More than 90% of drugs with preclinical activity fail in human trials, largely due to insufficient efficacy. We hypothesized that adequately powered trials of patient-derived xenografts (PDX) in mice ...could efficiently define therapeutic activity across heterogeneous tumors. To address this hypothesis, we established a large, publicly available repository of well-characterized leukemia and lymphoma PDXs that undergo orthotopic engraftment, called the Public Repository of Xenografts (PRoXe). PRoXe includes all de-identified information relevant to the primary specimens and the PDXs derived from them. Using this repository, we demonstrate that large studies of acute leukemia PDXs that mimic human randomized clinical trials can characterize drug efficacy and generate transcriptional, functional, and proteomic biomarkers in both treatment-naive and relapsed/refractory disease.
•PRoXe is an open-source repository of leukemia and lymphoma xenografts•PDXs capture transcriptional, genetic, and phenotypic disease diversity•Randomized phase II-like preclinical drug trials are feasible using PDXs•PDXs facilitate biomarker development and testing of relapsed/refractory disease
Townsend et al. create a large, publicly available repository of leukemia and lymphoma patient-derived xenografts with well-characterized molecular and clinical information, and illustrate the utility of this repository by performing a preclinical in vivo study that mimics randomized human clinical trials.
Summary
Background
A biosimilar is a copy version of an approved original biological medicine whose data protection has expired.
Aim
To provide an overview of the development of biosimilars ...worldwide.
Methods
Literature review of manufacturing processes of biosimilars, differences and similarities between biosimilars and the reference product, approval pathways for biosimilars, challenges in clinical trial study design and available data from clinical trials.
Results
Biosimilars have the same amino acid sequence and highly similar glycosylation patterns that overlap with the originator product. Both efficacy and toxicity are difficult to predict due to subtle molecular changes that might have profound effects on clinical efficacy, safety and immunogenicity. Their main advantage is related to cost savings. Direct evidence of safety and benefit from clinical trials, post‐marketing pharmacoviligance and unequivocal identification of the product as a biosimilar are requirements before approval. Non‐inferiority or equivalence trials are required by regulatory agencies. Over the past years, several biosimilars have been approved such as erythropoietin or growth factors. Recently, two monoclonal antibodies, Remsima and Inflectra, have been shown to be equivalent to infliximab (INX) in safety and efficacy in rheumatologic conditions. Interchangeability, automatic substitution and switching are key issues when treating patients with biosimilars in clinical practice.
Conclusions
Biosimilars represent a new generation of drugs in liver and gastrointestinal diseases. On June 27, 2013, Hospira's Inflectra (INX) was the first biosimilar monoclonal antibody to receive positive opinion from European Medicines Agency's Committee for Medicinal Products for Human Use for rheumatoid arthritis, inflammatory bowel disease and plaque psoriasis.
This study aims to understand the effects of toughness and hardness on two-body wear of nanostructured carbide-free bainitic steels. For this purpose, three different steel grades were austempered at ...250 °C to obtain carbide-free bainitic microstructures with different mechanical properties. The mechanical properties were determined in terms of fracture toughness and hardness. The wear tests were carried-out at three different loads with two different types of abrasive papers. The results show that a carbide-free bainitic steel with an optimum combination of hardness and fracture toughness exhibits the highest wear resistance. It has been seen that hardness is not the only parameter in determining the abrasive wear resistance and retained austenite has a beneficial effect on two-body abrasive wear.
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•Abrasive wear resistance of carbide-free bainitic steels does not only depend on hardness.•Carbide-free bainitic microstructure with an optimum combination of hardness and toughness offers the best wear resistance.•Retained austenite has a beneficial effect on reducing two-body abrasive wear.•During two-body abrasive wear, no significant strain hardening occurs beneath the worn surface.
Culture of preimplantation embryos affects gene expression. The magnitude of the effect on the global pattern of gene expression, however, is not known. We compared global patterns of gene expression ...in blastocysts cultured from the one-cell stage in either Whitten's medium or KSOM + amino acids (KSOM/AA) with that of blastocysts that developed in vivo, using the Affymetrix MOE430A chip. The analysis revealed that expression of 114 genes was affected after culture in Whitten's medium, whereas only 29 genes were mis-expressed after culture in KSOM/AA. Expression Analysis Systematic Explorer was used to identify biological and molecular processes that are perturbed after culture and indicated that genes involved in protein synthesis, cell proliferation and transporter function were down-regulated after culture in Whitten's medium. A common set of genes involved in transporter function was also down-regulated after culture in KSOM/AA. These results provide insights as to why embryos develop better in KSOM/AA than in Whitten's medium, and highlight the power of microarray analysis to assess global patterns of gene expression.
Original amphiphilic copolymers based on methylcellulose grafted on chitosan and hyaluronan are prepared and characterized. It is shown that the reductive amination is successful and may be realized ...in mild conditions such as to graft neutral methylcellulose chains randomly along the ionic polysaccharide backbone. The equilibrium between electrostatic repulsion between charged chains and hydrophobic attraction due to methylcellulose grafted chains controls the physical properties in solution. Especially, the presence of external salt or/and temperature increase favours a 3D-network formation or reinforce the gel-like behaviour of these systems. The new copolymers prepared are still biocompatible and may find application in a wide range of domains where thermo-sensitive physical gel formation is needed.
Cellular stress responses are frequently governed by the subcellular localization of critical effector proteins. Apoptosis-inducing Factor (AIF) or Glyceraldehyde 3-Phosphate Dehydrogenase (GAPDH), ...for example, can translocate from mitochondria to the nucleus, where they modulate apoptotic death pathways. Hypoxia-inducible gene domain 1A (HIGD1A) is a mitochondrial protein regulated by Hypoxia-inducible Factor-1α (HIF1α). Here we show that while HIGD1A resides in mitochondria during physiological hypoxia, severe metabolic stress, such as glucose starvation coupled with hypoxia, in addition to DNA damage induced by etoposide, triggers its nuclear accumulation. We show that nuclear localization of HIGD1A overlaps with that of AIF, and is dependent on the presence of BAX and BAK. Furthermore, we show that AIF and HIGD1A physically interact. Additionally, we demonstrate that nuclear HIGD1A is a potential marker of metabolic stress in vivo, frequently observed in diverse pathological states such as myocardial infarction, hypoxic-ischemic encephalopathy (HIE), and different types of cancer. In summary, we demonstrate a novel nuclear localization of HIGD1A that is commonly observed in human disease processes in vivo.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The association between assisted reproductive technologies (ARTs) and the body mass index (BMI) of children remains controversial. Confounding by morbidity and other factors associated with parental ...infertility may have biased studies comparing children born after ART with children born after no treatment. We investigated the associations between different fertility treatments and BMI in children at age 5 to 8 years, adjusting for and stratifying by causes of parental infertility.
This Danish cohort study included 327,301 children born between 2007 and 2012 (51% males, median age at follow-up 7 years). Of these, 13,675 were born after ART, 7,728 were born after ovulation induction with or without intrauterine insemination OI/IUI, and 305,898 were born after no fertility treatments. Using the International Obesity Task Force (IOTF) standards, we defined overweight (BMI ≥ IOTF-25) and obesity (BMI ≥ IOTF-30). We compared children born after ART versus OI/IUI; intracytoplasmic sperm injection (ICSI) versus conventional in vitro fertilization (IVF); and frozen-thawed versus fresh embryo transfer and estimated crude and adjusted prevalences of children with overweight or obesity at age 5 to 8 years, prevalence odds ratios (PORs), and differences in mean BMI z-scores. Adjustment was performed using stabilized inverse probability of treatment weights, including parity, year of conception, parental causes of infertility, age, educational level, comorbidities, maternal country of origin, BMI, and smoking as covariates. The crude prevalence of obesity was 1.9% in children born after ART, 2.0% in those born after OI/IUI, and 2.7% in those born after no fertility treatment. After adjustment, children born after ART and OI/IUI had the same prevalence of being overweight (11%; POR 1.00, 95% confidence interval CI 0.91 to 1.11; p = 0.95) or obese (1.9%; POR 1.01, 95% CI 0.79 to 1.29; p = 0.94). Comparison of ICSI with conventional IVF yielded similar pattern (POR 0.95, 95% CI 0.83 to 1.07; p = 0.39 for overweight and POR 1.16, 95% CI 0.84 to 1.61; p = 0.36 for obesity). Obesity was more prevalent after frozen-thawed (2.7%) than fresh embryo transfer (1.8%) (POR 1.54, 95% CI 1.09 to 2.17; p = 0.01). The associations between fertility treatments and BMI were only modestly different in subgroups defined by the cause of infertility. Study limitations include potential residual confounding, restriction to live births, and lack of detailed technical information about the IVF procedures.
We found no association with BMI at age 5 to 8 years when comparing ART versus OI/IUI or when comparing ICSI versus conventional IVF. However, use of frozen-thawed embryo transfer was associated with a 1.5-fold increased risk of obesity compared to fresh embryo transfer. Despite an elevated relative risk, the absolute risk difference was low.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This review covers the preparation, characterization, properties, and applications of methylcelluloses (MC). In particular, the influence of different chemical modifications of cellulose (under both ...heterogeneous and homogeneous conditions) is discussed in relation to the physical properties (solubility, gelation) of the methylcelluloses. The molecular weight (MW) obtained from the viscosity is presented together with the nuclear magnetic resonance (NMR) analysis required for the determination of the degree of methylation. The influence of the molecular weight on the main physical properties of methylcellulose in aqueous solution is analyzed. The interfacial properties are examined together with thermogelation. The surface tension and adsorption at interfaces are described: surface tension in aqueous solution is independent of molecular weight but the adsorption at the solid interface depends on the MW, the higher the MW the thicker the polymeric layer adsorbed. The two-step mechanism of gelation is confirmed and it is shown that the elastic moduli of high temperature gels are not dependent on the molecular weight but only on polymer concentration. Finally, the main applications of MC are listed showing the broad range of applications of these water soluble cellulose derivatives.
Abstract Traditionally, IBD diagnosis is based on clinical, radiological, endoscopic, and histological criteria. Biomarkers are needed in cases of uncertain diagnosis, or to predict disease course ...and therapeutic response. No guideline recommends the detection of antibodies (including ASCA and ANCA) for diagnosis or prognosis of IBD to date. However, many recent data suggest the potential role of new serological markers (anti-glycan (ACCA, ALCA, AMCA, anti-L and anti-C), anti-GP2 and anti-GM-CSF Ab). This review focuses on clinical utility of these new serological markers in diagnosis, prognosis and therapeutic monitoring of IBD. Literature review of anti-glycan, anti-GP2 and anti-GM-CSF Ab and their impact on diagnosis, prognosis and prediction of therapeutic response was performed in PubMed/MEDLINE up to June 2014. Anti-glycan, anti-GP2 and anti-GM-CSF Ab are especially associated with CD and seem to be correlated with complicated disease phenotypes even if results differ between studies. Although anti-glycan Ab and anti-GP2 Ab have low sensitivity in diagnosis of IBD, they could identify a small number of CD patients not detected by other tests such as ASCA. Anti-glycan Abs are associated with a progression to a more severe disease course and a higher risk for IBD-related surgery. Anti-GP2 Ab could particularly contribute to better stratify cases of pouchitis. Anti-GM-CSF Ab seems to be correlated with disease activity and could help predict relapses. These new promising biomarkers could particularly be useful in stratification of patients according to disease phenotype and risk of complications. They could be a valuable aid in prediction of disease course and therapeutic response but more prospective studies are needed.
The influence of the galactomannan characteristic ratios (
M/
G) on the temperature of gelation (
T
g) and the gel strength of mixtures of galactomannan with xanthan is reported. Two galactomannans ...were investigated: one highly substituted from the seeds of
Mimosa scabrella (
M/
G=11), and the other, less substituted, from the endosperm of
Schizolobium parahybae, with (
M/
G=30) Ganter JLMS, Zawadzki-Baggio SF, Leitner SC, Sierakowski MR, Reicher F. J Carbohydr Chem 1993;12:753. The xanthan:galactomannan systems (4:2 g l
−1, in 5 mM NaCl) showed a temperature of gel formation (
T
g) of 24°C for that of
S. parahybae Bresolin TMB, Milas M, Rinaudo M and Ganter JLMS. Int J Biol Macromol 1998;23:263 and 20°C for the galactomannan of
M. scabrella, determined by viscoelastic measurements and microcalorimetry. A
T
g of 40–50°C was found by Shatwell et al. Shatwell KP, Sutherland IW, Ross-Murphy SB, Dea ICM. Carbohydr Polym 1991;14:29 for locust bean gum-LBG (
M/
G=43). Lundin and Hermansson Lundin L, Hermansson AM. Carbohydr Polym 1995;26:129 reported a difference of 13°C for
T
g of two LBG samples with
M/
G=3 (40°C) and 5 (53°C), in mixtures with xanthan. It appears that the more substituted galactomannans have lower temperatures of gelation in the presence of xanthan. The mechanism of gelation depends also on the
M/
G ratio. For the lower values it involves only disordered xanthan chains in contrast to
M/
G ratios higher than 3. In addition, the presence of the galactomannan from
M. scabrella increased slightly the temperature of the conformational change (
T
m) of xanthan probably due to the ionic strength contribution of proteins (3.9%) present in the galactomannan. On the other hand, the galactomannans from
S. parahybae, with 1.5% of proteins and
M. scabrella, with 2.4% of protein, did not show this effect, the
T
m of xanthan alone or in a mixture being practically unchanged.
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