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Background The X-linked inhibitor of apoptosis (XIAP) protein is encoded by the XIAP gene and is critical for multiple cell responses. XIAP plays a role in preventing cell death.We report the clinical features and results of hemizygous mutation of the XIAP gene in a young male died due to Crohn’s disease complicated with Acute Heart Failure.A young male of 16 years of age died due to no available therapy. Case presentation A young male of 16 years of age was initially diagnosed with Crohn's disease based on evidence from endoscopic and histological findings. Although supporting care, anti-infective drugs and biologics were applied consecutively for 11 months, his clinical manifestations and laboratory indices (patient’s condition) were not improved. This was followed by poor a nutritional status and sustained weight loss. Subsequently, acute heart failure ledto exacerbation of the patient’s condition. Therefore, he was diagnosed with wet beriberi according to thiamine deficiency, but standard medical therapy for heart failure and thiamine supplementation did notreverse the adverse outcomes. Finally, comprehensive genetic analysis of peripheral blood-derived DNA revealed a novel hemizygous mutation of the XIAP gene (c.1259_1262 delACAG), which was inherited from his mother. Conclusion The novel XIAP mutation (c.1259_1262 delACAG) was identified in this study. It may be an important cause of Crohn's disease and plays an important role in the progression of heart failure. Additionally,thiamine deficiency triggers avicious cycle.

The spleen, an important tissue for the immune system, acts as a filter for blood within the immune system. Accumulating evidence suggests that the spleen affects a number of brain functions in health and diseases via immune modulation. Systemic inflammation or chronic social defeat stress (CSDS) can cause splenomegaly in rodents. Interestingly, the new antidepressant arketamine could normalize splenomegaly and depression-like behaviors in CSDS-susceptible mice. A recent study strongly supports the direct connection pathway between the brain and spleen, whereby the spleen can regulate the humoral immune defense by the two brain regions, such as corticotropin-related neurons in the paraventricular nucleus (PVN) and the central nucleus of the amygdala (CeA). Furthermore, afferent and efferent vagus nerve signaling may contribute to brain and spleen communication. In this article, we review recent findings of the brain-spleen axis in health and diseases.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a familial inherited cardiomyopathy associated with ventricular arrhythmias. With the development of molecular biology, histology, imaging, and other diagnostic techniques, the diagnosis rate and incidence of ARVC have gradually increased. However, ARVC remains rare in clinical practice. Currently, there is no specific treatment to eliminate arrhythmia. In this case report, we describe a clinical case of radiofrequency ablation in the treatment of ARVC with ventricular tachycardia and discuss the relevant literature.

Purpose: This study was prospectively designed to evaluate the early dynamic organ distribution and tumor detection ability of [68Ga]Ga-P16-093, which was compared with [68Ga]Ga-PSMA-617 in the same group of recurrent prostate cancer patients.Methods: Twenty patients with recurrent prostate cancer were enrolled. In two consecutive days, each patient underwent a 60-min dynamic PET/CT scan after intravenous administration of 148–185 MBq (4–5 mCi) [68Ga]Ga-P16-093 and [68Ga]Ga-PSMA-617, respectively. Following a low-dose CT scan, serial dynamic PET scans were performed from head to proximate thigh at 9 time points (30 sec/bed at 4, 7, 10, 13 and 16 min, 1 min/bed at 20, 30 and 45 min, and 2 min/bed at 60 min). Standardized uptake values were measured for semi-quantitative comparison.Results: [68Ga]Ga-P16-093 PET/CT revealed a significantly higher tumor uptake at 4 min (SUVmax 7.88 ± 5.26 vs. 6.01 ± 3.88, P < 0.001), less blood pool retention at 4 min (SUVmean 5.12 ± 1.16 vs. 6.14 ± 0.98, P < 0.001) and lower bladder accumulation at 60 min (SUVmean 31.33 ± 27.47 vs. 48.74 ± 34.01, P = 0.042) than [68Ga]Ga-PSMA-617 scan. Significantly higher [68Ga]Ga-P16-093 uptakes were also observed in the parotid gland, liver, spleen and kidney. Besides, [68Ga]Ga-P16-093 exhibited a better detection ability than [68Ga]Ga-PSMA-617 (366 vs. 321, P = 0.009).Conclusions: [68Ga]Ga-P16-093 showed advantages over [68Ga]Ga-PSMA-617 with higher tumor uptakes, tumor-to-blood pool ratio and detection ability, less blood pool and bladder accumulation in recurrent prostate cancer patients.Trial registration [68Ga]Ga-P16-093 and [68Ga]Ga-PSMA-617 PET/CT Imaging in the Same Group of Prostate Cancer Patients (NCT04796467, Registered 12 March 2021, retrospectively registered)URL of registry https://clinicaltrials.gov/ct2/show/NCT04796467

Background Thyroid dysfunction is a common adverse event after immune checkpoint inhibitor (ICI) therapy. The clinical manifestations of thyroid immune-related adverse events (irAEs) are variable and the underlying mechanism is unclear. Purpose To identify the clinical and biochemical characteristics of Chinese patients with ICI-related thyroid dysfunction. Methods We retrospectively reviewed patients with carcinoma who received ICI therapy and underwent evaluation of thyroid function during hospitalization at Peking Union Medical College Hospital between January 1, 2017 and December 31, 2020. Clinical and biochemical features were analyzed in patients who developed ICI-related thyroid dysfunction. Survival analyses were performed to determine the effect of thyroid autoantibodies on thyroid abnormalities and the impact of thyroid irAEs on clinical outcomes. Results The cohort included 270 patients with a median follow-up of 17.7 months; 120 (44%) of these patients developed thyroid dysfunction on immunotherapy. The most common thyroid irAE was overt hypothyroidism (with/without transient hyperthyroidism), which occurred in 38% of patients (n = 45), followed by subclinical thyrotoxicosis (n = 42), subclinical hypothyroidism (n = 27), and isolated overt thyrotoxicosis (n = 6). The median time to onset was 49 days (interquartile range 23, 93) for thyrotoxicosis and 98 days (interquartile range 51, 172) for hypothyroidism. In patients treated with PD-1 inhibitors, hypothyroidism was strongly associated with younger age (odds ratio [OR] 0.44, 95% confidence interval [CI] 0.29–0.67; P

This pilot study was prospectively designed to evaluate and compare the diagnostic value of PET/CT using a PSMA-specific tracer [Forty-two pathologically confirmed ccRCC patients were included. Within 1 week, each patient underwent [For primary ccRCC patients, [[

Background Aberrant expression of long noncoding RNAs (lncRNAs) has been found to enroll in the initiation and progression of bladder cancer (BC). Earlier results show cancer-associated region long noncoding RNA-7 (CARLo-7) can be a prognostic marker for BC, but its biological function and the underlying mechanism is still to be discovered. Our study aims to explore the effects of CARLo-7 on the initiation and progression of BC and the potential mechanisms. Methods The expression of CARLo-7 in BC tissues and cell lines was determined by quantitative real-time polymerase chain reaction (qRT-PCR). T24 and HT1197 cells were transfected with CARLo-7 expression vector or sh-CARLo-7, then cell viability assay, BrdU assay, flow cytometry, Transwell cell migration, and invasion assay, and western blot were conducted to evaluate cell proliferation, apoptosis, invasion, migration, and epithelial-mesenchymal transition (EMT). Results CARLo-7 was dramatically upregulated in BC tissues and cell lines. Silencing CARLo-7 by sh-CARLo-7 significantly suppressed proliferation and induced apoptosis of BC cells, while enforced CARLo-7 expression promoted cell proliferation. Meanwhile, silencing CARLo-7 attenuated migration, invasion, and EMT of BC cells, while CARLo-7 overexpression had the contrary effects. The β-catenin, p-JAK2 and p-STAT3 levels were decreased by CARLo-7 knockdown, while activation of Wnt/β-catenin or JAK2/STAT3 pathways abolished the effects of CARLo-7 knockdown on cell proliferation and migration. Conclusions Collectively, CARLo-7 plays a critical role in regulating BC development by regulating cell proliferation, migration, invasion, and EMT through Wnt/β-catenin and JAK2/STAT3 signaling. Therefore, CARLo-7 might be a promising therapeutic target for BC.

This study was designed to assess the safety and therapeutic response to (177)Lu-labeled Evans blue–modified prostate-specific membrane antigen (PSMA) 617 (EB-PSMA-617) treatment with escalating doses in patients with metastatic castration-resistant prostate cancer. Methods: With institutional review board approval and informed consent, patients were randomly divided into 3 groups: group A (n = 10) was treated with a 1.18 ± 0.09 GBq dose of (177)Lu-EB-PSMA. Group B (n = 10) was treated with a 2.12 ± 0.19 GBq dose of (177)Lu-EB-PSMA. Group C (n = 8) was treated with a 3.52 ± 0.58 GBq dose of (177)Lu-EB-PSMA. Eligible patients received up to 3 cycles of (177)Lu-EB-PSMA therapy, at 8-wk intervals. Results: Because of disease progression or bone marrow suppression, 4 of 10, 5 of 10, and 5 of 8 patients completed 3 cycles of therapy as planned in groups A, B, and C, respectively. The prostate-specific antigen response was correlated with treatment dose, and the prostate-specific antigen disease control rates were higher in groups B (70%) and C (75%) than in group A (10%) (P = 0.007), but no correlation between groups B and C was found. (68)Ga-PSMA PET/CT showed a response in all treatment groups; however, there was no significant difference among the 3 groups. A hematologic toxicity study found that platelets decreased more in groups B and C than in group A and that grade 4 thrombocytopenia occurred in 2 (25.0%) patients in group C. No serious nephritic or hepatic side effects were observed. Conclusion: This study demonstrated that a 2.12-GBq dose of (177)Lu-EB-PSMA seems to be safe and adequate in tumor treatment. Further investigations with an increased number of patients are warranted.

Background Maternally expressed gene 3 (MEG3) is a long non-coding RNA (lncRNA) and involved in progression of various human tumors. However, its underlying regulatory mechanism in tumorigenesis of bladder cancer (BC) remains unclear. To demonstrate effects of MEG3 on BC cell proliferation and elaborate its regulatory mechanism in BC. Methods Aberrant expressions of MEG3 and miR-93-5p were induced by cell transfection. The mRNA and protein expression were analyzed using qRT-PCR and western blot. Cell proliferation was examined by CCK-8 assay and EdU staining. The targeted regulation effect of MEG3 on miR-93-5p was confirmed by luciferase reporter assay. The number of LC3 punctated cells was detected by immunofluorescence. Xeno-graft mouse model was constructed for in vivo validation. Results MEG3 was down-regulated with increased expression of miR-93-5p in BC cells and tissues. Luciferase reporter assay showed that miR-93-5p was a direct target of MEG3 and was negatively regulated by MEG3. MEG3 overexpression inhibited cell proliferation and the expression of proliferation-, apoptosis- and autophagy-related proteins. The activation of PI3K/AKT/mTOR pathway was also suppressed with elevated cell apoptosis. miR-93-5p overexpression counteracted these results. In vivo experiments, we confirmed that miR-93-5p overexpression reversed the MEG3 overexpression-mediated suppression on tumor growth and protein expression. Conclusions lncRNA MEG3 could function as a competing endogenous RNA of miR-93 to regulate the tumorigenesis of BC via PI3K/AKT/mTOR pathway. The present research provided a new perspective to understanding the pathogenic mechanism of BC, and an effective therapeutic target for BC.

To study the anti-sliding performance of the two-component epoxy resin thin layer, a combination of accelerated loading test and mechanical test was used to focus on the influence of different aggregate types on its anti-sliding performance. SMA-10 and modified emulsified asphalt micro-surface were selected as a control group, accelerated loading test were carried out, the law of BPN value, TD value, and aggregate wear mass loss rate with wear time were analyzed; and the logarithmic formula was used to make a fitting regression of the attenuation law of anti-sliding performance. Through shear test and pull-out test, the influence of different aggregate types and asphalt on its mechanical properties was analyzed. The test results showed that the anti-sliding performance of the two-component epoxy resin anti-sliding layer was better than that of SMA-10 and the modified emulsified asphalt micro-surface; within 3h after the start of the accelerated loading test, the anti-sliding performance decayed rapidly, and the later decay rate was slow and showed a slow decreasing trend. Besides, the relationship between the TD value and the BPN value with abrasion time had a good correlation with the logarithmic formula. In addition, the shear strength and bonding strength between the anti-sliding thin layer and the asphalt concrete base surface are strong, and the failure surfaces of the specimens all appear inside the asphalt layer.

This study was prospectively designed to evaluate the early dynamic organ distribution and tumor detection capability of [Twenty patients with recurrent prostate cancer were enrolled. In 2 consecutive days, each patient underwent a 60-min dynamic PET/CT scan after intravenous administration of 148-185 MBq (4-5 mCi) [[[[

The surged systemic vascular inflammation after acute myocardial infarction (AMI) aggravates the atherosclerotic endothelial injury. To explore roles of miR‐499 released from cardiomyocytes during AMI in endothelial injury. Using qPCR and ELISA, we discovered that patients with AMI had significantly increased plasma miR‐499, which was directly correlated with serum thrombomodulin, a marker for endothelial injury. Plasma of AMI patients, when incubated with human umbilical vein endothelial cells (HUVECs), significantly increased the expression of endothelial injury markers, which could be abrogated by antagomiR‐499. In vitro, neonatal rat cardiomyocytes subjected to hypoxia/reoxygenation (HX/R) released miR‐499 that could be internalized into rat pulmonary microvascular endothelial cells (RPMECs), worsening the high glucose‐induced injury. In silico analysis demonstrated that CHRNA7 encoding α7‐nAchR is a target of miR‐499, which was validated in cell lines expressing endogenous α7‐nAchR. In high glucose‐induced RPMECs injury model, miR‐499 aggravated, whereas forced CHRNA7 expression ameliorated the injury. Moreover, the perfusate from Langendorff perfused rat heart subjected to HX/R contained higher level of miR‐499 that significantly impaired the Bradykinin‐mediated endothelium‐dependent relaxation in both conduit and resistance arteries, which could be partially abrogated by antagomiR‐499. Finally, the correlation between plasma miR‐499 and endothelial injury was further confirmed in another cohort of AMI patients. We conclude that miR‐499 released from injured cardiomyocytes contributes to the endothelial injury by targeting α7‐nAchR. This study implies that miR‐499 may serve as a potential target for the treatment of the surged vascular inflammation post‐AMI.

AIM: Combined (68)Ga-PSMA-617 positron emission tomography (PET) imaging and (177)Lu-PSMA-617 therapy is a precise targeted theranostic approach for patients with metastatic castration-resistant prostate cancer (mCRPC). The purpose of this study was to determine whether pretherapeutic standard uptake value (SUV) in (68)Ga-PSMA-617 PET could indicate the effective dose in the main organs and absorbed dose in tumor lesions. METHODS: Following institutional review board approval and informed consent, 9 patients with mCRPC were recruited and underwent (68)Ga-PSMA-617 PET/computed tomography (CT) scans. Five patients received (177)Lu-PSMA-617 (1.30–1.42 GBq, 35–38.4 mCi) and then underwent serial whole-body planar imaging and single-photon emission computed tomography/CT (SPECT/CT) imaging of both thoracic and abdominal regions at 0.5, 2, 24, 48, and 72 h time points. The other 4 patients received (177)Lu-EB-PSMA-617 (0.80–1.1 GBq, 21.5–30 mCi) and then underwent the same imaging procedures at 2, 24, 72, 120, and 168 h time points. The effective dose in the main organs and the absorbed dose in tumor lesions were calculated. Detailed correlations between the pretherapeutic SUV in (68)Ga-PSMA-617 PET and effective dose in the main organs, as well as absorbed dose in the tumor lesions were analyzed. RESULTS: SUV of (68)Ga-PSMA-617 PET was moderately correlated with effective dose in main organs (r = 0.610 for (177)Lu-PSMA-617, r = 0.743 for (177)Lu-EB-PSMA-617, both P < 0.001). SUV of tumor lesions in (68)Ga-PSMA-617 PET had high correlation with those in (177)Lu-PSMA-617 (r = 0.915, P < 0.001) and moderate correlation with those in (177)Lu-EB-PSMA-617 (r = 0.611, P = 0.002). CONCLUSIONS: Pretherapeutic (68)Ga-PSMA-617 PET may indicate the dosimetry of (177)Lu-PSMA-617 and (177)Lu-EB-PSMA-617. Both the effective dose in main organs and absorbed dose in tumor lesions correlate with SUV of (68)Ga-PSMA-617 PET. This relationship may help select appropriate candidates for peptide receptor radionuclide therapy (PRRT). Further investigations of larger cohorts are needed to confirm these initial findings.

Aim - To explore the role and possible mechanism of KNTC1 gene in the development of bladder cancer. Methods - The expression level of KNTC1 in bladder cancer tissues and adjacent tissues was detected by immuno-histochemistry. Mann-Whitney U, Spearman, and Kaplan-Meier analyses were used to analyze the correlation between KNTC1 expression level and various characteristics of bladder cancer cases. KNTC1 was knocked down by RNA interference to detect the proliferation, apoptosis, cell cycle, migration, and in vivo tumorigenesis of bladder cancer cells. Human apoptosis antibody array and Western blot were used to detect the expression level changes of related proteins after KNTC1 knockdown to explore the possible mechanism. Results - KNTC1 was highly expressed in bladder cancer tissues and was related to the pathological grade and overall survival rate of bladder cancer. Knockdown of KNTC1 can inhibit the proliferation, migration, and in vivo tumorigenesis of bladder cancer cells and promote apoptosis. KNTC1 knockdown changes the levels of many proteins in bladder cancer cells, including Caspase 3, Fas, p-Akt, CDK6, PIK3CA, and MAPK9. Conclusion - KNTC1 plays a crucial role in the development of bladder cancer, and our findings provide evidence for its use as a therapeutic target.

Objective: The purpose of this study is exploring the influence of physical exercise on the Traditional Chinese Medicine (TCM) constitution of college students and providing evidence for the intervention methods of college students' TCM constitution by the survey of the TCM Constitution and exercise habits of 672 students in the college of Shaanxi province. Methods: All 672 students who are from three grades in the university were investigated by using the Traditional Chinese Medicine Constitution Scale and the self-made questionnaire on exercise habits. Results: Among 672 college students, 203 students were in gentleness type (30.2%), 447 students were in biased types (66.5%).Among 447 biased types of students, 252 cases (37.5%) were in Yang-deficiency constitution, 236 cases (35.1%) were in Yin-deficiency constitution and 224 cases (33.3%) were in Qi-deficiency constitution. The probability of gentleness type of college students with exercise habit is higher than those doing little exercise, and the probability of biased types are lower than that without exercise habit. Among the college students who have the habits of exercising, the students doing aerobic exercises showed a lower level of biased types than those doing strength training or flexibility training. The exercise frequency was negatively correlated with Qi-deficiency constitution, Yang-deficiency constitution, Phlegm-dampness constitution and Qi-stagnation constitution (r=0.041, 0.003, 0.005, 0.024), the exercise time was negatively correlated with Phlegm-dampness constitution (r=0.026), and positively correlated with Special-diathesis constitution (r=0.038), all the differences were statistically significant (P

Myeloid differential protein-2 (MD2) has been shown to play a critical role in the progression of diabetic cardiomyopathy (DCM). This study aims to explore the non-inflammatory mechanisms mediated by MD2 in DCM and to test the therapeutic effects of MD2 inhibitor C30 on DCM. Streptozotocin (STZ) was used to construct DCM model in wild-type and MD2 knockout mice. The collected heart samples were subjected to RNA-sequencing assay. Gene set enrichment analysis of the RNA-seq data indicated that MD2 knockout was associated with energy metabolism pathways in diabetic mouse heart. Further data showed that AMPK pathway was impaired under high glucose condition, which was mediated by p38MAPK activation. MD2 knockout or pharmacological inhibitor C30 completely rescued AMPK signaling through p38MAPK inhibition. Importantly, C30 treatment significantly prevented myocardial damage and dysfunction in T1DM mice evidenced by improved cardiac function and reduced cardiomyocyte apoptosis and cardiac fibrosis. Furthermore, the therapeutic effect of C30 on DCM was correlated to p38MAPK inhibition and AMPK pathway activation in vivo and in vitro. In conclusion, MD2 inhibition exhibits therapeutic effects on DCM through p38MAPK inhibition and AMPK activation, which enables MD2 a promising target for DCM treatment by suppressing metaflammation and improving cardiac metabolism.

Additional file 1.

BACKGROUND This study investigated the effect and the possible mechanism of trimetazidine in atherosclerosis. MATERIAL AND METHODS We established an atherosclerotic rat model by high-fat diet and vitamin D injection. Rats were separated into 3 different groups: control, atherosclerosis, and trimetazidine (n=10). The aortic artery was isolated and its morphological features were examined by hematoxylin and eosin (HE) staining. Serum low-density lipoprotein cholesterol (LDL-c), total cholesterol (TC), and triglycerides (TG) were analyzed using an automatic biochemical analyzer. Human aortic smooth muscle cells (HASMCs) were cultured and divided into 5 groups: no treatment, H₂O₂ treatment only, trimetazidine preincubation before H₂O₂ treatment, oxidized low-density lipoprotein (oxLDL) treatment only, and trimetazidine preincubation before oxLDL treatment. HASMCs proliferation was tested using the Cell Counting Kit-8. Reactive oxygen species (ROS) and malondialdehyde (MDA) levels, superoxide dismutase (SOD) activity of the aortic artery, and HASMCs were measured using commercially available kits. RESULTS HE staining assay showed that trimetazidine suppressed the progression of atherosclerosis and reduced foam cell formation in the aortic artery without affecting serum lipid levels. HASMCs proliferation assay revealed that trimetazidine alleviated the inhibitory effect of H₂O₂ on HASMCs proliferation and inhibited oxLDL-induced proliferation of HASMCs. Moreover, trimetazidine ameliorated ROS up-regulation elicited by H₂O₂ or oxLDL in HASMCs. Additionally, trimetazidine restored SOD activity and reduced MDA content of HASMCs. CONCLUSIONS Trimetazidine suppressed the progression of atherosclerosis by enhancing energy value, decreasing ROS level of aortic artery, modulating HASMCs proliferation, and reducing oxidative stress in HASMCs.

The aim of the study was to perform a meta-analysis to compare the therapeutic effects and adverse events (AEs) of sorafenib in second-line treatments of metastatic renal cell carcinoma (mRCC). We searched online electronic databases: Pubmed, Embase, Cochrane library updated on November 2017.Trials of the effectiveness of sorafenib in second-line treatments of advanced RCC were included, of which the main outcomes were objective response rate (ORR), progression-free survival (PFS), overall survival (OS) and grade 3/4 AE. Other TAs significantly reduced the risk of PFS compared to sorafenib with respect to second-line treatment (HR = 0.74; 95% CI, 0.65–0.83; p

Epidemiological studies have shown a strong correlation between tumor and AF. However, the molecular link between tumor and AF remains unknown. ECRG4, a tumor suppressor gene that is expressed in the A-V node and in sporadic ventricular myocytes, inhibits tumorigenesis and monitors tissue homeostasis by functioning as a ‘sentinel’ molecule gauging inflammatory and cell proliferative responses. To explore the potential physiological function of Ecrg4 in heart, we evaluated its distribution in heart, analyzed its expression in patients with persistent AF and in a canine AF model, and dissected the molecular events downstream of Ecrg4. The results showed that the level of Ecrg4 expression is homogenously high in atria and the conduction systems and in sporadic ventricular myocytes. Importantly, the expression of Ecrg4 was significantly decreased in atrial appendages of AF patients than patients with SR. Moreover, in rapid pacing canine AF models, the expression of ECRG4 in atria was significantly decreased compared to that of the controls. Mechanistically, knockdown ECRG4 in atrial myocytes significantly shortened the APDs, inhibited the expression of Gja1, and activated pro-inflammatory cascades and genes involved in cardiac remodeling. These results suggest that Ecrg4 may play a critical role in the pathogenesis of AF.

Aims: To investigate the effects of ketamine on human hyperpolarization-activated cyclic nucleotide-gated (hHCN) 1, 2, 4 channel currents expressed in Xenopus oocytes and spontaneous action potentials (APs) of rabbit sinoatrial node (SAN). Methods: The 2-electrode voltage clamp and standard microelectrode techniques were respectively applied to record hHCN channels currents expressed in Xenopus oocytes and APs of SAN separated from rabbit heart. Results: Ketamine (1-625 µmol/L) blocked hHCN1, 2, and 4 currents with IC50 of 67.0, 89.1, and 84.0 µmol/L, respectively, in a concentration-dependent manner. The currents were rapidly blocked by ketamine and partially recovered after washout. The steady-state activation curves of hHCN1, 2, and 4 currents demonstrated a concentration-dependent shift to the left and the rates of activation were significantly decelerated. But ketamine blocked hHCN channels in a voltage-independence and non-use-dependent manner, and did not modify the voltage dependence of activation and reversal potentials. Furthermore, ketamine suppressed phase-4 spontaneous depolarization rate in isolated rabbit SAN and decreased the beat rates in a concentration-dependent manner. Conclusion: Ketamine could inhibit hHCN channels expressed in Xenopus oocytes in a concentration-dependent manner as a close-state blocker and decrease beat rates of isolated rabbit SAN. This study may provide novel insights into other unexplained actions of ketamine.

Bladder cancer (BC) is the second leading malignant tumors of the genitourinary system. CA 19-9 has served as a diagnostic and prognostic marker for pancreatic carcinoma for years. In recent year, although a few studies have evaluated the roles of CA 19-9 in BC, the results are conflicting and the number of the patients studied is very small.To investigate the potential of serum CA 19-9 to serve as a diagnostic and prognostic marker of BC in a larger number of patients.A total of 272 (144 BC patients and 128 healthy subjects) were enrolled. Patients were followed-up routinely at 3-month intervals for 5 years. Serum CA 19-9 level was detected by ELISA.CA 19-9 level was much higher than that in healthy subjects (43.69 ± 6.92 U/ml vs. 12.31 ± 4.39 U/ml, p0.001). However, when the value of 37 U/ml of serum CA 19-9 was used as the cut-off value for BC the sensitivity of CA 19-9 for BC was dropped to 38.8%. CA 19-9 was much higher in muscle invasive tumor subgroup than that in superficial tumor subgroup (38.09 ± 7.14 U/ml vs. 20.71 ± 4.15 U/ml, p0.027). CA 19-9 level was comparable in both subgroups (29.78 ± 5.07 U/ml vs. 26.13 ± 5.97 U/ml, p = 0.565). BC patients with more than 5 years survival time had lower serum CA 19-9 level than the rest (15.86 U/ml vs 46.68 U/ml, p0.001). Survival rate (5 years) of patients with lower CA 19-9 levels (29 U/ml) was significantly increased in comparison to those with elevated serum CA 19-9 levels (29 U/ml) (p0.001).serum CA 19-9 is not a good diagnostic maker, but a very powerful prognostic marker for BC. Such a study might be helpful for urologists to manage patients with BC.

Background The incidence of atrial fibrillation (AF) in rheumatic heart diseases (RHD) is very high and increases with age. Occurrence and maintenance of AF are very complicated process accompanied by many different mechanisms. Ion-channel remodeling, including the voltage-gated potassium channel Kv1.5, plays an important role in the pathophysiology of AF. However, the changes of Kv1.5 channel expression in Han Chinese patients with RHD and AF remain poorly understood. The aim of the present study was to investigate whether the Kv1.5 channels of the right atria may be altered with RHD, age, and sex to contribute to AF. Material/Methods Right atrial appendages were obtained from 20 patients with normal cardiac functions who had undergone surgery, and 26 patients with AF. Subjects were picked from 4 groups: adult and aged patients in normal sinus rhythm (SR) and AF. Patients were divided into non-RHD and RHD groups or men and women groups in normal SR and AF, respectively. The expression of Kv1.5 protein and messenger RNA (mRNA) were measured using Western blotting and polymerase chain reaction (PCR) method, respectively. Results Compared with the SR group, the expression of Kv1.5 protein decreased significantly in the AF group. However, neither Kv1.5 protein nor KCNA5 mRNA had significant differences in adult and aged groups, non-RHD and RHD group, and men and women group of AF. Conclusions The expression of Kv1.5 channel protein changes with AF but not with age, RHD, and sex in AF.

This study aims to document the first-in-human application of a 68Ga-labeled heterodimeric peptide BBN-RGD (bombesin-RGD) that targets both integrin αvβ3 and gastrin releasing peptide receptor (GRPR). We evaluated the safety and assessed the clinical diagnosis value of 68Ga- BBN-RGD positron emission tomography (PET)/x-ray computed tomography (CT) in prostate cancer patients in comparison with 68Ga-BBN. Methods: Five healthy volunteers (M 4, F 1, 28–53 y) were enrolled to validate the safety of 68Ga-BBN-RGD. Dosimetry was calculated using the OLINDA/EXM software. A total of 13 patients with prostate cancer (4 newly diagnosed and 9 post-therapy) were enrolled. All the patients underwent PET/CT scans 15–30 min after intravenous injection of 1.85 MBq (0.05 mCi) per kilogram body weight of 68Ga-BBN-RGD, and also accepted 68Ga-BBN PET/CT within 2 weeks for comparison. Results: With a mean injected dose of 107.3 ± 14.8 MBq per patient, no side effect was found during the whole procedure and 2 weeks follow-up, demonstrating the safety of 68Ga-BBN-RGD. A patient would be exposed to a radiation dose of 2.90 mSv with an injected dose of 129.5 MBq (3.5 mCi), which is much lower than the dose limit set by the Food and Drug Administration. In 13 patients with prostate cancer diagnosed by biopsy, 68Ga-BBN-RGD PET/CT detected 3 out of 4 primary tumors, 14 metastatic lymph nodes and 20 bone lesions with maximum standardized uptake values (SUVmax) of 4.46 ± 0.50, 6.26 ± 2.95, and 4.84 ± 1.57, respectively. Only 2/4 primary tumors, 5 lymph nodes and 12 bone lesions were positive on 68Ga-BBN PET/CT with the SUVmax of 2.98 ± 1.24, 4.17 ± 1.89, and 3.61 ± 1.85, respectively. Conclusion: This study indicates the safety and the efficiency of a new type of dual integrin αvβ3 and GRPR targeting PET radiotracer in prostate cancer diagnosis and staging.

The augmentation of late sodium current (IRabbit ventricular myocytes were prepared. The ITol (3-120 nmol/L) concentration-dependently inhibited the normal and Ver-augmented ITol inhibits normal and Ver-augmented I

Two new compounds, (H2en)3(H2enMe)4(H3O){CuI[MoV 6O12(OH)3(HPO4)(PO4)3]2} · 6H2O (1) and (H2enMe)4{CuICuII[MoV 6O12(OH)3(PO4)(HPO4)2(H2PO4)]2} · 3H2O (2), were hydrothermally synthesized and characterized by elemental analysis, IR, TGA, and single-crystal X-ray diffraction analysis. Crystallographic analysis reveals that 1 is constructed from cluster anions {CuI[MoV 6O12(OH)3(HPO4)(PO4)3]2}15−, protonated organic amines, and water molecules. Each cluster is bridged through hydrogen bonds to form a 3-D supermolecular structure. For 2, {CuI[MoV 6O12(OH)3(PO4)(HPO4)2(H2PO4)]2}11− are connected by CuII cations to form an infinite chain. The formation of 1 and 2 reveals that organoamines influence the structures of the crystals.

Ethnopharmacological relevance The root of Aconitum coreanum (Levl.) Raipaics has been extensively used to treat various kinds of disorders including cardiovascular disease in China for a long time. According to recent studies, its antiarrhythmic actions are attributable to the active component, acehytisine. However, the underlying mechanism remains poorly understood. Aim of the study The effects of acehytisine on the spontaneous activity in sinoatrial nodes and the electropharmacological action of this drug on If in pacemaker cells and hHCN4 channels in oocytes were to be investigated. Materials and methods Sinoatrial nodes were cut from rabbit heart, and transmembrane potentials were recorded by standard microelectrode technique. A whole-cell patch clamp technique was employed to record If isolated enzymatically from rabbit sinoatrial node pacemaker cells. Human HCN4 channels were heterologously expressed in Xenopus oocytes and studied using the two-electrode voltage clamp technique. Results Acehytisine decreased the pacemaker rate of firing and slope of diastolic depolarization, modified the action potential configurations and blocked If in rabbit sinoatrial node cells and hHCN4 channels expressed in Xenopus oocytes in a concentration-dependent, voltage-independent and non-use-dependent manner. Its electropharmacological properties were consistent with those of a close-state blocker. Conclusion Our findings are likely to shed light on the clinical application of acehytisine in the treatment of cardiovascular disorders.

The advent of stem cell therapy brings about the hope to restore the loss of cardiac pacemaker cells. However, it is largely unknown whether cardiac stem cells are able to differentiate into pacemaker cells. The purpose of this study was to determine whether the heart of large juvenile mammals contains cardiac stem cells (CSCs), which are suitable as seed cells for restoration of cardiac pacemaker cell. The c-kit(+) CSCs were isolated from one-month-old mongrel dogs. CSCs that we sorted were self-renewing, and they could proliferate by clonal expansion. CSCs could differentiate into cardiac muscle, smooth muscle and endothelial cells at rates of 10.5 ± 4.2%, 13.5 ± 5.1% and 12.9 ± 3.5%, respectively, at week 4, as judged by the expression of respective differentiation markers: cardiac troponin I, smooth muscle actin, and CD31. At week 8, the differentiation rates were further increased to 23.2 ± 3.6%, 25.9 ± 6.6% and 28.3 ± 6.1% (P < 0.05 for each marker). Some of cells derived from CSCs could express cardiac transcription factor GATA-4 after week 2 and express pacing-related genes, including hyperpolarization-activated cyclic nucleotide-gated 2 (HCN2) and HCN4 after week 4. Importantly, a fraction of CSCs demonstrated the presence of inward currents that indicate the expression of inward current channels. In conclusion, c-kit(+) CSCs may differentiate into cardiac muscle cell and sinus node-like cells, suggesting that CSCs would be useful as seed cells in treating sinus bradycardiac disorders or exploring the mechanism of pacemaker activity.

Much evidence indicates that increased persistent sodium current (I(Na.P)) is associated with cellular calcium overload and I(Na.P) is considered to be a potential target for therapeutic intervention in ischaemia and heart failure. By inhibiting type III phosphodiesterase, milrinone increases intracellular cyclic adenosine monophosphate (cAMP), with a positive inotropic effect. However, the effect of milrinone on increased I(Na.P) under pathological conditions remains unknown. Accordingly, we investigated the effect of milrinone on increased I(Na.P) induced by hypoxia or hydrogen dioxide in guinea pig ventricular myocytes. While milrinone (0.01 mM or 0.1mM) or cAMP (0.1 mM) decreased I(Na.P) respectively in control condition, application of 1 microM H-89, a selective cAMP-dependant protein kinase inhibitor, prevented the effect of 0.1mM milrinone in control condition. Milrinone (0.1 mM) reduced the increased I(Na.P) induced by hypoxia. Furthermore, 0.01 mM or 0.1mM milrinone reduced the enhanced I(Na.P) induced by 0.3 mM hydrogen peroxide. In addition, 0.01 mM or 0.1 mM milrinone shortened action potential duration at 90% repolarization (APD(90)). Bath application of 0.3 mM hydrogen dioxide markedly prolonged APD(90), while 2 microM tetrodotoxin (TTX) reversed the prolonged APD(90). In the other two groups, 0.01 mM or 0.1 mM milrinone shortened the prolonged APD(90) induced by 0.3 mM hydrogen peroxide, ultimately 2 microM TTX causing a further decurtation of APD(90). These findings demonstrate that milrinone inhibited I(Na.P) under normal condition, hypoxia or hydrogen dioxide-induced I(Na.P), and the APD(90) prolonged by hydrogen dioxide-induced I(Na.P) in ventricular myocytes, which is associated with the mechanism of milrinone increasing intracellular cAMP.