Multi-omics and pharmacological characterization of patient-derived glioma cell lines.

Glioblastoma (GBM) is the most common brain tumor and remains incurable. Primary GBM cultures are widely used tools for drug screening, but there is a lack of genomic and pharmacological characterization for these primary GBM cultures. Here, we collect 50 patient-derived glioma cell (PDGC) lines and characterize them by whole genome sequencing, RNA sequencing, and drug response screening. We identify three molecular subtypes among PDGCs: mesenchymal (MES), proneural (PN), and oxidative phosphorylation (OXPHOS). Drug response profiling reveals that PN subtype PDGCs are sensitive to tyrosine kinase inhibitors, whereas OXPHOS subtype PDGCs are sensitive to histone deacetylase inhibitors, oxidative phosphorylation inhibitors, and HMG-CoA reductase inhibitors. PN and OXPHOS subtype PDGCs stably form tumors in vivo upon intracranial transplantation into immunodeficient mice, whereas most MES subtype PDGCs fail to form tumors in vivo. In addition, PDGCs cultured by serum-free medium, especially long-passage PDGCs, carry MYC/MYCN amplification, which is rare in GBM patients. Our study provides a valuable resource for understanding primary glioma cell cultures and clinical translation and highlights the problems of serum-free PDGC culture systems that cannot be ignored.

Crocetin Enhances Temozolomide Efficacy in Glioblastoma Therapy Through Multiple Pathway Suppression.

BACKGROUND: Glioblastoma multiforme (GBM) is an aggressive type of brain tumor that is difficult to remove surgically. Research suggests that substances from saffron, namely crocetin and crocin, could be effective natural treatments, showing abilities to kill cancer cells. METHODS: Our study focused on evaluating the effects of crocetin on glioma using the U87 cell line. We specifically investigated how crocetin affects the survival, growth, and spread of glioma cells, exploring its impact at concentrations ranging from 75-150 µM. The study also included experiments combining crocetin with the chemotherapy drug Temozolomide (TMZ) to assess potential synergistic effects. RESULTS: Crocetin significantly reduced the viability, proliferation, and migration of glioma cells. It achieved these effects by decreasing the levels of Matrix Metallopeptidase 9 (MMP-9) and Ras homolog family member A (RhoA), proteins that are critical for cancer progression. Additionally, crocetin inhibited the formation of cellular structures necessary for tumor growth. It blocked multiple points of the Ak Strain Transforming (AKT) signaling pathway, which is vital for cancer cell survival. This treatment led to increased cell death and disrupted the cell cycle in the glioma cells. When used in combination with TMZ, crocetin not only enhanced the reduction of cancer cell growth but also promoted cell death and reduced cell replication. This combination therapy further decreased levels of high mobility group box 1 (HMGB1) and Receptor for Advanced Glycation End-products (RAGE), proteins linked to inflammation and tumor progression. It selectively inhibited certain pathways involved in the cellular stress response without affecting others. CONCLUSION: Our results underscore the potential of crocetin as a treatment for glioma. It targets various mechanisms involved in tumor growth and spread, offering multiple avenues for therapy. Further studies are essential to fully understand and utilize crocetin's benefits in treating glioma.

Continuous Positive Airway Pressure Treatment and Hypertensive Adverse Outcomes in Pregnancy: A Systematic Review and Meta-Analysis.

Importance: Pregnancy may contribute to the development or exacerbation of obstructive sleep apnea (OSA) and increase the risk of gestational complications. Continuous positive airway pressure (CPAP) is the first-line and criterion standard treatment for OSA and is regarded as the most feasible choice during pregnancy. However, the association between CPAP therapy in pregnant women with OSA and reduced gestational complications remains inconclusive. Objective: To investigate the association between CPAP therapy in pregnant women with OSA and the reduction of adverse hypertensive outcomes during gestation. Data Sources: Keyword searches of PubMed, Embase, and the Cochrane Database of Systematic Reviews and Clinical Trials were conducted from inception to November 5, 2023. Study Selection: Original studies reporting the treatment effect of CPAP use on lowering hypertension and preeclampsia risks in pregnant women with OSA were selected. Data Extraction and Synthesis: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline was followed in the reporting of reviews. Data were independently extracted by 2 authors. Random-effects model meta-analyses were performed and risk ratios (RRs) reported. Subgroup analysis, meta-regression based on age and body mass index (BMI; calculated as weight in kilograms divided by height in meters squared), and publication bias assessment were also conducted. Main Outcome and Measures: The primary outcome was the RR of gestational hypertension and preeclampsia between pregnant women with OSA receiving CPAP treatment and those who did not receive CPAP treatment. Results: Six original studies in 809 participants (mean age, 31.4 years; mean BMI, 34.0) were identified and systematically reviewed for meta-analysis. The pooled results showed significant differences between the intervention (CPAP use) and the control (non-CPAP use) groups in reducing the risk of gestational hypertension (RR, 0.65; 95% CI, 0.47-0.89; P = .008) and preeclampsia (RR, 0.70; 95% CI, 0.50-0.98; P = .04). Meta-regression revealed that patients' age (coefficient, -0.0190; P = .83) and BMI (coefficient, -0.0042; P = .87) were not correlated with reduction of risk of hypertension and preeclampsia. Conclusions and Relevance: These findings suggest that implementing CPAP treatment in pregnant women with OSA may reduce the risk of gestational hypertension and preeclampsia.

Mechanism exploration of synergistic photo-immunotherapy strategy based on a novel exosome-like nanosystem for remodeling the immune microenvironment of HCC.

The immunosuppressive tumor microenvironment (TME) has become a major challenge in cancer immunotherapy, with abundant tumor-associated macrophages (TAMs) playing a key role in promoting tumor immune escape by displaying an immunosuppressive (M2) phenotype. Recently, it was reported that M1 macrophage-derived nanovesicles (M1NVs) can reprogram TAMs to an anti-tumor M1 phenotype, thereby significantly alleviating the immunosuppressive TME and enhancing the anti-tumor efficacy of immunotherapy. Herein, we developed M1NVs loaded with mesoporous dopamine (MPDA) and indocyanine green (ICG), which facilitated the recruitment of M2 TAMs through synergistic photothermal and photodynamic therapy. Thereafter, M1NVs can induce M1 repolarization of TAMs, resulting in increased infiltration of cytotoxic T lymphocytes within the tumor to promote tumor regression. This study investigated the effect of phototherapy on the immune environment of liver cancer using single-cell RNA sequencing (scRNA-seq) by comparing HCC tissues before and after MPDA/ICG@M1NVs + NIR treatment. The results showed significant shifts in cell composition and gene expression, with decreases in epithelial cells, B cells, and macrophages and increases in neutrophils and myeloid cells. Additionally, gene analysis indicated a reduction in pro-inflammatory signals and immunosuppressive functions, along with enhanced B-cell function and anti-tumor immunity, downregulation of the Gtsf1 gene in the epithelial cells of the MPDA/ICG @M1NVs + NIR group, and decreased expression of the lars2 gene in immune subpopulations. Eno3 expression is reduced in M1 macrophages, whereas Clec4a3 expression is downregulated in M2 macrophages. Notably, the B cell population decreased, whereas Pou2f2 expression increased. These genes regulate cell growth, death, metabolism, and tumor environment, indicating their key role in HCC progression. This study highlights the potential for understanding cellular and molecular dynamics to improve immunotherapy.

[Characteristics of Soil Selenium-cadmium Migration and Accumulation and Its Bioeffectiveness in Typical Geological High Background Area].

The prevalence of selenium-cadmium （Se-Cd） symbiosis in soils of geologically high background areas directly affects the safe utilization of Se-rich land resources. To investigate the migration and accumulation characteristics and bio-effectiveness of Se-Cd in the soil-crop system in typical geological high background areas of Southwest China and to realize the safe use of natural Se-rich land resources in geological high background areas, we collected 84 samples of agricultural crops （maize） and their supporting root systems and analyzed the Se-Cd content and physicochemical properties. Se-Cd accumulation characteristics, influencing factors, and bio-effectiveness of the soil-crop system were evaluated using geostatistics, bioenrichment factors, and geographic detectors. The results showed that the Se-Cd content in the study area was significantly higher than the background value of the soil in the whole country and in Yunnan Province. Influenced by the geological background, secondary enrichment in the process of soil formation, and agricultural activities, the accumulation and enrichment characteristics of Se in the root soil varied from no enrichment to slightly enriched, and the occurrence form was dominated by the residue state. The accumulation index of soil Cd was mainly in the medium pollution level, and the occurrence form was mainly in the residual state and the combined state of iron and manganese. The Se-enrichment rate of crop seeds reached 98.8% （DB 50/T 524-2013 standard）, and the average value of bioconcentration factor was 5.8%. The exceeding rate of Cd content in crop seeds was only 1.19% （GB 2762-2022 standard）, and the average value of Cd bioconcentration factor was 2.11%, so the ecological risk of heavy metal Cd in crop seeds was relatively low. In the Se-Cd symbiosis area under geological background, the weak alkaline environment of the soil could effectively reduce the bioavailability of Cd in crop seeds, and the Se-rich soil could inhibit the uptake of Cd by the crops to a certain extent. Correlation analysis showed that the migration and accumulation of Se and Cd from soil to crop seeds in the soil-crop system were affected by the elemental accumulation pattern and the physical and chemical properties （pH） of the soil, and at the same time, there was a certain synergistic-antagonistic effect between Se and Cd in the soil-crop system. Correlation analysis showed that the migration and accumulation of Se and Cd from soil to crop seeds in the soil-crop system was influenced by the occurrence of elements, soil physicochemical properties （pH）, and other factors, and there was also a certain synergistic-antagonistic interaction between Se and Cd in the soil-crop system.

Investigation of Toxoplasma gondii Infection in Yunnan Semi-fine Wool Sheep (Ovis aries) and wild Rodents in Yunnan, China.

BACKGROUND: Toxoplasma gondii, a globally distributed zoonotic obligate intracellular parasite, infects a wide array of mammals, including humans, sheep, and birds. As a unique sheep breed in southwestern China, Yunnan semi-fine wool sheep occupies an important position in animal husbandry in Zhaotong due to its strong adaptability, high reproductive rate, and excellent wool quality. Lambs infected with T. gondii are prone to neurological symptoms and growth retardation, while T. gondii infection in ewes can cause abortions, stillbirths, and deformities, thus affecting sheep reproduction and sheep product quality. Meanwhile, mutton and dairy products contaminated with T. gondii can become potential sources of human infection, potentially threatening public health and safety. METHOD: To understand the T. gondii infection in semi-fine wool sheep in Zhaotong, Yunnan Province, 586 blood samples were collected and subjected to indirect hemagglutination assay (IHA) for T. gondii antibodies, and the infection-related factors were analyzed through cross-sectional analysis. In the meantime, nested PCR was conducted on a total of 217 samples collected from 31 rodents caught in and around the sheep breeding ground to test the T. gondii B1 gene in rodent tissues. RESULTS: A total of 94 sera tested positive for T. gondii antibodies, with a total positive rate of 16.04% (94/586) (95% CI: 14.77-20.89). Cross-sectional statistical analysis on factors related to semi-fine wool sheep infection rate, including sampling season, sex, age, and weight, suggested that age (< 6 months: 23.81%; 6-12 months: 11.74%; > 12 months: 15.83%) was a significant factor explaining the infection rate differences (P = 0.003 < 0.05, χ2 = 11.62, df = 2). Thus, age was considered a key risk factor for T. gondii infection in this study (odds ratio, OR = 2.35, 95% CI: 1.42-3.87). Nested PCR analysis on 217 (heart, liver, spleen, lung, kidney, brain, and muscle) tissues from the 31 rodents indicated that 11 tested positive. The total infection rate of rodents in and around the breeding ground was 35.48% (11/31), and 14 samples tested positive, with a positive infection rate of 6.45% (14/217). CONCLUSION: The T. gondii infection rates of semi-fine wool sheep and rodents from their breeding environment in Zhaotong, Yunnan Province, were high, necessitating enhanced prevention, control, and treatment measures to ensure the healthy breeding of semi-fine wool sheep and veterinary public health and safety.

Natural Products on Inflammatory Bowel Disease: Role of Gut Microbes.

Inflammatory bowel disease (IBD) refers to long-term medical conditions that involve inflammation of the digestive tract, and the global incidence and prevalence of IBD are on the rise. Gut microbes play an important role in maintaining the intestinal health of the host, and the occurrence, development, and therapeutic effects of IBD are closely related to the structural and functional changes of gut microbes. Published studies have shown that the natural products from traditional Chinese medicine have direct or indirect regulatory impacts on the composition and metabolism of the gut microbes. In this review, we summarize the research progress of several groups of natural products, i.e., flavonoids, alkaloids, saponins, polysaccharides, polyphenols, and terpenoids, for the therapeutic activities in relieving IBD symptoms. The role of gut microbes and their intestinal metabolites in managing the IBD is presented, with focusing on the mechanism of action of those natural products. Traditional Chinese medicine alleviated IBD symptoms by regulating gut microbes, providing important theoretical and practical basis for the treatment of variable inflammatory intestinal diseases.

Examining drivers of NFT purchase intention: The impact of perceived scarcity and risk.

The emergence of non-fungible tokens (NFTs) has elicited both excitement and apprehension among consumers, who find themselves influenced by the perceived scarcity and the perceived risks surrounding these novel digital assets. This study investigates the factors influencing consumer adoption of NFTs by integrating the concepts of perceived scarcity and perceived risks within the theoretical framework of the Theory of Planned Behavior (TPB). Employing structural equation modeling, the research evaluates the impact of perceived scarcity, perceived ease of use, attitudes, subjective norms, perceived behavioral control, and perceived risk on NFT purchase intentions. The findings reveal that perceived scarcity and perceived ease of use significantly positively affect consumers' intentions to purchase NFTs. Conversely, perceived risk exerts a negative effect on purchase intentions. Additionally, the study demonstrates that attitudes, subjective norms, and perceived behavioral control positively affect NFT purchase intentions. This study provides a behavioral roadmap for navigating the complex love-hate relationship consumers have with NFTs, shedding light on the factors that motivate individuals to embrace or avoid these digital collectibles.

Ultra-sensitive molecular residual disease detection through whole genome sequencing with single-read error correction.

While whole genome sequencing (WGS) of cell-free DNA (cfDNA) holds enormous promise for detection of molecular residual disease (MRD), its performance is limited by WGS error rate. Here we introduce AccuScan, an efficient cfDNA WGS technology that enables genome-wide error correction at single read-level, achieving an error rate of 4.2 × 10-7, which is about two orders of magnitude lower than a read-centric de-noising method. The application of AccuScan to MRD demonstrated analytical sensitivity down to 10-6 circulating variant allele frequency at 99% sample-level specificity. AccuScan showed 90% landmark sensitivity (within 6 weeks after surgery) and 100% specificity for predicting relapse in colorectal cancer. It also showed 67% sensitivity and 100% specificity in esophageal cancer using samples collected within one week after surgery. When AccuScan was applied to monitor immunotherapy in melanoma patients, the circulating tumor DNA (ctDNA) levels and dynamic profiles were consistent with clinical outcomes. Overall, AccuScan provides a highly accurate WGS solution for MRD detection, empowering ctDNA detection at parts per million range without requiring high sample input or personalized reagents.

Guidelines Versus Practice: Surgical Versus Transcatheter Aortic Valve Replacement in Adults < 60 Years.

BACKGROUND: Consensus guidelines recommend surgical aortic valve replacement (SAVR) over transcatheter aortic valve replacement (TAVR) in patients with severe aortic stenosis aged < 65 years. This analysis evaluates clinical practice and outcomes of TAVR and SAVR in patients < 60 years. METHODS: We identified 2,360 patients aged < 60 years including 523 TAVR (22.2%) and 1,837 SAVR (77.8%) procedures from 2013-2021 using the California Department of Health Care Access and Information database. The median follow-up time was 2.4 (IQR:1.1-4.5) years after TAVR and 4.9 (IQR:2.8-6.9) years after SAVR. The primary outcome was 5-year survival. Secondary outcomes included cumulative incidences of reoperation, endocarditis, stroke, and heart failure readmissions with death as a competing risk, compared using propensity score matching. RESULTS: Between 2013 and 2021 TAVR rates in patients aged < 60 years increased from 7.2% to 45.7% (annual increase of 4.7%, p<0.001). Thirty-day mortality was similar for SAVR and TAVR (0.2% vs. 0.4% (p=0.20). In 358 propensity-matched pairs, TAVR was associated with an increased hazard of 5-year mortality (HR 2.5, 95% CI 1.1-3.7, p=0.02). There was no significant difference in the cumulative incidences of reoperation (2.2% vs. 3.8%, p=0.25), stroke (1.1% vs. 0.8%, p=0.39), endocarditis (0.8% vs. 0.4%, p=0.38), and heart failure readmission (1.9% vs. 1.2%, p=0.10). CONCLUSIONS: TAVR use approaches SAVR use in patients aged < 60 years in California and is associated with significantly worse 5-year survival. This may indicate a need for randomized trials to inform best practice recommendations.

Corrigendum to "Digital capability and green innovation: The perspective of green supply chain collaboration and top management's environmental awareness" [Heliyon 10(11) (June 2024) e32290].

[This corrects the article DOI: 10.1016/j.heliyon.2024.e32290.].

A case report of high cervical spinal infarction after stenting with severe stenosis at the beginning of left vertebral artery.

BACKGROUND: Spinal cord infarction is an uncommon nervous system disorder. We present a case of high cervical cord infarction caused by stenting of the origin of the left vertebral artery (VA). The incidence of spinal cord infarction is minimal, and it must be distinguished from a number of other disorders. The diagnosis is primarily based on imaging, clinical symptoms, and history. Currently, there is no focused treatment for spinal cord infarction. Thrombolysis, high-dose glucocorticoid shocks, tube dilatation to promote circulation, and nutritional neurotropic medicines given early in the course of the disease can all help to slow the disease's progression. There is no agreement on the etiology, diagnosis, or therapy options for these people. CASE PRESENTATION: On October 7, 2023, an 81-year-old man was admitted to the hospital primarily for recurrent chest tightness and pain that had persisted for more than 2 years and 1 month. Cerebral angiography upon admission revealed significant blockage of the right VA and stenosis of the left vertebral arterial origin. Six days following admission, a drug-eluting stenting procedure was carried out under local anesthesia to open the left VA origin via the femoral artery. Following the procedure, the patient experienced a progressive loss of muscle strength in all 4 limbs and paraplegia below the cervical 3 spinal cord. One week following the procedure, the patient was released from the hospital. After the procedure, the patient was released 1 week later. After the procedure, the patient's symptoms persisted for a month. CONCLUSION: High awareness for high cervical cord infarction is required when neck discomfort and limb weakness with progressive progression arises after surgery. Complications of high cervical cord infarction following stenting for stenosis of VA origin are uncommon in clinical settings. Patients' prognoses can be improved by prompt diagnosis and care.

Clinical Predictors of Nontuberculous Mycobacteria Lung Disease and Coisolates of Potential Pathogenic Microorganisms in Noncystic Fibrosis Bronchiectasis.

Background: In bronchiectasis, nontuberculous mycobacteria (NTM) lung disease (NTM-LD) is a well-known coexisting infection. However, microorganism coisolates and clinical NTM-LD predictors are poorly studied. Methods: Patients with bronchiectasis diagnosed by means of computed tomography between January 2017 and June 2020 were screened, using the date of computed tomography as the index date. Those with a major bronchiectasis diagnosis in ≥2 follow-up visits after the index date were enrolled in the study, and NTM-LD occurrence and its association with pneumonia and hospitalization within 1 year were analyzed. Results: Of the 2717 participants, 79 (2.9%) had NTM-LD diagnosed. The factors associated with NTM-LD included hemoptysis, postinfectious bronchiectasis, a tree-in-bud score ≥2, a modified Reiff score ≥4, and chronic obstructive pulmonary disease (adjusted odds ratios, 1.80, 2.36, 1.78, 2.95, and 0.51, respectively). Compared with patients in the non-NTM group, those with NTM-LD had higher rates of hospitalization (15.9% vs 32.9%; P < .001) and pneumonia (9.8% vs 20.3%; P = .003). Pseudomonas aeruginosa was the most common microorganism in those with NTM-LD and those in the non-NTM group (10.1% vs 7.8%; P = .40). However, compared with those in the non-NTM group, Acinetobacter baumannii and Escherichia coli were more prevalent in patients with NTM-LD (0.7% vs 3.8% [P = .03%] and 1.0% vs 3.8% [P = .05], respectively). Conclusions: Postinfectious bronchiectasis with hemoptysis, higher radiological involvement, and a tree-in-bud pattern were associated with NTM-LD risk. The rate of A baumannii and E coli coisolation was higher in bronchiectasis populations with NTM-LD.

Comparison of Budesonide/formoterol versus Fluticasone furoate/vilanterol as maintenance and reliever therapy for asthma control: a real-world observational study.

BACKGROUND: Previous studies have reported reduced acute exacerbation rates and improved symptom control in asthma patients treated using inhaled corticosteroids plus formoterol maintenance and reliever therapy (MART). Fluticasone furoate (FF) and vilanterol (VIL) also provide rapid bronchodilation and sustained anti-inflammatory effects, however no studies have investigated FF/VIL as MART for asthma control. METHODS: From October 1, 2021 to September 30, 2023, this retrospective study included asthma patients classified as step 3 or 4 according to the Global Initiative for Asthma guidelines, who were then divided into two groups. One group received BUD/FOR as MART, while the other received FF/VIL as MART. Pulmonary function tests, exacerbation rates, Asthma Control Test (ACT), fractional exhaled nitric oxide (FeNO) levels, and blood eosinophil counts were measured before and after 12 months of treatment. RESULTS: A total of 161 patients were included, of whom 36 received BUD/FOR twice daily as MART, and 125 received FF/VIL once daily as MART. After 12 months of treatment, the FF/VIL group showed a significant increase in ACT scores by 1.57 (p < 0.001), while the BUD/FOR group had an increase of 0.88 (p = 0.11). In terms of FeNO levels, the BUD/FOR group experienced a decline of -0.2 ppb (p = 0.98), whereas the FF/VIL group had a mild increase of + 0.8 ppb (p = 0.7). Notably, there was a significant difference in the change of FeNO between the two groups (∆ FeNO: -0.2 ppb in BUD/FOR; + 0.8 ppb in FF/VIL, p < 0.001). There were no significant alterations observed in FEV1, blood eosinophil count, or acute exacerbation decline in either group. CONCLUSIONS: In the current study, patients treated with FF/VIL as MART showed improvements in ACT scores, while those treated with BUD/FOR as MART exhibited a reduction in FeNO levels. However, the difference between the two treatment groups did not reach clinical significance. Thus, FF/VIL as MART showed similar effectiveness to BUD/FOR as MART.

Inhibiting interferon-γ induced cancer intrinsic TNFRSF14 elevation restrains the malignant progression of glioblastoma.

BACKGROUND: Prolonged interferon-γ signaling activation induces cancer resistance to therapeutics, especially immunotherapy. However, the detailed mechanisms are not well characterized. In present study, we explored cancer intrinsic resistant mechanisms employing for evading immune checkpoint blockade (ICB) and searched for key immune checkpoints contributing to the constitution of suppressive immune microenvironment of glioblastoma (GBM). METHODS: We screened key immune checkpoint (IC) associated with IFN signaling activation in GBM according to integrated transcriptomic profiling on the ICs. Expression analysis and functional assays revealed that malignant cells elevated the key IC, TNFRSF14 expression under IFN-γ stimulation, which enhanced their proliferation and in vivo tumorigenicity. Therapeutic efficiency of TNFRSF14 disruption in GBM was evaluated with in vitro and in vivo functional assays, including immunofluorescence, transwell, RT-qPCR, flow cytometry, mass cytometry, and mice preclinical GBM models. Moreover, the improvement of TNFRSF14 blockade on the efficacy of PD-L1 treatment was examined in mice intracranial xenograft bearing models. RESULTS: TNFRSF14, a previously poorly characterized IC, was disclosed as a checkpoint with malignant intrinsic elevation closely associated with type II not type I IFN signaling activation in GBM. Anti-PD-L1 treatment induces compensatory TNFRSF14 elevation, while enhancing IFN-γ production. TNFRSF14 phosphorylates FAK at Y397 and consequently activates NF-κB, which not only strengthens the tumorigenicity of GBM cells, but also enhances TAMs recruitment through elevating CXCL1/CXCL5 secretion from GBM cells. TNFRSF14 ablation reduces the tumorigenicity of GBM cells, reshapes the immunosuppressive microenvironment, and enhances therapeutic efficacy of anti-PD-L1 in mouse orthotopic GBM model. CONCLUSION: Our findings highlight a malignant TNFRSF14/FAK axis as a potential target to blunt cancer-intrinsic resistance to ICB treatment, which may help improve the therapeutic efficiency of immunotherapy in malignancies.

A 3D bioreactor model to study osteocyte differentiation and mechanobiology under perfusion and compressive mechanical loading.

Osteocytes perceive and process mechanical stimuli in the lacuno-canalicular network in bone. As a result, they secrete signaling molecules that mediate bone formation and resorption. To date, few three-dimensional (3D) models exist to study the response of mature osteocytes to biophysical stimuli that mimic fluid shear stress and substrate strain in a mineralized, biomimetic bone-like environment. Here we established a biomimetic 3D bone model by utilizing a state-of-art perfusion bioreactor platform where immortomouse/Dmp1-GFP-derived osteoblastic IDG-SW3 cells were differentiated into mature osteocytes. We evaluated proliferation and differentiation properties of the cells on 3D microporous scaffolds of decellularized bone (dBone), poly(L-lactide-co-trimethylene carbonate) lactide (LTMC), and beta-tricalcium phosphate (ß-TCP) under physiological fluid flow conditions over 21 days. Osteocyte viability and proliferation were similar on the scaffolds with equal distribution of IDG-SW3 cells on dBone and LTMC scaffolds. After seven days, the differentiation marker alkaline phosphatase (Alpl), dentin matrix acidic phosphoprotein 1 (Dmp1), and sclerostin (Sost) were significantly upregulated in IDG-SW3 cells (p = 0.05) on LTMC scaffolds under fluid flow conditions at 1.7 ml/min, indicating rapid and efficient maturation into osteocytes. Osteocytes responded by inducing the mechanoresponsive genes FBJ osteosarcoma oncogene (Fos) and prostaglandin-endoperoxide synthase 2 (Ptgs2) under perfusion and dynamic compressive loading at 1 Hz with 5 % strain. Together, we successfully created a 3D biomimetic platform as a robust tool to evaluate osteocyte differentiation and mechanobiology in vitro while recapitulating in vivo mechanical cues such as fluid flow within the lacuno-canalicular network. STATEMENT OF SIGNIFICANCE: This study highlights the importance of creating a three-dimensional (3D) in vitro model to study osteocyte differentiation and mechanobiology, as cellular functions are limited in two-dimensional (2D) models lacking in vivo tissue organization. By using a perfusion bioreactor platform, physiological conditions of fluid flow and compressive loading were mimicked to which osteocytes are exposed in vivo. Microporous poly(L-lactide-co-trimethylene carbonate) lactide (LTMC) scaffolds in 3D are identified as a valuable tool to create a favorable environment for osteocyte differentiation and to enable mechanical stimulation of osteocytes by perfusion and compressive loading. The LTMC platform imitates the mechanical bone environment of osteocytes, allowing the analysis of the interaction with other cell types in bone under in vivo biophysical stimuli.

Impact of 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. OBJECTIVE: We aimed 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 preablation pulmonary vein computed tomography. Patients were assigned to groups on the basis of the presence of LIPV triggers 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 or drivers. The Dao-LIPV distance had a better predictive performance (area under the curve, 0.70) compared with persistent AF (area under the curve, 0.57). Multivariate logistic regression analysis showed that Dao-LIPV distance ≤2.5 mm (odds ratio, 3.96; 95% CI, 2.15-7.29; P < .001) and persistent AF (odds ratio, 1.73; 95% CI, 1.02-2.94]; P = .044) were independent predictors for the presence of LIPV triggers 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 ≤2.5 mm (11.4%), and both (15.0%). CONCLUSION: The 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 ≤2.5 mm significantly increase the risk of LIPV triggers or drivers, aiding electrophysiologists in preparing for and performing catheter ablation more effectively.

Stereotactic ablative radiotherapy versus conventional fractionated radiotherapy for clinical early-stage non-small-cell lung cancer: a population-based study.

INTRODUCTION: The use of stereotactic ablative radiotherapy (SABR) over conventional fractionated radiotherapy (CFRT) for early-stage non-small-cell lung cancer (NSCLC) has been advocated, but is also debated in the literature. METHODS: In this retrospective cohort study, we adopted a target trial emulation framework to identify eligible patients diagnosed between 2011 and 2021 using the Taiwan Cancer Registry. In the primary analysis, the overall survival (OS) was the primary endpoint, whereas incidences of lung cancer mortality and radiation pulmonary toxicity were the secondary endpoints. Extensive supplementary analyses were also conducted. RESULTS: We included 351 patients in the primary analysis and found that the OS was not significantly different between the SABR (n = 290) and CFRT (n = 61) groups. The propensity score weighting adjusted hazard ratio of death was 0.75 (95% confidence interval 0.53-1.07, p = 0.118). The secondary endpoints and supplementary analyses showed no significant differences. CONCLUSIONS: The OS of patients with early-stage NSCLC treated with SABR was not significantly different from that of patients treated with CFRT alone. The results of the relevant ongoing clinical trials are eagerly awaited.