In vitro phosphorylation as tool for modification of silk and keratin fibrous materials

An overview is given of the recent work on in vitro enzymatic phosphorylation of silk fibroin and human hair keratin. Opposing to many chemical "conventional" approaches, enzymatic phosphorylation is in fact a mild reaction and the treatment falls within "green chemistry" approach. Silk and keratin are not phosphorylated in vivo, but in vitro. This enzyme-driven modification is a major technological breakthrough. Harsh chemical chemicals are avoided, and mild conditions make enzymatic phosphorylation a real "green chemistry" approach. The current communication presents a novel approach stating that enzyme phosphorylation may be used as a tool to modify the surface charge of biocompatible materials such as keratin and silk

Endothelin-1 gene expression in human pheochromocytoma.

We examined expression of human endothelin-1 (ET-1) in adrenal tissues removed from five patients with pheochromocytomas and two patients with aldosterone-producing adenomas. The pheochromocytomas contained a 2.3 kilobase ET-1 transcript, which was not found int he aldosteronomas. Constitutive expression of ET-1 varied in magnitude among the pheochromocytomas but was generally at a low level. Immunohistochemical staining of the pheochromocytomas with an antiserum to human ET-1 showed the presence of immunoreactive ET-1 as well. The presence of ET-1 messenger ribonucleic acid and ET-1 immunoreactivity in human pheochromocytomas suggests a possible paracrine role for this peptide in human chromaffin cells

Extensive spherical amyloid deposition presenting as a pituitary tumor

A 71-yr-old man was admitted for further evaluation and trans-sphenoidal surgery of a pituitary tumor. He complained of impotence and decreased libido over a period of about 40 yr. Thirty-eight yr ago he was treated for bilateral gynecomastia with galactorrhea. Endocrinological investigation at presentation revealed only mild hyperprolactinemia and hypogonadotropic hypogonadism. Pituitary magnetic resonance imaging (MRI) showed a tumor up to 2.5 cm in diameter with infiltration of the sphenoid sinus and right cavernous sinus. The tumor exhibited a heterogeneous hyperintense signal on T1-weighted images and hypointense signal on T2-weighted images. Standard trans-sphenoidal surgery was performed and a brownish mass was found inside the sella, which was removed. Histological examination of the mass revealed extensive spherical amyloid deposits with strongly positive immunohistochemical staining for prolactin. Therefore, a prolactinoma with extensive spherical amyloid deposition was diagnosed. Extensive spherical amyloid deposition is a rare finding in prolactin-secreting pituitary adenomas. So far, characteristic radiological findings by MRI have been described only twice. Due to characteristic MRI findings, the diagnosis of extensive intrasellar amyloid deposition can be entertained pre-operatively. Trans-sphenoidal surgical resection is essential to confirm the diagnosis histologically and because of the potential lack of tumor shrinkage under dopaminagonist therapy in this type of prolactinom

Alterations in Ca2+ Signalling via ER-mitochondria contact site remodelling in cancer

Inter-organellar contact sites establish microdomains for localised Ca2+-signalling events. One of these microdomains is established between the ER and the mitochondria. Importantly, the so-called mitochondria-associated ER membranes (MAMs) contain, besides structural proteins and proteins involved in lipid exchange, several Ca2+-transport systems, mediating efficient Ca2+ transfer from the ER to the mitochondria. These Ca2+ signals critically control several mitochondrial functions, thereby impacting cell metabolism, cell death and survival, proliferation and migration. Hence, the MAMs have emerged as critical signalling hubs in physiology, while their dysregulation is an important factor that drives or at least contributes to oncogenesis and tumour progression. In this book chapter, we will provide an overview of the role of the MAMs in cell function and how alterations in the MAM composition contribute to oncogenic features and behaviours

Efficacy and safety of a fixed-ratio combination of insulin degludec and liraglutide (IDegLira) compared with its components given alone: Results of a phase 3, open-label, randomised, 26-week, treat-to-target trial in insulin-naive patients with type 2 diabetes

BACKGROUND: A fixed-ratio combination of the basal insulin analogue insulin degludec and the glucagon-like peptide-1 (GLP-1) analogue liraglutide has been developed as a once-daily injection for the treatment of type 2 diabetes. We aimed to compare combined insulin degludec-liraglutide (IDegLira) with its components given alone in insulin-naive patients. METHODS: In this phase 3, 26-week, open-label, randomised trial, adults with type 2 diabetes, HbA1c of 7-10% (inclusive), a BMI of 40 kg/m(2) or less, and treated with metformin with or without pioglitazone were randomly assigned (2:1:1) to daily injections of IDegLira, insulin degludec, or liraglutide (1\ub78 mg per day). IDegLira and insulin degludec were titrated to achieve a self-measured prebreakfast plasma glucose concentration of 4-5 mmol/L. The primary endpoint was change in HbA1c after 26 weeks of treatment, and the main objective was to assess the non-inferiority of IDegLira to insulin degludec (with an upper 95% CI margin of 0\ub73%), and the superiority of IDegLira to liraglutide (with a lower 95% CI margin of 0%). This study is registered with ClinicalTrials.gov, number NCT01336023. FINDINGS: 1663 adults (mean age 55 years [SD 10], HbA1c 8\ub73% [0\ub79], and BMI 31\ub72 kg/m(2) [4\ub78]) were randomly assigned, 834 to IDegLira, 414 to insulin degludec, and 415 to liraglutide. After 26 weeks, mean HbA1c had decreased by 1\ub79% (SD 1\ub71) to 6\ub74% (1\ub70) with IDegLira, by 1\ub74% (1\ub70) to 6\ub79% (1\ub71) with insulin degludec, and by 1\ub73% (1\ub71) to 7\ub70% (1\ub72) with liraglutide. IDegLira was non-inferior to insulin degludec (estimated treatment difference -0\ub747%, 95% CI -0\ub758 to -0\ub736, p<0\ub70001) and superior to liraglutide (-0\ub764%, -0\ub775 to -0\ub753, p<0\ub70001). IDegLira was generally well tolerated; fewer participants in the IDegLira group than in the liraglutide group reported gastrointestinal adverse events (nausea 8\ub78 vs 19\ub77%), although the insulin degludec group had the fewest participants with gastrointestinal adverse events (nausea 3\ub76%). We noted no clinically relevant differences between treatments with respect to standard safety assessments, and the safety profile of IDegLira reflected those of its component parts. The number of confirmed hypoglycaemic events per patient year was 1\ub78 for IDegLira, 0\ub72 for liraglutide, and 2\ub76 for insulin degludec. Serious adverse events occurred in 19 (2%) of 825 patients in the IDegLira group, eight (2%) of 412 in the insulin degludec group, and 14 (3%) of 412 in the liraglutide group. INTERPRETATION: IDegLira combines the clinical advantages of basal insulin and GLP-1 receptor agonist treatment, resulting in improved glycaemic control compared with its components given alone

Efficacy and safety of a fixed-ratio combination of insulin degludec and liraglutide (IDegLira) compared with its components given alone: results of a phase 3, open-label, randomised, 26-week, treat-to-target trial in insulin-naive patients with type 2 diabetes.

BACKGROUND: A fixed-ratio combination of the basal insulin analogue insulin degludec and the glucagon-like peptide-1 (GLP-1) analogue liraglutide has been developed as a once-daily injection for the treatment of type 2 diabetes. We aimed to compare combined insulin degludec-liraglutide (IDegLira) with its components given alone in insulin-naive patients. METHODS: In this phase 3, 26-week, open-label, randomised trial, adults with type 2 diabetes, HbA1c of 7-10% (inclusive), a BMI of 40 kg/m(2) or less, and treated with metformin with or without pioglitazone were randomly assigned (2:1:1) to daily injections of IDegLira, insulin degludec, or liraglutide (1·8 mg per day). IDegLira and insulin degludec were titrated to achieve a self-measured prebreakfast plasma glucose concentration of 4-5 mmol/L. The primary endpoint was change in HbA1c after 26 weeks of treatment, and the main objective was to assess the non-inferiority of IDegLira to insulin degludec (with an upper 95% CI margin of 0·3%), and the superiority of IDegLira to liraglutide (with a lower 95% CI margin of 0%). This study is registered with ClinicalTrials.gov, number NCT01336023. FINDINGS: 1663 adults (mean age 55 years [SD 10], HbA1c 8·3% [0·9], and BMI 31·2 kg/m(2) [4·8]) were randomly assigned, 834 to IDegLira, 414 to insulin degludec, and 415 to liraglutide. After 26 weeks, mean HbA1c had decreased by 1·9% (SD 1·1) to 6·4% (1·0) with IDegLira, by 1·4% (1·0) to 6·9% (1·1) with insulin degludec, and by 1·3% (1·1) to 7·0% (1·2) with liraglutide. IDegLira was non-inferior to insulin degludec (estimated treatment difference -0·47%, 95% CI -0·58 to -0·36, p<0·0001) and superior to liraglutide (-0·64%, -0·75 to -0·53, p<0·0001). IDegLira was generally well tolerated; fewer participants in the IDegLira group than in the liraglutide group reported gastrointestinal adverse events (nausea 8·8 vs 19·7%), although the insulin degludec group had the fewest participants with gastrointestinal adverse events (nausea 3·6%). We noted no clinically relevant differences between treatments with respect to standard safety assessments, and the safety profile of IDegLira reflected those of its component parts. The number of confirmed hypoglycaemic events per patient year was 1·8 for IDegLira, 0·2 for liraglutide, and 2·6 for insulin degludec. Serious adverse events occurred in 19 (2%) of 825 patients in the IDegLira group, eight (2%) of 412 in the insulin degludec group, and 14 (3%) of 412 in the liraglutide group. INTERPRETATION: IDegLira combines the clinical advantages of basal insulin and GLP-1 receptor agonist treatment, resulting in improved glycaemic control compared with its components given alone