Serum HE4: An Independent Prognostic Factor in Non-Small Cell Lung Cancer

Human epididymis secretory protein 4 (HE4) is a secreted glycosylated protein encoded by the WAP four-disulfide core domain 2 (WFDC2) gene, located on a chromosome 20 segment that is frequently amplified in many cancers. This study aimed at determining serum HE4 prognostic value in non-small cell lung cancer (NSCLC), following the REMARK guidelines. Serum samples from 346 consecutive patients with histologically proven and previously untreated NSCLC and 41 patients with benign pulmonary disease were collected at the Montpellier-Nimes Academic Hospital. Work-up investigations performed to determine the disease characteristics and treatment algorithms were congruent with international guidelines. HE4 levels in serum were measured with an ELISA test (Fujirebio Diagnostics) that uses two monoclonal antibodies, 2H5 and 3D8, against the C-WFDC domain of HE4. The area under the ROC curve (i.e., overall ability of HE4 to discriminate between controls and patients) was 0.78 (95% confidence interval [CI], 0.738–0.821; z test P <0.0001). Serum HE4 levels were significantly higher in patients with worse performance status, advanced TNM stage and positive nodal status. In the Cox model, overall survival was shorter in patients with high pretreatment serum HE4 (above 140 pmol/L) than in patients with serum H4 level ≤ 140 pmol/L [median survival: 17.7 weeks (95% CI, 11.9 to 24.9) and 46.4 weeks (95% CI, 38.6 to 56.3), respectively; hazard ratio: 1.48 (95% CI, 1.12 to 1.95) for high HE4; adjusted P = 0.0057]. High serum HE4 level at diagnosis is an independent determinant of poor prognosis in NSCLC.     

Identification des cercaires de Schistosoma africains émises par Bulinus umbilicatus,B. truncatus et B. forskalii

Résumé Trois indices chétotaxiques AD, AL et U, des cercaires de quatre espèces pré-identifiées de Schistosoma africains, émises par des Mollusques infestés naturellement ou expérimentalement, ont été calculés. AD et AL correspondant respectivement à la distance relative entre les papilles dorsales et les papilles latérales. U correspond au nombre total des papilles du tronc caudal. La simple comparaison des moyennes arithmétiques d'un ou deux de ces trois indices permet de distinguer les cercaires de Schistosoma haematobium et de S. curassoni émises par Bulinus umbilicatus; les cercaires de S. haematobium et S. bovis émises par B. truncatus; les cercaires de S. bovis et S. intercalatum émises par B. forskalii.

---

Identification des cercaires de Schistosoma africains émises par Bulinus umbilicatus, B. truncatus et B. forskalii

Three chaetotaxic indices, AD, AL and U, of cercariae of four pre-identified African Schistosoma species, obtained from natural or experimental infections, were established. AD and AL correspond respectively to the relative distance between the dorsal and lateral papillae. U corresponds to the total number of tail stem papillae. The simple comparison of average values of one or two of these three indices facilitated identification of the cercariae of Schistosoma haematobium and S. curassoni emitted by Bulinus umbilicatus, cercariae of S. haematobium and S. bovis shed by B. truncatus, and cercariae of S. bovis and S. intercalatum emitted by B. forskalii.

     

Peptide hormone-membrane interactions: the aggregational and conformational state of lipo-gastrin derivatives and their receptor binding affinity.

The (2RS)-1,2-dipalmitoyl-3-mercaptoglycerol/-, (2RS)-1,2-dimyristoyl-3-mercaptoglycerol/-, and (2RS)-1-myristoyl-2-palmitoyl-3-mercaptoglycerol/maleoyl-bet a-alanyl- [Nle15]-human-gastrin-(2-17) adducts were prepared as lipo-gastrin derivatives of explicitly primary amphiphilic properties. As representative of this class of lipo-gastrins, the dimyristoyl derivative has been thoroughly characterized in its aggregational state since, among the three compounds, theoretically it should exhibit the lowest degree of lipid character. It aggregates in aqueous solution to form monodispersed unilamellar spherical vesicles with dislocation of the peptide moiety at the bilayer surface in predominantly unordered structure. The liposomes are remarkably stable toward solubilization with trifluoroethanol and toward vesicle to micelle transition with neutral and negatively charged surfactants even above their critical micellar concentrations. Asymmetric fusion with the detergent micelles induces polydispersion of the liposomes in terms of shape and size without affecting in significant manner the mode of display of the gastrin portions at the bilayer surface. Only the positively charged hexadecyltrimethylammonium hydroxide provokes the collapse of the vesicles into mixed micelles with concomitant altered dislocation of the gastrin-peptide in the new aggregational state. Despite the lipid properties of the gastrin derivatives, i.e., formation of liposomes, they retain remarkable receptor affinities (IC50 = 1.5 x 10(-9) M for myristoyl-palmitoyl-gastrin, IC50 = 2.0 x 10(-9) M for di-myristoyl-gastrin and IC50 = 3.1 x 10(-9) M for di-palmitoyl-gastrin vs IC50 = 2.8 x 10(-10) M for Nle15-gastrin). Since the displacement of radiolabeled Nle15-gastrin from rat pancreatic acinar cell line membrane preparations by both the parent gastrin hormone and the three lipo-gastrins occurs in parallel manner, the data support a mechanism of receptor occupancy via accumulation of the gastrins at the membrane surface and their two-dimensional diffusion to the target receptor. Thereby the differentiated decrease of affinity in function of fatty acid chain length has to be attributed to the energetically more or less favored transfer of the monomers from the donor vesicles to the acceptor membranes. Moreover, according to this model migration of the lipo-gastrins with their interdigitating di-fatty-acyl moieties should be delayed, again in lipid structure-dependent manner, in comparison to the parent gastrin molecule, which is free to float in the membrane interfacial phase.     

Failure of testicular development associated with a rearrangement of 9p24.1 proximal to the SNF2 gene

In 46,XY individuals, testes are determined by the activity of the SRY gene (sex-determining region Y), located on the short arm of the Ychromosome. The other genetic components of the cascade that leads to testis formation are unknown and may be located on the Xchromosome or on the autosomes. Evidence for the existence of several loci associated with failure of male sexual development is indicated by reports of 46,XY gonadal dysgenesis associated with structural abnormalities of the Xchromosome or of autosomes (chromosomes9, 10, 11 and 17). In this report, we describe the investigation of a child presenting with multiple congenital abnormalities, mental retardation and partial testicular failure. The patient had a homogeneous de novo 46,XY,inv dup(9)(pter→p24.1::p21.1 →p23.3::p24.1→qter) chromosome complement. No deletion was found by either cytogenetic or molecular analysis. The SRY gene and DSS region showed no abnormalities. Southern blotting dosage analysis with 9p probes and fluorescent in situ hybridisation data indicated that the distal breakpoint of the duplicated fragment was located at 9p24.1, proximal to the SNF2 gene. We therefore suggest that a gene involved in normal testicular development and/or maintenance is present at this position on chromosome 9. Received: 20 January 1997 / Accepted: 5 November 1997     

Myocardium proteome remodelling after nutritional deprivation of methyl donors

Methyl donor (MD: folate, vitamin B12 and choline) deficiency causes hyperhomocysteinemia, a risk factor for cardiovascular diseases. However, the mechanisms of the association between MD deficiency, hyperhomocysteinemia, and cardiomyopathy remain unclear. Therefore, we performed a proteomic analysis of myocardium of pups from rat dams fed a MD-depleted diet to understand the impact of MD deficiency on heart at the protein level. Two-dimension gel electrophoresis and mass spectrometry-based analyses allowed us to identify 39 proteins with significantly altered abundance in MD-deficient myocardium. Ingenuity Pathway Analysis showed that 87% of them fitted to a single protein network associated with developmental disorder, cellular compromise and lipid metabolism. Concurrently increased protein carbonylation, the major oxidative post-translational protein modification, could contribute to the decreased abundance of many myocardial proteins after MD deficiency. To decipher the effect of MD deficiency on the abundance of specific proteins identified in vivo, we developed an in vitro model using the cardiomyoblast cell line H9c2. After a 4-day exposure to a MD-deprived (vs. complete) medium, cells were deficient of folate and vitamin B12, and released abnormal amounts of homocysteine. Western blot analyses of pup myocardium and H9c2 cells yielded similar findings for several proteins. Of specific interest is the result showing increased and decreased abundances of prohibitin and α-crystallin B, respectively, which underlines mitochondrial injury and endoplasmic reticulum stress within MD deficiency. The in vitro findings validate the MD-deficient H9c2 cells as a relevant model for studying mechanisms of the early metabolic changes occurring in cardiac cells after MD deprivation.