Discovery of the Highly Selective and Potent STAT3 Inhibitor for Pancreatic Cancer Treatment.

Signal transducer and activator of transcription 3 (STAT3) is an attractive cancer therapeutic target. Unfortunately, targeting STAT3 with small molecules has proven to be very challenging, and for full activation of STAT3, the cooperative phosphorylation of both tyrosine 705 (Tyr705) and serine 727 (Ser727) is needed. Further, a selective inhibitor of STAT3 dual phosphorylation has not been developed. Here, we identified a low nanomolar potency and highly selective small-molecule STAT3 inhibitor that simultaneously inhibits both STAT3 Tyr705 and Ser727 phosphorylation. YY002 potently inhibited STAT3-dependent tumor cell growth in vitro and achieved potent suppression of tumor growth and metastasis in vivo. More importantly, YY002 exhibited favorable pharmacokinetics, an acceptable safety profile, and superior antitumor efficacy compared to BBI608 (STAT3 inhibitor that has advanced into phase III trials). For the mechanism, YY002 is selectively bound to the STAT3 Src Homology 2 (SH2) domain over other STAT members, which strongly suppressed STAT3 nuclear and mitochondrial functions in STAT3-dependent cells. Collectively, this study suggests the potential of small-molecule STAT3 inhibitors as possible anticancer therapeutic agents.

Prevalence of coccidia in lagomorphs in China between 1981 and 2023: A systematic review and meta-analysis.

Lagomorpha coccidiosis, caused by coccidia, is a prevalent disease affecting rabbits, hares and pikas. This meta-analysis aimed to estimate the pooled prevalence of coccidia infection in lagomorphs and identify potential risk factors. A systematic search of six databases yielded 102 studies published between 1981 and 2023. The pooled prevalence of Eimeriidae, Sarcocystidae and Cryptosporidiidae in lagomorphs was 76.4%, 6.2% and 3.9%, respectively. Rabbits had the highest prevalence of Eimeriidae (76.8%) and Sarcocystidae (7.4%), while pikas had the highest prevalence of Cryptosporidiidae (6.2%). Juvenile rabbits exhibited the highest prevalence of Eimeriidae (84.6%) and Cryptosporidiidae (9.9%). Northwest China had the highest prevalence of Eimeriidae (87.8%). Over time, the prevalence of Eimeriidae declined (Coefficient: -0.0062; P<0.05), but remained high (65.0%) in the past five years. Our findings highlight the prevalence of Eimeriidae infection in lagomorphs and the need for further research on Sarcocystidae and Cryptosporidiidae infections. We emphasize the importance of developing lagomorpha coccidia vaccines and implementing vaccination schedules for juvenile rabbits to mitigate coccidia infections.

MHD-Net: Memory-aware Hetero-modal Distillation Network for Thymic Epithelial Tumor Typing with Missing Pathology Modality.

Fusing multi-modal radiology and pathology data with complementary information can improve the accuracy of tumor typing. However, collecting pathology data is difficult since it is high-cost and sometimes only obtainable after the surgery, which limits the application of multi-modal methods in diagnosis. To address this problem, we propose comprehensively learning multi-modal radiology-pathology data in training, and only using uni-modal radiology data in testing. Concretely, a Memory-aware Hetero-modal Distillation Network (MHD-Net) is proposed, which can distill well-learned multi-modal knowledge with the assistance of memory from the teacher to the student. In the teacher, to tackle the challenge in hetero-modal feature fusion, we propose a novel spatial-differentiated hetero-modal fusion module (SHFM) that models spatial-specific tumor information correlations across modalities. As only radiology data is accessible to the student, we store pathology features in the proposed contrast-boosted typing memory module (CTMM) that achieves type-wise memory updating and stage-wise contrastive memory boosting to ensure the effectiveness and generalization of memory items. In the student, to improve the cross-modal distillation, we propose a multi-stage memory-aware distillation (MMD) scheme that reads memory-aware pathology features from CTMM to remedy missing modal-specific information. Furthermore, we construct a Radiology-Pathology Thymic Epithelial Tumor (RPTET) dataset containing paired CT and WSI images with annotations. Experiments on the RPTET and CPTAC-LUAD datasets demonstrate that MHD-Net significantly improves tumor typing and outperforms existing multi-modal methods on missing modality situations.

Increased di-(2-ethylhexyl) phthalate exposure poses a differential risk for adult asthma clusters.

BACKGROUND: DEHP, a common plasticizer known for its hormone-disrupting properties, has been associated with asthma. However, a significant proportion of adult asthma cases are "non-atopic", lacking a clear etiology. METHODS: In a case-control study conducted between 2011 and 2015, 365 individuals with current asthma and 235 healthy controls from Kaohsiung City were enrolled. The control group comprised individuals without asthma, Type 2 Diabetes Mellitus (T2DM), hypertension, or other respiratory/allergic conditions. The study leveraged asthma clusters (Clusters A to F) established in a prior investigation. Analysis involved the examination of urinary DEHP metabolites (MEHP and MEHHP), along with the assessment of oxidative stress, sphingolipid metabolites, and inflammatory biomarkers. Statistical analyses encompassed Spearman's rank correlation coefficients, multiple logistic regression, and multinomial logistic regression. RESULTS: Asthma clusters (E, D, C, F, A) exhibited significantly higher ORs of MEHHP exposures compared to the control group. When considering asthma-related comorbidities (T2DM, hypertension, or both), patients without comorbidities demonstrated significantly higher ORs of the sum of primary and secondary metabolites (MEHP + MEHHP) and MEHHP compared to those with asthma comorbidities. A consistent positive correlation between urinary HEL and DEHP metabolites was observed, but a consistent negative correlation between DEHP metabolites and selected cytokines was identified. CONCLUSION: The current study reveals a heightened risk of MEHHP and MEHP + MEHHP exposure in specific asthma subgroups, emphasizing its complex relationship with asthma. The observed negative correlation with cytokines suggests a new avenue for research, warranting robust evidence from epidemiological and animal studies.

MeIS: DNA methylation-based immune response signatures for thyroid nodule diagnostics.

CONTEXT: Accurately distinguishing between benign thyroid nodules (BTNs) and papillary thyroid cancers (PTCs) with current conventional methods poses a significant challenge. OBJECTIVE: We identify DNA methylation markers of immune response-related genes for distinguishing BTNs and PTCs. METHODS: In this study, we analyzed a public reduced representative bisulfite sequencing (RRBS) dataset and revealed distinct methylation patterns associated with immune signals in PTCs and BTNs. Based on these findings, we developed a diagnostic classifier named as the Methylation-based Immune Response Signature (MeIS), which was composed of fifteen DNA methylation markers associated with immune response-related genes. We validated the MeIS's performance in two independent cohorts: ZS's retrospective cohort (50 PTC and 18 BTN surgery-leftover samples) and ZS's preoperative cohort (31 PTC and 30 BTN fine-needle aspiration (FNA) samples). RESULTS: The MeIS classifier demonstrated significant clinical promise, achieving AUCs of 0.96, 0.98, 0.89 and 0.90 in the training set, validation set, ZS's retrospective cohort, and ZS's preoperative cohort, respectively. For the cytologically indeterminate thyroid nodules, in the ZS's retrospective cohort, MeIS exhibited a sensitivity of 91% and a specificity of 82%; in the ZS's preoperative cohort, MeIS achieved a sensitivity of 84% and a specificity of 74%. Additionally, combining MeIS and BRAFV600E detection improved the detecting performance of cytologically indeterminate thyroid nodules, yielding sensitivities of 98% and 87%, and specificities of 82% and 74% in the ZS's retrospective cohort and ZS's preoperative cohort, respectively. CONCLUSIONS: The fifteen markers we identified can be employed to improve the diagnostic of cytologically indeterminate thyroid nodules.

5-Methoxytryptophan enhances the sensitivity of sorafenib on the inhibition of proliferation and metastasis for lung cancer cells.

BACKGROUND: Lung cancer is a leading cause of cancer-related mortality worldwide, and effective therapies are limited. Lung cancer is a leading cause of cancer-related mortality worldwide with limited effective therapy. Sorafenib is a multi-tyrosine kinase inhibitor frequently used to treat numerous types of malignant tumors. However, it has been demonstrated that sorafenib showed moderate antitumor activity and is associated with several side effects in lung cancer, which restricted its clinical application. This study aimed to examine the antitumor effect of the combination treatment of sorafenib and 5-methoxytryptophan (5-MTP) on cell growth and metastasis of Lewis lung carcinoma (LLC) cells. METHOD: The anticancer effect of the combination treatment of sorafenib and 5-MTP was determined through cytotoxicity assay and colony forming assays. The mechanism was elucidated using flow cytometry and western blotting. Wound healing and Transwell assays were conducted to evaluate the impact of the combination treatment on migration and invasion abilities. An in vivo model was employed to analyze the effect of the combination treatment on the tumorigenic ability of LLC cells. RESULT: Our results demonstrated that the sorafenib and 5-MTP combination synergistically reduced viability and proliferation compared to sorafenib or 5-MTP treatment alone. Reduction of cyclin D1 expression was observed in the sorafenib alone or combination treatments, leading to cell cycle arrest. Furthermore, the sorafenib-5-MTP combination significantly increased the inhibitory effect on migration and invasion of LLC cells compared to the single treatments. The combination also significantly downregulated vimentin and MMP9 levels, contributing to the inhibition of metastasis. The reduction of phosphorylated Akt and STAT3 expression may further contribute to the inhibitory effect on proliferation and metastasis. In vivo, the sorafenib-5-MTP combination further reduced tumor growth and metastasis compared to the treatment of sorafenib alone. CONCLUSIONS: In conclusion, our data indicate that 5-MTP sensitizes the antitumor activity of sorafenib in LLC cells in vitro and in vivo, suggesting that sorafenib-5-MTP has the potential to serve as a therapeutic option for patients with lung cancer.

Effect of His Bundle Pacing on Abnormal Myocardial Fatty Acid and Glucose Metabolism Induced by Right Ventricular Pacing.

BACKGROUND: Metabolic disorder is noted for pacing-induced cardiomyopathy. The benefits of His bundle pacing over right ventricular (RV) pacing in preventing pacing-induced cardiomyopathy from a metabolic perspective are yet to be fully understood. METHOD AND RESULTS: Three pig groups were established for this study: sham control, RV pacing (RV pacing for 6 months), and His pacing (RV pacing for 6 months, followed by His bundle pacing for 3 months). Complete atrioventricular block was created in the last 2 groups. Left ventricular function and dyssynchrony were assessed via echocardiography, while proteins linked to metabolism, endoplasmic reticulum stress, and inflammation in left ventricular myocardium were examined. The RV pacing group had significantly more left ventricular mechanical dyssynchrony compared with the other groups. The RV pacing group exhibited triglyceride and diacylglycerol accumulation in cardiomyocytes and higher expression of binding immunoglobulin protein and tumor necrosis factor-α than the other groups. Additionally, the expression of CD36 was activated, while the expression of hormone-sensitive lipase was downregulated in the RV pacing group compared with the His pacing and sham control groups. Furthermore, the expressions of GLUT4 and pyruvate dehydrogenase were higher in the RV pacing group than the sham control and His pacing groups. Notably, the abnormal fatty acid and glucose metabolic pathways in the left ventricular myocardium during RV pacing could be corrected by His bundle pacing. CONCLUSIONS: His bundle pacing can mitigate the abnormal metabolism disorders, endoplasmic reticulum stress, and inflammation induced during RV pacing and may contribute to the superiority of conduction system pacing over RV pacing in reducing heart failure hospitalization.

Efficacy and Safety of Vonoprazan-Amoxicillin Dual Regimen With Varying Dose and Duration for Helicobacter pylori Eradication: A Multicenter, Prospective, Randomized Study.

BACKGROUND & AIMS: Previous studies confirm vonoprazan-amoxicillin effectiveness for Helicobacter pylori. This study aims to investigate vonoprazan with varying amoxicillin dose and duration. METHODS: This multicenter, prospective, randomized controlled, noninferiority trial enrolled patients with treatment naive H pylori infection from 5 clinical centers. Eligible participants were randomly assigned to H-VA-10 (vonoprazan 20 mg twice a day (b.i.d.) + amoxicillin 750 mg 4 times a day, 10 days), L-VA-10 (vonoprazan 20 mg b.i.d. + amoxicillin 1000 mg b.i.d, 10 days), and H-VA-14 (vonoprazan 20 mg b.i.d + amoxicillin 750 mg 4 times a day, 14 days) in a 1:1:1 ratio. The eradication rate was assessed using the 13C-urea breath test at least 28 days after treatment. RESULTS: Of the 623 eligible patients, 516 patients were randomized. In both the intention-to-treat and per-protocol analyses, eradication rates were comparable between H-VA-10 and H-VA-14 groups (86.6% vs 89.5% and 90.9% vs 94.5%, P = .021 and .013 for noninferiority, respectively). However, eradication rates were significantly lower in the L-VA-10 group than the H-VA-14 group (79.7% vs 89.5% and 82.0% vs 94.5%, P = .488 and .759, respectively). Rates of study withdrawal, loss to follow-up, and adverse events were similar across study groups. CONCLUSIONS: H-VA-10 and H-VA-14 regimens provide satisfactory efficacy for H pylori infection, and the L-VA-10 regimen was inferior. CLINICALTRIALS: gov number: NCT05719831.

Regulation of regulatory T cells and tumor-associated macrophages in gastric cancer tumor microenvironment.

INTRODUCTION: Despite advancements in the methods for prevention and early diagnosis of gastric cancer (GC), GC continues to be the fifth in incidence among major cancers and the third most common cause of cancer-related death. The therapeutic effects of surgery and drug treatment are still unsatisfied and show notable differences according to the tumor microenvironment (TME) of GC. METHODS: Through screening Pubmed, Embase, and Web of Science, we identified and summarized the content of recent studies that focus on the investigation of Helicobacter pylori (Hp) infection, regulatory T cells (Tregs), and tumor-associated macrophages (TAMs) in the TME of GC. Furthermore, we searched and outlined the clinical research progress of various targeted drugs in GC treatment including CTLA-4, PD-1\PD-L1, and VEGF/VEGFR. RESULTS: In this review, the findings indicate that Hp infection causes local inflammation and leads to immunosuppressive environment. High Tregs infiltration in the TME of GC is associated with increased induction and recruitment; the exact function of infiltrated Tregs in GC was also affected by phenotypes and immunosuppressive molecules. TAMs promote the development and metastasis of tumors, the induction, recruitment, and function of TAMs in the TME of gastric cancer are also regulated by various factors. CONCLUSION: Discussing the distinct tumor immune microenvironment (TIME) of GC can deepen our understanding on the mechanism of cancer immune evasion, invasion, and metastasis, help us to reduce the incidence of GC, and guide the innovation of new therapeutic targets for GC eventually.

Multi-object distance determination by analysis of CoC variation for dynamic structured light.

A multi-object distance determination method can be achieved by 932 nm structured light with one camera as the data receiver. The structured light generated by a liquid crystal on silicon spatial light modulator (LCoS-SLM) facilitates dynamic image projection on targets. A series of moving light strip images were captured and collected for data analysis. This method lifted the limitation of single-object distance determination and the limitation of the angle requirement between the camera and the light source in the triangulation method. The average error of this method was approximately 3% in the range of 700 mm to 1900 mm away from LCoS-SLM without further optimization. It provides a potential compact design for indoor multi-object distance determination in the future.

Pain Care Disparities and the Use of Virtual Care Among Racial-Ethnic Minority Groups During COVID-19.

BACKGROUND AND OBJECTIVE: COVID-19 led to an unprecedented reliance on virtual modalities to maintain care continuity for patients living with chronic pain. We examined whether there were disparities in virtual specialty pain care for racial-ethnic minority groups during COVID-19. DESIGN AND PARTICIPANTS: This was a retrospective national cohort study with two comparison groups: primary care patients with chronic pain seen immediately prior to COVID-19 (3/1/19-2/29/20) (N = 1,649,053) and a cohort of patients seen in the year prior (3/1/18-2/28-19; n = 1,536,954). MAIN MEASURES: We assessed use of telehealth (telephone or video) specialty pain care, in-person care specialty pain care, and any specialty pain care for both groups at 6 months following cohort inclusion. We used quasi-Poisson regressions to test associations between patient race and ethnicity and receipt of care. KEY RESULTS: Prior to COVID-19, there were Black-White (RR = 0.64, 95% CI [0.62, 0.67]) and Asian-White (RR = 0.63, 95% CI [0.54, 0.75]) disparities in telehealth use, and these lessened during COVID-19 (Black-White: RR = 0.75, 95% CI [0.73, 0.77], Asian-White: RR = 0.81, 95% CI [0.74, 0.89]) but did not disappear. Individuals identifying as American Indian/Alaska Native used telehealth less than White individuals during early COVID-19 (RR = 0.98, 95% CI [0.85, 1.13] to RR = 0.87, 95% CI [0.79, 0.96]). Hispanic/Latinx individuals were less likely than non-Hispanic/Latinx individuals to use telehealth prior to COVID-19 but more likely during early COVID-19 (RR = 0.70, 95% CI [0.66, 0.75] to RR = 1.06, 95% CI [1.02, 1.09]). Disparities in virtual pain care occurred over the backdrop of overall decreased specialty pain care during the early phase of the pandemic (raw decrease of n = 17,481 specialty care encounters overall from pre-COVID to COVID-era), including increased disparities in any VA specialty pain care for Black (RR = 0.81, 95% CI [0.80, 0.83] to RR = 0.79, 95% CI [0.77, 0.80]) and Asian (RR = 0.91, 95% CI [0.86, 0.97] to RR = 0.88, 95% CI [0.82, 0.94]) individuals. CONCLUSIONS: Disparities in virtual specialty pain care were smaller during the early phases of the COVID-19 pandemic than prior to the pandemic but did not disappear entirely, despite the rapid growth in telehealth. Targeted efforts to increase access to specialty pain care need to be concentrated among racial-ethnic minority groups.

Selectively targeting BCL6 using a small molecule inhibitor is a potential therapeutic strategy for ovarian cancer.

Ovarian cancer is one of the tumors with the highest fatality rate among gynecological tumors. The current 5-year survival rate of ovarian cancer is <35%. Therefore, more novel alternative strategies and drugs are needed to treat ovarian cancer. The transcription factor B-cell lymphoma 6 (BCL6) is critically associated with poor prognosis and cisplatin resistance in ovarian cancer treatment. Therefore, BCL6 may be an attractive therapeutic target for ovarian cancer. However, the role of targeting BCL6 in ovarian cancer remains elusive. Here, we developed a novel BCL6 small molecule inhibitor, WK369, which exhibits excellent anti-ovarian cancer bioactivity, induces cell cycle arrest and causes apoptosis. WK369 effectively inhibits the growth and metastasis of ovarian cancer without obvious toxicity in vitro and in vivo. meanwhile, WK369 can prolong the survival of ovarian cancer-bearing mice. It is worth noting that WK369 also has significant anti-tumor effects on cisplatin-resistant ovarian cancer cell lines. Mechanistic studies have shown that WK369 can directly bind to the BCL6-BTB domain and block the interaction between BCL6 and SMRT, leading to the reactivation of p53, ATR and CDKN1A. BCL6-AKT, BCL6-MEK/ERK crosstalk is suppressed. As a first attempt, our study demonstrates that targeting BCL6 may be an effective approach to treat ovarian cancer and that WK369 has the potential to be used as a candidate therapeutic agent for ovarian cancer.

Effect of Ascending Aortic Curvature on Flow in the Sinus and Neo-sinus Following TAVR: A Patient-Specific Study.

Patient-specific aortic geometry and its influence on the flow in the vicinity of Transcatheter Aortic Valve (TAV) has been highlighted in numerous studies using both in silico and in vitro experiments. However, there has not yet been a detailed Particle Image Velocimetry (PIV) experiment conducted to quantify the relationship between the geometry, flow downstream of TAV, and the flow in the sinus and the neo-sinus. We tested six different patient-specific aorta models with a 26-mm SAPIEN 3 valve (Edwards Lifesciences, Irvine, CA, USA) in a left heart simulator with coronary flow. Velocities in all three cusps and circulation downstream of TAV were computed to evaluate the influence of the ascending aorta curvature on the flow field. The in vitro analysis showed that the patient-specific aortic curvature had positive correlation to the circulation in the ascending aorta (p = 0.036) and circulation had negative correlation to the particle washout time in the cusps (p = 0.011). These results showed that distinct vortical flow patterns in the ascending aorta as the main jet impinges on the aortic wall causes a recirculation region that facilitates the flow back into the sinus and the neo-sinus, thus reducing the risk of flow stagnation and washout time.

Traditional Chinese medicine in the treatment of patients with hyperuricemia: A randomized placebo-controlled double-blinded clinical trial.

BACKGROUND: Studies have demonstrated the association of hyperuricemia with hypertension, metabolic syndrome, cardiovascular disease, and chronic renal disease. Although Western medicine presents promising effects for treating hyperuricemia and gout, identifying a safe and effective alternative to traditional Chinese medicine (TCM) for treating hyperuricemia is essential. OBJECTIVE: To evaluate the efficacy and safety of TCM formulas, "Wu-Ling San" and "Yin Chen Wu-Ling San," in patients with hyperuricemia. METHODS: A randomized, double-blinded, placebo-controlled clinical trial in adults with hyperuricemia was conducted. Sixty patients with serum urate level higher than 8 mg/dL were enrolled in the study. Patients were then randomized into three arms: "Wu-Ling San," "Yin Chen Wu-Ling San," and placebo for 4 weeks. Efficacy and safety were evaluated at weeks 2, 4, and 8. Primary and secondary endpoints were set to evaluate the serum urate concentration and related indicators at weeks 2, 4, and 8. RESULTS: No significant differences were observed among the three arms in terms of the serum urate level (<6 mg/dL) at week 4. The serum urate level was lower in the "Yin Chen Wi-Ling" arm at week 8 (8.1 mg/dL vs. 9.1 mg/dL, p = .034). The serum urate levels were significantly different in both the "Wu-Ling San" and "Yin Chen Wu-Ling San" arms from those at the baseline (p < .05). CONCLUSIONS: Two TCM formulas were found to be relatively safe for the short-term treatment of the patients with hyperuricemia. No statistically significant difference was observed in reaching the target-serum urate level <6 mg/dL.

WB518, a novel STAT3 inhibitor, effectively alleviates IMQ and TPA-induced animal psoriasis by inhibiting STAT3 phosphorylation and Keratin 17.

OBJECTIVES: Psoriasis is a prevalent chronic inflammatory skin disease in humans that is characterized by frequent relapses and challenging to cure. WB518 is a novel small molecule compound with an undisclosed structure. Therefore, our study aimed to investigate the therapeutic potential of WB518 in vitro and in vivo for the treatment of psoriasis, specifically targeting the abnormal proliferation, aberrant differentiation of epidermal keratinocytes, and pathogenic inflammatory response. MATERIALS AND METHODS: We employed dual luciferase reporter assay to screen compounds capable of inhibiting STAT3 gene transcription. Flow cytometry was utilized to analyze CD3-positive cells. Protein and mRNA levels were assessed through Western blotting, immunofluorescence, immunohistochemistry, and real-time PCR. Cell viability was measured using the MTS assay, while in vivo models of psoriasis induced by IMQ and TPA were employed to study the anti-psoriasis effect of WB518. RESULTS: WB518 was found to significantly reduce the mRNA and protein levels of Keratin 17 (K17) in HaCaT cells by inhibiting the phosphorylation of STAT3 Tyr705 (Y705). In the IMQ and TPA-induced psoriasis mouse model, WB518 effectively improved scaling, epidermal hyperplasia, and inflammation. WB518 also suppressed the expression of inflammatory cytokines, such as interleukin (IL)-1ß, IL-6, IL-17, and IL-23. Furthermore, WB518 decreased the proportion of CD3-positive cells in the psoriatic skin of mice. CONCLUSIONS: WB518 exhibits promising potential as a treatment candidate for psoriasis.

Screening microRNAs as potential prognostic biomarkers for lung adenocarcinoma.

OBJECTIVE: To screen and identify microRNAs (miRNAs) associated with the prognosis of lung adenocarcinoma (LUAD) using clinical samples and construct a prediction model for the prognosis of LUAD. METHODS: 160 patient samples were used to screen and identify miRNAs associated with the prognosis of LUAD. Differentially expressed miRNAs were analyzed using gene chip technology. The selected miRNAs were validated using samples from the validation sample group. Cox proportional hazards regression was used to construct the model and Kaplan-Meier was used to plot survival curves. Model power was assessed by testing the prognosis of the constructed model using real-time polymerase chain reaction (RT-PCR) data. RESULTS: The data showed that miR-1260b, miR-21-3p and miR-92a-3p were highly expressed in the early recurrence and metastasis group, while miR-2467-3p, miR-4659a-3p, miR-4514, miR-1471 and miR-3621 were lowly expressed. It was further confirmed that miR-21-3p was significantly highly expressed in the early recurrence and metastasis group (p = 0.02). Receiver operating characteristic (ROC) curve results showed cut-off point value of 0.0172, sensitivity of 88.2% and specificity of 100%. The predictive results of the constructed model were in good agreement with the actual prognosis of patients by using the validation sample test (Kappa = 0.426, p < 0.001), with a model sensitivity of 74.4%, a specificity of 68.3%, and an accuracy of 71.3%. CONCLUSION: miRNAs associated with the prognosis of patients with stage I LUAD were screened and validated, and a risk model for predicting the prognosis of patients was constructed. This model has good consistency with the actual prognosis of patients.

Device-related infection and mortality in patients with chronic kidney disease receiving cardiac implantable electronic devices: a propensity score-matched cohort study.

BACKGROUND: Chronic kidney disease (CKD) was reported to be a risk factor of cardiac implantable electronic device (CIED) infection. The application of bundled skin antiseptic preparation before CIED implantation decreased the risk of CIED infection, even in patients undergoing complex procedures. However, the effect of bundled skin antiseptic preparation to prevent CIED infection in patients with CKD was not tested. METHODS: Between July 2012 and December 2019, 1668 patients receiving CIEDs comprised this retrospective cohort study and were categorized into two groups by the diagnosis of CKD: group with CKD (n = 750, 45%) and group without CKD (n = 918, 55%). The primary outcome was clinical CIED infection, including major and minor infection, and the secondary outcomes were cardiovascular mortality and all-cause mortality. Propensity score matching (PSM) was applied to reduce selection bias between the study groups. RESULTS: During a 4-year follow-up period, 30 patients (1.8%) had a CIED infection. After PSM, the incidence of CIED infection was similar between the patients with CKD and without CKD (1.0% vs. 1.8%). The incidences of cardiovascular mortality and all-cause mortality were higher in patients with CKD compared to patients without CKD (6.5% vs. 3.0%, P = 0.009; 22.8% vs. 11.8%, P < 0.001, respectively). CONCLUSION: The incidence of clinical CIED infection in patients with CKD was as lower as in patients without CKD after applying the bundled skin antiseptic preparation strategy. The cumulative incidences of cardiovascular mortality and all-cause mortality were significantly higher in the matched CIED recipients with CKD compared to the matched cohort without CKD.

Left bundle branch pacing preserved left ventricular myocardial work in patients with bradycardia.

Background: Left bundle branch pacing (LBBP) is an emerging physiological pacing modality. Left ventricular (LV) myocardial work (MW) incorporates afterload and LV global longitudinal strain to estimate global and segmental myocardial contractility. However, the effect of LBBP on LV MW remains unknown. This study aimed to evaluate the impact of LBBP on LV MW in patients receiving pacemaker for bradyarrhythmia. Methods: We prospectively enrolled 70 bradycardia patients with normal LV systolic function receiving LBBP (n = 46) and non-selective His-bundle pacing (NS-HBP) (n = 24). For comparative analysis, patients receiving right ventricular pacing (RVP) (n = 16) and control subjects (n = 10) were enrolled. Two-dimensional speckle tracking echocardiography was performed. The LV pressure-strain loop was non-invasively constructed to assess global LV MW. Results: After 6-month follow-up, LBBP group (with >40% ventricular pacing during 6 months) had shorter peak strain dispersion (PSD) compared with RVP group, and higher LV global longitudinal strain compared with RVP group and NS-HBP group, but had no difference in left intraventricular mechanical dyssynchrony, including septal-to-posterior wall motion delay and PSD, compared with NS-HBP group. During ventricular pacing, LBBP group had higher global MW index (GWI) (2,189 ± 527 vs. 1,493 ± 799 mmHg%, P = 0.002), higher global constructive work (GCW) (2,921 ± 771 vs. 2,203 ± 866 mmHg%, P = 0.009), lower global wasted work (GWW) (211 ± 161 vs. 484 ± 281 mmHg%, P < 0.001) and higher global MW efficiency (GWE) (91.4 ± 5.0 vs. 80.9 ± 8.3%, P < 0.001) compared with RVP group, and had lower GWW (211 ± 161 vs. 406 ± 234 mmHg%, P < 0.001) and higher GWE (91.4 ± 5.0 vs. 86.4 ± 8.1%, P < 0.001) compared with NS-HBP group. Conclusions: In this study we found that in patients with mid-term (6-month) high ventricular pacing burden (>40%), LBBP preserved more LV MW compared with NS-HBP and RVP. Further studies are warranted to assess the association between LV MW and long-term clinical outcomes in LBBP with high ventricular pacing burden.

Shielding analysis of the proton therapy facility at China Medical University Hospital: comparison of a simplified approach with Monte Carlo simulations.

This study comprehensively compared two approaches for analyzing the shielding design of the proton therapy facility at China Medical University Hospital. The first approach essentially involved two approximate models: one for estimating the transmitted radiation through thick shields, and one for estimating radiation streaming at locations near a maze entrance. The second approach relied on Monte Carlo simulations for predicting the radiation field in a complex environment. A total of 22 beam loss scenarios were considered, and dose rates at 32 locations around the facility were estimated using the two approaches. The comparison results demonstrated that the simplified approach proposed in this study can yield fairly accurate or conservative estimates for quickly performing shielding design or dose assessment in a real-world proton therapy facility.

Arsenic exposure and lung fibrotic changes-evidence from a longitudinal cohort study and experimental models.

Introduction: Arsenic (As) exposure is associated with lung toxicity and we aim to investigate the effects of arsenic exposure on lung fibrotic changes. Methods: Participants (n= 976) enrolled via a general health survey underwent chest low-dose computed tomography (LDCT), spirometry forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and urinary arsenic examination during 2016 and 2018. Lung fibrotic changes from LDCT were defined. AsLtoL, low arsenic levels in both 2016 and 2018; AsLtoH, low arsenic in 2016 but high levels in 2018; AsHtoL, high arsenic in 2016 but low levels in 2018; AsHtoH, high arsenic levels in both 2016 and 2018. Mice exposed to 0. 0.2mg/L, 2 mg/L, 50 mg/L of sodium arsenite (NaAsO2) through drinking water for 12 weeks and 24 weeks were applied for histological analysis. Cultured lung epithelial cells were exposed to NaAsO2 and the mesenchymal changes were examined. Results: AsHtoH increased the risk (OR= 1.65, 95% CI 1.10, 2.49) of Lung fibrotic positive to positive (reference: Lung fibrotic negative to negative) compared with AsLtoL. Moreover, the predicted mean of FVC and FEV1 in AsHtoH (-0.09 units, 95% CI: -0.27, -0.09; -0.09 units, 95% CI: -0.17, -0.01) and AsLtoH (-0.13 units, 95% CI: -0.30, -0.10; -0.13 units, 95% CI: -0.22, -0.04) was significantly lower than ASLtoL. Significant lung fibrotic changes including the increase of the alveolar septum thickness and collagen fiber deposition were observed upon 2 mg/L NaAsO2 treatment for 12 weeks, and the damage was dose- and time-dependent. In vitro, sodium arsenite treatment promotes the epithelial-mesenchymal transition (EMT)-like changes of the normal human bronchial epithelial cells, including upregulation of several fibrotic and mesenchymal markers (fibronectin, MMP-2, and Snail) and cell migration. Inhibition of reactive oxygen species (ROS) and MMP-2 impaired the arsenic-induced EMT changes. Administration of a flavonoid, apigenin, inhibited EMT in vitro and pulmonary damages in vivo with the reduction of mesenchymal markers. Discussion: we demonstrated that continued exposure to arsenic causes lung fibrosis in humans and mice. Targeting lung epithelial cells EMT is effective on the development of therapeutic strategy. Apigenin is effective in the inhibition of arsenic-induced pulmonary fibrosis and EMT.