Enhancing Glioblastoma Immunotherapy with Integrated Chimeric Antigen Receptor T Cells through the Re-Education of Tumor-Associated Microglia and Macrophages.

Glioblastoma (GBM) is an aggressive brain cancer that is highly resistant to treatment including chimeric antigen receptor (CAR)-T cells. Tumor-associated microglia and macrophages (TAMs) are major contributors to the immunosuppressive GBM microenvironment, which promotes tumor progression and treatment resistance. Hence, the modulation of TAMs is a promising strategy for improving the immunotherapeutic efficacy of CAR-T cells against GBM. Molecularly targeting drug pexidartinib (PLX) has been reported to re-educate TAMs toward the antitumorigenic M1-like phenotype. Here, we developed a cell-drug integrated technology to reversibly conjugate PLX-containing liposomes (PLX-Lip) to CAR-T cells and establish tumor-responsive integrated CAR-T cells (PLX-Lip/AZO-T cells) as a combination therapy for GBM. We used a mouse model of GBM to show that PLX-Lip was stably maintained on the surface of PLX-Lip/AZO-T cells in circulation and these cells could transmigrate across the blood-brain barrier and deposit PLX-Lip at the tumor site. The uptake of PLX-Lip by TAMs effectively re-educated them into the M1-like phenotype, which in turn boosted the antitumor function of CAR-T cells. GBM tumor growth was completely eradicated in 60% of the mice after receiving PLX-Lip/AZO-T cells and extended their overall survival time beyond 50 days; in comparison, the median survival time of mice in other treatment groups did not exceed 35 days. Overall, we demonstrated the successful fusion of CAR-T cells and small-molecule drugs with the cell-drug integrated technology. These integrated CAR-T cells provided a superior combination strategy for GBM treatment and presented a reference for the construction of integrated cell-based drugs.

Effective dose of intranasal remimazolam for preoperative sedation in preschool children: a dose-finding study using Dixon's up-and-down method.

Background: Most preschool children are distressed during anesthesia induction. While current pharmacological methods are useful, there is a need for further optimization to an "ideal" standard. Remimazolam is an ultra-short-acting benzodiazepine, and intranasal remimazolam for pre-induction sedation may be promising. Methods: This study included 32 preschool children who underwent short and minor surgery between October 2022 and January 2023. After pretreatment with lidocaine, remimazolam was administered to both nostrils using a mucosal atomizer device. The University of Michigan Sedation Score (UMSS) was assessed for sedation 6, 9, 12, 15, and 20 min after intranasal atomization. We used Dixon's up-and-down method, and probit and isotonic regressions to determine the 50% effective dose (ED50) and 95% effective dose (ED95) of intranasal remimazolam for pre-induction sedation. Results: Twenty-nine pediatric patients were included in the final analysis. The ED50 and ED95 of intranasal remimazolam for successful pre-induction sedation, when processed via probit analysis, were 0.65 (95% confidence interval [CI], 0.59-0.71) and 0.78 mg/kg (95% CI, 0.72-1.07), respectively. In contrast, when processed by isotonic regression, they were 0.65 (95% CI: 0.58-0.72 mg/kg) and 0.78 mg/kg (95% CI: 0.69-1.08 mg/kg), respectively. At 6 min after intranasal remimazolam treatment, 81.2% (13/16) of "positive" participants were successfully sedated with a UMSS ≧ 1. All the "positive" participants were successfully sedated within 9 min. Conclusion: Intranasal remimazolam is feasible for preschool children with a short onset time. For successful pre-induction sedation, the ED50 and ED95 of intranasal remimazolam were 0.65 and 0.78 mg/kg, respectively.

Ferroptosis biomarkers predict tumor mutation burden's impact on prognosis in HER2-positive breast cancer.

BACKGROUND: Ferroptosis has recently been associated with multiple degenerative diseases. Ferroptosis induction in cancer cells is a feasible method for treating neoplastic diseases. However, the association of iron proliferation-related genes with prognosis in HER2+ breast cancer (BC) patients is unclear. AIM: To identify and evaluate fresh ferroptosis-related biomarkers for HER2+ BC. METHODS: First, we obtained the mRNA expression profiles and clinical information of HER2+ BC patients from the TCGA and METABRIC public databases. A four-gene prediction model comprising PROM2, SLC7A11, FANCD2, and FH was subsequently developed in the TCGA cohort and confirmed in the METABRIC cohort. Patients were stratified into high-risk and low-risk groups based on their median risk score, an independent predictor of overall survival (OS). Based on these findings, immune infiltration, mutations, and medication sensitivity were analyzed in various risk groupings. Additionally, we assessed patient prognosis by combining the tumor mutation burden (TMB) with risk score. Finally, we evaluated the expression of critical genes by analyzing single-cell RNA sequencing (scRNA-seq) data from malignant vs normal epithelial cells. RESULTS: We found that the higher the risk score was, the worse the prognosis was (P < 0.05). We also found that the immune cell infiltration, mutation, and drug sensitivity were different between the different risk groups. The high-risk subgroup was associated with lower immune scores and high TMB. Moreover, we found that the combination of the TMB and risk score could stratify patients into three groups with distinct prognoses. HRisk-HTMB patients had the worst prognosis, whereas LRisk-LTMB patients had the best prognosis (P < 0.0001). Analysis of the scRNA-seq data showed that PROM2, SLC7A11, and FANCD2 were significantly differentially expressed, whereas FH was not, suggesting that these genes are expressed mainly in cancer epithelial cells (P < 0.01). CONCLUSION: Our model helps guide the prognosis of HER2+ breast cancer patients, and its combination with the TMB can aid in more accurate assessment of patient prognosis and provide new ideas for further diagnosis and treatment.

Spatiotemporally Controlled T-Cell Combination Therapy for Solid Tumor.

Due to multidimensional complexity of solid tumor, development of rational T-cell combinations and corresponding formulations is still challenging. Herein, a triple combination of T cells are developed with Indoleamine 2,3-dioxygenase inhibitors (IDOi) and Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i). To maximize synergism, a spatiotemporally controlled T-cell engineering technology to formulate triple drugs into one cell therapeutic, is established. Specifically, a sequentially responsive core-shell nanoparticle (SRN) encapsulating IDOi and CDK4/6i is anchored onto T cells. The yielded SRN-T cells migrated into solid tumor, and achieved a 1st release of IDOi in acidic tumor microenvironment (TME). Released IDOi restored tryptophan supply in TME, which activated effector T cells and inhibited Tregs. Meanwhile, 1st released core is internalized by tumor cells and degraded by glutathione (GSH), to realize a 2nd release of CDK4/6i, which induced up-regulated expression of C-X-C motif chemokine ligand 10 (CXCL10) and C-C motif chemokine ligand 5 (CCL5), and thus significantly increased tumor infiltration of T cells. Together, with an enhanced recruitment and activation, T cells significantly suppressed tumor growth, and prolonged survival of tumor-bearing mice. This study demonstrated rationality and superiority of a tri-drug combination mediated by spatiotemporally controlled cell-engineering technology, which provides a new treatment regimen for solid tumor.

Synovium microenvironment-responsive injectable hydrogel inducing modulation of macrophages and elimination of synovial fibroblasts for enhanced treatment of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a progressive autoimmune disease accompanied by joint swelling, cartilage erosion and bone damage. Drug therapy for RA has been restricted due to poor therapeutic effect, recurrence and adverse effects. Macrophages and synovial fibroblasts both play important roles in the pathology of RA. Macrophages secrete large amount of pro-inflammatory cytokines, while synovial fibroblasts are tightly correlated with hypoxia synovium microenvironment, cytokine release, recruitment of pro-inflammatory cells, bone and cartilage erosion. Therefore, in this timely research, an injectable and pH-sensitive peptide hydrogel loading methotrexate (MTX) and bismuthene nanosheet/polyethyleneimine (BiNS/PEI) has been developed to reduce the activity of macrophages and eliminate over-proliferated synovial fibroblasts simultaneously. MTX can reduce the cytokine secretion of macrophages/anti-apoptosis property of synovial fibroblasts and BiNS/PEI can eliminate synovial fibroblasts via photodynamic therapy (PDT) and photothermal therapy (PTT) routes. The hydrogel was injected into the acidic inflammatory synovium for precise targeting and served as a drug reservoir for pH responsive and sustained drug release, while improving the bioavailability and reducing the toxicity of MTX. Excellent therapeutic efficacy has been achieved in both in vivo and in vitro studies, and this unique drug delivery system provides a new and robust strategy to eliminate synovial fibroblasts and modulate immune system for RA treatment in clinical.

The potential role of hydrogen sulfide in cancer cell apoptosis.

For a long time, hydrogen sulfide (H2S) has been considered a toxic compound, but recent studies have found that H2S is the third gaseous signaling molecule which plays a vital role in physiological and pathological conditions. Currently, a large number of studies have shown that H2S mediates apoptosis through multiple signaling pathways to participate in cancer occurrence and development, for example, PI3K/Akt/mTOR and MAPK signaling pathways. Therefore, the regulation of the production and metabolism of H2S to mediate the apoptotic process of cancer cells may improve the effectiveness of cancer treatment. In this review, the role and mechanism of H2S in cancer cell apoptosis in mammals are summarized.

A Senescence-Associated Secretory Phenotype of Bone Marrow Mesenchymal Stem Cells Inhibits the Viability of Breast Cancer Cells.

Breast cancer, the most prevalent malignancy in women, often progresses to bone metastases, especially in older individuals. Dormancy, a critical aspect of bone-metastasized breast cancer cells (BCCs), enables them to evade treatment and recur. This dormant state is regulated by bone marrow mesenchymal stem cells (BMMSCs) through the secretion of various factors, including those associated with senescence. However, the specific mechanisms by which BMMSCs induce dormancy in BCCs remain unclear. To address this gap, a bone-specific senescence-accelerated murine model, SAMP6, was utilized to minimize confounding systemic age-related factors. Confirming senescence-accelerated osteoporosis, distinct BMMSC phenotypes were observed in SAMP6 mice compared to SAMR1 counterparts. Notably, SAMP6-BMMSCs exhibited premature senescence primarily due to telomerase activity loss and activation of the p21 signaling pathway. Furthermore, the effects of conditioned medium (CM) derived from SAMP6-BMMSCs versus SAMR1-BMMSCs on BCC proliferation were examined. Intriguingly, only CM from SAMP6-BMMSCs inhibited BCC proliferation by upregulating p21 expression in both MCF-7 and MDA-MB-231 cells. These findings suggest that the senescence-associated secretory phenotype (SASP) of BMMSCs suppresses BCC viability by inducing p21, a pivotal cell cycle inhibitor and tumor suppressor. This highlights a heightened susceptibility of BCCs to dormancy in a senescent microenvironment, potentially contributing to the increased incidence of breast cancer bone metastasis and recurrence observed with aging.

Interventions to Improve Endoscopic Screening Adherence of Cancer in High-Risk Populations: A Scoping Review.

Background: Colorectal, and gastric cancers have the second, and fourth mortality rates worldwide, respectively. Endoscopic screening is a crucial diagnostic tool for colorectal, and gastric cancers. Effective interventions can improve adherence to endoscopic screening in high-risk populations, which is important for cancer prevention and mortality reduction. This study aimed to identify interventions that could improve adherence to endoscopic screening for cancer in high-risk populations. Methods: Combination keywords including colorectal cancer, gastric cancer, screening adherence, and interventions were used to search for articles in PubMed, Web of Science, Cochrane Library, and MEDLINE Complete. The review methodology was guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-SCR). Results: A total of 12 articles were included in this review: 9 randomized controlled trials(RCT) and 3 quasi-experimental studies(QEDs). Among the extracted studies, 11 were about colorectal cancer, and 1 was about gastric cancer. Most studies used lecture-based or Information Technology-based health education interventions. Narrative interventions have proven to be novel and effective approaches for promoting adherence to endoscopic screening. Health education interventions included cancer epidemiology, cancer risk factors, warning symptoms, and screening methods. Conclusion: All interventions involved were effective in increasing individual knowledge of cancer-related endoscopic screening, willingness to undergo screening, and screening behaviors. These findings provide a reference for designing endoscopy-related cancer screening interventions.

Identification of Treg-related prognostic molecular subtypes and individualized characteristics in clear cell renal cell carcinoma through single-cell transcriptomes and bulk RNA sequencing.

BACKGROUND: In clear cell renal cell carcinoma (ccRCC), the role of Regulatory T cells (Treg cells) as prognostic and immunotherapy response predictors is not fully explored. METHODS: Analyzing renal clear cell carcinoma datasets from TISCH, TCGA, and GEO, we focused on 8 prognostic Treg genes to study patient subtypes in ccRCC. We assessed Treg subtypes in relation to patient prognosis, tumor microenvironment, metabolism. Using Cox regression and principal component analysis, we devised Treg scores for individual patient characterization and explored the molecular role of C1QL1, a critical gene in the Treg model, through in vivo and in vitro studies. RESULTS: Eight Treg-associated prognostic genes were identified, classifying ccRCC patients into cluster A and B. Cluster A patients showed poorer prognosis with distinct clinical and molecular profiles, potentially benefiting more from immunotherapy. Low Treg scores correlated with worse outcomes and clinical progression. Low scores also suggested that patients might respond better to immunotherapy and targeted therapies. In ccRCC, C1QL1 knockdown reduced tumor proliferation and invasion via NF-kb-EMT pathways and decreased Treg cell infiltration, enhancing immune efficacy. CONCLUSIONS: The molecular subtype and Treg score in ccRCC, based on Treg cell marker genes, are crucial in personalizing ccRCC treatment and underscore C1QL1's potential as a tumor biomarker and target for immunotherapy.

Coinfection with hepatic cystic and alveolar echinococcosis with abdominal wall abscess and sinus tract formation: A case report.

BACKGROUND: Hepatic cystic and alveolar echinococcosis coinfections, particularly with concurrent abscesses and sinus tract formation, are extremely rare. This article presents a case of a patient diagnosed with this unique presentation, discussing the typical imaging manifestations of both echinococcosis types and detailing the diagnosis and surgical treatment experience thereof. CASE SUMMARY: A 39-year-old Tibetan woman presented with concurrent hepatic cystic and alveolar echinococcosis, accompanied by abdominal wall abscesses and sinus tract formation. Initial conventional imaging examinations suggested only hepatic cystic echinococcosis, but intraoperative and postoperative pathological examination revealed the coinfection. Following radical resection of the lesions, the patient's condition improved, and she was discharged soon thereafter. Subsequent outpatient follow-ups confirmed no recurrence of the hydatid lesion and normal surgical wound healing. Though mixed hepatic cystic and alveolar echinococcosis with abdominal wall abscesses and sinus tract formations are rare, the general treatment approach remains consistent with that of simpler infections of alveolar echinococcosis. CONCLUSION: Lesions involving the abdominal wall and sinus tract formation, may require radical resection. Long-term prognosis includes albendazole and follow-up examinations.

Galactosyl BODIPY-based nanoparticles as a type-I photosensitizer for HepG2 cell targeted photodynamic therapy.

We report a galactosyl diiodo-BODIPY-based nanoparticles as type-I photosensitizer (PS) with high water solubility for HepG2 cell targeted photodynamic therapy. Functionalized galactoside and glucoside were introduced into diiodo-BODIPY to obtain BP1 and BP2, respectively. The glycolyl PSs could self-assemble to form the nanoparticles BP1-NP and BP2-NP with red-shifted near-infrared (NIR) absorption and fluorescence at 682 nm and 780 nm, as well as excellent chemo- and photo-stability. In comparison to the monomer in DMSO, the aggregated photosensitizers in the nanoparticles enabled the sensitization of oxygen to superoxide (O2˙-) through a type-I process, while repressing the generation of singlet oxygen (1O2) through a type-II process. The galactosyl-modified BP1-NPs could target and concentrate on HepG2 cells, subsequently generating O2˙- and 1O2 to trigger cell death under 660 nm light irradiation. This work provides an efficient strategy for the construction of glycoside-recognized type-I photosensitizers for tumor cell imaging and photodynamic therapy.

[A multicenter clinical study on the treatment of lateral epicondylitis of humerus by manipulation].

OBJECTIVE: To investigate clinical effect of tendons pulling,poking and kneading for the treatment of external humeral epicondylitis. METHODS: From January 2018 to December 2021,a multicenter randomized controlled study was performed to collect 192 patients with external humeral epicondylitis in Wangjing Hospital,Beijing Dianli Hospital,and Beijing Fengsheng Osteotraumatology Hospital,respectively,and they were divided into treatment group and control group by random number table method. There were 96 patients in treatment group,including 36 males and 60 females,aged from 28 to 60 years old with an average of (41.20±5.50) years old;the course of disease ranged from 1 to 14 days with an average of (5.24±1.35) days;they were treated once every other day for 2 weeks. There were 96 patients in control group ,including 33 males and 63 females,aged from 26 to 60 years old with an average of (43.35±7.75) years old;the course of disease ranged from 1 to 14 days with an average of (5.86±1.48) days;they were treated with topical voltaalin combined with elbow joint fixation for 2 weeks. Visual analogue scale (VAS) and Hospital for Surgery Scoring System (HSS) elbow pronation and supination angles,wrist metacarpal flexion and dorsal extension angles,elbow tenderness between two groups were compared before treatment and at 1,3,5,7,11 and 13 days after treatment;Hospital for Surgery Scoring System 2 (HSS2) was compared before treatment and the final treatment. RESULTS: All patients were followed up for 10 to 14 days with an average of (12±1.6) days. VAS between treatment group and control group before treatment were 6.83±1.36 and 6.79±1.58,respectively,and decreased to 1.49±1.09 and 2.11±1.81 after the final treatment. VAS of treatment group were significantly lower than those of control group at 1,3,5,7,9,11 and 13 days after treatment (P<0.05). HSS between two groups were 61.73±11.00 and 36.47±12.45 before treatment,respectively,and increased to 94.42±5.9 and 91.44±9.11 at the final treatment. HSS of treatment group were significantly higher than those of control group at 1,3,5,7,9,11 and 13 days after treatment (P<0.05). On the 5th day after treatment,the external and internal rotation angles of elbow in treatment group were (66.41±12.69) ° and (66.35±13.54) °,while those in control group were (62.08±16.03) ° and (61.77±16.35) °. On the 7th day after treatment,the external and internal rotation angles of elbow were (69.79±12.64) ° and (70.02±13.55) ° in treatment group,and (65.28±15.86) ° and (65.09±16.67) ° in control group. Elbow joint motion in treatment group was higher than that in control group (P<0.05). On the 5th day after treatment,angles of wrist dorsiflexion and palm flexion were (39.43±15.94) ° and (46.68±11.10) ° in treatment group,and (38.51±18.49) ° and (44.27±13.58) ° in control group. On the 7th day after treatment,angles of wrist dorsiflexion and palm flexion were (42.52±16.50) ° and (49.23±10.96) ° in treatment group,and (41.18±20.09) ° and (46.64±14.63) ° in control group. The motion of wrist joint in treatment group was higher than that in control group (P<0.05). On the 13th day after treatment,HSS2 in treatment group 93.61±6.32 were higher than those in control group 92.06±7.94(P<0.05). There was no significant difference in elbow tenderness between two groups at each time point (P>0.05). CONCLUSION: Voltaren external treatment combined with elbow fixation and tendons pulling,poking and kneading could effectively improve symptoms of external humeral epicondylitis. Compared with voltaren external treatment,tendons pulling,poking and kneading has advantages of longer analgesic time and better elbow function recovery.

CRDet: A circle representation detector for lung granulomas based on multi-scale attention features with center point calibration.

Lung granuloma is a very common lung disease, and its specific diagnosis is important for determining the exact cause of the disease as well as the prognosis of the patient. And, an effective lung granuloma detection model based on computer-aided diagnostics (CAD) can help pathologists to localize granulomas, thereby improving the efficiency of the specific diagnosis. However, for lung granuloma detection models based on CAD, the significant size differences between granulomas and how to better utilize the morphological features of granulomas are both critical challenges to be addressed. In this paper, we propose an automatic method CRDet to localize granulomas in histopathological images and deal with these challenges. We first introduce the multi-scale feature extraction network with self-attention to extract features at different scales at the same time. Then, the features will be converted to circle representations of granulomas by circle representation detection heads to achieve the alignment of features and ground truth. In this way, we can also more effectively use the circular morphological features of granulomas. Finally, we propose a center point calibration method at the inference stage to further optimize the circle representation. For model evaluation, we built a lung granuloma circle representation dataset named LGCR, including 288 images from 50 subjects. Our method yielded 0.316 mAP and 0.571 mAR, outperforming the state-of-the-art object detection methods on our proposed LGCR.

Geriatric Nutritional Risk Index Combined with Calf Circumference Can be a Good Predictor of Prognosis in Patients Undergoing Surgery for Gastric or Colorectal Cancer.

OBJECTIVES: To explore the effect of combined hematological and physical measurement indicators on the prognosis of patients undergoing surgery for gastric or colorectal cancer and to screen for the best prognostic indicators. INTRODUCTION: Gastric and colorectal cancer is a widespread health concern worldwide and one of the major contributors to cancer-related death. The hematological and physical measurement indicators have been shown to associate with the prognosis of patients undergoing surgery for gastric or colorectal cancer, respectively, but it is still unclear whether the combination of the two can reflect the prognosis more effectively. METHODS: Thirteen hematological indicators and 5 physical measurement indicators were selected in this study, and the most promising ones were screened using LASSO regression. Then, the best prognostic indicators were selected by time-ROC curves. Survival curves were constructed using the Kaplan-Meier method, and the effects of hematological and physical measurement indicators on the prognosis of patients undergoing surgery for gastric or colorectal cancers were evaluated by Cox proportional risk regression analysis. In addition, the relationship between hematological and physical measurement indicators on secondary outcomes, including length of stay, hospitalization costs, intensive care unit (ICU) admission, and patients' subjective global assessment scores (PGSGA), was explored. RESULTS: After initial screening, among the hematological indicators, the geriatric nutritional risk index (GNRI) showed the highest mean area under the curve (AUC) values. Among body measures, calf circumference (CC) showed the highest mean AUC value. Further analyses showed that the combination of combined nutritional prognostic index (GNRI) and calf circumference (CC) (GNRI-CC) had the best performance in predicting the prognosis of patients undergoing surgery for gastric or colorectal cancers. Low GNRI, low CC, and low GNRI-low CC increased the risk of death by 44%, 48%, and 104%, respectively. Sensitivity analyses showed the same trend. In addition, low GNRI-low CC increased the risk of malnutrition by 17%. CONCLUSION: This study emphasizes that a combination of blood measures and body measures is essential to accurately assess the prognosis of patients undergoing surgery for gastric or colorectal cancers. The GNRI-CC is a good prognostic indicator and can also assess the risk of possible malnutrition.

The Impact of Nursing Interventions on the Treatment Outcomes of Renal Cell Carcinoma with Postoperative Interleukin-2 and Recombinant Human Interferon.

Objective: This study investigates the impact of nursing interventions on treatment outcomes and adverse reaction rates in renal cell carcinoma (RCC) patients treated postoperatively with Interleukin-2 and recombinant human Interferon. Methods: In a retrospective analysis of 90 RCC patients, 43 received standard care (control group), while 47 received additional nursing interventions (intervention group), including psychological care, vital signs monitoring, dietary care, adverse reaction management, and post-discharge care. Patients with concurrent major diseases or other malignancies were excluded. Key assessments included clinical symptom improvement, treatment efficacy, and postoperative adverse reactions. Results: Among the 90 participants, no significant demographic differences were found between the two groups. The intervention group showed significant improvements in fever resolution, leukocyte normalization, and shorter hospital stays. The overall treatment effectiveness was similar in both groups (90.7% in the intervention group vs 91.5% in the control group). However, the intervention group experienced significantly fewer postoperative adverse reactions, including fever, gastrointestinal symptoms, bone marrow suppression, and neurological abnormalities (6.3% vs 23.2%). Conclusion: The study suggests that nursing interventions can improve treatment outcomes by reducing postoperative adverse reactions in RCC patients receiving postoperative Interleukin-2 and recombinant human Interferon. The overall effectiveness of treatment and care was comparable between the groups. Further extensive studies are needed to confirm these findings and fully understand the impact of nursing interventions on RCC patient outcomes.

Prognostic value of right atrial strains in arrhythmogenic right ventricular cardiomyopathy.

OBJECTIVES: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by progressive fibrofatty infiltration of atrial and ventricular myocardium resulting in adverse cardiac events. Atrial function has been increasingly recognized as prognostically important for cardiovascular disease. As the right atrial (RA) strain is a sensitive parameter to describe RA function, we aimed to analyze the prognostic value of the RA strain in ARVC. METHODS: RA strain parameters were derived from cardiac magnetic resonance (CMR) images of 105 participants with definite ARVC. The endpoint was defined as a combination of sudden cardiac death, survival cardiac arrest, and appropriate implantable cardioverter-defibrillator intervention. Cox regression and Kaplan-Meier survival analyses were performed to evaluate the association between RA strain parameters and endpoint. Concordance index (C index), net reclassification index (NRI), and integrated discrimination improvement (IDI) were calculated to assess the incremental value of RA strain in predicting the endpoint. RESULTS: After a median follow-up of 5 years, 36 (34.3%) reaching the endpoint displayed significantly reduced RA strain parameters. At Kaplan-Meier analysis, impaired RA reservoir (RARS) and booster strains (RABS) were associated with an increased risk of the endpoint. After adjusting for conventional risk factors, RARS (hazard ratio [HR], 0.956; p = 0.005) and RABS (HR, 0.906; p = 0.002) resulted as independent predictors for endpoint at Cox regression analyses. In addition, RARS and RABS improved prognostic value to clinical risk factors and CMR morphological and functional predictors (all p < 0.05). CONCLUSION: RARS and RABS were independent predictors for adverse cardiac events, which could provide incremental prognostic value for conventional predictors in ARVC. CRITICAL RELEVANCE STATEMENT: We evaluated the prognostic value of right atrial strain in ARVC patients and suggested cardiologists consider RA strain as a predictive parameter when evaluating the long-term outcome of ARVC patients in order to formulate better clinical therapy. KEY POINTS: • Patients with ARVC had significantly reduced RA strain and strain rates compared with healthy participants. • Participants with lower RA reservoir and booster stains were associated with a significantly higher risk of adverse cardiac events. • RA booster and reservoir strain provide incremental value to conventional parameters.

Time-resolved map of serum metabolome profiling in D-galactose-induced aging rats with exercise intervention.

Exercise, an intervention with wide-ranging effects on the whole body, has been shown to delay aging. Due to aging and exercise as modulator of metabolism, a picture of how exercise delayed D-galactose (D-gal)-induced aging in a time-resolved manner was presented in this paper. The mapping of molecular changes in response to exercise has become increasingly accessible with the development of omics techniques. To explore the dynamic changes during exercise, the serum of rats and D-gal-induced aging rats before, during, and after exercise was analyzed by untargeted metabolomics. The variation of metabolites was monitored to reveal the specific response to D-gal-induced senescence and exercise in multiple pathways, especially the basal amino acid metabolism, including glycine serine and threonine metabolism, cysteine and methionine metabolism, and tryptophan metabolism. The homeostasis was disturbed by D-gal and maintained by exercise. The paper was expected to provide a theoretical basis for the study of anti-aging exercise.

Pseudopterygia in Fuchs Superficial Marginal Keratitis: Clinical Course and Surgical Outcome.

PURPOSE: Surgery for pseudopterygia in Fuchs superficial marginal keratitis (FSMK) bears the risk of corneal perforation, as described in a few case reports. The aim of this case series was to understand the clinical course and surgical outcomes of pseudopterygia in FSMK. METHODS: A retrospective case series included patients meeting FSMK criteria with pseudopterygia in at least 1 eye. The severity grading of pseudopterygia and peripheral infiltration events at follow-up were analyzed. Pseudopterygia involving corneal central 3 mm diameter (grade III) received surgery. Peripheral corneal infiltrate events within 1 week after surgery were recorded. RESULTS: Thirty-three eyes of 19 patients (8 men, 11 women; age 40-85 years; mean, 65 years) were included, with an average 48.1-month follow-up (range 0-188.8 months). At presentation, 7 eyes (21%) had grade III pseudopterygia. One patient showed corneal perforation 3 days after "pterygium" surgery elsewhere. The contralateral eye met the diagnosis of FSMK. During follow-up, 16 eyes (49%) exhibited peripheral corneal infiltrates, and 7 eyes (21%) showed progression of pseudopterygia to higher grades before or without any surgery. Ten eyes with grade III pseudopterygia underwent surgery. The best-corrected visual acuity in Logarithm of the Minimum Angle of Resolution improved from 0.34 ± 0.18 (range 0.05-0.52) to 0.13 ± 0.11 (range 0.05-0.4) (P = 0.0023). Six eyes (60%) developed peripheral corneal infiltrates within 1 week after surgery, which responded well to topical corticosteroids. CONCLUSIONS: Pseudopterygia in FSMK may progress to threaten visual acuity. Surgical excision can be safe and can effectively improve vision on the condition that the patients are closely followed in the early postoperative period to notice the corneal infiltrates.

Retracted: Arsenic Trioxide Inhibits the Metastasis of Small Cell Lung Cancer by Blocking Calcineurin-Nuclear Factor of Activated T Cells (NFAT) Signaling.

This publication has been retracted by the Editor due to the identification of non-original figure images and manuscript content that raise concerns regarding the credibility and originality of the study. Reference: Jin-Cheng Zheng, Ke-Jie Chang, Yu-Xiang Jin, Xue-Wei Zhao, Bing Li, Meng-Hang Yang. Arsenic Trioxide Inhibits the Metastasis of Small Cell Lung Cancer by Blocking Calcineurin-Nuclear Factor of Activated T Cells (NFAT) Signaling. Med Sci Monit 2019; 25:2228-2237. DOI: 10.12659/MSM.913091.

Multifunctional metal-coordinated Co-assembled carrier-free nanoplatform based on dual-drugs for ferroptosis-mediated cocktail therapy of hepatocellular carcinoma growth and metastasis.

The heterogeneity of hepatocellular carcinoma (HCC) and the complexity of the tumor microenvironment (TME) pose challenges to efficient drug delivery and the antitumor efficacy of combined or synergistic therapies. Herein, a metal-coordinated carrier-free nanodrug (named as USFe3+ LA NPs) was developed for ferroptosis-mediated multimodal synergistic anti-HCC. Natural product ursolic acid (UA) was incorporated to enhance the sensitivity of tumor cells to sorafenib (SRF). Surface decoration of cell penetration peptide and epithelial cell adhesion molecule aptamer facilitated the uptake of USFe3+ LA NPs by HepG2 cells. Meanwhile, Fe3+ ions could react with intracellular hydrogen peroxide, generating toxic hydroxyl radical (·OH) for chemodynamical therapy (CDT) and amplified ferroptosis by cystine/glutamate antiporter system (System Xc-), which promoted the consumption of glutathione (GSH) and inhibited the expression of glutathione peroxidase 4 (GPX4). Notably, these all-in-one nanodrugs could inhibit tumor metastasis and induced immunogenic cell death (ICD). Last but not least, the nanodrugs demonstrated favorable biocompatibility, augmenting the immune response against the programmed death-ligand 1 (PD-L1) by increasing cytotoxic T cell infiltration. In vivo studies revealed significant suppression of tumor growth and distant metastasis. Overall, our work introduced a novel strategy for applications of metal-coordinated co-assembled carrier-free nano-delivery system in HCC combination therapy, especially in the realms of cancer metastasis prevention and immunotherapy.