Cervical neuroendocrine carcinoma in the third trimester: a rare case report and literature review.

BACKGROUND: The incidence of cervical neuroendocrine carcinoma (CNECC) during pregnancy is extremely rare. Insufficient awareness of gynecological tumor screening, as well as atypical and insidious initial clinical symptoms, may result in diagnostic delays and misdiagnosis. There is no standardized treatment for cervical cancer in pregnancy. Herein, we present a case of cervical neuroendocrine carcinoma diagnosed in the third trimester of pregnancy. CASE PRESENTATION: A 26-year-old female at 30 1/7 weeks of gestation presented with lower back and sacroiliac joint pain, abdominal distension, and lower limb dyskinesia. A pelvic examination revealed a large fungating gray mass that encompassed the entire cervix, with cervical contact bleeding testing positive. Imaging studies showed a significant cervical mass, diffuse liver changes, and metastasis to multiple sites. Biopsy results revealed poorly differentiated cervical carcinoma exhibiting high-grade neuroendocrine features, consistent with a diagnosis of large cell neuroendocrine carcinoma. The patient was diagnosed with stage IVB CNECC with HPV18 (+), and due to the gestational age of the fetus and her deteriorating condition, she underwent cesarean section delivery after receiving fetal lung maturation therapy. Following surgery, eight cycles of neoadjuvant chemotherapy were applied. Unfortunately, she succumbed to multiple tumor metastases six months post-treatment. Despite this tragic outcome, the infant was discharged in a healthy condition. CONCLUSIONS: CNECC during pregnancy, particularly the large-cell type, is an ultra-rare condition with poor prognosis. This case highlights the importance of individualized treatment approach and the need for better screening, early detection, and treatment. Given the rarity of the disease, further research is warranted to determine the prognostic factors and develop effective treatment strategies for this ultra-rare and aggressive malignancy.

Berberine attenuates sunitinib-induced cardiac dysfunction by normalizing calcium regulation disorder via SGK1 activation.

Sunitinib (SNT)-induced cardiotoxicity is associated with abnormal calcium regulation caused by phosphoinositide 3 kinase inhibition in the heart. Berberine (BBR) is a natural compound that exhibits cardioprotective effects and regulates calcium homeostasis. We hypothesized that BBR ameliorates SNT-induced cardiotoxicity by normalizing the calcium regulation disorder via serum and glucocorticoid-regulated kinase 1 (SGK1) activation. Mice, neonatal rat cardiomyocytes (NRVMs), and human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) were used to study the effects of BBR-mediated SGK1 activity on the calcium regulation disorder caused by SNT as well as the underlying mechanism. BBR offered prevention against SNT-induced cardiac systolic dysfunction, QT interval prolongation, and histopathological changes in mice. After the oral administration of SNT, the Ca2+ transient and contraction of cardiomyocytes was significantly inhibited, whereas BBR exhibited an antagonistic effect. In NRVMs, BBR was significantly preventive against the SNT-induced reduction of calcium transient amplitude, prolongation of calcium transient recovery, and decrease in SERCA2a protein expression; however, SGK1 inhibitors resisted the preventive effects of BBR. In hiPSC-CMs, BBR pretreatment significantly prevented SNT from inhibiting the contraction, whereas coincubation with SGK1 inhibitors antagonized the effects of BBR. These findings indicate that BBR attenuates SNT-induced cardiac dysfunction by normalizing the calcium regulation disorder via SGK1 activation.

Healing of the Torn Anterior Horn of Rabbit Medial Meniscus to Bone after Transtibial Pull-Out Repair and Autologous Platelet-Rich Plasma Gel Injection.

OBJECTIVES: The transtibial pull-out repair (TP) is a relatively new method for treating meniscal root tear; however, the clinical evaluation of its healing effect remains controversial. Due to ethical constraints and limitations of imaging techniques in humans, here we dynamically observe the healing effects of TP and TP with platelet-rich plasma gel (PRG) at the histological level using an animal model. METHODS: Platelet-rich plasma (PRP) and PRG of rabbits were prepared. Platelet-derived growth factor (PDGF) and transforming growth factor-ß1 (TGF-ß1) levels in PRP and PRG were determined using an enzyme-linked immunosorbent assay. A rabbit model of anterior horn tear of the medial meniscus and TP surgery were created. PRG was injected between the anterior horn of the medial meniscus and the tibial tunnel. Rabbits were divided into three groups: the anterior horn tear group (Tear group), the anterior horn tear + TP group (TP group), and the anterior horn tear + TP + PRG group (TP + PRG group). The healing effect was observed dynamically using histopathological studies and biomechanical experiments. RESULTS: The platelet content in PRP significantly increased to approximately 4.57 times that of whole blood. PDGF and TGF-ß1 concentrations in PRG increased to 2.46 and 4.15 times those in PRP, respectively. Hematoxylin and eosin (H&E) and Masson staining showed that the number of inflammatory cells in healing tissue decreased and the collagen fibers significantly increased in TP and TP + PRG groups at 4, 8, and 12 weeks postoperatively compared to those in Tear group. Neatly arranged, interlaced, and dense collagen fibers were found between the anterior horn and bone at 12 weeks. H&E and toluidine blue staining showed that the injury to the femoral condyle cartilage was alleviated. The healing performance in TP + PRG group was better and faster than that in TP group. The maximum tensile fracture strength of the meniscus progressively increased at 8 and 12 weeks postoperatively. CONCLUSIONS: Anterior horn injury of the medial meniscus in rabbits can be repaired using the TP technique, and the addition of autologous PRG to the bone tunnel promotes early healing of the meniscus and bone postoperatively. Meanwhile, both treatments can reduce the secondary damage to the cartilage due to osteoarthritis.

Piezo1 in endothelial cells is involved in vitamin D-induced vascular calcification.

The relationship between the Piezo1 channel of vascular endothelial cells and vascular calcification is unknown. In this study, after subcutaneous injection of vitamin D for 10 consecutive days, the mice showed an increase in serum calcium, aortic calcium content, vascular tension and pulse wave velocity. Piezo1channel antagonist, GsMTx4 alleviated arteriosclerosis and decreased the aortic calcium content, while Piezo1 agonist Yoda1 produced opposite effect. In addition, activation of Piezo1 by Yoda1 impaired the function of human umbilical vein endothelial cells (HUVECs), as evidenced by further decreased production of NO, reduction in expression levels of eNOS, MMP-2, PCNA and VEGFA. When co-culture of HUVECs and vascular smooth muscle cells (VSMCs), activation of Piezo1 in HUVECs enhanced expression levels of calcification-related SOX9 and Runx2 genes, increased ALP activity and calcium deposition in VSMCs. We concluded that Piezo1 in endothelial cells is involved in the pathogenesis of vascular calcification. This study provides a new experimental basis for the prevention and treatment of vascular calcification.

Pharmacological suppression of Nedd4-2 rescues the reduction of Kv11.1 channels in pathological cardiac hypertrophy.

The human ether-á-go-go-related gene (hERG) encodes the pore-forming subunit (Kv11.1), conducting a rapidly delayed rectifier K+ current (I Kr). Reduction of I Kr in pathological cardiac hypertrophy (pCH) contributes to increased susceptibility to arrhythmias. However, practical approaches to prevent I Kr deficiency are lacking. Our study investigated the involvement of ubiquitin ligase Nedd4-2-dependent ubiquitination in I Kr reduction and sought an intervening approach in pCH. Angiotensin II (Ang II) induced a pCH phenotype in guinea pig, accompanied by increased incidences of sudden death and higher susceptibility to arrhythmias. Patch-clamp recordings revealed a significant I Kr reduction in pCH cardiomyocytes. Kv11.1 protein expression was decreased whereas its mRNA level did not change. In addition, Nedd4-2 protein expression was increased in pCH, accompanied by an enhanced Nedd4-2 and Kv11.1 binding detected by immunoprecipitation analysis. Cardiac-specific overexpression of inactive form of Nedd4-2 shortened the prolonged QT interval, reversed I Kr reduction, and decreased susceptibility to arrhythmias. A synthesized peptide containing the PY motif in Kv11.1 C-terminus binding to Nedd4-2 and a cell-penetrating sequence antagonized Nedd4-2-dependent degradation of the channel and increased the surface abundance and function of hERG channel in HEK cells. In addition, in vivo administration of the PY peptide shortened QT interval and action potential duration, and enhanced I Kr in pCH. We conclude that Nedd4-2-dependent ubiquitination is critically involved in I Kr deficiency in pCH. Pharmacological suppression of Nedd4-2 represents a novel approach for antiarrhythmic therapy in pCH.

Downregulation of hERG channel expression by tyrosine kinase inhibitors nilotinib and vandetanib predominantly contributes to arrhythmogenesis.

Cardiotoxicity by tyrosine kinase inhibitors remains an important concern. Nilotinib and vandetanib clinically carry high proarrhythmic risk and the exact mechanism underlying arrhythmogenesis is not fully understood. In this study, we investigated the effects of nilotinib and vandetanib on the abundance of human ether-á-go-go-related gene (hERG) K+ channel and assessed the potential role of acute hERG blockage versus chronic effects in arrhythmogenesis. We found that both nilotinib and vandetanib prolonged the field potential duration reflecting the repolarisation process and induced cellrythmias of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in a time-and concentration-dependent manner after, after chronic exposure. Patch-clamp recordings revealed significant reductions of hERG current densities by nilotinib or vandetanib after chronic incubation with hERG-HEK293 cells in addition to the acute inhibition. Western blot analysis showed that nilotinib and vandetanib decreased mature hERG protein (155-kDa) expression, in a greater extent than that of the immature form (135-kDa). A serum and glucocorticoid kinase 1 (SGK1) activator, C4-ceramide, prevented the nilotinib-and vandetanib-induced hERG protein downregulation and thus the incidence of cellrrhythmias. Taken together, our data demonstrated that the downregulation of hERG channel abundance on the cellular membrane predominantly contributed to the proarrhythmic effect of nilotinib and vandetanib.

Joint optimization of mission abort and protective device selection policies for multistate systems.

For safety-critical systems such as aircrafts and submarines, mission abort is commonly deployed to enhance system survivability at the cost of reducing mission success probability. In addition to mission abort, protective device can also mitigate the failure risk of safety-critical systems by reducing the magnitude of external shocks. Considering the effect of protective device on system failure behavior, this article proposes a condition-based mission abort policy where a mission is terminated and rescue procedure starts immediately if the state of system is worse than a control limit. Based on the developed mission abort policy, mission reliability and system survivability are evaluated to analyze the risk of mission failure and system failure. The optimal mission abort threshold balancing the tradeoff between mission reliability and system survivability is investigated. Furthermore, the joint optimization of mission abort and protective device selection policies is explored by simultaneously optimizing the defensive factor and abort threshold. A numerical example on a hydraulic system is presented to illustrate the applicability of the proposed policies.

Inhibitory G-protein-mediated modulation of slow delayed rectifier potassium channels contributes to increased susceptibility to arrhythmogenesis in aging heart.

BACKGROUND: Slow delayed rectifier potassium current (IKs) is an important component of repolarization reserve during sympathetic nerve excitement. However, little is known about age-related functional changes of IKs and its involvement in age-dependent arrhythmogenesis. OBJECTIVE: The purpose of this study was to investigate age-related alteration of the IKs response to ß-adrenergic receptor (ßAR) activation. METHODS: Dunkin-Hartley guinea pigs were used. Whole-cell patch-clamp recording was used to record K+ currents. Optical mapping of membrane potential was performed in ex vivo heart. RESULTS: There was no difference in IKs density in ventricular cardiomyocytes between young and old guinea pigs. However, in contrast to IKs potentiation in young hearts, isoproterenol (ISO) evoked an acute inhibition on IKs in a concentration-dependent manner in old guinea pig hearts. The ß2AR antagonist, but not ß1AR antagonist, reversed the inhibitory response. Preincubation of cardiomyocytes with the inhibitory G protein (Gi) inhibitor pertussis toxin (PTX) also reversed the inhibitory response. In HEK293 cells cotransfected with cloned IKs channel and ß2AR, ISO enhanced the current but reduced it when cells were cotransfected with Gi2, and PTX restored the ISO-induced excitatory response. Moreover, in aging cardiomyocytes, Gßγ inhibitor gallein, PLC inhibitor U73122, or protein kinase C inhibitor Bis-1 prevented the reduction of IKs by ISO. Furthermore, cardiac-specific Gi2 overexpression in young guinea pigs predisposed the heart to ventricular tachyarrhythmias. PTX pretreatment protected the hearts from ventricular arrhythmias. CONCLUSION: ßAR activation acutely induces an inhibitory IKs response in aging guinea pig hearts through ß2AR-Gi signaling, which contributes to increased susceptibility to arrhythmogenesis in aging hearts.

Cardiac hERG K+ Channel as Safety and Pharmacological Target.

The human ether-á-go-go related gene (hERG, KCNH2) encodes the pore-forming subunit of the potassium channel responsible for a fast component of the cardiac delayed rectifier potassium current (IKr). Outward IKr is an important determinant of cardiac action potential (AP) repolarization and effectively controls the duration of the QT interval in humans. Dysfunction of hERG channel can cause severe ventricular arrhythmias and thus modulators of the channel, including hERG inhibitors and activators, continue to attract intense pharmacological interest. Certain inhibitors of hERG channel prolong the action potential duration (APD) and effective refractory period (ERP) to suppress premature ventricular contraction and are used as class III antiarrhythmic agents. However, a reduction of the hERG/IKr current has been recognized as a predominant mechanism responsible for the drug-induced delayed repolarization known as acquired long QT syndromes (LQTS), which is linked to an increased risk for "torsades de pointes" (TdP) ventricular arrhythmias and sudden cardiac death. Many drugs of different classes and structures have been identified to carry TdP risk. Hence, assessing hERG/IKr blockade of new drug candidates is mandatory in the drug development process according to the regulatory agencies. In contrast, several hERG channel activators have been shown to enhance IKr and shorten the APD and thus might have potential antiarrhythmic effects against pathological LQTS. However, these activators may also be proarrhythmic due to excessive shortening of APD and the ERP.

Age-dependent expression of the vitamin D receptor and the protective effect of vitamin D receptor activation on H2O2-induced apoptosis in rat intervertebral disc cells.

Accumulating evidence shows that genetic polymorphism of the vitamin D receptor (VDR) gene is associated with intervertebral disc degeneration (IDD), implying that VDR may be involved in the pathogenesis of IDD. However, the exact relationship between VDR and IDD remains unknown. The aim of this study was to investigate the age-dependent expression of VDR in rat intervertebral discs and to determine the effect of VDR on oxidative stress-induced cell apoptosis of the annulus fibrosus (AF) and the underlying mechanism. Sprague-Dawley rats were subjected to magnetic resonance imaging (MRI) and CT scans at young (2-3 months), adult (6-7 months), and old (14-15 months) ages. The images revealed age-related degeneration of the lumbar intervertebral discs and endplates. Immunohistochemistry demonstrated positive expression of VDR in the AF. The expression level of VDR in aged rats was significantly reduced compared with that in the young and adult animals and exhibited a negative correlation to IDD severity. Western blot analysis further demonstrated that the amount of VDR protein was significantly decreased in severe degenerative discs. AF cells were also isolated from young rat lumbar discs and subjected to different concentrations of hydrogen peroxide (H2O2) for various amounts of time. The results revealed that H2O2 inhibited the viability of AF cells and induced mitochondrial pathway apoptosis. However, pretreatment of AF cells with 10-7 and 10-8 M 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] effectively increased cell viability, increased mitochondrial membrane potential, decreased the level of reactive oxygen species, increased mitochondrial ATP content, reserved the activity of key enzymes in the oxidative respiratory chain, and thus protected the mitochondria from H2O2-induced damage. Whereas, siRNA knock-down of VDR abolished the protective effects of 1,25(OH)2D3. Moreover, 1,25(OH)2D3 inhibited H2O2-induced autophagy of AF cells through inhibition of the mTOR/p70S6K signal pathway. Our study demonstrated that decreased expression of VDR may play a role in age-related intervertebral disc degeneration in rats and that activation of VDR ameliorates oxidative stress-induced apoptosis in AF cells by preserving mitochondrial functions.

Exploring physicians' extended use of electronic health records (EHRs): A social influence perspective.

BACKGROUND: Once electronic health records (EHRs) have been fully implemented and integrated into the daily work of a healthcare organisation/hospital, there is considerable pressure on management to demonstrate the benefits that these systems can deliver to the organisation. One practical way to maximise the value and highlight the benefits of EHRs is to encourage physicians to increase and extend their use of EHR functions. OBJECTIVE: This study used a social influence theory context to examine the impact of mechanisms of social influence on the intentions of physicians to extend their use of EHRs. METHOD: A survey of physicians (n = 205) in a first-class comprehensive hospital in southern China was conducted approximately 2 years after the hospital's introduction of EHRs. A 16-item questionnaire was developed to measure the impact of four social influence factors (reward, punishment, social image and group norm) on physicians' intentions to extend their use of EHRs. The research model included two additional control variables (perceived usefulness and perceived ease of use) to account for potential covariance among social influence measures. RESULTS: The study's research model showed significant relationships between physicians' responses on two of the social influence measures (rewards and group norm) and their intentions to extend their use of EHRs. Punishment and social image measures did not influence physicians' intentions to increase their use of EHRs. CONCLUSION: These findings have suggested that for healthcare organisations to maximise the benefits of EHRs, the efforts of hospital management should be directed towards rewarding those physicians who increase their use of EHRs; and to promoting and reinforcing the increased usage of EHRs among physicians as a group norm.

One-pot, single-step deracemization of 2-hydroxyacids by tandem biocatalytic oxidation and reduction.

A facile and efficient one-pot, single-step method for deracemizing a broad range of 2-hydroxyacids to (R)-2-hydroxyacids was established by combination of resting cells of an (S)-hydroxyacid dehydrogenase-producing microorganism and an (R)-ketoacid reductase-producing microorganism.