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.

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.

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.

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.

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 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.

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.

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.

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.

Case Report: A Novel Intronic Mutation in AIFM1 Associated With Fatal Encephalomyopathy and Mitochondrial Disease in Infant.

Background: The AIFM1 gene is located on chromosome Xq26.1 and encodes a flavoprotein essential for nuclear disassembly in apoptotic cells. Mutations in this gene can cause variable clinical phenotypes, but genotype-phenotype correlations of AIFM1-related disorder have not yet been fully determined because of the clinical scarcity. Case Presentation: We describe a 4-month-old infant with mitochondrial encephalopathy, carrying a novel intronic variant in AIFM1 (NM_004208.4: c.1164 + 5G > A). TA cloning of the complementary DNA (cDNA) and Sanger sequencing revealed the simultaneous presence of an aberrant transcript with exon 11 skipping (89 bp) and a normal transcript through analysis of mRNA extracted from the patient's fibroblasts, which is consistent with direct RNA sequencing results. Conclusion: We verified the pathogenic effect of the AIFM1 c.1164 + 5G > A splicing variant, which disturbed normal mRNA splicing. Our findings expand the mutation spectrum of AIFM1 and point out the necessity of intronic sequence analysis and the importance for integrative functional studies in the interpretation of sequence variants.

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.

Primary cilia regulate gastric cancer-induced bone loss via cilia/Wnt/ß-catenin signaling pathway.

Cancer-associated bone disease is a frequent occurrence in cancer patients and is associated with pain, bone fragility, loss, and fractures. However, whether primary or non-bone metastatic gastric cancer induces bone loss remains unclear. Here, we collected clinical evidence of bone loss by analyzing serum and X-rays of 25 non-bone metastatic gastric cancer patients. In addition, C57BL mice were injected with the human gastric cancer cell line HGC27 and its effect on bone mass was analyzed by Micro-CT, immunoblotting, and immunohistochemistry. Furthermore, the degree of the proliferation and osteogenic differentiation of mesenchymal stem cells (MSCs) co-cultured with HGC-27 or SGC-7901 cells was analyzed by colony-formation assay, alizarin red staining, immunofluorescence, qPCR, immunoblotting, and alkaline phosphatase activity assay. These indicated that gastric cancer could damage bone tissue before the occurrence of bone metastases. We also found that cilia formation of MSCs was increased in the presence of HGC27 cells, which was associated with abnormal activation of the Wnt/ß-catenin pathway. Expression of DKK1 inhibited the Wnt/ß-catenin signaling pathway and partially rescued osteogenic differentiation of MSCs. In summary, our results suggest that gastric cancer cells might cause bone damage prior to the occurrence of bone metastasis via cilia-dependent activation of the Wnt/ß-catenin signaling pathway.

Tracer kinetic models as temporal constraints during brain tumor DCE-MRI reconstruction.

PURPOSE: To apply tracer kinetic models as temporal constraints during reconstruction of under-sampled brain tumor dynamic contrast enhanced (DCE) magnetic resonance imaging (MRI). METHODS: A library of concentration vs time profiles is simulated for a range of physiological kinetic parameters. The library is reduced to a dictionary of temporal bases, where each profile is approximated by a sparse linear combination of the bases. Image reconstruction is formulated as estimation of concentration profiles and sparse model coefficients with a fixed sparsity level. Simulations are performed to evaluate modeling error, and error statistics in kinetic parameter estimation in presence of noise. Retrospective under-sampling experiments are performed on a brain tumor DCE digital reference object (DRO), and 12 brain tumor in-vivo 3T datasets. The performances of the proposed under-sampled reconstruction scheme and an existing compressed sensing-based temporal finite-difference (tFD) under-sampled reconstruction were compared against the fully sampled inverse Fourier Transform-based reconstruction. RESULTS: Simulations demonstrate that sparsity levels of 2 and 3 model the library profiles from the Patlak and extended Tofts-Kety (ETK) models, respectively. Noise sensitivity analysis showed equivalent kinetic parameter estimation error statistics from noisy concentration profiles, and model approximated profiles. DRO-based experiments showed good fidelity in recovery of kinetic maps from 20-fold under-sampled data. In-vivo experiments demonstrated reduced bias and uncertainty in kinetic mapping with the proposed approach compared to tFD at under-sampled reduction factors >= 20. CONCLUSIONS: Tracer kinetic models can be applied as temporal constraints during brain tumor DCE-MRI reconstruction. The proposed under-sampled scheme resulted in model parameter estimates less biased with respect to conventional fully sampled DCE MRI reconstructions and parameter estimation. The approach is flexible, can use nonlinear kinetic models, and does not require tuning of regularization parameters.

The effects of cognitive reserve on predicting and moderating the cognitive and psychosocial functioning of patients with bipolar disorder.

BACKGROUND: Cognitive reserve (CR) reflects the resilience of the brain to cope with neuropathological changes and minimize clinical manifestations. In the present study, we explore the association between CR and cognitive and psychosocial functioning, and examined the potential moderating role of CR in patients with bipolar disorder (BD). METHODS: One hundred and twenty-five outpatients with BD type I and sixty healthy individuals were recruited. All participants were assessed with a neuropsychological battery examining attention and processing speed, working memory, visual memory and executive functioning, the Global Assessment of Functioning scale and the Cognitive Complaints in Bipolar Disorder Rating Assessment. Proxies for cognitive reserve included premorbid intelligence and educational level. RESULTS: Patients with bipolar disorder presented with worse cognitive performance and psychosocial functioning than healthy controls. Multiple regression models revealed that educational level negatively associated with all assessed domain-specific cognition scores and premorbid intelligence predicted attention and processing speed and psychosocial functioning. Notably, premorbid intelligence significantly moderated the associations between the number of episodes (total, hypo/manic and depressed) and neurocognitive functioning, and the educational level also moderated the relationships between the numbers of hypo/manic and total episodes and subjective cognitive functioning. CONCLUSIONS: Cognitive reserve contributes to functional outcomes in patients with BD and may emerge as a key factor contributing to the course and prognosis of patients with BD. In the future, cognitive reserve must be considered in both research and clinical interventions related to bipolar disorder.

Subjective cognitive dysfunction in patients with bipolar disorder: The prevalence, related factors and effects on predicting psychosocial functioning and suicidal ideation.

Persistent cognitive deficits are prevalent during all stages of bipolar disorder (BD). However, few studies have examined subjective cognitive complaints in patients with BD. This study aimed to investigate the prevalence and relevant factors of subjective cognitive functioning and its potential effects on predicting psychosocial functioning and suicidal ideation in BD. Ninety-two patients with BD type I (including 42 depressed patients and 50 euthymic patients) and 60 healthy individuals were recruited for this study. All participants were assessed with a battery of neuropsychological tests examining attention and processing speed, visual memory, working memory and executive functions, as well as the Cognitive Complaints in Bipolar Disorder Rating Assessment, the Global Assessment of Functioning scale and the Beck Scale for Suicide Ideation. Bipolar patients exhibited worse subjective cognitive dysfunction compared with healthy individuals, and depressed patients expressed more cognitive complaints than euthymic bipolar patients. In bipolar group, psychosocial functioning, suicidal ideation and occupational status were the main relevant factors of subjective cognitive functioning. Subjective cognitive functioning could also predict psychosocial functioning and suicidal ideation. Depressive symptoms moderated the associations between objective cognitive functioning and suicidal ideation, but could not moderate the correlations between cognitive functioning and psychosocial functioning. These findings suggest that subjective cognitive assessment should be further emphasized in clinical practice.

Targeting Pin1 by All-Trans Retinoic Acid (ATRA) Overcomes Tamoxifen Resistance in Breast Cancer via Multifactorial Mechanisms.

Breast cancer is the most prevalent tumor in women worldwide and about 70% patients are estrogen receptor positive. In these cancer patients, resistance to the anticancer estrogen receptor antagonist tamoxifen emerges to be a major clinical obstacle. Peptidyl-prolyl isomerase Pin1 is prominently overexpressed in breast cancer and involves in tamoxifen-resistance. Here, we explore the mechanism and effect of targeting Pin1 using its chemical inhibitor all-trans retinoic acid (ATRA) in the treatment of tamoxifen-resistant breast cancer. We found that Pin1 was up-regulated in tamoxifen-resistant human breast cancer cell lines and tumor tissues from relapsed patients. Pin1 overexpression increased the phosphorylation of ERα on S118 and stabilized ERα protein. ATRA treatment, resembling the effect of Pin1 knockdown, promoted ERα degradation in tamoxifen-resistant cells. Moreover, ATRA or Pin1 knockdown decreased the activation of ERK1/2 and AKT pathways. ATRA also reduced the nuclear expression and transcriptional activity of ERα. Importantly, ATRA inhibited cell viability and proliferation of tamoxifen-resistant human breast cancer cells in vitro. Slow-releasing ATRA tablets reduced the growth of tamoxifen-resistant human breast cancer xenografts in vivo. In conclusion, ATRA-induced Pin1 ablation inhibits tamoxifen-resistant breast cancer growth by suppressing multifactorial mechanisms of tamoxifen resistance simultaneously, which demonstrates an attractive strategy for treating aggressive and endocrine-resistant tumors.

The associations between subjective and objective cognitive functioning across manic or hypomanic, depressed, and euthymic states in Chinese bipolar patients.

BACKGROUND: Patients may present cognitive deficits during all stages of bipolar disorder (BD). Few studies have examined self-reported cognitive difficulties and its relation to neurocognitive dysfunction during symptomatic periods of BD. This study aimed to compare subjective cognitive functioning and explore associations between subjective and objective cognitive functioning across different BD clinical states, and investigate the predicting and moderating roles of mood symptoms. METHODS: Subjective cognitive functioning (measured by Cognitive Complaints in Bipolar Disorder Rating Assessment, COBRA) and several domains of cognitive functioning (assessed by a neuropsychological battery), including executive functions, attention and processing speed, and visual memory, were examined in 48 hypomanic or manic patients, 42 depressed bipolar patients, 50 euthymic bipolar patients and 60 healthy comparisons. RESULTS: All patients exhibited subjective and objective cognitive deficits in relation to healthy comparisons. There was a significant association between subjective and objective cognitive functioning in euthymic group, but the association was not significant in acute symptomatic groups, which could be moderated by depressive or manic symptoms in depressive or manic group, respectively. Subjective cognitive functioning was significantly correlated with mood symptoms, and the best predictor of subjective cognitive functioning was depressive symptoms. LIMITATIONS: This was a cross-sectional study with a mixed sample of inpatients and outpatients. The medication effect was not adjusted. CONCLUSIONS: The associations between subjective and objective cognitive dysfunction varied in clinical states, and mood symptoms moderated the associations. A neuropsychological test battery is required to substantiate actual cognitive dysfunction in clinical settings, irrespective of subjective cognitive deficits.

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.