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The inherited basis of hypergonadotropic hypogonadism
Published in Philip E. Harris, Pierre-Marc G. Bouloux, Endocrinology in Clinical Practice, 2014
Structurally, KAL1 is a modular protein comprising a large cysteine-rich N-terminal domain, a whey acidic protein (WAP)–like domain, four contiguous fibronectin-like type III (FnIII) repeats, and a small C-terminal domain rich in basic residues. The WAP domain is structurally similar to those of many serine protease inhibitors, whereas the FnIII repeats are structurally related to some cell adhesion molecules. Early indicators, gleaned from a human fetus carrying a chromosomal deletion at Xp22.3 that included KAL1, showed that GnRH cellular migration was abnormal, with GnRH neurons accumulating in the upper nasal region50; the olfactory bulbs were also absent. It was inferred that KAL1 gene mutations led to the failure of the later phases of GnRH neuronal migration (GnRH neuronal arrest in the subcribriform plate area) coupled with failed olfactory bulb development.
ras Genes Involvement in Carcinogenesis: Lessons From Animal Model Systems
Published in Juan Carlos Lacal, Frank McCormick, The ras Superfamily of GTPases, 2017
If ras activation was sufficient for tumorigenesis, one should expect the appearance of tumors with a short latency period in the targeted tissue of all the transgenic animals. One general conclusion deduced from experiments with transgenic mice is that this is not the case for the oncogenes thus far tested. The neu oncogene could be an exception to this statement, although contradictory reports have appeared.127,128 In ras-transgenic mice the tumor incidence is not very high or the tumors appear in all mice but after long latency periods, despite continuous ras expression in the targeted tissue. For example, mice carrying the H-ras oncogene downstream of the whey acidic protein (WAP) promoter develop mammary or salivary gland tumors after 9 to 10 months.128 The latency period for lung tumors developed in mice carrying the H-ras oncogene downstream of the SV40-T-Ag promoter can be one year.130 Other tissue-specific promoters used with ras transgenes are those from elastase,131 MMTV,126,132,133 albumin,98 and keratin.134 Altogether, these experiments indicate that activated H-ras induces proliferative hyperplasia. However, further secondary events are necessary for progression to a true malignant tumor. Moreover, the benign lesions induced in some ras-transgenic mice when the oncogene expression occurs in the epidermis show a high degree of differentiation.134,135 As pointed out above, ras activation is prevalent in chemically induced keratoacanthomas, which undergo an extensive differentiation process.42 It is noteworthy that transgenic mice carrying the H-ras oncogene under the control of the rat insulin II promoter suffer pancreatic β-cell degeneration and subsequent diabetes. Strikingly, this alteration is only detected in male transgenic mice.136 At least in one reported case, transgenic mice expressed a ras mutated gene without any abnormality in the target tissue (brain).137
Recombinant human C1 esterase inhibitor (Conestat alfa) for prophylaxis to prevent attacks in adult and adolescent patients with hereditary angioedema
Published in Expert Review of Clinical Immunology, 2018
Anna Valerieva, Sonia Caccia, Marco Cicardi
Conestat alpha is a rhC1-INH (Ruconest®, Pharming Technologies B.V., Leiden, The Netherlands) obtained through a purification process of transgenic New Zealand white rabbits’ milk (Oryctolagus cuniculus). The promoter used to drive expression of the hC1-INH transgene is the bovine alpha-S1-casein promoter, which is specific for the secretion of caseins in the milk. The protein content of rabbit milk is approximately 14% of which about 65% consists of various caseins aggregated in micelles. The remaining proteins in rabbit milk are whey proteins including transferrin, whey acidic protein, immunoglobulins, albumin, and lactalbumin. After collection, rabbit milk undergoes series of standard centrifugation, filtration, and chromatography steps that give rhC1-INH, 99% purity as assessed by sodium dodecyl sulfate polyacrylamide gel electrophoresis [43]. The 1% impurities are multimers and N-terminal cleaved C1-INH species. Host-related impurities were analyzed (ELISA) and measured to be approximately 10 ppm in the commercial batches and defined to consist of minimal traces of rabbit protein [43]. The activity of purified rhC1-INH is 6.1 U per mg of protein, the same as pdC1-INH [43]. Protein sequencing analysis of recombinant and plasma proteins reveals identical polypeptide N- and C-terminals for the two molecules. Nevertheless, the two proteins differ in molecular mass and this is explained by differences in glycosylation (21% and 26–28% carbohydrate content respectively) [43,44].
Proofs for implementation of higher HE4 and ROMA index cut-off values in ovarian cancer preoperative stratification
Published in Journal of Obstetrics and Gynaecology, 2019
Zvjezdana Špacir Prskalo, Petra Bulić, Sanja Langer, Mihaela Gaće, Mario Puljiz, Damir Danolić, Ilija Alvir, Ivica Mamić, Lucija Šušnjar, Ljiljana Mayer
HE4 belongs to the WAP (whey acidic protein) four-disulphide core (WFDC) family of proteins characterised as serine and threonine protease inhibitors (Zhu et al. 2013). HE4 was the first determined in the epithelium of the distal epididymis, but it is also found in ovarian tissue. An elevated mRNA expression of HE4 was found in the ovarian cancer tissues, especially in the serous type (Drapkin et al. 2005).
Novel heart failure biomarkers: why do we fail to exploit their potential?
Published in Critical Reviews in Clinical Laboratory Sciences, 2018
Arnold Piek, Weijie Du, Rudolf A. de Boer, Herman H. W. Silljé
The marker human epididymis protein 4 (HE4) is a recently discovered novel HF biomarker. HE4 is also known as the whey acidic protein four-disulfide core domain 2 (WFDC2 or WAP-4C). Though the exact function of HE4 is yet unknown, a role for HE4 in fibrosis formation has been suggested because it shows similarities to extracellular proteinase inhibitors [72,73]. In a mouse model of renal disease, reduced fibrosis was observed in mice treated with HE4-neutralizing antibodies [74]. In patients with both acute and chronic HF, HE4 levels were correlated with HF severity and could predict outcome in a multivariable model [75,76]. In both studies, HE4 levels in HF were correlated with Gal-3 and, therefore, probably with organ fibrosis. HE4, however, is not cardiac specific; its expression was first identified in the epididymis and later in many other tissues and organs [72,77,78]. Moreover, HE4 plasma levels are associated with several types of cancer [77–79], including ovarian cancer [80], and with chronic kidney disease (CKD) severity [81]. The association of HE4 levels with kidney function has also been replicated in cohorts comprised of acute and chronic HF patients [75,76]. It has been suggested that the elevated levels of HE4 in CKD patients may complicate its use in monitoring patients with epithelial ovarian cancer [82], and the same is probably true in the HF setting. These multi-disease effects on HE4 plasma levels will mean that HE4 will not be useful for HF diagnosis, but, as part of a multi-biomarker model, it may have potential in the stratification of HF patients. HE4 has been included in such a model as an instrument to identify populations with a distinct therapy response. Patients with acute HF were investigated for response to treatment with the selective A1 adenosine receptor antagonist, rolofylline; in this study, the authors assessed tools to distinguish responders from non-responders to therapy [83]. A multi-marker model, including HE4 plasma levels, tumor necrosis factor alpha receptor 1 (TNF-R 1α), sST2 and total cholesterol, appeared to be superior to clinical characteristics, including age, sex, and cardiac function, to differentiate non-responders from responders. This study showed that multi-marker tools provide opportunities to improve clinical testing of novel drugs [83]. Moreover, this study is an example of how plasma biomarkers can be used in a multi-marker setting for stratification of HF patients.