Influence of ganglioside combined with methylprednisolone sodium succinate on efficacy and neurological function in patients with acute myelitis.

BACKGROUND: Acute myelitis (AM) can lead to sudden sensory, motor and autonomic nervous dysfunction, which negatively affects their daily activities and quality of life, so it is necessary to explore optimization from a therapeutic perspective to curb the progression of the disease. AIM: To investigate the effect of ganglioside (GM) combined with methylprednisolone sodium succinate (MPSS) on the curative effect and neurological function of patients with AM. METHODS: First, we selected 108 AM patients visited between September 2019 and September 2022 and grouped them based on treatment modality, with 52 patients receiving gamma globulin (GG) + MPSS and 56 patients receiving GM + MPSS, assigned to the control group (Con) and observation group (Obs), respectively. The therapeutic effect, neurological function (sensory and motor function scores), adverse events (AEs), recovery (time to sphincter function recovery, time to limb muscle strength recovery above grade 2, and time to ambulation), inflammatory factors (IFs) [interleukin (IL)-6, C-reactive protein (CRP), and tumor necrosis factor (TNF)-α] and other data of the two groups were collected for evaluation and comparison. RESULTS: The Obs had: (1) A significantly higher response rate of treatment than the Con; (2) Higher scores of sensory and motor functions after treatment that were higher than the baseline (before treatment) and higher than the Con levels; (3) Lower incidence rates of skin rash, gastrointestinal discomfort, dyslipidemia, osteoporosis and other AEs; (4) Faster posttreatment recovery of sphincter function, limb muscle strength and ambulation; and (5) Markedly lower posttreatment IL-6, CRP and TNF-α levels than the baseline and the Con levels. CONCLUSION: From the above, it can be seen that GM + MPSS is highly effective in treating AM, with a favorable safety profile comparable to that of GG + MPSS. It can significantly improve patients' neurological function, speed up their recovery and inhibit serum IFs.

Expressive Arts Therapy Combined with Progressive Muscle Relaxation following Music for Perioperative Patients with Gynecological Malignancies: A Pilot Study.

Objective: We aimed to assess the impact of an expressive arts therapy combined with progressive muscle relaxation following music on mental health (anxiety and hope) in patients with gynecological malignancies undergoing surgery. Methods: This was a nonrandomized controlled trial. Eligible patients had a primary or recurrent gynecological malignancy scheduled to be treated with surgery. The intervention consisted of three sessions (preoperation, postoperation, and predischarge) during the perioperative period. Firstly, before starting the first session of intervention, all patients completed three questionnaires including a Hospital Anxiety and Depression Scale (HADS), a Herth Hope Index (HHI), and a State Anxiety Inventory (SAI), and the intervention group patients also had to complete the SAI questionnaire again after completing the intervention. Secondly, after the second session of intervention, all patients completed the SAI questionnaire, with the intervention group completed the SAI questionnaire before the intervention. Thirdly, after the third session of intervention, all patients completed HHI and SAI questionnaires, with the intervention group completed the SAI questionnaire before the intervention. Also, to subjectively rate the benefit of expressive arts therapy, the intervention group additionally completed a separate, supplemental questionnaire. Results: A total of 116 patients were enrolled and 110 included in the final analysis. No group differences were found for HHI scores between the intervention and control participants (Cohen's d = 0.19, P=0.31), although there was a substantial improvement in intervention participants' HHI scores compared to the standard care control participants. There was a statistically significant improvement in intervention participants' SAI from preintervention to postintervention of preoperation (Cohen's d = -0.23, P=0.002) and postoperation (Cohen's d = -0.34, P ≤ 0.001). However, no differences were observed for the predischarge period (Cohen's d = -0.09, P=0.118). Besides, a supplemental questionnaire indicated that 52 (98%) patients felt that expressive arts therapy was beneficial. Conclusions: Expressive art therapy combined with progressive muscle relaxation under music may be of some effect on alleviating perioperative anxiety in patients with gynecologic malignancies. Therefore, further relevant studies with large samples and multicenters are urgently needed to provide a reliable evidence-based basis for perioperative psychological care of patients with gynecologic malignancies and to promote rapid recovery of patients. It is recommended that further art therapy studies to examine the impact of patient-tailored arts therapy interventions on spiritual well-being in patients with gynecological malignancies, especially in the perioperative period.

BCAR1 plays critical roles in the formation and immunoevasion of invasive circulating tumor cells in lung adenocarcinoma.

Background: We investigated the roles of breast cancer anti-estrogen resistance 1 (BCAR1/p130Cas) in the formation and immunoevasion of invasive circulating tumor cells (CTCs) in lung adenocarcinoma (LUAD). Methods: Biomarkers of CTCs including BCAR1 and CD274, were evaluated by the CanPatrol method. Proteomics analysis of LUAD cells and exosomes after BCAR1 overexpression (BCAR1-OE) was performed by mass spectrometry. Cell functions and relevant signaling pathways were investigated after BCAR1 knockdown (BCAR1-KO) or BCAR1-OE in LUAD cells. Lastly, in vitro and in vivo experiments were performed to confirm the roles of BCAR1 in the formation and immunoevasion of CTCs. Results: High expression of BCAR1 by CTCs correlated with CD274 expression and epithelial-to-mesenchymal transition (EMT). RAC1, together with BCAR1, was found to play an important role in the carcinogenesis of LUAD. RAC1 functioned with BCAR1 to induce EMT and to enhance cell proliferation, colony formation, cell invasion and migration, and anoikis resistance in LUAD cells. BCAR1 up-regulated CD274 expression probably by shuttling the short isoform of BRD4 (BRD4-S) into the nucleus. CTCs, as well as tumor formation, were prohibited in nude mice xenografted with BCAR1-KO cells. The co-expression of BCAR1/RAC1 and BCAR1/CD274 was confirmed in LUAD. BCAR1 expression in LUAD is an indicator of poor prognosis, and it associates with immunoevasion. Conclusion: BCAR1, as a new target for the treatment of LUAD, plays roles in the formation and immunoevasion of invasive CTCs. The mechanism includes triggering EMT via RAC1 signaling and up-regulating CD274 expression by shuttling BRD4-S into the nucleus.

Circulating tumor cells with epithelial-mesenchymal transition markers as potential biomarkers for the diagnosis of lung cancer.

BACKGROUND: Circulating tumor cells (CTCs) can be clustered into three subtypes according to epithelial-mesenchymal transition (EMT) markers: CTCs with epithelial markers (E-CTCs), CTCs with mesenchymal markers (M-CTCs), and CTCs with both markers (E&M-CTCs). CTC detection has clinical implications in the diagnosis of lung cancer (LC). AIM: To clarify the diagnostic value of CTCs categorized by EMT markers in LC. METHODS: The study included 106 patients with lung adenocarcinoma, including 42 ground-glass opacities (GGO) and 64 solid lesions, who underwent surgery between July 2015 and December 2019. Eleven patients with benign tumors and seventeen healthy controls were included. CTCs in peripheral blood and associated EMT markers were detected preoperatively using the CanPatrolTM technique. The diagnostic power of CTCs for discriminating LC cases from controls was analyzed by the receiver operating characteristic (ROC) curve. The CytoploRare technique was used in 20 cases and 18 controls for validation, and Kappa values were calculated to evaluate consistency between techniques. RESULTS: Of the 106 LC cases, 94 (89.6%) had at least one CTC. CTCs were detectable in 35 (83.3%) of 42 GGO cases. Total CTCs and E&M-CTCs were significantly more frequent in LC cases than in benign or healthy controls. The proportion of M-CTCs plus E&M-CTCs increased gradually from healthy controls, to benign controls, to LC cases. The area under the ROC curve of total CTCs and E&M-CTCs was > 0.8 and > 10.75, respectively. The combined sensitivity of total-CTCs and E&M-CTCs was 85.85% for LC patients (80.95% for GGO patients) and the specificity was 78.57%. The Kappa value was 0.415, indicating relative consistency between CanPatrolTM and CytoploRare. CONCLUSION: CTC detection is valuable for distinguishing LC from controls, and particularly E&M-CTC detection warrants further study.

Interleukin-33 modulates lipopolysaccharide-mediated inflammatory response in rat primary astrocytes.

Astrocytes have a crucial role in the modulation of the neuroinflammatory response. However, the underlying mechanisms have yet to be fully defined. Interleukin-33 (IL-33) is constitutively expressed in astrocytes, which has been found to orchestrate inflammatory responses in a large variety of immune-mediated and inflammatory diseases of the nervous system. Thus, the purpose of this study was to elucidate the potential effect of IL-33 in the regulation of inflammatory response in primary cultured astrocytes. We investigated the role of IL-33 in the regulation of inflammatory responses in the lipopolysaccharide-stimulated astrocytes. This study utilized lentiviral short hairpin RNA vectors to target IL-33 (LV-shIL-33) for gene silencing. After lipopolysaccharide stimulation, the expression levels of interleukin-1ß (IL-1ß), IL-6, and tumor necrosis factor-α (TNF-α), as well as the activation of nuclear factor-kappa B (NF-κB) and extracellular signal-regulated kinase (ERK) signaling pathways, were evaluated to elucidate the mechanisms related to the contributions of IL-33 to the inflammatory response in astrocytes. We found that the expression IL-33 has increased in rat primary cultured astrocytes after lipopolysaccharide stimulation. Administration of LV-shIL-33 knocked down the expression of IL-33 and markedly reduced the overexpression of spinal IL-1ß, IL-6, and TNF-α, and attenuated the activation of ERK and NF-κB/p65. This study shows that IL-33 participates in regulating inflammatory responses in primary cultured astrocytes, which might provide additional targets for controlling inflammatory responses following neurological diseases. See Video abstract, http://links.lww.com/WNR/A627.

BCAR1 promotes proliferation and cell growth in lung adenocarcinoma via upregulation of POLR2A.

BACKGROUND: This study was designed to investigate the effects of a novel carcinogenetic molecule, p130cas (breast cancer antiestrogen resistance protein 1 or BCAR1) on proliferation and cell growth in lung adenocarcinoma. The study also aimed to identify the possible underlying signal networks of BCAR1. METHODS: First, we evaluated proliferation, cell colony formation, apoptosis, and cell cycle after BCAR1 was knocked out (KO) using CRISPR-Cas9 technology in H1975 and H1299 human lung adenocarcinoma cells. Subsequently, BCAR1 was upregulated in 293T cells and immunoprecipitation-mass spectrometry (IP-MS) was used with bioinformatics analysis to screen for potential networks of BCAR1 interacting proteins. Ultimately, we validated the correlated expressions of BCAR1 and a selected hub gene, RNA polymerase II subunit A (POLR2A), in 54 lung adenocarcinoma tissues, as well as in H1975 and H1299 cells. RESULTS: Cell proliferation of H1975 and H1299 was significantly inhibited following BCAR1-KO. Colony formation of H1975 cells was also significantly decreased following BCAR1-KO. IP-MS demonstrated 419 potential proteins that may interact with BCAR1. Among them, 68 genes were significantly positively correlated to BCAR1 expression, as verified by TCGA. Six hub genes were revealed by PPI String. High expression of POLR2A, MAPK3, MOV10, and XAB2 predicted poor prognosis in lung adenocarcinoma, as verified by the K-M plotter database. POLR2A and MAPK3 are involved in both catalytic activity and transferase activity. POLR2A and BCAR1 were significantly increased in lung cancer tissues as compared with matched normal tissues. High expression of POLR2A was significantly positively correlated to BCAR1 overexpression and predicted poor prognosis in 54 lung cancer cases. POLR2A expression was significantly decreased following BCAR1-KO in H1975 and H1299 cells. CONCLUSIONS: BCAR1 promotes proliferation and cell growth, probably via upregulation of POLR2A and subsequent enhancement of catalytic and transferase activities. However, additional robust studies are required to elucidate the mechanisms involved.

Circulating tumor cells prior to initial treatment is an important prognostic factor of survival in non-small cell lung cancer: a meta-analysis and system review.

BACKGROUND: Our study aimed to verify the prognostic value of circulating tumor cells (CTCs) prior to initial treatment on survival of non-small cell lung cancer (NSCLC) by using meta-analysis and system review of published studies. MATERIALS AND METHODS: The PubMed, EMBASE and Cochrane Library were searched, respectively, to identify all studies that addressed the issues of CTCs prior to initial treatment and progression-free survival (PFS) and overall survival (OS). Finally, ten citations were included for analysis and assessment of publication bias by using review manager 5.3 statistical software and STATA 15.0. RESULTS: Randomized model analyzing multivariate Cox Proportional Hazards Regression indicated that higher abundance of CTCs significantly predicts poorer prognosis of lung cancer cases basing both on PFS (Z = 2.31, P = 0.02) and OS of advanced cases (Z = 2.44, P = 0.01), and systematic study aslo indicated the similar results. CONCLUSION: High CTCs prior to initial treatment can predict shorter PFS and OS in NSCLC, and further studies are warranted in the future.

Effects of apoptosis on liver aging.

As an irreversible and perennial process, aging is accompanied by functional and morphological declines in organs. Generally, aging liver exhibits a decline in volume and hepatic blood flow. Even with a preeminent regenerative capacity to restore its functions after liver cell loss, its biosynthesis and metabolism abilities decline, and these are difficult to restore to previous standards. Apoptosis is a programmed death process via intrinsic and extrinsic pathways, in which Bcl-2 family proteins and apoptosis-related genes, such as p21 and p53, are involved. Apoptosis inflicts both favorable and adverse influences on liver aging. Apoptosis eliminates transformed abnormal cells but promotes age-related liver diseases, such as nonalcoholic fatty liver disease, liver fibrosis, cirrhosis, and liver cancer. We summarize the roles of apoptosis in liver aging and age-related liver diseases.

Roles of aging in sleep.

With aging, various factors deteriorate the normal sleep process that is essential for the restoration of functional and physical performance. Due to aging-related diseases, life changes, or aging itself, disturbances in normal sleep cycles can profoundly affect healthy aging. To understand the interconnections between aging and the factors influencing sleep, with emerging evidence accumulated in recent years, this study elaborates on the roles of aging in sleep from four perspectives: cortical thinning, white matter degeneration, neurotransmitter dysregulation, and circadian disorganization. In brief, with aging, cortical thinning can be induced by the deposition of neurotoxic substances, and white matter degeneration can be induced by vascular abnormalities. These alterations emerging in the brain jointly disrupt sleep spindles and slow waves, leading to sleep disturbances. Age-related dysregulation in neurotransmitters (including galanin, orexin, serotonin, and adenosine) directly impairs the sleep modulation system. Disorganization in the circadian system consisting of suprachiasmatic nucleus dysfunction, reduced light transmission, and local circadian clock disruption collectively interrupts circadian rhythms, also causing sleep disturbances in the older. Of note is the bidirectional relationship between aging and sleep, which required us to examine this issue from different perspectives.

Apoptosis in the aging liver.

Various changes in the liver during aging can reduce hepatic function and promote liver injury. Aging is associated with high morbidity and a poor prognosis in patients with various liver diseases, including nonalcoholic fatty liver disease, hepatitis C and liver cancer, as well as with surgeries such as partial hepatectomy and liver transplantation. In addition, apoptosis increases with liver aging. Because apoptosis is involved in regeneration, fibrosis and cancer prevention during liver aging, and restoration of the appropriate level of apoptosis can alleviate the adverse effects of liver aging, it is important to understand the mechanisms underlying this process. Herein, we elaborate on the causes of apoptosis during liver aging, with a focus on oxidative stress, genomic instability, lipotoxicity, endoplasmic reticulum stress, dysregulation of nutrient sensing, and liver stem/progenitor cell activity.

Aliskiren ameliorates pressure overload-induced heart hypertrophy and fibrosis in mice.

AIM: Aliskiren (ALK) is a renin inhibitor that has been used in the treatment of hypertension. The aim of this study was to determine whether ALK could ameliorate pressure overload-induced heart hypertrophy and fibrosis, and to elucidate the mechanisms of action. METHODS: Transverse aortic constriction (TAC) was performed in mice to induce heart pressure overload. ALK (150 mg·kg(-1)·d(-1), po), the autophagy inhibitor 3-methyladenine (10 mg·kg(-1) per week, ip) or the PKCßI inhibitor LY333531 (1 mg·kg(-1)·d-(1), po) was administered to the mice for 4 weeks. Heart hypertrophy, fibrosis and function were evaluated based on echocardiography, histological and biochemical measurements. Mechanically stretched cardiomyocytes of rats were used for in vitro experiments. The levels of signaling proteins were measured using Western blotting, while the expression of the relevant genes was analyzed using real-time QRT-PCR. RESULTS: TAC induced marked heart hypertrophy and fibrosis, accompanied by high levels of Ang II in plasma and heart, and by PKCßI/α and ERK1/2 phosphorylation in heart. Meanwhile, TAC induced autophagic responses in heart, i.e. increases in autophagic structures, expression of Atg5 and Atg16 L1 mRNAs and LC3-II and Beclin-1 proteins. These pathological alterations in TAC-mice were significantly ameliorated or blocked by ALK administration. In TAC-mice, 3-methyladenine administration also ameliorated heart hypertrophy, fibrosis and dysfunction, while LY333531 administration inhibited ERK phosphorylation and autophagy in heart. In mechanically stretched cardiomyocytes, CGP53353 (a PKCßI inhibitor) prevented ERK phosphorylation and autophagic responses, while U0126 (an ERK inhibitor) blocked autophagic responses. CONCLUSION: ALK ameliorates heart hypertrophy, fibrosis and dysfunction in the mouse model in setting of chronic pressure overload, via suppressing Ang II-PKCßI-ERK1/2-regulated autophagy.

RacA and Cdc42 regulate polarized growth and microsclerotium formation in the dimorphic fungus Nomuraea rileyi.

Small GTPases, RacA and Cdc42, act as molecular switches in fungi, regulating cell signaling, cytoskeletal organization, polar growth and reactive oxygen species (ROS) generation, the latter by influencing the activity of the NADPH oxidase complex. In this study, the racA and cdc42 genes from Nomuraea rileyi were cloned and shown to encode 218 and 184 amino acid proteins, respectively. To determine the functions of racA and cdc42, gene-silencing mutants (racARM, cdc42RM and racA&cdc42RM, respectively) were generated using RNA silencing technology. In racARM and cdc42RM, the conidial and microsclerotium (MS) yields, ROS production and virulence were reduced, the hyphal extension rate was decreased and the dimorphic switch was delayed. On the other hand, the double-silencing mutants showed growth retardation and virtually no conidia, MS or ROS production. The transcription levels of the noxA and noxR genes that regulate ROS generation were reduced in the three RNAi-silenced strains. Interestingly, when compared with the controls, racARM exhibited thicker hyphae and bigger conidia; moreover, the MS produced by racARM were bigger than those of the control and smaller than those of cdc42RM. Thus RacA and Cdc42 appear to share some essential functions in N. rileyi, including hyphal growth, conidiation, MS formation, ROS generation and virulence. Yet RacA appears to play a more pivotal role in the polar growth of N. rileyi.

Development of novel 5-fluorouracil carrier erythrocyte with pharmacokinetics and potent antitumor activity in mice bearing malignant ascites.

BACKGROUND: To investigate pharmacokinetics and potency of antitumor activity of a novel 5-fluorouracil carrier erythrocyte (RBC-FU) in mice bearing malignant ascites. METHODS: RBC-FU was synthesized with a hyperosmotic technique. The entrapment efficiency of targeted carrier erythrocytes was determined by reverse dialysis method with high-performance liquid chromatography (HPLC) for analyzing the quantity of 5-fluorouracil (5-FU). After a H22 hepatocarcinoma malignant ascites model was established in Kunming mice, 5-FU encapsulated by carrier erythrocytes (for Group A) and 5-FU solution (for Group B) at 20 mg per kg were injected into the peritoneal cavity of the mice, respectively. Blood and ascites samples were collected at different times to detect 5-FU quantity by HPLC. Body weight and survival time of mice were recorded in Group A, B and the Control Group in which mice were injected with normal saline only. RESULTS: 5-FU was effectively encapsulated into erythrocytes, with an encapsulating effect as 55 +/- 0.50%. In Group A, the maximum concentration (Cmax) and the area under curve (AUC) in peritoneal exudates were significantly higher than those of Group B (P < 0.05). On the other hand, 5-FU level in serum was significantly lower than that in peritoneal exudates of Group A and B (P < 0.05). High drug levels in the abdominal cavity in Group A were maintained longer than those in Group B. Compared with that in Group B and the control, the quantity of malignant ascites in Group A had significant regression and the survival time was prolonged. CONCLUSION: The hyperosmotic method described here could be suitable for producing this novel RBC-FU as a liposomal drug of potential value for treating malignant ascites by intraperitoneal administration.

Gene therapy with the angiogenesis inhibitor endostatin in an orthotopic lung cancer murine model.

Angiogenesis plays an important role in the growth of solid tumors. To date, no information has been acquired on the effectiveness of gene therapy in the orthotopic lung cancer model of syngeneic immunocompetent mice treated with an angiogenesis inhibitor. Here, we report the establishment of such a model in which Lewis lung carcinoma (LL/2) cell suspensions were orthotopically inoculated into the lung parenchyma of C57BL/6 mice, which were also injected with a recombinant adenoviral vector delivering the human endostatin gene (Ad-hE). We found that orthotopic implantation of LL/2 cells into the lung parenchyma produced a solitary tumor nodule in the lung followed by remote mediastinal lymph node metastasis. Conditioned medium from Ad-hE-transfected LL/2 cells apparently inhibited proliferation of human umbilical vein endothelial cells (HUVECs). The level of endostatin protein in serum could be identified by enzyme-linked immunosorbent assay. Treatment with Ad-hE resulted in inhibition of tumor growth and prolongation of survival time of tumor-bearing mice. Immunohistochemical analysis revealed that intratumoral angiogenesis was significantly suppressed. Furthermore, the finding of angiogenesis inhibition was also supported by measuring the number of circulating endothelial cells (CECs). Apoptotic cells were found to be increased within tumor tissues from mice treated with Ad-hE. In addition, treatment with Ad-hE combined with cis-diamminedichloroplatinum(II) (cisplatin) enhanced antitumor activity. These observations provide further evidence of the antitumor effect of endostatin gene therapy, and may be of importance for further exploration of potential application of this combined approach in the treatment of human lung cancer as well as other solid tumors.