Correlation between inflammatory cytokines and the likelihood of developing multiple types of digestive system cancers: A Mendelian randomization study.

OBJECTIVE: Inflammatory cytokines have been linked to digestive system cancers, yet their exact causal connection remains uncertain. Consequently, we conducted a Mendelian randomization (MR) analysis to gauge how inflammatory cytokines are linked to the risk of five prevalent digestive system cancers (DSCs). METHODS: We collected genetic variation data for 41 inflammatory cytokines from genome-wide association studies (GWAS), and the results data for five common diseases from the Finnish database. Our primary analytical approach involved employing the inverse-variance weighted, residual sum (IVW) method, complemented by the MR-Egger method, the weighted median method, simple mode analysis, and weighted mode analysis as supplementary analytical techniques. Furthermore, we conducted multiple sensitivity analyses. RESULTS: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), macrophage colony-stimulating factor (M-CSF), and interleukin (IL)-18 showed a negative association with the risk of hepatocellular carcinoma. Conversely, TRAIL was inversely linked to the risk of gastric cancer, while IL-16 exhibited a positive correlation with gastric cancer risk. Stem cell factor (SCF) acted as a protective factor against pancreatic cancer. For colorectal cancer, IL-7, IL-9, IL-13, and vascular endothelial growth factor (VEGF) were identified as risk factors. Notably, our results did not indicate a significant correlation between inflammatory cytokines and the risk of esophageal cancer. CONCLUSION: Our research unveils potential connections between 41 inflammatory cytokines and the risk of five common DSCs through a MR analysis. These associations offer valuable insights that could aid in the development of diagnostic biomarkers and the identification of novel therapeutic targets for DSCs.

Runx2 silencing sensitized human renal cell carcinoma cells to ABT-737 apoptosis.

The prognostic value of Runt-related transcription factor 2 (Runx2) and its involvement in cell growth and motility have been reported in patients diagnosed with renal cell carcinoma (RCC). Since Runx2 may have the potential to be a target for the purpose of antitumor intervention, there is an urgent need to gain insight into its oncogenic properties. Using human 786-O, Caki-1 and ACHN RCC cells as models, the silencing of cellular Runx2 expression brought about a reduction in cyclin D1 and ß-catenin expression, cell growth and migration without any significant cell death. Runx2-silenced cells turned into apoptosis vulnerable in the presence of ABT-737, a BH3 mimetic Bcl-2 inhibitor. Data from biochemical and molecular studies have revealed a positive correlation between Runx2 expression and Akt phosphorylation, Mcl-1 expression, and fibronectin expression. Results of genetic silencing studies have indicated the potential involvement of Mcl-1 and fibronectin in the decision of RCC cell ABT-737 resistance and sensitivity. The regulatory roles of the PI3K/Akt axis in the expression of Mcl-1 and fibronectin were suggested by means of the results taken from experiments involving pharmacological study of the PI3K/Akt. Since overexpression and prognostic roles of Runx2, activated Akt, Mcl-1, fibronectin, cyclin D1, and ß-catenin have been revealed in RCC, it is important to explore the precise mechanisms underlying Runx2 oncogenic effects. Although the linking details between Runx2 and PI3K/Akt have yet to be identified, our findings suggest that Mcl-1 and fibronectin are downstream effectors of Runx2 via a regulatory axis of the PI3K/Akt and their promotion of cell growth, migration, and ABT-737 resistance in RCC cells.

Para-aortic and pelvic lymphadenectomy in locally advanced cervical cancer with pelvic lymph node metastasis.

OBJECTIVE: This study sought to explore the efficiency of para-aortic and pelvic lymphadenectomy in the treatment of locally advanced cervical cancer (LACC) with pelvic lymph node (PLN) metastasis. METHODS: A total of 171 LACC patients with imaging-confirmed pelvic lymph node metastasis were included in this study. These patients were divided into two groups: the surgical staging group, comprising 58 patients who had received para-aortic and pelvic lymphadenectomy (surgical staging) along with concurrent chemoradiation therapy (CCRT), and the imaging staging group, comprising 113 patients who had received only CCRT. The two groups' progression-free survival (PFS), overall survival (OS) and treatment-related complications were compared. RESULTS: The surgical staging group started radiotherapy 10.2 days (range 9-12 days) later than the imaging staging group. The overall incidence of lymphatic cysts was 9.30%. In the surgical staging group, para-aortic lymph node metastasis was identified in 34.48% (20/58) of patients, while pathology-negative PLN was observed in 12.07% (7/58). Over a median follow-up period of 52 months, no significant differences in PFS and OS rates were found between the two groups (p > 0.05). Subgroup analysis of patients with lymph node diameters of ≥ 1.5 cm revealed a five-year PFS rate of 75.0% and an OS rate of 80.0% in the surgical staging group, compared to 41.5% and 50.1% in the imaging staging group, respectively, showing statistically significant differences (p = 0.022, HR:0.34 [0.13, 0.90] and p = 0.038, HR: 0.34 [0.12,0.94], respectively for PFS and OS). Additionally, in patients with two or more metastatic lymph nodes, the five-year PFS and OS rates were 69.2% and 73.1% in the surgical staging group, versus 41.0% and 48.4% in the imaging staging group, with these differences also being statistically significant (p = 0.025, HR: 0.41[0.19,0.93] and p = 0.046, HR: 0.42[0.18,0.98], respectively). CONCLUSION: Performing surgical staging before CCRT is safe and delivers accurate lymph node details crucial for tailoring radiotherapy. This approach merits further investigation, particularly in women with pelvic lymph nodes measuring 1.5 cm or more in diameter or patients with two or more imaging-positive PLNs.

Novel GSDMD inhibitor GI-Y1 protects heart against pyroptosis and ischemia/reperfusion injury by blocking pyroptotic pore formation.

Activation of gasdermin D (GSDMD) and its concomitant cardiomyocyte pyroptosis are critically involved in multiple cardiac pathological conditions. Pharmacological inhibition or gene knockout of GSDMD could protect cardiomyocyte from pyroptosis and dysfunction. Thus, seeking and developing highly potent GSDMD inhibitors probably provide an attractive strategy for treating diseases targeting GSDMD. Through structure-based virtual screening, pharmacological screening and subsequent pharmacological validations, we preliminarily identified GSDMD inhibitor Y1 (GI-Y1) as a selective GSDMD inhibitor with cardioprotective effects. Mechanistically, GI-Y1 binds to GSDMD and inhibits lipid- binding and pyroptotic pore formation of GSDMD-N by targeting the Arg7 residue. Importantly, we confirmed the cardioprotective effect of GI-Y1 on myocardial I/R injury and cardiac remodeling by targeting GSDMD. More extensively, GI-Y1 also inhibited the mitochondrial binding of GSDMD-N and its concomitant mitochondrial dysfunction. The findings of this study identified a new drug (GI-Y1) for the treatment of cardiac disorders by targeting GSDMD, and provide a new tool compound for pyroptosis research.

Assessment of Right Ventricular-Arterial Coupling by Echocardiography in Patients with Right Ventricular Pressure and Volume Overload.

Background: Right ventricle-pulmonary arterial (RV-PA) coupling is considered the gold standard for assessing right ventricular (RV) function and can be evaluated noninvasively by echocardiography. The ratios of tricuspid annular plane systolic excursion/pulmonary artery systolic pressure (TAPSE/PASP), RV global longitudinal strain (G-RVLS)/PASP, and stroke volume/end-systolic volume (SV/ESV) have been proposed as surrogates of RV-PA coupling. The relationship of these parameters remains incompletely understood in patients with volume and pressure loading conditions. We aimed to compare these parameters and evaluate their relationship with 3D RV data in patients with RV pressure and volume overload. Methods: This study was performed on 110 individuals who underwent 2D and 3D echocardiography. Fifty-four patients had RV volume overload (atrial septal defect (ASD) group), 34 patients had RV pressure overload (pulmonary hypertension (PH) group), and 22 were controls. TAPSE/PASP, G-RVLS/PASP and SV/ESV ratios were calculated. Correlations between parameters of RV-PA coupling and 3D data were assessed using general linear mixed models. Results: Compared with the ASD group, the PH group had lower TAPSE/PASP and G-RVLS/PASP ratios. The SV/ESV ratio had a strong correlation with right ventricle ejection fraction (RVEF) in both ASD and PH patients (r = 0.8703, p < 0.001 and r = 0.9388, p < 0.001, respectively). The G-RVLS/PASP ratio showed a strong or moderately negative relationship with end-diastolic volume (EDV), ESV and SV (r = -0.7768, p = 0.001; r = -0.7327, p = 0.0005 and r = -0.6816, p = 0.0018, respectively) in PH patients. The TAPSE/PASP ratio showed moderately negative correlations with EDV and ESV (r = -0.5712, p = 0.0012 and r = -0.5594, p = 0.0016, respectively) in PH patients. Conclusions: Non-invasive RV-PA coupling parameters derived from echocardiography appear similar, but not identical to profiles in pressure-overloaded and volume-overloaded patients. The correlations between non-invasive RV-PA coupling parameters and 3D data displayed various degrees of correlation.

Precise Regulation of Combustion Characteristics of High-Energy Composite Propellants by Incorporation of CL-20 Crystals Intercalated with Energetic Burn Rate Modifiers.

In this study, a 2D structured triaminoguanidine-glyoxal polymer with a high nitrogen content has been coordinated with metal ions to produce energetic metal complexes (TAGP-Ms) employed as energetic burn rate inhibitors. The metal ions (Ba2+, K+, and Ca2+) are elaborately selected based on their ability of suppressing the burn rate of composite propellants. The CL-20 crystals were intercalated with prepared TAGP-Ms materials via a solvent-antisolvent method for realization of the precise control on burning behaviors of studied propellants. The influence of TAGP-Ms inhibitors on thermal decomposition and combustion characteristics of high-energy composite propellants was evaluated using thermal analysis and a combustion diagnostic method. Results of TGA/DSC-FTIR measurements suggest that the thermal decomposition of CL-20-containing composite propellants was found to be constrained by varied degrees as a result of TAGP-Ms additions, in which the TAGP-K displays a stronger effect on suppressing the thermal decomposition of CL-20 compared with that of other TAGP-Ms. The FTIR spectra indicate that the primary gaseous phase products are composed of N2O, H2O, and CO2 in CL-20 decomposition, as well as by HCl, H2O, NO2, and N2O in the decomposition of AP for all studied composite propellants. The combustion characterizations show that the TAGP-K-containing composite propellant exhibits a significantly reduced rate of heat release but is associated with a higher flame radiation intensity increased by 4.2% compared with that of the reference propellant, which clearly implies that the TAGP-K is capable of suppressing the energy release rate while ensuring the high energetic features of propellants to be well maintained. Moreover, the burn rate pressure exponents are considerably decreased by ∼10% for the TAGP-K-containing propellants in comparison with those of propellants with the typical formulation, which strongly suggests that TGAP-Ms are promising candidates for tuning the combustion behaviors of composite propellants by influencing the decomposition processes of CL-20 and AP collectively.

Stabilization of AlH3 Crystals by the Coating of Hydrophobic PFPE and Resulted Reactivity with Ammonium Perchlorate.

Aluminum hydride (AlH3) is a promising fuel component of solid propellant, but its stabilization is still challenging. Herein, surface functionalization of hydrophobic perfluoropolyether (PFPE) followed by ammonium perchlorate (AP) coating has been implemented. In particular, AlH3@PFPE@xAP (x = 10, 30, 50, or 64.21%) composites (AHFPs) were prepared by a spray-drying technique. The PFPE-functionalized AlH3 with a hydrophobic surface shows an increased water contact angle (WCA) from 51.87° to 113.54°. Compared with pure AlH3, the initial decomposition temperatures of AHFPs were increased by 17 °C, and the decomposition properties of AP in the AHFPs were also enhanced with significantly decreased peak temperature and fairly increased energy output. Moreover, the decomposition induction time of AHFPs-30% was improved by almost 1.82 times that of raw AlH3, which indicates that the coatings of PFPE and AP could improve the stability of AlH3. The maximum flame radiation intensity of AHFPs-30% was 21.6 × 103, which is almost 7.71 times that of pure AlH3 (2.8 × 103).

Cardiac resynchronization therapy for patients with heart failure and nonspecific intraventricular conduction delay.

The efficacy of cardiac resynchronization therapy (CRT) in heart failure patients with left bundle branch block (LBBB) is well established with Class I or IIa recommendation according to 2021 ESC Guidelines on cardiac pacing and CRT, whereas non-LBBB morphology is less recommended. There is insufficient evidence that proves patients with NICD could benefit from CRT. As patients with NICD are characterized by heterogeneity, the effect of CRT on these patients is still controversial. Although the proportion of NICD in the population is lower than that of LBBB patients, it is still worth investigating the effects of CRT on patients with NICD in an era of His-Purkinje conduction system pacing (HPCSP).

α7 nicotinic acetylcholine receptor agonist improved brain injury and impaired glucose metabolism in a rat model of ischemic stroke.

Vagus nerve stimulation through the action of acetylcholine can modulate inflammatory responses and metabolism. α7 Nicotinic Acetylcholine Receptor (α7nAChR) is a key component in the biological functions of acetylcholine. To further explore the health benefits of vagus nerve stimulation, this study aimed to investigate whether α7nAChR agonists offer beneficial effects against poststroke inflammatory and metabolic changes and to identify the underlying mechanisms in a rat model of stroke established by permanent cerebral ischemia. We found evidence showing that pretreatment with α7nAChR agonist, GTS-21, improved poststroke brain infarction size, impaired motor coordination, brain apoptotic caspase 3 activation, dysregulated glucose metabolism, and glutathione reduction. In ischemic cortical tissues and gastrocnemius muscles with GTS-21 pretreatment, macrophages/microglia M1 polarization-associated Tumor Necrosis Factor-α (TNF-α) mRNA, Cluster of Differentiation 68 (CD68) protein, and Inducible Nitric Oxide Synthase (iNOS) protein expression were reduced, while expression of anti-inflammatory cytokine IL-4 mRNA, and levels of M2 polarization-associated CD163 mRNA and protein were increased. In the gastrocnemius muscles, stroke rats showed a reduction in both glutathione content and Akt Serine 473 phosphorylation, as well as an elevation in Insulin Receptor Substrate-1 Serine 307 phosphorylation and Dynamin-Related Protein 1 Serine 616 phosphorylation. GTS-21 reversed poststroke changes in the gastrocnemius muscles. Overall, our findings, provide further evidence supporting the neuroprotective benefits of α7nAChR agonists, and indicate that they may potentially exert anti-inflammatory and metabolic effects peripherally in the skeletal muscle in an acute ischemic stroke animal model.

Investigation of the Relationship between Body Parameters and mAs Using Non-Contact Two-Dimensional Thickness Measurement in Chest Digital Radiography.

The current study aimed to investigate the relationship between body parameters and the current-time product (mAs) in chest digital radiography using a non-contact infrared thickness-measurement sensor. An anthropomorphic chest phantom was first used to understand variations in mAs over multiple positionings during chest radiography when using the automatic exposure control (AEC) technique. In a human study, 929 consecutive male subjects who underwent regular chest examinations were enrolled, and their height (H), weight (W), and body mass index (BMI) were recorded. In addition, their chest thickness (T) was measured at exhalation using a non-contact infrared sensor, and chest radiography was then performed using the AEC technique. Finally, the relationship between four body parameters (T, BMI, T*BMI, and W/H) and mAs was investigated by fitting the body parameters to mAs using three curve models. The phantom study showed that the maximum mAs was 1.76 times higher than the lowest mAs during multiple positionings in chest radiography. In the human study, all chest radiographs passed the routine quality control procedure and had an exposure index between 100 and 212. In curve fitting, the comparisons showed that W/H had a closer relationship with mAs than the other body parameters, while the first-order power model with W/H fitted to mAs performed the best and had an R-square of 0.9971. We concluded that the relationship between W/H and mAs in the first-order power model may be helpful in predicting the optimal mAs and reducing the radiation dose for chest radiography when using the AEC technique.

Outcome and safety of intracardiac echocardiography guided left atrial appendage closure within zero-fluoroscopy atrial fibrillation ablation procedures.

BACKGROUND: Simultaneous atrial fibrillation (AF) catheter ablation and left atrial appendage closure (LAAC) are sometimes recommended for both rhythm control and stroke prevention. However, the advantages of intracardiac echocardiography (ICE) guidance for this combined procedure have been scarcely reported. We aim to evaluate the clinical outcomes and safety of ICE-guided LAAC within a zero-fluoroscopy catheter ablation procedure. METHODS AND RESULTS: From April 2019 to April 2020, 56 patients with symptomatic AF underwent concomitant catheter ablation and LAAC. ICE with a multi-angled imaging protocol mimicking the TEE echo windows was used to guide LAAC. Successful radiofrequency catheter ablation and LAAC were achieved in all patients. Procedure-related adverse event rate was 3.6%. During the 12-month follow-up, 75.0% of patients became free of arrhythmia recurrences and oral anticoagulants were discontinued in 96.4% of patients. No ischemic stroke occurred despite two cases of device-related thrombosis versus an expected stroke rate of 4.8% based on the CHA2 DS2 -VASc score. The overall major bleeding events rate was 1.8%, which represented a relative reduction of 68% versus an expected bleeding rate of 5.7% based on the HAS-BLED score of the patient cohort. The incidence of iatrogenic atrial septal defect secondary to single transseptal access dropped from 57.9% at 2 months to 4.2% at 12 months TEE follow-up. CONCLUSION: The combination of catheter ablation and LAAC under ICE guidance was safe and effective in AF patients with high stroke risk. ICE with our novel protocol was technically feasible for comprehensive and systematic assessment of device implantation.

Conduction system pacing following septal myectomy: Insights into site of conduction block.

INTRODUCTION: Septal myectomy for obstructive hypertrophic cardiomyopathy (HCM) is associated with conduction block; however, the electrophysiological characteristics of conduction block have not been well characterized. The aim of study was to assess the feasibility and safety of His bundle pacing (HBP) and left bundle branch area pacing (LBBAP) in patients with septal myectomy-associated conduction block. METHODS AND RESULTS: Patients with HCM and indications for pacing or cardiac resynchronization therapy after septal myectomy were included. Electrophysiological mapping was performed to identify the site of block. The success rates and pacing characteristics of HBP and LBBAP were also recorded. The echocardiographic data and complications were documented and tracked during follow-up. Ten patients with atrioventricular block (AVB) or left bundle branch block (LBBB) post-myectomy were included in the study. The site of block was infranodal in the nine patients with AVB. HBP failed due to the lack of distal His bundle capture (N = 7) or LBBB correction (N = 3). LBBAP was successful in nine patients and failed in one. QRS duration narrowed from 163.3 ± 16.6 ms after surgery to 123.6 ± 15.8 ms during LBBAP (p < .001). The mean depth of the leads was 13.3 ± 4.0 mm (range from 10 to 20 mm). At a mean follow-up of 5.3 ± 3.9 months, pacing parameters and left ventricular ejection fraction remained stable. CONCLUSIONS: Electrophysiological mapping revealed that the site of block was infra-Hisian and not correctable with HBP in patients with HCM post-myectomy. LBBAP appears to be a more feasible physiological strategy for these patients.

Atrial-His bundle pacing in fulminant myocarditis with ventricular arrhythmia: a case report.

BACKGROUND: Fulminant myocarditis is a clinical syndrome associated with threatening dysrhythmia which temporary pacemaker can be used for life-saving support. As a method of physiological pacing, His bundle pacing (HBP) maintain better cardiac synchronization than traditional right ventricular (RV) pacing. CASE PRESENTATION: It's a severe case of fulminant myocarditis in a 41-year-old patient who presented for recurrent arrhythmias with hemodynamic instability. Temporary His bundle pacing combined with optimal medical therapy and extracorporeal membrane oxygenators (ECMO) supported him through his critical period of hospitalization. CONCLUSIONS: During 1-year follow up, the cardiac function recovery was obvious without any pacing related complications. Echocardiography showed better atrioventricular and intra-ventricular synchronization during HBP in DDD mode. This is the first reported case of temporary His-purkinje conduction system pacing used for severe fulminant myocarditis.

Preliminary experience of permanent left bundle branch area pacing using stylet-directed pacing lead without delivery sheath.

BACKGROUND: Left bundle branch area pacing (LBBAP) aims to capture the cardiac conduction system in area of the left bundle branch. Currently, LBBAP is mainly performed using lumen-less pacing leads (LLLs) with preshaped sheath. However, the data on LBBAP with stylet-driven leads (SDLs) without sheath is limited. OBJECTIVE: This study presents the feasibility, safety, and pacing characteristics of LBBAP using SDLs without the support of sheath. METHODS: A total of 25 patients with bradycardia indications who received LBBAP implantation with an attempt of SDL (FINELINE II 4471 lead, Boston Scientific, MA, US) between August 2020 and April 2021 at Sir Run Run Shaw Hospital were included in this retrospective cohort study. Twenty of them finally were paced with SDL in priority (SDL-LBBAP group). Twenty propensity score matching patients who underwent LBBAP with LLL (Select Secure 3830 lead, Medtronic, MN, US) and 20 right ventricular septal pacing (RVSP) with regular active fixation lead respectively in the same period (the LLL-LBBAP group and RVSP group) were compared using ECG characteristics, pacing parameters and complications during 6-month follow-up. RESULTS: LBBAP was successful with SDL in 23 of 25 patients (92%) and 20 of them were paced with SDL first. In the SDL-LBBAP group, the average age was 70.4 ± 8.2 years, and 55% of patients were male. Paced QRS duration and the stimulus to peak left ventricular activation time (Sti-LVAT) in SDL-LBBAP group were similar with those in LLL-LBBAP group and significantly shorter than those in RVSP group (126.1±14.1 ms vs. 124.8±10.9 ms, p = 1.00; 77.7 ± 11.2 ms vs. 73.5 ± 9.3 ms, P = .75; 126.1 ± 14.1 ms vs. 147.7 ± 22.5 ms, P<.001; 77.7 ± 11.2 ms vs. 97.0 ± 13.2 ms, P<.001). The pacing threshold and R-wave amplitude of SDL-LBBAP group were 0.53 ± 0.18V and 11.53 ± 3.63 mV at baseline respectively, which were comparable with the other two groups. During the 6-month follow-up, the pacing parameters remained stable and no lead-related complications were recorded. CONCLUSION: It is feasible and safe to use stylet-directed pacing lead for permanent LBBAP without a delivery sheath. Similar to LLL, LBBAP using SDL showed stable parameters and narrower paced QRS duration compared with RVSP, which could be an alternative to LLL in LBBAP.

Anti-diabetic drug canagliflozin hinders skeletal muscle regeneration in mice.

Canagliflozin is an antidiabetic medicine that inhibits sodium-glucose cotransporter 2 (SGLT2) in proximal tubules. Recently, it was reported to have several noncanonical effects other than SGLT2 inhibiting. However, the effects of canagliflozin on skeletal muscle regeneration remain largely unexplored. Thus, in vivo muscle contractile properties recovery in mice ischemic lower limbs following gliflozins treatment was evaluated. The C2C12 myoblast differentiation after gliflozins treatment was also assessed in vitro. As a result, both in vivo and in vitro data indicate that canagliflozin impairs intrinsic myogenic regeneration, thus hindering ischemic limb muscle contractile properties, fatigue resistance recovery, and tissue regeneration. Mitochondrial structure and activity are both disrupted by canagliflozin in myoblasts. Single-cell RNA sequencing of ischemic tibialis anterior reveals a decrease in leucyl-tRNA synthetase 2 (LARS2) in muscle stem cells attributable to canagliflozin. Further investigation explicates the noncanonical function of LARS2, which plays pivotal roles in regulating myoblast differentiation and muscle regeneration by affecting mitochondrial structure and activity. Enhanced expression of LARS2 restores the differentiation of canagliflozin-treated myoblasts, and accelerates ischemic skeletal muscle regeneration in canagliflozin-treated mice. Our data suggest that canagliflozin directly impairs ischemic skeletal muscle recovery in mice by downregulating LARS2 expression in muscle stem cells, and that LARS2 may be a promising therapeutic target for injured skeletal muscle regeneration.

Projecting the impact of implementation of WHO MPOWER measures on smoking prevalence and mortality in Japan.

OBJECTIVE: This study aimed to quantify the long-term impact of implementing the WHO Framework Convention on Tobacco Control (FCTC) compliant tobacco control measures, MPOWER, on smoking prevalence and mortality in men and women aged ≥20 years in Japan. DESIGN: A Stock-and-Flow simulation model was used to project smoking prevalence and mortality from 2018 to 2050 under eight different scenarios: (1) maintaining the 2018 status quo, (2) implementation of smoke-free policies, (3) tobacco use cessation programmes, (4-5) health warning about the dangers of tobacco (labels, mass media), (6) enforcement of tobacco advertising bans or (7) tobacco taxation at the highest recommended level and (8) all these interventions combined. RESULTS: Under the status quo, the smoking prevalence in Japan will decrease from 29.6% to 15.5% in men and 8.3% to 4.7% in women by 2050. Full implementation of MPOWER will accelerate this trend, dropping the prevalence to 10.6% in men and 3.2% in women, and save nearly a quarter million deaths by 2050. This reduction implies that Japan will only attain the current national target of 12% overall smoking prevalence in 2033, 8 years earlier than it would with the status quo (in 2041), a significant delay from the national government's 2022 deadline. CONCLUSIONS: To bring forward the elimination of tobacco smoking and substantially reduce smoking-related deaths, the government of Japan should fulfil its commitment to the FCTC and adopt stringent tobacco control measures delineated by MPOWER and beyond.

Population pharmacokinetics of ciclosporin in allogeneic hematopoietic stem cell transplant recipients: C-reactive protein as a novel covariate for clearance.

WHAT IS KNOWN AND OBJECTIVES: Ciclosporin (CsA), a potent immunosuppressive agent used to prevent graft-versus-host disease in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients, is characterized by large inter-individual variability and a narrow therapeutic range. The aim of this study was to develop a population pharmacokinetic model for CsA in Chinese allo-HSCT recipients and to identify covariates influencing CsA pharmacokinetics. METHODS: A total of 758 retrospective drug monitoring data points were collected after intravenous infusion or oral administration of CsA from 59 patients. Population pharmacokinetic analysis was performed using nonlinear mixed effects modelling expressed by differential equations. Monte Carlo simulation was applied to optimize dosage regimens. The final model was validated using bootstrap and normalized prediction distribution errors. RESULTS AND DISCUSSION: The results showed that the daily CsA dose, haematocrit, total bile acid, C-reactive protein (CRP) and co-administration of triazole antifungal agent were identified as significant covariates for clearance (CL) of CsA. The typical value of CL was 19.8 L/h with an inter-individual variability of 13.1%. The volume of distribution was 1340 L. Bioavailability was 67.2% with an inter-individual variability of 8.5%. Dosing simulation based on the developed model indicated that patients with high CRP concentration required a higher daily dose to attain the therapeutic trough concentration. The influence of CRP ultimately on the therapy outcome of CsA is not clear, which needs further study. WHAT IS NEW AND CONCLUSION: CRP concentration was identified as a novel marker associated with CsA pharmacokinetics, which should be considered when determining the appropriate dosage of CsA in allo-HSCT recipients.

Rapid, Label-Free Prediction of Antibiotic Resistance in Salmonella typhimurium by Surface-Enhanced Raman Spectroscopy.

The rapid identification of bacterial antibiotic susceptibility is pivotal to the rational administration of antibacterial drugs. In this study, cefotaxime (CTX)-derived resistance in Salmonella typhimurium (abbr. CTXr-S. typhimurium) during 3 months of exposure was rapidly recorded using a portable Raman spectrometer. The molecular changes that occurred in the drug-resistant strains were sensitively monitored in whole cells by label-free surface-enhanced Raman scattering (SERS). Various degrees of resistant strains could be accurately discriminated by applying multivariate statistical analyses to bacterial SERS profiles. Minimum inhibitory concentration (MIC) values showed a positive linear correlation with the relative Raman intensities of I990/I1348, and the R2 reached 0.9962. The SERS results were consistent with the data obtained by MIC assays, mutant prevention concentration (MPC) determinations, and Kirby-Bauer antibiotic susceptibility tests (K-B tests). This preliminary proof-of-concept study indicates the high potential of the SERS method to supplement the time-consuming conventional method and help alleviate the challenges of antibiotic resistance in clinical therapy.

Endoplasmic Reticulum Stress Contributed to Dipyridamole-Induced Impaired Autophagic Flux and Glioma Apoptosis.

Elevation of intracellular cAMP levels has been implicated in glioma cell proliferation inhibition, differentiation, and apoptosis. Inhibition of phosphodiesterase is a way to elevate intracellular cAMP levels. The present study aimed to investigate the anti-glioma potential of dipyridamole, an inhibitor of phosphodiesterase. Upon treatment with dipyridamole, human U87 glioma cells decreased cell viability, clonogenic colonization, migration, and invasion, along with Noxa upregulation, Endoplasmic Reticulum (ER) stress, impaired autophagic flux, Yes-associated Protein 1 (YAP1) phosphorylation, and YAP1 reduction. Pharmacological and genetic studies revealed the ability of dipyridamole to initiate Noxa-guided apoptosis through ER stress. Additionally, the current study further identified the biochemical role of YAP1 in communicating with ER stress and autophagy under situations of dipyridamole treatment. YAP1 promoted autophagy and protected glioma cells from dipyridamole-induced apoptotic cell death. Dipyridamole impaired autophagic flux and rendered glioma cells more vulnerable to apoptotic cell death through ER stress-inhibitable YAP1/autophagy axis. The overall cellular changes caused by dipyridamole appeared to ensure a successful completion of apoptosis. Dipyridamole also duplicated the biochemical changes and apoptosis in glioma T98G cells. Since dipyridamole has additional biochemical and pharmacological properties, further research centered on the anti-glioma mechanisms of dipyridamole is still needed.

Metformin Mitigated Obesity-Driven Cancer Aggressiveness in Tumor-Bearing Mice.

Metformin may offer benefits to certain cancer populations experiencing metabolic abnormalities. To extend the anticancer studies of metformin, a tumor model was established through the implantation of murine Lewis Lung Carcinoma (LLC) cells to Normal Diet (ND)-fed and High-Fat Diet (HFD)-fed C57BL/6 mice. The HFD-fed mice displayed metabolic and pro-inflammatory alterations together with accompanying aggressive tumor growth. Metformin mitigated tumor growth in HFD-fed mice, paralleled by reductions in circulating glucose, insulin, soluble P-selectin, TGF-ß1 and High Mobility Group Box-1 (HMGB1), as well as tumor expression of cell proliferation, aerobic glycolysis, glutaminolysis, platelets and neutrophils molecules. The suppressive effects of metformin on cell proliferation, migration and oncogenic signaling molecules were confirmed in cell study. Moreover, tumor-bearing HFD-fed mice had higher contents of circulating and tumor immunopositivity of Neutrophil Extracellular Traps (NETs)-associated molecules, with a suppressive effect from metformin. Data taken from neutrophil studies confirmed the inhibitory effect that metformin has on NET formation induced by HMGB1. Furthermore, HMGB1 was identified as a promoting molecule to boost the transition process towards NETs. The current study shows that metabolic, pro-inflammatory and NET alterations appear to play roles in the obesity-driven aggressiveness of cancer, while also representing candidate targets for anticancer potential of metformin.