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Traditional antibody drug conjugates (ADC) combine monoclonal antibodies with cytotoxic drugs to accurately strike cancer cells, but there are still many shortcomings in stability, targeting, efficacy, and safety. Novel ADC, such as bi-specific, site-specific, dual-payload, and pro-drug type ADC, can be optimized by simultaneously binding 2 different antigens or epitopes, selecting more stable linkers, coupling with specific amino acid sites of antibodies, carrying different drug payloads, and adopting prodrug strategies, while retaining the characteristics of traditional ADC. Significantly improving the stability, targeting, efficacy and safety of drugs can better meet the needs of clinical treatment. Novel ADC will play a more important role in cancer treatment in the future. Discussing the progress of novel ADC in cancer treatment and analyzing their advantages and challenges can provide theoretical support for the development of anti-cancer strategies and provide directions for drug research and development.

The effect of dietary carbohydrate and calorie restriction on weight and metabolic health in overweight/obese individuals: a multi-center randomized controlled trial.

BACKGROUND: Both low-carbohydrate (LC) and calorie-restricted (CR) diets have been shown to have metabolic benefits. However, the two regimens have yet to be thoroughly compared. We conducted a 12-week randomized trial to compare the effects of these diets separately and in combination on both weight loss and metabolic risk factors in overweight/obese individuals. METHODS: A total of 302 participants were randomized to LC diet (n = 76), CR diet (n = 75), LC + CR diet (n = 76), or normal control (NC) diet (n = 75) using a computer-based random number generator. The primary outcome was the change in body mass index (BMI). The secondary outcomes included body weight, waist circumference, waist-to-hip ratio, body fat, and metabolic risk factors. All participants attended health education sessions during the trial. RESULTS: A total of 298 participants were analyzed. BMI change over 12 weeks was - 0.6 (95% CI, - 0.8 to - 0.3) kg/m2 in NC, - 1.3 (95% CI, - 1.5 to - 1.1) kg/m2 in CR, - 2.3 (95% CI, - 2.6 to - 2.1) kg/m2 in LC, and - 2.9 (95% CI, - 3.2 to - 2.6) kg/m2 in LC + CR. LC + CR diet was more effective than LC or CR diet alone at reducing BMI (P = 0.001 and P < 0.001, respectively). Furthermore, compared with the CR diet, the LC + CR diet and LC diet further reduced body weight, waist circumference, and body fat. Serum triglycerides were significantly reduced in the LC + CR diet group compared with the LC or CR diet alone. Plasma glucose, homeostasis model assessment of insulin resistance, and cholesterol concentrations (total, LDL, and HDL) did not change significantly between the groups during the 12-week intervention. CONCLUSIONS: The reduction of carbohydrate intake without restricting caloric intake is more potent to achieve weight loss over 12 weeks when compared to a calorie-restricted diet in overweight/obese adults. The combination of restricting carbohydrate and total calorie intake may augment the beneficial effects of reducing BMI, body weight, and metabolic risk factors among overweight/obese individuals. TRIAL REGISTRATION: The study was approved by the institutional review board of Zhujiang Hospital of Southern Medical University and registered at the China Clinical Trial Registration Center (registration number: ChiCTR1800015156).

Deep learning-driven multi-view multi-task image quality assessment method for chest CT image.

BACKGROUND: Chest computed tomography (CT) image quality impacts radiologists' diagnoses. Pre-diagnostic image quality assessment is essential but labor-intensive and may have human limitations (fatigue, perceptual biases, and cognitive biases). This study aims to develop and validate a deep learning (DL)-driven multi-view multi-task image quality assessment (M[Formula: see text]IQA) method for assessing the quality of chest CT images in patients, to determine if they are suitable for assessing the patient's physical condition. METHODS: This retrospective study utilizes and analyzes chest CT images from 327 patients. Among them, 1613 images from 286 patients are used for model training and validation, while the remaining 41 patients are reserved as an additional test set for conducting ablation studies, comparative studies, and observer studies. The M[Formula: see text]IQA method is driven by DL technology and employs a multi-view fusion strategy, which incorporates three scanning planes (coronal, axial, and sagittal). It assesses image quality for multiple tasks, including inspiration evaluation, position evaluation, radiation protection evaluation, and artifact evaluation. Four algorithms (pixel threshold, neural statistics, region measurement, and distance measurement) have been proposed, each tailored for specific evaluation tasks, with the aim of optimizing the evaluation performance of the M[Formula: see text]IQA method. RESULTS: In the additional test set, the M[Formula: see text]IQA method achieved 87% precision, 93% sensitivity, 69% specificity, and a 0.90 F1-score. Extensive ablation and comparative studies have demonstrated the effectiveness of the proposed algorithms and the generalization performance of the proposed method across various assessment tasks. CONCLUSION: This study develops and validates a DL-driven M[Formula: see text]IQA method, complemented by four proposed algorithms. It holds great promise in automating the assessment of chest CT image quality. The performance of this method, as well as the effectiveness of the four algorithms, is demonstrated on an additional test set.

Exploring heterogeneities of cardiovascular efficacy and effectiveness of SGLT2 inhibitors in patients with type 2 diabetes: an umbrella review of evidence from randomized clinical trials versus real-world observational studies.

PURPOSE: We aimed to explore possible contributors to discrepancies between randomized controlled trials (RCTs) and real-world observational studies (OS) in cardiovascular benefits of sodium-glucose cotransporter 2 (SGLT2) inhibitors in type 2 diabetes (T2D) patients. METHODS: We searched PubMed and EMBASE to identify meta-analyses of RCTs and OS on cardiovascular effects of SGLT2 inhibitors in T2D patients. Cardiovascular outcomes included major adverse cardiovascular events (MACE), myocardial infarction (MI), stroke, cardiovascular mortality (CVM), all-cause mortality (ACM), hospitalization for heart failure (HHF), and atrial fibrillation (AF). We examined the summary relative risk (RR) and 95% confidence interval (CI) for each endpoint from meta-analyses of RCTs. RESULTS: We identified and included 15 eligible meta-analyses, 13 for RCTs and 2 for OS, with moderately strong evidence. The results revealed a significant discrepancy between RCTs and OS for MI (RR, 95% CI 1.05, 0.82-1.38; I = 91.5% versus odds ratio (OR), 95% CI 0.77, 0.73-0.81; I = 15.0%), stroke (RR, 95% CI 0.99, 0.76-1.29; I = 93.4% versus OR, 95% CI 0.75, 0.72-0.78; I = 23.0%), and AF (RR, 95% CI 0.72, 0.62-0.85; I = 0.0% versus OR, 95% CI 0.92, 0.83-1.02; I = 0.0%). CONCLUSION: OS presented significant benefits of SGLT2 inhibitors both on primary and secondary preventions of MACE, MI, stroke, ACM, CVM, and HHF; RCTs did not. Given the spectrum of T2D patient characteristics and the strength of overall evidence, our review underscored the importance of constant integration of all available information and critical interpretation of all inconsistencies to optimize evidence-based diabetes care.

Low-frequency acoustic radiation from a flanged circular pipe at an inclined angle.

The generic problem of low-frequency acoustic radiation through quiescent air from a circular pipe that is inclined with respect to its exit flange is studied in this work. The exit flange is taken to extend as an infinite plane away from the pipe opening. The analysis implements a hybrid method that combines modal expansions with the boundary element method. The reflection coefficient and pipe end correction for Helmholtz numbers (based on the pipe radius) less than 2.5 are calculated for various inclination angles up to 75°. Calculations are validated using simulations from the finite-element solver of the commercial software package COMSOL. The reflection coefficient and end correction predictions agree closely with the validation simulations yet differ notably from the results available in the literature. The solution obtained from the hybrid method is subsequently used to analyse the acoustic field at the pipe exit and in the downstream space. The key aspects of the governing physics pertaining to practical engineering applications at low frequencies are captured in a low-order approximation, which significantly reduces the degrees of freedom of the problem and provides generally good estimates of the reflection coefficient and end correction, as well as the downstream acoustic field.

Long non-coding RNA DBCCR1-003 regulate the expression of DBCCR1 via DNMT1 in bladder cancer.

BACKGROUND: Many long non coding RNAs have been identified as key modulators in cancer development. A lncRNA, DBCCR1-003, derived from the locus of tumor suppressor gene DBCCR1 (deleted in bladder cancer chromosome region 1), has unknown function. In the present study, we explored function and molecular mechanism of DBCCR1-003 in bladder cancer (BC) development. METHODS: We evaluated the expression levels of DBCCR1-003 in tissues and cells with western blot and quantitative real-time polymerase chain reaction. Multiple approaches including chromatin immunoprecipitation assay and RNA immunoprecipitation were used to confirm the direct binding of DBCCR1-003 to DNMT1. The recombinant vector overexpressing DBCCR1-003 was constructed. Cell proliferation assay, colony formation assay and flow cytometric analysis were employed to measure the role of DBCCR1-003 in regulation of cell proliferation, cycle and apoptosis. RESULTS: Firstly we detected the expression of DBCCR1-003, DBCCR1, DNMT1 (DNA methyltransferase 1) and DNA methylation in the promoter of DBCCR1. We found low expression of DBCCR1-003, same as DBCCR1, while high expression of DNMT1 and hypermethylation of DBCCR1 gene promoter in BC tissues and T24 cells line. Further studies revealed that treatment of DNMT inhibitor, 5-aza-2-deoxycytidine(DAC), or overexpression of DBCCR1-003 led to increased DBCCR1 expression by reversion of promoter hypermethylation and DNMT1 binding to DBCCR1 promoter in T24 cells. Importantly, RNA immunoprecipitation (RIP) showed that DBCCR1-003 physically associates with DNMT1. The binding of them was increased with the inhibition of DBCCR1 promoter methylation, indicating that DBCCR1-003 may bind to DNMT1 and prevent DNMT1-mediated the methylation of DBCCR1. Furthermore, overexpression of DBCCR1-003 resulted in significant inhibition of T24 cells growth through the inducing G0/G1 arrest and apoptosis. CONCLUSIONS: Taken together, these findings demonstrated that a novel tumor suppressor DBCCR1-003 regulates the expression of DBCCR1 via binding to DNMT1 and preventing DNMT1-mediated the methylation of DBCCR1 in BC. LncRNA DBCCR1-003 may serve as a novel biomarker and therapeutic target for BC in future cancer clinic.

Regulators of G protein signaling are up-regulated in aspirin-resistant platelets from patients with metabolic syndrome.

G protein-coupled receptor signaling plays a crucial role in platelet function. Regulators of G protein signaling (RGSs), which accelerate the deactivation of G protein signaling, are expressed in platelets. However, RGS expression has not been studied in the context of aspirin resistance. We compared RGS mRNA levels in platelets from 39 aspirin-resistant patients and 50 aspirin-sensitive patients with metabolic syndrome. Although there were no clinical differences between the two groups, transcripts of RGS2, RGS10, and RGS18 were significantly higher in aspirin-resistant patients than in aspirin-sensitive patients. This study is the first to demonstrate that RGS transcripts are elevated in aspirin-resistant platelets from patients with metabolic syndrome.

Surgical margins and prognosis of borderline and malignant phyllodes tumors.

PURPOSE: To investigate the optimal surgical margin and prognostic risk factors for borderline and malignant phyllodes tumors (PTs). METHODS: A retrospective analysis was conducted on patients with borderline and malignant PTs at our hospital from 2011 to 2022. Univariate and multivariate Cox proportional hazard models were employed to analyze the effects of various variables on local recurrence-free survival (LRFS) and disease-free survival (DFS). RESULTS: This study comprised 150 patients, 85 classified as borderline and 65 as malignant. During a median follow-up of 66 months (range: 3-146 months), 34 cases (22.7%) experienced local recurrence, 9 cases (6.0%) exhibited distant metastasis, and 7 cases (4.7%) resulted in death. Irrespective of the histological subtypes, patients with surgical margins ≥ 1 cm exhibit significantly higher 5-year LRFS and 5-year DFS rates compared to those with margins < 1 cm. Among patients with initial margins < 1 cm, LRFS (P = 0.004) and DFS (P = 0.003) were improved in patients reoperated to achieve margins ≥ 1 cm. Surgical margin < 1 cm (HR = 2.567, 95%CI 1.137-5.793, P = 0.023) and age < 45 years (HR = 2.079, 95%CI 1.033-4.184, P = 0.040) were identified as independent risk factors for LRFS. Additionally, surgical margin < 1 cm (HR = 3.074, 95%CI 1.622-5.826, P = 0.001) and tumor size > 5 cm (HR = 2.719, 95%CI 1.307-5.656, P = 0.007) were determined to be independent risk factors for DFS. CONCLUSIONS: A negative surgical margin of at least 1 cm (with secondary resection if necessary) should be achieved for borderline and malignant PTs. Tumor size > 5 cm and age < 45 years were predictive of recurrence, suggesting multiple therapy modalities may be considered for these high-risk patients.

Molecular characterization and expression analysis of thyroid hormone receptors in protogynous rice field eel, Monopterus albus.

Thyroid hormones (THs) play important roles in growth, development, morphogenesis, reproduction, and so on. They are mainly meditated by binding to thyroid hormone receptors (TRs) in vertebrates. As important members of the nuclear receptor superfamily, TRs and their ligands are involved in many biological processes. To investigate the potential roles of TRs in the gonadal differentiation and sex change, we cloned and characterized the TRs genes in protogynous rice field eel (Monopterus albus). In this study, three types of TRs were obtained, which were TRαA, TRαB and TRß, encoding preproproteins of 336-, 409- and 415-amino acids, respectively. Multiple alignments of the three putative TRs protein sequences showed they had a higher similarity. Tissue expression analysis showed that TRαA mainly expressed in the gonad, while TRαB and TRß in the brain. During female-to-male sex reversal, the expression levels of all the three TRs showed a similar trend of increase followed by a decrease in the gonad. Intraperitoneal injection of triiodothyronine (T3) stimulated the expression of TRαA and TRαB, while it had no significant change on the expression of TRß in the ovary. Gonadotropin-releasing hormone analogue (GnRHa) injection also significantly upregulated the expression levels of TRαA and TRαB after 6 h, while it had no significant effect on TRß. These results demonstrated that TRs were involved in the gonadal differentiation and sex reversal, and TRα may play more important roles than TRß in reproduction by the regulation of GnRHa in rice field eel.

Clinical significance and biological function of interferon regulatory factor 1 in non-small cell lung cancer.

The clinical application and biological function of interferon regulatory factor 1 (IRF1) in non-small cell lung cancer (NSCLC) patients undergoing chemoimmunotherapy remain elusive. The aim of this study was to investigate the predictive and prognostic significance of IRF1 in NSCLC patients. We employed the cBioPortal database to predict frequency changes in IRF1 and explore its target genes. Bioinformatic methods were utilized to analyze the relationship between IRF1 and immune regulatory factors. Retrospective analysis of clinical samples was conducted to assess the predictive and prognostic value of IRF1 in chemoimmunotherapy. Additionally, A549 cells with varying IRF1 expression levels were constructed to investigate its effects on NSCLC cells, while animal experiments were performed to study the role of IRF1 in vivo. Our findings revealed that the primary mutation of IRF1 is deep deletion and it exhibits a close association with immune regulatory factors. KRAS and TP53 are among the target genes of IRF1, with interferon and IL-2 being the predominantly affected pathways. Clinically, IRF1 levels significantly correlate with the efficacy of chemoimmunotherapy. Patients with high IRF1 levels exhibited a median progression-free survival (mPFS) of 9.5 months, whereas those with low IRF1 levels had a shorter mPFS of 5.8 months. IRF1 levels positively correlate with PD-L1 distribution and circulating IL-2 levels. IL-2 enhances the biological function of IRF1 and recapitulates its role in vivo in the knockdown group. Therefore, IRF1 may possess predictive and prognostic value for chemoimmunotherapy in NSCLC patients through the regulation of the IL-2 inflammatory pathway.

A deep learning-based automatic image quality assessment method for respiratory phase on computed tomography chest images.

Background: Computed tomography (CT) chest scans have become commonly used in clinical diagnosis. Image quality assessment (IQA) for CT images plays an important role in CT examination. It is worth noting that IQA is still a manual and subjective process, and even experienced radiologists make mistakes due to human limitations (fatigue, perceptual biases, and cognitive biases). There are also kinds of biases because of poor consensus among radiologists. Excellent IQA methods can reliably give an objective evaluation result and also reduce the workload of radiologists. This study proposes a deep learning (DL)-based automatic IQA method, to assess whether the image quality of respiratory phase on CT chest images are optimal or not, so that the CT chest images can be used in the patient's physical condition assessment. Methods: This retrospective study analysed 212 patients' chest CT images, with 188 patients allocated to a training set (150 patients), validation set (18 patients), and a test set (20 patients). The remaining 24 patients were used for the observer study. Data augmentation methods were applied to address the problem of insufficient data. The DL-based IQA method combines image selection, tracheal carina segmentation, and bronchial beam detection. To automatically select the CT image containing the tracheal carina, an image selection model was employed. Afterward, the area-based approach and score-based approach were proposed and used to further optimize the tracheal carina segmentation and bronchial beam detection results, respectively. Finally, the score about the image quality of the patient's respiratory phase images given by the DL-based automatic IQA method was compared with the mean opinion score (MOS) given in the observer study, in which four blinded experienced radiologists took part. Results: The DL-based automatic IQA method achieved good performance in assessing the image quality of the respiratory phase images. For the CT sequence of the same patient, the DL-based IQA method had an accuracy of 92% in the assessment score, while the radiologists had an accuracy of 88%. The Kappa value of the assessment score between the DL-based IQA method and radiologists was 0.75, with a sensitivity of 85%, specificity of 91%, positive predictive value (PPV) of 92%, negative predictive value (NPV) of 93%, and accuracy of 88%. Conclusions: This study develops and validates a DL-based automatic IQA method for the respiratory phase on CT chest images. The performance of this method surpassed that of the experienced radiologists on the independent test set used in this study. In clinical practice, it is possible to reduce the workload of radiologists and minimize errors caused by human limitations.

Change of Peri-mitral Atrial Flutter into Single-loop Biatrial Flutter During Ablation.

Anterior line ablation for peri-mitral atrial flutter (AFL) is associated with biatrial flutter due to disruption of the electrical conduction in the left atrial septum. An AFL case with valvular disease, cardiac surgery, and prior ablation was confirmed to be counterclockwise peri-mitral flutter with isthmus on the left atrial septum. Ablation on the septum of the left atrium (LA) targeting the isthmus prolonged the tachycardia cycle length (TCL) from 266 to 286 ms. Left atrial mapping during AFL with a TCL of 286 ms showed that the activation remained peri-mitral counterclockwise, but there was interruption of the local activation time (LAT) sequence. Combined mapping of the LA and the right atrium (RA) showed a counterclockwise single-loop biatrial flutter, involving the whole LA and the RA septum, with Bachmann's bundle and the posteroinferior septum being the interatrial connections. The AFL was terminated by ablation at the right superior cavoatrial junction. RA mapping should be considered if there is prolongation of TCL but without termination of the peri-mitral AFL, and if there is interruption of the continuity of the LAT sequence during AFL with a longer TCL. The biatrial flutter can be terminated by ablation targeting the interatrial connections.

A real-world study and network pharmacology analysis of EGFR-TKIs combined with ZLJT to delay drug resistance in advanced lung adenocarcinoma.

OBJECTIVE: This study aimed to explore the efficacy and safety of combining epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) with ZiLongJin Tablet (ZLJT) in delaying acquired resistance in advanced EGFR-mutant lung adenocarcinoma (LUAD) patients. Furthermore, we employed network pharmacology and molecular docking techniques to investigate the underlying mechanisms. METHODS: A retrospective comparative study was conducted on stage IIIc/IV LUAD patients treated with EGFR-TKIs alone or in combination with ZLJT at the Second Affiliated Hospital of the Air Force Medical University between January 1, 2017, and May 1, 2023. The study evaluated the onset of TKI resistance, adverse reaction rates, safety indicators (such as aspartate aminotransferase, alanine aminotransferase, and creatinine), and inflammatory markers (neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio) to investigate the impact of EGFR-TKI combined with ZLJT on acquired resistance and prognostic indicators. Additionally, we utilized the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform, the Bioinformatics Analysis Tool for Molecular Mechanism of Traditional Chinese Medicine, PubChem, UniProt, and Swiss Target Prediction databases to identify the active ingredients and targets of ZLJT. We obtained differentially expressed genes related to EGFR-TKI sensitivity and resistance from the Gene Expression Omnibus database using the GSE34228 dataset, which included sensitive (n = 26) and resistant (n = 26) PC9 cell lines. The "limma" package in R software was employed to detect DEGs. Based on this, we constructed a protein‒protein interaction network, performed gene ontology and KEGG enrichment analyses, and conducted pathway network analysis to elucidate the correlation between the active ingredients in ZLJT and signaling pathways. Finally, molecular docking was performed using AutoDockVina, PYMOL 2.2.0, and Discovery Studio Client v19.1.0 software to simulate spatial and energy matching during the recognition process between predicted targets and their corresponding compounds. RESULTS: (1) A total of 89 patients were included, with 40 patients in the EGFR-TKI combined with ZLJT group (combination group) and 49 patients in the EGFR-TKI alone group (monotherapy group). The baseline characteristics of the two groups were comparable. There was a significant difference in the onset of resistance between the combination group and the monotherapy group (P < 0.01). Compared to the monotherapy group, the combination group showed a prolongation of 3.27 months in delayed acquired resistance. There was also a statistically significant difference in the onset of resistance to first-generation TKIs between the two groups (P < 0.05). (2) In terms of safety analysis, the incidence of adverse reactions related to EGFR-TKIs was 12.5% in the combination group and 14.3% in the monotherapy group, but this difference was not statistically significant (P > 0.05). There were no statistically significant differences in serum AST, ALT, CREA, TBIL, ALB and BUN levels between the two groups after medication (P > 0.05). (3) Regarding inflammatory markers, there were no statistically significant differences in the changes in neutrophil-to-lymphocyte Ratio(NLR) and Platelet-to-lymphocyte Ratio(PLR) values before and after treatment between the two groups (P > 0.05). (4) Network pharmacology analysis identified 112 active ingredients and 290 target genes for ZLJT. From the GEO database, 2035 differentially expressed genes related to resistant LUAD were selected, and 39 target genes were obtained by taking the intersection. A "ZLJT-compound-target-disease" network was successfully constructed using Cytoscape 3.7.0. GO enrichment analysis revealed that ZLJT mainly affected biological processes such as adenylate cyclase-modulating G protein-coupled receptor. In terms of cellular components, ZLJT was associated with the cell projection membrane. The molecular function primarily focused on protein heterodimerization activity. KEGG enrichment analysis indicated that ZLJT exerted its antitumor and anti-drug resistance effects through pathways such as the PI3K-Akt pathway. Molecular docking showed that luteolin had good binding activity with FOS (-9.8 kJ/mol), as did tanshinone IIA with FOS (-9.8 kJ/mol) and quercetin with FOS (-8.7 kJ/mol). CONCLUSION: ZLJT has potential antitumor progression effects. For patients with EGFR gene-mutated non-small cell LUAD, combining ZLJT with EGFR-TKI treatment can delay the occurrence of acquired resistance. The underlying mechanisms may involve altering signal transduction pathways, blocking the tumor cell cycle, inhibiting tumor activity, enhancing cellular vitality, and improving the bioavailability of combination therapy. The combination of EGFR-TKI and ZLJT represents an effective approach for the treatment of tumors using both Chinese and Western medicine.

The Evaluation of Prognostic Value and Immune Characteristics of Ferroptosis-Related Genes in Lung Squamous Cell Carcinoma.

Background The purpose of our study was to construct a prognostic model based on ferroptosis-related gene signature to improve the prognosis prediction of lung squamous carcinoma (LUSC). Methods The mRNA expression profiles and clinical data of LUSC patients were downloaded. LUSC-related essential differentially expressed genes were integrated for further analysis. Prognostic gene signatures were identified through random forest regression and univariate Cox regression analyses for constructing a prognostic model. Finally, in a preliminary experiment, we used the reverse transcription-quantitative polymerase chain reaction assay to verify the relationship between the expression of three prognostic gene features and ferroptosis. Results Fifty-six ferroptosis-related essential genes were identified by using integrated analysis. Among these, three prognostic gene signatures (HELLS, POLR2H, and POLE2) were identified, which were positively affected by LUSC prognosis but negatively affected by immune cell infiltration. Significant overexpression of immune checkpoint genes occurred in the high-risk group. In preliminary experiments, we confirmed that the occurrence of ferroptosis can reduce three prognostic gene signature expression. Conclusions The three ferroptosis-related genes could predict the LUSC prognostic risk of antitumor immunity.

Molecular Cloning and Expression Analysis of Thyrotropin-Releasing Hormone, and Its Possible Role in Gonadal Differentiation in Rice Field eel Monopterus albus.

Rice field eel (Monopterus albus), a protogynous hermaphrodite fish, is a good model for the research of sex determination and gonadal differentiation in teleosts. In this study, we cloned the full-length cDNA sequence of trh, which encoded a predicted protein with 270 amino acids. Trh mainly expressed in the brain, followed by the ovary, testis, muscle and pituitary, and had low levels in other peripheral tissues. During natural sex reversal, trh mRNA expression levels exhibited a significant increase at the late intersexual stage in the hypothalamus. In the gonad, trh mRNA expression levels showed a trend of increase followed by decrease, and only increased significantly at the middle intersexual stage. No matter static incubation or intraperitoneal (IP) injection, TRH had no significant effect on trh and thyroid-stimulating hormone ßsubunit (tshß) mRNA expression levels, and serum T3, T4 and TRH release. After static incubation of ovarian fragments by TRH, the expression of gonadal soma derived factor (gsdf) was up-regulated significantly at both the doses of 10 and 100 nM. IP injection of TRH stimulated the expression of gsdf, and inhibited the expression of ovarian aromatase gene (cyp19a1a), accompanied by the increase of serum 11-KT levels. The results indicated that TRH may play a novel role in gonadal differentiation by the regulation of gonadal differentiation-related gene expression and sex steroid hormone secretion in rice field eel.

How to perform extrathoracic venous access for cardiac implantable electronic device placement: Detailed description of techniques.

Venous access is needed for implantation of cardiac implantable electronic devices (CIEDs) with endocardial leads. Extrathoracic venous access in the prepectoral region has become the standard of care for CIED implantation because of lower risks for pneumothorax and likely less lead malfunction due to subclavian crush syndrome. The most common extrathoracic venous access sites in the pectoral region are extrathoracic subclavian vein access, axillary vein access, and cephalic vein access. This review provides a detailed description of the anatomy, technical considerations, and relative advantages and disadvantages of each of these extrathoracic venous access sites.

Roof-dependent Atrial Flutter Changed into Single-loop Biatrial Flutter During Ablation.

A single-loop biatrial flutter is an uncommon form of atypical atrial flutter, and it can occur with septal or anterior line ablation in the left atrium (LA). We report a case with a roof-dependent atrial flutter that changed into a single-loop biatrial flutter during roof-line ablation. The activation entered the right atrium (RA) at the septum/fossa ovalis and coronary sinus ostium, exited the RA likely via the Bachmann's bundle and/or septopulmonary bundle, and entered the LA posterior to the roof line. The biatrial flutter was terminated with linear ablation between the right and left inferior pulmonary veins. RA mapping and biatrial flutter should be considered if roof-dependent atrial flutter slowed down during the roof-line ablation without termination.

Regulator of G protein signaling 2 is a functionally important negative regulator of angiotensin II-induced cardiac fibroblast responses.

Cardiac fibroblasts play a key role in fibrosis development in response to stress and injury. Angiotensin II (ANG II) is a major profibrotic activator whose downstream effects (such as phospholipase Cß activation, cell proliferation, and extracellular matrix secretion) are mainly mediated via G(q)-coupled AT(1) receptors. Regulators of G protein signaling (RGS), which accelerate termination of G protein signaling, are expressed in the myocardium. Among them, RGS2 has emerged as an important player in modulating G(q)-mediated hypertrophic remodeling in cardiac myocytes. To date, no information is available on RGS in cardiac fibroblasts. We tested the hypothesis that RGS2 is an important regulator of ANG II-induced signaling and function in ventricular fibroblasts. Using an in vitro model of fibroblast activation, we have demonstrated expression of several RGS isoforms, among which only RGS2 was transiently upregulated after short-term ANG II stimulation. Similar results were obtained in fibroblasts isolated from rat hearts after in vivo ANG II infusion via minipumps for 1 day. In contrast, prolonged ANG II stimulation (3-14 days) markedly downregulated RGS2 in vivo. To delineate the functional effects of RGS expression changes, we used gain- and loss-of-function approaches. Adenovirally infected RGS2 had a negative regulatory effect on ANG II-induced phospholipase Cß activity, cell proliferation, and total collagen production, whereas RNA interference of endogenous RGS2 had opposite effects, despite the presence of several other RGS. Together, these data suggest that RGS2 is a functionally important negative regulator of ANG II-induced cardiac fibroblast responses that may play a role in ANG II-induced fibrosis development.

Mitral Valve Prolapse: An Innocent Bystander or Proarrhythmogenic Anomaly?

Mitral valve prolapse (MVP) is a relatively common finding in the general population, and it is associated with ventricular tachycardia (VT) and sudden cardiac death (SCD). In this report, we present a case involving a 63-year-old male who had been previously diagnosed with MVP complicated by multiple admissions for episodes of ventricular arrhythmias.