[Genetic diagnosis of microcephaly].

Objective: To explore the diagnostic value of chromosome karyotype analysis, chromosomal microarray analysis (CMA) and whole exome sequencing (WES) in microcephaly. Methods: A total of 9 cases of microcephaly fetuses diagnosed by prenatal ultrasound or children with microcephaly diagnosed after birth were selected from the Sixth Affiliated Hospital of Guangzhou Medical University from January 2014 to August 2022.Karyotype analysis and/or CMA were used to detect. The cases with negative karyotype analysis and CMA results were further sequenced by trio-based WES (Trio-WES). Then the coding genes contained in the pathogenic copy number variation (CNV) fragments were analyzed by gene ontology (GO) enrichment. The genes related to the development of the central nervous system contained in the pathogenic CNV and the pathogenic genes found by Trio-WES were combined for gene interaction network analysis. Results: In this study, 9 cases of microcephaly were recruited, with the time of diagnosis ranged from 23 weeks of gestation to 7 years after birth, and the head circumference of fetus or children ranged from 18.3 to 42.5 cm (-7SD to -2SD). Karyotype analysis was detected in all 9 cases and no abnormality result was found. Eight cases were detected by CMA, and one abnormal was found. Five cases were detected by Trio-WES, and two cases were detected with likely pathogenic genes. The GO enrichment analysis of the coding gene in the 4p16.3 microdeletion (pathogenic CNV) region showed that: in biological process, it was mainly concentrated in phototransduction, visible light; in terms of molecular function, it was mainly concentrated in fibroblast growth factor binding; in terms of cell components, it was mainly concentrated in rough endoplasmic reticulum. Gene interaction network analysis suggested that CDC42 gene could interact with CTBP1, HTT and ASPM gene. Conclusions: CMA could be used as a first-line detection technique for microcephaly. When the results of chromosome karyotype analysis and/or CMA are negative, Trio-WES could improve the detection rate of pathogenicity of microcephaly.

[Prenatal genetic diagnosis of the fetuses with isolated corpus callosum abnormality].

Objective: To explore the application value of chromosome karyotype analysis, chromosomal microarray analysis (CMA) and whole exome sequencing (WES) in prenatal diagnosis of isolated corpus callosum abnormality (CCA) fetus. Methods: Fetuses diagnosed with isolated CCA by ultrasound and MRI and receiving invasive prenatal diagnosis in Guangzhou Women and Children's Medical Center and Qingyuan People's Hospital from January 2010 to April 2021 were selected. Karyotype analysis and/or CMA [or copy number variation sequencing (CNV-seq)] were performed on all fetal samples, and WES was performed on fetal samples and their parents whose karyotype analysis and/or CMA (or CNV-seq) results were not abnormal. Results: Among 65 fetuses with isolated CCA, 38 cases underwent karyotype analysis, and 3 cases were detected with abnormal karyotypes, with a detection rate of 8% (3/38). A total of 49 fetuses with isolated CCA underwent CMA (or CNV-seq) detection, and 6 cases of pathogenic CNV were detected, the detection rate was 12% (6/49). Among them, the karyotype analysis results were abnormal, and the detection rate of further CMA detection was 1/1. The karyotype results were normal, and the detection rate of further CMA (or CNV-seq) detection was 14% (3/21). The detection rate of CMA as the first-line detection technique was 7% (2/27). A total of 25 fetuses with isolated CCA with negative results of karyotyping and/or CMA were tested by WES, and 9 cases (36%, 9/25) were detected with pathogenic genes. The gradient genetic diagnosis of chromosomal karyotyping, CMA and WES resulted in a definite genetic diagnosis of 26% (17/65) of isolated CCA fetuses. Conclusions: Prenatal genetic diagnosis of isolated CCA fetuses is of great clinical significance. The detection rate of CMA is higher than that of traditional karyotyping. CMA detection could be used as a first-line detection technique for fetuses with isolated CCA. WES could increase the pathogenicity detection rate of fetuses with isolated CCA when karyotype analysis and/or CMA test results are negative.

The effects of aerobic endurance exercise on pulse wave velocity and intima media thickness in adults: A systematic review and meta-analysis.

The aim of this study was to perform a systematic review and meta-analysis of randomized controlled trials (RCTs) or cohort studies that evaluated the effect of aerobic endurance exercise on pulse wave velocity (PWV) and intima media thickness (IMT) in adults. IMT and PWV were the most commonly used parameters for the assessment of arterial stiffness. The MEDLINE, Cochrane, ISI, and Ovid databases were searched between January 2000 and February 2015. A total of 1654 participants in 26 RCTs and two cohort studies were included in the meta-analysis. In studies for which PWV was the outcome, aerobic endurance exercise had a significant effect on reducing PWV [-0.67, 95% CI -0.97, -0.38; I(2) = 89%; heterogeneity, P < 0.0001]. Changes in peripheral arterial PWV were statistically greater than in central arterial PWV. In the RCTs for which IMT was the outcome, changes [-0.04, 95% CI -0.12, 0.04; I(2) = 95%; heterogeneity, P < 0.00001] in IMT did not reach statistical significance. In the two cohort studies, changes [-8.81, 95% CI -9.25, -8.37; I(2) = 22%; heterogeneity, P = 0.26] in IMT were statistically significant. Subgroup analysis indicated a longer duration aerobic exercise and a greater improvement in VO2max were associated with larger reductions in PWV. Reductions in IMT were observed in two cohort studies, but not in four RCTs.

Association between the composite dietary antioxidant index and metabolic syndrome: evidence from NHANES 2003-2018.

OBJECTIVE: A healthy and nutritional diet has been considered a promising approach to improve many adverse clinical outcomes. However, current evidence of the association of the intake of composite dietary antioxidants with metabolic syndrome (MetS) is limited. The current study was performed to explore the effect of the composite dietary antioxidant index (CDAI) on MetS and its components based on the National Health and Nutrition Examination Survey (NHANES) from 2003 to 2018. MATERIALS AND METHODS: The dietary consumption was evaluated using the 24-hour diet recall method, and a previously validated approach that included six antioxidants was used to calculate CDAI. The National Cholesterol Education Program-Adult Treatment Panel III (NCEP ATP III) was applied to evaluate MetS. ORs and 95%CIs were computed by logistic regression. The association between CDAI and MetS was determined by subgroup analyses and restricted cubic spline (RCS) regressions. RESULTS: This study included 24,705 individuals; approximately 18,378 (74.39%) participants were determined to be without MetS and 6,327 (25.61%) with MetS. After considering all confounders, compared to individuals of the lowest quartile of CDAI, those of the highest quartile showed a 31% lower risk of MetS (OR, 0.69, 95% CI: 0.57-0.82). RCS revealed a non-linear relationship between CDAI and MetS risk. CONCLUSIONS: A non-linear association was found between CDAI and decreased MetS risk, which indicated that selective combined intake of antioxidants could be a promising and effective approach to preventing MetS for the public.

Efficacy and safety evaluation of intensive statin therapy in older patients with coronary heart disease: a systematic review and meta-analysis.

PURPOSE: To reveal and evaluate the efficacy and safety of intensive statin therapy in older patients (age ≥ 65 years) with coronary heart disease (CHD). METHODS: Electronic databases were searched for randomized controlled trials (RCTs) that involved intensive statin therapy use in older patients with CHD. Data was extracted and used to calculate risk ratios (RR) by software Revman 5.1. RESULTS: Five RCTs and 11,132 patients were included in. Compared with non-intensive statin therapy, intensive statin therapy had significant effect on reducing low density lipoprotein cholesterol (LDL-C) levels (55.4 %) and total cholesterol (TC) and triglyceride (Tg). Although the results showed that intensive statin therapy had no superior effect on reduction of mortality (both all-cause mortality [RR = 0.97, p = 0.65] and cardiac death [RR = 0.95, p = 0.57]) and cardiac arrest (RR = 1.09, p = 0.81), it possessed significant effects on prevention of nonfatal myocardial infarction (MI) (RR = 0.78, p = 0.008), stroke (RR = 0.72, p = 0.02) and coronary revascularization (RR = 0.69, p = 0.007). In terms of side effects, intensive statin therapy was associated with small absolute increase in incidence of drug discontinuation, due to adverse events (3.9 %) and liver enzymes abnormalities (1.7 %). And the occurrence rates of myopathy, rhabdomyolysis and creatine kinase (CK) elevation were very low. CONCLUSIONS: This results show that intensive statin therapy has excellent effects on reduction of serum lipid level including LDL-C, TC, Tg, and also on prevention of nonfatal MI, stroke and coronary revascularization with small absolute increased risk of side effects. Our analysis supports the use of intensive statin therapy in patients ≥ 65 years old with CHD.

HLA DRB allele polymorphisms and risk of cervical cancer associated with human papillomavirus infection: a population study in China.

OBJECTIVE: Persistent infection with high-risk human papillomavirus (HPV) is the main cause of cervical cancer. Environmental, behavioral, and ill-defined genetic factors have also been implicated in the pathogenesis of this disease. To determine whether human leukocyte antigen (HLA) DRB alleles are associated with cervical cancer and HPV infections in the Chinese population, HLA genotypes were examined in 69 cervical cancer patients and 201 controls. MATERIALS AND METHODS: Polymorphisms in HLA-DRB genes were genotyped using oligoneucleotide arrays, and the magnitude of associations was determined by logistic regression analysis. RESULTS: HLA-DRB1*13 (OR = 4.01 95% CI, 1.703-9.442) and HLA-DRB1*3(17) (OR = 2.661 95% CI, 1.267-5.558) were associated with an increased risk of cervical cancer, and DRB1*09012 (OR = 0.182, 95% CI, 0.079-0.418 and DRB1*1201 (OR = 0.35 95% CI, 0.142-0.863 were associated with a decreased risk. The risk associations of HPV infection were increased in women carrying the HLA-DRB1*09012 (OR = 1.924; 95% CI, 1.08 -3.427) and DRB3(52)*0101 (OR = 7.527 95% CI, 0.909-62.347) alleles. Among cervical cancer patients, the risk associations differed between HPV positive and negative cases for several alleles; increased risk of cervical cancer was associated with DRB3 (52)*02/03 (OR, 12.794; 95% CI, 5.007-32.691) and DRB1*3(17) (OR = 3.48; 95% CI, 1.261-9.604), and decreased risk was associated with DRB1*09012 and DRB5(51)*01/02. Furthermore, HPV16-containing cervical cancer cases differed from non-HPV16 subjects in their positive association with DRB1*1501 (OR = 4.173; 95% CI, 1.065-16.356) and DRB5(51)*0101/0201, and their negative association with DRB4(53)*0101 (OR = 0.329; 95% CI,0.122-0.888). CONCLUSIONS: The present results provide further evidence that certain HLA class II allele polymorphisms are involved in the genetic susceptibility to cervical cancer and HPV infection in the Chinese population from an area with a high incidence of this neoplasia.

In vitro assessment of the DNA damage and senility of CD117+ stem cells collected from diabetic mice.

OBJECTIVE: Angiogenesis impairment is a common feature of diabetes mellitus (DM), whereas CD117+ bone marrow cells (BMCs) injury might be responsible for such complication. In this study, we studied the effect of hyperglycemia on the DNA damage and senility of CD117+ bone marrow cells. MATERIALS AND METHODS: We isolated CD117+ BMCs from the Streptozotocin (STZ) induced diabetes and healthy control mice. Oxidative stress was detected by flow cytometric analysis. γ-H2AX, which is the DNA damage mark, was detected by using Western blotting and immunofluorescence histochemistry. We also detected the expression of γ-H2AX and p16 by using Western blotting. RESULTS: Compared with the control mice, the level of reactive oxygen species (ROS) was increased significantly in the CD117+ BMCs collected from the diabetic mice (p<0.05), and the percentage of γ-H2AX positive cells was higher significantly (p<0.01). The expression of γ-H2AX and p16 was increased significantly in the CD117+ BMCs from the diabetic mice. CONCLUSIONS: Our experiments demonstrated the oxidative stress in CD117+ BMCs under DM conditions, while accelerating the DNA damage and senility in CD117+ BMCs as well.

Sulfolobus genome: from genomics to biology.

Major progress in sequencing the genome of Sulfolobus solfataricus has been closely concerted with the characterization and sequencing of many extrachromosomal genetic elements, including viruses, cryptic plasmids and conjugative plasmids, as well as mobile archaeal introns and transposons. The latter have provided a basis for developing the first generation of vectors that are now being used to study the genetics of Sulfolobus and other Archaea.

Resveratrol-induced activation of p53 and apoptosis is mediated by extracellular-signal-regulated protein kinases and p38 kinase.

Resveratrol, a phytoalexin found in grapes, berries, and peanuts, is one of the most promising agents for cancer prevention. Our previous study showed that the antitumor activity of resveratrol occurs through p53-mediated apoptosis. In this study, we have elucidated the potential signaling components underlying resveratrol-induced p53 activation and induction of apoptosis. We found that in a mouse JB6 epidermal cell line, resveratrol activated extracellular-signal-regulated protein kinases (ERKs), c-Jun NH2-terminal kinases (JNKs), and p38 kinase and induced serine 15 phosphorylation of p53. Stable expression of a dominant negative mutant of ERK2 or p38 kinase or their respective inhibitor, PD98059 or SB202190, repressed the phosphorylation of p53 at serine 15. In contrast, overexpression of a dominant negative mutant of JNKI had no effect on the phosphorylation. Most importantly, ERKs and p38 kinase formed a complex with p53 after treatment with resveratrol. Strikingly, resveratrol-activated ERKs and p38 kinase, but not JNKs, phosphorylated p53 at serine 15 in vitro. Furthermore, pretreatment of the cells with PD98059 or SB202190 or stable expression of a dominant negative mutant of ERK2 or p38 kinase impaired resveratrol-induced p53-dependent transcriptional activity and apoptosis, whereas constitutively active MEK1 increased the transcriptional activity of p53. These data strongly suggest that both ERKs and p38 kinase mediate resveratrol-induced activation of p53 and apoptosis through phosphorylation of p53 at serine 15.

Suppression of skin tumorigenesis in c-Jun NH(2)-terminal kinase-2-deficient mice.

Previous studies have shown that c-Jun NH(2)-terminal kinase (JNK) belongs to the mitogen-activated protein kinase (MAPK) family of signal transduction components that are rapidly initiated and activated by many extracellular stimuli. However, the potential role of JNK in mediating tumor promotion and carcinogenesis is unclear. We show here that in JNK2-deficient (Jnk2(-/-)) mice, the multiplicity of papillomas induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) was lower than that in wild-type mice. Papillomas on wild-type mice grew rapidly and were well vascularized compared with Jnk2(-/-) mice. After the 12th week of TPA treatment, the mean number of tumors per mouse was 4.13-4.86 in wild-type mice but only 1.13-2.5 in Jnk2(-/-) mice. TPA induced phosphorylation of extracellular signal-regulated kinases and activator protein-1 DNA binding activity in wild-type mice, but the phosphorylation of extracellular signal-regulated kinases and activator protein-1 DNA binding were inhibited in Jnk2(-/-) mice. These data suggest that JNK2 is critical in the tumor promotion process.

Allopurinol ameliorates cardiac function in non-hyperuricaemic patients with chronic heart failure.

OBJECTIVE: This study sought to observe the effects of allopurinol on the cardiac function of non-hyperuricaemic patients with chronic heart failure and determine the safety of allopurinol for clinical applications. PATIENTS AND METHODS: A group of 125 consecutive cases of non-hyperuricaemic patients with chronic heart failure who were treated at Chongqing Emergency Medical Centre between July 2011 and June 2012 were enrolled and were randomly divided into allopurinol (300 mg/day) group (n=62) and control group (n=63). During the six months treatment period, levels of cardiac function, brachial artery endothelial function, inflammatory cytokines, and biochemical markers were routinely examined. RESULTS: After three months of allopurinol treatment, patients exhibited an increase in flow-mediated vasodilatation (FMD) of brachial artery, whereas, after six months of treatment, the cardiac function classification was improved; plasma levels of brain natriuretic peptide and tumour necrosis factor-a were decreased; left ventricular internal diameter was diminished; and the ejection fraction was increased (p<0.01 for all the parameters) in patients. Serum uric acid level was decreased during the treatment period for both groups, with no significant difference between the two groups. Liver and kidney dysfunction was not observed among the study participants, and no significant increase in creatine kinase level was detected for either treatment group. CONCLUSIONS: For non-hyperuricaemic patients with chronic heart failure, the addition of six months of allopurinol therapy was safe and effective. Moreover, in these patients, allopurinol treatment not only can significantly ameliorate the left ventricular function and reduce the level of inflammatory factors but could also improve endothelial function.

Non-autonomous mobile elements in the crenarchaeon Sulfolobus solfataricus.

The genome of the archaeon Sulfolobus solfataricus P2 contains at least four types of short sequence elements lacking open reading frames which are similar to eukaryal non-autonomous mobile elements. The most- conserved elements SM1 (79-80 bp) and SM2 (183-186 bp), with 95 % sequence identity, are present in 40 and 25 copies, respectively. The less-conserved elements SM3 (127-139 bp) and SM4 (160-168 bp), with 75-97 % identity, occur in 44 and 34 copies, respectively. In total, the 143 SM elements constitute about 0.6 % of the genome. The wide distribution of each class of conserved element throughout the genome, and their precise locations, indicate that they are mobile. Direct evidence arises from the presence of SM1 and SM2 in only a fraction of genomic copies of a given class of insertion element, and within copies of open reading frames that are conserved in sequence. SM1 to SM4 are likely to be mobilized by transposases encoded by insertion elements ISC1048, ISC1217, ISC1058 and ISC1173, respectively. Furthermore, the occurrence of clusters of interwoven SM and insertion elements, in potentially mobile units, suggests a mechanism for the transfer of SM elements to other organisms.

Evolution of the family of pRN plasmids and their integrase-mediated insertion into the chromosome of the crenarchaeon Sulfolobus solfataricus.

Plasmid pHEN7 from Sulfolobus islandicus was sequenced (7.83 kb) and shown to belong to the archaeal pRN family, which includes plasmids pRN1, pRN2, pSSVx and pDL10 that share a large conserved sequence region. pHEN7 is most closely related to pRN1 in this conserved region. It also shares a large variant region containing several homologous genes with pDL10, which is absent from the other plasmids. The variant region is flanked by the sequence motif TTAGAATGGGGATTC and similar duplicated motifs occur in plasmids pRN1 and pRN2, separated by a few bases. It is inferred that recombination at these sites produces the main genetic variability in the plasmid family. The conserved region of the plasmid, and duplicated copies of the motif, are also present in the genome of Sulfolobus solfataricus P2. Moreover, they are bordered by a partitioned integrase gene (int) and by a 45 bp perfect direct repeat corresponding to the downstream half of a tRNA(Val) gene. The integrase and the direct repeat are highly similar in sequence to the integrase and the chromosomal integration site (att), respectively, of the SSV1 virus, which integrates into the chromosome of Sulfolobus shibatae. Recombination at the att repeats in S. solfataricus would produce a novel plasmid, pXQ1, which carries both an intact integrase gene and a single integration site (att). This strongly suggests that the same mechanism of site-specific integration at a tRNA gene is used for both viruses and plasmids in Sulfolobus.

Placental alkaline phosphatase, insulin, and adenine nucleotides or adenosine synergistically promote long-term survival of serum-starved mouse embryo and human fetus fibroblasts.

Earlier we showed that in serum-starved fibroblasts placental alkaline phosphatase (PALP) can exert growth factor-like effects. Here we report that in mouse embryo (NIH 3T3) and human fetus (HTB-157) fibroblasts, PALP (200 nM) alone provided full protection against serum starvation-induced cell death for 5 days. After 12 days, substantial effects of PALP on cell survival required the copresence of insulin (500 nM) and ATP or adenosine (100 microM). In serum-starved NIH 3T3 cells, PALP induced activating phosphorylation of p42/p44 mitogen-activated protein (MAP) kinases; insulin, but not ATP, had small additional effects. PALP also stimulated the expression of various cyclins; ATP both prolonged and enhanced PALP-induced expression of cyclins A and E. Finally, ATP/adenosine enhanced activation of Akt kinase by insulin. The results suggest that PALP may be a regulator of growth and remodeling of fetal tissues during the second and third trimester of pregnancy when it is expressed.

alpha(1)-antitrypsin can increase insulin-induced mitogenesis in various fibroblast and epithelial cell lines.

alpha(1)-Antitrypsin (AT), the archetypal member of the superfamily of serine proteinase inhibitors, inhibits leukocyte elastase activity and thereby can prevent lung damage. Here we show that in fibroblasts from human fetal lung and mouse embryo as well as in certain epithelial cells AT can also enhance the stimulatory effects of insulin on DNA synthesis and cell proliferation. Warming of AT at a moderate (41 degrees C) temperature for a longer time (21 h) or at a higher (65 degrees C) temperature for 30 min before treatment increased its stimulatory effects on both DNA synthesis and activating phosphorylation of p42/p44 mitogen-activated protein kinases. The results suggest that AT may promote regeneration of damaged tissues under pathophysiological conditions which are associated with fever.

Growth factor-like effects of placental alkaline phosphatase in human fetus and mouse embryo fibroblasts.

Human placental alkaline phosphatase (PALP) is synthesized in the placenta during pregnancy and is also expressed in many cancer patients; however, its physiological role is unknown. Here we show that in human fetus fibroblasts as well as normal and H-ras-transformed mouse embryo fibroblasts PALP stimulates DNA synthesis and cell proliferation in synergism with insulin, zinc and calcium. The mitogenic effects of PALP are associated with the activation of c-Raf-1, p42/p44 mitogen-activated protein kinases, p70 S6 kinase, Akt/PKB kinase and phosphatidylinositol 3'-kinase. The results suggest that in vivo PALP may promote fetus development as well as the growth of cancer cells which express oncogenic Ras.

The possible mechanism of synergistic effects of ethanol, zinc and insulin on DNA synthesis in NIH 3T3 fibroblasts.

In serum-starved NIH 3T3 fibroblast cultures, zinc (15-40 microM) enhanced both the individual and combined stimulatory effects of insulin and ethanol (EtOH) on DNA synthesis. Zinc, but not EtOH, also promoted the stimulatory effects of insulin on activating phosphorylation of p42/p44 mitogen-activated protein (MAP) kinases. In the presence of zinc, insulin induced premature expression of cyclin E during early G1 phase; EtOH partially restored the normal timing (late G1 phase) of cyclin E expression. The results suggest that zinc and EtOH promote insulin-induced DNA synthesis by different mechanisms; while zinc acts by enhancing the effects of insulin on MAP kinase activation, EtOH may act by ensuring timely zinc-dependent insulin-induced expression of cyclin E.

A BAC library and paired-PCR approach to mapping and completing the genome sequence of Sulfolobus solfataricus P2.

The original strategy used in the Sulfolobus solfataricus genome project was to sequence non overlapping, or minimally overlapping, cosmid or lambda inserts without constructing a physical map. However, after only about two thirds of the genome sequence was completed, this approach became counter-productive because there was a high sequence bias in the cosmid and lambda libraries. Therefore, a new approach was devised for linking the sequenced regions which may be generally applicable. BAC libraries were constructed and terminal sequences of the clones were determined and used for both end mapping and PCR screening. The PCR approaches included a novel chromosome walking method termed "paired-PCR". 21 gaps were filled by BAC end sequence analyses and 6 gaps were filled by PCR including three large ones by paired-PCR. The complete map revealed that 0.9 Mb remained to be sequenced and 34 BAC clones were selected for walking over small gaps and preparing template libraries for larger ones. It is concluded that an optimal strategy for sequencing microorganism genomes involves construction of a high-resolution physical map by BAC end analyses, PCR screening and paired-PCR chromosome walking after about half the genome sequence has been accumulated.

[Effect of octreotide on intragastric pH in patients with duodenal ulcer bleeding].

OBJECTIVE: To evaluate the effect of octreotide on the intragastric pH of patients with duodenal ulcer bleeding during the period of 24 hours and to observe if it can advance the effect of hemostasis by endoscopic injection of epinephrine. METHODS: Twenty-four patients with duodenal ulcer bleeding were randomly divided into three groups, eight in each. Patients in group 1 received an intravenous injection of 0.1 mg of octreotide followed by continuous intravenous drip of octreotide at a constant speed of 25 microg/h for 24 hours. The patients in group 2 received an intravenous injection of 0.1 mg of octreotide followed by continuous intravenous drip of octreotide at a constant speed of 42 microg/h for 24 hours. The patients in group 3 received an intravenous injection of 40 mg of omeprazole followed by continuous intravenous drip of omeprazole at a constant speed of 8 mg/h for 24 hours. Intragastric pH was continuously recorded with a pH meter. The patients with active ulcer bleeding was treated with injection of epinephrine via endoscope and then received intravenous drip of octreotide (with the same dosage as in group 1, n = 42) or omeprazole (with the same dosage as in group 3, n = 54) for 72 hours and were given omeprazole (20 mg Bid). RESULTS: The mean and median intragastric pH values among the patients in group 2 treated by a larger dosage of octreotide (6.7 +/- 0.5 and 6.9 +/- 0.4) were similar to those in the group 3 treated by omeprazole (6.8 +/- 0.4 and 7.0 +/- 0.4). There was no statistically significant difference between these two groups in percentage of intragastric pH above 4, 6, and 7 The mean and median of intragastric pH among the patients in group 1 treated by a smaller dosage of octreotide were statistically significantly smaller (5.2 +/- 0.5 and 5.4 +/- 0.4) than those in the omeprazole group. There was no statistically significant difference between octreotide treatment and omeprazole treatment in terms of volume of blood transfusion (0.7 +/- 0.5 vs. 0.6 +/- 0.4 L), rebleeding rate (11.6% vs. 12.9%), emergency operation rate (7.1% vs. 3.7%), and mortality (2.3% vs. 3.7%). CONCLUSION: Octreotide effectively inhibits the secretion of gastric acid. However, the dosage in common use clinically fails to increase the intragastric pH to the best situation needed for effective hemostasis. Only a large dosage (1.10 mg/d) works.

ERK and AKT signaling cooperate to translationally regulate survivin expression for metastatic progression of colorectal cancer.

The mitogen-activated extracellular signal-regulated kinase/extracellular signal-regulated kinase (MEK/ERK) and phosphatidylinositol 3-kinase (PI3K)/AKT pathways are often concurrently activated by separate genetic alterations in colorectal cancer (CRC), which is associated with CRC progression and poor survival. However, how activating both pathways is required for CRC metastatic progression remains unclear. Our recent study showed that both ERK and AKT signaling are required to activate eukaryotic translation initiation factor 4E (eIF4E)-initiated cap-dependent translation via convergent regulation of the translational repressor 4E-binding protein 1 (4E-BP1) for maintaining CRC transformation. Here, we identified that the activation of cap-dependent translation by cooperative ERK and AKT signaling is critical for promotion of CRC motility and metastasis. In CRC cells with coexistent mutational activation of ERK and AKT pathways, inhibition of either MEK or AKT alone showed limited activity in inhibiting cell migration and invasion, but combined inhibition resulted in profound effects. Genetic blockade of the translation initiation complex by eIF4E knockdown or expression of a dominant active 4E-BP1 mutant effectively inhibited migration, invasion and metastasis of CRC cells, whereas overexpression of eIF4E or knockdown of 4E-BP1 had the opposite effect and markedly reduced their dependence on ERK and AKT signaling for cell motility. Mechanistically, we found that these effects were largely dependent on the increase in mammalian target of rapamycin complex 1 (mTORC1)-mediated survivin translation by ERK and AKT signaling. Despite the modest effect of survivin knockdown on tumor growth, reduction of the translationally regulated survivin profoundly inhibited motility and metastasis of CRC. These findings reveal a critical mechanism underlying the translational regulation of CRC metastatic progression, and suggest that targeting cap-dependent translation may provide a promising treatment strategy for advanced CRC.