Cystine addiction of triple-negative breast cancer associated with EMT augmented death signaling.

This corrects the article DOI: 10.1038/onc.2016.394.

Cystine addiction of triple-negative breast cancer associated with EMT augmented death signaling.

Despite the advances in the diagnosis and treatment of breast cancer, breast cancers still cause significant mortality. For some patients, especially those with triple-negative breast cancer, current treatments continue to be limited and ineffective. Therefore, there remains an unmet need for a novel therapeutic approach. One potential strategy is to target the altered metabolic state that is rewired by oncogenic transformation. Specifically, this rewiring may render certain outside nutrients indispensable. To identify such a nutrient, we performed a nutrigenetic screen by removing individual amino acids to identify possible addictions across a panel of breast cancer cells. This screen revealed that cystine deprivation triggered rapid programmed necrosis, but not apoptosis, in the basal-type breast cancer cells mostly seen in TNBC tumors. In contrast, luminal-type breast cancer cells are cystine-independent and exhibit little death during cystine deprivation. The cystine addiction phenotype is associated with a higher level of cystine-deprivation signatures noted in the basal type breast cancer cells and tumors. We found that the cystine-addicted breast cancer cells and tumors have strong activation of TNFα and MEKK4-p38-Noxa pathways that render them susceptible to cystine deprivation-induced necrosis. Consistent with this model, silencing of TNFα and MEKK4 dramatically reduces cystine-deprived death. In addition, the cystine addiction phenotype can be abrogated in the cystine-addictive cells by miR-200c, which converts the mesenchymal-like cells to adopt epithelial features. Conversely, the introduction of inducers of epithelial-mesenchymal transition (EMT) in cystine-independent breast cancer cells conferred the cystine-addiction phenotype by modulating the signaling components of cystine addiction. Together, our data reveal that cystine-addiction is associated with EMT in breast cancer during tumor progression. These findings provide the genetic and mechanistic basis to explain how cystine deprivation triggers necrosis by activating pre-existing oncogenic pathways in cystine-addicted TNBC with prominent mesenchymal features.

A qualitative and quantitative analysis of the New Zealand media portrayal of Down syndrome.

BACKGROUND: There are only a small number of studies that systematically explore the tensions between the global shift to universal screening and the media representations of the people with Down syndrome. This paper contributes to the literature by analyzing the New Zealand media coverage of this topic. OBJECTIVE: To describe the content and quality of selected New Zealand media references to Down syndrome in light of the claim by New Zealand support group Saving Downs of state supported eugenics via universal screening. METHODS: Quantitative content analysis was conducted of 140 relevant New Zealand articles (from 2001 to 2011) and qualitative critical discourse analysis of 18 relevant articles (from 2009 to 2011) selected from television, magazine and newspaper. RESULTS: The content analysis showed no strong directional reporting although the quality of life for people with Down syndrome was represented as slightly negative. Most articles focused on issues of society, government and care rather than genetics. The qualitative analysis identified themes around quality of life, information and bias, preparedness, eugenics, the visualness of disability and the need for public debate around genetic screening and testing. CONCLUSION: The New Zealand print media coverage of these issues has been relatively balanced. Recent mixed media coverage of the topic is critical, complex and socially inclusive of people with Down syndrome.

Genetic and molecular characterization of uveal melanoma cell lines.

The recent identification of frequent activating mutations in GNAQ or GNA11 in uveal melanoma provides an opportunity to better understand the pathogenesis of this melanoma subtype and to develop rational therapeutics to target the cellular effects mediated by these mutations. Cell lines from uveal melanoma tumors are an essential tool for these types of analyses. We report the mutation status of relevant melanoma genes, expression levels of proteins of interest, and DNA fingerprinting of a panel of uveal melanoma cell lines used in the research community.

Gefitinib, a novel, orally administered agent for the treatment of cancer.

Traditional cytotoxic anticancer therapies do not differentiate between tumour and host cells, and research efforts have been focused on finding new agents that target tumour tissue. Gefitinib ('Iressa', ZD1839) is an orally active epidermal growth factor receptor tyrosine kinase inhibitor that blocks signal pathways implicated in solid tumour growth and metastasis. In phase II trials, gefitinib 250 mg/day demonstrated efficacy in the control of advanced non-small-cell lung cancer (NSCLC) in patients who had undergone prior chemotherapy. Response rates were 18.4 and 11.8%, and disease control rates were 54.4 and 42.2%, at 250 mg/day in two multicentre trials - IDEAL 1 and 2. Gefitinib also caused rapid relief from the symptoms of NSCLC in approximately 40% of patients, while displaying a generally good tolerability profile that most commonly included mild, reversible gastrointestinal and skin adverse events. Gefitinib 250 mg/day has been approved for use in advanced, previously treated NSCLC in several countries including the USA, Japan and Australia. As a monotherapy and combination therapy, it is being investigated for the treatment of several common tumour types in addition to NSCLC. The pharmacokinetics of gefitinib have shown it to be suitable for once daily dosing, with a terminal half-life of approximately 48 h in patients with cancer. Steady-state exposure is achieved after 10 days dosing, and exposure is dose proportional up to 250 mg/day. Gefitinib is cleared principally by the biliary route and in part by metabolism. This review summarizes relevant data from studies of gefitinib that inform its clinical administration.

Diphenyl(2-thioxo-1,3-dithiole-4,5-dithiolato-S,S')plumbane at 295 K and diphenyl(2-thioxo-1,3-dithiole-4,5-dithiolato-S,S')stannane at 150 K.

Molecules of diphenyl(2-thioxo-1,3-dithiole-4,5-dithiolato-S,S')plumbane, [Pb(C3S5)(C6H5)2], are linked into sheets via two intermolecular Pb...S(thione) interactions of 3.322 (4) and 3.827 (4) A; the Pb centre has a distorted octahedral geometry. In contrast, molecules of diphenyl(2-thioxo-1,3-dithiole-4,5-dithiolato-S,S')stannane, [Sn(C3S5)(C6H5)2], are linked into chains via a single intermolecular Sn--S(thione) interaction of 2.8174 (9) A; the Sn centre has a distorted trigonal-bipyramidal geometry.

(p-Nitrobenzoato)triphenyltin at 298 K.

The structure at 298 K described here, [Sn(C(6)H(5))(3)(C(7)H(4)NO(4))], completely confirms the results at 173 K obtained previously [Weng, Das & Robinson (1990), Malays. J. Sci. 12, 57]. In both structures, weak interaction between Sn and the carbonyl O atom of the benzoate group provides a distorted trigonal-pyramidal environment at the Sn atom derived from its pseudo-tetrahedral primary coordination in both molecules of the asymmetric unit.

Synovial cyst of the proximal tibiofibular joint with peroneal nerve compression after total knee arthroplasty.

Synovial or ganglion cysts of the proximal tibiofibular joint are less common than synovial cysts of the knee joint but may present in a similar manner and may be difficult to diagnose clinically. Although synovial cysts arising from the knee joint after prosthetic arthroplasty have already been described, we report a case in which a lateral knee mass compressing the peroneal nerve was found to be a synovial cyst arising from the tibiofibular joint.

Safety of 1-stage bilateral total knee arthroplasty.

Bilateral total knee replacements during a single operation with intramedullary femoral guide rods have been associated with the possible development of a fat embolism syndrome. To assess the safety of this procedure, in which the femoral canal was decompressed by the use of an overdrilled entrance hole and fluted guide rod, 17 unilateral and 18 bilateral consecutive total knee patients were evaluated. There were no differences between the groups on the basis of changes in chest radiographs, percentage of estimated pulmonary shunting, mental status changes, or fat and bone marrow elements drawn from a central venous catheter in the right atrium. Although no patient had free fat in the blood, bone marrow elements were found in 3 bilateral and 2 unilateral cases. No patient had clinical manifestations of a fat emboli syndrome. With appropriate femoral canal decompression, bilateral 1-stage total knee replacement appears to be a safe procedure.

Fatigue fractures of the sacrum in children: two case reports and a review of the literature.

We present the clinical and radiological features of two children with fatigue fractures of the sacrum. Both patients were active, had no underlying bone disease and presented with insidious onset of low back pain. Plain radiography was non-contributory to the diagnosis. In both patients a focal area of increased activity was present in the lateral aspect of the sacrum on bone scintigraphy, which corresponded to linear medullary sclerosis in the sacral ala demonstrated by computed tomography. Magnetic resonance imaging in one patient revealed a linear signal void in the sacral ala on T1- and T2-weighted images. This was surrounded by diffuse low marrow signal on T1-weighted images, and increased marrow signal on T2-weighted images. Fatigue fractures of the sacrum should be considered in the differential diagnosis of low back pain in children. An awareness of their appearance on magnetic resonance imaging is important as this modality is increasingly utilised, particularly in children.

Ileal duplication cyst causing massive bleeding in a child.

Intestinal duplication is a rare congenital anomaly; nonetheless, it comprises more than half of all alimentary duplication disorders. Our case report describes the hemorrhagic sequelae of this entity with surgical and pathologic findings. A review of anatomical classification, embryology, and natural history of duplication cyst follows; differentiating characteristics of duplication cyst versus Meckel's diverticulum are outlined. Intestinal duplication cyst should be considered in the differential diagnosis of GI bleeding, especially in children.