Ceramide kinase confers tamoxifen resistance in estrogen receptor-positive breast cancer by altering sphingolipid metabolism.

Dysregulated sphingolipid metabolism contributes to ER+ breast cancer progression and therapeutic response, whereas its underlying mechanism and contribution to tamoxifen resistance (TAMR) is unknown. Here, we establish sphingolipid metabolic enzyme CERK as a regulator of TAMR in breast cancer. Multi-omics analysis reveals an elevated CERK driven sphingolipid metabolic reprogramming in TAMR cells, while high CERK expression associates with worse patient prognosis in ER+ breast cancer. CERK overexpression confers tamoxifen resistance and promotes tumorigenicity in ER+ breast cancer cells. Knocking out CERK inhibits the orthotopic breast tumor growth of TAMR cells while rescuing their tamoxifen sensitivity. Mechanistically, the elevated EHF expression transcriptionally up-regulates CERK expression to prohibit tamoxifen-induced sphingolipid ceramide accumulation, which then inhibits tamoxifen-mediated repression on PI3K/AKT dependent cell proliferation and its driven p53/caspase-3 mediated apoptosis in TAMR cells. This work provides insight into the regulation of sphingolipid metabolism in tamoxifen resistance and identifies a potential therapeutic target for this disease.

3D dynamic MRI of the vocal tract during natural speech.

PURPOSE: To develop and evaluate a technique for 3D dynamic MRI of the full vocal tract at high temporal resolution during natural speech. METHODS: We demonstrate 2.4 × 2.4 × 5.8 mm3 spatial resolution, 61-ms temporal resolution, and a 200 × 200 × 70 mm3 FOV. The proposed method uses 3D gradient-echo imaging with a custom upper-airway coil, a minimum-phase slab excitation, stack-of-spirals readout, pseudo golden-angle view order in kx -ky , linear Cartesian order along kz , and spatiotemporal finite difference constrained reconstruction, with 13-fold acceleration. This technique is evaluated using in vivo vocal tract airway data from 2 healthy subjects acquired at 1.5T scanner, 1 with synchronized audio, with 2 tasks during production of natural speech, and via comparison with interleaved multislice 2D dynamic MRI. RESULTS: This technique captured known dynamics of vocal tract articulators during natural speech tasks including tongue gestures during the production of consonants "s" and "l" and of consonant-vowel syllables, and was additionally consistent with 2D dynamic MRI. Coordination of lingual (tongue) movements for consonants is demonstrated via volume-of-interest analysis. Vocal tract area function dynamics revealed critical lingual constriction events along the length of the vocal tract for consonants and vowels. CONCLUSION: We demonstrate feasibility of 3D dynamic MRI of the full vocal tract, with spatiotemporal resolution adequate to visualize lingual movements for consonants and vocal tact shaping during natural productions of consonant-vowel syllables, without requiring multiple repetitions.

Joint arterial input function and tracer kinetic parameter estimation from undersampled dynamic contrast-enhanced MRI using a model consistency constraint.

PURPOSE: To develop and evaluate a model-based reconstruction framework for joint arterial input function (AIF) and kinetic parameter estimation from undersampled brain tumor dynamic contrast-enhanced MRI (DCE-MRI) data. METHODS: The proposed method poses the tracer-kinetic (TK) model as a model consistency constraint, enabling the flexible inclusion of different TK models and TK solvers, and the joint estimation of the AIF. The proposed method is evaluated using an anatomic realistic digital reference object (DRO), and nine retrospectively down-sampled brain tumor DCE-MRI datasets. We also demonstrate application to 30-fold prospectively undersampled brain tumor DCE-MRI. RESULTS: In DRO studies with up to 60-fold undersampling, the proposed method provided TK maps with low error that were comparable to fully sampled data and were demonstrated to be compatible with a third-party TK solver. In retrospective undersampling studies, this method provided patient-specific AIF with normalized root mean-squared-error (normalized by the 90th percentile value) less than 8% at up to 100-fold undersampling. In the 30-fold undersampled prospective study, the proposed method provided high-resolution whole-brain TK maps and patient-specific AIF. CONCLUSION: The proposed model-based DCE-MRI reconstruction enables the use of different TK solvers with a model consistency constraint and enables joint estimation of patient-specific AIF. TK maps and patient-specific AIF with high fidelity can be reconstructed at up to 100-fold undersampling in k,t-space. Magn Reson Med 79:2804-2815, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Direct estimation of tracer-kinetic parameter maps from highly undersampled brain dynamic contrast enhanced MRI.

PURPOSE: The purpose of this work was to develop and evaluate a T1 -weighted dynamic contrast enhanced (DCE) MRI methodology where tracer-kinetic (TK) parameter maps are directly estimated from undersampled (k,t)-space data. THEORY AND METHODS: The proposed reconstruction involves solving a nonlinear least squares optimization problem that includes explicit use of a full forward model to convert parameter maps to (k,t)-space, utilizing the Patlak TK model. The proposed scheme is compared against an indirect method that creates intermediate images by parallel imaging and compressed sensing before to TK modeling. Thirteen fully sampled brain tumor DCE-MRI scans with 5-second temporal resolution are retrospectively undersampled at rates R = 20, 40, 60, 80, and 100 for each dynamic frame. TK maps are quantitatively compared based on root mean-squared-error (rMSE) and Bland-Altman analysis. The approach is also applied to four prospectively R = 30 undersampled whole-brain DCE-MRI data sets. RESULTS: In the retrospective study, the proposed method performed statistically better than indirect method at R ≥ 80 for all 13 cases. This approach provided restoration of TK parameter values with less errors in tumor regions of interest, an improvement compared to a state-of-the-art indirect method. Applied prospectively, the proposed method provided whole-brain, high-resolution TK maps with good image quality. CONCLUSION: Model-based direct estimation of TK maps from k,t-space DCE-MRI data is feasible and is compatible up to 100-fold undersampling. Magn Reson Med 78:1566-1578, 2017. © 2016 International Society for Magnetic Resonance in Medicine.

A fast and flexible MRI system for the study of dynamic vocal tract shaping.

PURPOSE: The aim of this work was to develop and evaluate an MRI-based system for study of dynamic vocal tract shaping during speech production, which provides high spatial and temporal resolution. METHODS: The proposed system utilizes (a) custom eight-channel upper airway coils that have high sensitivity to upper airway regions of interest, (b) two-dimensional golden angle spiral gradient echo acquisition, (c) on-the-fly view-sharing reconstruction, and (d) off-line temporal finite difference constrained reconstruction. The system also provides simultaneous noise-cancelled and temporally aligned audio. The system is evaluated in 3 healthy volunteers, and 1 tongue cancer patient, with a broad range of speech tasks. RESULTS: We report spatiotemporal resolutions of 2.4 × 2.4 mm2 every 12 ms for single-slice imaging, and 2.4 × 2.4 mm2 every 36 ms for three-slice imaging, which reflects roughly 7-fold acceleration over Nyquist sampling. This system demonstrates improved temporal fidelity in capturing rapid vocal tract shaping for tasks, such as producing consonant clusters in speech, and beat-boxing sounds. Novel acoustic-articulatory analysis was also demonstrated. CONCLUSION: A synergistic combination of custom coils, spiral acquisitions, and constrained reconstruction enables visualization of rapid speech with high spatiotemporal resolution in multiple planes. Magn Reson Med 77:112-125, 2017. © 2016 Wiley Periodicals, Inc.

Feasibility of through-time spiral generalized autocalibrating partial parallel acquisition for low latency accelerated real-time MRI of speech.

PURPOSE: To evaluate the feasibility of through-time spiral generalized autocalibrating partial parallel acquisition (GRAPPA) for low-latency accelerated real-time MRI of speech. METHODS: Through-time spiral GRAPPA (spiral GRAPPA), a fast linear reconstruction method, is applied to spiral (k-t) data acquired from an eight-channel custom upper-airway coil. Fully sampled data were retrospectively down-sampled to evaluate spiral GRAPPA at undersampling factors R = 2 to 6. Pseudo-golden-angle spiral acquisitions were used for prospective studies. Three subjects were imaged while performing a range of speech tasks that involved rapid articulator movements, including fluent speech and beat-boxing. Spiral GRAPPA was compared with view sharing, and a parallel imaging and compressed sensing (PI-CS) method. RESULTS: Spiral GRAPPA captured spatiotemporal dynamics of vocal tract articulators at undersampling factors ≤4. Spiral GRAPPA at 18 ms/frame and 2.4 mm2 /pixel outperformed view sharing in depicting rapidly moving articulators. Spiral GRAPPA and PI-CS provided equivalent temporal fidelity. Reconstruction latency per frame was 14 ms for view sharing and 116 ms for spiral GRAPPA, using a single processor. Spiral GRAPPA kept up with the MRI data rate of 18ms/frame with eight processors. PI-CS required 17 minutes to reconstruct 5 seconds of dynamic data. CONCLUSION: Spiral GRAPPA enabled 4-fold accelerated real-time MRI of speech with a low reconstruction latency. This approach is applicable to wide range of speech RT-MRI experiments that benefit from real-time feedback while visualizing rapid articulator movement. Magn Reson Med 78:2275-2282, 2017. © 2017 International Society for Magnetic Resonance in Medicine.

Real-time magnetic resonance imaging and electromagnetic articulography database for speech production research (TC).

USC-TIMIT is an extensive database of multimodal speech production data, developed to complement existing resources available to the speech research community and with the intention of being continuously refined and augmented. The database currently includes real-time magnetic resonance imaging data from five male and five female speakers of American English. Electromagnetic articulography data have also been presently collected from four of these speakers. The two modalities were recorded in two independent sessions while the subjects produced the same 460 sentence corpus used previously in the MOCHA-TIMIT database. In both cases the audio signal was recorded and synchronized with the articulatory data. The database and companion software are freely available to the research community.

Reversal of the tamoxifen­resistant breast cancer malignant phenotype by proliferation inhibition with bromosulfonamidine amino­podophyllotoxin.

One of the lignans isolated from plants within the genus Podophyllum is podophyllotoxin (PPT). PPT and its derivatives are pharmacologically active compounds with potential antiproliferative properties in several kinds of tumors. Although these compounds have been used to treat other malignancies, no PPT derivative-based chemotherapeutic agent has been used to cure tamoxifen (TAM)-resistant breast cancer in clinical trials, to the best of our knowledge. Thus, using TAM-resistant breast cancer as a disease model, the present study assessed the effects of a recently synthesized PPT derivative, bromosulfonamidine amino-PPT (BSAPPT), on TAM-resistant breast cancer. Using the tamoxifen-resistant breast cancer cell model (MCF-7/TAMR) in vitro, Cell Counting Kit-8 and colony formation assays were adopted to evaluate the effect of BSAPPT on cell proliferation. Cell apoptosis and cell cycle assays were used to assess the influence of BSAPPT on cell apoptosis and the cell cycle in MCF-7/TAMR. The targets of the potential mechanism of action were analyzed by RT-qPCR and western blotting. The present study demonstrated that BSAPPT suppressed MCF-7/TAMR cell proliferation in a dose-dependent manner. By modulating the level of expression of genes linked to both apoptosis and the cell cycle, BSAPPT triggered MCF-7/TAMR cells to undergo apoptosis and prevented them from entering the cell cycle. Consequently, BSAPPT blocked these cells from proliferating, thereby halting the malignant advancement of TAM-resistant breast cancer. Therefore, these findings indicate that new therapeutic agents involving BSAPPT may be developed to facilitate the treatment of TAM-resistant breast cancer.

CRP inhibits the osteoblastic differentiation of OPCs via the up-regulation of primary cilia and repression of the Hedgehog signaling pathway.

Inflammation disrupts bone metabolism and leads to bone damage. C-reactive protein (CRP) is a typical inflammation marker. Although CRP measurement has been conducted for many decades, how osteoblastic differentiation influences molecular mechanisms remains largely unknown. The present study attempted to investigate the effects of CRP on primary cultured osteoblast precursor cells (OPCs) while elucidating the underlying molecular mechanisms. OPCs were isolated from suckling Sprague-Dawleyrats. Fewer OPCs were observed after recombinant C-reactive protein treatment. In a series of experiments, CRP inhibited OPC proliferation, osteoblastic differentiation, and the OPC gene expression of the hedgehog (Hh) signaling pathway. The inhibitory effect of CRP on OPC proliferation occurred via blockade of the G1-S transition of the cell cycle. In addition, the regulation effect of proto cilium on osteoblastic differentiation was analyzed using the bioinformatics p. This revealed the primary cilia activation of recombinant CRP effect on OPCs through in vitro experiments. A specific Sonic Hedgehog signaling agonist (SAG) rescued osteoblastic differentiation inhibited by recombinant CRP. Moreover, chloral hydrate, which removes primary cilia, inhibited the Suppressor of Fused (SUFU) formation and blocked Gli2 degradation. This counteracted osteogenesis inhibition caused by CRP. Therefore, these data depict that CRP can inhibit the proliferation and osteoblastic differentiation of OPCs. The underlying mechanism could be associated with primary cilia activation and Hh pathway repression.

Impaired arginine/ornithine metabolism drives severe HFMD by promoting cytokine storm.

Introduction: The Hand, Foot and Mouth Disease (HFMD), caused by enterovirus 71 infection, is a global public health emergency. Severe HFMD poses a significant threat to the life and well-being of children. Numerous studies have indicated that the occurrence of severe HFMD is associated with cytokine storm. However, the precise molecular mechanism underlying cytokine storm development remains elusive, and there are currently no safe and effective treatments available for severe HFMD in children. Methods: In this study, we established a mouse model of severe HFMD to investigate the molecular mechanisms driving cytokine storm. We specifically analyzed metabolic disturbances, focusing on arginine/ornithine metabolism, and assessed the potential therapeutic effects of spermine, an ornithine metabolite. Results: Our results identified disturbances in arginine/ornithine metabolism as a pivotal factor driving cytokine storm onset in severe HFMD cases. Additionally, we discovered that spermine effectively mitigated the inflammatory injury phenotype observed in mice with severe HFMD. Discussion: In conclusion, our findings provide novel insights into the molecular mechanisms underlying severe HFMD from a metabolic perspective while offering a promising new strategy for its safe and effective treatment.

MicroRNA 34c gene down-regulation via DNA methylation promotes self-renewal and epithelial-mesenchymal transition in breast tumor-initiating cells.

Tumor-initiating cells (T-ICs), a subpopulation of cancer cells with stem cell-like properties, are related to tumor relapse and metastasis. Our previous studies identified a distinct profile of microRNA (miRNA) expression in breast T-ICs (BT-ICs), and the dysregulated miRNAs contribute to the self-renewal and tumorigenesis of these cells. However, the underlying mechanisms for miRNA dysregulation in BT-ICs remain obscure. In the present study, we demonstrated that the expression and function of miR-34c were reduced in the BT-ICs of MCF-7 and SK-3rd cells, a breast cancer cell line enriched for BT-ICs. Ectopic expression of miR-34c reduced the self-renewal of BT-ICs, inhibited epithelial-mesenchymal transition, and suppressed migration of the tumor cells via silencing target gene Notch4. Furthermore, we identified a single hypermethylated CpG site in the promoter region of miR-34c gene that contributed to transcriptional repression of miR-34c in BT-ICs by reducing DNA binding activities of Sp1. Therefore, miR-34c reduction in BT-ICs induced by a single hypermethylated CpG site in the promoter region promotes self-renewal and epithelial-mesenchymal transition of BT-ICs.

A Predictive Model for Contrast-Induced Acute Kidney Injury After Percutaneous Coronary Intervention in Elderly Patients with ST-Segment Elevation Myocardial Infarction.

Purpose: Development and validation of a nomogram model to predict the risk of Contrast-Induced Acute Kidney Injury (CI-AKI) after emergency percutaneous coronary intervention (PCI) in elderly patients with acute ST-segment elevation myocardial infarction (STEMI). Patients and Methods: Retrospective analysis of 542 elderly (≥65 years) STEMI patients undergoing emergency PCI in our hospital from January 2019 to June 2022, with all patients randomized to the training cohort (70%; n=380) and the validation cohort (30%; n=162). Univariate analysis, LASSO regression, and multivariate logistic regression analysis were used to determine independent risk factors for developing CI-AKI in elderly STEMI patients. R software is used to generate a nomogram model. The predictive power of the nomogram model was compared with the Mehran score 2. The area under the ROC curve (AUC), calibration curves, and decision curve analysis (DCA) was used to evaluate the prediction model's discrimination, calibration, and clinical validity, respectively. Results: The nomogram model consisted of five variables: diabetes mellitus (DM), left ventricular ejection fraction (LVEF), Systemic immune-inflammatory index (SII), N-terminal pro-brain natriuretic peptide (NT-proBNP), and highly sensitive C-reactive protein(hsCRP). In the training cohort, the AUC is 0.84 (95% CI: 0.790-0.890), and in the validation cohort, it is 0.844 (95% CI: 0.762-0.926). The nomogram model has better predictive ability than Mehran score 2. Based on the calibration curves, the predicted and observed values of the nomogram model were in good agreement between the training and validation cohort. Decision curve analysis (DCA) and clinical impact curve showed that the nomogram prediction model has good clinical utility. Conclusion: The established nomogram model can intuitively and specifically screen high-risk groups with a high degree of discrimination and accuracy and has a specific predictive value for CI-AKI occurrence in elderly STEMI patients after PCI.

Prognostic Value of Systemic Immune-Inflammation Index and NT-proBNP in Patients with Acute ST-Elevation Myocardial Infarction.

Objective: Our aim was to assess systemic immune-inflammation index (SII) and NT-proBNP value either in singly or in combination to predict acute ST-elevation myocardial infarction (STEMI) patient prognosis. Methods: Analyzed retrospectively the clinical features and laboratory data of STEMI confirmed patients in our hospital from January to December 2020. The levels of SII and NT-proBNP were detected. The Kaplan-Meier approach and Spearman's rank correlation coefficient were used to construct the overall major adverse cardiac event (MACE) curve. Multivariate Cox regression analysis was applied to detect MACE predictors. In addition, the Delong test and receiver operating characteristic (ROC) curve analyzed each factor performance on its own and composite multivariate index to predict MACEs. Results: The MACE group showed statistically significant differences in SII, NT- proBNP in comparison to the non-MACE group (P=0.003, P <0.001). Based on Kaplan-Meier analysis, SII and NT-proBNP showed positive correlation with MACE (log-rank P < 0.001). SII and NT-proBNP were independent predicting factors for long-term MACEs in multivariate Cox regression analysis (P <0.001, HR: 2.952, 95% CI 1.565-5.566; P <0.001, HR: 2.112, 95% CI 1.662-2.683). SII and NT-proBNP exhibited a positive correlation (R = 0.187, P < 0.001) in correlation analysis. According to the ROC statistical analysis, the combination exhibited 78.0% sensitivity and 88.0% specificity in the prediction of MACE. According to the results of the AUC and Delong test, the combined SII and NT-proBNP performed better as a prognostic index than each of the individual factor indexes separately (Z = 2.622, P = 0.009; Z = 3.173, P < 0.001). Conclusion: SII and NT-proBNP were independent indicators of clinical prognosis in acute STEMI patients, and they correlated positively. These factors could be combined to improve clinical prognosis.

Predictive value of systemic immune-inflammatory index combined with CHA2DS2-VASC score for contrast-induced acute kidney injury in patients with acute coronary syndrome undergoing percutaneous coronary intervention.

OBJECTIVE: To investigate the value of systemic immune-inflammation index (SII) combined with CHA2DS2-VASC score in predicting the risk of contrast-induced acute kidney injury (CI-AKI) in patients with acute coronary syndrome (ACS) after percutaneous coronary intervention (PCI) treatment. METHODS: 1531 consecutive patients with ACS and undergoing PCI were recruited from January 2019 to December 2021. All patients were divided into CI-AKI and non-CI-AKI groups according to the pre-procedure and post-procedure creatinine changes, and the baseline data were compared between the two groups. Binary logistic regression analysis was used to investigate the factors influencing CI-AKI in ACS patients after PCI. Receiver operating characteristic (ROC) curves were plotted to evaluate the predictive value of SII, CHA2DS2-VASC, and their combined levels on CI-AKI after PCI. RESULTS: Patients with high SII and high CHA2DS2-VASC score had a higher incidence of CI-AKI. For SII, the area under the ROC curve (AUC) for predicting CI-AKI was 0.686. The optimal cut-off value was 736.08 with a sensitivity of 66.8% and a specificity of 66.3% [95% confidence interval (CI) 0.662-0.709; P < 0.001]. For CHA2DS2-VASC score, the AUC was 0.795, the optimal cut-off value was 2.50 with a sensitivity of 80.3% and a specificity of 62.7% (95% CI 0.774-0.815; P < 0.001). When combining SII and CHA2DS2-VASC score, the AUC was 0.830, the optimal cut-off value was 0.148 with a diagnostic sensitivity of 76.1% and a specificity of 75.2% (95% CI 0.810-0.849; P < 0.001). The results showed that SII combined with CHA2DS2-VASC score resulted in improved predictive accuracy of CI-AKI. Multifactorial logistic regression analysis showed that albumin level (OR = 0.967, 95% CI 0.936-1.000; P = 0.047), lnSII level (OR = 1.596, 95% CI 1.010-1.905; P < 0.001), and CHA2DS2-VASC score level (OR = 1.425, 95% CI 1.318-1.541; P < 0.001) were independent risk factors for CI-AKI in patients with ACS treated with PCI. CONCLUSION: High SII and high CHA2DS2-VASC score are risk factors for the development of CI-AKI, and the combination of the two improves the accuracy of predicting the occurrence of CI-AKI in patients with ACS undergoing PCI.

Prognostic Nutritional Index Combined with Triglyceride-Glucose Index to Contrast a Nomogram for Predicting Contrast-Induced Kidney Injury in Type 2 Diabetes Mellitus Patients with Acute Coronary Syndrome After Percutaneous Coronary Intervention.

Objective: Our objective was to develop and validate a nomogram model aiming at predicting the risk of contrast-induced acute kidney injury (CI-AKI) following percutaneous coronary intervention (PCI) in patients suffering from type 2 diabetes mellitus (T2DM) and also diagnosed with acute coronary syndrome (ACS). Methods: The study gathered data from 722 T2DM patients with ACS who received PCI treatment at the Affiliated Hospital of Xuzhou Medical University between February 2019 and December 2022, serving as the training set. Considering the validation set, the study included 217 patients who received PCI at the East Affiliated Hospital of Xuzhou Medical University. The patients were classified into CI-AKI and non-CI-AKI groups. The study employed univariate and multivariate logistic analysis for identifying independent risk factors for CI-AKI, followed by developing a predictive nomogram model for CI-AKI risk using R software. The predictive performance and clinical utility of the nomogram were assessed through internal and external validation, utilizing the areas under the receiver operating characteristic curve (AUC-ROC), the Hosmer-Lemeshow test and calibration correction curve, and decision curve analysis (DCA). Results: The nomogram comprised four variables: age, estimated glomerular filtration rate (eGFR), triglyceride-glucose (TyG) index, and prognostic nutritional index (PNI). The AUC-ROC were 0.785 (95% confidence interval (CI) 0.729-0.841) and 0.802 (95% CI 0.699-0.905) for the training and validation cohorts, respectively, indicating a high discriminative ability of the nomogram. The calibration assessment and decision curve analysis have substantiated the strong concordance and clinical usefulness of the aforementioned. Conclusion: The nomogram exhibits favorable discrimination and accuracy, enabling it to visually and individually identify pre-procedure high-risk patients, and possesses a predictive capacity regarding CI-AKI incidence after PCI in patients diagnosed with both T2DM and ACS.

A novel multimode biosensor for sensitive detection of AFB1 in food based on Mxenes nano enzymes.

In this work, Ti3C2 nano-enzymes (Ti3C2 NEs) materials with simulated peroxidase activity and fluorescence quenching properties were prepared. Then Ti3C2 NEs was functionalized using 6-carboxyfluorescein (FAM) labeled Aflatoxin B1 (AFB1) aptamers to construct a novel multimode nano enzyme biosensor for the detection of AFB1 in peanuts. Based on the fluorescence quenching characteristics and the superior simulated peroxidase activity of Ti3C2 NES and the specific binding of the aptamer to AFB1, the sensitive and rapid fluorescence/colorimetric/smart phone detection of AFB1 have been achieved, with detection limits of 0.09 ng mL-1, 0.61 ng mL-1 and 0.96 ng mL-1, respectively. The analytical method provided can not only detect AFB1 in multiple modes, but also has a wider detection range, lower limit of detection (LOD) and better recovery rate, and can achieve on-site accurate detection of AFB1 content in peanuts, which has great application potential in the field of food quality testing.

Clinical and immunological features of an APLAID patient caused by a novel mutation in PLCG2.

Background: The APLAID syndrome is a rare primary immunodeficiency caused by gain-of-function mutations in the PLCG2 gene. We present a 7-year-old APLAID patient who has recurrent blistering skin lesions, skin infections in the perineum, a rectal perineal fistula, and inflammatory bowel disease. Methods: To determine the genetic cause of our patient, WES and bioinformatics analysis were performed. Flow cytometry was used for phenotyping immune cell populations in peripheral blood. Cytokines released into plasma were analyzed using protein chip technology. The PBMCs of patient and a healthy child were subjected to single-cell RNA-sequencing analysis. Results: The patient carried a novel de novo missense mutation c.2534T>C in exon 24 of the PLCG2 gene that causes a leucine to serine amino acid substitution (p.Leu845Ser). Bioinformatics analysis revealed that this mutation had a negative impact on the structure of the PLCγ2 protein, which is highly conserved in many other species. Immunophenotyping by flow cytometry revealed that in addition to the typical decrease in circulating memory B cells, the levels of myeloid dendritic cells (mDCs) in the children's peripheral blood were significantly lower, as were the CD4+ effector T cells induced by their activation. Single-cell sequencing revealed that the proportion of different types of cells in the peripheral blood of the APLAID patient changed. Conclusions: We present the first case of APLAID with severely reduced myeloid dendritic cells carrying a novel PLCG2 mutation, and conducted a comprehensive analysis of immunological features in the ALPAID patient, which has not been mentioned in previous reports. This study expands the spectrum of APLAID-associated immunophenotype and genotype. The detailed immune analyses in this patient may provide a basis for the development of targeted therapies for this severe autoinflammatory disease.

A novel Nb2C MXene based aptasensor for rapid and sensitive multi-mode detection of AFB1.

Rapid and accurate on-site detection of aflatoxin B1 (AFB1) is of great significance for ensuring food safety. This work developed a dual mode aptasensor and a dual channel artificial neural network (ANN) intelligent sensor detection platform for simple and convenient quantitative detection of AFB1 in food. This sensor was prepared by encoding manganese ion (Mn2+) mediated surface concave niobium carbide MXene nanomaterials (Nb2C-MNs) using fluorescent group labeled aptamers (ssDNA-FAM). Mn2+-mediated Nb2C-MNs exhibited better peroxidase-like and fluorescence quenching properties. Moreover, ssDNA-FAM as a fluorescent probe for the sensor also significantly enhanced the enzyme activity of Nb2C-MNs. When AFB1 existed, ssDNA-FAM preferentially bonded to AFB1, resulting in fluorescence signal recovery and colorimetric signal weakening. Consequently, the multimodal biosensor could achieve fluorescence/colorimetric detection without the need for material and reagent replacement. In on-site detection, both ratio fluorescence and colorimetric signals could be collected using smartphones and analyzed and modeled on the developed ANN platform, achieving visual intelligent sensing. This multimodal biosensor had a detection line as low as 0.0950 ng/mL under optimal conditions, and also had the advantages of simple operation, fast and sensitive, and high specificity, which can meet the real-time on-site detection needs of AFB1 in remote areas.

Preprocedural SII Combined with High-Sensitivity C-Reactive Protein Predicts the Risk of Contrast-Induced Acute Kidney Injury in STEMI Patients Undergoing Percutaneous Coronary Intervention.

Objective: To investigate the relationship between the incidence of contrast-induced acute kidney injury (CI-AKI) and the levels of the systemic immune-inflammatory index (SII, platelet × neutrophil/lymphocyte ratio) and high-sensitivity C-reactive protein (hsCRP) in patients with ST-segment elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI), to analyze further the predictive value of the combination of SII and hsCRP for CI-AKI. Methods: Retrospectively analyze the clinical data of STEMI patients who underwent PCI in our cardiology department from November 2019 to March 2021. Restricted cubic splines were used to determine the correlation between SII and hsCRP and the risk of CI-AKI. Patients were divided into the CI-AKI group (n=71) and the non-CI-AKI group (n=344) according to postoperative creatinine changes. Logistic regression was used to analyze the factors influencing CI-AKI. ROC curves were used to evaluate the predictive value of SII, hsCRP, and their combined levels on CI-AKI. Results: Restricted cubic spline analysis showed that when SII>653.73×109/L and hsCRP>5.52mg/dl, there was a positive correlation with the incidence of CI-AKI. And the incidence of CI-AKI rose with the inflammation status. The receiver operating characteristic curve of SII combined with hsCRP was 0.831, which was higher than SII or hsCRP alone. The logistic regression analysis showed that high-risk factors of CI-AKI were diabetes mellitus, platelet count, and highly elevated SII and hsCRP. Conclusion: Within a certain range, elevated inflammatory biomarkers SII and hsCRP were risk factors for CI-AKI after PCI in patients with STEMI. This study suggests that the combination of SII and hsCRP predicts the risk of CI-AKI more accurately than either biomarker alone.

A New Preparation Method for Peroral Endoscopic Myotomy in Patients with Achalasia Can Effectively Reduce the Esophageal Residual Contents: A Comparative Retrospective Study.

METHODS: This retrospective study enrolled 65 achalasia patients who underwent POEM from June 2017 to October 2021. Based on the preoperative diet strategies, patients were divided into carbonated beverage group (n = 48) and control group (n = 17). Demographic and clinical data, duration of preoperative endoscopy, quality of esophagus cleansing, and patient satisfaction on preoperative procedure were collected and compared. In the current study, we established the quality of esophagus cleansing: Grade A, no remnants or only liquid or frothy discharge; Grade B, a little amount of solid content remained; and Grade C, a large amount of solid content remained. RESULTS: There were 41 Grade A, 6 Grade B, and 1 Grade C patients in the carbonated beverage group, while there were 8 Grade A, 6 Grade B, and 3 Grade C patients in the control group (p value = 0.001). The esophagus cleansing degrees were significantly ameliorated after drinking carbonated beverages in all the three subtypes of achalasia according to the degree of dilatation. The mean duration of preoperative endoscopy was 6.54 ± 2.250 minutes in the carbonated beverage group and 10.27 ± 4.788 minutes in the control group (p value = 0.010). The score of patient satisfaction concerning the procedure before the POEM in the carbonated beverage group was 4.5 ± 0.652, while the score in the control group was 4.35 ± 0.702 (p value = 0.436). In the multivariate analysis, patient satisfaction was significantly associated with male (odds ratio 0.296, 95% CI: 0.097-0.905, p value = 0.033). CONCLUSIONS: Drinking carbonated beverages reduce the duration of preoperative endoscopy and ameliorate the esophagus cleansing degrees without impairing patient satisfaction.