A positive feedback loop between PFKP and c-Myc drives head and neck squamous cell carcinoma progression.

BACKGROUND: The aberrant expression of phosphofructokinase-platelet (PFKP) plays a crucial role in the development of various human cancers by modifying diverse biological functions. However, the precise molecular mechanisms underlying the role of PFKP in head and neck squamous cell carcinoma (HNSCC) are not fully elucidated. METHODS: We assessed the expression levels of PFKP and c-Myc in tumor and adjacent normal tissues from 120 HNSCC patients. A series of in vitro and in vivo experiments were performed to explore the impact of the feedback loop between PFKP and c-Myc on HNSCC progression. Additionally, we explored the therapeutic effects of targeting PFKP and c-Myc in HNSCC using Patient-Derived Organoids (PDO), Cell Line-Derived Xenografts, and Patients-Derived Xenografts. RESULTS: Our findings indicated that PFKP is frequently upregulated in HNSCC tissues and cell lines, correlating with poor prognosis. Our in vitro and in vivo experiments demonstrate that elevated PFKP facilitates cell proliferation, angiogenesis, and metastasis in HNSCC. Mechanistically, PFKP increases the ERK-mediated stability of c-Myc, thereby driving progression of HNSCC. Moreover, c-Myc stimulates PFKP expression at the transcriptional level, thus forming a positive feedback loop between PFKP and c-Myc. Additionally, our multiple models demonstrate that co-targeting PFKP and c-Myc triggers synergistic anti-tumor effects in HNSCC. CONCLUSION: Our study demonstrates the critical role of the PFKP/c-Myc positive feedback loop in driving HNSCC progression and suggests that simultaneously targeting PFKP and c-Myc may be a novel and effective therapeutic strategy for HNSCC.

Transient paper-based electrochemical biosensor Fabricated by superadditive Cu-TCPP(Fe)/Mxene for Multipathway non-invasive, highly sensitive detection of Bodily metabolites.

Current advances in non-invasive fluid diagnostics highlight unique benefits for monitoring metabolic diseases. However, the low concentrations and complex compositions of biomarkers in fluids such as sweat, urine, and saliva impose stringent demands on the sensitivity and stability of detection technologies. Here, we developed a high-sensitivity, low-cost instantaneous electrochemical sensor based on the superadditive effect mechanism of Cu-TCPP(Fe)/Mxene (MMs Paper-ECL Sensor), which has been successfully applied for the simultaneous real-time detection of glucose and uric acid. Strong interfacial interactions between Mxene and Cu-TCPP(Fe) were revealed through precise simulation calculations and multi-dimensional characterization analysis, significantly enhancing the sensor's electrocatalytic performance and reaction kinetics. Experimentally, this exceptional electrocatalytic activity was demonstrated in its unprecedented high sensitivity and wide linear detection range for glucose and uric acid, with a non-invasive linear range from 0.001 nM to 5 mM, 0.025 nM-5 mM, detection limits as low as 1.88 aM and 5.80 pM, and stability extending up to 100 days. This represents not only a breakthrough in sensitivity and stability but also provides an effective, low-cost solution that overcomes the limitations of existing electronic devices, enabling multi-channel simultaneous detection. The universality of this sensor holds vast potential for application in the field of non-invasive fluid diagnostics.

Iodine/soluble starch cryogel: An iodine-based antiseptic with instant water-solubility, improved stability, and potent bactericidal activity.

Iodine (I2) as a broad-spectrum antiseptic has been widely used for treating bacterial infections. However, I2 has low water-solubility and sublimes under ambient conditions, which limits its practical antibacterial applications. The highly specific and sensitive reaction between I2 and starch discovered 200 years ago has been extensively applied in analytical chemistry, but the antibacterial activity of the I2-starch complex is rarely investigated. Herein, we develop a novel type of iodine-based antiseptics, iodine-soluble starch (I2-SS) cryogel, which can dissolve in water instantly and almost completely kill bacteria in 10 min at 2 µg/mL of I2. Although KI3 and the commercially available povidone­iodine (I2-PVP) solutions show similar antibacterial efficacy, the high affinity of I2 to SS largely enhances the shelf stability of the I2-SS solution with ∼73 % I2 left after one-week storage at room temperature. In sharp contrast, ∼8.5 % and âˆ¼2.5 % I2 are detected in KI3 and I2-PVP solutions, respectively. Mechanistic study reveals that the potent antibacterial effect of I2-SS originates from its attack on multiple bacterial targets. The outstanding antibacterial activity, capability of accelerating wound healing, and good biocompatibility of I2-SS are verified through further in vivo experiments. This work may promote the development of next-generation iodine-based antiseptics for clinical use.

Development of a PAK4-targeting PROTAC for renal carcinoma therapy: concurrent inhibition of cancer cell proliferation and enhancement of immune cell response.

BACKGROUND: Finding the oncogene, which was able to inhibit tumor cells intrinsically and improve the immune answers, will be the future direction for renal cancer combined treatment. Following patient sample analysis and signaling pathway examination, we propose p21-activated kinase 4 (PAK4) as a potential target drug for kidney cancer. PAK4 exhibits high expression levels in patient samples and plays a regulatory role in the immune microenvironment. METHODS: Utilizing AI software for peptide drug design, we have engineered a specialized peptide proteolysis targeting chimera (PROTAC) drug with selectivity for PAK4. To address challenges related to drug delivery, we developed a nano-selenium delivery system for efficient transport of the peptide PROTAC drug, termed PpD (PAK4 peptide degrader). FINDINGS: We successfully designed a peptide PROTAC drug targeting PAK4. PpD effectively degraded PAK4 with high selectivity, avoiding interference with other homologous proteins. PpD significantly attenuated renal carcinoma proliferation in vitro and in vivo. Notably, PpD demonstrated a significant inhibitory effect on tumor proliferation in a fully immunocompetent mouse model, concomitantly enhancing the immune cell response. Moreover, PpD demonstrated promising tumor growth inhibitory effects in mini-PDX and PDO models, further underscoring its potential for clinical application. INTERPRETATION: This PAK4-targeting peptide PROTAC drug not only curtails renal cancer cell proliferation but also improves the immune microenvironment and enhances immune response. Our study paves the way for innovative targeted therapies in the management of renal cancer. FUNDING: This work is supported by Research grants from non-profit organizations, as stated in the Acknowledgments.

CK2-dependent degradation of CBX3 dictates replication fork stalling and PARP inhibitor sensitivity.

DNA replication is a vulnerable cellular process, and its deregulation leads to genomic instability. Here, we demonstrate that chromobox protein homolog 3 (CBX3) binds replication protein A 32-kDa subunit (RPA2) and regulates RPA2 retention at stalled replication forks. CBX3 is recruited to stalled replication forks by RPA2 and inhibits ring finger and WD repeat domain 3 (RFWD3)-facilitated replication restart. Phosphorylation of CBX3 at serine-95 by casein kinase 2 (CK2) kinase augments cadherin 1 (CDH1)-mediated CBX3 degradation and RPA2 dynamics at stalled replication forks, which permits replication fork restart. Increased expression of CBX3 due to gene amplification or CK2 inhibitor treatment sensitizes prostate cancer cells to poly(ADP-ribose) polymerase (PARP) inhibitors while inducing replication stress and DNA damage. Our work reveals CBX3 as a key regulator of RPA2 function and DNA replication, suggesting that CBX3 could serve as an indicator for targeted therapy of cancer using PARP inhibitors.

Performance of preferentially expressed antigen in melanoma (PRAME) immunohistochemistry for metastatic melanoma in cytology specimens.

BACKGROUND: Preferentially expressed antigen in melanoma (PRAME) has been introduced as a new melanoma marker and potential target for immunotherapy. While PRAME immunohistochemistry (IHC) is well documented in surgical pathology, similar data in cytology are limited. Metastatic melanoma is frequently diagnosed via cytology samples in which IHC plays an important role. We aimed to accordingly evaluate the performance of PRAME IHC in diagnosing metastatic melanoma in cytology samples relative to other commonly used melanoma markers. MATERIALS AND METHODS: The study included 156 archival cytology cases, of which 93 were melanoma cases and 63 nonmelanoma cases (controls). All cases underwent PRAME IHC staining on cell blocks. Nuclear staining of PRAME was evaluated using a quantitative and qualitative scale. Other melanocytic IHC stain results (SOX10, S-100, Melan-A, and HMB45) were also documented. RESULTS: PRAME was detected in tumor cells in 86% of melanoma cases, which was significantly lower than SOX10 (100%) (p < .01), and similar to HMB45 (84%) and Melan-A (82%). S-100 had the lowest sensitivity of 71%. In comparison to other types of melanomas, spindle cell melanoma exhibited higher negativity for PRAME IHC (4/10 = 40%). PRAME was also expressed in some nonmelanocytic malignancies including carcinoma (5/22 = 23%), sarcoma (5/15 = 33%), and hematologic malignancies (1/9 = 11%). Overall, PRAME showed a sensitivity of 86%, specificity of 82%, positive predictive value of 70%, and negative predictive value of 92% for metastatic melanoma. CONCLUSIONS: PRAME is a useful marker for the diagnosis of melanoma in cytology material, but it is less sensitive than SOX10. PRAME is also expressed in other nonmelanocytic tumors which limits its specificity.

Augmented ERO1α upon mTORC1 activation induces ferroptosis resistance and tumor progression via upregulation of SLC7A11.

BACKGROUND: The dysregulated mechanistic target of rapamycin complex 1 (mTORC1) signaling plays a critical role in ferroptosis resistance and tumorigenesis. However, the precise underlying mechanisms still need to be fully understood. METHODS: Endoplasmic reticulum oxidoreductase 1 alpha (ERO1α) expression in mTORC1-activated mouse embryonic fibroblasts, cancer cells, and laryngeal squamous cell carcinoma (LSCC) clinical samples was examined by quantitative real-time PCR (qRT-PCR), western blotting, immunofluorescence (IF), and immunohistochemistry. Extensive in vitro and in vivo experiments were carried out to determine the role of ERO1α and its downstream target, member 11 of the solute carrier family 7 (SLC7A11), in mTORC1-mediated cell proliferation, angiogenesis, ferroptosis resistance, and tumor growth. The regulatory mechanism of ERO1α on SLC7A11 was investigated via RNA-sequencing, a cytokine array, an enzyme-linked immunosorbent assay, qRT-PCR, western blotting, IF, a luciferase reporter assay, and a chromatin immunoprecipitation assay. The combined therapeutic effect of ERO1α inhibition and the ferroptosis inducer imidazole ketone erastin (IKE) on mTORC1-activated cells was evaluated using cell line-derived xenografts, LSCC organoids, and LSCC patient-derived xenograft models. RESULTS: ERO1α is a functional downstream target of mTORC1. Elevated ERO1α induced ferroptosis resistance and exerted pro-oncogenic roles in mTORC1-activated cells via upregulation of SLC7A11. Mechanically, ERO1α stimulated the transcription of SLC7A11 by activating the interleukin-6 (IL-6)/signal transducer and activator of transcription 3 (STAT3) pathway. Moreover, ERO1α inhibition combined with treatment using the ferroptosis inducer IKE exhibited synergistic antitumor effects on mTORC1-activated tumors. CONCLUSIONS: The ERO1α/IL-6/STAT3/SLC7A11 pathway is crucial for mTORC1-mediated ferroptosis resistance and tumor growth, and combining ERO1α inhibition with ferroptosis inducers is a novel and effective treatment for mTORC1-related tumors.

Immunoactivation by Cutaneous Blue Light Irradiation Inhibits Remote Tumor Growth and Metastasis.

An improved innate immunity will respond quickly to pathogens and initiate efficient adaptive immune responses. However, up to now, there have been limited clinical ways for effective and rapid consolidation of innate immunity. Here, we report that cutaneous irradiation with blue light of 450 nm rapidly stimulates the innate immunity through cell endogenous reactive oxygen species (ROS) regulation in a noninvasive way. The iron porphyrin-containing proteins, mitochondrial cytochrome c (Cyt-c), and cytochrome p450 (CYP450) can be mobilized by blue light, which boosts electron transport and ROS production in epidermal and dermal tissues. As a messenger of innate immune activation, the increased level of ROS activates the NF-κB signaling pathway and promotes the secretion of immunomodulatory cytokines in skin. Initiated from skin, a regulatory network composed of cytokines and immune cells is established through the circulation system for innate immune activation. The innate immunity activated by whole-body blue light irradiation inhibits tumor growth and metastasis by increasing the infiltration of antitumor neutrophils and tumor-associated macrophages. Our results elucidate the remote immune modulation mechanism of blue light and provide a clinically applicable way for innate immunity activation.

IL-13 facilitates ferroptotic death in asthmatic epithelial cells via SOCS1-mediated ubiquitinated degradation of SLC7A11.

Th2-high asthma is characterized by elevated levels of type 2 cytokines, such as interleukin 13 (IL-13), and its prevalence has been increasing worldwide. Ferroptosis, a recently discovered type of programmed cell death, is involved in the pathological process of Th2-high asthma; however, the underlying mechanisms remain incompletely understood. In this study, we demonstrated that the serum level of malondialdehyde (MDA), an index of lipid peroxidation, positively correlated with IL-13 level and negatively correlated with the predicted forced expiratory volume in 1 s (FEV1%) in asthmatics. Furthermore, we showed that IL-13 facilitates ferroptosis by upregulating of suppressor of cytokine signaling 1 (SOCS1) through analyzing immortalized airway epithelial cells, human airway organoids, and the ovalbumin (OVA)-challenged asthma model. We identified that signal transducer and activator of transcription 6 (STAT6) promotes the transcription of SOCS1 upon IL-13 stimulation. Moreover, SOCS1, an E3 ubiquitin ligase, was found to bind to solute carrier family 7 member 11 (SLC7A11) and catalyze its ubiquitinated degradation, thereby promoting ferroptosis in airway epithelial cells. Last, we found that inhibiting SOCS1 can decrease ferroptosis in airway epithelial cells and alleviate airway hyperresponsiveness (AHR) in OVA-challenged wide-type mice, while SOCS1 overexpression exacerbated the above in OVA-challenged IL-13-knockout mice. Our findings reveal that the IL-13/STAT6/SOCS1/SLC7A11 pathway is a novel molecular mechanism for ferroptosis in Th2-high asthma, confirming that targeting ferroptosis in airway epithelial cells is a potential therapeutic strategy for Th2-high asthma.

Bioorthogonal/Ultrasound Activated Oncolytic Pyroptosis Amplifies In Situ Tumor Vaccination for Boosting Antitumor Immunity.

Personalized in situ tumor vaccination is a promising immunotherapeutic modality. Currently, seeking immunogenic cell death (ICD) to generate in situ tumor vaccines is still mired by insufficient immunogenicity and an entrenched immunosuppressive tumor microenvironment (TME). Herein, a series of tetrazine-functionalized ruthenium(II) sonosensitizers have been designed and screened for establishing a bioorthogonal-activated in situ tumor vaccine via oncolytic pyroptosis induction. Based on nanodelivery-augmented bioorthogonal metabolic glycoengineering, the original tumor is selectively remolded to introduce artificial target bicycle [6.1.0] nonyne (BCN) into cell membrane. Through specific bioorthogonal ligation with intratumoral BCN receptors, sonosensitizers can realize precise membrane-anchoring and synchronous click-activation in desired tumor sites. Upon ultrasound (US) irradiation, the activated sonosensitizers can intensively disrupt the cell membrane with dual type I/II reactive oxygen species (ROS) generation for a high-efficiency sonodynamic therapy (SDT). More importantly, the severe membrane damage can eminently evoke oncolytic pyroptosis to maximize tumor immunogenicity and reverse immunosuppressive TME, ultimately eliciting powerful and durable systemic antitumor immunity. The US-triggered pyroptosis is certified to effectively inhibit the growths of primary and distant tumors, and suppress tumor metastasis and recurrence in "cold" tumor models. This bioorthogonal-driven tumor-specific pyroptosis induction strategy has great potential for the development of robust in situ tumor vaccines.

Eosinophilic gastritis and gluten-sensitive enteropathy manifested as hypoproteinemia and treated with omalizumab: a case report.

BACKGROUND: Eosinophilic gastritis (EoG) has rarely been reported in conjunction with gluten-sensitive enteropathy (GSE). When this does occur, patients typically present with gastrointestinal symptoms. To our knowledge, hypoproteinemia has not been reported as the primary manifestation. Anti-IgE therapy, such as omalizumab, lowers eosinophil counts in the blood, lungs, and gut. Its efficiency in treating active EoG remain unknown. CASE PRESENTATION: We report a 33-month-old boy with a history of food allergy and atopic dermatitis who developed recurrent edema, hypoproteinemia, and eosinophilia at the age of 14 months. The diagnoses of EoG and GSE were confirmed based on the clinical presentation and results of gastrointestinal biopsies and serological testing. Although prednisone and dietary intervention were initially effective, the boy developed prednisone-related facial swelling. After stopping prednisone, his symptoms relapsed. Subsequent treatment with omalizumab, combined with dietary intervention, showed good efficacy and safety. CONCLUSIONS: To our knowledge, this is the first case of concurrent EoG and GSE that presented primarily with hypoproteinemia. We highlight the rare manifestations of these two diseases to raise clinical suspicion and prevent missed and delayed diagnoses. The pathogenesis of EoG is heterogeneous and complex. Omalizumab showed good efficacy, indicating that IgE-mediated processes may be involved in the pathogenesis of this patient's diseases.

Food Insecurity Prevalence and Risk Factors at a Large Academic Medical Center in Michigan.

Importance: Health care systems are increasingly adopting methods to screen for and integrate food insecurity and other social risk factors into electronic health records. However, there remain knowledge gaps regarding the cumulative burden of food insecurity in large clinical settings, which patients are most at risk, and the extent to which patients are interested in social assistance through their health care system. Objective: To evaluate the 5-year prevalence and associated risk factors of food insecurity among adult primary care patients, and to examine factors associated with patients' interest in social assistance among those with food insecurity. Design, Setting, and Participants: This cross-sectional analysis of a retrospective cohort study took place at a tertiary care academic medical center (encompassing 20 primary care clinics) in Michigan. Participants included adult patients who completed screening for social risk factors between August 1, 2017, and August 1, 2022. Data analysis was performed from November 2022 to June 2023. Exposure: Food insecurity was assessed using the Hunger Vital Sign. Main Outcomes and Measures: The primary outcome was patients' interest in social assistance, and associated factors were examined using multivariate logistic regression models, adjusting for patients' demographic and health characteristics. Results: Over the 5-year period, 106 087 adult primary care patients (mean [SD] age, 52.9 [17.9] years; 61 343 women [57.8%]) completed the standardized social risk factors questionnaire and were included in the analysis. The overall prevalence of food insecurity was 4.2% (4498 patients), with monthly trends ranging from 1.5% (70 positive screens) in August 2018 to 5.0% (193 positive screens) in June 2022. Food insecurity was significantly higher among patients who were younger, female, non-Hispanic Black or Hispanic, unmarried or unpartnered, and with public health insurance. Food insecurity was significantly associated with a higher cumulative burden of social needs, including social isolation, medical care insecurity, medication nonadherence, housing instability, and lack of transportation. Only 20.6% of patients with food insecurity (927 patients) expressed interest in social assistance. Factors associated with interest in social assistance including being non-Hispanic Black, unmarried or unpartnered, a current smoker, and having a higher burden of other social needs. Conclusions and Relevance: In this retrospective cohort study, the overall prevalence of food insecurity was 4.2%, of whom approximately 1 in 5 patients with food insecurity expressed interest in assistance. This study highlights ongoing challenges in ensuring all patients complete routine social determinants of health screening and gaps in patients' interest in assistance for food insecurity and other social needs through their health care system.

In Situ Construction of Elastic Solid-State Polymer Electrolyte with Fast Ionic Transport for Dendrite-Free Solid-State Lithium Metal Batteries.

Solid-state lithium metal batteries (LMBs) have been extensively investigated owing to their safer and higher energy density. In this work, we prepared a novel elastic solid-state polymer electrolyte based on an in situ-formed elastomer polymer matrix with ion-conductive plasticizer crystal embedded with Li6.5La3Zr1.5Ta0.5O12 (LLZTO) nanoparticles, denoted as LZT/SN-SPE. The unique structure of LZT/SN-SPE shows excellent elasticity and flexibility, good electrochemical oxidation tolerance, high ionic conductivity, and high Li+ transference number. The role of LLZTO filler in suppressing the side reactions between succinonitrile (SN) and the lithium metal anode and propelling the Li+ diffusion kinetics can be affirmed. The Li symmetric cells with LZT/SN-SPE cycled stably over 1100 h under a current density of 5 mA cm-2, and Li||LiFePO4 cells realized an excellent rate (92.40 mAh g-1 at 5 C) and long-term cycling performance (98.6% retention after 420 cycles at 1 C). Hence, it can provide a promising strategy for achieving high energy density solid-state LMBs.

MYC induces CDK4/6 inhibitors resistance by promoting pRB1 degradation.

CDK4/6 inhibitors (CDK4/6i) show anticancer activity in certain human malignancies, such as breast cancer. However, their application to other tumor types and intrinsic resistance mechanisms are still unclear. Here, we demonstrate that MYC amplification confers resistance to CDK4/6i in bladder, prostate and breast cancer cells. Mechanistically, MYC binds to the promoter of the E3 ubiquitin ligase KLHL42 and enhances its transcription, leading to RB1 deficiency by inducing both phosphorylated and total pRB1 ubiquitination and degradation. We identify a compound that degrades MYC, A80.2HCl, which induces MYC degradation at nanomolar concentrations, restores pRB1 protein levels and re-establish sensitivity of MYC high-expressing cancer cells to CDK4/6i. The combination of CDK4/6i and A80.2HCl result in marked regression in tumor growth in vivo. Altogether, these results reveal the molecular mechanisms underlying MYC-induced resistance to CDK4/6i and suggest the utilization of the MYC degrading molecule A80.2HCl to potentiate the therapeutic efficacy of CDK4/6i.

Intestinal Delivery of Probiotics: Materials, Strategies, and Applications.

Probiotics with diverse and crucial properties and functions have attracted broad interest from many researchers, who adopt intestinal delivery of probiotics to modulate the gut microbiota. However, the major problems faced for the therapeutic applications of probiotics are the viability and colonization of probiotics during their processing, oral intake, and subsequent delivery to the gut. The challenges of simple oral delivery (stability, controllability, targeting, etc.) have greatly limited the use of probiotics in clinical therapies. Nanotechnology can endow the probiotics to be delivered to the intestine with improved survival rate and increased resistance to the adverse environment. Additionally, the progress in synthetic biology has created new opportunities for efficiently and purposefully designing and manipulating the probiotics. In this article, a brief overview of the types of probiotics for intestinal delivery, the current progress of different probiotic encapsulation strategies, including the chemical, physical, and genetic strategies and their combinations, and the emerging single-cell encapsulation strategies using nanocoating methods, is presented. The action mechanisms of probiotics that are responsible for eliciting beneficial effects are also briefly discussed. Finally, the therapeutic applications of engineered probiotics are discussed, and the future trends toward developing engineered probiotics with advanced features and improved health benefits are proposed.

Artificial intelligence for human gunshot wound classification.

Certain features are helpful in the identification of gunshot entrance and exit wounds, such as the presence of muzzle imprints, peripheral tears, stippling, bone beveling, and wound border irregularity. Some cases are less straightforward and wounds can thus pose challenges to an emergency room doctor or forensic pathologist. In recent years, deep learning has shown promise in various automated medical image classification tasks. This study explores the feasibility of using a deep learning model to classify entry and exit gunshot wounds in digital color images. A collection of 2418 images of entrance and exit gunshot wounds were procured. Of these, 2028 entrance and 1314 exit wounds were cropped, focusing on the area around each gunshot wound. A ConvNext Tiny deep learning model was trained using the Fastai deep learning library, with a train/validation split ratio of 70/30, until a maximum validation accuracy of 92.6% was achieved. An additional 415 entrance and 293 exit wound images were collected for the test (holdout) set. The model achieved an accuracy of 87.99%, precision of 83.99%, recall of 87.71%, and F1-score 85.81% on the holdout set. Correctly classified were 88.19% of entrance wounds and 87.71% of exit wounds. The results are comparable to what a forensic pathologist can achieve without other morphologic cues. This study represents one of the first applications of artificial intelligence to the field of forensic pathology. This work demonstrates that deep learning models can discern entrance and exit gunshot wounds in digital images with high accuracy.

Efficacy and indications of gamma knife radiosurgery for recurrent low-and high-grade glioma.

PURPOSE: To investigate the indications and efficacy of gamma knife radiosurgery (GKRS) as a salvage treatment for recurrent low-and high-grade glioma. METHODS: This retrospective study of 107 patients with recurrent glioma treated with GKRS between 2009 and 2022, including 68 high-grade glioma (HGG) and 39 low-grade glioma (LGG) cases. The Kaplan-Meier method was used to calculate the overall survival (OS) and progression-free survival (PFS). The log-rank test was used to analyze the multivariate prognosis of the Cox proportional hazards model. Adverse reactions were evaluated according to the Common Terminology Criteria for Adverse Events version 4.03. The prognostic value of main clinical features was estimated, including histopathology, Karnofsky performance status (KPS), recurrence time interval, target location, two or more GKRS, surgery for recurrence, site of recurrence, left or right side of the brain and so on. RESULTS: The median follow-up time was 74.5 months. The median OS and PFS were 17.0 months and 5.5 months for all patients. The median OS and PFS were 11.0 months and 5.0 months for HGG, respectively. The median OS and PFS were 49.0 months and 12.0 months for LGG, respectively. Multivariate analysis showed that two or more GKRS, left or right side of the brain and brainstem significantly affected PFS. Meanwhile, the KPS index, two or more GKRS, pathological grade, and brainstem significantly affected OS. Stratified analysis showed that surgery for recurrence significantly affected OS and PFS for LGG. KPS significantly affected OS and PFS for HGG. No serious adverse events were noted post-GKRS. CONCLUSION: GKRS is a safe and effective salvage treatment for recurrent glioma. Moreover, it can be applied after multiple recurrences with tolerable adverse effects.

GOLM1 Promotes Pulmonary Fibrosis through Upregulation of NEAT1.

Idiopathic pulmonary fibrosis (IPF) is a lethal progressive disease with elusive molecular mechanisms and limited therapeutic options. Aberrant activation of fibroblasts is a central hallmark of lung fibrosis. Here, we report that Golgi membrane protein 1 (GOLM1, also known as GP73 or GOLPH2) was increased in the lungs of patients with pulmonary fibrosis and mice with bleomycin (BLM)-induced pulmonary fibrosis. Loss of GOLM1 inhibited proliferation, differentiation, and extracellular matrix deposition of fibroblasts, whereas overexpression of GOLM1 exerted the opposite effects. Similarly, worsening pulmonary fibrosis after BLM treatment was observed in GOLM1-knock-in mice, whereas BLM-treated Golm1-knockout mice exhibited alleviated pulmonary fibrosis and collagen deposition. Furthermore, we identified long noncoding RNA NEAT1 downstream of GOLM1 as a potential mediator of pulmonary fibrosis through increased GOLM1 expression. Depletion of NEAT1 inhibited fibroblast proliferation and extracellular matrix production and reversed the profibrotic effects of GOLM1 overexpression. Additionally, we identified KLF4 as a downstream mediator of GOLM1 signaling to NEAT1. Our findings suggest that GOLM1 plays a pivotal role in promoting pulmonary fibrosis through the GOLM1-KLF4-NEAT1 signaling axis. Targeting GOLM1 and its downstream pathways may represent a novel therapeutic strategy for treating pulmonary fibrosis.

MiR-29b Downregulation by p53/Sp1 Complex Plays a Critical Role in Bleb Scar Formation After Glaucoma Filtration Surgery.

Purpose: To investigate the function and mechanism of tumor protein p53 in pathological scarring after glaucoma filtration surgery (GFS) using human Tenon's fibroblasts (HTFs) and a rabbit GFS model. Methods: The expression of p53 in bleb scarring after GFS and transforming growth factor-ß (TGF-ß)-induced HTFs (myofibroblasts [MFs]) was examined by western blot and immunochemical analysis. The interaction between p53 and specificity protein 1 (Sp1) was investigated by immunoprecipitation. The role of p53 and Sp1 in the accumulation of collagen type I alpha 1 chain (COL1A1) and the migration of MFs was evaluated by western blot, quantitative real-time polymerase chain reaction (qRT-PCR), wound healing, and Transwell assay. The regulatory mechanisms among p53/Sp1 and miR-29b were detected via qRT-PCR, western blot, luciferase reporter assay, and chromatin immunoprecipitation assay. The therapeutic effect of mithramycin A, a specific inhibitor of Sp1, on scarring formation was evaluated in a rabbit GFS model. Results: p53 was upregulated in bleb scar tissue and MFs. p53 and Sp1 form a transcription factor complex that induces the accumulation of COL1A1 and promotes the migration of MFs through downregulation of miR-29b, a known suppressor of COL1A1. The p53/Sp1 axis inhibits miR-29b expression by the direct binding promoter of the miR-29b gene. Mithramycin A treatment attenuated bleb scar formation in vivo. Conclusions: The p53/Sp1/miR-29b signaling pathway plays a critical role in bleb scar formation after GFS. This pathway could be targeted for therapeutic intervention of pathological scarring after GFS. Translational Relevance: Our research indicates that inhibition of p53/Sp1/miR-29b is a promising therapeutic strategy for preventing post-GFS pathological scarring.

Knocking down AR promotes osteoblasts to recruit prostate cancer cells by altering exosomal circ-DHPS/miR-214-3p/CCL5 pathway.

ABSTRACT: Tumor-derived exosomes have been shown to play a key role in organ-specific metastasis, and the androgen receptor regulates prostate cancer (PCa) progression. It is unclear whether the androgen receptor regulates the recruitment of prostate cancer cells to the bone microenvironment, even bone metastases, through exosomes. Here, we found that exosomes isolated from PCa cells after knocking down androgen receptor (AR) or enzalutamide treatment can facilitate the migration of prostate cancer cells to osteoblasts. In addition, AR silencing or treatment with the AR antagonist enzalutamide may increase the expression of circular RNA-deoxyhypusine synthase (circ-DHPS) in PCa cells, which can be transported to osteoblasts by exosomes. Circ-DHPS acts as a competitive endogenous RNA (ceRNA) against endogenous miR-214-3p to promote C-C chemokine ligand 5 (CCL5) levels in osteoblasts. Increasing the level of CCL5 in osteoblasts could recruit more PCa cells into the bone microenvironment. Thus, blocking the circ-DHPS/miR-214-3p/CCL5 signal may decrease exosome-mediated migration of prostate cancer cells to osteoblasts.