Increased incidence of pathogenic variants in ATM in the context of testing for breast and ovarian cancer predisposition.

Pathogenic Variants (PV) in major cancer predisposition genes are only identified in approximately 10% of patients with Hereditary Breast and Ovarian Cancer (HBOC) syndrome. Next Generation Sequencing (NGS) leads to the characterization of incidental variants in genes other than those known to be associated with HBOC syndrome. The aim of this study was to determine if such incidental PV were specific to a phenotype. The detection rates of HBOC-associated and incidental PV in 1812 patients who underwent genetic testing were compared with rates in control groups FLOSSIES and ExAC. The rates of incidental PV in the PALB2, ATM and CHEK2 genes were significantly increased in the HBOC group compared to controls with, respective odds ratios of 15.2 (95% CI = 5.6-47.6), 9.6 (95% CI = 4.8-19.6) and 2.7 (95% CI = 1.3-5.5). Unsupervised Hierarchical Clustering on Principle Components characterized 3 clusters: by HBOC (P = 0.01); by ExAC and FLOSSIES (P = 0.01 and 0.02 respectively); and by HBOC, ExAC and FLOSSIES (P = 0.01, 0.04 and 0.04 respectively). Interestingly, PALB2 and ATM were grouped in the same statistical cluster defined by the HBOC group, whereas CHEK2 was in a different cluster. We identified co-occurrences of PV in ATM and BRCA genes and confirmed the Manchester Scoring System as a reliable PV predictor tool for BRCA genes but not for ATM or PALB2. This study demonstrates that ATM PV, and to a lesser extent CHEK2 PV, are associated with HBOC syndrome. The co-occurrence of ATM PV with BRCA PV suggests that such ATM variants are not sufficient alone to induce cancer, supporting a multigenism hypothesis.

A derivative of ascorbic acid modulates cAMP production.

We reported, in previous experiments, that AA is a global regulator of cAMP pools. In this study, we demonstrate that K873, an analog of AA we synthesized and presenting antiproliferative properties, has also an impact on cAMP production. However, K873 has no antioxidant activity, at the contrary of AA. It definitively demonstrates that action of AA on the cAMP production is not linked to antioxidant activity. These data suggest that AA, and derivatives of this molecule, could be promising drug acting on biological processes that are under the control of cAMP dependent pathway.

[Philippe Maupas : hepatitis B vaccine discoverer]. / Philippe Maupas: inventeur du vaccin contre L'Hépatite B.

Philippe Maupas Day 8th February 1981, an official ceremony with all the Profession, the Tours Faculty of Pharmacy was called Philippe Maupas, Hepatitis B vaccine discoverer - Galien Prize 1981. This communication presents the man, the scientist and the teacher. Born on 30th June 1939 in Toulon (south of France), married and the father of two children, Ph. Maupas was a man of action and an humanist. Full of enthusiasm, always available, passionate about his work, he never hesitated to brave the odds if he felt it would be of use to the community. With a pluridisciplinary training - Veterinary Doctor (1965), Pharmacist (1970), Science Doctor (1970) and Physician Doctor (1976) - he was Professor of Microbiology and Dean of the Faculty of Pharmacy of Tours. His scientific career fully illustrates his thirst for knowledge and his unflagging struggle against infectious diseases. Ph. Maupas approached his research work in a relaxed, imaginative frame of mind. Always passionate about his work and fired by spirit of Louis Pasteur, he was moved by a preoccupation of efficacy and a will of prevention in Public Health. He carried out research into both animal and human infectious diseases as well as anthropozoonosis. Ph. Maupas's most remarkable discoveries concerned the hepatitis B virus: he produced the first vaccine against hepatitis B and applied it to the prevention in man of this disease (1976); he confirmed the aetiological link between the hepatitis B and primary liver cancer.

Antibody response to preS1 in hepatitis-B-virus-induced liver disease and after immunization.

Antibodies to the pre-S1-encoded sequence of hepatitis B virus (HBV) envelope were detected by ELISA using a synthetic peptide analogue of preS1 proteins, in different groups of HBV-infected subjects and also in hepatitis B vaccine recipients. Such antibodies were specifically found in only 1% of HBsAg chronic carriers including patients with cirrhosis and primary liver cancer. Anti-preS1 were detected in patients with acute hepatitis; in 13% of the HBsAg+ sera obtained before recovery and in 37% of the sera obtained after recovery. Anti-preS1 antibodies were detected in recipients of a plasma-derived vaccine, but not in those receiving a recombinant vaccine. The results indicate that anti-preS1 is an earlier serum marker of HBV clearance than anti-preS2 and anti-S antibodies.

Prevalence of hepatitis C virus infection in Africa: anti-HCV antibodies in the general population and in patients suffering from cirrhosis or primary liver cancer.

Anti-hepatitis-C-virus (anti-HCV) antibody was tested for in sera from 410 adults living in Tunisia, Senegal, Burundi and Madagascar, and in 209 Tunisian and Senegalese patients suffering from liver diseases. Anti-HCV antibodies were detected in 4.2% of the adult population from Africa, in 51% of patients suffering from liver cirrhosis and in 37% of patients suffering from primary liver cancer. However, higher proportions of anti-HCV antibodies were detected in HBsAg+ patients than in HBsAg- patients. To assess the role of HCV in the development of both cirrhosis and primary liver cancer, a confirmation test is needed.

Anti-pre-S2 antibodies in natural hepatitis B virus infection and after immunization.

Anti-pre-S2 antibodies were detected by enzyme-linked immuno-absorbant assay using a synthetic peptide analogue of pre-S2 protein, in different groups of hepatitis-B-infected subjects, including patients presenting with cirrhosis and liver cancer, and also in infants immunized with hepatitis B vaccine. Anti-pre-S2 antibodies were not detected in hepatitis B surface antigen (HBsAg) chronic carriers, including patients with cirrhosis or primary liver cancer. Anti-pre-S2 antibodies were not detected in HBsAg-positive sera during the early phase of acute hepatitis. They were only noted upon recovery, when anti-HBs antibodies are detectable at the same time as HBsAg. After recovery, anti-pre-S2 antibodies were noted in 57% of test sera and were still detectable in 16% of anti-HBs-positive sera obtained years after HBV infection. Anti-pre-S2 antibodies were detected in 70% of infants immunized with 2 or 5 micrograms doses of Hevac B Pasteur vaccine, confirming that this vaccine contains pre-S2 antigen. Anti-pre-S2 detection was correlated with the anti-HBs antibody titre.

[Hepatitis B virus infection in Tunisia]. / Infection par le virus de l'hépatite B en Tunisie.

Recent reports show that the frequency of HBsAg varies around 4 to 6% in most Mediterranean and Middle East countries. Those areas are therefore considered as areas of intermediate endemicity for hepatitis B virus (HBV) infection. The purpose of this study is to investigate the HBV global situation in Tunisia, by means of third generation testing methods. Blood samples were obtained from 3 distinct population groups from Tunis: blood donors, consisting of young male adults staff members and patients from 4 haemodialysis units patients with either acute hepatitis or liver cirrhosis They were tested for HBsAg, anti-HBs and anti-HBc by radioimmunoassay tests. HBsAg was detected in 6.5% of the young male adults, and approximately 60% had either anti-HBs or anti-HBc antibodies. Haemodialysis staff members and patients respectively displayed 9.1% and 19.5% of HBsAg positivity, but an increase of HBsAg positivity and of all HBV serum markers in relation to the amount of time spent in dialysis units was shown among the patients. After 3 years of dialysis sessions, none remained seronegative. HBsAg was detected in approximately two-thirds of the patients with acute hepatitis or liver cirrhosis, and all cirrhosis patients had at least one HBV serum marker. These global results stress the importance of HBV infection in Tunisia. Immunization against hepatitis B virus therefore has to be considered. Nevertheless, the immunization strategy must take into account the epidemiological and economic characteristics of the country.

[Vaccination of the newborn against hepatitis B in Burundi]. / Vaccination du nouveau-né contre l'hépatite B au Burundi.

Vaccination against hepatitis B is carried out at birth in the Bujumbura Hospital in Burundi. The vaccination protocol comprises only two injections, the first being given during the first 48 hours after birth and the second two months later. A booster is given at the age of one year. The results of this vaccination programme are compared with those obtained in a control population. At the time of the booster, 82% of vaccinated subjects had anti-HBs antibodies, compared with 3% of control subjects. Six months after the second injection, all vaccinated subjects had anti-HBs antibodies.

Immune response to hepatitis B vaccine in infants and newborns: control trial in an endemic area (Senegal).

In 1978 it was suggested that hepatitis B (HB) vaccine should be used to prevent the early hepatitis B surface antigen (HBsAg) carrier state in children. Immunization was effected by 3 injections of HB vaccine at one-month intervals followed by a booster injection after one year. Children in a control group were immunized with DT-polio vaccine according to the same schedule. The anti-HBs response of the children to HB vaccination was studied in relation to their hepatitis B virus (HBV) serum markers prior to immunization. Of the seronegative children, 70.5% responded to immunization after 2 injections of 5- g doses of HB vaccine and 94% after the third injection. The efficacy of the vaccine was demonstrated by comparison of HB events after one year in 309 seronegative children immunized with HB vaccine and 252 seronegative children immunized with DT-polio vaccine, and after two years in 101 and 119 children, respectively. The incidence of the HBsAg carrier state was reduced by 80% in susceptible children. In order to eliminate the perinatal transmission occurring in newborns with HBsAg-positive mothers, a study of immunization at birth has been instituted. A total of 86 newborns responded to the vaccination as well as older children, irrespective of the HBV status of their mothers. After one year, the incidence of the HBsAg carrier state was reduced by 80%. In Africa, immunization teams have a limited amount of time to devote to each rural community. The immunogenic effect of 2 doses of HB vaccine given at an interval of 2 or 6 months has therefore been investigated. All were given a booster dose one year after the first injection of vaccine. No difference was observed in the seroconversion rate or in the anti-HBs titres as between the two protocols. These results demonstrate that 2 doses of 5 micrograms of HB vaccine are sufficient to obtain a high immunogenic effect in infants. In addition, an investigation was carried out on the immune response to HBsAg and tetanus toxoid antigen when administered simultaneously to children as HB vaccine and DT-polio vaccine. The immune response was at least equal to that observed after administration of these vaccines separately.

Hepatitis B virus serological markers in Africans with liver cirrhosis and hepatocellular carcinoma.

Serum samples were collected at the time of hospitalization from 221 black Africans suffering from cirrhosis and 453 suffering from hepatocellular carcinoma (HCC). These patients came from Senegal, Burundi and Mali, and 6655 adults from different population groups in these countries were used as controls. Hepatitis B virus (HBV) serum markers, including hepatitis B surface antigen (HBsAg), anti-HBs, antibody to hepatitis B core antigen (anti-HBc), HBeAg and anti-HBe, were determined by radioimmunoassay, while alpha-fetoprotein and complexes between HBsAg and IgM were detected by ELISA tests. HBsAg was detected in 11.8-17.6% of controls as opposed to 63.3% of patients suffering from cirrhosis and 62.7% of patients suffering from HCC. There was less evidence for HBV replication in cirrhosis and HCC in older patients. A significant increase in the frequency of HBsAg/IgM complexes was found in passing from the HBsAg chronic carrier state (13.9%) to cirrhosis (29.9%) and finally to HCC (33.7%).

[Epidemiology and pathologic results of chronic carriers state of hepatitis B in Mali]. / Epidémiologie et conséquences pathologiques du portage chronique du virus de l'hépatite B au Mali.

The HB antigen of the hepatitis B (HB) virus, studied by counter immunoelectrophoresis shows a prevalence of 8.7% in 1,860 rural Malians and 11.3% in 764 blood donors from Bamako. Amongst 1,350 hospitalised patients, no correlation could be established between the HBs antigen chronic carriers state and other infectious diseases, malnutrition or genetic deficiencies. On the other hand, the prevalence of HBs antigen is particularly high in hepatic infections: acute and chronic hepatitis (53.5%), cirrhosis (31.5%) and hepatomas (25.3%). The study of the prevalence of hepatitis B by radioimmunoassay of the HBV seric markers was carried out in: --176 "healthy" town dwellers of which 97.2% were carriers of at least one marker--HBs Ag: 16.5%; anti-HBc alone: 34.1%; anti-HBs: 46.6%--. --30 subjects with cirrhosis--HBs Ag: 66.7%; anti-HBc alone: 10.0%; anti-HBs: 23.3%--. --42 subjects with PHC--HBs Ag: 47.6%; anti-HBc alone: 23.8%; anti-HBs: 28.6%--. The difference in HBs Ag carrier state between patients (cirrhosis and PHC) and controls, cross-matched for sex and age, is highly significative--p = 0,0001--.

Primary hepatocellular carcinoma in intertropical Africa: relationship between age and hepatitis B virus etiology.

Clinical observations of patients with primary hepatocellular carcinoma (PHC) at Le Dantec Hospital, Dakar, Senegal, were studied to determine a correlation with hepatitis B virus (HBV) infection. Of the 103 patients with PHC, 80 had an active HBV infection (HBsAg and/or anti-HBc); 23 showed signs of previous HBV infection (anti-HBs and anti-HBc). The two groups were similar in the detection of alpha-fetoprotein (approximately 60%) and in the major clinical findings: hepatomegaly, 76.25% and 86.96%, respectively; and ascites, 57.50% and 47.83%, respectively. Jaundice, however, was three times more frequent (P < 0.01) in the group of patients with signs of active HBV replication. Distribution of HBV markers as a function of age at onset of PHC revealed that the presence of HBsAg was primarily confined to the sera of the younger patients (< 50 yr old). When compared with leprosy patients and blood donors, the younger PHC patients differed in the frequency of detection of HBsAg and anti-HBs. The older people (> 50 yr old) in the three groups (PHC patients, leprosy patients, and blood donors) had identical HBV markers.

Hepatitis B virus antigens in human primary hepatocellular carcinoma tissues.

The presence of hepatitis B virus (HBV) antigens was examined in specimens of liver tissue obtained at necropsy from black Senegalese patients suffering from primary hepatocellular carcinoma (PHC). The results were correlated with markers of hepatitis B infection in serum. Hepatitis B surface antigen (HBsAg) and core antigen (HBcAg) were sought for in 15 liver extracts. HBsAg was found in the liver in 10 of 12 cases with HBsAg-positive serum. HBcAg was detected in three livers. The HBsAg was detected in seven of eight livers by immunofluorescence and orcein staining. HBsAg-positive cells were mainly located in the peri-tumoral cirrhotic tissue, although positive hepatocytes were also found in tumour nodules in liver from one of the patients. HBcAg was found in five of seven cases by immunofluorescence in hepatocytes of the cirrhotic areas. HBcAg fluorescence was primarily nuclear but, in some lobules, a patchy cytoplasmic fluorescence was observed. This suggests a cytoplasm-nucleus pathway in the synthesis of the HBV core antigen. Electron microscopy was performed on two HBsAg- and HBcAg-positive cases. Fibrillar and crystalline cytoplasmic inclusions were observed in tumour cells. In the same cells, 20-25 nm virus-like particles were present in swollen cisternae of the endoplasmic reticulum.

Hepatitis A infection and primary hepatocellular carcinoma.

The prevalence of antibody to the hepatitis A antigen (anti-HAV) has been studied in Senegal, among patients suffering from primary hepatocellular carcinoma (PHC) and among healthy blood donors. Anti-HAV was found in 62.5% of 64 cases of PHC as compared to 64% of 50 blood donors. Anti-HAV was as prevalent among PHC patients who evidenced chronic hepatitis B infection as among those without markers of chronic hepatitis B infection. These data suggest that hepatitis A infection is not associated with PHC in Senegal.