Ultrasound manifestations and clinical analysis of 50 cases of heterotopic pregnancy.

OBJECTIVE: To investigate the value of ultrasonography in the diagnosis of heterotopic pregnancy and the follow-up. METHODS: A retrospective analysis of 50 cases of clinically diagnosed heterotopic pregnancy in our hospital was performed, the clinical characteristics and ultrasonographic manifestations of the patients were summarized, the reasons for initial ultrasound missed diagnosis and misdiagnosis were analyzed, and the pregnancy outcomes were followed up. RESULTS: Among the 50 cases, the initial ultrasound diagnoses of intrauterine pregnancy were all gestational sac type, 32 cases of ectopic pregnancy were located in the fallopian tube, and 10 cases were located in the uterine horn, 1 case at cervix, and 1 case at caesarean section scar. Forty-one cases were consistent with surgery and/or pathology, representing initial ultrasound diagnosis coincidence rate of about 82%. Six cases were missed in the initial ultrasound examination (12%), and three cases were misdiagnosed (6%). The maximum diameter of the intrauterine gestational sac was 9-48 mm, the average was about 24.90 ± 9.56 mm, the maximum diameter of the ectopic pregnancy gestational sac or mass was 11-63 mm, and the average was about 31.45 ± 13.82 mm (p < 0.05). Intrauterine pregnancy outcomes were followed up, 45 patients with complete data and 5 patients were lost to follow-up. The follow-up rate was about 90%. CONCLUSION: Combining the patient's medical history and clinical characteristics can reduce missed diagnosis and misdiagnosis of heterotopic pregnancy. Ultrasonography has important value in the assessment of intrauterine pregnancy growth and development, and the integrity of maternal uterus.

Predicting intraoperative hemorrhage during curettage treatment of cesarean scar pregnancy using free-breathing GRASP DCE-MRI.

OBJECTIVE: To explore the feasibility of the golden-angle radial sparse parallel (GRASP) dynamic magnetic resonance imaging (MRI) technique in predicting the intraoperative bleeding risk of scar pregnancy. METHODS: A total of 49 patients with cesarean scar pregnancy (CSP) who underwent curettage and GRASP-MRI imaging were retrospectively selected between January 2021 and July 2022. The pharmacokinetic parameters, including Wash-in, Wash-out, time to peck (TTP), initial area under the curve (iAUC), the transfer rate constant (Ktrans), constant flow rate (Kep), and volume of extracellular space (Ve), were calculated. The amount of intraoperative bleeding was recorded by a gynecologist who performed surgery, after which patients were divided into non-hemorrhage (blood loss ≤ 200 mL) and hemorrhage (blood loss > 200 mL) groups. The measured pharmacokinetic parameters were statistically compared using the t-test or Mann-Whitney U test with a significant level set to be p < 0.05. The receiver operating characteristic (ROC) curve was constructed, and the area under the curve (AUC) was calculated to evaluate each parameter's capability in intraoperative hemorrhage subgroup classification. RESULTS: Twenty patients had intraoperative hemorrhage (blood loss > 200 mL) during curettage. The hemorrhage group had larger Wash-in, iAUC, Ktrans, Ve, and shorter TTP than the non-hemorrhage group (all P > 0.05). Wash-in had the highest AUC value (0.90), while Ktrans had the lowest value (0.67). Wash-out and Kep were not significantly different between the two groups. CONCLUSION: GRASP DCE-MRI has the potential to forecast intraoperative hemorrhage during curettage treatment of CSP, with Wash-in exhibiting the highest predictive performance. This data holds promise for advancing personalized treatment. However, further study is required to compare its effectiveness with other risk factors identified through anatomical MRI and ultrasound.

Diagnostic value of Kaiser score combined with breast vascular assessment from breast MRI for the characterization of breast lesions.

Objectives: The Kaiser scoring system for breast magnetic resonance imaging is a clinical decision-making tool for diagnosing breast lesions. However, the Kaiser score (KS) did not include the evaluation of breast vascularity. Therefore, this study aimed to use KS combined with breast vascular assessment, defined as KS*, and investigate the effectiveness of KS* in differentiating benign from malignant breast lesions. Methods: This retrospective study included 223 patients with suspicious breast lesions and pathologically verified results. The histopathological diagnostic criteria were according to the fifth edition of the WHO classification of breast tumors. The KS* was obtained after a joint evaluation combining the original KS and breast vasculature assessment. The receiver operating characteristic (ROC) curve was used for comparing differences in the diagnostic performance between KS* and KS, and the area under the receiver operating characteristic (AUC) was compared. Results: There were 119 (53.4%) benign and 104 (46.6%) malignant lesions in total. The overall sensitivity, specificity, and accuracy of increased ipsilateral breast vascularity were 69.2%, 76.5%, and 73.1%, respectively. The overall sensitivity, specificity, and accuracy of AVS were 82.7%, 76.5%, and 79.4%, respectively. For all lesions included the AUC of KS* was greater than that of KS (0.877 vs. 0.858, P = 0.016). The largest difference in AUC was observed in the non-mass subgroup (0.793 vs. 0.725, P = 0.029). Conclusion: Ipsilaterally increased breast vascularity and a positive AVS sign were significantly associated with malignancy. KS combined with breast vascular assessment can effectively improve the diagnostic ability of KS for breast lesions, especially for non-mass lesions.

MRI-based scoring model to predict massive hemorrhage during dilatation and curettage in patients with cesarean scar pregnancy.

OBJECTIVE: To construct a scoring model based on MRI signs to predict massive hemorrhage during dilatation and curettage in cesarean scar pregnancy (CSP) patients. MATERIALS AND METHODS: The MRIs of CSP patients admitted to a tertiary referral hospital between February 2020 and July 2022 were retrospectively reviewed. The included patients were randomly assigned to the training and validation cohorts. The univariate and multivariate logistic regression analyses were adopted to identify the independent risk factors for massive hemorrhage (the amount of bleeding ≥ 200 ml) during the dilatation and curettage. A scoring model predicting intraoperative massive hemorrhage was established where each positive independent risk factor was assigned 1 point, and the predictive power of this model was evaluated both in the training and validation cohorts via the receiver operating characteristic curve. RESULTS: A total of 187 CSP patients were enrolled, who were divided into the training cohort (31 in 131 patients had massive hemorrhage) and validation cohort (10 in 56 patients had massive hemorrhage). The independent risk factors for intraoperative massive hemorrhage included cesarean section diverticulum area (OR = 6.957, 95% CI 1.993-21.887; P = 0.001), uterine scar thickness (OR = 5.113, 95% CI 2.086-23.829; P = 0.025) and gestational sac diameter (OR = 3.853, 95% CI 1.103-13.530; P = 0.025). A scoring model with a total point of 3 was developed and the CSP patients were divided into low-risk (Total points < 2) and high-risk groups (Total points ≥ 2) for intraoperative massive hemorrhage accordingly. This model possessed high prediction performance both in the training cohort (area under the curve [AUC] = 0.896, 95% CI 0.830-0.942) and validation cohort (AUC = 0.915, 95% CI 0.785-1.000). CONCLUSION: We first constructed a MRI-based scoring model for predicting intraoperative massive hemorrhage in CSP patients, which could help the decision-making of the patients' therapy strategies. Low-risk patients can be cured by D&C alone to reduce the financial burden, while high-risk patients require more adequate preoperative preparation or consideration of changing surgical approaches to reduce bleeding risk.

Deficiency of mitochondrial calcium uniporter abrogates iron overload-induced cardiac dysfunction by reducing ferroptosis.

Iron overload associated cardiac dysfunction remains a significant clinical challenge whose underlying mechanism(s) have yet to be defined. We aim to evaluate the involvement of the mitochondrial Ca2+ uniporter (MCU) in cardiac dysfunction and determine its role in the occurrence of ferroptosis. Iron overload was established in control (MCUfl/fl) and conditional MCU knockout (MCUfl/fl-MCM) mice. LV function was reduced by chronic iron loading in MCUfl/fl mice, but not in MCUfl/fl-MCM mice. The level of mitochondrial iron and reactive oxygen species were increased and mitochondrial membrane potential and spare respiratory capacity (SRC) were reduced in MCUfl/fl cardiomyocytes, but not in MCUfl/fl-MCM cardiomyocytes. After iron loading, lipid oxidation levels were increased in MCUfl/fl, but not in MCUfl/fl-MCM hearts. Ferrostatin-1, a selective ferroptosis inhibitor, reduced lipid peroxidation and maintained LV function in vivo after chronic iron treatment in MCUfl/fl hearts. Isolated cardiomyocytes from MCUfl/fl mice demonstrated ferroptosis after acute iron treatment. Moreover, Ca2+ transient amplitude and cell contractility were both significantly reduced in isolated cardiomyocytes from chronically Fe treated MCUfl/fl hearts. However, ferroptosis was not induced in cardiomyocytes from MCUfl/fl-MCM hearts nor was there a reduction in Ca2+ transient amplitude or cardiomyocyte contractility. We conclude that mitochondrial iron uptake is dependent on MCU, which plays an essential role in causing mitochondrial dysfunction and ferroptosis under iron overload conditions in the heart. Cardiac-specific deficiency of MCU prevents the development of ferroptosis and iron overload-induced cardiac dysfunction.

Molecular identification and physiological functional analysis of NtNRT1.1B that mediated nitrate long-distance transport and improved plant growth when overexpressed in tobacco.

Although recent physiological studies demonstrate that flue-cured tobacco preferentially utilizes nitrate ( NO 3 - ) or ammonium nitrate (NH4NO3), and possesses both high- and low-affinity uptake systems for NO 3 - , little is known about the molecular component(s) responsible for acquisition and translocation in this crop. Here we provide experimental data showing that NtNRT1.1B with a 1,785-bp coding sequence exhibited a function in mediating NO 3 - transport associated with tobacco growth on NO 3 - nutrition. Heterologous expression of NtNRT1.1B in the NO 3 - uptake-defective yeast Hp△ynt1 enabled a growth recovery of the mutant on 0.5 mM NO 3 - , suggesting a possible molecular function of NtNRT1.1B in the import of NO 3 - into cells. Transient expression of NtNRT1.1B::green fluorescent protein (GFP) in tobacco leaf cells revealed that NtNRT1.1B targeted mainly the plasma membrane, indicating the possibility of NO 3 - permeation across cell membranes via NtNRT1.1B. Furthermore, promoter activity assays using a GFP marker clearly indicated that NtNRT1.1B transcription in roots may be down-regulated by N starvation and induced by N resupply, including NO 3 - , after 3 days' N depletion. Significantly, constitutive overexpression of NtNRT1.1B could remarkably enhance tobacco growth by showing a higher accumulation of biomass and total N, NO 3 - , and even NH 4 + in plants supplied with NO 3 - ; this NtNRT1.1B-facilitated N acquisition/accumulation could be strengthened by short-term 15N- NO 3 - root influx assays, which showed 15%-20% higher NO 3 - deposition in NtNRT1.1B-overexpressors as well as a high affinity of NtNRT1.1B for NO 3 - at a K m of around 30-45 µM. Together with the detection of NtNRT1.1B promoter activity in the root stele and shoot-stem vascular tissues, and higher NO 3 - in both xylem exudate and the apoplastic washing fluid of NtNRT1.1B-transgenic lines, NtNRT1.1B could be considered as a valuable molecular breeding target aiming at improving crop N-use efficiency by manipulating the absorption and long-distance distribution/transport of nitrate, thus adding a new functional homolog as a nitrate permease to the plant NRT1 family.

Benzoyl isothiocyanate modified surface of silica gel as the extraction material for adsorbing steroid hormones in water.

Steroid hormones have been listed as priority pollutants in the environment, and their detection and pollution control deserve our extensive attention. In this study, a modified silica gel adsorbent material was synthesized by benzoyl isothiocyanate reaction with hydroxyl groups on the silica gel surface. The modified silica gel was used as a solid phase extraction filler for the extraction of steroid hormones from water, which was further analyzed by the HPLC-MS/MS method. The FT-IR, TGA, XPS, and SEM analysis indicated that benzoyl isothiocyanate was successfully grafted on the surface of silica gel to form a bond with an isothioamide group and benzene ring as the tail chain. The modified silica gel synthesized at 40 °C showed excellent adsorption and recovery rates for three steroid hormones in water. Methanol at pH 9.0 was selected as the optimal eluent. The adsorption capacity of the modified silica gel for epiandrosterone, progesterone, and megestrol acetate was 6822 ng mg-1, 13 899 ng mg-1, and 14 301 ng mg-1, respectively. Under optimal conditions, the limit of detection (LOD) and limit of quantification (LOQ) for 3 steroid hormones by modified silica gel extraction with HPLC-MS/MS detection were 0.02-0.88 µg L-1 and 0.06-2.22 µg L-1, respectively. The recovery rate of epiandrosterone, progesterone, and megestrol was between 53.7% and 82.9%, respectively. The modified silica gel has been successfully used to analyze steroid hormones in wastewater and surface water.

Whole-exome sequencing expands the roles of novel mutations of organic anion transporting polypeptide, ATP-binding cassette transporter, and receptor genes in intrahepatic cholestasis of pregnancy.

Background: Intrahepatic cholestasis of pregnancy (ICP) is associated with a high incidence of fetal morbidity and mortality. Therefore, revealing the mechanisms involved in ICP and its association with fetal complications is very important. Methods: Here, we used a whole-exome sequencing (WES) approach to detect novel mutations of organic anion transporting polypeptide (OTAP) genes, ATP-binding cassette transporter (ABC) genes, and receptor genes associated with ICP in 249 individuals and 1,029 local control individuals. Two available tools, SIFT and PolyPhen-2, were used to predict protein damage. Protein structuremodeling and comparison between the reference and modified protein structures were conducted by SWISS-MODEL and Chimera 1.14rc software, respectively. Results: A total of 5,583 mutations were identified in 82 genes related to bile acid transporters and receptors, of which 62 were novel mutations. These novel mutations were absent in the 1,029 control individuals and three databases, including the 1,000 Genome Project (1000G_ALL), Exome Aggregation Consortium (ExAC), and Single-Nucleotide Polymorphism Database (dbSNP). We classified the 62 novel loci into two groups (damaging and probably damaging) according to the results of SIFT and PolyPhen-2. Out of the 62 novel mutations, 24 were detected in the damaging group. Of these, five novel possibly pathogenic variants were identified that were located in known functional genes, including ABCB4 (Ile377Asn), ABCB11 (Ala588Pro), ABCC2 (Ile681Lys and Met688Thr), and NR1H4 (Tyr149Ter). Moreover, compared to the wild-type protein structure, ABCC2 Ile681Lys and Met688Thr protein structures showed a slight change in the chemical bond lengths of ATP-ligand binding amino acid side chains. The combined 32 clinical data points indicate that the mutation group had a significantly (p = 0.04) lower level of Cl ions than the wild-type group. Particularly, patients with the 24 novel mutations had higher average values of alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), total bile acids (TBA), high-density lipoprotein (HDL), and low-density lipoprotein (LDL) than patients with the 38 novel mutations in the probably damaging group and the local control individuals. Conclusion: The present study provides new insights into the genetic architecture of ICP involving these novel mutations.

Identification of two novel pathogenic variants of the NR1H4 gene in intrahepatic cholestasis of pregnancy patients.

BACKGROUND: Intrahepatic cholestasis of pregnancy (ICP) can cause adverse pregnancy outcomes, such as spontaneous preterm delivery and stillbirth. It is a complex disease influenced by multiple factors, including genetics and the environment. Previous studies have reported that functioning nuclear receptor subfamily 1 group H member 4 (NR1H4) plays an essential role in bile acid (BA) homeostasis. However, some novel variants and their pathogenesis have not been fully elucidated. Therefore, this research aimed to investigate the genetic characteristics of the NR1H4 gene in ICP. METHODS: In this study, we sequenced the entire coding region of NR1H4 in 197 pregnant women with ICP disease. SIFT and PolyPhen2 were used to predict protein changes. Protein structure modelling and comparisons between NR1H4 reference and modified protein structures were performed by SWISS-MODEL and Chimera 1.14rc, respectively. T-tests were used to analyse the potential significant differences between NR1H4 mutations and wild types for 29 clinical features. Fisher's test was conducted to test the significance of differences in mutation frequencies between ICP and the three databases. RESULTS: We identified four mutations: two novel missense mutations, p.S145F and p.M185L; rs180957965 (A230S); and rs147030757 (N275N). The two novel missense mutations were absent in 1029 controls and three databases, including the 1000 Genomes Project (1000G_ALL), Exome Aggregation Consortium (ExAC) and ChinaMAP. Two web-available tools, SIFT and PolyPhen2, predicted that these mutations are harmful to the function of the protein. Moreover, compared to the wild-type protein structure, the NR1H4 p.S145F and p.M185L protein structure showed a slight change in the chemical bond in two zinc finger structures. Combined clinical data indicate that the mutation group had higher levels of total bile acid (TBA) than the wild-type group. Therefore, we hypothesized that these two mutations altered the protein structure of NR1H4, which impaired the function of NR1H4 itself and its target gene and caused an increase in TBA. CONCLUSIONS: To our knowledge, this is the first study to identify the novel p.S145F and p.M185L mutations in 197 ICP patients. Our present study provides new insights into the genetic architecture of ICP involving the two novel NR1H4 mutations.

Electrically Induced Underwater Superaerophilicity/Superaerophobicity Switching on Polypyrrole-Coated Mesh Films for Selective Bubble Permeation.

Recently, materials with controllable superwettability have attracted much attention. However, almost all studies focused on controlling wetting of water and oil; research on underwater gas bubble wetting control is still rare. Herein, we report a mesh film prepared by coating polypyrrole (PPy) film on Ti mesh. Briefly, the film mesh is underwater superaerophilic when PPy is doped with perfluorooctanesulfonate ions (PFOS- ), and becomes underwater superaerophobic as the PFOS- are removed. The transition of the wettability can be triggered by electrical stimuli, which is attributed to the cooperative effect between the rough structure and chemical components variation. The controllable wettability allows adjustable bubble permeation. It can be envisioned that the film will provide potential applications in the future, such as underwater bubble capture/release and microfluidic devices.

Construction and validation of a prognostic model for stage IIIC endometrial cancer patients after surgery.

BACKGROUND: To explore the most predictive lymph node (LN) scheme for stage IIIC endometrial cancer (EC) patients after hysterectomy and develop a scheme-based nomogram. METHODS: Data from 2626 stage IIIC EC patients, diagnosed between 2010 and 2014, were extracted from the Surveillance, Epidemiology, and End Results (SEER) registry. The predictive ability of four LN schemes was assessed using C-index and Akaike information criterion (AIC). A nomogram based on the most predictive LN scheme was constructed and validated. The comparison of the predictive ability between nomogram and FIGO stage was conducted using the area under the receiver operating characteristic curve (AUC) and decision curve analysis (DCA). RESULTS: FIGO stage (stage IIIC1/stage IIIC2) was not an independent risk factor for OS in stage IIIC EC patients (P = 0.672) and log odds of positive lymph nodes (LODDS) had the best predictive ability (C-index: 0.742; AIC: 8228.95). A nomogram based on LODDS was constructed and validated, which had a decent C-index of 0.742 (0.723-0.762). The nomogram showed a better predictive ability than that of the FIGO staging system. CONCLUSION: FIGO IIIC1/FIGO IIIC2 could not differentiate the prognosis for stage IIIC EC patients. We developed and validated a nomogram based on LODDS to predict OS for post-operative patients with stage IIIC EC.

Analysis of CYP27A1 mutations in Han Chinese women with intrahepatic cholestasis of pregnancy.

OBJECTIVE: To explore the cytochrome P450 family 27 subfamily A member 1 (CYP27A1) gene mutations in Chinese women with intrahepatic cholestasis of pregnancy (ICP) and the correlation between CYP27A gene mutations and BA (bile acid) level changes. METHODS: In this study, the entire coding region of the CYP27A1 gene was sequenced in 151 Han Chinese women with ICP and 1029 matched samples, and the pathogenicity of identified CYP27A1 gene mutations was judged through evolutionary conservation analysis, computational analysis and protein structure modeling. Finally, we verified the relationship between gene mutations and total serum bile acid (TBA) and cholesterol (CHOL) levels through experiments in cell culture. RESULTS: We identified five heterozygous CYP27A1 missense mutations in five ICP samples. Three online tools, Polyphen-2, MutationTaster and SIFT, predicted that the five CYP27A1 mutations were pathogenic. Furthermore, all five mutations caused marked protein structural changes. Experiments in cells showed that the intracellular and medium levels of TBA in the mutant groups were lower than those in the wild-type group, while the CHOL levels were higher in all mutants except for the R158H mutant. CONCLUSIONS: CYP27A1 mutations are associated with the levels of TBA and CHOL, suggesting that CYP27A1 mutations contribute to abnormal total cholesterol and BA levels, which leads to ICP.

A real-world, population-based study of the trends for incidence and prognosis in high-grade neuroendocrine tumor of cervix.

To explore the incidence and prognosis trends for high-grade cervical neuroendocrine tumor (HGCNET) and construct a nomogram to predict prognosis for HGCNET. Annual age-adjusted incidence of HGCNET from 1975 to 2015 was retrieved from the Surveillance, Epidemiology, and End Results program, the linear regression, poisson regression and annual percentage changes were used to assess the incidence trend. Also, trends for relative survival (RS) and overall survival (OS) in HGCNET patients from 1975 to 2015 were evaluated. From 1988 to 1975, 514 HGCNET patients were selected and divided into two cohorts with a ratio of 7:3. Nomogram to predict OS for these patients was constructed and validated. The incidence trend for HGCNET was unchanged in the past four decades (P = 0.734), but the proportion of HGCNET in diagnosed cervical cancer slightly increased from 0.9% in 1975 to 1.9% in 2015 (P < 0.001). The 5-year RS and OS for HGCNET in the study periods decreased steadily (RS: P = 0.009; OS: P = 0.008). Nomogram incorporating age, T stage, lymph-node positive, distant metastasis and surgery was constructed. The C-index of the nomogram was 0.716 (0.680-0.752), which was higher than the FIGO staging system. The incidence of HGCNET remained unchanged in the past four decades but the proportion of HGCNET has slightly increased. Besides, a steadily decreasing survival for HGCNET was observed in the study periods. A nomogram was constructed to better predict prognosis for HGCNET.

Calcium and Heart Failure: How Did We Get Here and Where Are We Going?

The occurrence and prevalence of heart failure remain high in the United States as well as globally. One person dies every 30 s from heart disease. Recognizing the importance of heart failure, clinicians and scientists have sought better therapeutic strategies and even cures for end-stage heart failure. This exploration has resulted in many failed clinical trials testing novel classes of pharmaceutical drugs and even gene therapy. As a result, along the way, there have been paradigm shifts toward and away from differing therapeutic approaches. The continued prevalence of death from heart failure, however, clearly demonstrates that the heart is not simply a pump and instead forces us to consider the complexity of simplicity in the pathophysiology of heart failure and reinforces the need to discover new therapeutic approaches.

Comparison of Different Lymph Node Staging Schemes for Predicting Survival Outcomes in Node-Positive Endometrioid Endometrial Cancer Patients.

Objective: To compare the prognostic predictive performance of six lymph node (LN) staging schemes: American Joint Committee on Cancer (AJCC) N stage, number of retrieved lymph nodes (NRLN), number of positive lymph nodes (NPLN), number of negative lymph nodes (NNLN), lymph node ratio (LNR), and log odds of positive lymph nodes (LODDS) among node-positive endometrioid endometrial cancer (EEC) patients. Methods: A total of 3,533 patients diagnosed with node-positive EEC between 2010 and 2016 from the Surveillance, Epidemiology, and End Results (SEER) database were retrospectively analyzed. We applied X-tile software to identify the optimal cutoff value for different staging schemes. Univariate and multivariate Cox regression models were used to assess the relationships between different LN schemes and survival outcomes [disease-specific survival (DSS) and overall survival (OS)]. Moreover, Akaike information criterion (AIC) and Harrell concordance index (C-index) were used to evaluate the predictive performance of each scheme in both continuous and categorical patterns. Results: N stage (N1/N2) was not an independent prognostic factor for node-positive EEC patients based on multivariate analysis (DSS: p = 0.235; OS: p = 0.145). Multivariate model incorporating LNR demonstrated the most superior goodness of fit regardless of continuous or categorical pattern. Regarding discrimination power of the models, LNR outperformed other models in categorical pattern (OS: C-index = 0.735; DSS: C-index = 0.737); however, LODDS obtained the highest C-index in continuous pattern (OS: 0.736; DSS: 0.739). Conclusions: N stage (N1/N2) was unable to differentiate the prognosis for node-positive EEC patients in our study. However, LNR and LODDS schemes seemed to have a better predictive performance for these patients than other number-based LN schemes whether in DSS or OS, which revealed that LNR and LODDS should be more helpful in prognosis assessment for node-positive EEC patients than AJCC N stage.

Conditional survival for high-risk early-stage cervical cancer patients with lymph node metastasis after hysterectomy.

BACKGROUND: To estimate conditional survival (CS) for high-risk early-stage cervical cancer patients with lymph node metastasis after hysterectomy. METHODS: 1964 T1-2N1M0 cervical cancer patients who underwent primary hysterectomy from 2004 to 2015 were extracted from the Surveillance, Epidemiology, and End Result (SEER) Program. Univariate and multivariate cox regression analysis were used to identify independent risk factors. 5-year conditional disease-specific survival (CDS5) and 5-year conditional relative survival (CRS5) were estimated. CDS5 and CRS5 stratified by risk factors were further calculated. RESULTS: CDS5 and CRS5 increased from 71.0% and 73.7% at 0-year to 89.2% and 91.7% at 5-year, respectively. Inversely, the actuarial disease-specific survival and RS dropped from 71.0% and 73.7% at 5-year to 63.3% and 67.6% at 10-year, respectively. Patients with unfavorable factors had a bigger gap between actuarial survival and CS. Both CDS5 and CRS5 curves across stratas of each prognostic factor had a tendency to level off with time elapsing. Notably, CRS5 couldn't exceed 95% even after 5-year follow-up except for patients with grade I disease (CRS5 at 5-year: 100%) or tumor size less than 2 cm (CRS5 at 5-year: 96%). CONCLUSION: CS increased over time while actuarial survival decreased as time passed. Patients with unfavorable factors had bigger improvement in CS than those with favorable factors. Excess mortality still existed in these patients after 5-year follow-up compared to the general population except for patients with grade I disease or tumor size <2 cm, who might gradually decrease follow-up times after 5-year.

Activation of TRPC (Transient Receptor Potential Canonical) Channel Currents in Iron Overloaded Cardiac Myocytes.

BACKGROUND: Arrhythmias and heart failure are common cardiac complications leading to substantial morbidity and mortality in patients with hemochromatosis, yet mechanistic insights remain incomplete. We investigated the effects of iron (Fe) on electrophysiological properties and intracellular Ca2+ (Ca2+i) handling in mouse left ventricular cardiomyocytes. METHODS: Cardiomyocytes were isolated from the left ventricle of mouse hearts and were superfused with Fe3+/8-hydroxyquinoline complex (5-100 µM). Membrane potential and ionic currents including TRPC (transient receptor potential canonical) were recorded using the patch-clamp technique. Ca2+i was evaluated by using Fluo-4. Cell contraction was measured with a video-based edge detection system. The role of TRPCs in the genesis of arrhythmias was also investigated by using a mathematical model of a mouse ventricular myocyte with the incorporation of the TRPC component. RESULTS: We observed prolongation of the action potential duration and induction of early and delayed afterdepolarizations in myocytes superfused with 15 µmol/L Fe3+/8-hydroxyquinoline complex. Iron treatment decreased the peak amplitude of the L-type Ca2+ current and total K+ current, altered Ca2+i dynamics, and decreased cell contractility. During the final phase of Fe treatment, sustained Ca2+i waves and repolarization failure occurred and ventricular cells became unexcitable. Gadolinium abolished Ca2+i waves and restored the resting membrane potential to the normal range. The involvement of TRPC activation was confirmed by TRPC channel current recordings in the absence or presence of functional TRPC channel antibodies. Computer modeling captured the same action potential and Ca2+i dynamics and provided additional mechanistic insights. CONCLUSIONS: We conclude that iron overload induces cardiac dysfunction that is associated with TRPC channel activation and alterations in membrane potential and Ca2+i dynamics.

Proteomic analysis of mitochondrial biogenesis in cardiomyocytes differentiated from human induced pluripotent stem cells.

Mitochondria play key roles in the differentiation and maturation of human cardiomyocytes (CMs). As human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) hold potential in the treatment of heart diseases, we sought to identify key mitochondrial pathways and regulators, which may provide targets for improving cardiac differentiation and maturation. Proteomic analysis was performed on enriched mitochondrial protein extracts isolated from hiPSC-CMs differentiated from dermal fibroblasts (dFCM) and cardiac fibroblasts (cFCM) at time points between 12 and 115 days of differentiation, and from adult and neonatal mouse hearts. Mitochondrial proteins with a twofold change at time points up to 120 days relative to 12 days were subjected to ingenuity pathway analysis (IPA). The highest upregulation was in metabolic pathways for fatty acid oxidation (FAO), the tricarboxylic acid (TCA) cycle, oxidative phosphorylation (OXPHOS), and branched chain amino acid (BCAA) degradation. The top upstream regulators predicted to be activated were peroxisome proliferator-activated receptor γ coactivator 1 α (PGC1-α), the insulin receptor (IR), and the retinoblastoma protein (Rb1) transcriptional repressor. IPA and immunoblotting showed upregulation of the mitochondrial LonP1 protease-a regulator of mitochondrial proteostasis, energetics, and metabolism. LonP1 knockdown increased FAO in neonatal rat ventricular cardiomyocytes (nRVMs). Our results support the notion that LonP1 upregulation negatively regulates FAO in cardiomyocytes to calibrate the flux between glucose and fatty acid oxidation. We discuss potential mechanisms by which IR, Rb1, and LonP1 regulate the metabolic shift from glycolysis to OXPHOS and FAO. These newly identified factors and pathways may help in optimizing the maturation of iPSC-CMs.

Phenotypical evidence of effective amelioration of ammonium-inhibited plant (root) growth by exogenous low urea.

Ammonium and nitrate are major soil inorganic-nitrogen sources for plant growth, but many species cultivated with even low millimolar NH4+ as a sole N form display a growth retardation. To date, critical biological components and applicable approaches involved in the effective enhancement of NH4+ tolerance remain to be thoroughly explored. Here, we report phenotypical traits of urea-dependent improvement of NH4+-suppressed plant/root growth. Urea at 0.1 mM was sufficient to remarkably stimulate NH4+ (3 mM)-fed cotton growth, showing a 2.5∼4-fold increase in shoot- and root-biomass and total root-length, 20 % higher GS activity, 18 % less NH4+-accumulation in roots, and a comparable plant total-N content compared to the control, implying a novel role for urea in cotton NH4+detoxification. A similar phenomenon was observed in tobacco and rice. Moreover, comparisons between twelve NH4+-grown Arabidopsis accessions revealed a great degree of natural variation in their root-growth response to low urea, with WAR and Blh-1 exhibiting the most significant increase in primary- and lateral-root length and numbers, and Sav-0 and Edi-0 being the most insensitive. Such phenotypical evidence suggests a common ability of plants to accommodate NH4+-stress by responding to exogenous urea, providing a novel aspect for further understanding the process of urea-dependent plant NH4+ tolerance.