Pre- and Post-treatment Double-Sequential-Point Dynamic Radiomic Model in the Response Prediction of Gastric Cancer to Neoadjuvant Chemotherapy: 3-Year Survival Analysis.

BACKGROUND: Prognosis prediction of patients with gastric cancer after neoadjuvant chemotherapy is suboptimal. This study aims to develop and validate a dynamic radiomic model for prognosis prediction of patients with gastric cancer on the basis of baseline and posttreatment features. PATIENTS AND METHODS: This single-center cohort study included patients with gastric adenocarcinoma treated with neoadjuvant chemotherapy from June 2009 to July 2015 in the Gastrointestinal Cancer Center of Peking University Cancer Hospital. Their clinicopathological data, pre-treatment and post-treatment computed tomography (CT) images, and pathological reports were retrieved and analyzed. Four prediction models were developed and validated using tenfold cross-validation, with death within 3 years as the outcome. Model discrimination was compared by the area under the curve (AUC). The final radiomic model was evaluated for calibration and clinical utility using Hosmer-Lemeshow tests and decision curve analysis. RESULTS: The study included 205 patients with gastric adenocarcinoma [166 (81%) male; mean age 59.9 (SD 10.3) years], with 71 (34.6%) deaths occurring within 3 years. The radiomic model alone demonstrated better discrimination than the pathological T stage (ypT) stage model alone (cross-validated AUC 0.598 versus 0.516, P = 0.009). The final radiomic model, which incorporated both radiomic and clinicopathological characteristics, had a significantly higher cross-validated AUC (0.769) than the ypT stage model (0.516), the radiomics alone model (0.598), and the ypT plus other clinicopathological characteristics model (0.738; all P < 0.05). Decision curve analysis confirmed the clinical utility of the final radiomic model. CONCLUSIONS: The developed radiomic model had good accuracy and could be used as a decision aid tool in clinical practice to differentiate prognosis of patients with gastric cancer.

Observation of Nonlinear Exceptional Points with a Complete Basis in Dynamics.

The exotic physics associated with exceptional points (EPs) is always under the scrutiny of theoretical and experimental science. Recently, considerable effort has been invested in the combination of nonlinearity and non-Hermiticity. The concept of nonlinear EPs (NEPs) has been introduced, which can avoid the loss of completeness of the eigenbasis in dynamics while retaining the key features of linear EPs. Here, we present the first direct experimental demonstration of a NEP based on two non-Hermition coupled circuit resonators combined with a nonlinear saturable gain. At the NEP, the response of the eigenfrequency to perturbations demonstrates a third-order root law and the eigenbasis of the Hamiltonian governing the system dynamics is still complete. Our results bring this counterintuitive aspect of the NEP to light and possibly open new avenues for applications.

Nomogram predictive models for adult patients with acute lymphoblastic leukaemia based on real-world treatment outcomes.

This study aimed to analyse the characteristics and treatment outcomes of adult patients with acute lymphoblastic leukaemia (ALL) and construct nomogram predictive models for prognosis prediction. Between January 2017 and June 2022, 462 adult patients with ALL were included in this retrospective analysis. Patients' ages ranged from 14 to 84 years. B-cell origin was observed in 82.7% of these patients, while 17.3% of the cases were of T-cell origin. The BCR/ABL1 fusion gene was detected in 32.9% of those with B-ALL. Complete remission was achieved in 83.7% of the patients after induction chemotherapy. The median disease-free survival (DFS) and overall survival (OS) of patients were 19.0 and 39.1 months, respectively. The 5-year DFS and OS rates were 29.5% and 41.8%, respectively. The BCR/ABL1 fusion gene had a significant adverse impact on DFS and OS when patients were treated with tyrosine kinase inhibitors (TKIs) and chemotherapy; however, this effect was eliminated when patients underwent transplantation. Multivariate analysis identified that age ≥ 35 years, white blood cell count ≥ 30 × 109/L, platelet count < 100 × 109/L, failure to achieve complete remission after induction chemotherapy, positive measurable residual disease (MRD), and absence of transplantation were independent adverse prognostic factors for DFS and/or OS. Nomogram predictive models constructed by the rms package in R software based on these prognostic factors demonstrated precise predictive value. In conclusion, adult patients with ALL experience poor survival. TKIs in combination with transplantation can eliminate the adverse effects of BCR/ABL1 fusion genes on prognosis. Nomogram predictive models were accurate for prognostic prediction and will be useful in clinical practice.

Association of Controlling Nutritional Status Score with Mortality in Patients with Chronic Limb-threatening Ischemia Following Endovascular Revascularization.

BACKGROUND: Chronic limb-threatening ischemia (CLTI) represents the severest manifestation of peripheral artery disease. Malnutrition is closely associated with poor clinical outcomes in patients with chronic diseases. The Controlling Nutritional Status (CONUT) score is a tool to evaluate the systemic inflammation and nutritional status. This study aimed to investigate the association of baseline CONUT score with mortality in patients with CLTI following endovascular revascularization. METHODS: A single-center retrospective analysis of patients with CLTI undergoing endovascular revascularization between January 2015 and December 2022 was performed. Preoperative nutritional status was evaluated using CONUT score, which was calculated using the serum albumin concentration, total peripheral lymphocyte count, and total cholesterol concentration. A CONUT score ≥5 indicates moderate or severe malnutrition. The Kaplan-Meier and multivariate Cox proportional hazards regression were used for survival analysis and to evaluate the risk factors associated with mortality. RESULTS: Among 232 enrolled patients, 20.7% of patients had moderate or severe malnutrition defined by the CONUT score. During a median follow-up of 2.1 (interquartile ranges, 1.0-3.5) years, 87 (37.5%) patients died. The 3-year overall survival rate in patients with CLTI who underwent endovascular revascularization was 63.7%. The high CONUT (≥5) group had significantly worse 3-year overall survival (42.0% versus 68.8%, P=0.004) and limb salvage (73.3% versus 84.1%, P=0.005) rates than the low CONUT (<5) group. Multivariate analysis showed that high CONUT score was significantly associated with increased risk for mortality in patients with CLTI after endovascular revascularization (hazard ratio, 1.687; 95% confidence interval, 1.031-2.759; P=0.037). CONCLUSION: The present study indicated that moderate or severe malnutrition defined by the CONUT score was significantly associated with increased mortality in patients with CLTI following endovascular revascularization. Future study is required to evaluate the efficacy of nutritional intervention in these patients.

Decoding the effects of varied peer victimization forms on depression and anxiety among Chinese adolescents: An exploration through latent transition analysis.

This study aims to examine co-occurrence patterns of depression and anxiety among Chinese adolescents and their associations with various forms of peer victimization. We collected longitudinal data from 1005 middle school students using the Multidimensional Peer Victimization Scale, Center for Epidemiological Studies Depression Scale, and State-Trait Anxiety Inventory. Then we conducted latent profile analysis, latent transition analysis, and logistic regression analysis. The results reveal the presence of three depression-anxiety profiles among participants: low depression-anxiety group, moderate depression-anxiety group, and high depression-anxiety group. As verbal and relational victimization increase, adolescents are more likely to transition to a higher level of depression-anxiety profile. However, an increase in physical and property victimization predicts a transition to a lower level of depression-anxiety profile. The diverse effects resulting from different forms of victimization exhibit gender differences. For boys, an increase in relational victimization made participants in the moderate depression-anxiety group more likely to transition to the high depression-anxiety group, whereas this effect was not significant among girls. This study is theoretically significant for understanding the link between depression, anxiety, and their influencing factors. It suggests that educators, while addressing verbal and relational harm in adolescents, should reconsider the potential impact of physical and property harm. Opportunities to transform negative events into positive ones should be explored. Educators should tailor their focus based on gender, with a particular emphasis on addressing relational harm among male students. This underscores the need for differentiated approaches to effectively support students.

Nonlinear Exceptional Points with a Complete Basis in Dynamics.

Exceptional points (EPs) are special spectral singularities at which two or more eigenvalues, and their corresponding eigenvectors, coalesce and become identical. In conventional wisdom, the coalescence of eigenvectors inevitably leads to the loss of completeness of the eigenbasis. Here, we show that this scenario breaks down in general at nonlinear EPs (NEPs). As an example, we realize a fifth-order NEP (NEP_{5}) within only three coupled resonators with both a theoretical model and simulations in circuits. One stable and another four auxiliary steady eigenstates of the nonlinear Hamiltonian coalesce at the NEP_{5}, and the response of eigenfrequency to perturbations demonstrates a fifth-order root law. Intriguingly, the biorthogonal eigenbasis of the Hamiltonian governing the system dynamics is still complete, and this fact is corroborated by a finite Petermann factor instead of a divergent one at conventional EPs. Consequently, the amplification of noise, which diverges at other EPs, converges at our NEP_{5}. Our finding transforms the understanding of EPs and shows potential for miniaturizing various key applications operating near EPs.

CT features combined with RECIST 1.1 criteria improve progression assessments of sunitinib-treated gastrointestinal stromal tumors.

OBJECTIVES: To explore the auxiliary value of combining CT features with existing response evaluation criteria in the prediction of progressive disease (PD) in gastrointestinal stromal tumors (GIST) patients treated with sunitinib. MATERIAL AND METHODS: Eighty-one patients with GISTs who received sunitinib were included in this retrospective multicenter study and divided into training and external validation cohorts. Progression at six months was determined as a reference standard. The predictive performance of the RECIST 1.1 and Choi criteria was compared. CT features at baseline and the first follow-up were analyzed. Logistic regression analyses were used to determine the most significant predictors and develop modified criteria. RESULTS: A total of 216 lesions showed a good response and 107 showed a poor response in 81 patients. The RECIST 1.1 criteria performed better than the Choi criteria in predicting progression (AUC, 0.75 vs. 0.69, p = 0.04). The expanded/intensified high-enhancement area, blurred tumor-tissue interface, and progressive enlarged vessels feeding or draining the mass (EVFDM) differed significantly between lesions with good and poor responses in the training cohort (p = 0.001, 0.003, and 0.000, respectively). Multivariate analysis revealed that the expanded/intensified high-enhancement area (p = 0.001), progressive EVFDM (p = 0.000), and RECIST PD (p = 0.000) were independent predictive factors. Modified RECIST (mRECIST) criteria were developed and showed significantly higher AUCs in the training and external validation cohorts than the RECIST 1.1 criteria (training: 0.81 vs. 0.73, p = 0.002; validation: 0.82 vs. 0.77, p = 0.04). CONCLUSION: The mRECIST criteria, combining CT features with the RECIST 1.1 criteria, demonstrated superior performance in the prediction of early progression in GIST patients receiving sunitinib. CLINICAL RELEVANCE STATEMENT: The mRECIST criteria, which combine CT features with the RECIST 1.1 criteria, may facilitate the early detection of progressive disease in GIST patients treated with sunitinib, thereby potentially guiding the timely switch to late-line medications or combination with surgical excision. KEY POINTS: • The RECIST 1.1 criteria outperformed the Choi criteria in identifying progression of GISTs in patients treated with sunitinib. • GISTs displayed different morphologic features on CT depending on how they responded to sunitinib. • Combining CT morphologic features with the RECIST 1.1 criteria allowed for the prompt and accurate identification of progressing GIST lesions.

Pathogenesis of psoriasis via miR-149-5p/AKT1axis by long noncoding RNA BLACAT1.

BACKGROUND: Psoriasis is a chronic, complicated, and recurrent inflammatory skin disease, whose precise molecular mechanisms need to be further explored. The lncRNA bladder cancer-associated transcript 1 (BLACAT1) is aberrantly expressed in many cancers and associated with cellular hyperproliferation and may play a role in the pathogenesis of psoriasis. Thus, this study aimed at identifying the primary mechanism associated with BLACAT1 in psoriasis pathogenesis. MATERIALS AND METHODS: Quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) was performed to detect the expression of BLACAT1 in psoriasis tissues. Cell proliferation and apoptosis were assessed using cell counting kit-8 and apoptosis assays, respectively. In vivo experiments and histopathological examinations were performed to investigate the effects of BLACAT1 on psoriasis. Dual-luciferase Reporter and RNA immunoprecipitation assays were used to evaluate the relationship among BLACAT1 and miR-149-5p and AKT1. RESULTS: BLACAT1 was upregulated in psoriasis tissues. Overexpression exacerbated the clinical manifestation of psoriasis and increased the epidermal thickness in imiquimod-induced mice. BLACAT1 could promote proliferation and inhibit apoptosis of keratinocytes. Further studies demonstrated that BLACAT1 positively regulated AKT1 expression, functioning as a competing endogenous RNA (ceRNA) by sponging miR-149-5p. CONCLUSIONS: The combination of lncRNA BLACAT1 and miR-149-5p regulates AKT1 expression and promotes psoriasis formation thus may provide a new direction for psoriasis treatment.

Fault Diagnosis of Power Transformer Based on Time-Shift Multiscale Bubble Entropy and Stochastic Configuration Network.

In order to accurately diagnose the fault type of power transformer, this paper proposes a transformer fault diagnosis method based on the combination of time-shift multiscale bubble entropy (TSMBE) and stochastic configuration network (SCN). Firstly, bubble entropy is introduced to overcome the shortcomings of traditional entropy models that rely too heavily on hyperparameters. Secondly, on the basis of bubble entropy, a tool for measuring signal complexity, TSMBE, is proposed. Then, the TSMBE of the transformer vibration signal is extracted as a fault feature. Finally, the fault feature is inputted into the stochastic configuration network model to achieve an accurate identification of different transformer state signals. The proposed method was applied to real power transformer fault cases, and the research results showed that TSMBE-SCN achieved 99.01%, 99.1%, 99.11%, 99.11%, 99.14% and 99.02% of the diagnostic rates under different folding numbers, respectively, compared with conventional diagnostic models MBE-SCN, TSMSE-SCN, MSE-SCN, TSMDE-SCN and MDE-SCN. This comparison shows that TSMBE-SCN has a strong competitive advantage, which verifies that the proposed method has a good diagnostic effect. This study provides a new method for power transformer fault diagnosis, which has good reference value.

In vivo assessment of Lauren classification for gastric adenocarcinoma using diffusion MRI with a fractional order calculus model.

OBJECTIVES: To evaluate the performance of a fractional order calculus (FROC) diffusion model for imaging-based assessment of Lauren classification in gastric adenocarcinoma. METHODS: In this study, 43 patients (15 females, 28 males) with gastric adenocarcinoma underwent MRI at 1.5 T. According to pathology-based Lauren classification, 10 patients had diffuse-type, 20 had intestinal-type, and 13 had mixed-type lesions. The diffuse and mixed types were combined as diffuse-and-mixed type to be differentiated from the intestinal type using diffusion MRI. Diffusion-weighted images were acquired by using eleven b-values (0-2000 s/mm2). Three FROC model parameters comprising diffusion coefficient D, intravoxel diffusion heterogeneity ß, and a microstructural quantity µ, together with a conventional apparent diffusion coefficient (ADC), were estimated. The mean parameter values in the tumour were computed by using a percentile histogram analysis. Individual or linear combinations of the mean parameters in the tumour were used to differentiate the diffuse-and-mixed type from the intestinal type using descriptive statistics and receiver operating characteristic (ROC) analyses. RESULTS: Significant differences were observed between diffuse-and-mixed-type and intestinal-type lesions in D (0.99 ± 0.20 µm2/ms vs. 1.11 ± 0.23 µm2/ms; p = 0.036), ß (0.37 ± 0.08 vs. 0.43 ± 0.11; p = 0.043), µ (7.92 ± 2.79 µm vs. 9.87 ± 1.52 µm; p = 0.038), and ADC (0.81 ± 0.34 µm2/ms vs. 0.96 ± 0.19 µm2/ms; p = 0.033). Among the individual parameters, µ produced the largest area under the ROC curve (0.739). The combinations of (D, ß, µ) and (ß and µ) produced the best overall performance with a sensitivity of 0.739, specificity of 0.750, accuracy of 0.744, and area under the curve of 0.793 (95% confidence interval: 0.657-0.929). CONCLUSION: Diffusion MRI with the FROC model holds promise for non-invasive assessment of Lauren classification for gastric adenocarcinoma. KEY POINTS: • High b-value diffusion MRI with a FROC model that is sensitive to tissue microstructures can differentiate the diffuse-and-mixed type from intestinal type of gastric adenocarcinoma. • The combination of FROC parameters produced the best result for distinguishing the diffuse-and-mixed type from the intestinal type with an area under the receiver operating characteristic curve of 0.793. • The FROC model parameters, individually or conjointly, hold promise for repeated, non-invasive evaluations of gastric adenocarcinoma at various time points throughout disease progression or regression to complement conventional Lauren classification.

Radiomics in Antineoplastic Agents Development: Application and Challenge in Response Evaluation.

The recent spring up of the antineoplastic agents and the prolonged survival bring both challenge and chance to radiological practice. Radiological methods including CT, MRI and PET play an increasingly important role in evaluating the efficacy of these antineoplastic drugs. However, different antineoplastic agents potentially induce different radiological signs, making it a challenge for radiological response evaluation, which depends mainly on one-sided morphological response evaluation criteria in solid tumors (RECIST) in the status quo of clinical practice. This brings opportunities for the development of radiomics, which is promising to serve as a surrogate for response evaluations of anti-tumor treatments. In this article, we introduce the basic concepts of radiomics, review the state-of-art radiomics researches with highlights of radiomics application in predictions of molecular biomarkers, treatment response, and prognosis. We also provide in-depth analyses on major obstacles and future direction of this new technique in clinical investigations on new antineoplastic agents.

Comparative Effectiveness of Drug-Coated Balloon vs Balloon Angioplasty for the Treatment of Arteriovenous Fistula Stenosis: A Meta-analysis.

Purpose: To compare the effectiveness and safety outcomes of drug-coated balloon angioplasty (DCBA) vs conventional balloon angioplasty (BA) for arteriovenous fistula (AVF) stenosis. Materials and Methods: A systematic review was conducted of PubMed and Embase databases from 1966 to May 2019 to identify English-language articles evaluating DCBA vs BA for the treatment of AVF stenosis. Data extracted from each study were synthesized to evaluate target lesion revascularization (TLR), technical success, and mortality for the 2 approaches. Meta-analyses were performed on these outcomes using random effects models to estimate the odds ratios (ORs) and 95% confidence intervals (CIs). Subgroup and sensitivity analyses were performed. Results: Twelve studies [6 randomized controlled trials (RCTs) and 6 cohort studies] comprising 979 patients were included in this meta-analysis. The pooled results showed that AVFs treated with DCBA had significantly fewer TLRs at 6 months (OR 0.31, 95% CI 0.14 to 0.69, p=0.004) and 12 months (OR 0.45, 95% CI 0.21 to 0.97, p=0.04) than BA. The 2 approaches had similar technical success rates (OR 0.22, 95% CI 0.03 to 1.43, p=0.11). Additionally, the pooled OR of 12-month mortality was 0.71 (95% CI 0.20 to 2.51, p=0.60), indicating no significant difference between DCBA and BA. Subgroup analysis based on study design showed the superiority of DCBA to BA in cohort studies but not RCTs, which had high heterogeneity. Significant publication bias was found in the cohort studies. Conclusion: In de novo or recurrent AVF stenosis, DCBA appears to be an effective procedure associated with lower 6- and 12-month TLR compared with BA. However, larger and randomized controlled studies are warranted to draw definitive conclusions.

High oxygen modifies vasodilator effect of cysteine via enhanced oxidative stress and thromboxane production in the rat mesenteric artery.

Whether high oxygen is harmful to the vascular function is unclear. The present study examined if high oxygen modifies vasodilator effect of cysteine via enhanced oxidative stress and thromboxane production. Rat mesenteric arteries with endothelium at 95 or 50 % oxygen were subjected to isometric force recordings, measurement of thromboxane B2 levels, determination of superoxide and peroxynitrite levels and evaluation of NADPH oxidase subunit protein expression, respectively. L-cysteine (0.01-3 mM) constricted or dilated arteries at 95 and 50 % oxygen, respectively. Thromboxane receptor antagonist SQ-29,548 (1 µM) abolished the constriction at 95 % oxygen. L-cysteine (3 mM) increased levels of thromboxane B2 in arteries upon 95 % oxygen application. L-cysteine relaxed arteries treated with superoxide inhibitor tiron (2 mM) or NADPH oxidase inhibitor gp91ds-tat (1 µM) irrespective of the oxygen concentration while ATP-sensitive K(+) channel inhibitor glibenclamide (1 µM) and cystathionine-γ-lyase (CSE) inhibitor DL-propargylglycine (10 mM) similarly abolished the relaxation. L-cysteine (3 mM) with 95 % oxygen augmented levels of superoxide as well as nitrotyrosine within the artery, concomitantly with enhanced membrane protein expression of NADPH oxidase subunit p47phox. The higher concentration of oxygen attenuates L-cysteine-induced vasodilation via superoxide production mediated by NADPH oxidase along with thromboxane A2 production, resulting in vasoconstriction. The increased levels of superoxide, as well as peroxynitrite, coexist with the impaired vasodilation related to ATP-sensitive K(+) channels and CSE. Higher oxygen with plasma cysteine may cause oxidative stress and vasoconstrictor prostanoid production in blood vessels.

Propofol reduces liver dysfunction caused by tumor necrosis factor-α production in Kupffer cells.

PURPOSE: The present study, conducted in rats, investigated whether propofol attenuates lipopolysaccharide (LPS)-triggered liver dysfunction via regulation of tumor necrosis factor (TNF)-α production in activated Kupffer cells. METHODS: Rats received LPS (500 µg/kg) under Urethane™ sedation (1 g/kg) in combination with propofol (5 mg/kg/h) or Intralipid™ from 1 h before to 6 h after LPS administration. Some rats were treated with 10 mg/kg gadolinium chloride (GdCl3) to induce Kupffer cell depletion. The serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST), TNF-α mRNA and protein expression, caspase-3 activation and apoptosis were evaluated in hepatocytes. Immunofluorescence staining revealed expression of the pan-macrophage marker CD68 as well as TNF-α in Kupffer cells. RESULTS: ALT and AST serum levels increased approximately four-fold in LPS-exposed rats compared with Intralipid™-treated rats at 6 h after LPS administration, whereas propofol and GdCl3 reduced the LPS-induced increases. LPS simultaneously augmented TNF-α expression in Kupffer cells, followed by increased caspase-3 activity and apoptosis in hepatocytes. Immunofluorescence staining and immunoblotting assay showed that TNF-α expression in Kupffer cells was inhibited by propofol and GdCl3, resulting in a reduction of caspase-3 activity and apoptosis in LPS-treated rat hepatocytes. CONCLUSIONS: Propofol (5 mg/kg/h) attenuated LPS-triggered liver dysfunction via inhibition of TNF-α production in activated Kupffer cells. These results suggest that propofol is capable of inhibiting inflammation-induced liver dysfunction in vivo.

Kynurenine causes vasodilation and hypotension induced by activation of KCNQ-encoded voltage-dependent K(+) channels.

Kynurenine is a potential contributor to hypotension in animal and human sepsis. The present study was designed to examine whether the voltage-dependent K(+) channels encoded by the KCNQ gene family (Kv7 channels) mediate vasodilator effects of kynurenine and whether modulation of these channels ameliorates hypotension caused by this compound. Rat aortas and mesenteric arteries or human omental arteries without endothelium were used. Some rings were incubated with the selective Kv7 channel inhibitor linopirdine (10 µM). l-Kynurenine (10 µM-1 mM) induced concentration-dependent relaxation in rat aortas and mesenteric arteries as well as human omental arteries, whereas linopirdine abolished the relaxation. l-Kynurenine (1 mM) produced hyperpolarization of vascular smooth muscle, which was reversed by linopirdine (10 µM). Wistar rats received l-kynurenine (1 mM) iv and subsequent linopirdine (10 µM) iv under 3% sevoflurane inhalation. l-Kynurenine iv caused hypotension, whereas linopirdine iv partially reversed it. In conclusion, kynurenine dilates arteries from rats as well as humans via Kv7 channels in the vascular smooth muscle. In rats, this tryptophan metabolite causes hypotension, which is partly counteracted by Kv7 channel inhibition. These results suggest that modulation of Kv7 channels may be a novel strategy to treat hypotension induced by the kynurenine.

Association between serum osmolality and 28-day all-cause mortality in patients with heart failure and reduced ejection fraction: a retrospective cohort study from the MIMIC-IV database.

Background: Previous studies have not thoroughly explored the impact of serum osmolality levels on early mortality in heart failure and reduced ejection fraction (HFrEF) patients. The purpose of this study was to investigate the relationship between serum osmolality levels and early all-cause mortality in patients with HFrEF. Methods: The open access MIMIC-IV database was the source of data for our study. We collected demographic data, vital signs, laboratory parameters, and comorbidities of the included patients and divided them into 3 groups based on their initial serum osmolality on admission, with the primary outcome being all-cause mortality within 28 days of admission. Smoothing Spline Fitting Curve, the Kaplan-Meier survival curve, and Threshold effect analysis were used to assess the relationship between serum osmolality and early mortality in HFrEF patients. Results: A total of 6228 patients (55.31% male) were included. All-cause mortality within 28 days on admission was 18.88% in all patients. After adjusting for confounders, higher serum osmolality levels were independently associated with an increased risk of 28-days all-cause mortality compared with the reference group (Reference group Q2: 290-309 mmol/L, Q4: HR, 1.82 [95% CI 1.19-2.78] P<0.05, Q5: HR, 1.99 [95% CI 1.02-3.91] P<0.05). Smooth spline fitting revealed a U-shaped association between serum osmolality and 28-days all-cause mortality. Further threshold effect analysis results suggested that each unit increase in serum osmolality level was associated with a 2% increase in 28-days all-cause mortality when serum osmolality levels were ≥ 298.8 mmol/L (HR, 1.019 [95% CI 1.012-1.025] P<0.05). Conclusion: A U-shaped correlation between initial serum osmolality and 28-days all-cause mortality in HFrEF patients was identified, revealing higher osmolality levels significantly increase mortality risk. These results underscore serum osmolality's critical role in early mortality among HFrEF patients, highlighting the need for further, larger-scale studies for validation.

Circular RNA circLIFR suppresses papillary thyroid cancer progression by modulating the miR-429/TIMP2 axis.

PURPOSE: Circular RNAs (circRNAs) are increasingly recognized for their important roles in various cancers, including papillary thyroid cancer (PTC). The specific mechanisms by which the circLIF receptor subunit alpha (circLIFR, hsa_circ_0072309) influences PTC progression remain largely unknown. METHODS: In our study, CircLIFR, miR-429, and TIMP2 levels were assessed using reverse transcription-quantitative PCR. The roles of circLIFR and miR-429 in PTC cells were determined using Cell Counting Kit-8, colony formation, wound healing, and Transwell assays. Western blotting was utilized to examine the levels of TIMP2. The direct interaction between circLIFR, TIMP2, and miR-429 was confirmed using dual-luciferase reporter, RNA immunoprecipitation, and fluorescence in situ hybridization assays. RESULTS: In PTC tissues and cells, a decrease in circLIFR and TIMP2 levels, accompanied by an increase in miR-429 levels, was observed. Overexpression of circLIFR or downregulation of miR-429 effectively suppressed the proliferation and migration of PTC cells. Conversely, the knockdown of circLIFR or overexpression of miR-429 had the opposite effect. Furthermore, circLIFR overexpression suppressed tumor growth in vivo. Mechanistically, circLIFR modulated TIMP2 expression by serving as a sponge for miR-429. Rescue experiments indicated that the antitumor effect of circLIFR could be reversed by miR-429. CONCLUSION: This study confirmed circLIFR as a novel tumor suppressor delayed PTC progression through the miR-429/TIMP2 axis. These findings suggested that circLIFR held promise as a potential therapeutic target for PTC.

[Correlation of miR-155 Expression with Drug Sensitivity of FLT3-ITD+ Acute Myeloid Leukemia Cell Line and Its Mechanism].

OBJECTIVE: To investigate the correlation of miR-155 expression with drug sensitivity of FLT3-ITD+ acute myeloid leukemia (AML) cell line and its potential regulatory mechanism. METHODS: By knocking out miR-155 gene in FLT3-ITD+ AML cell line MV411 through CRISPR/Cas9 gene-editing technology, monoclonal cells were screened. The genotype of these monoclonal cells was validated by PCR and Sanger sequencing. The expression of mature miRNA was measured by RT-qPCR. The treatment response of doxorubicin, quizartinib and midostaurin were measured by MTT assay and IC50 of these drugs were calculated to identify the sensitivity. Transcriptome sequencing was used to analyze change of mRNA level in MV411 cells after miR-155 knockout, gene set enrichment analysis to analyze change of signaling pathway, and Western blot to verify expressions of key molecules in signaling pathway. RESULTS: Four heterozygotes with gene knockout and one heterozygote with gene insertion were obtained through PCR screening and Sanger sequencing. RT-qPCR results showed that the expression of mature miR-155 in the monoclonal cells was significantly lower than wild-type clones. MTT results showed that the sensitivity of MV411 cells to various anti FLT3-ITD+ AML drugs increased significantly after miR-155 knockout compared with wild-type clones. RNA sequencing showed that the mTOR signaling pathway and Wnt signaling pathway were inhibited after miR-155 knockout. Western blot showed that the expressions of key molecules p-mTOR, Wnt5α and ß-catenin in signaling pathway were down-regulated. CONCLUSION: Drug sensitivity of MV411 cells to doxorubicin, quizartinib and midostaurin can be enhanced significantly after miR-155 knockout, which is related to the inhibition of multiple signaling pathways including mTOR and Wnt signaling pathways.

High expression of SLC27A2 predicts unfavorable prognosis and promotes inhibitory immune infiltration in acute lymphoblastic leukemia.

Solute carrier family 27 member 2 (SLC27A2) is involved in fatty acid metabolism in tumors and represents a prospective target for cancer therapy. However, the role and mechanism of action of SLC27A2 in acute lymphoblastic leukemia (ALL) remain unclear. In this study, we aimed to explore the intrinsic associations between SLC27A2 and ALL and evaluate the prognostic significance, biological functions, and correlation with immune infiltration. We used the transcriptome and clinical data from the TARGET dataset. Differentially expressed genes (DEGs) in the SLC27A2 low- and high-expression groups were analyzed for prognostic implications and functional enrichment. Furthermore, we analyzed the relationship between SLC27A2 gene expression and immune cell infiltration using the ESTIMATE method, which was evaluated using the TIGER platform. Finally, we knocked down SLC27A2 in the Jurkat ALL cell line and conducted cell proliferation, western blotting, flow cytometry, and CCK-8 assays to elucidate the biological function of SLC27A2 in ALL. Patients with ALL who have higher expression levels of SLC27A2 have poorer overall survival and event-free survival. According to gene set enrichment analysis, the DEGs were primarily enriched with immune system processes and the PI3K-Akt signaling pathway. There was an inverse relationship between SLC27A2 expression and immune cell invasion, suggesting involvement of the former in tumor immune evasion. In vitro experiments showed that knockdown of SLC27A2 inhibited cell proliferation and protein expression and altered the Akt pathway, with a reduced proportion of B cells. In conclusion, SLC27A2 plays a vital role in the development of ALL.

Management of complications associated with percutaneous left atrial appendage closure with or without ablation: experience from 512 cases over a 4-year period.

Background: Percutaneous left atrial appendage closure (LAAC) serves as an alternative prophylactic strategy for patients with non-valvular atrial fibrillation (AF) who cannot undergo anti-coagulation therapy. Proper management of associated complications is crucial to enhancing the procedure's success rate and mitigating perioperative risks and adverse events during follow-up. Aims: This study aims to summarize our center's experience and strategies in managing procedural-related complications encountered in 512 cases of LAAC with or without ablation for AF conducted from January 2020 to December 2023. Results: We identified 11 significant intervention-requiring complications associated with LAAC with or without Ablation procedure. These included three cases of intraoperative thrombosis, three instances of pericardial effusion or tamponade, one case of device-related thrombosis, one peri-device leak, one systemic embolism, one bleeding episode, and one additional device-related complication. The categorization of intraoperative thrombosis was as follows: one patient exhibited heparin resistance; one experienced thrombosis due to prolonged device implantation during the LAAC with ablation procedure; and one had unexplained intraoperative thrombosis. The pericardial effusion or tamponade likely resulted from damage to the atrial appendage during LAAC device insertion. Two patients encountered device-related thrombosis and systemic embolism events possibly caused by non-standard postoperative antithrombotic medication use; one patient's peri-device leak may have resulted from incomplete endothelialization of the occluder post-surgery; one patient experienced postoperative bladder bleeding; and one patient's device-related complications occurred due to a dislodged strut frame that damaged the left atrial appendage, leading to pericardial effusion. Our proactive interventions enabled all patients with these surgical-related complications to be safely discharged, with subsequent follow-ups showing no adverse events. Conclusion: Implementing targeted interventions for immediate procedural-related complications during the LAAC with or without ablation procedures enhances procedural success rates, diminishes postoperative mortality and patient disability, and bolsters stroke prevention efforts. This approach underscores the importance of a strategic response to complications, affirming the procedure's viability and safety in managing non-valvular AF in patients contraindicated for anticoagulation.