Treatment-free remission after discontinuation of tyrosine kinase inhibitors in patients with chronic myeloid leukemia in the chronic phase: a systematic review and meta-analysis.

BACKGROUND: Treatment-free remission (TFR) is a new long-term goal for treating selected patients with chronic myeloid leukemia in the chronic phase (CML-CP). Still, the appropriate group in which TFR can be attempted and the factors influencing it have not yet been identified. This meta-analysis aimed to explore TFR in CML-CP patients who achieved a deep molecular response (DMR) before Tyrosine kinase inhibitors (TKIs) discontinuation and to explore possible factors influencing TFR and the safety of discontinuation. METHODS: We performed a systematic review and single-arm meta-analysis with a systematic search of published literature up to September 2023 in PubMed, Embase, Web of Science, Cochrane Library, and CNKI databases. The assessment was performed using the MINORS scale. Random-effects models were used to calculate outcome metrics, including overall mean TFR rates at 12 and 24 months and subgroup differences. Data synthesis and analysis were done by Stata17.0 software. RESULTS: A total of 19 single-arm trials involving 2336 patients were included in this meta-analysis, with an overall mean TFR rate of 59% [95CI:0.56-0.63] at 12 months and 55% [95CI:0.52-0.59] at 24 months, and no CML-related deteriorations or deaths reported during the TFR period. Our subgroup analysis showed that better TFR was associated with prior interferon therapy (P = 0.003), and molecular response depth MR5.0 (P = 0.020). CONCLUSION: Our study demonstrated that prior interferon therapy and attainment of a molecular response depth of MR5.0 or greater were associated with higher TFR rates, with patients who attained MR5.0 or greater achieving a TFR rate of up to 62% in the second year after TKI discontinuation. Considering the high heterogeneity of the included trials, the above influences still require further validation and more detailed subgroup analysis in future discontinuation trials. SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/ (Registration No. CRD42023471334).

Cerebellar transcranial magnetic stimulation for improving balance capacity and activity of daily living in stroke patients: a systematic review and meta-analysis.

BACKGROUND: The application of cerebellar transcranial magnetic stimulation (TMS) in stroke patients has received increasing attention due to its neuromodulation mechanisms. However, studies on the effect and safety of cerebellar TMS to improve balance capacity and activity of daily living (ADL) for stroke patients are limited. This systematic review and meta-analysis aimed to investigate the effect and safety of cerebellar TMS on balance capacity and ADL in stroke patients. METHOD: A systematic search of seven electronic databases (PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure, Wanfang and Chinese Scientific Journal) were conducted from their inception to October 20, 2023. The randomized controlled trials (RCTs) of cerebellar TMS on balance capacity and/or ADL in stroke patients were enrolled. The quality of included studies were assessed by Physiotherapy Evidence Database (PEDro) scale. RESULTS: A total of 13 studies involving 542 participants were eligible. The pooled results from 8 studies with 357 participants showed that cerebellar TMS could significantly improve the post-intervention Berg balance scale (BBS) score (MD = 4.24, 95%CI = 2.19 to 6.29, P < 0.00001; heterogeneity, I2 = 74%, P = 0.0003). The pooled results from 4 studies with 173 participants showed that cerebellar TMS could significantly improve the post-intervention Time Up and Go (TUG) (MD=-1.51, 95%CI=-2.8 to -0.22, P = 0.02; heterogeneity, I2 = 0%, P = 0.41). The pooled results from 6 studies with 280 participants showed that cerebellar TMS could significantly improve the post-intervention ADL (MD = 7.75, 95%CI = 4.33 to 11.17, P < 0.00001; heterogeneity, I2 = 56%, P = 0.04). The subgroup analysis showed that cerebellar TMS could improve BBS post-intervention and ADL post-intervention for both subacute and chronic stage stroke patients. Cerebellar high frequency TMS could improve BBS post-intervention and ADL post-intervention. Cerebellar TMS could still improve BBS post-intervention and ADL post-intervention despite of different cerebellar TMS sessions (less and more than 10 TMS sessions), different total cerebellar TMS pulse per week (less and more than 4500 pulse/week), and different cerebellar TMS modes (repetitive TMS and Theta Burst Stimulation). None of the studies reported severe adverse events except mild side effects in three studies. CONCLUSIONS: Cerebellar TMS is an effective and safe technique for improving balance capacity and ADL in stroke patients. Further larger-sample, higher-quality, and longer follow-up RCTs are needed to explore the more reliable evidence of cerebellar TMS in the balance capacity and ADL, and clarify potential mechanisms.

The correlation between lung ultrasound scores and outcomes of high-flow nasal cannula therapy in infants with severe pneumonia.

OBJECTIVE: The study aimed to explore the effectiveness of bedside lung ultrasound (LUS) combined with the PaO2/FiO2 (P/F) ratio in evaluating the outcomes of high-flow nasal cannula (HFNC) therapy in infants with severe pneumonia. METHODS: This retrospective study analyzed the clinical data of 150 infants diagnosed with severe pneumonia and treated with HFNC therapy at our hospital from January 2021 to December 2021. These patients were divided into two groups based on their treatment outcomes: the HFNC success group (n = 112) and the HFNC failure group (n = 38). LUS was utilized to evaluate the patients' lung conditions, and blood gas results were recorded for both groups upon admission and after 12 h of HFNC therapy. RESULTS: At admission, no significant differences were observed between the two groups in terms of age, gender, respiratory rate, partial pressure of oxygen, and partial pressure of carbon dioxide. However, the P/F ratios at admission and after 12 h of HFNC therapy were significantly lower in the HFNC failure group (193.08 ± 49.14, 228.63 ± 80.17, respectively) compared to the HFNC success group (248.51 ± 64.44, 288.93 ± 57.17, respectively) (p < 0.05). Likewise, LUS scores at admission and after 12 h were significantly higher in the failure group (18.42 ± 5.3, 18.03 ± 5.36, respectively) than in the success group (15.09 ± 4.66, 10.71 ± 3.78, respectively) (p < 0.05). Notably, in the success group, both P/F ratios and LUS scores showed significant improvement after 12 h of HFNC therapy, a trend not observed in the failure group. Multivariate regression analysis indicated that lower P/F ratios and higher LUS scores at admission and after 12 h were predictive of a greater risk of HFNC failure. ROC analysis demonstrated that an LUS score > 20.5 at admission predicted HFNC therapy failure with an AUC of 0.695, a sensitivity of 44.7%, and a specificity of 91.1%. A LUS score > 15.5 after 12 h of HFNC therapy had an AUC of 0.874, with 65.8% sensitivity and 89.3% specificity. An admission P/F ratio < 225.5 predicted HFNC therapy failure with an AUC of 0.739, 60.7% sensitivity, and 71.1% specificity, while a P/F ratio < 256.5 after 12 h of HFNC therapy had an AUC of 0.811, 74.1% sensitivity, and 73.7% specificity. CONCLUSION: Decreased LUS scores and increased P/F ratio demonstrate a strong correlation with successful HFNC treatment outcomes in infants with severe pneumonia. These findings may provide valuable support for clinicians in managing such cases.

Patient Versus Physician Perspective in the Management of Chronic Myeloid Leukemia During Treatment with Tyrosine Kinase Inhibitors.

INTRODUCTION: Chronic myeloid leukemia (CML) is a chronic disease with treatment-free remission (TFR) increasingly regarded as a feasible goal of treatment. However, various factors may influence adherence to international guidelines for CML management. This study aimed to compare the reporting of care between patients with CML and their treating doctors. METHODS: Parallel patient and physician online surveys were conducted between September 22, 2021, and March 15, 2022, which focused on the perceptions of 1882 adult patients with CML and 305 physicians regarding tyrosine kinase inhibitor (TKI) treatment options, monitoring and toxicities, TFR, and challenges faced. RESULTS: Among the enrolled patients, 69.9% received first-line imatinib treatment, 18.6% received nilotinib, and 4.7% received dasatinib. Among the patients treated with imatinib, 36.7% switched to other TKIs due to imatinib resistance/intolerance (71.1%), exploration of more potent TKIs to achieve TFR (8.9%), and treating physicians' recommendation (14.0%), with a median duration of initial treatment of 14 months [interquartile range (IQR) 6-36]. Most (91.8%) physicians agreed that the breakpoint cluster region-Abelson 1 (BCR::ABL1) transcript level should be assessed every 3 months, but only 42.7% of individuals committed to 3-monthly testing and only 17.8% strictly followed their treating physicians' recommendation. Half of the patients aimed for TFR; however, just 45.2% of physicians considered TFR as one of the top three goals for their patients. The major concern in obtaining TFR was patients' adherence. Fatigue was often distressing for patients with TKIs, while physicians were more concerned about platelet and neutrophil counts. A total of 12% and 20.8% of patients reported moderate/severe anxiety and depression, respectively, while only 53.7% of physicians had concerns about their patients' mental health. During the coronavirus disease 2019 (COVID-19) pandemic, 69.2% of patients reported a reduction in their income. Among these patients, 61.8% maintained their current treatment, while 7.3% switched to cheaper alternatives or discontinued treatment, with over 80% of these patients belonging to the low-income group. CONCLUSIONS: Overcoming challenges in patient-physician communication and treatment access is key to improving disease management and quality of life, especially for patients with low income. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT05092048.

Comparative Analysis of High-Flow Nasal Cannula Oxygen Therapy and Invasive Mechanical Ventilation in the Management of Severe Pneumonia: A Retrospective Study.

Background: Severe pneumonia continues to be a prominent cause of hospitalization and global mortality. There is ongoing debate regarding the effectiveness of different oxygen therapy modalities, particularly high-flow nasal cannula (HFNC) oxygen therapy and invasive mechanical ventilation (IMV), in the treatment of severe pneumonia. Objective: This study investigated the risk factors associated with mechanical ventilation in pediatric patients with severe pneumonia. Methods: This retrospective study included a cohort of 240 pediatric patients with severe pneumonia treated at Zhangzhou Hospital, affiliated with Fujian Medical University, from January 2019 to December 2020. Patients were categorized into two groups: the HFNC group and the IMV group. Comparative analysis was performed on general patient information, infection markers, arterial blood gas values, as well as the prevalence of underlying conditions and complications between the two groups. Multivariate logistic regression analysis was employed to identify the risk factors for invasive mechanical ventilation in children with severe pneumonia. Results: Patients in the HFNC group experienced shorter hospitalization durations, and the average age in this group was lower compared to the IMV group (P < .05). Upon admission, respiratory rate and heart rate were higher in the HFNC group compared to the IMV group (P < .05). The IMV group demonstrated higher oxygenation index (OI) and infection markers, while the pH level was lower in the IMV group than in the HFNC group (P < .05). The prevalence of underlying conditions and complications in the IMV group was significantly higher than in the HFNC group (P < .05). Basic conditions such as heart disease, prematurity, heart failure, low OI, toxic encephalopathy, and influenza virus infection were identified as risk factors for IMV. Conclusions: High-flow nasal cannula therapy has shown therapeutic efficacy in pediatric patients with severe pneumonia. However, children with underlying medical conditions may require prompt tracheal intubation and invasive mechanical ventilation.

DAMS-Net: Dual attention and multi-scale information fusion network for 12-lead ECG classification.

Automated 12-lead electrocardiographic (ECG) classification algorithms play an important role in the diagnosis of clinical arrhythmias. Current methods that perform well in the field of automatic ECG classification are usually based on Convolutional Neural Networks (CNN) or Transformer. However, due to the intrinsic locality of convolution operations, CNN can't extract long-dependence between series. On the other side, the Transformer design includes a built-in global self-attention mechanism, but it doesn't pay enough attention to local features. In this paper, we propose DAMS-Net, which combines the advantages of Transformer and CNN, introducing a spatial attention module and a channel attention module using a CNN-Transformer hybrid encoder to adaptively focus on the significant features of global and local parts between space and channels. In addition, our proposal fuses multi-scale information to capture high and low-level semantic information by skip-connections. We evaluate our method on the 2018 Physiological Electrical Signaling Challenge dataset, and our proposal achieves a precision rate of 83.6%, a recall rate of 84.7%, and an F1-score of 0.839. The classification performance is superior to all current single-model methods evaluated in this dataset. The experimental results demonstrate the promising application of our proposed method in 12-lead ECG automatic classification tasks.

Expression and Functional Study of BcWRKY1 in Baphicacanthus cusia (Nees) Bremek.

Baphicacanthus cusia (Nees) Bremek (B. cusia) is an important medicinal plant. Its effective substances including indigo and indirubin are metabolites in indoleacetate metabolic pathway. Based on a previous transcriptome sequencing analysis, a WRKY transcription factor, BcWRKY1, in B. cusia was identified, showing significant correlation with effective substances from B. cusia. In this study, BcWRKY1 was cloned by reverse transcription-polymerase chain reaction (RT-PCR). Further analysis showed that the BcWRKY1 gene was 916 bp in length, containing three exons and two introns. The open reading frame (ORF) of BcWRKY1 was 534 bp in length and encoded a WRKY domain-containing protein with 177 amino acids residues. Subcellular localization showed that BcWRKY1 protein was mainly localized in the nucleus. It could bind to the W-box motif and its role in transcriptional activation was confirmed in yeast. The function of BcWRKY1 was investigated by overexpressing BcWRKY1 in Arabidopsis thaliana. Metabolic profiles in wild type and BcWRKY1-OX1 transgenic Arabidopsis thaliana were analyzed with LC-MS. Results showed that the metabolic profile was significantly changed in BcWRKY1-OX1 transgenic Arabidopsis thaliana compared with wild type. Furthermore, indole-related metabolites were significantly increased in BcWRKY1-OX1 transgenic Arabidopsis thaliana, and the metabolic pathway analysis showed that flavonoid biosynthesis was significantly enriched. Overexpression of BcWRKY1 significantly changed flavonoid and indole metabolism and indole-related metabolites were significantly upregulated. We postulated that the BcWRKY1 transcription factor might be involved in the regulation of effective substances metabolism in B. cusia.

Benzo[a]pyrene inhibits myoblast differentiation through downregulating the Hsp70-MK2-p38MAPK complex.

Cigarette smoking causes skeletal muscle dysfunction and worse prognosis for patients with diverse systemic diseases. Benzo[a]pyrene (BaP), one major constituent that is inhaled during smoking, is particularly known for its ability to impair neurodevelopment, impede reproductivity, or reduce birth weight. Here, we found that BaP exposure led to the inhibition of C2C12 myoblasts differentiation in a dose-dependent manner and reduced the expression of both early and late myogenic differentiation markers. BaP exposure significantly decreased the expression of p38 mitogen-activated protein kinase (p38MAPK), but not AKT, which are both critical during myogenic differentiation. Mechanistically, BaP downregulated the expression levels of MAPK-activated protein kinase 2 (MK2) and heat shock protein 70 (Hsp70), both of which stabilize p38MAPK. Interestingly, treatment of proteasome inhibitor MG132 was able to reverse BaP-induced degradation of Hsp70/ MK2 and p38MAPK in myoblasts, implying BaP-mediated p38MAPK degradation is proteasome-dependent. Overexpression of p38MAPK also rescued the defective differentiation phenotype of C2C12 induced by BaP. Taken together, we suggest that BaP exposure induces MK2/Hsp70/p38MAPK complex degradation in C2C12 myoblasts and impairs myogenic differentiation by proteasomal-dependent mechanisms. As application of the proteasome inhibitor MG132 or overexpression of p38MAPK could reverse impaired differentiation of myoblasts induced by BaP, this may suggest potential related strategies for preventing tobacco-related skeletal muscle diseases or for respiratory rehabilitation.

ROS Signaling-Mediated Novel Biological Targets: Brf1 and RNA Pol III Genes.

Biomolecule metabolism produces ROS (reactive oxygen species) under physiological and pathophysiological conditions. Dietary factors (alcohol) and carcinogens (EGF, DEN, and MNNG) also induce the release of ROS. ROS often causes cell stress and tissue injury, eventually resulting in disorders or diseases of the body through different signaling pathways. Normal metabolism of protein is critically important to maintain cellular function and body health. Brf1 (transcript factor II B-related factor 1) and its target genes, RNA Pol III genes (RNA polymerase III-dependent genes), control the process of protein synthesis. Studies have demonstrated that the deregulation of Brf1 and its target genes is tightly linked to cell proliferation, cell transformation, tumor development, and human cancers, while alcohol, EGF, DEN, and MNNG are able to induce the deregulation of these genes through different signaling pathways. Therefore, it is very important to emphasize the roles of these signaling events mediating the processes of Brf1 and RNA Pol III gene transcription. In the present paper, we mainly summarize our studies on signaling events which mediate the deregulation of these genes in the past dozen years. These studies indicate that Brf1 and RNA Pol III genes are novel biological targets of ROS.

Prevalence of mild cognitive impairment in patients with hypertension: a systematic review and meta-analysis.

Mild cognitive impairment (MCI) is common in patients with hypertension. Prevalence estimates of MCI in hypertensive patients are needed to guide both public health and clinical decision making. A literature search was conducted in four databases, including PubMed, Embase, Cochrane Library, and Web of Science, from their inception to February 2021. The methodological quality assessment used the risk of bias tool. The pooled prevalence of MCI in hypertensive patients was determined by a random-effects model. Heterogeneity was explored using sensitivity analysis, subgroup analysis, and random effects meta-regression. Of 2314 references, 11 studies (47,179 participants) were included in the meta-analysis. The overall pooled prevalence of MCI in patients with hypertension was 30% (95% CI, 25-35), with significant heterogeneity present (I2 = 99.3%, p < 0.001). In subgroup analyses, Asian and European samples had a prevalence of 26% (95% CI, 20-31) and 40% (95% CI, 14-66), respectively; cross-sectional and cohort studies had a prevalence of 28% (95% CI, 24-32) and 38% (95% CI, -5-81); age older than 60 years had a prevalence of 28% (95% CI, 23-33); community-based and clinic-based samples had a prevalence of 17% (95% CI, 15-19) and 42% (95% CI, 23-62); and MCI diagnosis using the MoCA, NIA-AA, MMSE, and Peterson criteria had a prevalence of 64% (95% CI, 59-68), 18% (95% CI, 16-19), 19% (95% CI, 15-23), and 13% (95% CI, 9-17). Meta-regression analysis showed that different MCI diagnostic criteria could be the source of heterogeneity in the pooled results. MCI is common in patients with hypertension, with an overall prevalence of 30%. Earlier cognitive screening and management in hypertensive patients should be advocated.

Mitofusin-2 is a novel anti-angiogenic factor in pancreatic cancer.

BACKGROUND: Aberrant expression of mitofusin-2 (MFN2) has been found to be associated with vascular endothelial growth factor A (VEGFA)-mediated angiogenesis in human umbilical vein endothelial cells (HUVECs). This study aimed to investigate the expression of MFN2 in pancreatic cancer (PC) and the role of MFN2 in vascular endothelial cell growth and angiogenesis. METHODS: Protein and mRNA expression of MFN2 and VEGFA were measured. The CCK-8 assay, tube formation assay, flow cytometry, and transmission electron microscopy were used to examine the effects of MFN2 overexpression on HUVEC growth, angiogenesis, and apoptosis. Western blot and immunocytochemical staining were conducted to measure alterations in cell cycle and apoptosis regulators and vascular endothelial growth factor receptor 2 (VEGFR2), angiopoietin-1 gene (ANGPT1), and tissue inhibitor of metalloproteinase 1 (TIMP1) expression in HUVECs. RESULTS: The results showed that MFN2 levels were significantly decreased in tumor tissues. Contrasting results were observed for VEGFA mRNA levels. MFN2 overexpression inhibited cell growth while promoting the formation of apoptotic bodies in HUVECs. Additionally, MFN2 overexpression enhanced the protein expression of p21 and p27 while attenuating the expression of proliferating cell nuclear antigen, VEGFA, VEGFR2, ANGPT1, and TIPM1 in HUVECs. CONCLUSIONS: In conclusion, MFN2 expression negatively correlates with VEGFA expression in PC and inhibits endothelial cell growth and angiogenesis.

Exploring the Role and Mechanism of pAMPKα-Mediated Dysregulation of Brf1 and RNA Pol III Genes.

TF IIB-related factor 1 (Brf1) is a key transcription factor of RNA polymerase III (Pol III) genes. Our early studies have demonstrated that Brf1 and Pol III genes are epigenetically modulated by histone H3 phosphorylation. Here, we have further investigated the relationship of the abnormal expression of Brf1 with a high level of phosphorylated AMPKα (pAMPKα) and explored the role and molecular mechanism of pAMPKα-mediated dysregulation of Brf1 and Pol III genes in lung cancer. Brf1 is significantly overexpressed in lung cancer cases. The cases with high Brf1 expression display short overall survival times. Elevation of Brf1 expression is accompanied by a high level of pAMPKα. Brf1 and pAMPKα colocalize in nuclei. Further analysis indicates that the carcinogen MNNG induces pAMPKα to upregulate Brf1 expression, resulting in the enhancement of Pol III transcription. In contrast, inhibiting pAMPKα decreases cellular levels of Brf1, resulting in the reduction of Pol III gene transcription to attenuate the rates of cell proliferation and colony formation of lung cancer cells. These outcomes demonstrate that high Brf1 expression reveals a worse prognosis in lung cancer patients. pAMPKα-mediated dysregulation of Brf1 and Pol III genes plays important roles in cell proliferation, colony formation, and tumor development of lung cancer. Brf1 may be a biomarker for establishing the prognosis of lung cancer. It is a new mechanism that pAMPKα mediates dysregulation of Brf1 and Pol III genes to promote lung cancer development.

Study on the anti-infection ability of vancomycin cationic liposome combined with polylactide fracture internal fixator.

A polylactide composite fracture fixator loaded with vancomycin cationic liposome (PLA@VL) was prepared by reverse evaporation method. The method of cationic liposome encapsulating vancomycin could effectively improve antibacterial property and achieve drug sustained release effect, so as to reduce toxicity of antibiotics in vivo. Scanning electron microscope (SEM) was used to observe morphology and Fourier transform infrared spectroscopy (FTIR) was used to detect the composition of the internal fixator. In vitro drug release model, in vitro degradation model and body fluid osteogenesis model were designed in this study. On the other hand, the experiments of inhibition zone and MC3T3-E1 osteoblasts in mice were conducted to explore antibacterial property, cell activity and adhesion of the PLA@VL composite internal fixator. Alkaline phosphatase (ALP) staining method and alizarin red assay were used to detect the osteogenic induction ability of the composite internal fixator. Finally, mice fracture models were established to verify osteogenic and anti-infection abilities of the composite internal fixator in vivo. The results showed that MC3T3-E1 cells had better adhesion and proliferation abilities on the PLA@VL composite internal fixator than on the PLA fixator, which indicated that the PLA@VL composite internal fixator possessed excellent osteogenic and anti-infection abilities both in vivo and in vitro. Therefore, the above experiments showed that the fracture internal fixator combined with vancomycin cationic liposome had better biocompatibility, antibacterial ability and osteogenic ability, which provides a promising anti-infection material for the clinical field of fracture.

Identification of the hub genes and pathways involved in acute myeloid leukemia using bioinformatics analysis.

BACKGROUND: We identified the hub genes and pathways dysregulated in acute myeloid leukemia and the potential molecular mechanisms involved. METHODS: We downloaded the GSE15061 gene expression dataset from the Gene Expression Omnibus database and used weighted gene co-expression network analysis to identify hub genes. Differential expression of the genes was evaluated using the limma package in R software. Subsequently, we built a protein-protein interaction network followed by functional enrichment analysis. Then, the prognostic significance of gene expression was explored in terms of overall survival. Finally, transcription factor-mRNA (ribonucleic acid) and microRNA-mRNA interaction analysis was also explored. RESULTS: We identified 100 differentially expressed hub genes. Functional enrichment analysis indicated that the genes were principally involved in immune system regulation, host defense, and negative regulation of apoptosis and myeloid cell differentiation. We identified 4 hub genes, the expression of which was significantly correlated with overall survival. Finally, 26 key regulators for hub genes and 38 microRNA-mRNA interactions were identified. CONCLUSION: We performed a comprehensive bioinformatics analysis of hub genes potentially involved in acute myeloid leukemia development. Further molecular biological experiments are required to confirm the roles played by these genes.

Role of betaine in inhibiting the induction of RNA Pol III gene transcription and cell growth caused by alcohol.

Alcohol has been classified as carcinogenic to humans by the International Agency for Research on Cancer (IARC). Studies have demonstrated that alcohol intake increases the risk of breast cancer, and alcohol also stimulates breast cancer cell growth. Deregulation of Pol III genes is tightly associated with tumour development. Transcription factor II-B (TFIIB)-related factor 1 (Brf1) is a transcription factor that specifically regulates Pol III gene transcription. Our in vivo and in vitro studies have indicated that alcohol enhances the transcription of Pol III genes to cause an alteration of cellular phenotypes, which is closely related with human breast cancer. Betaine is a vegetable alkaloid and has antitumor functions. Most reports about betaine show that the consumption level of betaine is inversely associated with a risk of breast cancer. Although different mechanisms of betaine against tumour have been investigated, nothing has been reported on the effect of betaine on the deregulation of Brf1 and Pol III genes. In this study, we determine the role of betaine in breast cancer cell growth and colony formation and explore its mechanism. Our results indicate that alcohol increases the rates of growth and colony formation of breast cancer cells, whereas betaine is able to significantly inhibit the effects of alcohol on these cell phenotypes. Betaine decreases the induction of Brf1 expression and Pol III gene transcription caused by ethanol to reduce the rates of cell growth and colony formation. Together, these studies provide novel insights into the role of betaine in alcohol-caused breast cancer cell growth and deregulation of Brf1 and Pol III genes. These results suggest that betaine consumption is able to prevent alcohol-associated human cancer development.

Triptolide induces atrophy of myotubes by triggering IRS-1 degradation and activating the FoxO3 pathway.

Triptolide is an active ingredient isolated from an ancient Chinese herb (Tripterygium wilfordii Hook. f) for inflammatory and immune disorders. It has been shown to inhibit the proliferation of skeletal muscle; however, mechanisms of this effect remain unclear. We used mouse C2C12 myotubes as an in vitro model to investigate the effects of triptolide on skeletal muscle. Triptolide markedly inhibited the expression of myosin heavy chain and upregulated the expression of muscle atrophy-related proteins, leading to atrophy of the myotubes. Triptolide dose-dependently decreased the phosphorylation of Forkhead box O3 (FoxO3) and activated FoxO3 transcription activity, which regulates the expression of muscle atrophy-related proteins. Furthermore, triptolide inhibited the phosphorylation of Akt on the site of S473 and T308, and decreased the phosphorylation of insulin receptor substrate-1 (IRS-1) on the site of S302. In addition, triptolide reduced the protein level, but not mRNA level of IRS-1, whereas other upstream regulators of the Akt signaling pathway were not affected. Finally, a time-course experiment showed that the triptolide-induced degradation of IRS-1 in myotubes occurred 12 h prior to both inhibition of Akt activity and the activation of FoxO3. These data indicate that triptolide triggers IRS-1 degradation to promote FoxO3 activation, which subsequently led to atrophy of myotubes, providing us a potential target to prevent triptolide-induced skeletal muscle atrophy.

The behavioral and neural basis of foreign language effect on risk-taking.

Recent studies show that people exhibit a reduced decision bias in a foreign language relative to their native language. However, the underlying mechanism remains unknown. Using functional magnetic resonance imaging (fMRI) combined with an even-probability gambling task in which gambling feedback was presented in either a native language or a foreign language after each decision, we assessed the neural correlates of language modulated behavioral changes in decision making. In both foreign and native language contexts, participants showed a behavioral pattern resembles the Gambler's fallacy that losing a gamble leads to more betting than winning a gamble. While there was no language difference in gambling, bilateral caudate and amygdala gain signals were exaggerated by foreign language in relative to native language, suggesting that foreign language enhanced neural responses to rewards. Moreover, the individual difference in foreign language-induced Gambler's fallacy-like decision bias was associated with activation in the right amygdala and ventromedial prefrontal cortex, as well as functional connectivity between right amygdala and right putamen/right posterior insula. Our results confirm that outcome processing in emotion-related regions may underlie individual differences in foreign language effects in judgment and decision making.

Correction: Color adaptation induced from linguistic description of color.

[This corrects the article DOI: 10.1371/journal.pone.0173755.].

Role and mechanism of cardiac insulin resistance in occurrence of heart failure caused by myocardial hypertrophy.

Cardiac insulin resistance plays an important role in the development of heart failure, but the underlying mechanisms remain unclear. Here, we found that hypertrophic hearts exhibit normal cardiac glucose oxidation rates, but reduced fatty acid oxidation rates, compared to Sham controls under basal (no insulin) conditions. Furthermore, insulin stimulation attenuated insulin's effects on cardiac substrate utilization, suggesting the development of cardiac insulin resistance. Consistent with insulin resistance, p38-MAPK protein levels were reduced in hypertrophic hearts. By contrast, systemic hyperinsulin-euglycemic clamp indicated normal insulin sensitivity. Finally, electron microscopy revealed severe mitochondrial damage in the hypertrophic myocardium. Our results indicate that that cardiac insulin resistance caused by cardiac hypertrophy is associated with mitochondrial damage and cardiac dysfunction. Moreover, our findings suggest that cardiac insulin resistance is independent of systemic insulin resistance, which is also a risk factor for heart failure.

Chimeric Antigen Receptor-T Cells with 4-1BB Co-Stimulatory Domain Present a Superior Treatment Outcome than Those with CD28 Domain Based on Bioinformatics.

BACKGROUND: The second-generation CD19-chimeric antigen receptor (CAR)-T co-stimulatory domain that is commonly used in clinical practice is CD28 or 4-1BB. Previous studies have shown that the persistence of CAR-T in the 4-1BB co-stimulatory domain appears to be longer. METHODS: The expression profile data of GSE65856 were obtained from GEO database. After data preprocessing, the differentially expressed genes (DEGs) between the mock CAR versus CD19-28z CAR T cells and mock CAR versus CD19-BBz CAR T cells were identified using the limma package. Subsequently, functional enrichment analysis of DEGs was performed using the DAVID tool. Then, the protein-protein international (PPI) network of these DEGs was visualized by Cytoscape, and the miRNA-target gene-disease regulatory networks were predicted using Webgestal. RESULTS: A total of 18 common DEGs, 6 CD19-28z specific DEGs and 206 CD19-BBz specific DEGs were identified. Among CD19-28z specific DEGs, down-regulated PAX5 might be an important node in the PPI network and could be targeted by miR-496. In CD19-BBz group, JUN was a hub node in the PPI network and involved in the regulations of miR520D - early growth response gene 3 (EGR3)-JUN and mi-R489-AT-rich interaction domain 5A (ARID5A)-JUN networks. CONCLUSION: The 4-1BB co-stimulatory domain might play in important role in the treatment of CAR-T via miR-520D-EGR3-JUN and miR489-ARID5A-JUN regulation network, while CD28 had a negative effect on CAR-T treatment.