Aristolochic acids-hijacked p53 promotes liver cancer cell growth by inhibiting ferroptosis.

Aristolochic acids (AAs) have been identified as a significant risk factor for hepatocellular carcinoma (HCC). Ferroptosis is a type of regulated cell death involved in the tumor development. In this study, we investigated the molecular mechanisms by which AAs enhanced the growth of HCC. By conducting bioinformatics and RNA-Seq analyses, we found that AAs were closely correlated with ferroptosis. The physical interaction between p53 and AAs in HepG2 cells was validated by bioinformatics analysis and SPR assays with the binding pocket sites containing Pro92, Arg174, Asp207, Phe212, and His214 of p53. Based on the binding pocket that interacts with AAs, we designed a mutant and performed RNA-Seq profiling. Interestingly, we found that the binding pocket was responsible for ferroptosis, GADD45A, NRF2, and SLC7A11. Functionally, the interaction disturbed the binding of p53 to the promoter of GADD45A or NRF2, attenuating the role of p53 in enhancing GADD45A and suppressing NRF2; the mutant did not exhibit the same effects. Consequently, this event down-regulated GADD45A and up-regulated NRF2, ultimately inhibiting ferroptosis, suggesting that AAs hijacked p53 to down-regulate GADD45A and up-regulate NRF2 in HepG2 cells. Thus, AAs treatment resulted in the inhibition of ferroptosis via the p53/GADD45A/NRF2/SLC7A11 axis, which led to the enhancement of tumor growth. In conclusion, AAs-hijacked p53 restrains ferroptosis through the GADD45A/NRF2/SLC7A11 axis to enhance tumor growth. Our findings provide an underlying mechanism by which AAs enhance HCC and new insights into p53 in liver cancer. Therapeutically, the oncogene NRF2 is a promising target for liver cancer.

Preliminary construction of non-coding RNAs and ceRNA regulatory networks mediated by exosomes in porcine follicular fluid.

BACKGROUND: Follicles are fundamental units of the ovary, regulated intricately during development. Exosomes and ovarian granulosa cells (OGCs) play pivotal roles in follicular development, yet the regulatory mechanisms governing exosomes remain elusive. RESULTS: High-throughput sequencing was employed to evaluate the complete transcript expression profiles of six samples (three porcine ovarian granulosa cells-exosome co-culture samples (GCE) and three porcine ovarian granulosa cells (POGCs) samples). Differential expression analysis revealed 924 lncRNAs, 35 circRNAs, 49 miRNAs, and 9823 mRNAs in the GCE group. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses indicated enrichment of differentially expressed transcripts in pathways related to cell proliferation and apoptosis. Furthermore, a ceRNA regulatory network comprising 43 lncRNAs, 6 circRNAs, 11 miRNAs, and 126 mRNAs was constructed based on intergene co-expression correlations. Seven miRNAs associated with cell proliferation and apoptosis regulation were identified within this network, encompassing 92 subnet pairs as candidate genes for further exploration of exosome regulatory mechanisms. Additionally, preliminary verification at the cellular level demonstrated that exosomal miR-200b enhances the viability of POGCs. CONCLUSIONS: Transcriptome analysis unveiled a pivotal candidate ceRNA network potentially implicated in exosome-mediated regulation of granulosa cell proliferation and apoptosis, thereby influencing porcine follicular development. These findings offer insights into the molecular mechanisms of follicular fluid exosome regulation, encompassing both coding and non-coding RNA perspectives.

Two-dimensional confined topotactic transformation to produce Co-Pi/Co3O4 hybrid porous nanosheets for promoted water oxidation.

Exploring advanced electrocatalyst for the oxygen evolution reaction (OER) is of great importance in pursuing efficient and sustainable hydrogen production via electrolytic water splitting. Considering the structure-activity-stability relationship for designing advanced OER catalysts, two-dimensional (2D) porous catalyst with single crystallinity is deemed to be an ideal platform which could simultaneously endow enriched active sites, facile mass and charge transport ability as well as robust structural stability. Herein, we proposed a facile 2D confined topotactic phase transformation approach, which realizes the fabrication of highly porous single-crystalline Co3O4 nanosheets with in-situ surface modification of amorphous Co-Pi active species. Benefitted from the highly exposed undercoordinated cobalt sites, facilitated mass transport and facile 2D charge transfer pathway, the Co-Pi/Co3O4 hybrid porous nanosheets display enhanced OER activity with obvious pre-oxidation-induced activation. In addition, the operational stability was significantly improved owing to the strengthened structural stability which effectively buffers the internal strains and avoids the structural collapse during the electrochemical process. This work proposed a facile and mild method for the synthesis of amorphous/single-crystalline hybrid porous materials, and the achievement of synergistic modulation of active site density and charge transfer ability via targeted microstructural construction will shed light on catalyst design in the future.

Nonmetal Doping Modulates Fe Single-Atom Catalysts for Enhancement in Peroxidase Mimicking via Symmetry Disruption, Distortion, and Charge Transfer.

Developing biomimetic catalysts with excellent peroxidase (POD)-like activity has been a long-standing goal for researchers. Doping nonmetallic atoms with different electronegativity to boost the POD-like activity of Fe-N-C single-atom catalysts (SACs) has been successfully realized. However, the introduction of heteroatoms to regulate the coordination environment of the central Fe atom and thus influence the activation of the H2O2 molecule in the POD-like reaction has not been extensively explored. Herein, the effect of different doping sites and numbers of heteroatoms (P, S, B, and N) on the adsorption and activation of H2O2 molecules of Fe-N sites is thoroughly investigated by density functional theory (DFT) calculations. In general, alternation in the catalytic efficiency directly depends on the transfer of electrons and the geometrical shifts near the Fe-N site. First, the symmetry disruption of the Fe-N4 site by P, S, and B doping is beneficial to the activation of H2O2 due to a significant reduction in the adsorption energies. In some cases, without Fe-N4 site disruption, the configurations fail to modulate the adsorption behavior of H2O2. Second, Fe-N-P/S configurations exhibit a stronger affinity for H2O2 molecules due to the significant out-of-plane distortions induced by larger atomic radii of P and S. Moreover, the synergistic effects of Fe and doping atoms P, S, and B with weaker electronegativity than that of N atoms promote electron donation to generated oxygen-containing intermediates, thus facilitating subsequent electron transfer with other substrates. This work demonstrates the critical role of tuning the coordinating environment of Fe-N active centers by heteroatom doping and provides theoretical guidance for controlling the types by breaking the symmetry of SACs to achieve optimal POD-like catalytic activity and selectivity.

Targeting AGTPBP1 inhibits pancreatic cancer progression via regulating microtubules and ERK signaling pathway.

BACKGROUND: AGTPBP1 is a cytosolic carboxypeptidase that cleaves poly-glutamic acids from the C terminus or side chains of α/ß tubulins. Although its dysregulated expression has been linked to the development of non-small cell lung cancer, the specific roles and mechanisms of AGTPBP1 in pancreatic cancer (PC) have yet to be fully understood. In this study, we examined the role of AGTPBP1 on PC in vitro and in vivo. METHODS: Immunohistochemistry was used to examine the expression of AGTPBP1 in PC and non-cancerous tissues. Additionally, we assessed the malignant behaviors of PC cells following siRNA-mediated AGTPBP1 knockdown both in vitro and in vivo. RNA sequencing and bioinformatics analysis were performed to identify the differentially expressed genes regulated by AGTPBP1. RESULTS: We determined that AGTPBP1 was overexpressed in PC tissues and the higher expression of AGTPBP1 was closely related to the location of tumors. AGTPBP1 inhibition can significantly decrease cell progression in vivo and in vitro. Moreover, the knockdown of AGTPBP1 inhibited the expression of ERK1/2, P-ERK1/2, MYLK, and TUBB4B proteins via the ERK signaling pathway. CONCLUSION: Our research indicates that AGTPBP1 may be a putative therapeutic target for PC.

Crystal structure of 4-bromo-5,7-dimeth-oxy-2,3-di-hydro-1H-inden-1-one.

In the title mol-ecule, C11H11BrO3, the di-hydro-indene moiety is essentially planar but with a slight twist in the saturated portion of the five-membered ring. The meth-oxy groups lie close to the above plane. In the crystal, π-stacking inter-actions between six-membered rings form stacks of mol-ecules extending along the a-axis direction, which are linked by weak C-H⋯O and C-H⋯Br hydrogen bonds. A Hirshfeld surface analysis was performed showing H⋯H, O⋯H/H⋯O and Br⋯H/H⋯Br contacts make the largest contributions to inter-molecular inter-actions in the crystal.

A robust ensemble deep learning framework for accurate diagnoses of tuberculosis from chest radiographs.

Introduction: Tuberculosis (TB) stands as a paramount global health concern, contributing significantly to worldwide mortality rates. Effective containment of TB requires deployment of cost-efficient screening method with limited resources. To enhance the precision of resource allocation in the global fight against TB, this research proposed chest X-ray radiography (CXR) based machine learning screening algorithms with optimization, benchmarking and tuning for the best TB subclassification tasks for clinical application. Methods: This investigation delves into the development and evaluation of a robust ensemble deep learning framework, comprising 43 distinct models, tailored for the identification of active TB cases and the categorization of their clinical subtypes. The proposed framework is essentially an ensemble model with multiple feature extractors and one of three fusion strategies-voting, attention-based, or concatenation methods-in the fusion stage before a final classification. The comprised de-identified dataset contains records of 915 active TB patients alongside 1,276 healthy controls with subtype-specific information. Thus, the realizations of our framework are capable for diagnosis with subclass identification. The subclass tags include: secondary tuberculosis/tuberculous pleurisy; non-cavity/cavity; secondary tuberculosis only/secondary tuberculosis and tuberculous pleurisy; tuberculous pleurisy only/secondary tuberculosis and tuberculous pleurisy. Results: Based on the dataset and model selection and tuning, ensemble models show their capability with self-correction capability of subclass identification with rendering robust clinical predictions. The best double-CNN-extractor model with concatenation/attention fusion strategies may potentially be the successful model for subclass tasks in real application. With visualization techniques, in-depth analysis of the ensemble model's performance across different fusion strategies are verified. Discussion: The findings underscore the potential of such ensemble approaches in augmenting TB diagnostics with subclassification. Even with limited dataset, the self-correction within the ensemble models still guarantees the accuracies to some level for potential clinical decision-making processes in TB management. Ultimately, this study shows a direction for better TB screening in the future TB response strategy.

Ce12V6 Clusters with Multi-Enzymatic Activities for Sepsis Treatment.

Artificial enzymes, especially nanozymes, have attracted wide attention due to their controlled catalytic activity, selectivity, and stability. The rising Cerium-based nanozymes exhibit unique SOD-like activity, and Vanadium-based nanozymes always hold excellent GPx-like activity. However, most inflammatory diseases involve polymerase biocatalytic processes that require multi-enzyme activities. The nanocomposite can fulfill multi-enzymatic activity simultaneously, but large nanoparticles (>10 nm) cannot be excreted rapidly, leading to biosafety challenges. Herein, atomically precise Ce12V6 clusters with a size of 2.19 nm are constructed. The Ce12V6 clusters show excellent glutathione peroxidase (GPx) -like activity with a significantly lower Michaelis-Menten constant (Km, 0.0125 mM versus 0.03 mM of natural counterpart) and good activities mimic superoxide dismutase (SOD) and peroxidase (POD). The Ce12V6 clusters exhibit the ability to scavenge the ROS including O2 ·- and H2O2 via the cascade reactions of multi-enzymatic activities. Further, the Ce12V6 clusters modulate the proinflammatory cytokines including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and interleukin-1ß (IL-1ß) and consequently rescue the multi-organ failure in the lipopolysaccharide (LPS)-induced sepsis mouse model. With excellent biocompatibility, the Ce12V6 clusters show promise in the treatment of sepsis.

Application of fecal immunochemical test in colorectal cancer screening: A community-based, cross-sectional study in average-risk individuals in Hainan.

BACKGROUND: The incidence of colorectal cancer (CRC) in China is steadily rising, with a high proportion of advanced-stage diagnoses. This highlights the significance of early detection and prevention measures to enhance survival rates. Fecal immunochemical testing (FIT) is a globally recommended CRC screening method; however, limited research has been conducted on its application in Hainan. AIM: To assess the efficacy and adherence of FIT screening among average-risk individuals in Hainan, while also examining the risk factors associated with positive FIT results. METHODS: This population-based cross-sectional study implemented FIT screening for CRC in 2000 asymptomatic participants aged 40-75 years from five cities and 21 community health centers in Hainan Province. The study was conducted from August 2022 to April 2023, employing a stratified sampling method to select participants. Individuals with positive FIT results subsequently underwent colonoscopy. Positive predictive values for confirmed CRC and advanced adenoma were calculated, and the relationship between relevant variables and positive FIT results was analyzed using χ 2 tests and multivariate logistic regression. RESULTS: A total of 1788 participants completed the FIT screening, with a median age of 57 years (interquartile range: 40-75). Among them, 503 (28.1%) were males, and 1285 (71.9%) were females, resulting in an 89.4% compliance rate for FIT screening. The overall positivity rate of FIT was 4.4% [79 out of 1788; 95% confidence interval (CI): 3%-5%]. The specific positivity rates for Haikou, Sanya, Orient City, Qionghai City, and Wuzhishan City were 9.6% (45 of 468; 95%CI: 8%-11%), 1.3% (6 of 445; 95%CI: 0.1%-3.1%), 2.7% (8 of 293; 95%CI: 1.2%-4.3%), 3.3% (9 of 276; 95%CI: 1.0%-6.3%), and 4.2% (11 of 406; 95%CI: 1.2%-7.3%), respectively. Significant associations were found between age, dietary habits, and positive FIT results. Out of the 79 participants with positive FIT results, 55 underwent colonoscopy, demonstrating an 82.2% compliance rate. Among them, 10 had a clean gastrointestinal tract, 43 had polyps or adenomas, and 2 were confirmed to have CRC, yielding a positive predictive value of 3.6% (95%CI: 0.9%-4.2%). Among the 43 participants with polyps or adenomas, 8 were diagnosed with advanced adenomas, resulting in an advanced adenoma rate of 14.5% (95%CI: 10.1%-17.7%). CONCLUSION: In the Hainan region, FIT screening for CRC among asymptomatic individuals at average risk is feasible and well-received.

Plasminogen activator inhibitor-1 mediates cerebral ischemia-induced astrocytic reactivity.

Although ischemia increases the abundance of plasminogen activator inhibitor-1 (PAI-1), its source and role in the ischemic brain remain unclear. We detected PAI-1-immunoreactive cells with morphological features of reactive astrocytes in the peri-ischemic cortex of mice after an experimentally-induced ischemic lesion, and of a chimpanzee that suffered a naturally-occurring stroke. We found that although the abundance of PAI-1 increases 24 hours after the onset of the ischemic injury in a non-reperfusion murine model of ischemic stroke, at that time-point there is no difference in astrocytic reactivity and the volume of the ischemic lesion between wild-type (Wt) animals and in mice either genetically deficient (PAI-1-/-) or overexpressing PAI-1 (PAI-1Tg). In contrast, 72 hours later astrocytic reactivity and the volume of the ischemic lesion were decreased in PAI-1-/- mice and increased in PAI-1Tg animals. Our immunoblottings and fractal analysis studies show that the abundance of astrocytic PAI-1 rises during the recovery phase from a hypoxic injury, which in turn increases the abundance of glial fibrillary acidic protein (GFAP) and triggers morphological features of reactive astrocytes. These studies indicate that cerebral ischemia-induced release of astrocytic PAI-1 triggers astrocytic reactivity associated with enlargement of the necrotic core.

Renin-angiotensin system inhibitors and risk of hepatocellular carcinoma among patients with hepatitis B virus infection.

BACKGROUND: Hepatitis B virus (HBV) infection is a common cause of liver-related morbidity and mortality. Evidence suggests that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) decrease liver fibrosis, an intermediate step between liver injury and hepatocellular carcinoma (HCC). Our aim was to investigate the association between the use of ACEIs and ARBs on incident HCC and liver-related mortality among patients with HBV infection. METHODS: We conducted a population-based study on a new-user cohort of patients seen at 24 hospitals across China. We included adult patients with HBV infection who started ACEIs or ARBs (ACEIs/ARBs), or calcium channel blockers or thiazide diuretics (CCBs/THZs) from January 2012 to December 2022. The primary outcome was incident HCC; secondary outcomes were liver-related mortality and new-onset cirrhosis. We used propensity score matching and Cox proportional hazards regression to estimate the hazard ratio (HR) and 95% confidence intervals (CIs) of study outcomes. RESULTS: Among 32 692 eligible patients (median age 58 [interquartile range (IQR) 48-68] yr, and 18 804 male [57.5%]), we matched 9946 pairs of patients starting ACEIs/ARBs or CCBs/THZs. During a mean follow-up of 2.3 years, the incidence rate of HCC per 1000 person-years was 4.11 and 5.94 among patients who started ACEIs/ARBs and CCBs/THZs, respectively, in the matched cohort. Use of ACEIs/ARBs was associated with lower risks of incident HCC (HR 0.66, 95% CI 0.50-0.86), liver-related mortality (HR 0.77, 95% CI 0.64-0.93), and new-onset cirrhosis (HR 0.81, 95% CI 0.70-0.94). INTERPRETATION: In this cohort of patients with HBV infection, new users of ACEIs/ARBs had a lower risk of incident HCC, liver-related mortality, and new-onset cirrhosis than new users of CCBs/THZs.

Croconaine-based NIR-II fluorescence imaging-guided tumor photothermal therapy induces long-term antitumor immune memory.

Photothermal therapy (PTT) for cancers guided by optical imaging has recently shown great potential for precise diagnosis and efficient therapy. The second near-infrared window (NIR-II, 1000-1700 nm) fluorescence imaging (FLI) is highly desirable owing to its good spatial and temporal resolution, deep tissue penetration, and negligible tissue toxicity. Organic small molecules are attractive as imaging and treatment agents in biomedical research because of their low toxicity, fast clearance rate, diverse structures, ease of modification, and excellent biocompatibility. Various organic small molecules have been investigated for biomedical applications. However, there are few reports on the use of croconaine dyes (CRs), especially NIR-II emission CRs. To our knowledge, there have been no prior reports of NIR-II emissive small organic photothermal agents (SOPTAs) based on CRs. Herein, we report a croconaine dye (CR-TPE-T)-based nanoparticle (CR NP) with absorption and fluorescence emission in the NIR-I and NIR-II windows, respectively. The CR NPs exhibited intense NIR absorption, outstanding photothermal properties, and good biological compatibility. In vivo studies showed that CR NPs not only achieved real-time, noninvasive NIR-II FLI of tumors, but also induced significant tumor ablation with laser irradiation guided by imaging, without apparent side effects, and promoted the formation of antitumor immune memory in a colorectal cancer model. In addition, the CR NPs displayed efficient inhibition of breast tumor growth, improved longevity of mice and triggered efficient systemic immune responses, which further inhibited tumor metastasis to the lungs. Our study demonstrates the great potential of CRs as therapeutic agents in the NIR-II region for cancer diagnosis.

Comparing risk factors and neonatal outcomes in women with intrahepatic cholestasis of pregnancy between assisted reproductive technology and spontaneous conception.

OBJECTIVE: The aim of the present study was to investigate the incidence of intrahepatic cholestasis of pregnancy (ICP) as well as neonatal outcomes between conception via in vitro fertilization (IVF) compared with spontaneous conception (SC) and screen the risk factors of ICP in IVF. METHODS: This retrospective cohort study included 4467 puerperae who conceived via IVF, and 28 336 puerperae who conceived spontaneously and linked the information from neonates. The general linear model (GLM), multivariate logistic regression analysis, a forest plot, and nomogram were used to assess impact factors and risk prediction. RESULTS: Logistic analysis adjusted for confounders revealed significant differences in the ICP rate of singleton delivery (4.24% vs 3.41%, adjusted OR [aOR] = 1.26; 95% confidence interval [CI] 1.03-1.53, P = 0.025) and in groups with total bile acids (TBA) ≥40 and <100 µmol/L (14.77% vs 10.39%, aOR = 1.31; 95% CI: 1.06-1.63, P = 0.023) between IVF and SC. When we divided newborns into singleton and twins delivery, the GLM revealed a higher rate with Apgar score <7 (13.44% vs 3.87%, aOR = 3.85; 95% CI: 2.07-7.17, P < 0.001) and fetal distress for IVF in comparison with SC (19.32% vs 5.55%, OR = 3.48; 95% CI: 2.39-6.95, P < 0.001) in the singleton group. In multivariate logistic regression analysis, body mass index (BMI) (aOR = 1.29; P = 0.031), number of embryo transfers (ET) (single ET vs double ET, aOR = 2.82; P < 0.001), E2 level on the ET day (aOR = 2.79; P = 0.011), fresh ET which compared with frozen ET (FET) (aOR = 1.45; P = 0.014), embryo stage (cleavage embryo vs blastocyst, aOR = 1.75; P = 0.009) and severe ovarian hyperstimulation syndrome (OHSS) which compared with non-OHSS (aOR = 3.73; P = 0.006) were independent predictors of ICP. These predictive factors in the logistic regression model were integrated into the nomogram (C-index = 0.735; 95% CI: 0.702-0.764); for each patient, higher total points indicated a higher risk of ICP. CONCLUSION: We observed that the ICP rate of singleton delivery was higher in IVF than in SC. In ICP patients, there were higher rates of neonatal Apgar score <7 and fetal distress in IVF than SC and found the predictors of ICP in IVF.

Mendelian Randomization Studies: Opening a New Window in the Study of Metabolic Diseases and Chronic Kidney Disease.

It is widely recognized that a strong correlation exists between metabolic diseases and chronic kidney disease (CKD). Based on bibliometric statistics, the overall number of Mendelian randomization (MR) analysis in relation to metabolic diseases and CKD has increased since 2005. In recent years, this topic has emerged as a significant area of research interest. In clinical studies, RCTs are often limited due to the intricate causal interplay between metabolic diseases and CKD, which makes it difficult to ascertain the precise etiology of these conditions definitively. In MR studies, genetic variation is incorporated as an instrumental variable (IV). They elucidate the possible causal relationships between associated risk factors and disease risks by including individual innate genetic markers. It is widely believed that MR avoids confounding and can reverse effects to the greatest extent possible. As an increasingly popular technology in the medical field, MR studies have become a popular technology in causal relationships investigation, particularly in epidemiological etiology studies. At present, MR has been widely used for the investigation of medical etiologies, drug development, and decision-making in public health. The article aims to offer insights into the causal relationship between metabolic diseases and CKD, as well as strategies for prevention and treatment, through a summary of MR-related research on these conditions.

Application Repetition and Electrode-Tissue-Contact Results in Deeper Lesions Using a Pulsed-Field Ablation Circular Variable Loop Catheter.

BACKGROUND: Pulsed field ablation (PFA) is a novel, myocardial-selective, non-thermal ablation modality used to target cardiac arrhythmias. Although prompt EGM signal disappearance is observed immediately after PFA application in the pulmonary veins, whether this finding results in adequate transmural lesions is unknown. STUDY AIM: If application repetition and catheter-tissue contact impact on lesion formation during PFA. METHODS: A circular loop PFA catheter was used to deliver repeated energy applications with various levels of contact-force. A benchtop vegetal potato model and a beating heart ventricular myocardial model were utilized to evaluate the impact of application repetition, contact force, and catheter repositioning on contiguity and lesion depth. Lesion development occurred over 18 hours in the vegetal model and over 6 hours in the porcine model. RESULTS: Lesion formation was found to be dependent on application repetition and contact. In porcine ventricles, single and multiple stacked applications led to a lesion depth of 3.5 ± 0.7 mm and 4.4 ± 1.3 mm, respectively (p =0.002). Furthermore, the greater the catheter-tissue contact, the more contiguous and deeper the lesions in the vegetal model (1.0±0.9 mm with no contact Vs. 5.4±1.4 mm with 30 g of force; p=.0001). CONCLUSION: PFA delivered via a circular catheter showed that both repetition and catheter contact led independently to deeper lesion formation. These findings indicate that endpoints for effective PFA ablation are more related to PFA biophysics than mere EGM attenuation.

Three-Dimensional Visualization of Breast Cancer Pathology Evolution in Clinical Patient Tissues with NIR-II Imaging.

Breast cancer (BC) is the most common tumor worldwide and requires crucial molecular typing for treatment and prognosis assessment. Currently, approaches like pathological staining, immunohistochemistry (IHC), and immunofluorescence (IF) face limitations due to the low signal-to-background ratio (SBR) and high tumor heterogeneity, resulting in a high misdiagnosis rate. Fluorescent assay in the second near-infrared region (NIR-II, 1000-1700 nm) exhibits ultrahigh SBR owing to diminished scattering and tissue autofluorescence. Here, we present a NIR-II strategy for accurate BC molecular typing and three-dimensional (3D) visualization based on the atomically precise fluorescent Au24Pr1 clusters. Single-atom Pr doping results in 3.9-fold fluorescence enhancement and long-term photostability. The Au24Pr1 clusters possess high fluorescence centered at ∼1100 nm and the SBR on pathological section diagnosis was 4 times higher than that of NIR-I imaging. This enables high spatial resolution 3D visualization of biopsy specimens, which can surmount tissue heterogeneity for clinical diagnosis of BC.

Pre-Excited Atrial Fibrillation in Wolff-Parkinson-White (WPW) Syndrome: A Case Report and a Review of the Literature.

Wolff-Parkinson-White (WPW) syndrome is defined by specific electrocardiogram (ECG) changes resulting in ventricular pre-excitation (the so-called WPW pattern), related to the presence of an accessory pathway (AP), combined with recurrent tachyarrhythmias. WPW syndrome is characterized by different supraventricular tachyarrhythmias (SVT), including atrioventricular re-entry tachycardia (AVRT) and atrial fibrillation (AF) with rapid ventricular response, with AVRT being the most common arrhythmia associated with WPW, and AF occurring in up to 50% of patients with WPW. Several mechanisms might be responsible for AF development in the WPW syndrome, and a proper electrocardiographic interpretation is of pivotal importance since misdiagnosing pre-excited AF could lead to the administration of incorrect treatment, potentially inducing ventricular fibrillation (VF). Great awareness of pre-excited AF's common ECG characteristics as well as associated causes and its treatment is needed to increase diagnostic performance and improve patients' outcomes. In the present review, starting from a paradigmatic case, we discuss the characteristics of pre-excited AF in the emergency department and its management, focusing on the most common ECG abnormalities, pharmacological and invasive treatment of this rhythm disorder.

Arsenic trioxide regulates the glycolytic pathway to treat acute promyelocytic leukemia by inhibiting RPL22L1.

OBJECTIVE: To investigate the relationship between the treatment of acute promyelocytic leukemia (APL) with arsenic trioxide (ATO) and glycolysis, as well as its underlying molecular mechanism. METHODS: The GEO database was used to analyze alterations in the expression of RPL22L1 in APL patients and its correlation with glycolysis. The levels of RPL22L1 and glycolysis were assessed in 9 paired clinical samples. NB4 cells and NB4 cells with knockdown of RPL22L1 were treated with ATO. The protein and mRNA of RPL22L1 were detected using RT-PCR and Western blot, and the content was determined by using glucose, pyruvate, and lactate detection kits. Finally, detection of cell proliferation using CCK8, migration by scratch assay, and apoptosis by flow cytometry, and the biological function of ATO in NB4 cells was examined. RESULTS: The expression of RPL22L1 in GSE213742 and GSE234103 datasets exhibited a significant increase in human APL cells, specifically NB4 cells. RPL22L1 in GSE213742 and GSE234103 gene expression matrix was significantly elevated in human APL cells NB4 cells, and further analysis found RPL22L1 showed a strong positive correlation with glycolysis. Cellular experiments showed that ATO inhibited RPL22L1 in NB4 cells and inhibited glycolysis in APL cells. The ATO played a pivotal role in suppressing the proliferation, migration, as well as invasion of NH4 cells. CONCLUSION: ATO regulates the blycolytic pathway in APL by inhibiting RPL22L1 expression, and this may contribute to its therapeutic effects.

Close relationship with the glandular capsule：a highly sensitive diagnostic indicator of major salivary gland metastatic malignancies in ultrasound.

OBJECTIVES: To investigate the ultrasound (US) characteristics of metastatic malignancies (MM) in the major salivary glands and to assess the diagnostic value of the close relationship with the glandular capsule in identifying MM. METHODS: From January 2016 and April 2022, 122 patients with major salivary gland malignancies, including 20 patients with MM and 102 patients with primary malignancies (PM) confirmed by histopathological examination, were enrolled in this study. Their clinicopathologic and US data were recorded and analyzed. The diagnostic performance of the close relationship with the glandular capsule for differentiating MM from PM was analyzed. RESULTS: The mean age of MM were older than that of PM (59.50 ± 14.57 vs. 49.96 ± 15.73, p = 0.013). Compared with PM patients, MM were associated with a higher prevalence of local pain symptoms (p = 0.007) and abnormal facial nerve function (p < 0.001). MM were also more frequently characterized by unclear borders, rough margins, irregular shapes, heterogeneous internal echos, absence of cystic areas, presence of calcifications, close relationship with the glandular capsule, and US-reported positive cervical lymph nodes (all p < 0.05). The close relationship with the glandular capsule showed to be a good indicator in distinguishing between MM and PM, with an area under the receiver operating characteristic curve of 0.863, a sensitivity of 100%, a specificity of 72.5%, and an accuracy of 92.2%. Positive and negative predictive were calculated at 41.7% and 100%, respectively. CONCLUSIONS: The US finding of a close relationship with the glandular capsule is a highly sensitive diagnostic indicator for MM. Following this finding, US-guided needle biopsy should be recommended to further confirm the diagnosis.

Fully and Weakly Supervised Deep Learning for Meniscal Injury Classification, and Location Based on MRI.

Meniscal injury is a common cause of knee joint pain and a precursor to knee osteoarthritis (KOA). The purpose of this study is to develop an automatic pipeline for meniscal injury classification and localization using fully and weakly supervised networks based on MRI images. In this retrospective study, data were from the osteoarthritis initiative (OAI). The MR images were reconstructed using a sagittal intermediate-weighted fat-suppressed turbo spin-echo sequence. (1) We used 130 knees from the OAI to develop the LGSA-UNet model which fuses the features of adjacent slices and adjusts the blocks in Siam to enable the central slice to obtain rich contextual information. (2) One thousand seven hundred and fifty-six knees from the OAI were included to establish segmentation and classification models. The segmentation model achieved a DICE coefficient ranging from 0.84 to 0.93. The AUC values ranged from 0.85 to 0.95 in the binary models. The accuracy for the three types of menisci (normal, tear, and maceration) ranged from 0.60 to 0.88. Furthermore, 206 knees from the orthopedic hospital were used as an external validation data set to evaluate the performance of the model. The segmentation and classification models still performed well on the external validation set. To compare the diagnostic performances between the deep learning (DL) models and radiologists, the external validation sets were sent to two radiologists. The binary classification model outperformed the diagnostic performance of the junior radiologist (0.82-0.87 versus 0.74-0.88). This study highlights the potential of DL in knee meniscus segmentation and injury classification which can help improve diagnostic efficiency.