Glutamine synthetase licenses APC/C-mediated mitotic progression to drive cell growth.

Tumors can reprogram the functions of metabolic enzymes to fuel malignant growth; however, beyond their conventional functions, key metabolic enzymes have not been found to directly govern cell mitosis. Here, we report that glutamine synthetase (GS) promotes cell proliferation by licensing mitotic progression independently of its metabolic function. GS depletion, but not impairment of its enzymatic activity, results in mitotic arrest and multinucleation across multiple lung and liver cancer cell lines, patient-derived organoids and xenografted tumors. Mechanistically, GS directly interacts with the nuclear pore protein NUP88 to prevent its binding to CDC20. Such interaction licenses activation of the CDC20-mediated anaphase-promoting complex or cyclosome to ensure proper metaphase-to-anaphase transition. In addition, GS is overexpressed in human non-small cell lung cancer and its depletion reduces tumor growth in mice and increases the efficacy of microtubule-targeted chemotherapy. Our findings highlight a moonlighting function of GS in governing mitosis and illustrate how an essential metabolic enzyme promotes cell proliferation and tumor development, beyond its main metabolic function.

Life-threatening complications of ascariasis in trauma patients: a review of the literature.

BACKGROUND: Ascariasis is one of the most common human parasitic infections worldwide. In some rare cases, ascariasis may cause serious consequences even sudden death. This study was undertaken to review the life-threatening complications of ascariasis in trauma patients reported in the literature. DATA SOURCES: Relevant articles about ascariasis and trauma were searched from Pubmed, Google scholar, Scirus, and Wanfang databases. RESULTS: Twenty-four patients with ascariasis were collected from 21 articles searched. Most of these patients were from tropical and subtropical countries. Of the 24 patients, 12 were children. Their major complications occurred in the airway passage and digestive tract. There were 3 fatal cases in these patients. Twelve of the 24 patients described in 10 articles were reported in the last 10 years. CONCLUSIONS: Early diagnosis and prompt intervention are essential to minimize the high morbidity and mortality of these serious complications in trauma patients. Physicians should be aware of the possibility of Ascaris infection in a trauma patient from endemic area of ascariasis. History of Ascaris infection and routine examination of feces for Ascaris eggs may be helpful to make a correct diagnosis.

Mechanical stretch suppresses microRNA-145 expression by activating extracellular signal-regulated kinase 1/2 and upregulating angiotensin-converting enzyme to alter vascular smooth muscle cell phenotype.

Phenotype modulation of vascular smooth muscle cells (VSMCs) plays an important role in the pathogenesis of various vascular diseases, including hypertension and atherosclerosis. Several microRNAs (miRNAs) were found involved in regulating the VSMC phenotype with platelet-derived growth factor (PDGF) treatment, but the role of miRNAs in the mechanical stretch-altered VSMC phenotype is not clear. Here, we identified miR-145 as a major miRNA contributing to stretch-altered VSMC phenotype by miRNA array, quantitative RT-PCR and gain- and loss-of-function methods. Our data demonstrated that 16% stretch suppressed miR-145 expression, with reduced expression of contractile markers of VSMCs cultured on collagenI; overexpression of miR-145 could partially recover the expression in stretched cells. Serum response factor (SRF), myocardin, and Kruppel-like factor 4 (KLF4) are major regulators of the VSMC phenotype. The effect of stretch on myocardin and KLF4 protein expression was altered by miR-145 mimics, but SRF expression was not affected. In addition, stretch-activated extracellular signal-regulated kinase 1/2 (ERK1/2) and up-regulated angiotensin-converting enzyme (ACE) were confirmed to be responsible for the inhibition of miR-145 expression. Mechanical stretch inhibits miR-145 expression by activating the ERK1/2 signaling pathway and promoting ACE expression, thus modulating the VSMC phenotype.

Mechanical stretch modulates microRNA 21 expression, participating in proliferation and apoptosis in cultured human aortic smooth muscle cells.

OBJECTIVES: Stretch affects vascular smooth muscle cell proliferation and apoptosis, and several responsible genes have been proposed. We tested whether the expression of microRNA 21 (miR-21) is modulated by stretch and is involved in stretch-induced proliferation and apoptosis of human aortic smooth muscle cells (HASMCs). METHODS AND RESULTS: RT-PCR revealed that elevated stretch (16% elongation, 1 Hz) increased miR-21 expression in cultured HASMCs, and moderate stretch (10% elongation, 1 Hz) decreased the expression. BrdU incorporation assay and cell counting showed miR-21 involved in the proliferation of HASMCs mediated by stretch, likely by regulating the expression of p27 and phosphorylated retinoblastoma protein (p-Rb). FACS analysis revealed that the complex of miR-21 and programmed cell death protein 4 (PDCD4) participated in regulating apoptosis with stretch. Stretch increased the expression of primary miR-21 and pre-miR-21 in HASMCs. Electrophoretic mobility shift assay (EMSA) demonstrated that stretch increased NF-κB and AP-1 activities in HASMCs, and blockade of AP-1 activity by c-jun siRNA significantly suppressed stretch-induced miR-21 expression. CONCLUSIONS: Cyclic stretch modulates miR-21 expression in cultured HASMCs, and miR-21 plays important roles in regulating proliferation and apoptosis mediated by stretch. Stretch upregulates miR-21 expression at least in part at the transcription level and AP-1 is essential for stretch-induced miR-21 expression.

Kindlin-1 Is required for RhoGTPase-mediated lamellipodia formation in keratinocytes.

Kindlin-1 is an epithelial-specific member of the novel kindlin protein family, which are regulators of integrin functions. Mutations in the gene that encodes Kindlin-1, FERMT1 (KIND1), cause the Kindler syndrome (KS), a human disorder characterized by mucocutaneous fragility, progressive skin atrophy, ulcerative colitis, photosensitivity, and propensity to skin cancer. Our previous studies indicated that loss of kindlin-1 resulted in abnormalities associated with integrin functions, such as adhesion, proliferation, polarization, and motility of epidermal cells. Here, we disclosed novel FERMT1 mutations in KS and used them, in combination with small-interfering RNA, protein, and imaging studies, to uncover new functions for kindlin-1 in keratinocytes and to discern the molecular pathology of KS. We show that kindlin-1 forms molecular complexes with beta1 integrin, alpha-actinin, migfilin, and focal adhesion kinase and regulates cell shape and migration by controlling lamellipodia formation. Kindlin-1 governs these processes by signaling via Rho family GTPases, and it is required to maintain the pool of GTP-bound, active Rac1, RhoA and Cdc42, and the phosphorylation of their downstream effectors p21-activated kinase 1, LIM kinase, and cofilin. Loss of these kindlin-1 functions forms the biological basis for the epithelial cell fragility and atrophy in the pathology of KS.

Effect of atorvastatin versus rosuvastatin on levels of serum lipids, inflammatory markers and adiponectin in patients with hypercholesterolemia.

PURPOSE: To compare the short-term effect of treatment with atorvastatin and rosuvastatin on levels of serum lipids, inflammatory markers and adiponectin in patients with hypercholesterolemia. METHODS: Sixty-nine patients with hypercholesterolemia were randomly assigned to receive 10 mg/day of atorvastatin or rosuvastatin for 12 weeks. Inflammatory biomarkers, including highsensitivity C-reactive protein (hs-CRP), tumor necrosis factor (TNF)-alpha, matrix metalloproteinase-9 (MMP-9), and endothelin (ET-1), plasminogen activator inhibitor type 1 (PAI-1) and plasma tissue plasminogen activator (tPA), adiponectin, and lipid profiles were measured before and after statin therapy. RESULTS: Atorvastatin and rosuvastatin both lowered levels of hs-CRP, MMP-9, PAI-1, total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) from baseline values, with rosuvastatin lowering TC and LDL-C to a greater extent than atorvastatin (P < 0.05). Adiponectin level increase was 15% higher than that at baseline with atorvastatin (P > 0.05) but 67% higher with rosuvastatin (P < 0.05). CONCLUSIONS: Therapy with both statins not only significantly improved lipid profiles but also decreased levels of vascular biomarkers hs-CRP, MMP-9, and PAI-1; however, only rosuvastatin increased serum adiponectin levels significantly in patients with hypercholesterolemia, which could imply a beneficial effect in coronary artery disease.

[The causes of death and risk factors in patients of war wound and trauma of extremities by logistic regression model].

OBJECTIVE: To explore the causes of death and risk factors in patients of war wound and trauma of extremities. METHODS: This retrospective study involved 352 patients of war wound and trauma of extremities admitted to 303rd Hospital of People's Liberation Army during the period between 1968 to 2002. All the data were reviewed and the causes of death of 15 patients were analyzed by autopsy, and a computer's logistic regression model analysis was performed to approach the risk factors of death. RESULTS: Fifteen of the three hundred and fifty-two patients were died (4.3 %). The causes of death included acute renal failure (ARF) (46.7%, 7/15), lung embolism (20.0%, 3/15), clostridial myonecrosis (20.0%, 3/15) and multiple organ system failure (MOSF) (13.3%, 2/15). In the univariate analysis, the risk of death increased by shock, time admitted to hospital, amputation, time of tourniquet, associated injury of head, thoracic region, abdomen or blood vessel (P < 0. 05). In the logistic regression model analysis, shock and amputation were the two factors most strongly associated with the death of patients of war wound and trauma. (P < 0. 05). CONCLUSION: Acute renal failure (ARF) was the main cause of death of patients of war wound and trauma of extremities. Its should be helpful for minimize the mortality of patients of war wound and trauma to manage the shock in time and have a correct choice of amputation promptly.

Assessment of ischemic myocardium by strain-rate imaging during adenosine stress echocardiography.

OBJECTIVE: Strain rate (SR) provides a quantitative segmental analysis of myocardial function. However, the use of SR with stress echocardiography to determine the ischemic myocardium has not been completely investigated. The present study aimed to determine the changes in systolic function of the ischemic myocardium by strain-rate imaging (SRI) with adenosine stress echocardiography. METHODS: Stenosis and complete occlusion of coronary arteries were produced in 11 canine models by constricting the left anterior descending coronary artery (LAD). Myocardial longitudinal strain with adenosine was measured at baseline and during ischemia and infarction. RESULTS: Strain and SR did not differ during ischemia and infarction as compared with that at baseline in non-LAD segments or after adenosine treatment. As compared with baseline, during ischemia, LAD segments showed significantly decreased peak systolic SR (SR(peak sys)) (P < 0.05) and significantly increased ratio of postsystolic strain (epsilon(ps)) to strain during ejection time (epsilon(et)) (epsilon(ps)/epsilon(et)) (P < 0.05); epsilon(max) and epsilon(et) were reduced slightly, epsilon(ps) and the ratio of epsilon(ps) to maximal systolic strain (epsilon(max))(epsilon(ps)/epsilon(max)) were increased minimally, but had no significance(P > 0.05). During infarction, the epsilon(ps) and the ratios of epsilon(ps)/epsilon(max) and epsilon(ps)/epsilon(et) were increased markedly (P < 0.01) and epsilon(et) and SR(peak sys) decreased as compared with that at baseline and during ischemia, whereas epsilon(max) was reduced only with at baseline (P < 0.01). After adenosine treatment, in the non-LAD segments, the values of strain and SR did not change at baseline or during ischemia and infarction and in LAD segments, values did not change at baseline and during infarction. However, during ischemia, SR(peak sys) and epsilon(et) were significantly reduced (P < 0.05), whereas epsilon(ps), epsilon(ps)/epsilon(max) and epsilon(ps)/epsilon(et) were increased (P < 0.05 and < 0.01, respectively). CONCLUSION: Combined with adenosine stress echocardiography, SRI can quantitatively differentiate the ischemic from non-ischemic myocardium. epsilon(ps)/epsilon(max) and epsilon(ps)/epsilon(et) can be used as objective indices to identify the ischemic myocardium.