The Impact of Close Proximity of Left Atrium to Descending Aorta on Left Inferior Pulmonary Vein Triggers or Drivers of Atrial Fibrillation: A Risk Score Model.

BACKGROUND: Prior studies have investigated cardiac anatomy and clinical parameters as predictors for pulmonary vein and non-pulmonary vein triggers. OBJECTIVES: To assess the link between the descending aorta to left inferior pulmonary vein (Dao-LIPV) distance and the occurrence of triggers and drivers in atrial fibrillation (AF) ablation procedures. METHODS: Drug-refractory AF patients who underwent first-time index catheter ablation from January 2010 to December 2019 were retrospectively assembled. The Dao-LIPV distance was measured from pre-ablation pulmonary vein computed tomography. Patients were categorized based on the presence of LIPV triggers and/or drivers. Multivariate logistic regression was used to identify risk factors. RESULTS: A total of 886 consecutive patients with drug-refractory AF were studied, and 63 (7.1%) patients were identified to have LIPV triggers and/or drivers. The Dao-LIPV distance had a better predictive performance (AUC: 0.70) compared to persistent AF (AUC: 0.57). Multivariate logistic regression analysis showed that Dao-LIPV distance ≤ 2.5 mm (Odds ratio [OR] 3.96 [95% CI 2.15-7.29], p <0.001) and persistent AF (OR 1.73 [95% CI 1.02-2.94], p=0.044) were independent predictors for the presence of LIPV triggers and/or drivers. A risk score model was established to predict the probability of LIPV triggers or drivers with persistent AF (10.2%), Dao-LIPV distance ≤ 2.5mm (11.4%), and both (15.0%). CONCLUSIONS: The close proximity of the Dao-LIPV was correlated to the presence of LIPV triggers or drivers. We developed a risk score model indicating that persistent AF and Dao-LIPV distances ≤ 2.5mm significantly increase the risk of LIPV triggers/drivers, aiding electrophysiologists in preparing for and performing catheter ablation more effectively.

Thyroid Cancer Incidence Among Korean Individuals: A Comparison of South Korea and the United States.

OBJECTIVE: To compare thyroid cancer incidence rates and trends between Korean, non-Korean Asian, and non-Hispanic White populations in the United States, and between the US Korean population and the South Korean population. METHOD: Population-based analysis of cancer incidence data. Cases of thyroid cancer diagnosed during 1999-2014 from the Korean Central Cancer Registry (KCCR) and the Surveillance, Epidemiology, and End Results (SEER) 9 detailed Asian/Pacific Islander subgroup incidence and population dataset were included. Incidence rates were obtained from the datasets, and annual percent change (APC) of the incidence rates was calculated using Joinpoint regression analysis. RESULTS: Thyroid cancer incidence rate for 1999-2014 was significantly higher for South Korea (48.05 [95% CI 47.89-48.22] per 100,000 person-years) than for the US Korean population (11.12 [95% CI 10.49-11.78] per 100,000 person-years), which was slightly higher than the Non-Korean Asian population (10.23 [95% CI 10.02-10.43] per 100,000 person-years), and slightly lower than the Non-Hispanic White population (12.78 [95% CI 12.69-12.87] per 100,000 person-years). Incidence rates in South Korea increased dramatically (average APC 17.9, 95% CI 16.0-19.9), significantly higher than the US Korean population (average APC 5.0, 95% CI 3.1-6.8), which was similar to the non-Korean Asian (average APC 2.5, 95% CI 0.9-4.2) and the non-Hispanic White (average APC 5.1, 95% CI 4.7-5.6) populations. CONCLUSIONS: South Korea's high thyroid cancer incidence rates cannot be attributed to genetic factors, but are likely due to health care system factors. LEVEL OF EVIDENCE: 3 Laryngoscope, 2024.

Signal-averaged electrocardiography as a noninvasive tool for evaluating the ventricular substrate in patients with nonischemic cardiomyopathy: reassessment of an old tool.

Introduction: Signal-averaged electrocardiography (SAECG) provides diagnostic and prognostic information regarding cardiac diseases. However, its value in other nonischemic cardiomyopathies (NICMs) remains unclear. This study aimed to investigate the role of SAECG in patients with NICM. Methods and results: This retrospective study included consecutive patients with NICM who underwent SAECG, biventricular substrate mapping, and ablation for ventricular arrhythmia (VA). Patients with baseline ventricular conduction disturbances were excluded. Patients who fulfilled at least one SAECG criterion were categorized into Group 1, and the other patients were categorized into Group 2. Baseline and ventricular substrate characteristics were compared between the two groups. The study included 58 patients (39 men, mean age 50.4 ± 15.5 years), with 34 and 24 patients in Groups 1 and 2, respectively. Epicardial mapping was performed in eight (23.5%) and six patients (25.0%) in Groups 1 and 2 (p = 0.897), respectively. Patients in Group 1 had a more extensive right ventricular (RV) low-voltage zone (LVZ) and scar area than those in Group 2. Group 1 had a larger epicardial LVZ than Group 2. Epicardial late potentials were more frequent in Group 1 than in Group 2. There were more arrhythmogenic foci within the RV outflow tract in Group 1 than in Group 2. There was no significant difference in long-term VA recurrence. Conclusion: In our NICM population, a positive SAECG was associated with a larger RV endocardial scar, epicardial scar/late potentials, and a higher incidence of arrhythmogenic foci in the RV outflow tract.

Update on Pediatric Thyroid Cancer Incidence and Mortality Trends in the United States, 2000-2018.

Thyroid cancer is the most common endocrine malignancy in the pediatric population. A recent study has revealed a recent decline in overall US thyroid cancer incidence rates. The aim of this study is to assess whether there has been a corresponding decline in incidence rates in the pediatric population. We used the Surveillance, Epidemiology, and End Results (SEER) database to analyze the pediatric thyroid cancer incidence rate. The results demonstrate that the incidence rate of pediatric thyroid cancer continued to increase from 2000 to 2018. Future studies are needed to understand how recent changes in guidelines are affecting incidence rates.

Provider's exposure to diversity contributes to socioeconomic disparities in lumbar and cervical fusion outcomes.

Background: Studies report patient race, income, and education influence spinal fusion outcomes; fewer studies, however, examine the influence of provider factors such as exposure to diversity or cultural sensitivity. Objective: To examine how providers' experience with diverse patient populations affects spinal fusion outcomes. Methods: Retrospective review of 39,680 patients undergoing lumbar and cervical fusions, 2003-2021, in Clinformatics® Data Mart national database. We used the provider patient racial diversity index (pRDI)-a published metric of physician exposure to diverse patients-to divide patients into groups based their provider's category (I, II, III) where patients treated by category III providers had surgeons with the most diverse patient populations. Multivariate regression models on propensity score-matched cohorts examined the association between patient SES and provider category on post-operative outcomes. Results: Black patients had decreased discharge home (OR 0.67; 95% CI 0.54-0.83) compared to white patients. Patients treated by category III providers had increased length of stay (Coeff. 0.62; 95% CI 0.43-0.81), charge (Coeff. 36800; 95% CI 29,200-44,400), and decreased discharge home (OR 0.90; 95% CI 0.83-0.97) compared to patients treated by category I providers. Asian patients treated by category II providers had decreased readmission (OR 0.38; 95% CI 0.14-0.96), and Black patients treated by category III providers had increased discharge home (OR 1.41; 95% CI 1.1-1.9) compared to those treated by category I providers. Conclusion: While our study found two specific instances of improved spine surgery outcomes for minority patients treated by providers serving diverse patient populations, we present mixed findings overall. This study serves as the foundation for future research to better understand how provider pRDI affects outcomes in patients undergoing lumbar and cervical spine surgery.

Accurate drone corner position estimation in complex backgrounds with boundary classification.

This study develops an efficient approach for precise channel frame detection in complex backgrounds, addressing the critical need for accurate drone navigation. Leveraging YOLACT and group regression, our method outperforms conventional techniques that rely solely on color information. We conducted extensive experiments involving channel frames placed at various angles and within intricate backgrounds, training the algorithm to effectively recognize them. The process involves initial edge image detection, noise reduction through binarization and erosion, segmentation of channel frame line segments using the Hough Transform algorithm, and subsequent classification via the K-means algorithm. Ultimately, we obtain the regression line segment through linear regression, enabling precise positioning by identifying intersection points. Experimental validations validate the robustness of our approach across diverse angles and challenging backgrounds, making significant advancements in UAV applications.

Dissecting the Genetic Basis of Yield Traits and Validation of a Novel Quantitative Trait Locus for Grain Width and Weight in Rice.

Grain yield in rice is a complex trait and it is controlled by a number of quantitative trait loci (QTL). To dissect the genetic basis of rice yield, QTL analysis for nine yield traits was performed using an F2 population containing 190 plants, which was developed from a cross between Youyidao (YYD) and Sanfenhe (SFH), and each plant in the population evaluated with respect to nine yield traits. In this study, the correlations among the nine yield traits were analyzed. The grain yield per plant positively correlated with six yield traits, except for grain length and grain width, and showed the highest correlation coefficient of 0.98 with the number of filled grains per plant. A genetic map containing 133 DNA markers was constructed and it spanned 1831.7 cM throughout 12 chromosomes. A total of 36 QTLs for the yield traits were detected on nine chromosomes, except for the remaining chromosomes 5, 8, and 9. The phenotypic variation was explained by a single QTL that ranged from 6.19% to 36.01%. Furthermore, a major QTL for grain width and weight, qGW2-1, was confirmed to be newly identified and was narrowed down to a relatively smaller interval of about ~2.94-Mb. Collectively, we detected a total of 36 QTLs for yield traits and a major QTL, qGW2-1, was confirmed to control grain weight and width, which laid the foundation for further map-based cloning and molecular design breeding in rice.

Perfusable adipose decellularized extracellular matrix biological scaffold co-recellularized with adipose-derived stem cells and L6 promotes functional skeletal muscle regeneration following volumetric muscle loss.

Muscle tissue engineering is a promising therapeutic strategy for volumetric muscle loss (VML). Among them, decellularized extracellular matrix (dECM) biological scaffolds have shown certain effects in restoring muscle function. However, researchers have inconsistent or even contradictory results on whether dECM biological scaffolds can efficiently regenerate muscle fibers and restore muscle function. This suggests that therapeutic strategies based on dECM biological scaffolds need to be further optimized and developed. In this study, we used a recellularization method of perfusing adipose-derived stem cells (ASCs) and L6 into adipose dECM (adECM) through vascular pedicles. On one hand, this strategy ensures sufficient quantity and uniform distribution of seeded cells inside scaffold. On the other hand, auxiliary L6 cells addresses the issue of low myogenic differentiation efficiency of ASCs. Subsequently, the treatment of VML animal experiments showed that the combined recellularization strategy can improve muscle regeneration and angiogenesis than the single ASCs recellularization strategy, and the TA of former had greater muscle contraction strength. Further single-nucleus RNA sequencing (snRNA-seq) analysis found that L6 cells induced ASCs transform into a new subpopulation of cells highly expressing Mki67, CD34 and CDK1 genes, which had stronger ability of oriented myogenic differentiation. This study demonstrates that co-seeding ASCs and L6 cells through vascular pedicles is a promising recellularization strategy for adECM biological scaffolds, and the engineered muscle tissue constructed based on this has significant therapeutic effects on VML. Overall, this study provides a new paradigm for optimizing and developing dECM-based therapeutic strategies.

Ginsenoside Rg3 decreases breast cancer stem-like phenotypes through impairing MYC mRNA stability.

Breast cancer stem cells (BCSCs) are responsible for breast cancer metastasis, recurrence and treatment resistance, all of which make BCSCs potential drivers of breast cancer aggression. Ginsenoside Rg3, a traditional Chinese herbal medicine, was reported to have multiple antitumor functions. Here, we revealed a novel effect of Rg3 on BCSCs. Rg3 inhibits breast cancer cell viability in a dose- and time-dependent manner. Importantly, Rg3 suppressed mammosphere formation, reduced the expression of stemness-related transcription factors, including c-Myc, Oct4, Sox2 and Lin28, and diminished ALDH(+) populations. Moreover, tumor-bearing mice treated with Rg3 exhibited robust delay of tumor growth and a decrease in tumor-initiating frequency. In addition, we found that Rg3 suppressed breast cancer stem-like properties mainly through inhibiting MYC expression. Mechanistically, Rg3 accelerated the degradation of MYC mRNA by enhancing the expression of the let-7 family, which was demonstrated to bind to the MYC 3' untranslated region (UTR). In conclusion, our findings reveal the remarkable suppressive effect of Rg3 on BCSCs, suggesting that Rg3 is a promising therapeutic treatment for breast cancer.

Feasibility of Auto-Quantified Epicardial Adipose Tissue in Predicting Atrial Fibrillation Recurrence After Catheter Ablation.

BACKGROUND: The aim of this study was to build an auto-segmented artificial intelligence model of the atria and epicardial adipose tissue (EAT) on computed tomography (CT) images, and examine the prognostic significance of auto-quantified left atrium (LA) and EAT volumes for AF.Methods and Results: This retrospective study included 334 patients with AF who were referred for catheter ablation (CA) between 2015 and 2017. Atria and EAT volumes were auto-quantified using a pre-trained 3-dimensional (3D) U-Net model from pre-ablation CT images. After adjusting for factors associated with AF, Cox regression analysis was used to examine predictors of AF recurrence. The mean (±SD) age of patients was 56±11 years; 251 (75%) were men, and 79 (24%) had non-paroxysmal AF. Over 2 years of follow-up, 139 (42%) patients experienced recurrence. Diabetes, non-paroxysmal AF, non-pulmonary vein triggers, mitral line ablation, and larger LA, right atrium, and EAT volume indices were linked to increased hazards of AF recurrence. After multivariate adjustment, non-paroxysmal AF (hazard ratio [HR] 0.6; 95% confidence interval [CI] 0.4-0.8; P=0.003) and larger LA-EAT volume index (HR 1.1; 95% CI 1.0-1.2; P=0.009) remained independent predictors of AF recurrence. CONCLUSIONS: LA-EAT volume measured using the auto-quantified 3D U-Net model is feasible for predicting AF recurrence after CA, regardless of AF type.

Exploring the novel antioxidant peptides in low-salt dry-cured ham: Preparation, purification, identification and molecular docking.

Dry-cured ham is important source of bioactive peptides. In this study, the antioxidant activities of peptides and components from low and fully salted dry-cured hams were compared by peptidomics. And novel antioxidant peptides were identified and characterized. The results showed that the peptides (<3 KDa) extracted from low-salt dry-cured ham had higher antioxidant activity. Therefore, the antioxidant peptides in low-salt dry-cured ham were further characterized and the mechanism of their antioxidant activity was investigated. From the five candidate peptides selected, we found DWPDARGIWHND (DD12) to be highly stable, non-sensitizing, and non-toxic with the highest free radical scavenging activity. Molecular docking predicted that DD12 interacted with Keap1 through hydrogen-bond formation and hydrophobic interactions, suggesting that DD12 had good cellular antioxidant activity. DD12 peptide can bind to DPPH• and ABTS•+, resulting in strong free radical scavenging activity. Our findings support the development and application of natural antioxidant peptides in dry-cured ham.

Catheter ablation in patients with atrial fibrillation and dilated cardiomyopathy.

Introduction: Catheter ablation is an effective and safe strategy for treating atrial fibrillation patients. Nevertheless, studies on the long-term outcomes of catheter ablation in patients with dilated cardiomyopathy are limited. This study aimed to assess the electrophysiological characteristics of atrial fibrillation patients with dilated cardiomyopathy and compare the long-term clinical outcomes between patients undergoing catheter ablation and medical therapy. Method: Patient baseline characteristics and electrophysiological parameters were examined to identify the predictors of atrial fibrillation recurrence following catheter ablation. The clinical outcomes of catheter ablation and medical therapy were compared using the propensity score matched method. Results: A total of 343 patients were enrolled, with 46 in the catheter ablation group and 297 in the medical therapy group. Among the catheter ablation group, 58.7% (n = 27) had persistent atrial fibrillation. The recurrence rate of atrial arrhythmia was 30.4% (n = 14) after an average follow-up duration of 7.7 years following catheter ablation. The only predictive factor for atrial fibrillation recurrence after catheter ablation was the left atrial diameter. When compared to medical therapy, catheter ablation demonstrated significantly better outcomes in terms of overall survival, freedom from heart failure hospitalization, improvement in left ventricular ejection fraction, and a greater reduction in left ventricular diameter and left atrial diameter after propensity score matching. Conclusions: Therefore, catheter ablation proves to be effective in providing long-term control of atrial fibrillation in patients with dilated cardiomyopathy. In addition to standard heart failure care, catheter ablation significantly enhanced both morbidity and mortality outcomes and reversed structural remodeling when compared to heart failure medication alone.

Utilization and outcomes of the 21-gene recurrence score in de novo metastatic breast cancer.

BACKGROUND: Limited data exist regarding the utility and validity of the 21-gene recurrence score (RS) in patients with de novo metastatic breast cancer (dnMBC). This study aimed to investigate the practice patterns as well as associated survival outcomes based on 21-gene RS in dnMBC. RESEARCH DESIGN AND METHODS: The Surveillance, Epidemiology, and End Results Oncotype database was queried for women with hormone receptor-positive and Her2-negative dnMBC. RESULTS: A total of 153 patients were identified, including 62.7% and 37.3% of patients who had RS < 26 and ≥ 26, respectively. Patients with RS ≥ 26 were more likely to receive chemotherapy compared to those with RS < 26 (61.4% vs. 28.1%, p < 0.001). Patients with RS ≥ 26 had an inferior breast cancer-specific survival (BCSS) (2-year BCSS: 84.3% vs. 89.5, p = 0.067) and overall survival (OS) compared to those with RS < 26 (2-year OS: 76.9% vs. 87.4%, p = 0.018). The multivariate Cox proportional hazard models showed that those with RS ≥ 26 had a significantly inferior BCSS (hazard ratio [HR] 2.251, 95% confidence interval [CI] 1.056-4.799, p = 0.036) and OS (HR 2.151, 95%CI 1.123-4.120, p = 0.021) compared to those with RS < 26. CONCLUSIONS: The 21-gene RS assay is an important prognostic factor in patients with dnMBC.

Thoracic and Lumbar Spine Injury: Evidence-Based Diagnosis, Management, and Outcomes.

BACKGROUND: Traumatic thoracolumbar spine injuries are associated with significant morbidity and mortality. Targeted for non-spine specialist trauma surgeons, this systematic scoping review aimed to examine literature for up-to-date evidence on presentation, management, and outcomes of thoracolumbar spine injuries in adult trauma patients. METHODS: This review was reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist. We searched four bibliographic databases: PubMed, EMBASE, Web of Science, and the Cochrane Library. Eligible studies included experimental, observational, and evidence-synthesis articles evaluating patients with thoracic, lumbar, or thoracolumbar spine injury, published in English between January 1, 2010 and January 31, 2021. Studies which focused on animals, cadavers, cohorts with N <30, and pediatric cohorts (age <18 years old), as well as case studies, abstracts, and commentaries were excluded. RESULTS: A total of 2501 studies were screened, of which 326 unique studies were fully text reviewed and twelve aspects of injury management were identified and discussed: injury patterns, determination of injury status and imaging options, considerations in management, and patient quality of life. We found: (1) imaging is a necessary diagnostic tool, (2) no consensus exists for preferred injury characterization scoring systems, (3) operative management should be considered for unstable fractures, decompression, and deformity, and (4) certain patients experience significant burden following injury. DISCUSSION: In this systematic scoping review, we present the most up-to-date information regarding the management of traumatic thoracolumbar spine injuries. This allows non-specialist trauma surgeons to become more familiar with thoracolumbar spine injuries in trauma patients and provides a framework for their management.

PDLIM1 interacts with HK2 to promote gastric cancer progression through enhancing the Warburg effect via Wnt/ß-catenin signaling.

PDZ and LIM domain protein 1 (PDLIM1) is a cytoskeletal protein and is associated with the malignant pathological features of several tumors. However, the prognostic value of PDLIM1 and the molecular mechanisms by which it is involved in the metabolism and progression in gastric cancer (GC) are still unclear. The GEPIA database was used to predict the expression and prognosis of PDLIM1 in GC. qRT-PCR and western blot assays were applied to detect the mRNA and protein expression in GC tissues and cells. Loss- and gain-of-function experiments were performed to evaluate the biological role of PDLIM1 in GC cells. The Warburg effect was detected by a battery of glycolytic indicators. The interaction of PDLIM1 and hexokinase 2 (HK2) was determined by a co-immunoprecipitation assay. Furthermore, the modulatory effects of PDLIM1 and HK2 on Wnt/ß-catenin signaling were assessed. The results showed that PDLIM1 expression was upregulated in GC tissues and cells and was associated with a poor prognosis for GC patients. PDLIM1 inhibition reduced GC cell proliferation, migration and invasion and promoted cell apoptosis. In the glucose deprivation (GLU-D) condition, the PDLIM1 level was reduced and PDLIM1 overexpression led to an increase in glycolysis. Besides, mechanistic investigation showed that PDLIM1 interacted with HK2 to mediate biological behaviors and the glycolysis of GC through Wnt/ß-catenin signaling under glucose deprivation. In conclusion, PDLIM1 interacts with HK2 to promote gastric cancer progression by enhancing the Warburg effect via Wnt/ß-catenin signaling.

Skin sympathetic nerve activity in different ablation settings for atrial fibrillation.

BACKGROUND: Modifying the autonomic system after catheter ablation may prevent the recurrence of atrial fibrillation (AF). Evaluation of skin sympathetic nerve activity (SKNA) is a noninvasive method for the assessment of sympathetic activity. However, there are few studies on the effects of different energy settings on SKNA. OBJECTIVE: To investigate the changes in SKNA in different energy settings and their relationship to AF ablation outcomes. METHODS: Seventy-two patients with paroxysmal and persistent AF were enrolled. Forty-three patients received AF ablation with the conventional (ConV) energy setting (low power for long duration), and 29 patients using a high-power, short-duration (HPSD) strategy. The SKNA was acquired from the right arm 1 day before and after the radiofrequency ablation. We analyzed the SKNA and ablation outcomes in the different energy settings. RESULTS: Both groups had a similar baseline average SKNA (aSKNA). We found that the median aSKNA increased significantly from 446.82 µV to 805.93 µV (p = 0.003) in the ConV group but not in the HPSD group. In the ConV group, patients without AF recurrence had higher aSKNA values. However, the 1-year AF recurrence rate remained similar between both groups (35 % vs. 28 %, p = 0.52). CONCLUSION: The post-ablation aSKNA levels increased significantly in the ConV group but did not change significantly in the HPSD group, which may reflect different neuromodulatory effects. However, the one-year AF recurrence rates were similar for both groups. These results demonstrate that the HPSD strategy has durable lesion creation but less lesion depth, which may reduce collateral damage.

Socioeconomic Influence on Cervical Fusion Outcomes.

STUDY DESIGN: A retrospective observational study. OBJECTIVE: The aim of this study was to compare postoperative outcomes following cervical fusion based on socioeconomic status (SES) variables including race, education, net worth, and homeownership status. SUMMARY OF BACKGROUND DATA: Previous studies have demonstrated the effects of patient race and income on outcomes following cervical fusion procedures. However, no study to date has comprehensively examined the impact of multiple SES variables. We hypothesized that race, education, net worth, and homeownership influence important outcomes following cervical fusion. MATERIALS AND METHODS: Optum's de-identified Clinformatics Data Mart (CDM) database was queried for patients undergoing first-time inpatient cervical fusion from 2003 to 2021. Patient demographics, SES variables, and the Charlson comorbidity index were obtained. Primary outcomes were hospital length of stay and 30-day rates of reoperation, readmission, and postoperative complications. Secondary outcomes included postoperative emergency room visits, discharge status, and total hospital charges. RESULTS: A total of 111,914 patients underwent cervical spinal fusion from 2003 to 2021. Multivariate analysis revealed that after controlling for age, sex, and Charlson comorbidity index, Black race was associated with a higher rate of 30-day readmissions [odds ratio (OR): 1.11, 95% CI: 1.03-1.20]. Lower net worth (vs. >$500K) and renting (vs. owning a home) were significantly associated with both higher rates of 30-day readmissions (OR: 1.29, 95% CI: 1.17-1.41; OR: 1.34, 95% CI: 1.22-1.49), and emergency room visits (OR: 1.29, 95% CI: 1.18-1.42; OR: 1.11, 95% CI: 1.00-1.23). Lower net worth (vs. >$500K) was also associated with increased complications (OR: 1.22, 95% CI: 1.14-1.31). CONCLUSION: Socioeconomic variables, including patient race, education, and net worth, influence postoperative metrics in cervical spinal fusion surgery. Future studies should focus on developing and implementing targeted interventions based on patient SES to reduce disparity.

A novel TNKS/USP25 inhibitor blocks the Wnt pathway to overcome multi-drug resistance in TNKS-overexpressing colorectal cancer

Modulating Tankyrases (TNKS), interactions with USP25 to promote TNKS degradation, rather than inhibiting their enzymatic activities, is emerging as an alternative/specific approach to inhibit the Wnt/β-catenin pathway. Here, we identified UAT-B, a novel neoantimycin analog isolated from Streptomyces conglobatus, as a small-molecule inhibitor of TNKS-USP25 protein-protein interaction (PPI) to overcome multi-drug resistance in colorectal cancer (CRC). The disruption of TNKS-USP25 complex formation by UAT-B led to a significant decrease in TNKS levels, triggering cell apoptosis through modulation of the Wnt/β-catenin pathway. Importantly, UAT-B successfully inhibited the CRC cells growth that harbored high TNKS levels, as demonstrated in various in vitro and in vivo studies utilizing cell line-based and patient-derived xenografts, as well as APCmin/+ spontaneous CRC models. Collectively, these findings suggest that targeting the TNKS-USP25 PPI using a small-molecule inhibitor represents a compelling therapeutic strategy for CRC treatment, and UAT-B emerges as a promising candidate for further preclinical and clinical investigations.

Misdiagnosis of pneumorrhagia leptospirosis as common CAP: A case report and literature review.

Background: The incidence of critical leptospirosis manifested as massive pulmonary hemorrhage has been significantly reduced, which has been rarely reported in recent years, while the mortality rate is extremely high once it occurs. Case presentation: A 54-year-old man with no HIV infection was admitted to the local county hospital due to high-grade continuous fever lasting four days (38.5-40.5C), upper limb and shoulder-back muscle pain, and general fatigue. The chest CT (Aug 26, 2021) showed "multiple patchy, cloudy, and fuzzy shadows in both lungs, mainly under the pleura of the upper and lower lobes of both lungs; some lymph nodes in the mediastinum are enlarged". Despite being diagnosed with "common community-acquired pneumonia" and starting injectable levofloxacin, the symptoms worsened, and massive hemoptysis occurred. However, after being transferred to our hospital, the patient was diagnosed with the "pulmonary hemorrhage type of leptospirosis" through comprehensive dynamic analysis. The patient recovered very well after undergoing "penicillin 3MIU q6h" alone for two weeks to fight the infection. Conclusions: Leptospirosis has a high mortality rate when it becomes critical or severe. Diagnosis typically relies on factors such as epidemiology, clinical symptoms, and pathogenetic testing. Metagenomic next-generation sequencing (mNGS) is more effective in sensitivity and speed than traditional detection methods, making it an excellent option for diagnosing challenging and severe infections in emergencies. Additionally, when experiencing sudden coughing up of blood, it's important to consider the possibility of pulmonary hemorrhage as a type of leptospirosis.

An In-Situ Visual Analytics Framework for Deep Neural Networks.

The past decade has witnessed the superior power of deep neural networks (DNNs) in applications across various domains. However, training a high-quality DNN remains a non-trivial task due to its massive number of parameters. Visualization has shown great potential in addressing this situation, as evidenced by numerous recent visualization works that aid in DNN training and interpretation. These works commonly employ a strategy of logging training-related data and conducting post-hoc analysis. Based on the results of offline analysis, the model can be further trained or fine-tuned. This strategy, however, does not cope with the increasing complexity of DNNs, because (1) the time-series data collected over the training are usually too large to be stored entirely; (2) the huge I/O overhead significantly impacts the training efficiency; (3) post-hoc analysis does not allow rapid human-interventions (e.g., stop training with improper hyper-parameter settings to save computational resources). To address these challenges, we propose an in-situ visualization and analysis framework for the training of DNNs. Specifically, we employ feature extraction algorithms to reduce the size of training-related data in-situ and use the reduced data for real-time visual analytics. The states of model training are disclosed to model designers in real-time, enabling human interventions on demand to steer the training. Through concrete case studies, we demonstrate how our in-situ framework helps deep learning experts optimize DNNs and improve their analysis efficiency.