Ferritins: furnishing proteins with iron

Ferritins are a superfamily of iron oxidation, storage and mineralization proteins found throughout the animal, plant, and microbial kingdoms. The majority of ferritins consist of 24 subunits that individually fold into 4-α-helix bundles and assemble in a highly symmetric manner to form an approximately spherical protein coat around a central cavity into which an iron-containing mineral can be formed. Channels through the coat at inter-subunit contact points facilitate passage of iron ions to and from the central cavity, and intrasubunit catalytic sites, called ferroxidase centers, drive Fe2+ oxidation and O2 reduction. Though the different members of the superfamily share a common structure, there is often little amino acid sequence identity between them. Even where there is a high degree of sequence identity between two ferritins there can be major differences in how the proteins handle iron. In this review we describe some of the important structural features of ferritins and their mineralized iron cores and examine in detail how three selected ferritins oxidise Fe2+ in order to explore the mechanistic variations that exist amongst ferritins. We suggest that the mechanistic differences reflect differing evolutionary pressures on amino acid sequences, and that these differing pressures are a consequence of different primary functions for different ferritins

Oxaliplatin and protracted venous infusion of 5-fluorouracil in patients with advanced or relapsed 5-fluorouracil pretreated colorectal cancer

The purpose of this study was to evaluate the activity and safety of oxaliplatin and protracted venous infusion of 5-fluorouracil (PVI 5-FU) in patients with advanced or relapsed 5-FU pretreated colorectal cancer. 38 patients with advanced or metastatic colorectal carcinoma with documented progression on or within 6 months following 5-FU or thymidylate synthase inhibitor containing chemotherapy were recruited between June 1997 and September 2000. Oxaliplatin (100 mg m−2) was given every 2 weeks and PVI 5-FU (300 mg m−2day−1) was administered. Median age of patients was 61 years. 17 patients had >2 sites of disease involvement. 10 had received 5-FU based adjuvant chemotherapy. 16 received oxaliplatin and PVI 5-FU as second-line chemotherapy for advanced disease and 22 as third or subsequent lines. Median follow up was 6.1 months. The best achieved objective tumour response rate was 29% (11 partial responses 95% confidence interval [CI] = 15–46%). 20 patients (52.6%) had stable disease. The median duration of response was 3.9 months. Even for patients who had previously received both 5-FU and irinotecan (n= 22), 27.3% had partial response with oxaliplatin and PVI 5-FU. 37 patients had symptoms on entry into the study. 25 patients had pain, 10 had anorexia and 28 had lethargy. 64%, 70% and 17.9% had symptomatic improvement after treatment respectively. Grade 3–4 toxicities were anaemia 10.6%, neutropenia 2.6%, thrombocytopenia 5.2%, diarrhoea 18.9%, nausea and vomiting 2.7%, infection 5.4% and lethargy 37.8%. The median survival was 9.1 months. Probability of overall survival at 6 months was 58.4% (95% CI = 38.7–73.7%). The median failure-free survival was 4 months. Oxaliplatin and PVI 5FU is an active and well tolerated regimen in patients with heavily pre-treated advanced colorectal cancer. © 2001 Cancer Research Campaig

A phase II study of biweekly oxaliplatin plus infusional 5-fluorouracil and folinic acid (FOLFOX-4) as first-line treatment of advanced gastric cancer patients

The aim of the study was to assess the toxicity and the clinical activity of biweekly oxaliplatin in combination with infusional 5-fluorouracil (5-FU) and folinic acid (FA) administered every 2 weeks (FOLFOX-4 regimen) in patients with advanced gastric cancer (AGC). A total of 61 previously untreated AGC patients were treated with oxaliplatin 85 mg m−2 on day 1, FA 200 mg m−2 as a 2 h infusion followed by bolus 5-FU 400 mg m−2 and a 22 h infusion of 5-FU 600 mg m−2, repeated for 2 consecutive days every 2 weeks. All patients were assessable for toxicity and response to treatment. Four (7%) complete responses and 19 partial responses were observed (overall response rate, 38%). Stable disease was observed in 22 (36%) patients, with progressive disease in the other six (10%) patients. Median time to progression (TTP) and median overall survival (OS) were 7.1 and 11.2 months, respectively. National Cancer Institute Common Toxicity Criteria grade 3 and 4 haematologic toxicities were neutropenia, anaemia and thrombocytopenia in 36, 10 and 5% of the patients, respectively. Grade 3 peripheral neuropathy was recorded in three (5%) patients. FOLFOX-4 is an active and well-tolerated chemotherapy. Response rate (RR), TTP and OS were comparable with those of other oxaliplatin-based regimens, suggesting a role for this combination in gastric cancer

Phase I study of docetaxel plus ifosfamide in patients with advanced cancer

The aim of this study was to determine the maximum tolerated dose of a fixed dose of docetaxel when combined with continuous infusion ifosfamide, with and without G-CSF support, in the treatment of advanced cancer, and to evaluate anti-tumour activity of this combination. Thirty-one patients with advanced malignancies were treated with docetaxel 75 mg/m2 intravenously on days 1, and ifosfamide at increasing dose levels from 1500 mg/m2/day to 2750 mg/m2/day as a continuous infusion from day 1–3, every 3 weeks. A total of 107 cycles of treatment were administered. Without G-CSF support dose-limiting toxicity of grade 4 neutropenia greater than 5 days duration occurred at dose level 1. With the addition of G-CSF the maximum tolerated dose was docetaxel 75 mg/m2 on day 1 and ifosfamide 2750 mg/m2/day on days 1–3. Dose limiting toxicity (DLT) included ifosfamide-induced encephalopathy, febrile neutropenia and grade three mucositis. Three complete responses and 3 partial responses were seen. This combination of docetaxel and infusional ifosfamide is feasible and effective. The recommended dose for future phase II studies is docetaxel 75 mg/m2 on day 1 and ifosfamide 2500 mg/m2/day continuous infusion on days 1–3

A systematic review on 'Foveal Crowding' in visually impaired children and perceptual learning as a method to reduce Crowding

Contains fulltext : 102577.pdf (publisher's version ) (Open Access)Background - This systematic review gives an overview of foveal crowding (the inability to recognize objects due to surrounding nearby contours in foveal vision) and possible interventions. Foveal crowding can have a major effect on reading rate and deciphering small pieces of information from busy visual scenes. Three specific groups experience more foveal crowding than adults with normal vision (NV): 1) children with NV, 2) visually impaired (VI ) children and adults and 3) children with cerebral visual impairment (CVI). The extent and magnitude of foveal crowding as well as interventions aimed at reducing crowding were investigated in this review. The twofold goal of this review is : [A] to compare foveal crowding in children with NV, VI children and adults and CVI children and [B] to compare interventions to reduce crowding. Methods - Three electronic databases were used to conduct the literature search: PubMed, PsycINFO (Ovid), and Cochrane. Additional studies were identified by contacting experts. Search terms included visual perception, contour interaction, crowding, crowded, and contour interactions. Results - Children with normal vision show an extent of contour interaction over an area 1.5-3x as large as that seen in adults NV. The magnitude of contour interaction normally ranges between 1-2 lines on an acuity chart and this magnitude is even larger when stimuli are arranged in a circular configuration. Adults with congenital nystagmus (CN) show interaction areas that are 2x larger than those seen adults with NV. The magnitude of the crowding effect is also 2x as large in individuals with CN as in individuals with NV. Finally, children with CVI experience a magnitude of the crowding effect that is 3x the size of that experienced by adults with NV. Conclusions - The methodological heterogeneity, the diversity in paradigms used to measure crowding, made it impossible to conduct a meta-analysis. This is the first systematic review to compare crowding ratios and it shows that charts with 50% interoptotype spacing were most sensitive to capture crowding effects. The groups that showed the largest crowding effects were individuals with CN, VI adults with central scotomas and children with CVI. Perceptual Learning seems to be a promising technique to reduce excessive foveal crowding effects.14 p

Role of Factor VII in Correcting Dilutional Coagulopathy and Reducing Re-operations for Bleeding Following Non-traumatic Major Gastrointestinal and Abdominal Surgery

Objective The objective of this study is to evaluate the effectiveness of rfVIIa in reducing blood product requirements and re-operation for postoperative bleeding after major abdominal surgery. Background Hemorrhage is a significant complication after major gastrointestinal and abdominal surgery. Clinically significant bleeding can lead to shock, transfusion of blood products, and re-operation. Recent reports suggest that activated rfVIIa may be effective in correcting coagulopathy and decreasing the need for re-operation. Methods This study was a retrospective review over a 4-year period of 17 consecutive bleeding postoperative patients who received rfVIIa to control hemorrhage and avoid re-operation. Outcome measures were blood and clotting factor transfusions, deaths, thromboembolic complications, and number of re-operations for bleeding. Results Seventeen patients with postoperative hemorrhage following major abdominal gastrointestinal surgery (nine pancreas, four sarcoma, two gastric, one carcinoid, and one fistula) were treated with rfVIIa. In these 17 patients, rfVIIa was administered for 18 episodes of bleeding (dose 2,400-9,600 mcg, 29.8-100.8 mcg/kg). Transfusion requirement of pRBC and FFP were each significantly less than pre-rfVIIa. Out of the 18 episodes, bleeding was controlled in 17 (94%) without surgery, and only one patient returned to the operating room for hemorrhage. There were no deaths and two thrombotic complications. Coagulopathy was corrected by rfVIIa from 1.37 to 0.96 (p<0.0001). Conclusion Use of rfVIIa in resuscitation for hemorrhage after non-traumatic major abdominal and gastrointestinal surgery can correct dilutional coagulopathy, reducing blood product requirements and need for re-operation

Angiogenesis in cancer of unknown primary: clinicopathological study of CD34, VEGF and TSP-1

BACKGROUND: Cancer of unknown primary remains a mallignancy of elusive biology and grim prognosis that lacks effective therapeutic options. We investigated angiogenesis in cancer of unknown primary to expand our knowledge on the biology of these tumors and identify potential therapeutic targets. METHODS: Paraffin embedded archival material from 81 patients diagnosed with CUP was used. Tumor histology was adenocarcinoma (77%), undifferentiated carcinoma (18%) and squamous cell carcinoma (5%). The tissue expression of CD34, VEGF and TSP-1 was assessed immunohistochemically by use of specific monoclonal antibodies and was analyzed against clinicopathological data. RESULTS: VEGF expression was detected in all cases and was strong in 83%. Stromal expression of TSP-1 was seen in 80% of cases and was strong in 20%. The expression of both proteins was not associated with any clinical or pathological parameters. Tumor MVD was higher in tumors classified as unfavorable compared to more favorable and was positively associated with VEGF and negatively with TSP-1. CONCLUSION: Angiogenesis is very active and expression of VEGF is almost universal in cancers of unknown primary. These findings support the clinical investigation of VEGF targeted therapy in this clinical setting

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015

SummaryBackground The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation