Anterior segment intraocular metallic foreign body causing chronic hypopyon uveitis

Intraocular foreign body (IOFB) is a common association of penetrating ocular trauma. Early diagnosis and removal of IOFBs especially if they are metallic is very important to determine further management and the final result of treatment. Missed IOFB may present in different clinical aspects that may limit its detection and symptoms may only become apparent after a prolonged period of time. We report a case of a missed metallic intraocular foreign body in the anterior chamber over a 2-year period without causing severe inflammatory reaction and presented with uveitis later. A 42-year-old man presented with a progressive blurring of vision, pain, photophobia, and redness in the left eye for 3 months. He had a history of traffic accident 2 years ago and he was accepted to intensive care unit for 3 days. Three months ago, in another center, he was admitted to hospital for 1 week and intravitreal antibiotics and medical treatment were given for pain, photophobia, and redness in his left eye. In five o’ clock meridian of the angle, there was an IOFB coated with hypopyon was observed under biomicrocopic magnification. Plain X-ray and computed tomography confirmed the foreign body in the left eye. After obtaining informed consent from the patient, the foreign body was removed under local anesthesia

Alterations of tumor suppressor gene p16(INK4a )in pancreatic ductal carcinoma

BACKGROUND: Cell cycle inhibitor and tumor suppressor gene p16 / MTS-1 has been reported to be altered in a variety of human tumors. The purpose of the study was to evaluate primary pancreatic ductal adenocarcinomas for potentially inactivating p16 alterations. METHODS: We investigated the status of p16 gene by polymerase chain reaction (PCR), nonradioisotopic single strand conformation polymorphism (SSCP), DNA sequencing and hypermethylation analysis in 25 primary resected ductal adenocarcinomas. In addition, we investigated p16 protein expression in these cases by immunohistochemistry (IHC) using a monoclonal antibody clone (MS-887-PO). RESULTS: Out of the 25 samples analyzed and compared to normal pancreatic control tissues, the overall frequency of p16 alterations was 80% (20/25). Aberrant promoter methylation was the most common mechanism of gene inactivation present in 52% (13/25) cases, followed by coding sequence mutations in 16% (4/25) cases and presumably homozygous deletion in 12% (3/25) cases. These genetic alterations correlated well with p16 protein expression as complete loss of p16 protein was found in 18 of 25 tumors (72%). CONCLUSION: These findings confirm that loss of p16 function could be involved in pancreatic cancer and may explain at least in part the aggressive behaviour of this tumor type

SFRP1 reduction results in an increased sensitivity to TGF-β signaling

Background Transforming growth factor (TGF)-β plays a dual role during mammary gland development and tumorigenesis and has been shown to stimulate epithelial-mesenchymal transition (EMT) as well as cellular migration. The Wnt/β-catenin pathway is also implicated in EMT and inappropriate activation of the Wnt/β-catenin signaling pathway leads to the development of several human cancers, including breast cancer. Secreted frizzled-related protein 1 (SFRP1) antagonizes this pathway and loss of SFRP1 expression is frequently observed in breast tumors and breast cancer cell lines. We previously showed that when SFRP1 is knocked down in immortalized non-malignant mammary epithelial cells, the cells (TERT-siSFRP1) acquire characteristics associated with breast tumor initiating cells. The phenotypic and genotypic changes that occur in response to SFRP1 loss are consistent with EMT, including a substantial increase in the expression of ZEB2. Considering that ZEB2 has been shown to interact with mediators of TGF-β signaling, we sought to determine whether TGF-β signaling is altered in TERT-siSFRP1 cells. Methods Luciferase reporter assays and real-time PCR analysis were employed to measure TGF-β transcriptional targets. Western blot analysis was used to evaluate TGF-β-mediated ERK1/2 phosphorylation. Migration chamber assays were utilized to quantify cellular migration. TERT-siSFRP1 cells were transfected with Stealth RNAi™ siRNA in order to knock-down the expression of ZEB2. Results TERT-siSFRP1 cells exhibit a significant increase in both TGF-β-mediated luciferase activity as well as TGF-β transcriptional targets, including Integrin β3 and PAI-1. Phosphorylation of ERK1/2 is increased in TERT-siSFRP1 cells in response to enhanced TGF-β signaling. Furthermore, when the TGF-β pathway is blocked with a TGF-βR antagonist (LY364947), cellular migration is significantly hindered. Finally, we found that when ZEB2 is knocked-down, there is a significant reduction in the expression of exogeneous and endogenous TGF-β transcriptional targets and cellular migration is impeded. Conclusions We demonstrate that down-regulation of SFRP1 renders mammary epithelial cells more sensitive to TGF-β signaling which can be partially ameliorated by blocking the expression of ZEB2

The multiple faces of self-assembled lipidic systems

Lipids, the building blocks of cells, common to every living organisms, have the propensity to self-assemble into well-defined structures over short and long-range spatial scales. The driving forces have their roots mainly in the hydrophobic effect and electrostatic interactions. Membranes in lamellar phase are ubiquitous in cellular compartments and can phase-separate upon mixing lipids in different liquid-crystalline states. Hexagonal phases and especially cubic phases can be synthesized and observed in vivo as well. Membrane often closes up into a vesicle whose shape is determined by the interplay of curvature, area difference elasticity and line tension energies, and can adopt the form of a sphere, a tube, a prolate, a starfish and many more. Complexes made of lipids and polyelectrolytes or inorganic materials exhibit a rich diversity of structural morphologies due to additional interactions which become increasingly hard to track without the aid of suitable computer models. From the plasma membrane of archaebacteria to gene delivery, self-assembled lipidic systems have left their mark in cell biology and nanobiotechnology; however, the underlying physics is yet to be fully unraveled

Northern Eurasia Future Initiative (NEFI): facing the challenges and pathways of global change in the 21st century

During the past several decades, the Earth system has changed significantly, especially across Northern Eurasia. Changes in the socio-economic conditions of the larger countries in the region have also resulted in a variety of regional environmental changes that can have global consequences. The Northern Eurasia Future Initiative (NEFI) has been designed as an essential continuation of the Northern Eurasia Earth Science Partnership Initiative (NEESPI), which was launched in 2004. NEESPI sought to elucidate all aspects of ongoing environmental change, to inform societies and, thus, to better prepare societies for future developments. A key principle of NEFI is that these developments must now be secured through science-based strategies co-designed with regional decision makers to lead their societies to prosperity in the face of environmental and institutional challenges. NEESPI scientific research, data, and models have created a solid knowledge base to support the NEFI program. This paper presents the NEFI research vision consensus based on that knowledge. It provides the reader with samples of recent accomplishments in regional studies and formulates new NEFI science questions. To address these questions, nine research foci are identified and their selections are briefly justified. These foci include: warming of the Arctic; changing frequency, pattern, and intensity of extreme and inclement environmental conditions; retreat of the cryosphere; changes in terrestrial water cycles; changes in the biosphere; pressures on land-use; changes in infrastructure; societal actions in response to environmental change; and quantification of Northern Eurasia's role in the global Earth system. Powerful feedbacks between the Earth and human systems in Northern Eurasia (e.g., mega-fires, droughts, depletion of the cryosphere essential for water supply, retreat of sea ice) result from past and current human activities (e.g., large scale water withdrawals, land use and governance change) and potentially restrict or provide new opportunities for future human activities. Therefore, we propose that Integrated Assessment Models are needed as the final stage of global change assessment. The overarching goal of this NEFI modeling effort will enable evaluation of economic decisions in response to changing environmental conditions and justification of mitigation and adaptation efforts

Mortality from gastrointestinal congenital anomalies at 264 hospitals in 74 low-income, middle-income, and high-income countries: a multicentre, international, prospective cohort study

Background: Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. // Methods: We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung's disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. // Findings: We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung's disease) from 264 hospitals (89 in high-income countries, 166 in middle-income countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p<0·0001 between all country income groups). Gastroschisis had the greatest difference in mortality between country income strata (nine [90·0%] of ten in low-income countries, 97 [31·9%] of 304 in middle-income countries, and two [1·4%] of 139 in high-income countries; p≤0·0001 between all country income groups). Factors significantly associated with higher mortality for all patients combined included country income status (low-income vs high-income countries, risk ratio 2·78 [95% CI 1·88–4·11], p<0·0001; middle-income vs high-income countries, 2·11 [1·59–2·79], p<0·0001), sepsis at presentation (1·20 [1·04–1·40], p=0·016), higher American Society of Anesthesiologists (ASA) score at primary intervention (ASA 4–5 vs ASA 1–2, 1·82 [1·40–2·35], p<0·0001; ASA 3 vs ASA 1–2, 1·58, [1·30–1·92], p<0·0001]), surgical safety checklist not used (1·39 [1·02–1·90], p=0·035), and ventilation or parenteral nutrition unavailable when needed (ventilation 1·96, [1·41–2·71], p=0·0001; parenteral nutrition 1·35, [1·05–1·74], p=0·018). Administration of parenteral nutrition (0·61, [0·47–0·79], p=0·0002) and use of a peripherally inserted central catheter (0·65 [0·50–0·86], p=0·0024) or percutaneous central line (0·69 [0·48–1·00], p=0·049) were associated with lower mortality. // Interpretation: Unacceptable differences in mortality exist for gastrointestinal congenital anomalies between low-income, middle-income, and high-income countries. Improving access to quality neonatal surgical care in LMICs will be vital to achieve Sustainable Development Goal 3.2 of ending preventable deaths in neonates and children younger than 5 years by 2030

RANK-Fc inhibits malignancy via inhibiting ERK activation and evoking caspase-3-mediated anoikis in human osteosarcoma cells

Osteosarcoma (OS) is the most common primary malignant bone tumour, mainly afflicting the young. While there has been substantial improvement in treatment of OS with surgery and chemotherapy in the past two decades, this disease remains a significant health problem, warranting efforts to find better therapeutic options. In this study, we examined the RANK/RANKL axis in OS cells, using a RANK-Fc protein to perturb this coupling in an effort to reduce OS cell growth. RANK-Fc suppressed OS cell migration (P\0.005), invasion ability (P\0.05), and anchorage-independent ability in collagen- 1 gel (P\0.005) following induction of anoikis and activation of caspase-3. OS cell proliferation was not perturbed by RANK-Fc. The anti-invasion and anti-metastasis capability of RANK-Fc is attributed to reduced extracellular signal-regulated protein kinase (ERK) signaling via RANKFc, though activation of NFjB, and altered expression of Akt, p38, JNK, and matrix metalloproteinase (MMP)-2 and -9 were ruled out. In vivo, activity of the RANK-Fc against OS cell migration and invasion was confirmed in a model strictly monitoring metastasis. Thus, RANK-Fc, given its ability to directly reduce OS aggression, is a potential drug candidate

A novel orthotopic murine model provides insights into cellular and molecular characteristics contributing to human osteosarcoma

As a reliable model for osteosarcoma is lacking, three human cell lines (SaOS-2, U2OS and 143B) were evaluated in cell-based assays for proliferation, adhesion, migration, invasion, anchorage-independent growth, angiogenesis, mineralised nodule formation, plasmid transfection and oligonucleotide transfection. Tumor take and metastasis after orthotopic injection of the three cell lines into mice was monitored. The levels of expression of typical bone markers were determined with semi-quantitative RT-PCR in cultured cells, primary tumors, and for the SaOS-2 cell line, the metastases. Tumors grew and spread to the lungs within 3 and 5 weeks respectively, mimicking the clinical progression of the disease as analysed by x-ray. Expression of molecular markers in SaOS-2 indicated a mostly differentiated cell type at the primary and secondary sites. The ability of osteosarcoma cells to interact with collagen-1 and to form mineralised deposits correlated positively with tumor aggression in vivo. Expression of alkaline phosphatase was a common theme in both tumor models at the primary site. The newly established SaOS-2 model should allow the testing of candidate anti-osteosarcoma agents as well as dissection of more intricate mechanisms involved in human osteosarcoma