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Catalase (CAT) is an important antioxidant enzyme that breaks down H2O2 into water and oxygen. Inhibitor-modulating CAT activity in cancer cells is emerging as a potential anticancer strategy. However, the discovery of CAT inhibitors towards the heme active center located at the bottom of long and narrow channel has made little progress. Therefore, targeting new binding site is of great importance for the development of efficient CAT inhibitors. Here, the first NADPH-binding site inhibitor of CAT, BT-Br, was designed and synthesized successfully. The cocrystal structure of BT-Br-bound CAT complex was determined with a resolution of 2.2 Å (PDB ID:8HID), which showed clearly that BT-Br bound at the NADPH-binding site. Furthermore, BT-Br was demonstrated to induce ferroptosis in castration-resistant prostate cancer (CRPC) DU145 cells and eventually reduce CRPC tumors in vivo effectively. The work indicates that CAT has potential as a novel target for CRPC therapy based on ferroptosis inducing.

Summary: Age-associated neurodegenerative disorders such as Parkinson’s and Alzheimer’s diseases are mainly caused by protein aggregation. The etiologies of these neurodegenerative diseases share a chemical environment. However, how chemical cues modulate neurodegeneration remains unclear. Here, we found that in Caenorhabditis elegans, exposure to pheromones in the L1 stage accelerates neurodegeneration in adults. Perception of pheromones ascr#3 and ascr#10 is mediated by chemosensory neurons ASK and ASI. ascr#3 perceived by G protein-coupled receptor (GPCR) DAF-38 in ASK activates glutamatergic transmission into AIA interneurons. ascr#10 perceived by GPCR STR-2 in ASI activates the secretion of neuropeptide NLP-1, which binds to the NPR-11 receptor in AIA. Activation of both ASI and ASK is required and sufficient to remodel neurodevelopment via AIA, which triggers insulin-like signaling and inhibits autophagy in adult neurons non-cell-autonomously. Our work reveals how pheromone perception at the early developmental stage modulates neurodegeneration in adults and provides insights into how the external environment impacts neurodegenerative diseases.

Abstract Objective The objective of this study is to investigate clinical features and prognostic factors of antimelanoma differentiation‐associated gene 5 (anti‐MDA5)‐positive dermatomyositis with rapidly progressive interstitial lung disease (RP‐ILD) in Chinese patients. Methods Clinical features and prognostic factors of patients with newly diagnosed or recurrent dermatomyositis patients were retrospectively analyzed. All patients were divided into the anti‐MDA5‐positive or negative dermatomyositis, and with or without RP‐ILD groups. Clinical features and prognostic factors were statistically compared among different groups. Results The serum ferritin (SF) levels (1500.0 [658.80, 1844.0]) and γ‐glutamyl transpeptidase (γ‐GT) (125.5 [61.0, 232.0] vs. 28 [16.0, 41.0], Z = 5.528; p

Abstract Background The non-local module has been primarily used in literature to capturing long-range dependencies. However, it suffers from prohibitive computational complexity and lacks the interactions among positions across the channels. Methods We present a deformed non-local neural network (DNL-Net) for medical image segmentation, which has two prominent components; deformed non-local module (DNL) and multi-scale feature fusion. The former optimizes the structure of the non-local block (NL), hence, reduces the problem of excessive computation and memory usage, significantly. The latter is derived from the attention mechanisms to fuse the features of different levels and improve the ability to exchange information across channels. In addition, we introduce a residual squeeze and excitation pyramid pooling (RSEP) module that is like spatial pyramid pooling to effectively resample the features at different scales and improve the network receptive field. Results The proposed method achieved 96.63% and 92.93% for Dice coefficient and mean intersection over union, respectively, on the intracranial blood vessel dataset. Also, DNL-Net attained 86.64%, 96.10%, and 98.37% for sensitivity, accuracy and area under receiver operation characteristic curve, respectively, on the DRIVE dataset. Conclusions The overall performance of DNL-Net outperforms other current state-of-the-art vessel segmentation methods, which indicates that the proposed network is more suitable for blood vessel segmentation, and is of great clinical significance.

Polymyxin B is a viable option for treating antibiotic‐resistant infections; however, current data on its pharmacokinetics, particularly in patients with renal insufficiency, remain inconclusive and necessitates further investigation. To address this gap, we conducted an open‐label, single‐center, single‐dose, parallel‐group pharmacokinetic study. Participants received an intravenous dose of 0.75 mg/kg of polymyxin B and were categorized based on their renal function: those with normal function (creatinine clearance [CLcr] ≥ 90 mL/min), mild renal insufficiency (CLcr 60–89 mL/min), and end‐stage kidney disease patients on intermittent hemodialysis (IHD) (CLcr < 10 mL/min). The pharmacokinetic parameters assessed included the area under the curve (AUC), maximum concentration (Cmax), clearance rate (CL), volume of distribution (Vz), and half‐life (t1/2). Results indicated that subjects with mild renal insufficiency exhibited pharmacokinetic profiles similar to healthy individuals. Nevertheless, in patients undergoing long‐term IHD, we observed significant differences: the AUC was 58% higher, Cmax was 29% lower, CL was 42% lower, Vz was 60% larger, and t1/2 was extended by 10 h compared to healthy controls. Secondary outcomes revealed good tolerability of polymyxin B across all groups, with no serious adverse effects related to renal function. In summary, while kidney function may have a slight impact on the pharmacokinetic of polymyxin B, it does not compromise the drug's therapeutic effectiveness. [ABSTRACT FROM AUTHOR]

This study aims to develop a deep learning model to predict peritoneal dialysis (PD) failure within the next three months using data from the preceding three months. Background: PD patients typically perform treatments at home and visit the clinic only once per month, leading to significant gaps in clinical care and increased risks of PD failure, which may necessitate a transition to hemodialysis (HD). Current studies on PD patients largely focus on predicting PD failure, mortality risk, and hospitalization through traditional machine learning methods, with limited application of deep learning for this purpose. Methods: We collected comprehensive patient data, including demographic information, comorbidities, medication history, biochemical test results, dialysis prescriptions, and peritoneal equilibrium test outcomes. After preprocessing, we employed time-series deep learning models to train and make predictions. Results: The model achieved a prediction accuracy of 89% and an AUROC of 92%, outperforming previous methods used for PD failure prediction. Conclusion: This approach not only improves prediction accuracy but also identifies key features that can aid clinicians in developing more precise treatment plans and enhancing patient care. [ABSTRACT FROM AUTHOR]

IntroductionA negative association between C-terminal fibroblast growth factor 23 (cFGF23) and hemoglobin (Hb) levels has been reported in patients with predialysis chronic kidney disease. In dialysis patients, the dominant form of serum FGF23 is intact FGF23 (iFGF23); however, its association with the Hb level remains unclear. Therefore, simultaneously monitoring iFGF23 and cFGF23 levels is crucial. In this study, we investigated the associations between both forms of FGF23 (iFGF23 and cFGF23) and renal anemia in chronic hemodialysis (CHD) patients.MethodsWe included 166 CHD patients from two hospitals in this cross-sectional, observational study. The primary predictors were serum iFGF23, cFGF23, and iFGF23/cFGF23 levels. The main outcome was the Hb level.ResultsAmong the CHD patients included, 60.8% were men with a mean age of 59.4 ± 12.7 years. In the crude analysis, iFGF23 and iFGF23/cFGF23 levels showed a significant negative association (−0.27, p = 0.004 and −0.22, p = 0.034, respectively) with the Hb level. Even after adjusting for multiple variables (a parsimonious model), every increment of natural log transformation by 1 for (ln)iFGF23 and ln(iFGF23/cFGF23) levels showed a negative correlation with the Hb level (estimate: −0.27 [95%CI: −0.44, −0.10, p = 0.001]; −0.19 [95%CI: −0.37, −0.01, p = 0.042], respectively), whereas both were positively associated with erythropoietin-stimulating agent (ESA) hyporesponsiveness (odds ratio [OR]: [95%CI: 2.30, 1.26–4.17], p = 0.006; 1.95 [95%CI: 1.08–3.50], p = 0.025). Moreover, these abovementioned associations were more dominant in patients with diabetes who used angiotensin receptor blockers.DiscussionIn conclusion, a negative association between serum iFGF23 or iFGF23/cFGF23 level and the Hb level was observed in our CHD patients. Meanwhile, a higher iFGF23 or iFGF23/cFGF23 level may predispose patients to ESA hyporesponsiveness.

Abstract. Decidualization is the differentiation of endometrial stromal cells into secretory decidual stromal cells. Human decidualization involves some amount of signaling molecules and pathways as well as genetic reprogramming, which is driven by the postovulatory rise in progesterone levels and local cyclic adenosine monophosphate production. Decidualization extends from the primary decidual zone to the secondary decidual zone, and then exits through apoptosis. Evidences support that decidual fibroblasts function as the pool of decidual stromal cells during pregnancy. Decidualization undergoes an acute inflammatory phase, an anti-inflammatory secretory phase to the final recession phase. The decidualization of the inner layer of endometrium, termed decidua, is the most critical determinant of pregnancy success, which can promote placenta formation, modulate immune tolerance, foster resistance to oxidative stress, sense embryo quality, and control labor. Failure to adequate decidualization in terms of hormones, biochemistry, and immunology leads to adverse pregnancy outcomes, including diseases such as preeclampsia, miscarriage, premature labor, repeated implantation failures, and some age-related decline in reproductive capacity. The development of animal models and in vitro culture systems combined with emerging technologies provides a powerful system to explore the mechanism of decidualization. However, decidualization is a dynamic, multi-step process, and translating of current research progress into disease predictions and interventions for pregnancy complications remains to be achieved. The study of periodic regeneration and spontaneous decidualization of the endometrium will be beneficial to the diagnosis and treatment of pregnancy diseases.

Current treatments for advanced hepatocellular carcinoma (HCC) have limited success in improving patients’ quality of life and prolonging life expectancy. The clinical need for more efficient and safe therapies has contributed to the exploration of emerging strategies. Recently, there has been increased interest in oncolytic viruses (OVs) as a therapeutic modality for HCC. OVs undergo selective replication in cancerous tissues and kill tumor cells. Strikingly, pexastimogene devacirepvec (Pexa-Vec) was granted an orphan drug status in HCC by the U.S. Food and Drug Administration (FDA) in 2013. Meanwhile, dozens of OVs are being tested in HCC-directed clinical and preclinical trials. In this review, the pathogenesis and current therapies of HCC are outlined. Next, we summarize multiple OVs as single therapeutic agents for the treatment of HCC, which have demonstrated certain efficacy and low toxicity. Emerging carrier cell-, bioengineered cell mimetic- or nonbiological vehicle-mediated OV intravenous delivery systems in HCC therapy are described. In addition, we highlight the combination treatments between oncolytic virotherapy and other modalities. Finally, the clinical challenges and prospects of OV-based biotherapy are discussed, with the aim of continuing to develop a fascinating approach in HCC patients.

Environmental stressors such as salinity have pronounced impacts on the growth, productivity, nutrition, and flavor of horticultural crops, though yield loss sometimes is inevitable. In this study, the salinity influences were evaluated using hydroponic Chinese chive (Allium tuberosum) treated with different concentrations of sodium chloride. The results demonstrated that lower salinity could stimulate plant growth and yield. Accordingly, the contents of soluble sugar, ascorbic acid, and soluble protein in leaf tissues increased, following the decrease of the nitrate content, under mild salinity (6.25 or 12.5 mM NaCl). However, a higher level of salinity (25 or 50 mM NaCl) resulted in growth inhibition, yield reduction, and leaf quality deterioration of hydroponic chive plants. Intriguingly, the chive flavor was boosted by the salinity, as evidenced by pungency analysis of salinity-treated leaf tissues. UPLC-MS/MS analysis reveals that mild salinity promoted the accumulation of glutamic acid, serine, glycine, and proline in leaf tissues, and thereby enhanced the umami and sweet flavors of Chinese chive upon salinity stress. Considering the balance between yield and flavor, mild salinity could conduce to hydroponic Chinese chive cultivation. Transcriptome analysis revealed that enhanced pungency could be ascribed to a salt stress-inducible gene, AtuFMO1, associated with the biosynthesis of S-alk(en)yl cysteine sulphoxides (CSOs). Furthermore, correlation analysis suggested that two transcription factors, AtubHLH and AtuB3, were potential regulators of AtuFMO1 expressions under salinity. Thus, these results revealed the molecular mechanism underlying mild salinity-induced CSO biosynthesis, as well as a practical possibility for producing high-quality Chinese chive hydroponically.

Coxsackievirus B3 (CVB3) was one of the most common pathogens to cause viral myocarditis. Circular RNAs as novel non-coding RNAs with a closed loop molecular structure have been confirmed to be involved in virus infectious diseases, but the function in CVB3 infection was not systematically studied. In this study, we identified that hsa_circ_0063331 (circDDX17) was drastically decreased after CVB3 infection by circRNA microarray. In vivo and in vitro, when cells or mice were infected with CVB3, the expression of circDDX17 was significantly reduced, as demonstrated by quantitative real-time PCR assays. Additionally, circDDX17 enhanced CVB3 replication by downregulating the expression of miR-1248 in HeLa and HL-1 cells, and miR-1248 regulated CVB3 replication through interacting with the gene coding for NOTCH Receptor 2 (NOTCH2), and NOTCH2 could upregulate methyltransferase-like protein 3 (METTL3). Taken together, this study suggested that circDDX17 promoted CVB3 replication and regulated NOTCH2 by targeting miR-1248 as a miRNAs sponge.

Changes in neurotransmitter receptor abundance at post-synaptic elements play a pivotal role in regulating synaptic strength. For this reason, there is significant interest in identifying and characterizing the scaffolds required for receptor localization at different synapses. Here we analyze the role of two C. elegans post-synaptic scaffolding proteins (LIN-2/CASK and FRM-3/FARP) at cholinergic neuromuscular junctions. Constitutive knockouts or muscle specific inactivation of lin-2 and frm-3 dramatically reduced spontaneous and evoked post-synaptic currents. These synaptic defects resulted from the decreased abundance of two classes of post-synaptic ionotropic acetylcholine receptors (ACR-16/CHRNA7 and levamisole-activated AChRs). LIN-2's AChR scaffolding function is mediated by its SH3 and PDZ domains, which interact with AChRs and FRM-3/FARP, respectively. Thus, our findings show that post-synaptic LIN-2/FRM-3 complexes promote cholinergic synaptic transmission by recruiting AChRs to post-synaptic elements.

Abstract Chinese chive (Allium tuberosum) is widely cultivated around the world for its unique flavor, nutrient, and medicinal values, yet its molecular mechanism on flavor formation and other metabolic pathways remains intangible. The elucidation of these complex processes begins with investigating the expression of the genes of interest, however the appropriate reference genes (RGs) for normalizing the gene expression are still unavailable in A. tuberosum. To fill this lacuna, transcriptome-wide screening was undertaken to identify the most stable genes according to the analysis of their FPKM values. The expression stability of the RGs was further evaluated using geNorm, NormFinder, BestKeeper, and RefFinder algorithms. The comprehensive analysis showed that GLY1 and SKP1, instead of two traditionally used RGs (eIF1α and ACT2), were the most stable genes across diverse A. tuberosum tissues, indicating the necessity to carefully validate the stability of RGs prior to their use for normalizations. As indicated by geNorm, the normalizations with at least two RGs could give more accurate results. qRT-PCR experiments were conducted with randomly selected genes, demonstrating that normalization with a combination of GLY1 and SKP1 resulted in reliable normalization results. Our finding represents the first attempt toward establishing a standardized qRT-PCR analysis in this economically important vegetable.

The transition metal catalyzed cyclization of alkene‐tethered carbamoyl chloride has emerged as a tool to construct oxindoles bearing quaternary centers. Most of these reactions proceed via carbometalation‐initiated 5‐exo‐trig cyclization followed by nucleophilic trapping of the resulting σ alkyl‐metal species to achieve diverse functionalized oxindoles. The 6‐endo‐trig type cyclization of alkene‐tethered carbamoyl chloride has been rarely reported. Herein, a zinc‐mediated carbamoyl amination of alkylidenecyclopropane‐tethered carbamoyl chlorides with anilines for the synthesis of functionalized 2‐quinolones was developed. A range of different substituted 2‐quinolones were prepared in 65–89% yield from alkylidenecyclopropane‐tethered carbamoyl chlorides and aniline derivatives using a Zn/TMSCl system. [ABSTRACT FROM AUTHOR]

Summary: Background: Optimal glycaemic control has well‐established health benefits in patients with diabetes mellitus (DM). It is uncertain whether optimal glycaemic control can benefit liver‐related outcomes. Aims: To examine the association of optimal glycaemic control with hepatocellular carcinoma (HCC) and liver‐related mortality. Methods: In a population‐based cohort, we identified patients with newly diagnosed DM between 2001 and 2016 in Hong Kong. Optimal glycaemic control was defined as mean haemoglobin A1c (HbA1c) <7% during the 3‐year lead‐in period after DM diagnosis. By applying propensity score matching to balance covariates, we analysed glycaemic control via competing risk models with outcomes of interest being HCC and liver‐related mortality. Results: We identified 146,430 patients (52.2% males, mean age 61.4 ± 11.8 years). During a median follow‐up duration of 7.0 years, 1099 (0.8%) and 978 (0.7%) patients developed HCC and liver‐related deaths. Optimal glycaemic control, when compared to suboptimal glycaemic control, was associated with reduced risk of HCC (subdistribution hazard ratio [SHR] 0.70, 95% CI 0.61–0.79). The risk of HCC increased with incremental HbA1c increases beyond >7% (SHR 1.29–1.71). Significant associations with HCC were also found irrespective of age (SHR 0.54–0.80), sex (SHR 0.68–0.69), BMI <25 or ≥25 kg/m2 (SHR 0.63–0.75), smoking (SHR 0.61–0.72), hepatic steatosis (SHR 0.67–0.68) and aspirin/statin/metformin use (SHR 0.67–0.75). A lower risk of liver‐related mortality in relation to optimal glycaemic control was also observed (SHR 0.70, 95% CI 0.61–0.80). Conclusions: Glycaemic control is an independent risk factor for HCC and liver‐related mortality, and should be incorporated into oncoprotective strategies in the general DM population. [ABSTRACT FROM AUTHOR]

Background and Aim: We aimed to investigate the effect of metabolic dysfunction‐associated steatotic liver disease (MASLD) on three‐dose BNT162b2 immunogenicity to the omicron variant. Methods: Adult recipients of three doses of BNT162b2 were prospectively recruited between May and December 2021. The serology of the neutralizing antibody by live virus microneutralization (vMN) to the omicron variant was measured at baseline, day 180, and day 360 after the first dose. The primary outcome was seroconversion (vMN titer ≥ 10) at day 360. Exposure of interest was MASLD, defined as hepatic steatosis (controlled attenuation parameter ≥ 248 dB/m on transient elastography) plus at least one of five cardiometabolic risk factors. Subjects with prior COVID‐19 were excluded. A multivariable logistic regression model was used to derive the adjusted odds ratio of seroconversion with MASLD by adjusting for age, sex, antibiotic use, and proton pump inhibitor use. Results: One hundred forty‐eight BNT162b2 recipients (male: 48 [32.4%]; median age: 51.0 years [interquartile range, IQR: 44.5–57.3]) were recruited. The median time from the first dose to the third dose was 8.5 months (IQR: 7.9–8.9). MASLD subjects had a lower seroconversion rate than non‐MASLD ones (89.6% vs 99.0%; P = 0.007). MASLD was the only independent risk factor for seroconversion (adjusted odds ratio: 0.051, 95% confidence interval: 0.002–0.440). Subgroup analysis of immunogenicity at 4 months after the third dose shows significantly lower vMN titer (13.06 [IQR: 7.69–22.20] vs 33.49 [IQR: 24.05–46.53]; P = 0.004) and seroconversion rate (76.9% vs 97.4%; P = 0.016) in MASLD than non‐MASLD subjects, but not within 4 months from the third dose (vMN titer: 46.87 [IQR: 33.12–66.02] vs 41.86 [IQR: 34.47–50.91], P = 0.240; seroconversion rate: 94.3% vs 100%, P = 0.131). Conclusion: Metabolic dysfunction‐associated steatotic liver disease was a risk factor for poorer immunogenicity to the omicron variant, with a more pronounced waning effect compared among three‐dose BNT162b2 recipients. [ABSTRACT FROM AUTHOR]

Continuous scanning laser Doppler vibrometry (CSLDV) enables fast and full-field vibration measurement in an intact area of a structure. This paper further proposes a novel adaptive CSLDV method that can obtain the operational deflection shapes (ODS) and mode shape of structures with holes. Firstly, an adaptive path planning method is applied to the surface of the tested structure, which can automatically adapt to the size and position of round and square holes, as well as the resolution requirements for the measurement. Secondly, based on the symmetry and other characteristics of the planned path, the time domain signal is processed by delay optimization and demodulation to obtain the ODS of each vibration mode. Finally, a modal test is conducted on a flat structure with a square and circular holes as an example. A validation experiment is also performed using SLDV. The results show that the mode shapes obtained from both methods are consistent and the modal assurance criterion between them are all above 0.96. The method can realize CSLDV of flat plate structures with arbitrary square and round holes, and has the advantages of high efficiency and dense measurement points, which enhances its engineering applicability. [ABSTRACT FROM AUTHOR]

Osteoporotic fracture is a prevalent noncommunicable disease globally, causing significant mortality, morbidity, and disability. As the population ages, the healthcare and economic burden of osteoporotic fracture is expected to increase further. Due to its multifactorial features, the development of osteoporotic fracture involves a complex interplay of multiple risk factors, including genetic, environmental, and lifestyle factors. Helicobacter pylori, which infects approximately 43% of the world's population, has been associated with increased fracture risk due to hypochlorhydria from atrophic gastritis and systemic inflammation from elevated pro‐inflammatory cytokines. However, the potential impact of H. pylori infection and eradication on fracture risk remains contentious among various studies due to the study design and inadequate adjustment of confounding factors including baseline gastritis phenotype. In this review, we provided a comprehensive evaluation of the current evidence focusing on the underlying mechanisms and clinical evidence of the association between H. pylori infection and osteoporotic fracture. We also discussed the potential benefits of H. pylori eradication on fracture risk. [ABSTRACT FROM AUTHOR]

Introduction: The Baveno criteria for assessing advanced liver fibrosis were mainly determined by transient elastography (TE), and its pathology-based validation studies in two-dimensional shear wave elastography (2D-SWE) remain limited. We aimed to validate the Baveno criteria through use of 2D-SWE. Method: Consecutive patients who underwent liver biopsies for various benign liver diseases were prospectively recruited. Liver stiffness measurement (LSM) was simultaneously evaluated by TE and 2D-SWE. The optimal cutoff value to predict advanced liver fibrosis was determined by the Youden Index, and the diagnostic performance was estimated using area under the receiver operating characteristic (AUROC) analysis. Results: A total of 101 patients were enrolled having a median age of 55.0 (IQR: 46.0–63.5) years, with 53 (52.48%) of them being male. Using <9 and >14 kPa as the optimal dual cutoffs, the AUROC values in TE and 2D-SWE were 0.92 (95% CI: 0.83–0.97) and 0.93 (95% CI: 0.84–0.98), respectively (p = 0.61). The sensitivity and specificity of LSM by TE/2D-SWE achieved rates of 94.44%/94.44% and 86.00%/88.00%, respectively. However, using the Baveno criteria, the AUROC values in TE and 2D-SWE could remain achieving 0.91 (95% CI: 0.82–0.97) and 0.93 (95% CI: 0.84–0.98), respectively (p = 0.36). The sensitivity and specificity in TE/2D-SWE were 88.24%/88.24% and 86.79%/90.57%, respectively. Conclusion: This study establishes the compatibility of the Baveno dual cutoff criteria with 2D-SWE, positioning it as an easily used criteria in clinical practice and research. [ABSTRACT FROM AUTHOR]

Background/Aim: In this study, we introduce an innovative deep-learning model architecture aimed at enhancing the accuracy of detecting and classifying organizing pneumonia (OP), a condition characterized by the presence of Masson bodies within the alveolar spaces due to lung injury. The variable morphology of Masson bodies and their resemblance to adjacent pulmonary structures pose significant diagnostic challenges, necessitating a model capable of discerning subtle textural and structural differences. Our model incorporates a novel architecture that integrates advancements in three key areas: Semantic segmentation, texture analysis, and structural feature recognition. Materials and Methods: We employed a dataset of whole slide imaging from 20 patients, totaling 100 slides of OP, segmented into training, validation, and testing sets to reflect real-world application scenarios. Our approach utilizes a modified multi-head self-attention mechanism combined with ResUNet for semantic segmentation, enhanced by superpixel concepts. This method facilitates the generation of representative token features through iterative super-token blocks, creating high-resolution token maps that leverage local and high-level feature information for improved accuracy. Results: Benefiting from token features and distribution for enhanced texture alignment with fewer falsepositives, the super-token transformer (STT) model achieved a mean intersection over union (mIOU) of 72.42%, with a sensitivity of 47.81%, specificity of 99.83%, positive predictive value of 64.03%, and negative predictive value of 99.94%, highlighting superior efficacy in Masson body segmentation in complex cross-tissue analyses. Conclusion: Our team developed an iterative learning model based on the STT approach, emphasizing token features of super token, including texture and distribution, that enable enhanced alignment with the unique textures of Masson bodies to improve sensitivity and mIOU, The development of this STT model presents a significant advancement in the field of medical image analysis for OP that offers a promising avenue for improving diagnostic precision and patient outcomes in pulmonary pathology. [ABSTRACT FROM AUTHOR]

Background: We compared efficacy of vonoprazan‐dual or triple therapies and bismuth‐quadruple therapy for treatment‐naive Helicobacter pylori (HP) infection in Southern China, where primary resistance rates of clarithromycin and levofloxacin are >30%. Methods: This was an investigator‐initiated, three‐arm, randomized clinical trial in Southern China. Between March 2022 and August 2023, treatment‐naïve HP‐infected adults were randomly assigned to receive one of three 14‐day regimens (1:1:1 ratio): vonoprazan‐dual (VA‐dual; vonoprazan 20 mg twice daily and amoxicillin 1 g thrice daily), vonoprazan‐triple (VAC‐triple; vonoprazan 20 mg/amoxicillin 1 g/clarithromycin 500 mg twice daily), or bismuth‐quadruple therapy containing bismuth, esomeprazole, tetracycline, and metronidazole. Primary outcome was noninferiority in HP eradication, evaluated by UBT 4–6 weeks post‐treatment by intention‐to‐treat (ITT) and per‐protocol (PP) analysis (based on subjects who completed 14‐day treatment and rechecked UBT). Bonferroni‐adjusted p‐value of <0.017 was used to determine statistical significance. Results: A total of 298 subjects (mean age: 35.7 ± 8.4 years; male: 134 [45.0%]; VC‐dual: 100, VAC‐triple: 98, bismuth‐quadruple: 100) were enrolled, and 292 (98.0%) had UBT rechecked. ITT analysis showed that both VA‐dual (eradication rate of 96.0%) and VAC‐triple therapies (95.9%) were noninferior to bismuth‐quadruple therapy (92.0%) (difference: 4.0%, 95% CI: −2.9% to 11.5%, p < 0.001; and 3.9%, 95% CI: −3.1% to 11.5%, p < 0.001, respectively). PP analysis also revealed noninferiority (96.7% or 96.7% vs. 97.4%, with difference: −2.9% and −2.9%, p = 0.009 and 0.010, respectively). The frequency of adverse events was 39.0%, 56.1%, and 71.0% in VA‐dual, VAC‐triple, and bismuth‐quadruple therapies, respectively. Conclusions: VA‐dual and VA‐triple therapies are highly effective and noninferior to bismuth‐quadruple therapy in Southern China. Given the lower adverse effects and fewer antibiotic use, VA‐dual therapy is the preferred first‐line treatment for HP infection. Trial Registration: Chinese Clinical Trial Registry (No. ChiCTR2200056375). Registered on February 4, 2022, https://www.chictr.org.cn/showproj.aspx?proj=14131. [ABSTRACT FROM AUTHOR]

Object: Long non-coding RNAs (lncRNAs) exert critical roles in cancer progression. However, the function of SNHG22 in epithelial ovarian carcinoma (EOC) still needs to be clarified. Methods: qRT-PCR was carried out to explore SNHG22 expression. Receiver operating characteristic (ROC) curve was used to evaluate the predictive ability. Glucose uptake and lactate secretion were used to monitor cancer cell glycolysis. Luciferase reporter and ChIP assays were conducted to investigate the molecular mechanism of SNHG22. Results: SNHG22 was found notably overexpressed in tumor tissues, cells and serum samples, which was regulated by SP1 with the stimulation of SNHG22 promoter activity. And SNHG22 expression in serum was an effective biomarker by ROC analysis. Moreover, SNHG22 facilitated glycolysis in EOC cells. Conclusions: Aberrant SNHG22 expression in serum could be used as a promising biomarker for EOC and SNHG22 promotes in glycolysis.

Subject: Perioperative regulation of coagulation function through heparin in patients undergoing cardiac surgery with cardiopulmonary bypass is an important part of performing cardiac surgery, and postoperative bleeding due to abnormal coagulation function caused by differences in heparin sensitivity in different individuals is an independent risk factor for postoperative complications and death.Method: Using an online database, 10 miRNAs interacting with AT-III and FX genes were predicted. Patients were divided into three groups according to the difference in activated clotting time (ACT) after the first dose of heparin (2.5 mg kg−1): group A: hyposensitive group (ACT < 480 s); group B: sensitive group (480 s ≤ ACT ≤ 760 s); and group C: hypersensitive group (ACT > 760 s). Perioperative and 24 h postoperative blood loss and other clinical data of patients in the three groups were recorded. Blood samples were collected before surgery, and RT-PCR was used to detect the levels of AT-III and FX gene mRNA and the levels of predicted 10 miRNAs.Result: Heparin sensitivity was positively correlated with AT-III mRNA levels and negatively correlated with FX gene mRNA levels in the three groups, and the blood loss in group B was significantly lower than that in groups A and C, which was statistically significant (p < 0.05). miR-3064-5p and miR-4745-5p expression levels were significantly different among group A, group B, and group C (p < 0.05) and were closely correlated with AT-III and FX gene mRNA expression levels, respectively.Conclusion: Differences in heparin sensitivity in patients undergoing cardiac surgery were associated with the mRNA expression of AT-III and FX genes, and the expression levels of miR-3064-5p and miR-4745-5p were found to be closely related to the AT-III and FX gene mRNA, respectively, indicating that miR-3064-5p and miR-4745-5p affect the differences in heparin sensitivity among different individuals by regulating the mRNA expression levels of AT-III and FX genes.Clinical Trial Registration:http://www.chictr.org.cn/abouten.aspx, identifier registration number: ChiCTR-2100047348

Pancreatic neuroendocrine neoplasms (PNEN) are tumors that originate from neuroendocrine cells. Only about 1% patients are related to mutation of tuberous sclerosis complex gene. Here, we reported a rare case with involvement of multiple organs and space-occupying lesions. Initially, the patient was thought to have metastasis of a pancreatic tumor. However, the patient was diagnosed as pancreatic neuroendocrine tumors, liver perivascular epithelioid tumors, splenic hamartoma, and renal angiomyolipoma by pathological examination after surgery. We performed genetic mutation detection to identify that tuberous sclerosis complex 2 gene presented with a heterozygous variant. Tuberous sclerosis often presents with widespread tumors, but it is less common to present with pancreatic neuroendocrine tumors and liver perivascular tumors as highlighted in the case. So we analyzed the relationship between TSC gene mutations and related tumors. And we also reviewed the current molecular mechanisms and treatments for tuberous sclerosis complex.

Abstract. Introduction:. Dieulafoy's lesion (DL) presented with small bowel bleeding constitutes a group of rare and potentially life-threatening prognosis. Several case series have described this condition, yet it remains unclear as to what is the optimal treatment and predicted outcome for patients who have been diagnosed. Patient concerns:. We present a 21-year-old male experiencing bloody stool for 1 day. Diagnosis:. Computed tomography of the abdomen exhibited active contrast extravasations and segmental wall thickening in the jejunum, and enteroscopy showed one 15-millimeter sized subepithelial tumor at the proximal jejunum. Interventions:. Due to unstable vital signs he received an emergent transcatheter arterial embolization, and surgeon performed a laparoscopic surgical resection thereafter under the impression of potential malignancy. The pathologist confirmed jejunal DL with organizing thrombus. Outcomes:. He was discharged on the 8th day of hospitalization without recurrent bleeding. Conclusion:. A systematic literature review of 98 published cases taken from PubMed dating back to 1978 was undertaken, and the patients with DL and small bowel bleeding involved mainly the jejunum, followed by the duodenum and ileum. Meanwhile, DL-related duodenal bleeding was diagnosed mostly by an enteroscopy, as well as endoscopic interventions. Jejunal and ileal bleeding due to DL was surveyed through endoscopy and surgery, while surgical resection remained the choice for bleeding cessation. Only anticoagulant use (OR = 18.16; P = .08) was associated with a higher risk of overall mortality, although it was non-significant in univariate analysis. We emphasize that individualized treatment as well as prompt measurement should be implemented accordingly.

Abstract Domain engineering in ferroelectrics endows flexibility for different functional applications. Whereas the domain engineering strategy for single crystals and thin films is diverse, there is only a limited number of strategies for bulk ceramics. Here, a domain engineering strategy for achieving a compact domain architecture with increased domain‐wall density in (K,Na)NbO3 (KNN)‐based ferroelectric ceramics via mesoscopic chemical inhomogeneity (MCI) is developed. The MCI‐induced interfaces can effectively hinder domain continuity and modify the domain configuration. Besides, the MCI effect also results in diffused phase transitions, which is beneficial for achieving enhanced thermal stability. Modulation of chemical inhomogeneity demonstrates great potential for engineering desirable domain configuration and properties in ferroelectric ceramics. Additionally, the MCI can be easily controlled by regulating the processing condition during solid‐state synthesis, which is advantageous to industrial production.

If a technical failure occurs during peritoneal dialysis (PD), the patients undergoing PD may be transitioned to hemodialysis (HD). However, the clinical outcomes of patients who have undergone such a transition are under studied. This study assessed whether patients undergoing HD who have transitioned from PD have the same clinical outcomes as HD-only patients. This research was a retrospective cohort study by searching a National Health Insurance research database for data on patients in Taiwan who had undergone HD between January 2006 and December 2013. The patients were divided into two groups, namely a case group in which the patients were transitioned from PD to HD and a HD-only control group, through propensity score matching at a ratio of 1:4 (n = 1,100 vs. 4,400, respectively). We used the Cox regression model to estimate the hazard ratios (HRs) for all-cause death, all-cause hospitalization, infection-related admission, and major adverse cardiac events (MACE). Those selected patients will be followed until death or the end of the study period (December, 2017), whichever occurs first. Over a mean follow-up of 3.2 years, 1,695 patients (30.8%) died, 3,825 (69.5%) required hospitalization, and 1,142 (20.8%) experienced MACE. Patients transitioning from PD had a higher risk of all-cause death (HR: 1.36; 95% CI: 1.21–1.53) than HD-only patients. However, no significant difference was noted in terms of MACE (HR: 0.91; 95% CI: 0.73–1.12), all-cause hospitalization (HR: 1.07; 95% CI: 0.96–1.18), or infection-related admission (HR: 0.97, 95% CI: 0.80–1.18) between groups. Because of the violation of the proportional hazard assumption, the piecewise-HRs showed that the risk of mortality in the case group was significant within 5 months of the transition (HR: 2.61; 95% CI: 2.04–3.35) not in other partitions of the time axis. In conclusion, patients undergoing HD who transitioned from PD had a higher risk of death than the HD-only patients, especially in the first 5 months after transition (a 161% higher risk). Therefore, more caution and monitoring may be required for patients undergoing HD who transitioned from PD.

The poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi) Olaparib is a widely used targeted therapy for a variety of solid tumors with homologous recombination deficiency (HRD) caused by mutation of BRCA1/2 or other DNA repair genes. The anti-tumor activity of Olaparib has been largely attributed to its ability to inhibit PARP enzymes and block DNA single-strand break (SSB) repair, which eventually leads to the most detrimental DNA damage, double-strand breaks (DSB), in HRD cells. Although PARPi was found to induce p53-dependent cell death, the underlying molecular mechanism remains incompletely understood. Here, we report that Olaparib treatment leads to p53 stabilization and activation of its downstream target genes in a dose- and time-dependent manner. Mechanistically, Olaparib triggers nucleolar stress by inhibiting biosynthesis of the precursor of ribosomal RNAs (pre-rRNA), resulting in enhanced interaction between ribosomal proteins (RPs), RPL5 and RPL11, and MDM2. Consistently, knockdown of RPL5 and RPL11 prevents Olaparib-induced p53 activation. More importantly, Olaparib efficiently suppresses breast and colorectal cancer cell survival and proliferation through activation of p53. Altogether, our study demonstrates that Olaparib activates the nucleolar stress-RPs-p53 pathway, suggesting rRNA biogenesis as a novel target for PARPi.

BackgroundAcute myocardial infarction (AMI) can occur in patients with atherosclerotic disease, with or without plaque rupture. Previous studies have indicated a set of immune responses to plaque rupture. However, the specific circulating immune cell subsets that mediate inflammatory plaque rupture remain elusive.MethodsTen AMI patients were enrolled in our study (five with and five without plaque rupture; plaque characteristics were identified by optical coherence tomography). By single-cell RNA sequencing, we analyzed the transcriptomic profile of peripheral blood mononuclear cells.ResultsWe identified 27 cell clusters among 82,550 cells, including monocytes, T cells, NK cells, B cells, megakaryocytes, and CD34+ cells. Classical and non-classical monocytes constitute the major inflammatory cell types, and pro-inflammatory genes such as CCL5, TLR7, and CX3CR1 were significantly upregulated in patients with plaque rupture, while the neutrophil activation and degranulation genes FPR2, MMP9, and CLEC4D were significantly expressed in the intermediate monocytes derived from patients without plaque rupture. We also found that CD4+ effector T cells may contribute to plaque rupture by producing a range of cytokines and inflammatory-related chemokines, while CD8+ effector T cells express more effector molecules in patients without plaque rupture, such as GZMB, GNLY, and PRF1, which may contribute to the progress of plaque erosion. Additionally, NK and B cells played a significant role in activating inflammatory cells and promoting chemokine production in the plaque rupture. Cell–cell communication elaborated characteristics in signaling pathways dominated by inflammatory activation of classical monocytes in patients with plaque rupture.ConclusionsOur studies demonstrate that the circulating immune cells of patients with plaque rupture exhibit highly pro-inflammatory characteristics, while plaque erosion is mainly associated with intermediate monocyte amplification, neutrophil activation, and degranulation. These findings may provide novel targets for the precise treatment of patients with AMI.

Abstract Background Breast augmentation with polyacrylamide gel (PAAG) injection was approved in China in 1998 and later banned in 2006. The ban ensued numerous complaints from patients such as pain, induration, deformation, infection, displacement, and milk deposition associated with PAAG injection. To date, no study has investigated the long-term effect of PAAG migration on autoimmune diseases. Case presentation We report a rare case of a 49-year-old female patient with familial vitiligo who receiving PAAG injection for breast augmentation. The patient reported to have felt persistent movement of PAAG in her thoracoabdominal area for almost 20 years. Furthermore, the PAAG-induced chronic inflammation that aggravated vitiligo, which in turn promoted skin sclerosis. This damaged the breast contracture, increased chest tightness and induced mild breathing problems. Conclusion Here, we present a rare case in which a patient with a family history of vitiligo experienced long-term complications after receiving PAAG injection for breast augmentation. This case highlights the relationship between vitiligo, migration of PAAG and tissue hardening and skin contraction. Level of evidence: Level V