Right Ventricular Strain Derived from Cardiac MRI Feature Tracking for the Diagnosis and Prognosis of Arrhythmogenic Right Ventricular Cardiomyopathy.

Purpose To demonstrate the myocardial strain characteristics of patients with arrhythmogenic right ventricular cardiomyopathy (ARVC), based on revised Task Force Criteria (rTFC), and to explore the prognostic value of strain analysis in ARVC. Materials and Methods This retrospective study included 247 patients (median age, 38 years [IQR, 28-48 years]; 167 male, 80 female) diagnosed with ARVC, based on rTFC, between 2014 and 2018. Patients were divided into "possible" (n =25), "borderline" (n = 40), and "definite" (n = 182) ARVC groups following rTFC. Biventricular global strain parameters were calculated using cardiac MRI feature tracking (FT). The primary outcome was defined as a composite of cardiovascular events, including cardiovascular death, heart transplantation, and appropriate implantable cardioverter defibrillator discharge. Univariable and multivariable cumulative logistic regression and Cox proportional hazards regression analysis were used to evaluate the diagnostic and prognostic value of right ventricle (RV) strain parameters. Results Patients with definite ARVC had significantly reduced RV global strain in all three directions compared with possible or borderline groups (all P < .001). RV global longitudinal strain (GLS) was an independent predictor for disease (odds ratio, 1.09 [95% CI: 1.02, 1.16]; P = .009). During a median follow-up of 3.4 years (IQR, 2.0-4.9 years), 55 patients developed primary end point events. Multivariable analysis showed that RV GLS was independently associated with the occurrence of cardiovascular events (hazard ratio, 1.15 [95% CI: 1.07, 1.24]; P < .001). Kaplan-Meier analysis showed that patients with RV GLS worse than median had a higher risk of combined cardiovascular events (log-rank P < .001). Conclusion RV GLS derived from cardiac MRI FT demonstrated good diagnostic and prognostic value in ARVC. Keywords: MR Imaging, Image Postprocessing, Cardiac, Right Ventricle, Cardiomyopathies, Arrhythmogenic Right Ventricular Cardiomyopathy, Revised Task Force Criteria, Cardiovascular MR, Feature Tracking, Cardiovascular Events Supplemental material is available for this article. © RSNA, 2024.

Exploring Derivatives of Quinolizidine Alkaloid Sophoridine in the Design and Biological Mechanistic Evaluation of Histone Deacetylase Inhibitors against Triple-Negative Breast Cancer.

As a critical epigenetic modulator of gene expression, histone deacetylases (HDACs) have been involved in the pathogenesis and therapeutic investigation of cancer. Quinolizidine alkaloid sophoridine is known to have anticancer efficacy but with limited indication. By incorporating the pharmacophore of the HDAC inhibitor into the ring-opened sophoridine core, a new series of sophoridine hydroxamic acid derivatives were synthesized. After structure-activity studies, a selected compound was found to exert significant cytotoxicity in triple-negative breast cancer CAL-51 cells (IC50 1.17 µM), and demonstrated low nanomolar inhibitory potency toward HDAC1/3/6. Cellular functional assays indicated that this compound was able to induce apoptosis and cause accumulation of cells in the S phase of the cell cycle. Western blot analysis revealed it to decrease the expression of DNMT1, DNMT3a and DNMT3b by down-regulating phosphor-ERK1/2. Furthermore, treatment with this compound proved to block the PI3K/AKT/mTOR signaling in the PI3KCA and PTEN-mutant CAL-51 cells. Collectively, this work provides a novel lead compound for the development of potential therapeutics against triple-negative breast cancers, possibly mesenchymal-like subtype.

Synthesis and biological evaluation of (4-hydroxy-2-(substitued sulfonamido)pyrimidine-5-carbonyl)glycines as oral erythropoietin secretagogues.

Erythropoietin (EPO) is the predominant regulating factor in erythropoiesis. Herein we describe the identification of (4-hydroxy-2-(substitued sulfonamido)pyrimidine-5-carbonyl) glycine-based oral EPO secretagogues. Most of these compounds obviously increased the EPO level in Hep3B cells by stabilizing the hypoxia-inducible factor-α (HIF-α). Furthermore, their potential inhibitory activities against HIF prolyl hydroxylase domain (PHD) revealed their function as PHD inhibitors in PHD-HIF pathway. Compound 6i, with a biphenyl substituent on the sulfonamido group, particularly increased plasma EPO level in mice and could serve as a candidate of EPO stimulating agent for anemia treatment.

Kinetics-Favorable Ultrathin NiCo-MOF Nanosheets with Boosted Pseudocapacitive Charge Storage for Quasi-Solid-State Hybrid Supercapacitors.

Bimetallic metal-organic frameworks (MOFs) with an ultrathin configuration are compelling materials for developing high-performance energy storage devices on account of their unique structural merits. Herein, a hydrangea-like NiCo-MOF is well prepared using controllable solvothermal and cation-exchange processes, synchronously achieving bimetallic nodes and hierarchical ultrathin architecture. The structural superiority enables NiCo-MOF of expanded electrons' transfer pathways and multitudinous electrolytes' diffusion channels, resulting in a significant enhancement in pseudocapacitive performance. Coupling with the bimetallic nature and constructional advantages, NiCo-MOF shows superior gravimetric capacity (832.6 C g-1 at 1 A g-1) and electrochemical kinetics to those of monometallic Ni-MOF and Co-MOF. Importantly, the quasi-solid-state hybrid supercapacitor (HSC) based on the NiCo-MOF cathode and active carbon (AC) anode delivers a desirable energy density (45.3 Wh kg-1 at 847.8 W kg-1), a favorable power density (7160.0 W kg-1 at 23.3 Wh kg-1), a remarkable cyclability (82.4% capacity retention over 7000 cycles), and a capability of driving miniature electronics, exhibiting its potential in practical applications. This work presents an efficient design strategy to develop kinetics-favorable MOF materials for energy storage.

Sophoridine Derivatives Induce Apoptosis and Autophagy to Suppress the Growth of Triple-Negative Breast Cancer through Inhibition of mTOR Signaling.

In order to improve the antitumor potency and therapeutic margins of natural product sophoridine, its novel nitrogen mustard carbamate derivatives were designed and synthesized. In screening their in vitro activity, we found all the tested compounds were more potent against the highly aggressive triple-negative breast cancer cell line MDA-MB-231. Cellular functional assays showed that representative compounds could induce G1-phase arrest and trigger apoptosis, evidenced by the alteration of Bax, Bcl-2, caspase-3 and PARP levels. Furthermore, these compounds significantly enhanced the autophagic flux with increased expression of LC3-II and Beclin-1, as well as decreased level of p62, which may attribute to simultaneously inhibition of the phosphorylation of p70S6K, 4E-BP1 and AKT, the key substrates of the mTOR signaling pathway. In vivo, two compounds revealed potent antitumor activity in mice bearing MDA-MB-231. Altogether, our work describes novel leads to yield more potent chemotherapeutics against triple-negative breast cancers, possibly mesenchymal stem-like subtype.

Clinical analysis on the root fracture of the maxillary first molar.

OBJECTIVES: This study aimed to investigate the common types and directions of root fractures of the maxillary first molar and the influence of root canal treatment on the prevalent sites of root fractures. METHODS: A total of 274 maxillary first molars with root fractures diagnosed via cone beam computed tomography were included. The root fractures of nonendodontically and endodontically treated teeth were identified to be spontaneous and secondary root fractures, respectively. The sites, types, and directions of spontaneous and secondary root fractures were determined. RESULTS: Among the spontaneous root fractures, the proportion of palatal root fractures (56.1%) was higher than those of mesial buccal root fractures (36.1%) and distal buccal root fractures (7.8%). Among the secondary root fractures, the proportion of mesial buccal root fractures (52.7%) was higher than those of palatal root fractures (36.5%) and distal buccal root fractures (10.8%). The distribution of predominant fracture sites was statistically significant (P<0.05), and vertical root fracture was the most common type. Palatal and buccal roots were commonly fractured at the mesiodistal and buccal-palatal directions, respectively. CONCLUSIONS: This study provided an epidemiological basis for the clinical features of root fractures of the maxillary first molar. During the dia-gnosis and treatment of the maxillary first molar, the possibility of palatal root fractures should be considered. The occurrence of mesial buccal root fractures may be related to root canal treatment. Therefore, the risk of mesial buccal root fractures caused by iatrogenic factors should be minimized.

Controllable broadband asymmetric transmission of terahertz wave based on Dirac semimetals.

We present a dynamic metamaterial based on Dirac semimetals and capable of realizing broadband and tunable asymmetric transmission in the terahertz region. The Dirac semimetal resonators have a chiral structure patterned with double-T resonators that results in partial polarization conversion of waves incident upon the material, leading to asymmetric transmission across a wide frequency range. We show how the gradual shift of the semimetal Fermi energy permits a method of control over the asymmetric total transmission.

Novel Copper Complexes That Inhibit the Proteasome and Trigger Apoptosis in Triple-Negative Breast Cancer Cells.

Five innovative ternary copper(II) complexes [Cu(OH-PIP)(Phe)Cl](1), [Cu(OH-PIP)(Gly)(H2O)]NO3·2H2O (2), [Cu(OH-PIP)(Ala)(Cl)]·H2O (3), [Cu(OH-PIP)(Met)]PF6·2H2O (4), and [Cu(OH-PIP)(Gln)(H2O)](Cl)·3H2O (5) have been synthesized and characterized by infrared spectroscopy, elemental analysis, and single crystal X-ray diffraction analysis. X-ray crystallography indicates that all Cu atoms are five-coordinated in a square-pyramidal configuration. The complexes have been screened for cytotoxicity against human breast cancer cell lines MCF-7, MDA-MB-231, and CAL-51. The best anticancer activity is obtained with triple-negative breast cancer CAL-51 and MDA-MB-231 cell lines, with IC50 values in the range of 0.082-0.69 µM. Importantly, the copper compounds were more effective than carboplatin at triggering cell death. Mechanistically, the complexes inhibit proteasomal chymotrypsin-like activity, and docking studies reveal their 20S proteasome binding sites. As a consequence, they cause the accumulation of ubiquitinated proteins, inhibit cell proliferation, and induce apoptosis. In addition, these copper complexes decrease the stemness of triple-negative breast cancer cells and have synergistic effects with CBP on TNBC cells, indicating their great potential as a novel therapy for triple-negative breast cancer.

A bispecific broadly neutralizing antibody against enterovirus 71 and coxsackievirus A16 with therapeutic potential.

Enterovirus 71 (EV71) and coxsackievirus A16 (CA16) are the major pathogens of hand, foot and mouth disease (HFMD), which affects children worldwide and is often associated with neurological complications. At present, there is no vaccine or cure available for simultaneous EV71 and CA16 infection, posing a great need to develop novel strategies for the treatment of this disease. Here, we engineered four bispecific antibodies using variable fragments of monoclonal antibodies (mAbs) from EV71- and CA16-specific neutralizing antibodies. The engineered bispecific antibody Bs(scFv)4-IgG-1 exhibits remarkable cross-reactivity against EV71 and CA16 and has a more potent cross-neutralization than its parental antibodies. Furthermore, we showed that Bs(scFv)4-IgG-1 conferred 100% therapeutic efficacy against single or mixed EV71 and CA16 infections in mice. Our study provides important insights into bispecific antibody engineering against enterovirus and will inform new curative treatment options for HFMD.

Novel Sophoridine Derivatives Bearing Phosphoramide Mustard Moiety Exhibit Potent Antitumor Activities In Vitro and In Vivo.

Novel mustard functionalized sophoridine derivatives were synthesized and evaluated for their cytotoxicity against of a panel of various cancer cell lines. They were shown to be more sensitive to S180 and H22 tumor cells with IC50 values ranging from 1.01⁻3.65 µM, and distinctly were more cytotoxic to cancer cells than normal cell L929. In addition, compounds 7a, 7c, and 7e displayed moderate tumor suppression without apparent organ toxicity in vivo against mice bearing H22 liver tumors. Furthermore, they arrested tumor cells in the G1 phase and induced cellular apoptosis. Their potential binding modes with DNA-Top I complex have also been investigated.

MicroRNA­195 is associated with regulating the pathophysiologic process of human laryngeal squamous cell carcinoma.

MicroRNAs (miRNAs) have been reported to be associated with the modulation of tumor development, including alterations associated with the development of human laryngeal squamous cell carcinoma (LSCC). The present study was designed to investigate whether miRNA­195 was associated with the pathophysiologic process of human LSCC and to identify its potential roles and underlying molecular mechanisms. To determine whether miRNA­195 serves a role in LSCC, reverse transcription­quantitative polymerase chain reaction was used to detect miRNA­195 expression in LSCC tissues. The tumor­suppressive effect of miRNA­195 was determined by in vitro assays. Gain­of­function studies using miRNA­195 mimics were performed to investigate cell viability, migration and invasion, and apoptosis in the AMC­HN­8 cell line. Western blotting was performed to reveal the molecular mechanisms of miRNA­195 and its downstream signaling pathways in the LSCC AMC­HN­8 cell line. The present study demonstrated that miRNA­195 is downregulated in primary LSCC tumors. Upregulating miRNA­195 in vitro suppressed cell viability, migration and invasion in AMC­HN­8 cells. Overexpression of miRNA­195 alone in AMC­HN­8 cells was sufficient to induce cell apoptosis, as identified by terminal deoxynucleotidyl transferase dUTP nick end labeling assay. Compared with the high expression of miRNA­195 in AMC­HN­8 cells, the expression levels of vascular endothelial growth factor receptor­II protein and downstream signaling pathway proteins, which were associated with cell viability, migration, invasion and apoptosis, were markedly decreased compared with control or miRNA­195 negative control treatment group. Together, these data suggest the therapeutic potential of miRNA­195 in modulating cell growth, migration and apoptosis during the pathophysiological progression of LSCC and that miRNA­195 may serve as a potential therapeutic target in human LSCC.

Broken adaptive ridge regression and its asymptotic properties.

This paper studies the asymptotic properties of a sparse linear regression estimator, referred to as broken adaptive ridge (BAR) estimator, resulting from an L 0-based iteratively reweighted L 2 penalization algorithm using the ridge estimator as its initial value. We show that the BAR estimator is consistent for variable selection and has an oracle property for parameter estimation. Moreover, we show that the BAR estimator possesses a grouping effect: highly correlated covariates are naturally grouped together, which is a desirable property not known for other oracle variable selection methods. Lastly, we combine BAR with a sparsity-restricted least squares estimator and give conditions under which the resulting two-stage sparse regression method is selection and estimation consistent in addition to having the grouping property in high- or ultrahigh-dimensional settings. Numerical studies are conducted to investigate and illustrate the operating characteristics of the BAR method in comparison with other methods.

Effect of TERT on the growth of fibrosarcoma via caspase-3, survivin and PKB.

The present study explored the effect of telomerase reverse transcriptase (TERT) on the growth and apoptosis of fibrosarcoma, and investigated the potential molecular signalling pathways underlying its effect. A plasmid was constructed in order to overexpress TERT and siRNA was used to knockdown TERT. The effect of TERT on fibrosarcoma cells in vitro was studied by performing reverse transcription-quantitative PCR and western blotting to determine the expression of p53, survivin, caspase-3, caspase-7 and PKB. Knockdown of TERT suppressed cell growth, decreased fibrosarcoma volume, decreased survivin and PKB expression, and increased caspase-3 expression. The results of the present study suggest that TERT regulates the growth of fibrosarcoma in vitro and in vivo, and that this is associated with the expression of caspase-3 and survivin, in addition to the PKB signalling pathway.

Myocardial extracellular volume fraction quantified by cardiovascular magnetic resonance is increased in hypertension and associated with left ventricular remodeling.

OBJECTIVES: To determine whether extracellular volume fraction (ECV) quantification by cardiac magnetic resonance (CMR) can demonstrate left ventricle (LV) abnormalities and relationship between ECV and LV remodeling in hypertension (HTN) patients METHODS: ECV quantification was prospectively performed in 134 consecutive HTN patients and 97 healthy subjects. Individual and regional ECV were compared to the regions on late gadolinium enhancement (LGE) images. Statistical analysis of the relationship between LV global functional parameters and ECV was carried out using Pearson's correlation, Student's t test and multiple regressions. RESULTS: In the HTN group, 70.1% (94/134) were LGE negative and 29.9% (40/134) LGE positive. The mean ECV after adjusting for age, sex, BMI, diabetes, smoking and dyslipidaemia in healthy controls and LGE-negative patients were 26.9 ± 2.67% and 28.5 ± 2.9% (p < 0.001), respectively. The differences in ECV reached statistical significance among the regions of LGE, LGE-Peri, LGE remote and the normal area between the control and LGE-positive subgroup (all p < 0.05). Global ECV significantly correlated with LVEF (r = -0.466, p < 0 .001) and LV hypertrophy (r = 0.667, p < 0.001). CONCLUSIONS: ECV can identify LV abnormalities at an early stage in HTN patients without LGE. These abnormalities may reflect an increase in diffuse myocardial fibrosis and are associated with LV remodeling. KEY POINTS: • Diffuse myocardial fibrosis may develop in hypertensive cardiomyopathy before conventional MRI detectable LGE. • ECV can identify myocardial fibrosis at an early stage in hypertensive patients. • Elevated ECV is associated with decreased LV global function and LV remodeling in hypertension.

CMR assessment of the left ventricle apical morphology in subjects with unexplainable giant T-wave inversion and without apical wall thickness ≥15 mm.

AIMS: Patients with unexplainable giant T-wave inversion in the precordial leads and apical wall thickness <15 mm have been reported. These patients cannot be diagnosed as apical hypertrophic cardiomyopathy (AHCM) according to the current criteria. The objective of this study was to evaluate the apical morphological features of this type of patients using cardiac magnetic resonance. METHODS AND RESULTS: Institutional ethics approval and written informed consent were obtained. A total of 60 subjects with unexplainable giant T-wave inversion and 76 healthy volunteers were prospectively enrolled in the study. The segmented left ventricular (LV) wall thickness was measured according to the American Heart Association 17-segmented model. The apical angle (apA) as well as the regional variations in LV wall thickness was analysed. Considerable variation in LV wall thickness in normals was observed with progressive thinning from the base to apex (male and female, P < 0.01). The apical thickness of subjects with giant T-wave inversion was 8.10 ± 1.67 mm in male, which is thicker than that of controls (4.14 ± 1.17 mm, P < 0.01). In female, the apical thickness was also significantly different from controls (5.85 ± 2.16 vs. 2.99 ± 0.65 mm, P < 0.01). Compared with normals, the apA decreased significantly in male (87.44 ± 13.86 vs.115.03 ± 9.90°, P < 0.01) and female (90.69 ± 8.84 vs. 110.07 ± 13.58°, P < 0.01) subjects, respectively. CONCLUSION: Although the absolute thickness of apical wall was below the current diagnostic criteria of AHCM, the apical morphological features of subjects with unexplainable giant T-wave inversion were significantly different from normals. Whether these subjects should be included into a preclinical scope of AHCM needs further investigations.

Synthesis, structure-activity relationship and biological evaluation of novel nitrogen mustard sophoridinic acid derivatives as potential anticancer agents.

A series of novel nitrogen mustard sophoridinic acid derivatives were designed, synthesized and evaluated for their cytotoxicity. Of the newly synthesized compounds, compound 6 exhibited a potent effect against hepatocellular carcinoma in vitro and in vivo. SAR analysis indicated that introduction of a nitrogen mustard group to the structure of sophoridinic acid significantly enhance the antitumor activity. Moreover, molecular docking study exhibited benzyl group introduced to the nitrogen atom at the 12-position and aryl nitrogen mustard group at the 4'-carboxyl region for compound 6 were beneficial for the higher anticancer activity. This work provides useful information for further structural modifications of these compounds and for the synthesis of new, potent antitumor agents.

Prenatal care in combination with maternal educational level has a synergetic effect on the risk of neonatal low birth weight: new findings in a retrospective cohort study in Kunshan City, China.

OBJECTIVES: To investigate the dose-response relationship and synergetic effect of the maternal educational level and two measures of prenatal care on neonatal low birth weight (LBW) risk. METHODS: Data were derived from the Perinatal Health Care Surveillance System (PHCSS) from January 2001 to September 2009 in Kunshan City, Jiangsu province, eastern China, which included data on 31412 women with a normal birth weight delivery and 640 women with a LBW delivery. Logistic modelling was performed to estimate the association including the joint effects with odds ratio (OR) and 95% confidence interval (CI) between the prenatal care measures and LBW risk after adjusting for the potential confounders. The dose-response relationship between the number of prenatal care visits and the risk of LBW was investigated by modeling the quantitative exposure with restricted cubic splines (RCS). RESULTS: There was a significant synergetic effect on the LBW risk between maternal educational attainment and the number of prenatal care visits (χ(2) = 4.98, P = 0.0257), whereas no significant maternal educational attainment interaction was found with the week of initiation of prenatal care after adjusting for relevant confounding factors (χ(2) = 2.04, P = 0.1530), and the LBW risk displayed a 'U-shape' curve tendency among the different number of prenatal care visits (P for nonlinearity = 0.0002) using RCS. In particular, the ORs were approaching the curve's bottom when the women had 9 or 10 prenatal care visits. Comparing with 5 prenatal care visits, the ORs and 95%CI of LBW risk for 7, 9, 11 and ≥ 13 visits were 0.92 (0.82-1.03), 0.50 (0.38-0.66), 0.62 (0.47-0.82), and 0.99 (0.61-1.60), respectively. CONCLUSIONS: Our findings suggest that appropriate prenatal care, in combination with a higher maternal educational level, can produce a protective interaction effect on LBW risk. Reasonable health resource assignment for different social statuses should be taken into account by policy-makers in developing countries.

[Interaction of prenatal care and level of maternal education on the risk of neonatal low birth weight].

OBJECTIVE: To investigate the interaction of prenatal care indexes including weeks of initiation of prenatal care, number of prenatal care visits and maternal educational level on the risk of neonatal low birth weight (LBW). METHODS: Logistic Regression Model was performed to estimate the association including the interaction with OR and 95%CI between prenatal care indexes and LBW risk in all the subjects. Three educational levels(junior high, senior high, junior college) of mothers were also assessed. New variables of the prenatal care indexes were transformed using the quartiles, according to the distribution of the original variables on pregnant women with newborns of normal birth weight. RESULTS: Whether the pregnant women were stratified by educational level, with the increasing number of prenatal care visits, LBW risk was shown a U-type tendency in different strata of educational levels, when comparing with the reference group, respectively. Compared to the baseline group, the OR and 95% CI of the third quartile on number of prenatal care visits were 0.48 (0.35-0.64), 0.55 (0.32-0.95), 0.50 (0.32-0.80), 0.36(0.20-0.66) in all subjects who had received educational levels as junior middle school, senior middle school or junior college degree ect., respectively. A significant interaction was shown between the number of prenatal care visits and maternal educational level on the neonatal LBW risk (χ² = 4.650 2, P = 0.031 1). However, no interaction was found between the week of initiation of prenatal care and maternal educational level on the neonatal LBW risk (χ² = 0.929 7, P = 0.334 9). CONCLUSION: Data from our study indicated that there was a protective interaction on reducing the neonatal LBW risk between maternal educational level and the number of prenatal care visits, but not the weeks on the initiation of prenatal care. More prenatal care programs should be implemented among the pregnant women with lower educational level.