Targeting glutamine metabolism exhibits anti-tumor effects in thyroid cancer.

BACKGROUND: Effective treatment for patients with advanced thyroid cancer is lacking. Metabolism reprogramming is required for cancer to undergo oncogenic transformation and rapid tumorigenic growth. Glutamine is frequently used by cancer cells for active bioenergetic and biosynthetic needs. This study aims to investigate whether targeting glutamine metabolism is a promising therapeutic strategy for thyroid cancer. METHODS: The expression of glutaminase (GLS) and glutamate dehydrogenase (GDH) in thyroid cancer tissues was evaluated by immunohistochemistry, and glutamine metabolism-related genes were assessed using real time-qPCR and western blotting. The effects of glutamine metabolism inhibitor 6-diazo-5-oxo-l-norleucine (DON) on thyroid cancer cells were determined by CCK-8, clone formation assay, Edu incorporation assay, flow cytometry, and Transwell assay. The mechanistic study was performed by real time-qPCR, western blotting, Seahorse assay, and gas chromatography-mass spectrometer assay. The effect of DON prodrug (JHU-083) on thyroid cancer in vivo was assessed using xenograft tumor models in BALB/c nude mice. RESULTS: GLS and GDH were over-expressed in thyroid cancer tissues, and GLS expression was positively associated with lymph-node metastasis and TNM stage. The growth of thyroid cancer cells was significantly inhibited when cultured in glutamine-free medium. Targeting glutamine metabolism with DON inhibited the proliferation of thyroid cancer cells. DON treatment did not promote apoptosis, but increased the proportion of cells in the S phase, accompanied by the decreased expression of cyclin-dependent kinase 2 and cyclin A. DON treatment also significantly inhibited the migration and invasion of thyroid cancer cells by reducing the expression of N-cadherin, Vimentin, matrix metalloproteinase-2, and matrix metalloproteinase-9. Non-essential amino acids, including proline, alanine, aspartate, asparagine, and glycine, were reduced in thyroid cancer cells treated with DON, which could explain the decrease of proteins involved in migration, invasion, and cell cycle. The efficacy and safety of DON prodrug (JHU-083) for thyroid cancer treatment were verified in a mouse model. In addition to suppressing the proliferation and metastasis potential of thyroid cancer in vivo, enhanced innate immune response was also observed in JHU-083-treated xenograft tumors as a result of decreased expression of cluster of differentiation 47 and programmed cell death ligand 1. CONCLUSIONS: Thyroid cancer exhibited enhanced glutamine metabolism, as evidenced by the glutamine dependence of thyroid cancer cells and high expression of multiple glutamine metabolism-related genes. Targeting glutamine metabolism with DON prodrug could be a promising therapeutic option for advanced thyroid cancer.

The influencing mechanism of mTOR signal pathway mediated by mitofusin-2 in development of follicle.

OBJECTIVE: To investigate the influencing mechanism of mammalian target of rapamycin (mTOR) signal pathway mediated by mitofusin-2 (Mfn2) in the development of follicle. MATERIALS AND METHODS: We selected 20 healthy Sprague Dawley (SD) female rats aging between 6 and 8 weeks were divided into the control group and the polycystic ovarian syndrome (PCOS) model group. Rats in PCOS group received the lavage using 0.4 mL 1% carboxymethyl cellulose solution containing letrozole (1 mg/kg/d) consecutively for 20 to 25d. We compared the body weight and ovary weight of rats, and detected levels of sera E2, T, P, FSH and LH through RIA measurement. We also observed the histological morphology of ovary through hematoxylin eosin (HE) staining, as well as the positive expression and location of rMfn2 through immunohistochemistry staining. Finally, we detected the expressions of mTOR, p-Akt, ß-catenin, caspase-3, Bcl-2 and Bax in Mfn2 and mTOR signal pathways in the tissues through RT-PCR and Western blot assay. RESULTS: In the PCOS group, the body weight of rats was lower than that of the control group, but the ovary weight of rats was higher than that in the control group. The levels of T and LH in serum were elevated, the levels of E2, P and FSH were decreased (p < 0.05). In the model group, typical polycystic changes were observed in the rats under the microscope, but no corpus luteum was observed, and a significant decrease was identified in the layers of the granular cell of the follicle. Mfn2 was widely expressed in the granular cells of the ovary, follicular fluid, inner theca cells, corpus luteum, and ovarian stroma. However, the expression in the outer theca cells was relatively low. In the observation group, the positive expression rate of Mfn2 was significantly lower (p < 0.05) than that in the control group. In the PCOS group, the mRNA and protein relative expression levels of mTOR, p-Akt, ß-catenin, and Bcl-2 were significantly lower (p < 0.05) than those in the control group. Conversely, the levels of caspase-3 and Bax were significantly higher (p < 0.05) than those in the control group. CONCLUSIONS: Downregulated expression of Mfn2 may affect the regular development of follicle through the mediation of mTOR signal pathway.

Retraction of articles by H. Zhong et al.

A series of 41 papers by H. Zhong et al. are retracted.

catena-Poly[[(1,10-phenanthroline-κN,N')praseodymium(III)]-di-µ-phenoxy-acetato-κO:O'-[(1,10-phenanthroline-κN,N')praseodymium(III)]-di-µ-phenoxy-acetato-κO:O'-di-µ-phenoxy-acetato-κO,O':O;κO:O,O'].

The title complex, [Pr(2)(C(8)H(7)O(3))(6)(C(12)H(8)N(2))(2)](n), which has an inversion centre midway between the two Pr(III) atoms of the structural unit, forms a one-dimensional polymer bridged alternately by either two bidentate, or two bidentate and two terdentate, phenoxy-acetate carboxyl-ate groups. Each Pr(III) atom is thus nine-coordinated by two N atoms of a 1,10-phenanthroline ligand and seven O atoms from six phenoxy-acetate ligands. The coordination geometry at the Pr(III) atom is distorted tricapped trigonal prismatic. One phenyl ring is disordered over two positions; the site occupancy factors are ca 0.6 and 0.4.

Bis(4-phenyl-pyridinium) tetra-kis(nitrato-κO,O')stannate(IV). Retraction.

The paper by Zhong, Zeng, Yang & Luo [Acta Cryst. (2007), E63, m1567] is retracted.

Bis(4,4'-bipyridine-κN)tetra-kis(nitrato-κO,O')tin(IV). Retraction.

The paper by Zhong, Zeng, Yang & Luo [Acta Cryst. (2007), E63, m1566] is retracted.

A new covered stent designed for intracranial vasculature: application in the management of pseudoaneurysms of the cranial internal carotid artery.

BACKGROUND AND PURPOSE: The management of intracranial pseudoaneurysms is controversial. The purpose of this study was to provide a preliminary evaluation of the clinical efficacy of a Willis covered stent specially designed for the intracranial vasculature in the management of a pseudoaneurysm of the cranial internal carotid artery (CICA). MATERIALS AND METHODS: Eight patients with pseudoaneurysms of the CICA were treated with use of the Willis covered stent. The flexibility of the entire stent system was gauged from the resistance met when reaching the target lesion and was categorized as no resistance, no apparent resistance, or resistance that could be overcome. The apposition of the Willis stent after deployment was scored as excellent with no endoleak, good with a small endoleak, or bad with an apparent endoleak. Follow-up angiography was performed 3 to 12 months after placement of the stent, and angiographic assessments were categorized as endoleak, stenosis of the covered segment of vessel, or occlusion of parent arteries. Follow-up clinical evaluations were also performed, and outcomes were graded as full recovery, improvement, unchanged, and aggravation. RESULTS: Endovascular treatment was technically successful in all aneurysms without procedural-related complications, and all of the stents were easily navigated to the targeted lesions in the CICA. Complete resolution of the pseudoaneurysm was observed in 6 patients immediately after the procedure, and a minimal endoleak into the aneurysm persisted in 2 patients. No morbidity or mortality and no technical adverse event occurred. A follow-up angiogram confirmed complete reconstruction of the internal carotid artery, with no recurrent aneurysmal filling and no occurrence of stenosis in the area of the stent. By the final follow-up visit, 4 patients had fully recovered, 3 had improved, and 1 patient's condition was unchanged. CONCLUSION: On the basis of our preliminary experience, the Willis covered stent specially designed for the intracranial vasculature can manage a CICA pseudoaneurysm safely and effectively, but longer follow-up and expanded clinical trials are needed.

Mapping QTL associated with resistance to Fusarium head blight in the Nanda2419 x Wangshuibai population. II: type I resistance.

Fusarium head blight (FHB) is a serious disease in wheat and barley affecting both yield and quality. To identify genes for resistance to infection, the RIL population derived from 'Nanda2419' x 'Wangshuibai' and the parents were evaluated for percentage of infected spikes (PIS) in four different environments. Using a 2,960 cM marker framework map constructed for this population, ten chromosome regions were detected for their association with type I resistance through interval mapping with Mapmaker/QTL, among which QTLs mapped in the intervals of Xwmc349--Xgwm149 on chromosome 4B, of Xwmc96--Xgwm304 on chromosome 5A and of Xgwm408--Xbarc140 on chromosome 5B were revealed in at least three environments and have Wangshuibai as the source of resistance alleles. Qfhi.nau-4B and Qfhi.nau-5A had larger effects and explained up to 17.5 and 27.0% of the phenotypic variance, respectively. To detect epistasis QTLs, two-locus interactions were examined by whole genome scan. Interactions of five locus pairs were found to have significant effects on type I resistance with the LOD score ranging 3.8-6.5 and four of them conferred resistance in parental phase. The one with the most significant effect was Xcfd42--Xgwm469 (6D)/Xwmc390-2--Xbd04 (2A) pair. No QTL x E interaction was detected for PIS. It was found that flowering time did not have significant effects on PIS in this population. Our studies indicated that Wangshuibai is useful for breeding for both type I and type II scab resistance and the markers associated with the QTLs could be used in marker-assisted selection and isolation of scab-resistance QTLs.

[Study on schistosomiasis control strategy in Ertan reservoir].

OBJECTIVE: To explore means and strategies of preventing the spread of schistosomasis transmission due to the building of Ertan Dam. METHODS: To eliminate the infection sources and Oncomelania snails. To install concrete irrigation and piping system of water supply. To encourage the immigrants to build methane-generating tanks and improve sanitary facilities and conditions for families who live near the water-retaining line. RESULTS: 2,360 people and 152 cattle were treated for schistosome infection. Mollusciciding and environmental modification were made for eliminating snails at an area of 3,634,580 m2 and 67,105.5 m2 respectively. The length of concrete irrigation and piping system installed was 51.13 and 104.895 km respectively. Methane-generating tanks, water-heating instruments using solar energy and other sanitary facilities were established in 1,781 households. After three-year intervention, no infected snails were found and no infected human being, cattle and wild rats were detected. CONCLUSION: Schistosomiasis control was financially supported since the very beginning of the Ertan Dam project, which provided a condition for sustainable development. Continued surveillance of snails and infection sources should be carried out, which will provide scientific basis for schistosomiasis control in the Three Gorges region as well as other new projects of hydropower and water conservancy in endemic area.