APC mutations disrupt ß-catenin destruction complex condensates organized by Axin phase separation.

The Wnt/ß-catenin pathway is critical to maintaining cell fate decisions. Recent study showed that liquid-liquid-phase separation (LLPS) of Axin organized the ß-catenin destruction complex condensates in a normal cellular state. Mutations inactivating the APC gene are found in approximately 80% of all human colorectal cancer (CRC). However, the molecular mechanism of the formation of ß-catenin destruction complex condensates organized by Axin phase separation and how APC mutations impact the condensates are still unclear. Here, we report that the ß-catenin destruction complex, which is constructed by Axin, was assembled condensates via a phase separation process in CRC cells. The key role of wild-type APC is to stabilize destruction complex condensates. Surprisingly, truncated APC did not affect the formation of condensates, and GSK 3ß and CK1α were unsuccessfully recruited, preventing ß-catenin phosphorylation and resulting in accumulation in the cytoplasm of CRCs. Besides, we propose that the phase separation ability of Axin participates in the nucleus translocation of ß-catenin and be incorporated and concentrated into transcriptional condensates, affecting the transcriptional activity of Wnt signaling pathway.

StMLP1, as a Kunitz trypsin inhibitor, enhances potato resistance and specifically expresses in vascular bundles during Ralstonia solanacearum infection.

Miraculin-like proteins (MLPs), members of the Kunitz trypsin inhibitor (KTI) family that are present in various plants, have been discovered to have a role in defending plants against pathogens. In this study, we identified a gene StMLP1 in potato that belongs to the KTI family. We found that the expression of StMLP1 gradually increases during Ralstonia solanacearum (R. solanacearum) infection. We characterized the promoter of StMLP1 as an inducible promoter that can be triggered by R. solanacearum and as a tissue-specific promoter with specificity for vascular bundle expression. Our findings demonstrate that StMLP1 exhibits trypsin inhibitor activity, and that its signal peptide is essential for proper localization and function. Overexpression of StMLP1 in potato can enhance the resistance to R. solanacearum. Inhibiting the expression of StMLP1 during infection accelerated the infection by R. solanacearum to a certain extent. In addition, the RNA-seq results of the overexpression-StMLP1 lines indicated that StMLP1 was involved in potato immunity. All these findings in our study reveal that StMLP1 functions as a positive regulator that is induced and specifically expressed in vascular bundles in response to R. solanacearum infection.

Free ISG15 inhibits Pseudorabies virus infection by positively regulating type I IFN signaling.

Interferon-stimulated gene 15 (ISG15) is strongly upregulated during viral infections and exerts pro-viral or antiviral actions. While many viruses combat host antiviral defenses by limiting ISG expression, PRV infection notably increases expression of ISG15. However, studies on the viral strategies to regulate ISG15-mediated antiviral responses are limited. Here, we demonstrate that PRV-induced free ISG15 and conjugated proteins accumulation require viral gene expression. Conjugation inhibition assays showed that ISG15 imposes its antiviral effects via unconjugated (free) ISG15 and restricts the viral release. Knockout of ISG15 in PK15 cells interferes with IFN-ß production by blocking IRF3 activation and promotes PRV replication. Mechanistically, ISG15 facilitates IFNα-mediated antiviral activity against PRV by accelerating the activation and nuclear translocation of STAT1 and STAT2. Furthermore, ISG15 facilitated STAT1/STAT2/IRF9 (ISGF3) formation and ISGF3-induced IFN-stimulated response elements (ISRE) activity for efficient gene transcription by directly interacting with STAT2. Significantly, ISG15 knockout mice displayed enhanced susceptibility to PRV, as evidenced by increased mortality and viral loads, as well as more severe pathology caused by excessive production of the inflammatory cytokines. Our studies establish the importance of free ISG15 in IFNα-induced antiviral immunity and in the control of viral infections.

The relationship between healthy lifestyles and cognitive function in Chinese older adults: the mediating effect of depressive symptoms.

BACKGROUND: Previous studies have proven the positive relationship between healthy lifestyles and cognitive function in older adults. However, the specific impacts and mechanisms require further investigation. Therefore, this study aimed to investigate whether healthy lifestyles and cognitive function were associated with Chinese older adults and whether depressive symptoms mediated their association. METHODS: 8272 valid samples were included using the latest data from the Chinese Longitudinal Healthy Longevity Survey (CLHLS). Pearson's test was applied to investigate the relationship between the key variables. Regression models were employed to examine the mediating effects of healthy lifestyles, using Sobel's test and the bootstrap method to confirm path effects. RESULTS: There was a significant correlation between healthy lifestyles, depressive symptoms, and cognitive function (p < 0.01). Healthy lifestyles directly impact cognitive function (ß = 0.162, p < 0.01). Healthy lifestyles had a significant effect on depressive symptoms (ß=-0.301, p < 0.01), while depressive symptoms have a significant impact on cognitive function (ß=-0.108, p < 0.01). Depressive symptoms partially mediated the effect of healthy lifestyles on cognitive function (ß = 0.032, p < 0.01). The Sobel and bootstrap tests confirmed the robustness of the regression analysis results. CONCLUSION: Depressive symptoms mediate the relationship between healthy lifestyles and cognitive function. Our findings suggest that prevention strategies for cognitive impairment in older adults should focus on healthy lifestyles and mental health.

Study on predictive models for swallowing risk in patients with AECOPD.

BACKGROUND: Dysphagia is considered a complication in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). However, AECOPD may have risk factors for dysphagia. METHODS: Through a cross-sectional study, which included 100 patients with AECOPD. General information, Pulmonary function, COPD assessment test (CAT) and modified Medical Research Council (mMRC) were collected by questionnaire. The questionnaires were administered by uniform-trained investigators using standard and neutral language, and swallowing risk was assessed by using a water swallow test (WST) on the day of patient admission. RESULTS: Among the 100 included patients, 50(50%) were at risk of swallowing. Multivariate analysis using logistic regression analysis showed that age ≥ 74 years old, mMRC ≥ level 2, hospitalization days ≥ 7 days and the use of BIPAP assisted ventilation were important influencing factors for swallowing risk in patients with AECOPD. CONCLUSION: Patients with AECOPD are at risk for dysphagia, assessing age, mMRC, hospitalization days and the use of BIPAP assisted ventilation can be used to screen for swallowing risk, thus contributing to the implementation of early prevention measures.

Advance of echocardiography in cardiac amyloidosis.

Cardiac amyloidosis (CA) occurs when the insoluble fibrils formed by misfolded precursor proteins deposit in cardiac tissues. The early clinical manifestations of CA are not evident, but it is easy to progress to refractory heart failure with an inferior prognosis. Echocardiography is the most commonly adopted non-invasive modality of imaging to visualize cardiac structures and functions, and the preferred modality in the evaluation of patients with cardiac symptoms and suspected CA, which plays a vital role in the diagnosis, prognosis, and long-term management of CA. The present review summarizes the echocardiographic manifestations of CA, new echocardiographic techniques, and the application of multi-parametric echocardiographic models in CA diagnosis.

Protein phosphatase StTOPP6 negatively regulates potato bacterial wilt resistance by modulating MAPK signaling.

Potato (Solanum tuberosum) is an important crop globally and is grown across many regions in China, where it ranks fourth in the list of staple foods. However, its production and quality are severely affected by bacterial wilt caused by Ralstonia solanacearum. In this study, we identified StTOPP6, which belongs to the type one protein phosphatase (TOPP) family, and found that transient knock down of StTOPP6 in potato increased resistance against R. solanacearum. RNA-seq analysis showed that knock down of StTOPP6 activated immune responses, and this defense activation partly depended on the mitogen-activated protein kinase (MAPK) signal pathway. StTOPP6 inhibited the expression of StMAPK3, while overexpression of StMAPK3 enhanced resistance to R. solanacearum, supporting the negative role of StTOPP6 in plant immunity. Consistent with the results of knock down of StTOPP6, overexpressing the phosphatase-dead mutation StTOPP6m also attenuated infection and up-regulated MAPK3, showing that StTOPP6 activity is required for disease. Furthermore, we found that StTOPP6 affected the StMAPK3-mediated downstream defense pathway, eventually suppressing the accumulation of reactive oxygen species (ROS). Consistent with these findings, plants with knock down of StTOPP6, overexpression of StTOPP6m, and overexpression of StMAPK3 all displayed ROS accumulation and enhanced resistance to R. solanacearum. Taken together, the findings of our study demonstrate that StTOPP6 negatively regulates resistance to bacterial wilt by affecting the MAPK3-mediated pathway.

Review of Atom Chips for Absolute Gravity Sensors.

As a powerful tool in scientific research and industrial technologies, the cold atom absolute gravity sensor (CAGS) based on cold atom interferometry has been proven to be the most promising new generation high-precision absolute gravity sensor. However, large size, heavy weight, and high-power consumption are still the main restriction factors of CAGS being applied for practical applications on mobile platforms. Combined with cold atom chips, it is possible to drastically reduce the complexity, weight, and size of CAGS. In this review, we started from the basic theory of atom chips to chart a clear development path to related technologies. Several related technologies including micro-magnetic traps, micro magneto-optical traps, material selection, fabrication, and packaging methods have been discussed. This review gives an overview of the current developments in a variety of cold atom chips, and some actual CAGS systems based on atom chips are also discussed. We summarize by listing some of the challenges and possible directions for further development in this area.

A transgene-encoded truncated human epidermal growth factor receptor for depletion of anti- B-cell maturation antigen CAR-T cells.

BACKGROUND: Chimeric antigen receptor T cells (CAR-T) against B-cell maturation antigen (BCMA) has been used to treat multiple myeloma (MM). CAR-T cells co-expressing a truncated human EGFR (tEGFR) has been proposed for in vivo cell ablation. METHODS: We designed and tested a novel anti-BCMA CAR. We transduced T cells with retroviral vectors encoding CAR and tEGFR. The anti-BCMA-CAR-transduced T cells were evaluated for the functions including cytokine production, proliferation, cytotoxicity, and in vivo tumor eradication of BCMA. Cetuximab was used for in vivo cell ablation. RESULTS: The CAR-T cells could specifically recognize BCMA, and anti-BCMA CAR-T cells could exhibit interferon-γ and cytotoxicity specifically produced by BCMA and eradicate tumor in vivo. Cetuximab could mediate antibody-dependent cellular cytotoxicity and in vivo elimination. CONCLUSIONS: We confirm that BCMA is a suitable target for CAR- T cells and tEGFR is a effective tool for cellular ablation.

Diallyl thiosulfinate enhanced the anti-cancer activity of dexamethasone in the side population cells of multiple myeloma by promoting miR-127-3p and deactivating the PI3K/AKT signaling pathway.

BACKGROUND: Side population (SP) cells, which have similar features to those of cancer stem cells, show resistance to dexamethasone (Dex) treatment. Thus, new drugs that can be used in combination with Dex to reduce the population of SP cells in multiple myeloma (MM) are required. Diallyl thiosulfinate (DATS, allicin), a natural organosulfur compound derived from garlic, has been shown to inhibit the proliferation of SP cells in MM cell lines. Therefore, we investigated the effect of a combination of DATS and Dex (DAT + Dex) on MM SP cells. METHODS: SP cells were sorted from MM RPMI-8226 and NCI-H929 cell lines using Hoechst 33342-labeled fluorescence-activated cell sorting. The growth of SP cells was evaluated using the cell counting kit-8 assay. Cell cycle and apoptosis assays were conducted using a BD Calibur flow cytometer. miRNA expression was measured using quantitative reverse transcription-polymerase chain reaction. Phosphoinositide 3-kinase (PI3K), phosphorylated AKT (p-AKT), AKT, p-mechanistic target of rapamycin (mTOR), and mTOR levels were measured using western blot analysis. RESULTS: Our results showed that the combination of DATS+Dex inhibited sphere formation, colony formation, and proliferation of MM SP cells by inducing apoptosis and cell cycle arrest in the G1/S phase. In addition, the combination of DATS+Dex promoted miR-127-3p expression and inhibited PI3K, p-AKT, and p-mTOR expression in SP cells. Knockdown of miR-127-3p expression weakened the effect of DATS+Dex on cell proliferation, colony formation, apoptosis, and cell cycle of MM SP cells. Additionally, knockdown of miR-127-3p activated the PI3K/AKT/mTOR signaling pathway in MM SP cells cotreated with DATS+Dex. CONCLUSION: We demonstrated that cotreatment with DATS+Dex reduced cell proliferation, promoted apoptosis, and caused cell cycle arrest of MM SP cells by promoting miR-127-3p expression and deactivating the PI3K/AKT/mTOR signaling pathway.

Transcriptome analysis of genes related to gonad differentiation and development in Muscovy ducks.

BACKGROUND: Sex-related genes play a crucial role in gonadal differentiation into testes or ovaries. However, the genetic control of gonadal differentiation in Muscovy ducks remains unknown. Therefore, the objective of our study was to screen new candidate genes associated with ovarian and testicular development. RESULTS: In this study, 24 males before gonadal differentiation (MB), 24 females before gonadal differentiation (FB), 24 males after gonadal differentiation (MA) and 24 females after gonadal differentiation (FA) were selected from Putian Muscovy ducks, forming 4 groups. RNA-Seq revealed 101.76 Gb of clean reads and 2800 differentially expressed genes (DEGs), including 46 in MB vs FB, 609 in MA vs FA, 1027 in FA vs FB, and 1118 in MA vs MB. A total of 146 signalling pathways were enriched by KEGG analysis, among which 20, 108, 108 and 116 signalling pathways were obtained in MB vs FB, MA vs MB, MA vs FA and FA vs FB, respectively. In further GO and KEGG analyses, a total of 21 candidate genes related to gonad differentiation and development in Muscovy ducks were screened. Among these, 9 genes were involved in the differentiation and development of the testes, and 12 genes were involved in the differentiation and development of the ovaries. In addition, RNA-Seq data revealed 2744 novel genes. CONCLUSIONS: RNA-Seq data revealed 21 genes related to gonadal differentiation and development in Muscovy ducks. We further identified 12 genes, namely, WNT5B, HTRA3, RSPO3, BMP3, HNRNPK, NIPBL, CREB3L4, DKK3, UBE2R2, UBPL3KCMF1, ANXA2, and OSR1, involved in the differentiation and development of ovaries. Moreover, 9 genes, namely, TTN, ATP5A1, DMRT1, DMRT3, AMH, MAP3K1, PIK3R1, AGT and ADAMTSL1, were related to the differentiation and development of testes. Moreover, after gonadal differentiation, DMRT3, AMH, PIK3R1, ADAMTSL1, AGT and TTN were specifically highly expressed in males. WNT5B, ANXA2 and OSR1 were specifically highly expressed in females. These results provide valuable information for studies on the sex control of Muscovy ducks and reveal novel candidate genes for the differentiation and development of testes and ovaries.

Effect of antidepressants on death in patients with heart failure: a systematic review and meta-analysis.

Depression is associated with an increased risk of death in patients with heart failure (HF); however, the association between the use of antidepressants and HF prognoses remains controversial. Therefore, this meta-analysis aimed to evaluate the effect of antidepressants on the risk of death in HF patients. We retrieved data from the PubMed and EMBASE databases until August 2019 for studies reporting the use of antidepressants in HF patients. Data were extracted from the eligible articles, and a random effects model was used to pool the effect estimates (risk ratios (RRs) and 95% confidence intervals (CIs)). A total of 8 studies were included in this meta-analysis. Overall, the use of antidepressants was associated with increased risks of all-cause death (RR = 1.27; 95% CI, 1.21-1.34) and cardiovascular death (RR = 1.14; 95% CI, 1.08-1.20) in HF patients with or without depression. Specifically, HF patients with depression taking antidepressants had increased risks of all-cause death (RR = 1.21; 95% CI, 1.16-1.27) and cardiovascular death (RR = 1.21; 95% CI, 1.13-1.30). Compared with nonusers, the use of selective serotonin reuptake inhibitors (SSRIs), tricyclics (TCAs), and selective serotonin reuptake inhibitors (SNRIs) significantly increased the rate of all-cause death (SSRIs (RR = 1.26; 95% CI, 1.19-1.32), TCAs (RR = 1.30; 95% CI, 1.16-1.46), and SNRIs (RR = 1.17; 95% CI, 1.08-1.26)) but not cardiovascular death (SSRIs (RR = 1.03; 95% CI, 0.84-1.26), TCAs (RR = 1.02; 95% CI, 0.86-1.21), and SNRIs (RR = 0.92; 95% CI, 0.48-1.78)). Based on current publications, the use of antidepressants could increase the risk of all-cause death in HF patients, regardless of whether they have depression or the type of antidepressants they use. Further study is needed to determine the relationship between antidepressant use and cardiovascular death.

Non-vitamin K antagonist oral anticoagulants in patients with hypertrophic cardiomyopathy and atrial fibrillation: a systematic review and meta-analysis.

Several studies have explored the use of NOACs compared with vitamin K antagonists (VKAs) in patients with hypertrophic cardiomyopathy (HCM) and atrial fibrillation (AF); and therefore, we aimed to compare the efficacy and safety outcomes of NOACs with VKAs in this population. We systematically searched the PubMed and Embase databases until August 5, 2019 for studies that compared the effect of NOACs with VKAs in patients with HCM and AF. The risk ratios (RRs) with 95% confidence intervals (CIs) were pooled using a random-effects model. A total of four observational studies were included in this meta-analysis. Overall, compared with VKAs use, the use of NOACs was associated with reduced risks of ischemic stroke (RR 0.49, 95% CI 0.34-0.69), all-cause death (RR 0.44, 95% CI 0.35-0.55), and intracranial hemorrhage (RR 0.43, 95% CI 0.24-0.77). There were no differences in the risks of stroke or systemic embolism, major or clinically relevant bleeding, and gastrointestinal bleeding in patients with NOACs versus VKAs. Re-analyses with a fixed-effects model produced the similar results as the main analyses. For the efficacy and safety outcomes, comparisons of NOACs versus warfarin produced the similar results as those of NOACs versus VKAs. Based on current data from observational studies, compared with VKAs, NOACs had similar or lower risks of thromboembolic and bleeding events in patients with HCM and AF.

Ankyrin-B Q1283H Variant Linked to Arrhythmias Via Loss of Local Protein Phosphatase 2A Activity Causes Ryanodine Receptor Hyperphosphorylation.

BACKGROUND: Human loss-of-function variants of ANK2 (ankyrin-B) are linked to arrhythmias and sudden cardiac death. However, their in vivo effects and specific arrhythmogenic pathways have not been fully elucidated. METHODS: We identified new ANK2 variants in 25 unrelated Han Chinese probands with ventricular tachycardia by whole-exome sequencing. The potential pathogenic variants were validated by Sanger sequencing. We performed functional and mechanistic experiments in ankyrin-B knockin (KI) mouse models and in single myocytes isolated from KI hearts. RESULTS: We detected a rare, heterozygous ANK2 variant (p.Q1283H) in a proband with recurrent ventricular tachycardia. This variant was localized to the ZU5C region of ANK2, where no variants have been previously reported. KI mice harboring the p.Q1283H variant exhibited an increased predisposition to ventricular arrhythmias after catecholaminergic stress in the absence of cardiac structural abnormalities. Functional studies illustrated an increased frequency of delayed afterdepolarizations and Ca2+ waves and sparks accompanied by decreased sarcoplasmic reticulum Ca2+ content in KI cardiomyocytes on isoproterenol stimulation. The immunoblotting results showed increased levels of phosphorylated ryanodine receptor Ser2814 in the KI hearts, which was further amplified on isoproterenol stimulation. Coimmunoprecipitation experiments demonstrated dissociation of protein phosphatase 2A from ryanodine receptor in the KI hearts, which was accompanied by a decreased binding of ankyrin-B to protein phosphatase 2A regulatory subunit B56α. Finally, the administration of metoprolol or flecainide decreased the incidence of stress-induced ventricular arrhythmias in the KI mice. CONCLUSIONS: ANK2 p.Q1283H is a disease-associated variant that confers susceptibility to stress-induced arrhythmias, which may be prevented by the administration of metoprolol or flecainide. This variant is associated with the loss of protein phosphatase 2A activity, increased phosphorylation of ryanodine receptor, exaggerated delayed afterdepolarization-mediated trigger activity, and arrhythmogenesis.

[Genetic analysis of a case with atypical neonatal Cri-du-chat syndrome].

OBJECTIVE To analyze the clinical features and genetic mutations in a neonate with atypical Cri-du-chat syndrome, whom only featured with weak cry but had no dysmorphic facial features and congenital heart disease. METHODS G-banding karyotyping was performed on the child and her parents. The result was validated by fluorescence in situ hybridization (FISH). Chromosome microarray (CMA) was used to further delineate the mutation. RESULTS G-banding analysis suggested that the child had a karyotype of 46,XX,del(5)(p14p15), while both of his parents had a normal karyotype. FISH confirmed the absence of D5S23 and D5S721 at 5p15.2. A 25.7 Mb deletion was detected in the 5p15.33p14.1 region by CMA. CONCLUSION The phenotype of Cri-du-chat syndrome can vary significantly among patients, particularly in neonates, and can be easily mis-diagnosed. Combined cytogenetic and molecular analysis can identify the missing fragments with greater precision.

Analysis of clinical effects of neoadjuvant chemotherapy in advanced epithelial ovarian cancer.

PURPOSE: To investigate the role and significance of neoadjuvant chemotherapy in advanced ovarian cancer. METHODS: 128 patients clinically diagnosed with stage IIC-IV advanced epithelial ovarian cancer (EOC) were randomized into neoadjuvant chemotherapy (NACT) combined with interval cytoreductive surgery (ICS) group (n=66) and primary cytoreductive surgery (PCS) group (n=62). Chemotherapy in the PCS group was administered after cytoreductive surgery. RESULTS: Age, body mass index, clinical symptoms, clinical staging, histopathological grading and histopathological type had no differences between PCS and ICS groups (p>0.05). In NACT-ICS group, the mean operation time was shorter, the bleeding was less, the rate of optimal debulking surgery was higher and the total effective rate of clinical remission was higher, compared with those in PCS group (p<0.05). No significant differences were found in the survival rate, progression-free survival (PFS) and overall survival (OS) between the two groups. CONCLUSIONS: In comparison to PCS, NACT-ICS can improve the intraoperative conditions, increase the cytoreductive rate, reduce the bleeding of operation, reduce the operation time and increase the clinical remission rate, but it has no impact on PFS and OS.

Association Between C1q/TNF-Related Protein-1 Levels in Human Plasma and Epicardial Adipose Tissues and Congestive Heart Failure.

BACKGROUND/AIMS: C1q and tumour necrosis factor-related protein 1 (CTRP1) possesses anti-atherogenic and anti-inflammatory effects. This study investigated whether the CTRP1 levels in the plasma and epicardial adipose tissue (EAT) were associated with congestive heart failure (CHF) and to disclose possible molecular mechanisms. METHODS: Plasma and tissue samples were obtained from subjects with or without CHF. Plasma levels of CTRP1 were measured by ELISA. The mRNA levels of CTRP1 and inflammatory cytokines were detected by RT-PCR. The protein levels of CTRP1, aldosterone synthase (CYP11B2) and mitogen-activated protein kinase were examined by Western blotting. RESULTS: The levels of CTRP1 in the plasma and EAT were higher in the CHF patients than those in the controls. There were no differences in the CTRP1 levels in cardiomyocytes between the CHF group and the non-CHF group. An exploratory survival analysis showed that higher CTRP1 values at admission were associated with a worse prognosis after discharge. CTRP1 increased the IL-6 mRNA level in H295R cells. CTRP1 recruited ERK1/2 and Jak-2 for aldosterone release by modulating the CYP11B2 protein level, and brain natriuretic peptide repressed the CTRP1-induced aldosterone release through the JAK2-STAT3 signalling pathways. CONCLUSION: The CTRP1 levels in the plasma and EAT were increased in the CHF patients. CTRP1 is involved in the pathogenesis of CHF by modulating IL-6 levels and aldosterone release.

Phenotype and Functional Analyses in a Transgenic Mouse Model of Left Ventricular Noncompaction Caused by a DTNA Mutation.

DTNA encoding dystrobrevin-α (α-DB) is a putative causal gene associated with left ventricular noncompaction cardiomyopathy (LVNC). The aim of the study was to investigate the causal role of DTNA in LVNC using a transgenic mouse model.A missense mutation (c.146A > G, p.N49S) of DTNA was identified in a patient with LVNC by Sanger sequencing. Six independent lines of transgenic mice expressing the mutant DTNA under a myosin heavy chain 6 (Myh6) promoter were generated (Myh6:DtnaN49S). Phenotypic characteristics of DTNA-p.N49S mutations were evaluated by echocardiography, histological observation, and immunoblotting. Multiple trabeculation and a higher ratio of non-compacted to compact myocardial layer were found in the Myh6:DtnaN49S mice compared to the controls. The transgenic mice also showed left ventricular (LV) dilation and cardiac systolic dysfunction. In conclusion, overexpression of the DTNA-p.N49S mutation in a mouse heart can be responsible for the phenotype of deep trabeculation, dilated cardiomyopathy, and cardiac dysfunction, which resembles the phenotype of LVNC.

Genotype-based clinical manifestation and treatment of Chinese long QT syndrome patients with KCNQ1 mutations - R380S and W305L.

UNLABELLED: Aim Most long QT syndrome patients are associated with genetic mutations. We aimed to investigate the clinical and biochemical characteristics and look for genotype-based preventive implications in Chinese long QT syndrome patients. Methods and results We identified two missense mutations of the KCNQ1 gene in two independent Chinese families, including a previously reported mutation R380S in the C-terminus and a novel mutation W305L in the P-loop domain of the Kv7.1 channel, respectively. The proband with R380S was an 11-year-old girl who suffered a prolonged corrected QT interval of 660 ms, recurrent syncope, and sudden cardiac death, whose father was an asymptomatic carrier. The mutation W305L was detected in a 36-year-old woman with long QT syndrome and her immediate family members including the proband's younger sister with an unexplained syncope, her son, and her elder daughter without symptoms. Metoprolol appeared to be effective in preventing arrhythmias and syncope in long QT syndrome patients with mutation W305L. Both R380S and W305L mutations led to "loss-of-function" of the Kv7.1 channel accounting for the clinical phenotypes. CONCLUSIONS: We first show two missense KCNQ1 mutations - R380S and W305L - in Chinese long QT syndrome patients, resulting in the loss of protein function. Mutation W305L in the P-loop domain of the Kv7.1 may derive a pronounced benefit from ß-blocker therapy in symptomatic long QT syndrome patients, whereas mutation R380S located in the C-terminus may be associated with a high risk of sudden cardiac death.

[Combination of Jianpi Liqi Yiliu Formula with Cytokine-induced Killer Cell Treatment for Advanced Hepatocellular Carcinoma].

OBJECTIVE: To evaluate the clinical efficacy of Jianpi Liqi Yiliu Formula (JLYF) combined with cytokine-induced killer (CIK) cells for treating patients with advanced hepatocellular carcinoma (HCC). METHODS: Between January 2011 and January 2014, 60 advanced HCC patients were enrolled in this study, who were assigned to the treatment group and the control group according to their willingness for taking JLYF, 30 cases in each group. All patients received CIK cell treatment: 1 x 109-3 x 109 each time, by intravenous dripping from the 1st day to the 3rd day, once per day. Besides, patients in the treatment group took JLYF decoction, while those in the control group took Chinese medical decoction by syndrome typing. All patients received treatment of at least two cycles. The time to progression (TTP) , overall survival (OS), disease control rate (DCR), performance status scale (PS), Child-Pugh scale, and adverse reactions were observed, and subgroup analyzed. RESULTS: To May 31, 2014, all patients reached the clinical endpoint. TTP was 3.5 months (95% Cl: 3.30-4.10) in the treatment group, better than that (2.5 months, 95% CI: 2.32-2.68) of the control group (P < 0.05). DCR was 36.7% in the treatment group and 30.0% in the control group (P > 0.05). OS was 5.2 months (95% CI: 4.53-5.87) in the treatment group and 4.6 months (95% CI: 4.06-5.14) in the control group (P > 0.05). The PS scale was 1.60 ± 0.10 after treatment, lower than that (1.80 ± 0.09) before treatment in the treatment group (P < 0.05). When the PS scale was 0-2 or Child-Pugh scale was class A, TTP was longer in the treatment group than in the control group (P < 0.05). No adverse reaction occurred in the two groups during the treatment course. CONCLUSIONS: The combination of JLYF with ClK cell treatment could prolong advanced HCC patients' TTP, improve PS scale, as compared with syndrome typed Chinese medical decoction treatment group. Besides, when the PS scale was 0-2 or Child-Pugh scale was class A, it was a better treatment program for advanced HCC patients.