Relationship between maternal ABO blood groups and pregnancy outcomes: a retrospective cohort study in Dongguan, China.

The purpose of this study was to study the relationship between maternal ABO blood groups and pregnancy outcomes. A total of 29,658 couples in Dongguan were selected as the research subjects. We obtained data on ABO blood groups and pregnancy outcomes and explored the relationship between them through log binomial regression and survival analysis. Compared to mothers with type B blood, the RR of foetal stillbirth in mothers with type A blood was 2.87 (95% CI: 1.70, 4.85), and compared to mothers with type O blood, the RR was 1.72 (95% CI: 1.16, 2.55). Compared with foetuses of other three blood type mothers, foetuses of A blood type mothers have a higher median birth weight (P = 0.011). Other pregnancy outcomes, including preterm birth, macrosomia, caesarean section, multiple births, birth defects, low birth weight, foetal sex, gestational days, birth length, and APGAR score, were not significantly different. The relationship between maternal ABO blood type and pregnancy outcomes was not affected by paternal blood type. More studies are needed to confirm these results.

What is already known on this subject? The relationship between blood type and disease is being increasingly studied. With regard to the relationship between maternal blood type and pregnancy outcomes, some studies have focused on people undergoing in vitro fertilisation. There are few reports on healthy women.What do the results of this study add? Compared to mothers with type B blood, the RR of foetal stillbirth in mothers with type A blood was 2.87 (95% CI: 1.70, 4.85), and compared to mothers with type O blood, the RR was 1.72 (95% CI: 1.16, 2.55). Compared with foetuses of other three blood type mothers, foetuses of A blood type mothers have a higher median birth weight (P = 0.011).What are the implications of these findings for clinical practice and/or further research? This study is the first to explore the relationship between blood type and pregnancy outcomes in healthy women.These results can provide some clues for the study of the mechanism of pregnancy outcomes.

History of IUD utilization and the risk of preterm birth: a cohort study.

OBJECTIVE: To explore whether a history of IUD use could increase the risk of subsequent preterm birth. METHODS: We performed a cohort study of 24,496 multipara aged 19-48 years in Dongguan City. Each subject was followed up for 1 year, and 12,508 women obtained pregnancy outcomes. They were divided into 2 groups: 2130 subjects with IUD use history (exposure group), and 10,378 subjects without IUD use history (control group). The exposure group will remove the IUD before pregnancy. The primary outcomes were preterm birth (less than 37 weeks of gestation) and early preterm birth (less than 34 weeks of gestation). We used log-binomial regression to estimate adjusted risk ratios (aRR) of preterm birth and early preterm birth for women with a history of IUD. According to the different adjusted baseline data, three regression models were established, and the propensity matching score method was also used to verify the stability of the results. RESULTS: The delivery rate of women with IUD history was 51.24%, and that of women without IUD was 51.03% (2 = 0.063, P = 0.802). Six hundred and eighty-five women had preterm birth (5.48%, 95% CI 5.08-5.88) and 133 women had early preterm birth (1.06%, 95% CI 0.83-1.24). Compared with the control group, the incidence of preterm birth and early preterm birth in the exposure group were significantly lower. The results are stable in all four models. Subgroup analysis also supported the result. This study also found that the longer the women used IUD before pregnancy, the younger the age of first using IUD, and the shorter the time from condom removal to pregnancy, the lower the incidence of premature birth. CONCLUSION: The women with a history of IUD use are less likely to have premature birth after the IUD is removed. More prospective studies are needed to confirm it.

MTA2 promotes the metastasis of esophageal squamous cell carcinoma via EIF4E-Twist feedback loop.

Metastasis-associated protein 2 (MTA2) is frequently amplified in many types of cancers; however, the role and underlying molecular mechanism of MTA2 in esophageal squamous cell carcinoma (ESCC) remain unknown. Here, we reported that MTA2 is highly expressed in ESCC tissue and cells, and is closely related to the malignant characteristics and poor prognosis of patients with ESCC. Through in vitro and in vivo experiments, we demonstrated that MTA2 significantly promoted ESCC growth, metastasis, and epithelial-mesenchymal transition (EMT) progression. This integrative analysis combined with expression microarray showed that MTA2 could interact with eukaryotic initiation factor 4E (EIF4E), which positively regulates the expression of Twist, known as a master regulator of EMT. Moreover, the results of chromatin immunoprecipitation revealed that MTA2 was recruited to the E-cadherin promoter by Twist, which reduced the acetylation level of the promoter region and thus inhibited expression of E-cadherin, and subsequently promoted the aggressive progression of ESCC. Collectively, our study provided novel evidence that MTA2 plays an aggressive role in ESCC metastasis by a novel EIF4E-Twist positive feedback loop, which may provide a potential therapeutic target for the management of ESCC.

Sanguinarine inhibits Rac1b-rendered cell survival enhancement by promoting apoptosis and blocking proliferation.

AIM: Small GTPase Rac1 is a member of the Ras superfamily, which plays important roles in regulation of cytoskeleton reorganization, cell growth, proliferation, migration, etc. The aim of this study was to determine how a constitutively active Rac1b regulated cell proliferation and to investigate the effects of the Rac1b inhibitor sanguinarine. METHODS: Three HEK293T cell lines stably overexpressing GFP, Rac1-GFP or Rac1b-GFP were constructed by lentiviral infection. The cells were treated with sanguinarine (1 µmol/L) or its analogue berberine (1 µmol/L) for 4 d. Cell proliferation was evaluated by counting cell numbers and with a BrdU incorporation assay. The levels of cleaved PARP-89 (an apoptosis marker) and cyclin-D1 (a proliferative index) were measured using Western blotting. RESULTS: In 10% serum-containing media, overexpressing either Rac1 or Rac1b did not significantly change the cell proliferation. In the serum-starved media, however, the survival rate of Rac1b cells was significantly increased, whereas that of Rac1 cells was moderately increased. The level of cleaved PARP-89 was significantly increased in serum-starved Rac1 cells, but markedly reduced in serum-starved Rac1b cells. The level of cyclin-D1 was significantly increased in both serum-starved Rac1 and Rac1b cells. Treatment with sanguinarine, but not berberine, inhibited the proliferation of Rac1b cells, which was accompanied by significantly increased the level of PARP-89, and decreased both the level of cyclin-D1 and the percentage of BrdU positive cells. CONCLUSION: Rac1b enhances the cell proliferation under a growth-limiting condition via both anti-apoptotic and pro-proliferative mechanisms. Sanguinarine, as the specific inhibitor of Rac1b, is a potential therapeutic agent for malignant tumors with up-regulated Rac1b.

History of induced abortion and the risk of preterm birth: a retrospective cohort study.

OBJECTIVES: To explore the relationship between a history of induced abortion and follow-up preterm birth. METHODS: We performed a retrospective cohort study of 27,176 women aged 19 to 48 years old in the city of Dongguan. Participants were divided into two groups according to the history of induced abortion. We used log-binomial regression to estimate adjusted risk ratios of preterm birth (gestation at less than 37 weeks) and early preterm birth (gestation at less than 34 weeks) for women with a history of induced abortion. Four models adjusted for different baseline data were used to verify the stability of the results. We also performed a subgroup analysis and mediation effect analysis to control for the influence of confounding factors and analyzed the relationship between the number of abortions and subsequent preterm birth. RESULTS: Our study included 2,985 women who had undergone a prior induced abortion. Women who reported having a prior induced abortion were more likely to have preterm births before 37 weeks and 34 weeks, with risk ratios of 1.18 (95% CI 1.02-1.36) and 1.65 (95% CI 1.23-2.21), respectively. The above associations were stable in all models. We also found that a history of induced abortion was independently associated with a higher risk of preterm birth and early preterm birth in the subgroups. After controlling for the indirect effect of demographic data, the direct effect of abortion history on follow-up preterm delivery was still significantly different. The higher the number of abortions, the greater the risk of subsequent preterm birth. CONCLUSIONS: This study suggests that induced abortion increases the risk of subsequent preterm birth.

[Clinical study of oral alendronate in the treatment of pediatric osteogenesis imperfecta].

OBJECTIVE: To explore the clinical efficacy and safety of oral alendronate in children with osteogenesis imperfecta (OI). METHODS: Eleven OI children were recruited from August 2008 to April 2011 at Shanghai Institute of Pediatric Research to receive alendronate for a duration of (1.7 ± 0.3) years. The growth, fracture incidence, physical activity, the quality of daily life and safety parameters were evaluated. RESULTS: All patients obtained marked improvement. The rates of bone fractures decreased more remarkably than that at pre-treatment (0 - 1.2 fractures per year vs 0.5 - 5.0 fractures per year, medium 0 vs 1.40 fractures per year) (P = 0.003). Their levels of physical activities improved significantly (median level from 4 to 3, P = 0.004). There was significant post-treatment improvement in the self-care activity scores (median score from 43 to 73, P = 0.003). The bone density of lumbar vertebrae, long bones and metaphysis improved at post-treatment. The radiographic examinations revealed the thickness of bone cortex. The change in height did not show any significant difference. No change was found in the serum levels of calcium, phosphorus, parathyroid hormone, alkaline phosphate or other biochemical markers. No adverse reaction occurred throughout treatment. CONCLUSION: Oral alendronate treatment reduces the incidence of bone fracture and improves physical activity and life quality in OI children, and as a well-tolerated regimen, it is both safe and effective in clinical practice.

Research on fuzi based on animal thermotropism behavior to discover if it has fewer "hot" characteristics without Ganjiang.

OBJECTIVE: To investigate whether fuzi (Radix Aconiti Praeparata) has fewer "hot" characteristics when administered without Ganjiang (Rhizoma Zingiberis). METHODS: Differences in the thermotropism behaviors of mice treated either with fuzi (Radix Aconiti Praeparata), Ganjiang (Rhizoma Zingiberis) or the combination of the two given intragastrically were investigated using the Animal Thermotropism Behavior Surveillance System. The water intake volume, oxygen consumption volume, adenosine triphosphatase (ATPase) activity, total antioxidant capacity (T-AOC) and total superoxide dismutase (T-SOD) activity were determined during the investigation. RESULTS: When fuzi and ganjiang were administered together, the rate at which mice remained on a warm plate ("remaining rate") and the times and distances of their movement were all significantly reduced (P < 0.05). Compared with the Normal group, the reduction was 55.1%, 48.3% and 44.8%, while compared with the Fuzi group, the reduction was 57.6%, 34.3% and 36.0%, indicating that "cold" tropism was significantly increased. Compared with the normal and fuzi groups, the ATPase activity and the respiratory oxygen consumption volume of the fuzi + ganjiang group were significantly increased (P < 0.05), suggesting an improvement in energy metabolism and showing a "hot" characteristic when Fuzi and Ganjiang are present together. Additionally, the T-AOC and T-SOD activity were significantly enhanced (P < 0.05). CONCLUSION: The behavior of mice tending toward "cold" tropism can be regarded as a quantitative reflection of Fuzi having fewer characteristics consistent with a "hot" nature when not used with Ganjiang, the functional mechanism of which may be a change in the ATPase activity in liver tissue.

p-Hydroxylcinnamaldehyde from cochinchinamomordica seed reverses resistance to TRAIL in human oesophageal squamous cell carcinoma via the activation of the p38 mitogen-activated protein kinase signalling pathway.

BACKGROUND: Our previous studies have showed that p-Hydroxylcinnamaldehyde (CMSP) could induce the differentiation of ESCC cells via the cAMP-RhoA-MAPK signalling pathway, which suggests a new potential strategy for ESCC treatment. Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potent inducer of apoptosis in several tumour cells by binding to the death receptors DR4 and DR5. However, TRAIL has little effect on oesophageal squamous cell carcinoma (ESCC) cells due to the loss of the receptors. The present study determined the effect of CMSP, the firstly found chemical constituent of Cochinchinamomordica seed (CMS), on TRAIL-induced apoptosis and its mechanism in ESCC cells. METHODS: MTS assays were performed to examine the CMSP- and TRAIL-mediated inhibition of ESCC cell growth. Flow cytometry and Hoechst 33258 staining assays were used to detect apoptosis in ESCC cells treated with CMSP combined with TRAIL. Western blotting was used to determine the effect of CMSP on the expression of p38, p-p38, DR4, DR5, Bid and caspase-3/8 in ESCC cells treated with CMSP combined with TRAIL. Additionally, immunodeficient Balb-c/null mouse model was used to determine the chemotherapeutic efficacy of CMSP and TRAIL against ESCC tumour xenograft growth in vivo. RESULTS: We found that the combination of CMSP and TRAIL had a greater inhibitory effect on ESCC cell viability in vitro than CMSP or TRAIL alone. CMSP enhanced the TRAIL-induced apoptosis in ESCC cells by upregulating the expression of DR4 and DR5 via the p38 MAPK signalling pathway. Furthermore, the increased expression of DR4 and DR5 upon TRAIL-induced apoptosis in ESCC cells was mediated at least in part by subsequent caspase-3 and caspase-8 activation. Moreover, the in vivo model showed that tumour growth was significantly slower in CMSP and TRAIL combination-treated mice than in mice treated with CMSP or TRAIL alone. CONCLUSION: Taken together, our findings indicate that CMSP as an extract from TCM, might be as a potential sensitizer of TRAIL and thus provide a novel strategy for the clinical treatment of ESCC.

Crucial Role of ROCK2-Mediated Phosphorylation and Upregulation of FHOD3 in the Pathogenesis of Angiotensin II-Induced Cardiac Hypertrophy.

Cardiac hypertrophy is characterized by increased myofibrillogenesis. Angiotensin II (Ang-II) is an essential mediator of the pressure overload-induced cardiac hypertrophy in part through RhoA/ROCK (small GTPase/Rho-associated coiled-coil containing protein kinase) pathway. FHOD3 (formin homology 2 domain containing 3), a cardiac-restricted member of diaphanous-related formins, is crucial in regulating myofibrillogenesis in cardiomyocytes. FHOD3 maintains inactive through autoinhibition by an intramolecular interaction between its C- and N-terminal domains. Phosphorylation of the 3 highly conserved residues (1406S, 1412S, and 1416T) within the C terminus (CT) of FHOD3 by ROCK1 is sufficient for its activation. However, it is unclear whether ROCK-mediated FHOD3 activation plays a role in the pathogenesis of Ang-II-induced cardiac hypertrophy. In this study, we detected increases in FHOD3 expression and phosphorylation in cardiomyocytes from Ang-II-induced rat cardiac hypertrophy models. Valsartan attenuated such increases. In cultured neonate rat cardiomyocytes, overexpression of phosphor-mimetic mutant FHOD3-DDD, but not wild-type FHOD3, resulted in myofibrillogenesis and cardiomyocyte hypertrophy. Expression of a phosphor-resistant mutant FHOD3-AAA completely abolished myofibrillogenesis and attenuated Ang-II-induced cardiomyocyte hypertrophy. Pretreatment of neonate rat cardiomyocytes with ROCK inhibitor Y27632 reduced Ang-II-induced FHOD3 activation and upregulation, suggesting the involvement of ROCK activities. Silencing of ROCK2, but not ROCK1, in neonate rat cardiomyocytes, significantly lessened Ang-II-induced cardiomyocyte hypertrophy. ROCK2 can directly phosphorylate FHOD3 at both 1412S and 1416T in vitro and is more potent than ROCK1. Both kinases failed to phosphorylate 1406S. Coexpression of FHOD3 with constitutively active ROCK2 induced more stress fiber formation than that with constitutively active ROCK1. Collectively, our results demonstrated the importance of ROCK2 regulated FHOD3 expression and activation in Ang-II-induced myofibrillogenesis, thus provided a novel mechanism for the pathogenesis of Ang-II-induced cardiac hypertrophy.

Besides an ITIM/SHP-1-dependent pathway, CD22 collaborates with Grb2 and plasma membrane calcium-ATPase in an ITIM/SHP-1-independent pathway of attenuation of Ca2+i signal in B cells.

CD22 is a surface immunoglobulin implicated in negative regulation of B cell receptor (BCR) signaling; particularly inhibiting intracellular Ca2+ (Ca2+i)signals. Its cytoplasmic tail contains six tyrosine residues (Y773/Y783/Y817/Y828/Y843/Y863, designated Y1~Y6 respectively), including three (Y2/5/6) lying within immunoreceptor tyrosine-based inhibitory motifs (ITIMs) that serve to recruit the protein tyrosine phosphatase SHP-1 after BCR activation-induced phosphorylation. The mechanism of inhibiting Ca2+i by CD22 has been poorly understood. Previous study demonstrated that CD22 associated with plasma membrane calcium-ATPase (PMCA) and enhanced its activity (Chen, J. et al. Nat Immunol 2004;5:651-7). The association is dependent on BCR activation-induced cytoplasmic tyrosine phosphorylation, because CD22 with either all six tyrosines mutated to phenylalanines or cytoplasmic tail truncated loses its ability to associate with PMCA. However, which individual or a group of tyrosine residues determine the association and how CD22 and PMCA interacts, are still unclear. In this study, by using a series of CD22 tyrosine mutants, we found that ITIM Y2/5/6 accounts for 34.3~37.1% Ca2+i inhibition but is irrelevant for CD22/PMCA association. Non-ITIM Y4 and its YEND motif contribute to the remaining 69.4~71.7% Ca2+i inhibition and is the binding site for PMCA-associated Grb2. Grb2, independently of BCR cross-linking, is constitutively associated with and directly binds to PMCA in both chicken and human B cells. Knockout of Grb2 by CRISPR/Cas9 completely disrupted the CD22/PMCA association. Thus, our results demonstrate for the first time that in addition to previously-identified ITIM/SHP-1-dependent pathway, CD22 holds a major pathway of negative regulation of Ca2+i signal, which is ITIM/SHP-1-independent, but Y4/Grb2/PMCA-dependent.

Rac1b enhances cell survival through activation of the JNK2/c-JUN/Cyclin-D1 and AKT2/MCL1 pathways.

Rac1b is a constitutively activated, alternatively spliced form of the small GTPase Rac1. Previous studies showed that Rac1b promotes cell proliferation and inhibits apoptosis. In the present study, we used microarray analysis to detect genes differentially expressed in HEK293T cells and SW480 human colon cancer cells stably overexpressing Rac1b. We found that the pro-proliferation genes JNK2, c-JUN and cyclin-D1 as well as anti-apoptotic AKT2 and MCL1 were all upregulated in both lines. Rac1b promoted cell proliferation and inhibited apoptosis by activating the JNK2/c-JUN/cyclin-D1 and AKT2/MCL1 pathways, respectively. Very low Rac1b levels were detected in the colonic epithelium of wild-type Sprague-Dawley rats. Knockout of the rat Rac1 gene exon-3b or knockdown of endogenous Rac1b in HT29 human colon cancer cells downregulated only the AKT2/MCL1 pathway. Our study revealed that very low levels of endogenous Rac1b inhibit apoptosis, while Rac1b upregulation both promotes cell proliferation and inhibits apoptosis. It is likely the AKT2/MCL1 pathway is more sensitive to Rac1b regulation.