Retention of asbestos bodies in the lungs of welders

Examination of asbestos bodies (AB) retained in the lungs is a useful way of assessing past occupational exposure to this material. AB retention has been extensively studied in workers directly exposed to asbestos, but less so in those end users, such as welders, who use asbestos-containing products. We therefore retrospectively studied AB retention in 211 welders, for whom biological testing procedures had been requested by a chest physician, between 1988 and 1991. Optical microscopy of AB was performed on samples of sputum (40 subjects), bronchoalveolar lavage fluid (BAL) (147 subjects), and lung tissue obtained after thoracotomy (38 subjects). Information on previous jobs and exposure was obtained using a questionnaire (the mean duration of welding activities was 16.6 years). Eighty-two subjects (38.9%) had elevated lung retention of AB in all the samples studied. Significant AB retention occurred in only 30% of sputum samples, but in 40.1% of BAL samples and 39.5% of lung tissue samples. The duration of welding activities correlated with the density of AB in BAL or lung tissue (r = 0.31, p < 0.01 and r = 0.49, p < 0.05, respectively). On the basis of the questionnaire, only two of the welders with significant AB retention had other occupational exposure to asbestos. Our findings suggest that welding activities may increase lung retention of AB, and consequently might produce higher risks of fibrotic and/or malignant pulmonary diseases. These potential risks need to be brought to the attention of doctors; a longitudinal follow-up may also be warranted in such populations, even after individuals have ceased their welding jobs.     

Experimental Evidence of Intrinsic Disorder and Amyloid Formation by the Henipavirus W Proteins

Henipaviruses are severe human pathogens within the Paramyxoviridae family. Beyond the P protein, the Henipavirus P gene also encodes the V and W proteins which share with P their N-terminal, intrinsically disordered domain (NTD) and possess a unique C-terminal domain. Henipavirus W proteins antagonize interferon (IFN) signaling through NTD-mediated binding to STAT1 and STAT4, and prevent type I IFN expression and production of chemokines. Structural and molecular information on Henipavirus W proteins is lacking. By combining various bioinformatic approaches, we herein show that the Henipaviruses W proteins are predicted to be prevalently disordered and yet to contain short order-prone segments. Using limited proteolysis, differential scanning fluorimetry, analytical size exclusion chromatography, far-UV circular dichroism and small-angle X-ray scattering, we experimentally confirmed their overall disordered nature. In addition, using Congo red and Thioflavin T binding assays and negative-staining transmission electron microscopy, we show that the W proteins phase separate to form amyloid-like fibrils. The present study provides an additional example, among the few reported so far, of a viral protein forming amyloid-like fibrils, therefore significantly contributing to enlarge our currently limited knowledge of viral amyloids. In light of the critical role of the Henipavirus W proteins in evading the host innate immune response and of the functional role of phase separation in biology, these studies provide a conceptual asset to further investigate the functional impact of the phase separation abilities of the W proteins.     

The Functions of the Demethylase JMJD3 in Cancer

Cancer is a major cause of death worldwide. Epigenetic changes in response to external (diet, sports activities, etc.) and internal events are increasingly implicated in tumor initiation and progression. In this review, we focused on post-translational changes in histones and, more particularly, the tri methylation of lysine from histone 3 (H3K27me3) mark, a repressive epigenetic mark often under- or overexpressed in a wide range of cancers. Two actors regulate H3K27 methylation: Jumonji Domain-Containing Protein 3 demethylase (JMJD3) and Enhancer of zeste homolog 2 (EZH2) methyltransferase. A number of studies have highlighted the deregulation of these actors, which is why this scientific review will focus on the role of JMJD3 and, consequently, H3K27me3 in cancer development. Data on JMJD3’s involvement in cancer are classified by cancer type: nervous system, prostate, blood, colorectal, breast, lung, liver, ovarian, and gastric cancers.     

Human bladder cancers and normal bladder mucosa present the same hot spot of heterozygous chromosome-9 deletion

Loss of heterozygosity (LOH) on chromosome 9 is the most frequent genetic alteration in bladder cancer identified to date, suggesting the presence of key gene(s) for this pathology. In this study, we examined 44 bladder tumors and 21 normal bladder samples for LOH on both arms of chromosome 9. Sixteen microsatellite markers, 12 on the short arm (encompassing 9p21-22) and 4 on the long arm (encompassing 9q33-34), were chosen for their highly frequent alterations in bladder cancer. LOH for at least one marker was identified in 42 tumor samples (95.5%), and 14 tumors (32%) displayed LOH for all informative tested markers. Detailed analysis showed that 2 markers on chromosome 9p (D9S157 and D9S156) had the highest frequencies of allelic loss (about 70%), independent of tumor grade and stage. The same study was performed on the 21 normal bladder mucosa samples: 50% of informative cases presented a single specific LOH at the D9S156 locus. Normal samples showing LOH at this locus were therefore screened with 3 novel microsatellite markers in the 810-kb region incorporating D9S156. Using this marker, we found no further heterozygous loss in this region. This result allows different interpretations of the D9S156 loss in normal bladder mucosa, and suggests that D9S156 may be more an indicator of bladder epithelium impairment than a tumor-initiation marker. Similarly, this unexpected result calls in question the interpretation of LOH studies.     

In vivo modifications of AcSDKP metabolism and haematopoiesis in mice treated with 5-fluorouracil and Goralatide

BACKGROUND: The tetrapeptide acetyl-Ser-Asp-Lys-Pro (AcSDKP), a physiological inhibitor of the proliferation of haematopoietic stem cells, is degraded by the angiotensin-I-converting enzyme (ACE). Whereas synthetic AcSDKP (Goralatide) protects normal mice from the haematological toxicity of chemotherapy, it has a lower beneficial effect in humans. This discrepancy could be dependent on Goralatide administration schedules, as well as on the endogenous concentrations of AcSDKP and ACE, which vary during chemotherapy. METHODS: We investigated the effect of one myelotoxic dose of 5-fluorouracil (5-FU, 200 mg kg-1) administered without or with Goralatide on blood, bone marrow (BM) and spleen AcSDKP concentrations, ACE activity, nucleated cell counts and survival of the primitive haematopoietic progenitors high proliferative potential colony-forming cells (HPP-CFCs). RESULTS: The 5-FU treatment dramatically decreased the BM concentrations of AcSDKP by 73% and increased the ACE activity in plasma by 50% during the period of active BM regeneration. Repeated injections of Goralatide from 24 h before to 36 h after the i.p. injection of 5-FU spared BM HPP-CFCs. As an injection of 10 mg of Goralatide induced a short peak of plasma AcSDKP without modifying its BM concentrations, we suggest that its protective effect on HPP-CFCs could be mediated by its interference with other plasma molecules targeting to the BM. CONCLUSION: By improving our knowledge of the biology of AcSDKP in vivo during chemotherapy, our results could help to better define the therapeutic use of Goralatide.     

Electrophoresis of BRCA1 oncosuppressor

BRCA1 is a familial breast and ovarian cancer susceptibility gene and encodes proteins that function as tumor suppressors in human breast cancer cells. To elucidate the biological function of BRCA1, knowledge of cellular localization is needed. This can be achieved by using specific antibodies, so in a first step, we characterized by Western blot analysis the rabbit polyclonal antibodies (K-18) and (D-20) raised against the amino-terminus of human BRCA1 protein, and the polyclonal antibodies (C-20) and (I-20) raised against the carboxy terminus of human BRCA1 protein. The 220-kDa band corresponding to BRCA1 protein was recognized by the four tested antibodies in two mammary carcinoma cell lines (HBL100 and MCF7).     

Intrapleural treatment with recombinant gamma-interferon in early stage malignant pleural mesothelioma

BACKGROUND: This report presents the results of a prospective multi-institutional study of intrapleural treatment with gamma-interferon in patients with Butchart's Stages I and II epithelial or mixed malignant pleural mesothelioma. METHODS: Interferon was administered at a dose of 40 million units twice a week for 8 weeks intrapleurally via a catheter or an implantable port. Thoracoscopic or surgical biopsy was performed if computed tomography scan 2 weeks after the end of treatment demonstrated a reduction in tumor size. Survival was calculated after a follow-up of at least 18 months. Prognostic factors were identified by univariate and multivariate analyses (Cox model). RESULTS: Eighty-nine patients were included over 46 months. Eight histologically confirmed complete responses and nine partial responses with at least a 50% reduction in tumor size were obtained. The overall response rate was 20%. Most responses were achieved in patients with early stage disease. The response rate for patients with Stage I disease was 45%. Tolerance of interferon was good. Treatment was performed on an outpatient basis. The main side effects were hyperthermia, liver toxicity, neutropenia, and catheter-related infection. CONCLUSIONS: Gamma-interferon is effective mainly in Stage I mesothelioma, especially if the tumor is confined to the parietal or diaphragmatic pleura (Stage IA).     

Verification of methods of analysis for soft missile impact problems

As part of a research project on the dynamic response of nuclear power plant structures subjected to impact loading, several computer programs have been developed to evaluate the reaction vs. time curve for ‘soft’ missiles impinging against fixed or moving targets. The mathematical-mechanical features of these computer programs are outlined, and reaction-time curves obtained by means of these programs are compared with experimental results. The influence of model discretization and of relevant input parameters is discussed, and areas in which further research is needed are indicated. It is shown that the mean reaction-time curve at the interface between missiles impinging against rigid or very stiff targets can be reliably predicted if the crushing strength of the missile is known.