The IRDiRC Chrysalis Task Force: making rare disease research attractive to companies.

Background: The International Rare Diseases Research Consortium (IRDiRC) is an international initiative that aims to use research to facilitate rapid diagnosis and treatment of rare diseases. Objective: IRDiRC launched the Chrysalis Task Force to identify key financial and nonfinancial factors that make rare disease research and development attractive to companies. Methods: The Chrysalis Task Force was comprised of thought leaders from companies, patient advocacy groups, regulatory agencies, and research funders. The Task Force created a survey that was distributed to companies of different sizes with varied investment portfolios and interests in rare disease research. Based on the survey results, the Task Force then conducted targeted interviews. Results: The survey and interview respondents identified several factors that make rare disease research and development attractive (e.g. a good understanding of the underlying biology) as well as barriers (e.g. absence of an advocacy organization representing the affected community's needs). The concept of Return On Investment allowed the exploration of factors that were weighed differently by survey and interview respondents, depending on a number of intrinsic and extrinsic issues. Conclusions: The Chrysalis Task Force identified factors attributable to rare disease research and development that may be of interest to and actionable by funders, academic researchers, patients and their families, companies, regulators, and payers in the medium term to short term. By addressing the identified challenges, involved parties may seek solutions to significantly advance the research and development of treatments for rare diseases.

Making rare disease research attractive to companies The International Rare Diseases Research Consortium (IRDiRC) is an international initiative that aims to speed the diagnosis and treatment of rare diseases through research. The IRDiRC Chrysalis Task Force, comprised of thought leaders from companies, patient advocacy groups, regulatory agencies, and research funders, identified key factors that make rare disease research and development attractive to companies. The Task Force distributed a survey to companies with varied investment portfolios and interests in rare disease research, followed by in-depth interviews based on the survey results. The survey and interview respondents identified both attractive factors and barriers to rare disease research and development. The concept of Return On Investment was used to frame discussion of factors that companies weighed differently, depending on a number of issues that were a function of both the company itself and outside factors. The identified challenges can be addressed by funders, academic researchers, patients and their families, companies, regulators, and payers, which hopefully will lead to significant advances in the research and development of treatments for rare diseases.

Guidelines for the Li-Fraumeni and heritable TP53-related cancer syndromes.

Fifty years after the recognition of the Li-Fraumeni syndrome (LFS), our perception of cancers related to germline alterations of TP53 has drastically changed: (i) germline TP53 alterations are often identified among children with cancers, in particular soft-tissue sarcomas, adrenocortical carcinomas, central nervous system tumours, or among adult females with early breast cancers, without familial history. This justifies the expansion of the LFS concept to a wider cancer predisposition syndrome designated heritable TP53-related cancer (hTP53rc) syndrome; (ii) the interpretation of germline TP53 variants remains challenging and should integrate epidemiological, phenotypical, bioinformatics prediction, and functional data; (iii) the penetrance of germline disease-causing TP53 variants is variable, depending both on the type of variant (dominant-negative variants being associated with a higher cancer risk) and on modifying factors; (iv) whole-body MRI (WBMRI) allows early detection of tumours in variant carriers and (v) in cancer patients with germline disease-causing TP53 variants, radiotherapy, and conventional genotoxic chemotherapy contribute to the development of subsequent primary tumours. It is critical to perform TP53 testing before the initiation of treatment in order to avoid in carriers, if possible, radiotherapy and genotoxic chemotherapies. In children, the recommendations are to perform clinical examination and abdominal ultrasound every 6 months, annual WBMRI and brain MRI from the first year of life, if the TP53 variant is known to be associated with childhood cancers. In adults, the surveillance should include every year clinical examination, WBMRI, breast MRI in females from 20 until 65 years and brain MRI until 50 years.

Oxidative-Nitrative Stress and Poly (ADP-Ribose) Polymerase Activation 3 Years after Pregnancy.

BACKGROUND: Oxidative-nitrative stress and poly (ADP-ribose) polymerase activation have been previously observed in healthy and gestational diabetic pregnancies, and they were also linked to the development of metabolic diseases. The aim of the present study was to examine these parameters and their correlation to known metabolic risk factors following healthy and gestational diabetic pregnancies. METHODS: Fasting and 2 h postload plasma total peroxide level, protein tyrosine nitration, and poly (ADP-ribose) polymerase activation were measured in circulating leukocytes three years after delivery in women following healthy, "mild" (diet-treated) or "severe" (insulin-treated) gestational diabetic pregnancy during a standard 75 g OGTT. Nulliparous women and men served as control groups. RESULTS: Fasting plasma total peroxide level was significantly elevated in women with previous pregnancy (B = 0.52 ± 0.13; p < 0.001), with further increase in women with insulin-treated gestational diabetes (B = 0.36 ± 0.17; p < 0.05) (R2 = 0.419). Its level was independently related to previous pregnancy (B = 0.47 ± 0.14; p < 0.01) and current CRP levels (B = 0.06 ± 0.02; p < 0.05) (R2 = 0.306). CONCLUSIONS: Elevated oxidative stress but not nitrative stress or poly (ADP-ribose) polymerase activation can be measured three years after pregnancy. The increased oxidative stress may reflect the cost of reproduction and possibly play a role in the increased metabolic risk observed in women with a history of severe gestational diabetes mellitus.

The Relationship between 25-hydroxyvitamin D Levels, Insulin Sensitivity and Insulin Secretion in Women 3 Years after Delivery.

OBJECTIVES: There is a direct correlation between 25-hydroxyvitamin D (25[OH]D) levels and insulin sensitivity. Furthermore, women with gestational diabetes (GDM) may have lower levels of 25(OH)D compared to controls. The present study intended to investigate 25(OH)D levels and their association with insulin sensitivity and insulin secretion in women with prior GDM and in controls 3.2 years after delivery. METHODS: A total of 87 patients with prior GDM and 45 randomly selected controls (age range, 22 to 44 years) with normal glucose tolerance during pregnancy nested within a cohort of all deliveries at Saint Margit Hospital, Budapest, between January 1 2005, and December 31 2006, were examined. Their 25(OH) D levels were measured by radioimmunoassay. Insulin sensitivity and fasting insulin secretion were estimated using the homeostasis model asssessment (HOMA) calculator and early insulin secretion by the insulinogenic index based on a 75 g oral glucose tolerance test. RESULTS: There was no significant difference in 25(OH)D levels between cases and controls (27.2±13.1 [±SD] vs. 26.9±9.8 ng/L). There was a positive association between HOMA insulin sensitivity and 25(OH)D levels (beta = 0.017; 95% CI 0.001 to 0.034/1 ng/mL) that was robust to adjustment for age and body mass index. There was a nonsignificant association between HOMA insulin secretion and 25(OH)D (p=0.099), while no association was found with the insulinogenic index. CONCLUSIONS: Prior GDM status was not associated with 25(OH)D levels; however, 25(OH) D levels were associated with HOMA insulin sensitivity. It is hypothesized that the association between HOMA insulin secretion and 25(OH)D levels is related to the autoregulation of fasting glucose levels because no association between 25(OH)D and insulinogenic index was found.

[The severity of gestational diabetes mellitus affects microvascular dysfunction measured three years after pregnancy that may be related to increased oxidative stress]. / A gestatiós diabetes mellitus súlyossága befolyásolja a három évvel a szülést követoen mért microvascularis diszfunkció mértékét, amely kapcsolatban állhat az emelkedett szisztémás oxidatív stresszel.

INTRODUCTION: Oxidative-nitrative stress and poly(ADP-ribose) polymerase activation observed in gestational diabetes may play role in the increased cardiovascular risk in later life. AIM: The present study aimed to examine the influence of the severity of previous gestational diabetes (insulin need) on vascular function three years after delivery. Furthermore, the authors investigated the relation of vascular function with oxidative-nitrative stress and poly(ADP-ribose) polymerase activation. METHOD: Macrovascular function was measured by applanation tonometry; microvascular reactivity was assessed by provocation tests during Laser-Doppler flowmetry in 40 women who had gestational diabetes 3 years before the study. Oxidative-nitrative stress and poly(ADP-ribose) polymerase activity in blood components were determined by colorimetry and immunohistochemistry. RESULTS: Three years after insulin treated gestational diabetes impaired microvascular function and increased oxidative stress was observed compared to mild cases. CONCLUSIONS: The severity of previous gestational diabetes affects microvascular dysfunction that is accompanied by elevated oxidative stress. Nitrative stress and poly(ADP-ribose) polymerase activity correlates with certain vascular factors not related to the severity of the disease.

Placental protein 13 (galectin-13) has decreased placental expression but increased shedding and maternal serum concentrations in patients presenting with preterm pre-eclampsia and HELLP syndrome.

Placental protein 13 (PP13) is a galectin expressed by the syncytiotrophoblast. Women who subsequently develop preterm pre-eclampsia have low first trimester maternal serum PP13 concentrations. This study revealed that third trimester maternal serum PP13 concentration increased with gestational age in normal pregnancies (p < 0.0001), and it was significantly higher in women presenting with preterm pre-eclampsia (p = 0.02) and hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome (p = 0.01) than in preterm controls. Conversely, placental PP13 mRNA (p = 0.03) and protein, as well as cytoplasmic PP13 staining of the syncytiotrophoblast (p < 0.05) was decreased in these pathological pregnancies compared to controls. No differences in placental expression and serum concentrations of PP13 were found at term between patients with pre-eclampsia and control women. In contrast, the immunoreactivity of the syncytiotrophoblast microvillous membrane was stronger in both term and preterm pre-eclampsia and HELLP syndrome than in controls. Moreover, large syncytial cytoplasm protrusions, membrane blebs and shed microparticles strongly stained for PP13 in pre-eclampsia and HELLP syndrome. In conclusion, parallel to its decreased placental expression, an augmented membrane shedding of PP13 contributes to the increased third trimester maternal serum PP13 concentrations in women with preterm pre-eclampsia and HELLP syndrome.