Role of Cytokines and Chemokines in Alcohol-Induced Tumor Promotion

Excessive chronic alcohol consumption has become a worldwide health problem. The oncogenic effect of chronic alcohol consumption is one of the leading concerns. The mechanisms of alcohol-induced tumorigenesis and tumor progression are largely unknown, although many factors have been implicated in the process. This review discusses the recent progress in this research area with concentration on alcohol-induced dysregulation of cytokines and chemokines. Based on the available evidence, we propose that alcohol promotes tumor progression by the dysregulation of the cytokine/chemokine system. In addition, we discuss specific transcription factors and signaling pathways that are involved in the action of these cytokines/chemokines and the oncogenic effect of alcohol. This review provides novel insight into the mechanisms of alcohol-induced tumor promotion

Estimator: An Effective and Scalable Framework for Transportation Mode Classification over Trajectories

Transportation mode classification, the process of predicting the class labels of moving objects transportation modes, has been widely applied to a variety of real world applications, such as traffic management, urban computing, and behavior study. However, existing studies of transportation mode classification typically extract the explicit features of trajectory data but fail to capture the implicit features that affect the classification performance. In addition, most of the existing studies also prefer to apply RNN-based models to embed trajectories, which is only suitable for classifying small-scale data. To tackle the above challenges, we propose an effective and scalable framework for transportation mode classification over GPS trajectories, abbreviated Estimator. Estimator is established on a developed CNN-TCN architecture, which is capable of leveraging the spatial and temporal hidden features of trajectories to achieve high effectiveness and efficiency. Estimator partitions the entire traffic space into disjointed spatial regions according to traffic conditions, which enhances the scalability significantly and thus enables parallel transportation classification. Extensive experiments using eight public real-life datasets offer evidence that Estimator i) achieves superior model effectiveness (i.e., 99% Accuracy and 0.98 F1-score), which outperforms state-of-the-arts substantially; ii) exhibits prominent model efficiency, and obtains 7-40x speedups up over state-of-the-arts learning-based methods; and iii) shows high model scalability and robustness that enables large-scale classification analytics.Comment: 12 pages, 8 figure

Palmitoylation of the β4-Subunit Regulates Surface Expression of Large Conductance Calcium-activated Potassium Channel Splice Variants

Regulatory β-subunits of large conductance calcium- and voltage-activated potassium (BK) channels play an important role in generating functional diversity and control of cell surface expression of the pore forming α-subunits. However, in contrast to α-subunits, the role of reversible post-translational modification of intracellular residues on β-subunit function is largely unknown. Here we demonstrate that the human β4-subunit is S-acylated (palmitoylated) on a juxtamembrane cysteine residue (Cys-193) in the intracellular C terminus of the regulatory β-subunit. β4-Subunit palmitoylation is important for cell surface expression and endoplasmic reticulum (ER) exit of the β4-subunit alone. Importantly, palmitoylated β4-subunits promote the ER exit and surface expression of the pore-forming α-subunit, whereas β4-subunits that cannot be palmitoylated do not increase ER exit or surface expression of α-subunits. Strikingly, however, this palmitoylation- and β4-dependent enhancement of α-subunit surface expression was only observed in α-subunits that contain a putative trafficking motif (… REVEDEC) at the very C terminus of the α-subunit. Engineering this trafficking motif to other C-terminal α-subunit splice variants results in α-subunits with reduced surface expression that can be rescued by palmitoylated, but not depalmitoylated, β4-subunits. Our data reveal a novel mechanism by which palmitoylated β4-subunit controls surface expression of BK channels through masking of a trafficking motif in the C terminus of the α-subunit. As palmitoylation is dynamic, this mechanism would allow precise control of specific splice variants to the cell surface. Our data provide new insights into how complex interplay between the repertoire of post-transcriptional and post-translational mechanisms controls cell surface expression of BK channels

Alcohol Consumption Promotes Colorectal Carcinoma Metastasis via a CCL5-Induced and AMPK-Pathway-Mediated Activation of Autophagy

There is a definite relationship between alcohol consumption and colorectal cancer (CRC) development. We investigated effect of alcohol consumption on CRC patients’ progression and prognosis by utilizing epidemiological data and found patients with alcohol consumption increased risks of tumor-node-metastasis (TNM), organ metastasis and poorer prognosis. Because their tumor tissues displayed increased expression of C-C chemokine ligand 5 (CCL5), we hypothesized CCL5 might participate in cancer progression in such patients. Ethanol increased the secretion of CCL5 in two CRC cell lines, HT29 and DLD-1. Treatment with CCL5 directly increased migratory ability of these cells, whereas neutralization or knockdown of CCL5 can partially block alcohol-stimulated migration. We further investigated underlying mechanism of CCL5-induced migration. Our results indicated that effects of CCL5 on migration are mediated by the ability of CCL5 to induce autophagy, a cellular process known to be critical for migration. Using high-throughput sequencing and western blotting, we found induction of autophagy by CCL5 takes place via AMPK pathway. Aforementioned ethanol increases CCL5 secretion, CCL5 activates autophagy through AMPK pathway, and autophagy increases migration was confirmed by experiments with autophagy or AMPK inhibitors. To sum up, our study demonstrates that chronic alcohol consumption may promote metastasis of CRC through CCL5-induced autophagy

A novel image integration technology mapping system significantly reduces radiation exposure during ablation for a wide spectrum of tachyarrhythmias in children

ObjectiveRadiofrequency catheter ablation (RFCA) has evolved into an effective and safe technique for the treatment of tachyarrhythmia in children. Concerns about children and involved medical staff being exposed to radiation during the procedure should not be ignored. “Fluoroscopy integrated 3D mapping”, a new 3D non-fluoroscopic navigation system software (CARTO Univu Module) could reduce fluoroscopy during the procedure. However, there are few studies about the use of this new technology on children. In the present study, we analyzed the impact of the CARTO Univu on procedural safety and fluoroscopy in a wide spectrum of tachyarrhythmias as compared with CARTO3 alone.MethodsThe data of children with tachyarrhythmias who underwent RFCA from June 2018 to December 2021 were collected. The CARTO Univu was used for mapping and ablation in 200 cases (C3U group) [boys/girls (105/95), mean age (6.8 ± 3.7 years), mean body weight (29.4 ± 7.9 kg)], and the CARTO3 was used in 200 cases as the control group (C3 group) [male/female (103/97), mean age (7.2 ± 3.9 years), mean body weight (32.3 ± 19.0 kg)]. The arrhythmias were atrioventricular reentrant tachycardia (AVRT, n = 78), atrioventricular node reentrant tachycardia (AVNRT, n = 35), typical atrial flutter (AFL, n = 12), atrial tachycardia (AT, n = 20) and ventricular arrhythmias [VAs, premature ventricular complexes or ventricular tachycardia, n = 55].Results① There was no significant difference in the acute success rate, recurrence rate, and complication rate between the C3 and C3U groups [(94.5% vs. 95.0%); (6.3% vs. 5.3%); and (2.0% vs. 1.5%); P > 0.05]. ② The CARTO Univu reduced radiation exposure: fluoroscopy time: AVRT C3: 8.5 ± 7.2 min vs. C3U: 4.5 ± 2.9 min, P < 0.05; AVNRT C3: 10.7 ± 3.2 min vs. C3U: 4.3 ± 2.6 min, P < 0.05; AT C3: 15.7 ± 8.2 min vs. C3U: 4.5 ± 1.7 min, P < 0.05; AFL C3: 8.7 ± 3.2 min vs. C3U: 3.7 ± 2.7 min, P < 0.05; VAs C3: 7.7 ± 4.2 min vs. C3U: 3.9 ± 2.3 min, P < 0.05. Corresponding to the fluoroscopy time, the fluoroscopy dose was also reduced significantly. ③ In the C3U group, the fluoroscopy during VAs ablation was lower than that of other arrhythmias (P < 0.05).ConclusionThe usage of the “novel image integration technology” CARTO Univu might be safe and effective in RFCA for a wide spectrum of tachyarrhythmias in children, which could significantly reduce fluoroscopy and has a more prominent advantage for VAs ablation

Successful treatment discontinuation in CML patients with full-dose and low-dose TKI: Results from real-world practice

Background: In clinical studies, some patients who achieve deep molecular response (DMR) can successfully discontinue tyrosine kinase inhibitor (TKI). TKI dose reduction is also an important aspect of alleviating adverse effects and improving quality of life. This study aimed to explore the outcome after drug withdrawal in Chinese CML patients.Methods: We conducted a retrospective analysis of the outcome of 190 patients who stopped TKI. 27 patients experienced dose reduction before TKI discontinuation. The median duration of TKI treatment and MR4 before discontinuation was 82 months and 61 months.Results: With median follow-up after stopping TKI treatment of 17 months, the estimated TFR (Treatment Free Remission) were 76.9% (95%CI, 70.2%–82.4%), 68.8% (95%CI, 61.3%–75.2%), and 65.5% (95%CI, 57.4%–72.5%) at 6, 12 and 24 months. For full-dose and low-dose TKI groups, the TFR at 24 months was 66.7% and 55.8% (p = 0.320, log-rank). Most patients (56/57) quickly achieved MMR after restarting TKI treatment. Multivariable analysis showed that patients with TKI resistance had a higher risk of molecular relapse than patients without TKI resistance (p < 0.001).Conclusion: TFR rates were not impaired in patients experiencing dose reduction before TKI discontinuation compared to patients with full-dose TKI. Our data on Chinese population may provide a basis for the safety and feasibility of TKI discontinuation, including discontinuation after dose reduction, in clinical practice