Widespread association of the Argonaute protein AGO2 with meiotic chromatin suggests a distinct nuclear function in mammalian male reproduction.

Argonaute 2 (AGO2) is a ubiquitously expressed protein critical for regulation of mRNA translation and vital to animal development. AGO2 protein is found in both cytoplasmic and nuclear compartments, and although its cytoplasmic role is well studied, the biological relevance of nuclear AGO2 is unclear. Here, we address this problem in vivo using spermatogenic cells as a model. We find that AGO2 transiently binds both chromatin and nucleus-specific mRNA transcripts of hundreds of genes required for sperm production during male meiosis in mice, and that germline conditional knockout (cKO) of Ago2 causes depletion of the encoded proteins. Correspondingly, Ago2 cKO males show abnormal sperm head morphology and reduced sperm count, along with reduced postnatal viability of offspring. Together, our data reveal an unexpected nuclear role for AGO2 in enhancing expression of developmentally important genes during mammalian male reproduction.

Clinical Characteristics and Diagnosis of Ph-Positive Mixed Phenotype Acute Leukemia.

BACKGROUND: The goal was to improve the clinical cognition of Ph-positive mixed phenotype acute leukemia and avoid misdiagnosis or delayed diagnosis. METHODS: The clinical manifestations and laboratory results (bone marrow cell morphology, multiparameter flow cytometry, and cytogenetics) of a case of Ph-positive mixed phenotype acute leukemia were analyzed, and related literature was reviewed. RESULTS: Blood routine: WBC 386.35 x 109/L, HGB 117.00 g/L, PLT 31 x 109/L; 80% of the original cells can be seen by artificial classification. Morphological examination of bone marrow cells showed that the proliferation of nucleated cells was obviously active, and the original cells accounted for 76%. The size of the original cells was somewhat uniform, most of the cells had less mass, were stained light grayish blue, the cytoplasm particles were not obvious, the nuclei were mostly round or quasi-round, some of them showed distortion and nuclear notch, and the chromatin was coarse. Some of the cells were rich in mass, small azurin granules were seen, the nuclei were regular, most of them were round, the chromatin was fine, the myeloperoxidase and esterase staining were negative, the eosinophils accounted for 2.5%, and the basophils accounted for 0.5%. Flow cytometry immunotyping: Two groups of abnormal cells were seen in the bone marrow. 1. A group included 12.32% of nuclear cells and showed abnormal myeloid primitive cell phenotype. Main expression: CD117, CD34, CD38, HLA-DR, CD33, CD64, CD123, weak expression: CD13, CD19. 2. The other group included 45.61% of the nuclear cells and had a B-lymphoblastic phenotype. Main expression: CD34, CD38, HLA-DR, CD123, CD19, CD10, CD9, cCD79a, TDT, weak expression of CD13, CD22. Mixed phenotype acute leukemia (M/B) immunophenotype was considered. Chromosome: 46,XY,t(9; 22)(q34;q11.2) [20]. BCR-ABL (P210) fusion gene was positive. CONCLUSIONS: Mixed phenotype acute leukemia (MPAL) is a rare type of malignant hematologic disease. Its diagnosis is based on the comprehensive evaluation of bone marrow cell morphology, immunophenotype, molecular and cytogenetic features.

Drug Analysis of Voriconazole Combined with Granulocyte Colony Stimulating Factor.

BACKGROUND: The aim of the study was to improve the clinical cognition of leukemia-like reaction caused by voriconazole and granulocyte colony-stimulating factor and to avoid misdiagnosis or delayed diagnosis. METHODS: A case of drug analysis of Voriconazole combined with granulocyte colony stimulating factor was retrospectively analyzed and related literature was reviewed. RESULTS: Blood routine of the patient on July 29: WBC 13.48 x 109/L, neutrophil 85.3%, lymphocyte 13.4%, hemoglobin 111 g/L, platelet 285 x 109/L. Vancomycin was given to prevent intracranial infection. Lumbar puncture was performed on July 30, cerebrospinal fluid was sent for routine and biochemical examination, leukocytes were 0.15 x 109/L, monocytes 45%, polynuclear cells 55%, protein 1.172 g/L, Acinetobacter baumannii and Candida clorbicus were detected in sputum culture, vancomycin and meropenem static sites were given to prevent intracranial secondary infection. Fungi were detected in urine culture, and voriconazole was given to prevent fungal infection. Blood routine: White blood cell 0.61 x 109/L, neutrophil 23%, lymphocyte 73.8%, red blood cell 2.65 x 1012/L, hemoglobin 77 g/L, platelet 17 x 109/L, bone marrow was extracted after medication. Bone marrow images show poor myelodysplasia, with granulocytes dominated by protoearly cells. Subsequent flow cytometry, chromosomal karyotype, and fusion gene analysis were performed to exclude the possibility of leukemia. Flow cytometry showed that the proportion of myeloid primordial cells was not high, the granulocytes were mainly at the early and young stage, no abnormal phenotype was observed in erythrocytes, monocytes and NK cells, no obvious mature B lymphocytes were observed, and the ratio of CD4+/CD8+ was decreased. Karyotype results showed that there was no mitotic phase. The results of fusion gene analysis showed that the fusion gene was negative or lower than the detection sensitivity. Voliconazole was stopped first, and granulocyte colony stimulating factor was stopped 3 days later. Two weeks later, blood and bone marrow images basically recovered, white blood cell 7.88 x 109/L, neutrophil 46.3%, lymphocyte 48.2%, hemoglobin 126 g/L, platelet 142 x 109/L, bone marrow hyperplasia active. The proportion of three series is roughly normal. CONCLUSIONS: The reason for the occurrence of leukemia-like reaction in this patient was considered to be related to voriconazole and granulocyte colony stimulating factor, cessation of voriconazole and granulocyte colony stimulating factor, and recovery of blood and bone marrow images. In the clinical use of voriconazole and granulocyte colony stimulating factor, close attention should be paid to the drug interaction and individualized medication should be carried out to ensure the safety of medication.

A Case Report of Mixed Phenotype Acute Leukemia with Plasmacytoid Dendritic Cell Proliferation.

BACKGROUND: The goal was to improve the understanding of mixed phenotypic acute leukemia (MPAL) complicated with plasmacytoid dendritic cell (PDC) proliferation. METHODS: A case of mixed phenotype acute leukemia with plasmacytoid dendritic cell hyperplasia was reported. The clinical characteristics, treatment, and prognosis were analyzed by reviewing relevant literature. RESULTS: The patient was a young female with clinical manifestations of splenomegaly and lymph node enlargement. The bone marrow smear showed hyperactive proliferation, 95% of protoblastic cells. The protoblastic cell body is large, more cell mass, stained gray blue, a small amount of azurophilicgranule can be seen in some cytoplasm, pseudopodia, drag tail, and other phenomena. The nucleus was twisted and folded. Chromatin is fine with nucleoli and Auer rods seen in the cytoplasm. Immune typing: Abnormal primordial cells accounted for 44.75%, and the primordial cells expressed both myeloid markers (CD33, CD13, MPO) and T-series markers (CD7, CD5, Ccd3), which were considered MPAL (M/T) according to WHO diagnostic criteria. In addition, a group of plasmoid dendritic cells occupied an increased proportion of 10.31% of nuclear cells. No obvious phenotypic abnormalities were observed. BCR/ABL fusion genes P190/P210 were negative. NRAS, NOTCH1, and DNMT3A mutations were detected by polymerase chain reaction. Combined with the above results, acute mixed cell leukemia (M/T) with plasmacytoid dendritic cell proliferation was diagnosed. CONCLUSIONS: The diagnosis of mixed phenotype acute leukemia with plasmacytoid dendritic cell proliferation needs to be integrated with clinical manifestations, cytomorphology, immunology, cytogenetics, and molecular biology, etc. Disease should be diagnosed and treated as early as possible.

A Case of AML1/ETO Positive Child with Acute Myeloid Leukemia with Poor Prognosis.

BACKGROUND: The aim was to improve the understanding of an AML1/ETO positive child with acute myeloid leukemia with poor prognosis. METHODS: A case of AML1/ETO positive child with acute myeloid leukemia with poor prognosis was reported. The bone marrow cell morphology, multi-parameter flow cytometry, cytogenetic or molecular genetic test results were analyzed by reviewing relevant literature. RESULTS: The patient was a young girl with clinical manifestations of respiratory tract infection. Bone marrow smears showed that myeloid primordial cells accounted for 13%, some granulocyte cell bodies are enlarged, visible pathological phenomena such as cytoplasmic vacuoles, binuclear grains, ring rods, and pseudo pelgerhuet malformations were seen (Figure 1). Flow cytometry: abnormal myeloid original cells (12.33%), expression of CD34 and HLA - DR, CD38, CD56, part of the expression of CD117, weak expression of CD13, CD33, MPO, CD19, cCD79a (Figure 2). Chromosome karyotype analysis showed that the chromosome karyotype of peripheral blood was 46, XX, t(8;21)(q22;q22). The quantitative detection result of AML1/ETO fusion gene was 42.15%, and mutations of NRAS, ASXL2, TP53 and TET2 genes were detected by second-generation sequencing. Combined with the above results, AML1/ETO positive with acute myeloid leukemia was diagnosed. CONCLUSIONS: Cytogenetics or molecular genetics is the gold standard for identification of positive AML1/ETO fusion gene. Morphological heterogeneity of AML1/ETO positive AML cells is large, which limits the morphological diagnosis of bone marrow cells to a certain extent, and the comprehensive diagnostic efficiency is significantly better than that of morphology. Leukemia fusion gene AML1/ETO refers to the fusion of AML1 gene located on human chromosome 21q22 and ETO gene 8q22, which is the most common fusion gene in acute myeloid leukemia (AML). This paper reports a case of an AML1/ETO positive child with acute myeloid leukemia with poor prognosis admitted to our hospital and reviews relevant literature.

General practitioners' attitudes towards and frequency of collaboration with pharmacists in China: a cross-sectional study.

BACKGROUND: Building interprofessional working relationships between general practitioners (GPs) and pharmacists is essential to ensure high-quality patient care. However, there is limited Chinese literature on GP-pharmacist collaboration, and few studies have explored GPs' experiences with pharmacist integration into general practices. This study aimed to investigate GPs' attitudes towards and frequency of collaboration with pharmacists in China. METHODS: This cross-sectional study used an online self-administered questionnaire integrating two scales, ATCI-GP and FICI-GP, which had been translated and validated to investigate 3,248 GPs from February 15 to March 15, 2023 across Zhejiang Province, China. Descriptive analyses were used, and the factors associated with GPs' frequency of collaboration with pharmacists were explored using logistic regression analysis. RESULTS: A total of 2,487 GPs (76.6%) responded and consented to participate in the survey; 52.3% were male and the mean age was 35.4 years. Most GPs agreed that they shared common goals and objectives with pharmacists when caring for patients (90.0%), and pharmacists were open to working with them on patients' medication management (80.8%). However, half of the GPs did not change or seldom changed the patient's medication on the pharmacist's advice (51.4%). Logistic regression analysis showed that GPs who were older and had more years of practice were more likely to agree that pharmacists were willing to collaborate, had common goals for treatment and that they would change the patient's medication on the advice of the pharmacist. GPs who had regular communication protocols (adjusted odds ratio1 [aOR1] = 1.88, 95% CI 1.45-2.45; aOR2 = 3.33, 95% CI 2.76-4.02), participated in joint continuing education (aOR1 = 1.87, 95% CI 1.44-2.43; aOR2 = 2.27, 95% CI 1.91-2.70), provided recommendations for medication review (aOR1 = 3.01, 95% CI 2.07-4.38; aOR2 = 3.50, 95% CI 2.51-4.86), and communicated with pharmacists during resident training (aOR1 = 2.15, 95% CI 1.78-2.60; aOR2 = 1.38, 95% CI 1.18-1.62) were associated with a more positive attitude towards and higher frequency of cooperation. CONCLUSIONS: GPs in China displayed a positive attitude towards cooperating with pharmacists, but they did not demonstrate a similar level of practice. As environmental determinants impact interdisciplinary collaboration, healthcare managers and policy-makers need to implement measures that foster a supportive environment conducive to interdisciplinary collaboration.

Cytochrome P450 Mediated Cyclization in Eunicellane Derived Diterpenoid Biosynthesis.

Terpene cyclization, one of the most complex chemical reactions in nature, is generally catalyzed by two classes of terpene cyclases (TCs). Cytochrome P450s that act as unexpected TC-like enzymes are known but are very rare. In this study, we genome-mined a cryptic bacterial terpenoid gene cluster, named ari, from the thermophilic actinomycete strain Amycolatopsis arida. By employing a heterologous production system, we isolated and characterized three highly oxidized eunicellane derived diterpenoids, aridacins A-C (1-3), that possess a 6/7/5-fused tricyclic scaffold. In vivo and in vitro experiments systematically established a noncanonical two-step biosynthetic pathway for diterpene skeleton formation. First, a class I TC (AriE) cyclizes geranylgeranyl diphosphate (GGPP) into a 6/10-fused bicyclic cis-eunicellane skeleton. Next, a cytochrome P450 (AriF) catalyzes cyclization of the eunicellane skeleton into the 6/7/5-fused tricyclic scaffold through C2-C6 bond formation. Based on the results of quantum chemical computations, hydrogen abstraction followed by electron transfer coupled to barrierless carbocation ring closure is shown to be a viable mechanism for AriF-mediated cyclization. The biosynthetic logic of skeleton construction in the aridacins is unprecedented, expanding the catalytic capacity and diversity of P450s and setting the stage to investigate the inherent principles of carbocation generation by P450s in the biosynthesis of terpenoids.

Effect of estradiol as a continuous variable on breast cancer survival by menopausal status: a cohort study in China.

High levels of circulating estradiol (E2) are associated with increased risk of breast cancer, whereas its relationship with breast cancer prognosis is still unclear. We evaluated the effect of E2 concentration on survival endpoints among 8766 breast cancer cases diagnosed between 2005 and 2017 from the Tianjin Breast Cancer Cases Cohort. Levels of serum E2 were measured in pre-menopausal and post-menopausal women. Multivariable-adjusted Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI) between quartile of E2 levels and overall survival (OS) and progression-free survival (PFS) of breast cancer. The penalized spline was then used to test for non-linear relationships between E2 (continuous variable) and survival endpoints. 612 deaths and 982 progressions occurred over follow-up through 2017. Compared to women in the quartile 3, the highest quartile of E2 was associated with reduced risk of both PFS in pre-menopausal women (HR 1.79, 95% CI 1.17-2.75, P = 0.008) and OS in post-menopausal women (HR 1.35, 95% CI 1.04-1.74, P = 0.023). OS and PFS in pre-menopausal women exhibited a nonlinear relation ("L-shaped" and "U-shaped", respectively) with E2 levels. However, there was a linear relationship in post-menopausal women. Moreover, patients with estrogen receptor-negative (ER-negative) breast cancer showed a "U-shaped" relationship with OS and PFS in pre-menopausal women. Pre-menopausal breast cancer patients have a plateau stage of prognosis at the intermediate concentrations of E2, whereas post-menopausal patients have no apparent threshold, and ER status may have an impact on this relationship.

Perfluoroalkyl substances (PFASs) as risk factors for breast cancer: a case-control study in Chinese population.

BACKGROUND: Perfluoroalkyl substances (PFASs) are a large family of synthetic chemicals, some of which are mammary toxicants and endocrine disruptors. Recent studies have implicated exposure to PFASs as a risk factor for breast cancer in Europe and America. Little is known about the role of PFASs with respect to breast cancer in the Chinese population. METHODS: Participants who were initially diagnosed with breast cancer at Tianjin Medical University Cancer Institute and Hospital between 2012 and 2016 were recruited as cases. The controls were randomly selected from the participants with available blood samples in the Chinese National Breast Cancer Screening Program (CNBCSP) cohort. Ultimately, we enrolled 373 breast cancer patients and 657 controls. Plasma PFASs were measured by an ultra-performance liquid chromatography (UPLC) system coupled to a 5500 Q-Trap triple quadrupole mass spectrometer. A logistic regression model with least absolute shrinkage and selection operator (LASSO) regularization was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) to assess the relationships between PFASs and breast cancer. The three most predictive variables in the LASSO model were selected from 17 PFASs, which was based on the optimal penalty coefficient (λ = 0.0218) identified with the minimum criterion. Additionally, Bayesian kernel machine regression (BKMR) and quantile g-computation models were applied to evaluate the associations between separate and mixed exposure to PFASs and breast cancer. RESULTS: Perfluorooctanesulfonic acid (PFOS) exhibited the highest concentration in both the cases and controls. Perfluorooctanoic acid (PFOA) and perfluoro-n-decanoic acid (PFDA) were positively associated with breast cancer, and perfluoro-n-tridecanoic acid (PFTrDA) was negatively associated with breast cancer according to both the continuous-PFASs and the quartile-PFASs logistic regression models. Of note, PFOA was associated with the occurrence of estrogen receptor (ER)-, progesterone receptor (PR)-, and human epidermal growth factor receptor 2 (HER2)-positive breast cancer (ORER+ = 1.47, 95% CI: 1.19, 1.80; ORPR+ = 1.36, 95% CI: 1.09, 1.69; ORHER2 = 1.62, 95% CI: 1.19, 2.21). CONCLUSIONS: Overall, we observed that PFASs were associated with breast cancer in Chinese women. Prospective cohort studies and mechanistic experiments are warranted to elucidate whether these associations are causal.

Detection rate is not higher for women with BBD history in breast cancer screening.

BACKGROUND: To investigate whether women with benign breast disease (BBD) history have higher breast cancer detection rate in screening. METHODS: We reviewed data for 33 001 female participants in Multi-modality Independent Screening Trial (MIST). Corresponding data for 6823 breast cancer patients were retrieved from the Tianjin Breast Cancer Cases Cohort (TBCCC) and analyzed for comparison. RESULTS: The breast cancer detection rate was 2.83‰ among women with BBD history and 3.28‰ in women without. Moreover, the proportion of carcinoma in situ (CIS) was also lower in women with BBD history than women without (7.69 versus 20.31%). In contrast, analysis of TBCCC data revealed a higher proportion of CIS in patients with BBD history (5.05%) than patients without (3.26%). Our data showed that a larger proportion of women with BBD history had undergone previous breast examinations. Additionally, among participants diagnosed with both breast cancer and BBD in MIST, we found a lower proportion of CIS in women with BBD history (11.76%) compared to women without (32.14%). CONCLUSIONS: Women with BBD history were not found to have higher detection rate in breast cancer screening. Women with BBD history were more likely to be proactive in seeking breast examinations and to have breast cancer be diagnosed in clinic.

Antifungal Activity and Action Mechanism Study of Coumarins from Cnidium monnieri Fruit and Structurally Related Compounds.

The increasing resistance of plant diseases caused by phytopathogenic fungi highlights the need for highly effective and environmentally benign agents. The antifungal activities of Cnidium monnieri fruit extracts and five isolated compounds as well as structurally related coumarins against five plant pathogenic fungi were evaluated. The acetone extract, which contained the highest amount of five coumarins, showed strongest antifungal activity. Among the coumarin compounds, we found that 4-methoxycoumarin exhibited stronger and broader antifungal activity against five phytopathogenic fungi, and was more potent than osthol. Especially, it could significantly inhibit the growth of Rhizoctonia solani mycelium with an EC50 value of 21 µg mL-1 . Further studies showed that 4-methoxycoumarin affected the structure and function of peroxisomes, inhibited the ß-oxidation of fatty acids, decreased the production of ATP and acetyl coenzyme A, and then accumulated ROS by damaging MMP and the mitochondrial function to cause the cell death of R. solani mycelia. 4-Methoxycoumarin presented antifungal efficacy in a concentration- dependent manner in vivo and could be used to prevent the potato black scurf. This study laid the foundation for the future development of 4-methoxycournamin as an alternative and friendly biofungicide.

A multicenter retrospective study on survival rate and complications of very preterm infants. / æžæ—©äº§å„¿å­˜æ´»çŽ‡å’Œå¹¶å‘ç—‡çš„å¤šä¸­å¿ƒå›žé¡¾æ€§ç ”ç©¶.

OBJECTIVES: To study the survival rate and the incidence of complications of very preterm infants and the factors influencing the survival rate and the incidence of complications. METHODS: The medical data of the very preterm infants with a gestational age of <32 weeks and who were admitted to the Department of Neonatology in 11 hospitals of Jiangsu Province in China from January 2018 to December 2019 were retrospectively reviewed. Their survival rate and the incidence of serious complications were analyzed. A multivariate logistic regression analysis was used to evaluate the risk factors for death and serious complications in very preterm infants. RESULTS: A total of 2 339 very preterm infants were enrolled, among whom 2 010 (85.93%) survived and 1 507 (64.43%) survived without serious complications. The groups with a gestational age of 22-25+6 weeks, 26-26+6 weeks, 27-27+6 weeks, 28-28+6 weeks, 29-29+6 weeks, 30-30+6 weeks, and 31-31+6 weeks had a survival rate of 32.5%, 60.6%, 68.0%, 82.9%, 90.1%, 92.3%, and 94.8% respectively. The survival rate tended to increase with the gestational age (P<0.05) and the survival rate without serious complications in each gestational age group was 7.5%, 18.1%, 34.5%, 52.2%, 66.7%, 75.7%, and 81.8% respectively, suggesting that the survival rate without serious complications increased with the gestational age (P<0.05). The multivariate logistic regression analysis showed that high gestational age, high birth weight, and prenatal use of glucocorticoids were protective factors against death in very preterm infants (P<0.05), and 1-minute Apgar score ≤3 was a risk factor for death in very preterm infants (P<0.05); high gestational age and high birth weight were protective factors against serious complications in very preterm infants who survived (P<0.05), while 5-minute Apgar score ≤3 and maternal chorioamnionitis were risk factors for serious complications in very preterm infants who survived (P<0.05). CONCLUSIONS: The survival rate is closely associated with gestational age in very preterm infants. A low 1-minute Apgar score (≤3) may increase the risk of death in very preterm infants, while high gestational age, high birth weight, and prenatal use of glucocorticoids are associated with the reduced risk of death. A low 5-minute Apgar score (≤3) and maternal chorioamnionitis may increase the risk of serious complications in these infants, while high gestational age and high birth weight may reduce the risk of serious complications.

Bioassay-guided isolation of two antifungal compounds from Magnolia officinalis, and the mechanism of action of honokiol.

Magnolia officinalis, as a well-known herb worldwide, has been widely used to treat multiple diseases for a long time. In this study, the petroleum ether extract from M. officinalis showed effective antifungal activity against seven plant pathogens (particularly against R. solani with an inhibition rate of 100.00% at 250 µg/mL). Honokiol and magnolol, isolated by the bioassay-guided method, exhibited greater antifungal activity than tebuconazole (EC50 = 3.07 µg/mL, p ≤ 0.001) against R. solani, which EC50 values were 2.18 µg/mL and 3.48 µg/mL, respectively. We used transcriptomics to explore the mechanism of action of honokiol against R. solani. Results indicated that honokiol may exert antifungal effects by blocking the oxidative phosphorylation metabolic pathway. Further studies indicated that honokiol induced ROS overproduction, disrupted the mitochondrial function, affected respiration, and blocked the TCA cycle, which eventually inhibited ATP production. Besides, honokiol also damaged cell membranes and caused morphological changes. This study demonstrated that the lignans isolated from M. officinalis possess the potential to be developed as botanical fungicides.

Biological and RNA regulatory function of MOV10 in mammalian germ cells.

BACKGROUND: RNA regulation by RNA-binding proteins (RBPs) involve extremely complicated mechanisms. MOV10 and MOV10L1 are two homologous RNA helicases implicated in distinct intracellular pathways. MOV10L1 participates specifically in Piwi-interacting RNA (piRNA) biogenesis and protects mouse male fertility. In contrast, the functional complexity of MOV10 remains incompletely understood, and its role in the mammalian germline is unknown. Here, we report a study of the biological and molecular functions of the RNA helicase MOV10 in mammalian male germ cells. RESULTS: MOV10 is a nucleocytoplasmic protein mainly expressed in spermatogonia. Knockdown and transplantation experiments show that MOV10 deficiency has a negative effect on spermatogonial progenitor cells (SPCs), limiting proliferation and in vivo repopulation capacity. This effect is concurrent with a global disturbance of RNA homeostasis and downregulation of factors critical for SPC proliferation and/or self-renewal. Unexpectedly, microRNA (miRNA) biogenesis is impaired due partially to decrease of miRNA primary transcript levels and/or retention of miRNA via splicing control. Genome-wide analysis of RNA targetome reveals that MOV10 binds preferentially to mRNAs with long 3'-UTR and also interacts with various non-coding RNA species including those in the nucleus. Intriguingly, nuclear MOV10 associates with an array of splicing factors, particularly with SRSF1, and its intronic binding sites tend to reside in proximity to splice sites. CONCLUSIONS: These data expand the landscape of MOV10 function and highlight a previously unidentified role initiated from the nucleus, suggesting that MOV10 is a versatile RBP involved in a broader RNA regulatory network.

Protective effects of S-carvedilol on doxorubicin-induced damages to human umbilical vein endothelial cells and rats.

Doxorubicin (DOX) is a highly active anticancer drug with severe cytotoxicity, which is strongly associated with oxidative stress. Carvedilol (CAR), used as its racemate with S-CAR and R-CAR (1:1), has been previously reported to ameliorate the DOX-induced cytotoxicity. However, the main contributor from CAR of its protective effects has not been clear. Therefore, in this study, we aimed to investigate further the different effects of CAR enantiomers on DOX-induced cytotoxicity in human umbilical vein endothelial cells and rats, respectively. Results indicated that S-CAR could significantly attenuate DOX-induced cell death, apoptotic morphological changes, decrease the mitochondrial membrane potential and oxidative stress responses by increasing the superoxide dismutase and catalase activities, and decreasing malondialdehyde contents and reactive oxygen species levels via the phosphoinositide 3-kinase/AKT/endothelial nitric oxide synthase pathway in vitro. Consistent with the in vitro study, the protective effects of S-CAR on the myocardial tissues and hemodynamics were also detected in rats suffering because of DOX treatment. With the obtained results, we can first conclude that S-CAR provides superior protection to injury induced by DOX relative to that of racemic CAR and R-CAR.

Dysregulation of CUL4A and CUL4B Ubiquitin Ligases in Lung Cancer.

The Cullin-RING ubiquitin ligase 4 (CRL4) is implicated in controlling cell cycle, DNA damage repair, and checkpoint response based on studies employing cell lines and mouse models. CRL4 proteins, including CUL4A and CUL4B, are often highly accumulated in human malignancies. Elevated CRL4 attenuates DNA damage repair and increases genome instability that is believed to facilitate tumorigenesis. However, this has yet to be evaluated in human patients with cancer. In our study, 352 lung cancer and 62 normal lung specimens of Asian origin were constructed into tissue microarrays of four distinct lung cancer subtypes. Expression of CUL4A, CUL4B, and their substrates was detected by immunohistochemistry and analyzed statistically for their prognostic value and association with DNA damage response and genomic instability. Our results show that both CUL4A and CUL4B are overexpressed in the majority of lung carcinomas (PCUL4A <0.001 and PCUL4B <0.001) and significantly associated with tumor size (PCUL4A <0.001 and PCUL4B = 0.002), lymphatic invasion (PCUL4A = 0.004 and PCUL4B <0.001), metastasis (PCUL4A = 0.019 and PCUL4B = 0.006), and advanced TNM stage (PCUL4A <0.001 and PCUL4B <0.001), which parallels gene amplification and abnormal activation of the canonical WNT signaling. Moreover, overexpression of CUL4A, but not CUL4B, is significantly associated with tobacco smoking (p = 0.01) and is inversely correlated with XPC and P21, both of which are substrates of CUL4A (PCUL4A = 0.019 and PCUL4B = 0.006). Higher levels of CUL4A or CUL4B are significantly associated with the overall survival of patients (PCUL4A <0.001 and PCUL4B <0.001) and progression-free survival (PCUL4A <0.001 and PCUL4B = 0.001). Our findings revealed that CUL4A and CUL4B are differentially associated with etiologic factors for pulmonary malignancies and are independent prognostic markers for the survival of distinct lung cancer subtypes.

Mutational landscape of gastric adenocarcinoma in Chinese: implications for prognosis and therapy.

Gastric cancer (GC) is a highly heterogeneous disease. To identify potential clinically actionable therapeutic targets that may inform individualized treatment strategies, we performed whole-exome sequencing on 78 GCs of differing histologies and anatomic locations, as well as whole-genome sequencing on two GC cases, each with three primary tumors and two matching lymph node metastases. The data showed two distinct GC subtypes with either high-clonality (HiC) or low-clonality (LoC). The HiC subtype of intratumoral heterogeneity was associated with older age, TP53 (tumor protein P53) mutation, enriched C > G transition, and significantly shorter survival, whereas the LoC subtype was associated with younger age, ARID1A (AT rich interactive domain 1A) mutation, and significantly longer survival. Phylogenetic tree analysis of whole-genome sequencing data from multiple samples of two patients supported the clonal evolution of GC metastasis and revealed the accumulation of genetic defects that necessitate combination therapeutics. The most recurrently mutated genes, which were validated in a separate cohort of 216 cases by targeted sequencing, were members of the homologous recombination DNA repair, Wnt, and PI3K-ERBB pathways. Notably, the drugable NRG1 (neuregulin-1) and ERBB4 (V-Erb-B2 avian erythroblastic leukemia viral oncogene homolog 4) ligand-receptor pair were mutated in 10% of GC cases. Mutations of the BRCA2 (breast cancer 2, early onset) gene, found in 8% of our cohort and validated in The Cancer Genome Atlas GC cohort, were associated with significantly longer survivals. These data define distinct clinicogenetic forms of GC in the Chinese population that are characterized by specific mutation sets that can be investigated for efficacy of single and combination therapies.

Analysis of estrogen receptor ß gene methylation in autistic males in a Chinese Han population.

Autism spectrum disorder (ASD) is a neurodevelopment disorder with abnormalities of social interaction, communication and repetitive behaviors. The higher prevalence of ASD in men implies a potential relationship between sex hormones and ASD etiology. The ESR2 gene encodes estrogen receptor beta (ESR2) and plays an important role during brain development. A relationship between ESR2 and ASD has been suggested by studies on single nucleotide polymorphisms and mRNA and protein expression levels in ASD patients. Here, we explored the possible epigenetic regulation of the ESR2 gene in autism. We collected genomic DNA from the peripheral blood of Chinese Han males with autism and age-matched normal males and measured DNA methylation of CpG islands in the ESR2 gene, which consisted of 41 CpG sites among the proximal promoter region and an untranslated exon, by bisulfite sequencing. We also investigated a relationship between DNA methylation and phenotypic features of autism, as assessed by the Children Autism Rating Scale. We found little overall difference in the DNA methylation of the ESR2 5'-flanking region in individuals with autism compared with normal individuals. However, detailed analyses revealed that eight specific CpG sites were hypermethylated in autistic individuals and that four specific CpG sites were positively associated with the severity of autistic symptoms. Our study indicates that the epigenetic dysregulation of ESR2 may govern the development of autism.

Considering the Optimal Timing of Breast Reconstruction With Abdominal Flaps With Adjuvant Irradiation in 370 Consecutive Pedicled Transverse Rectus Abdominis Myocutaneous Flap and Free Deep Inferior Epigastric Perforator Flap Performed in a Chinese Oncology Center: Is There a Significant Difference Between Immediate and Delayed?

PURPOSE: There is an ongoing debate on the optimal sequence of radiation and breast reconstruction. The purpose of this article was to (a) assess the impact of radiation on autologous breast reconstruction and (b) analyze the best timing for autologous breast reconstruction in the setting of radiation in a Chinese population. METHODS: A retrospective review of patients undergoing breast reconstruction with autologous lower abdominal flaps between 2001 and 2014 in the Tianjin Medical University and Cancer Hospital was performed. Patients were grouped by their irradiation status (irradiated vs nonirradiated). The irradiated group was further stratified into 2 groups by the timing of irradiation (immediate breast reconstruction followed by radiation vs prior radiation and delayed breast reconstruction). The primary outcomes were early and late breast complications, secondary and revision surgeries to the reconstructed breast, whereas the secondary outcomes were aesthetic and psychological evaluations of the patients. Logistic regression was used to assess the potential association between irradiation, patient and treatment variables, and surgical outcomes. RESULTS: Three hundred sixty patients with 370 reconstructed breasts were included in the study. Two hundred seventy-eight cases were nonirradiated, of which 158 were immediate and 120 were delayed. Ninety-two cases were irradiated, of which 61 were immediate, and 31 were delayed. Three hundred thirty-two cases underwent pedicled transverse rectus abdominis myocutaneous flap, 38 had deep inferior epigastric perforator flap. The irradiated group had a significant increase in secondary surgery due to fat necrosis (P < 0.001) and in late complications (P = 0.011). A significant increase in flap contracture (P = 0.043) and an increasing trend in the severity of fat necrosis were observed when radiation was performed after breast reconstruction. However, radiation and its timing did not have an adverse impact on patients' aesthetic and psychological evaluations by the Breast-Q survey. CONCLUSIONS: Radiation administered to the reconstructed breast mound increased the rate of late complications and the need for secondary surgery with increased abdominal flap shrinkage and contracture and the severity of flap fat necrosis. Irradiation on the reconstructed breast did not lead to worse aesthetic outcomes due to the generally different expectation in the Chinese female patients in that they were more focused on the breast shape when clothed. Immediate breast reconstruction followed by irradiated was a generally successful treatment sequence in the Chinese module.