. The rate of treatment-related deterioration was 14.7% after microsurgery and 6.2% after embolization. After partial treatment, the acute and gradual deterioration rates were 4.1%/year and 6.6%/year, respectively. Lack of spontaneous recovery after onset was an independent predictor of embolization-related deterioration (OR 17.905, p = 0.007) and long-term gradual deterioration after partial treatment (HR 2.325, p = 0.021). After a median follow-up period of 32.55 months, prognosis was unfavorable in 16.7% of patients, with the sole independent risk factor being the absence of spontaneous recovery after onset (OR 2.476, p = 0.018). CONCLUSIONS: The outcomes of patients with cervical SCAVS were generally favorable, even in patients with only partial obliteration of the lesions. However, patients who did not show a trend toward spontaneous recovery after onset had a significantly elevated risk of unfavorable prognosis, highlighting the need for prompt clinical intervention.

Gingival-derived mesenchymal stem cells alleviate allergic asthma inflammation via HGF in animal models.

Allergic asthma is a chronic non-communicable disease characterized by lung tissue inflammation. Current treatments can alleviate the clinical symptoms to some extent, but there is still no cure. Recently, the transplantation of mesenchymal stem cells (MSCs) has emerged as a potential approach for treating allergic asthma. Gingival-derived mesenchymal stem cells (GMSCs), a type of MSC recently studied, have shown significant therapeutic effects in various experimental models of autoimmune diseases. However, their application in allergic diseases has yet to be fully elucidated. In this study, using an OVA-induced allergic asthma model, we demonstrated that GMSCs decrease CD11b+CD11c+ proinflammatory dendritic cells (DCs), reduce Th2 cells differentiation, and thus effectively diminish eosinophils infiltration. We also identified that the core functional factor, hepatocyte growth factor (HGF) secreted by GMSCs, mediated its effects in relieving airway inflammation. Taken together, our findings indicate GMSCs as a potential therapy for allergic asthma and other related diseases.

Multisource Differential Fusion Driven Monocular Endoscope Hybrid 3-D Tracking for Advanced Endoscopic Navigation Surgery.

Surgical navigation systems involve various technologies of segmentation, calibration, registration, tracking, and visualization. These systems aim to superimpose multisource information in the surgical field and provide surgeons with a composite overlay (augmented-reality) view, improving the operative precision and experience. Surgical 3-D tracking is the key to build these systems. Unfortunately, surgical 3-D tracking is still a challenge to endoscopic and robotic navigation systems and easily gets trapped in image artifacts, tissue deformation, and inaccurate positional (e.g., electromagnetic) sensor measurements. This work explores a new monocular endoscope hybrid 3-D tracking method called spatially constrained adaptive differential evolution that combines two spatial constraints with observation-recall adaptive propagation and observation-based fitness computing for stochastic optimization. Specifically, we spatially constraint inaccurate electromagnetic sensor measurements to the centerline of anatomical tubular structures to keep them physically locating inside the tubes, as well as interpolate these measurements to reduce jitter errors for smooth 3-D tracking. We then propose observation-recall adaptive propagation with fitness computing to precisely fuse the constrained sensor measurements, preoperative images, and endoscopic video sequences for accurate hybrid 3-D tracking. Additionally, we also propose a new marker-free hybrid registration strategy to precisely align positional sensor measurements to preoperative images. Our new framework was evaluated on a large amount of clinical data acquired from various surgical endoscopic procedures, with the experimental results showing that it certainly outperforms current surgical 3-D approaches. In particular, the position and rotation errors were significantly reduced from (6.55, 11.4) to (3.02 mm, 8.54 °).

miRNA-148a-containing GMSC-derived EVs modulate Treg/Th17 balance via IKKB/NF-κB pathway and treat a rheumatoid arthritis model.

Mesenchymal stem cells (MSCs) have demonstrated potent immunomodulatory properties that have shown promise in the treatment of autoimmune diseases, including rheumatoid arthritis (RA). However, the inherent heterogeneity of MSCs triggered conflicting therapeutic outcomes, raising safety concerns and limiting their clinical application. This study aimed to investigate the potential of extracellular vesicles derived from human gingival mesenchymal stem cells (GMSC-EVs) as a therapeutic strategy for RA. Through in vivo experiments using an experimental RA model, our results demonstrate that GMSC-EVs selectively homed to inflamed joints and recovered Treg and Th17 cell balance, resulting in the reduction of arthritis progression. Our investigations also uncovered miR-148a-3p as a critical contributor to the Treg/Th17 balance modulation via IKKB/NF-κB signaling orchestrated by GMSC-EVs, which was subsequently validated in a model of human xenograft versus host disease (xGvHD). Furthermore, we successfully developed a humanized animal model by utilizing synovial fibroblasts obtained from patients with RA (RASFs). We found that GMSC-EVs impeded the invasiveness of RASFs and minimized cartilage destruction, indicating their potential therapeutic efficacy in the context of patients with RA. Overall, the unique characteristics - including reduced immunogenicity, simplified administration, and inherent ability to target inflamed tissues - position GMSC-EVs as a viable alternative for RA and other autoimmune diseases.

Roles of IRF4 in various immune cells in systemic lupus erythematosus.

Interferon regulatory factor 4 (IRF4) is a member of IRF family of transcription factors which mainly regulates the transcription of IFN. IRF4 is restrictively expressed in immune cells such as T and B cells, macrophages, as well as DC. It is essential for the development and function of these cells. Since these cells take part in the homeostasis of the immune system and dysfunction of them contributes to the initiation and progress of systemic lupus erythematosus (SLE), the roles of IRF4 in the SLE development becomes an important topic. Here we systemically discuss the biological characteristics of IRF4 in various immune cells and analyze the pathologic effects of IRF4 alteration in SLE and the potential targeting therapeutics of SLE.

Favre-Racouchot Syndrome.

This case report describes multiple solitary open black comedones located bilaterally on the malar cheeks and temples as well as yellowish, smooth-surfaced papulonodular lesions in close association with the comedones.

The current status and prospect of immunotherapy in colorectal cancer

Metastatic colorectal cancer (mCRC) is a heterogeneous disease. We reviewed the current clinical trials on immunotherapy in metastatic colorectal cancer with high microsatellite instability and microsatellite stability. Owing to the advances in immunotherapy, its use has gradually expanded from second- and third-line therapies to first-line, early neoadjuvant, and adjuvant therapies. Based on current research results, immunotherapy has shown very good results in dMMR/MSI-H patients, whether it is neoadjuvant therapy for operable patients or first-line or multi-line therapy for advanced patients. KEYNOTE 016 study also showed that patients with MSS were basically ineffective in single immunotherapy. Moreover, immunotherapy for colorectal cancer may also require identification of new biomarkers (AU)

Infusion of GMSCs relieves autoimmune arthritis by suppressing the externalization of neutrophil extracellular traps via PGE2-PKA-ERK axis.

INTRODUCTION: Rheumatoid arthritis (RA) is a systemic autoimmune disease with limited treatment success, characterized by chronic inflammation and progressive cartilage and bone destruction. Accumulating evidence has shown that neutrophil extracellular traps (NETs) released by activated neutrophils are important for initiating and perpetuating synovial inflammation and thereby could be a promising therapeutic target for RA. K/B × N serum transfer-induced arthritis (STIA) is a rapidly developed joint inflammatory model that somehow mimics the inflammatory response in patients with RA. Human gingival-derived mesenchymal stem cells (GMSCs) have been previously shown to possess immunosuppressive effects in arthritis and humanized animal models. However, it is unknown whether GMSCs can manage neutrophils in autoimmune arthritis. OBJECTIVES: To evaluate whether infusion of GMSCs can alleviate RA by regulating neutrophils and NETs formation. If this is so, we will explore the underlying mechanism(s) in an animal model of inflammatory arthritis. METHODS: The effects of GMSCs on RA were assessed by comparing the symptoms of the K/B × N serum transfer-induced arthritis (STIA) model administered either with GMSCs or with control cells. Phenotypes examined included clinical scores, rear ankle thickness, paw swelling, inflammation, synovial cell proliferation, and immune cell frequency. The regulation of GMSCs on NETs was examined through immunofluorescence and immunoblotting in GMSCs-infused STIA mice and in an in vitro co-culture system of neutrophils with GMSCs. The molecular mechanism(s) by which GMSCs regulate NETs was explored both in vitro and in vivo by silencing experiments. RESULTS: We found in this study that adoptive transfer of GMSCs into STIA mice significantly ameliorated experimental arthritis and reduced neutrophil infiltration and NET formation. In vitro studies also showed that GMSCs inhibited the generation of NETs in neutrophils. Subsequent investigations revealed that GMSCs secreted prostaglandin E2 (PGE2) to activate protein kinase A (PKA), which ultimately inhibited the downstream extracellular signal-regulated kinase (ERK) pathway that is essential for NET formation. CONCLUSION: Our results demonstrate that infusion of GMSCs can ameliorate inflammatory arthritis mainly by suppressing NET formation via the PGE2-PKA-ERK signaling pathway. These findings further support the notion that the manipulation of GMSCs is a promising stem cell-based therapy for patients with RA and other autoimmune and inflammatory diseases.

The current status and prospect of immunotherapy in colorectal cancer.

Metastatic colorectal cancer (mCRC) is a heterogeneous disease. We reviewed the current clinical trials on immunotherapy in metastatic colorectal cancer with high microsatellite instability and microsatellite stability. Owing to the advances in immunotherapy, its use has gradually expanded from second- and third-line therapies to first-line, early neoadjuvant, and adjuvant therapies. Based on current research results, immunotherapy has shown very good results in dMMR/MSI-H patients, whether it is neoadjuvant therapy for operable patients or first-line or multi-line therapy for advanced patients. KEYNOTE 016 study also showed that patients with MSS were basically ineffective in single immunotherapy. Moreover, immunotherapy for colorectal cancer may also require identification of new biomarkers.

Heterogeneous ferroptosis susceptibility of macrophages caused by focal iron overload exacerbates rheumatoid arthritis.

Focal iron overload is frequently observed in patients with rheumatoid arthritis (RA), yet its functional significance remains elusive. Herein, we report that iron deposition in lesion aggravates arthritis by inducing macrophage ferroptosis. We show that excessive iron in synovial fluid positively correlates with RA disease severity as does lipid hyperoxidation of focal monocyte/macrophages. Further study reveals high susceptibility to iron induced ferroptosis of the anti-inflammatory macrophages M2, while pro-inflammatory M1 are less affected. Distinct glutathione peroxidase 4 (GPX4) degradation depending on p62/SQSTM1 in the two cell types make great contribution mechanically. Of note, ferroptosis inhibitor liproxstatin-1 (LPX-1) can alleviate the progression of K/BxN serum-transfer induced arthritis (STIA) mice accompanied with increasing M2 macrophages proportion. We thus propose that the heterogeneous ferroptosis susceptibility of macrophage subtypes as well as consequent inflammation and immune disorders are potential biomarkers and therapeutic targets in RA.

Epithelial SIRT6 governs IL-17A pathogenicity and drives allergic airway inflammation and remodeling.

Dysregulation of IL-17A is closely associated with airway inflammation and remodeling in severe asthma. However, the molecular mechanisms by which IL-17A is regulated remain unclear. Here we identify epithelial sirtuin 6 (SIRT6) as an epigenetic regulator that governs IL-17A pathogenicity in severe asthma. Mice with airway epithelial cell-specific deletion of Sirt6 are protected against allergen-induced airway inflammation and remodeling via inhibiting IL-17A-mediated inflammatory chemokines and mesenchymal reprogramming. Mechanistically, SIRT6 directly interacts with RORγt and mediates RORγt deacetylation at lysine 192 via its PPXY motifs. SIRT6 promotes RORγt recruitment to the IL-17A gene promoter and enhances its transcription. In severe asthma patients, high expression of SIRT6 positively correlates with airway remodeling and disease severity. SIRT6 inhibitor (OSS_128167) treatment significantly attenuates airway inflammation and remodeling in mice. Collectively, these results uncover a function for SIRT6 in regulating IL-17A pathogenicity in severe asthma, implicating SIRT6 as a potential therapeutic target for severe asthma.

Targeting kinase ITK treats autoimmune arthritis via orchestrating T cell differentiation and function.

IL-2 inducible T cell kinase (ITK) is critical in T helper subset differentiation and its inhibition has been suggested for the treatment of T cell-mediated inflammatory diseases. T follicular helper (Tfh), Th17 and regulatory T cells (Treg) also play important roles in the development of rheumatoid arthritis (RA), while the role of ITK in the development of RA and the intricate balance between effector T and regulatory T cells remains unclear. Here, we found that CD4+ T cells from RA patients presented with an elevated ITK activation. ITK inhibitor alleviated existing collagen-induced arthritis (CIA) and reduced antigen specific antibody production. Blocking ITK kinase activity interferes Tfh cell generation. Moreover, ITK inhibitor effectively rebalances Th17 and Treg cells by regulating Foxo1 translocation. Furthermore, we identified dihydroartemisinin (DHA) as a potential ITK inhibitor, which could inhibit PLC-γ1 phosphorylation and the progression of CIA by rebalancing Th17 and Treg cells. Out data imply that ITK activation is upregulated in RA patients, and therefore blocking ITK signal may provide an effective strategy to treat RA patients and highlight the role of ITK on the Tfh induction and RA progression.

Phase-field lattice Boltzmann equation for wettable particle fluid dynamics.

In this paper a phase-field based lattice Boltzmann equation (LBE) is developed to simulate wettable particles fluid dynamics together with the smoothed-profile method (SPM). In this model the evolution of a fluid-fluid interface is captured by the conservative Allen-Cahn equation (CACE) LBE, and the flow field is solved by a classical incompressible LBE. The solid particle is represent by SPM, and the fluid-solid interaction force is calculated by direct force method. Some benchmark tests including a single wettable particle trapped at the fluid-fluid interface without gravity, capillary interactions between two wettable particles under gravity, and sinking of a horizontal cylinder through an air-water interface are carried out to validate present CACE LBE for fluid-fluid-solid flows. Raft sinking of multiple horizontal cylinders (up to five cylinders) through an air-water interface is further investigated with the present CACE LBE, and a nontrivial dynamics with an unusual nonmonotonic motion of the multiple cylinders is observed in the vertical plane. Numerical results show that the predictions by the present LBE are in good agreement with theoretical solutions and experimental data.

Periampullary tumors in a patient with pancreatic divisum and neurofibromatosis type 1: a case report.

INTRODUCTION: We present a case of a male patient with neurofibromatosis type 1 diagnosed with pancreatic divisum and several gastrointestinal tumors. A 55-year-old man was admitted to the hospital with recurrent chronic pancreatitis, indicating a large mass in the ampulla. In addition, genetic testing revealed two unique germline mutations in the neurofibromin (NF1) gene, and their potential interaction in promoting cancer was further investigated. CONCLUSION: The first similar case was reported in 2020. The current case was distinct from other cases since an additional two NF1 mutations were found in the patient. In conjunction with prior case reports, our findings imply that genetic testing in patients diagnosed with neurofibromatosis type 1 could be helpful in the development of effective treatments.