The Experience of HIV-Positive Transgender Women Engaging in Physical Activity: An Interpretative Phenomenological Analysis.

Regular physical activity should benefit HIV-positive transgender women because they are a particularly vulnerable population. However, engaging in physical activity seems particularly difficult among this population. To inform the development of interventions to increase adherence to physical activity, we explored perceptions of physical activity in 10 semi-structured interviews with HIV-positive transgender women. Interviews were subjected to a qualitative approach named interpretative phenomenological analysis (IPA). Inspired by Cooley's theory, we chose to illustrate the results according to a three-level structure, i.e., confronting oneself to oneself with a specific identity, then confronting oneself with others on an interpersonal level, and eventually confronting oneself with society as a normative frame through the specific prism of physical activity, and thus relationship to one's body. The idea of practicing physical activity meant for them: having to face what they tried to be kept hidden, being ostracized by the cis population, and facing social heteronormativity. The fears about health were mostly about HIV and the transitioning process side effects. The psychological issues were mostly about the fear of developing male shaped bodies and worsened by traumatic life stories. External factors were often related to the passing concept and violence caused by stigma and discrimination. The group appeared as a strong motivation factor, facilitating self-acceptance and socialization.

A computerized decision support system (CDSS) for antibiotic prescription in primary care-Antibioclic: implementation, adoption and sustainable use in the era of extended antimicrobial resistance.

OBJECTIVES: To describe the implementation and use of a computerized decision support system (CDSS) for antibiotic prescription in primary care in France (Antibioclic). The CDSS targets 37 infectious diseases and has been freely available on a website since 2011. METHODS: Description and implementation of the architecture of a CDSS for antibiotic prescription in general practice. Analysis of the queries made between 2012 and 2018 on the CDSS by GPs. Analysis of two cross-sectional studies of users in 2014 and 2019. RESULTS: The number of queries increased from a median of 796/day [IQR, 578-989] in 2012 to 11 125/day [5592-12 505] in 2018. Unique users increased from 414/day [245-494] in 2012 to 5365/day [2891-5769] in 2018. Time taken to make a query was 2 min [1.9-2.1]. Among 3 542 347 queries in 2018, 78% were for adults. Six situations accounted for ≥50% of queries: cystitis; acute otitis media; acute sinusitis; community-acquired pneumonia; sore throat; and pyelonephritis. Queries concerned pathologies for which antibiotic prescription was necessary (64%), was conditional on additional clinical steps (34%) or was not recommended (2%). Most users (81%) were GPs, with median age of 38 years [31-52] and 58% were female. Among the 4016 GPs who responded to the surveys, the vast majority (96%) reported using the CDSS during the consultation, with 24% systematically using Antibioclic to initiate an antibiotic course and 93% having followed the CDSS recommendation for the latest prescription. Most GPs were comfortable using the CDSS in front of a patient. CONCLUSIONS: Antibioclic has been adopted and is widely used in primary care in France. Its interoperability could allow its adaptation and implementation in other countries.

Correction to: Prevalence of anal symptoms in general practice: a prospective study.

Following publication of the original article [1], the authors reported an error to one of the 'study groups' in the authorship section.

Prevalence of anal symptoms in general practice: a prospective study.

BACKGROUND: Anal disorders are largely underestimated in general practice. Studies have shown patients conceal anal symptoms leading to late diagnosis and treatment. Management by general practitioners is poorly described. The aim of this study is to assess the prevalence of anal symptoms and their management in general practice. METHODS: In this prospective, observational, national study set in France, all adult patients consulting their general practitioner during 2 days of consultation were included. Anal symptoms, whether spontaneously revealed or not, were systematically collected and assessed. For symptomatic patients, the obstacles to anal examination were evaluated. The general practitioner's diagnosis was collected and a proctologist visit was systematically proposed in case of anal symptoms. If the proctologist was consulted, his or her diagnosis was collected. RESULTS: From October 2014 to April 2015, 1061 patients were included by 57 general practitioners. The prevalence of anal symptoms was 15.6% (95% CI: 14-18). However, 85% of these patients did not spontaneously share their symptoms with their doctors, despite a discomfort rating of 3 out of 10 (range 1-5). Although 65% of patients agreed to an anal examination, it was not proposed in 45% of cases with anal symptoms. Performing the examination was associated with a significantly higher diagnosis rate of 76% versus 20% (p < 0.001). Proctologist and general practitioner diagnoses were consistent in 14 out of 17 cases. CONCLUSIONS: Patients' concealed anal symptoms are significant in general practice despite the impact on quality of life. Anal examination is seldom done. Improved training of general practitioners is required to break the taboo.

[Highly pathogenic influenza pandemic: results of a feasibility study in a general practice (SIMUGRIP-MG2)]. / Pandémie grippale à virus hautement pathogène : étude de faisabilité en cabinet (SIMUGRIP-MG2).

The French Pandemic Influenza Plan ("Plan National de Prévention et de Lutte Pandémie Grippale") places general practitioners at the heart of the provision of care to patients through consultations and house calls. The purpose of this study was to determine whether GP practices are able to provide treatment to flu patients within their premises in the event of a highly pathogenic influenza pandemic. A simulation exercise conducted in a GP practice (SIMUGRIP-MG2) was carried out in the autumn of 2009. 3 general practitioners, the practice secretary, 33 patients and care staff took part in the exercise during a half day of practice. The study found that the quality of some hygiene practices and procedures was inadequate: the duration of handwashing was too short (mean: 11.8 seconds), gloves were not worn, and FFP2 masks were often handled. The study found that the implementation of these procedures required increased effort and attention from GPs. It was also found that this type of consultation requires additional preparation time (refitting, supply of materials) and generates additional costs (linked, for example, to storage issues). In seeking to improve the quality of care provided to infected patients in the event of an influenza pandemic, several factors must be considered, including recent data on the effectiveness of countermeasures, additional training to improve hygiene practices, and infrastructure modernization to improve ergonomics in GP practices.

[A simulation exercise in a flu clinic]. / Exercice sur le terrain dans un Centre de Consultation Dédié à la grippe (SIMUGRIP-MG1).

A simulation exercise aimed at assessing the management and provision of ambulatory care in the context of a highly pathogenic influenza pandemic was conducted in a specifically dedicated consultation center (Centre de Consultation Dédié (CCD) à la grippe) based on official French guidelines. The exercise was carried out in a school in Paris equipped to simulate a "flu clinic". 3 practitioners provided treatment lasting 2 hours to nursing students acting as patients. The exercise highlighted a number of major organizational issues. Staff were found to be unable to manage the center and to perform patient transfers; face masks were not routinely and consistently worn by doctors and patients; and communication between professionals within the clinic was limited. The exercise showed that much remains to be done to ensure that "flu clinics" are effective and functional. The results suggest that the exercise will need to be repeated on a larger scale and over a longer period.

Self-reported asthma prevalence and management in adults in France in 2018: ASTHMAPOP survey.

BACKGROUND: There is a paucity of epidemiological data on asthma classified by disease severity in France. The ASTHMAPOP cross-sectional study aimed to review the prevalence and current management of asthma in people aged ≥18 years in France. METHODS: A self-administered questionnaire was mailed to 19 676 people representative of the French population in age, gender, region, and socio-economic status. Asthma was classified by treatment steps per the 2017 Global Initiative for Asthma (GINA) report, according to prescribed treatments. Analyses were mostly descriptive. RESULTS: The questionnaire return rate was 81.7% (n = 16 083), and 15 587 questionnaires were analyzed. The prevalence of lifetime asthma was 12.8% (95% confidence interval (CI):12.3-13.3%; n = 1 989) in 2018. The prevalence of current asthma (i.e., 12 months before the survey) was 6.4% (95% CI: 6.0-6.8%; n = 993); most of these respondents (95.3% [n = 946]) were receiving asthma treatment, and 49.4% (n = 491) were treated for mild asthma (GINA step 1 or 2). Of people with current asthma, 47.6% reported ≥1 asthma exacerbation in the past 12 months-defined as episodes (several days) during which symptoms (cough, sputum, and dyspnea) were worse than usual; 14.3% had ≥1 emergency visit, and 3.1% had ≥1 hospitalization due to asthma. Of those taking continuous asthma controller medications who answered all Morisky Medication Adherence Scale questions (n = 501), 46.4% were adherent (score=4) to their treatment regimen. Based on the 6-item Asthma Control Questionnaire scores, asthma was partially controlled or uncontrolled in 47.7% of 969 people. CONCLUSIONS: The prevalence of asthma in France has remained stable since 2006, but levels of asthma control and treatment adherence continue to be relatively poor. Asthma management in France requires improvement.

[Prevac B: prevention of hepatitis B among migrants from subsaharian Africa and Asia]. / Prévac B: prévention de i'hépatite B dans les populations migrantes originaires de zones de forte endémie, Afrique subsaharienne et Asie.

CONTEXT: In 2004, 22% of French citizen were vaccinated against Hepatitis B Virus (HBV), 7.3% had previously been protected by a contact with HBV, and 0.65% were carriers of HBV Those rates are not known among migrant people, especially if they have no health insurance. It is not known whether those people have adequate personal strategies of prevention. AIMS AND METHOD: Prospective study to assess the effectiveness of an internet-accessible expert system in helping the GP to determine the most accurate strategy of prevention, related to the serologic HBV profile of each patient, and to apply this strategy, among migrant people coming from subsaharian Africa and Asia, attending their GP. The prevalence of each serologic profile was measured. RESULTS: From 11.5.2007 to 12.31.2008, 28 GPs included 547 migrant people. 8% are HBV carriers, 33% have been protected by a contact with HBV, 16% are vaccinated, and 23% have had no contact with virus nor vaccination. A full accurate preventive information strategy could be carried out with help of the expert system, respectively among 100% of HBV carriers, 100% of vaccinated people, 98% of people protected by HBV contact, and 40% of people who had no marker A vaccination has been done among 64% of people who required it. For people whose only marker of HBV infection was anti HBc, 41% was considered protected by HBV contact, 48% was vaccinated, this result can be related to a lack of accuracy in international guidelines in this situation. CONCLUSION: Prevalence of contact with HBV is much higher in migrant people coming from subsaharian Africa and Asia, than in the average French population. An internet-accessible expert system is a useful tool for GPs in order to enhance strategies of prevention in HBV infection.

The acceptability and effectiveness of a questionnaire for the identification of risk factors for HIV and hepatitis B and C: An observational study in general practice.

BACKGROUND: Many people in Europe remain undiagnosed for human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV). OBJECTIVES: To evaluate acceptability and effectiveness of a questionnaire designed to facilitate identification of risk factors for these viruses. METHODS: We performed an observational study, in a prospectively enrolled cohort of patients in Paris (France) seen in 2014. Eighteen GPs administered a questionnaire to the first 50 patients, collecting information about risk factors. GPs were randomized into two groups: A (self-administered questionnaire) and B (GP-administered questionnaire). We used the overall response rate to assess the acceptability of the questionnaire. We used the rate of newly identified risk factors and compared the number of tests performed one year before and immediately after the intervention to assess the effectiveness of the questionnaire. RESULTS: 842 patients were randomized: 349 (41.5%) in group A and 493 (58.5%) in group B. Acceptability was 88.5% (95%CI: 86.3-90.6); 93.1% (95%CI: 90.5-95.8) in-group A and 85.2% (95%CI: 82.1-88.3) in group B (P = 0.0004). Prevalence of risk factors was 51.8% (95%CI: 48.2-54.4) and 58.3% were newly identified (95%CI: 52.9-63.7). The number of HIV tests performed during the four weeks after intervention increased by 27% compared to the same period one year before (P = 0.22). It increased by 113% (P = 0.005) and 135% (P = 0.005) for HBV and HCV, respectively. CONCLUSION: The questionnaire proved acceptable and effective in identifying risk factors for HIV, HBV and HCV in general practice.

Real-life experience of quality of life, treatment satisfaction, and adherence in patients receiving oral anticoagulants for atrial fibrillation.

INTRODUCTION: Direct oral anticoagulants (DOACs) have shown noninferiority to vitamin K antagonists (VKA) in stroke prevention in patients with atrial fibrillation. DOAC treatment may be less demanding than VKA, improving quality of life. To date, there have been no studies of the real-life experience of outpatients receiving anticoagulation therapy for atrial fibrillation in France. METHODS: An observational descriptive real-life epidemiological study used three validated questionnaires (EQ-5D, PACT-Q2, and MMAS-8 French Translation) to assess quality of life, treatment satisfaction, and adherence, respectively, in 200 patients managed on an outpatient basis for atrial fibrillation who were receiving anticoagulation therapy by VKA or DOAC for at least 3 months. Patients were distributed between four groups: primary VKA (P-VKA), switch from VKA to DOAC (S-DOAC), primary DOAC (P-DOAC), and switch from DOAC to VKA (S-VKA). RESULTS: Two hundred patients responded to the questionnaires: 89, 50, 52, and 9 in the P-VKA, S-DOAC, P-DOAC and S-VKA groups, respectively. Only the first three groups were compared statistically, because of the small size of the S-VKA group. Quality of life and satisfaction were good in all three groups, with no significant difference in quality of life but significantly greater satisfaction with respect to the "convenience" and "satisfaction" dimensions for DOACs (S-DOAC and P-DOAC groups versus P-VKA group; p<0.001, for both dimensions). Adherence did not significantly differ between groups. CONCLUSION: The experience of patients under oral anticoagulation therapy for atrial fibrillation managed on an outpatient basis was good, with comparable quality of life under DOACs and VKA, and significantly greater satisfaction under DOACs, without impact on adherence. Taking account of patient preference in "shared decision-making" for the choice of type of anticoagulant could improve the patients' experience of treatment.

[Evaluation of a screening programme for diabetic retinopathy (DODIA study)]. / Dépistage de la rétinopathie diabétique par des photographies do fond d'oeil. Evaluation d'un programme en médecine libérale (étude DODIA).

CONTEXT: In France, 43% to 63% of diabetics have an annual fundoscopy. Do the new screening tools, coupled with teletransmission of the images, allow for satisfying ophthalmological screening? It is an important matter given the foreseeable reduction in the number of French ophthalmologists in the forthcoming years. OBJECTIVES: To measure the quality of screening for diabetic retinopathy (DR), in the framework of a network, by the provision of a retinograph by numeric camera (with teletransmission of the images and centralised interpretation), in a screening centre located in town. METHOD: The study evaluated the quality of screening obtained in two comparable groups of general practitioners, one using the retinograph and the other using the classical method of screening by ophthalmologist. The screening was targeted at diabetics who had not had a fundoscopy in the preceding year, nor had known DR or a treating ophthalmologist (for the retinography group only). RESULTS: 667 patients were sampled in the retinography group (456 included) and 707 in the control group (426 included) between 1/04/02 and 1/11/02; 417 patients were followed until the end of the study in the 2 groups. A screening examination was considered effective if it was performed within the six months following its request, and by the presence of a report in the file of the general practitioner. The percentage of patients thus screened was 74% in the retinography group and 71,5% in the other group (not significant). 16% of diabetics in the retinography group had DR compared with 10% of patients in the control group. The analysis of the level of satisfaction of patients tended to show a preference for the system of screening by fundal photography. CONCLUSION: In the framework of a healthcare network, the availability of a retinograph by numeric camera, with the interpretation of photos by teletransmission of the images, obtained a high level of quality of screening for diabetic retinopathy that was at least as good as that obtained by a healthcare network using the classical ophthalmological screening method.

Assessment of quality of life, satisfaction with anticoagulation therapy, and adherence to treatment in patients receiving long-course vitamin K antagonists or direct oral anticoagulants for venous thromboembolism.

INTRODUCTION: Direct oral anticoagulants (DOACs) have shown non-inferiority and ease of use compared to vitamin K antagonists (VKA) in the treatment of venous thromboembolism (VTE). No study so far has been directed toward real-life experience of outpatients receiving anticoagulants for VTE in France. METHODS: This is an observational descriptive real-life epidemiological study, using three validated questionnaires (Morisky Medication Adherence Scale-8, EQ-5D, and part 2 of the Perception of Anticoagulant Treatment Questionnaire), to assess adherence, quality of life, and satisfaction in 100 VTE outpatients receiving anticoagulation therapy by VKA (primary or switched from DOAC to VKA) or by DOAC (primary or switched from VKA to DOAC). RESULTS: Patients were very much satisfied with their treatment in both DOAC and VKA groups. Despite advantages of DOACs, therapeutic adherence was only moderate. The best adherence scores were observed in the primary VKA switched to DOAC for at least 3 months (S-DOAC) subgroup. Quality of life was better in the DOAC group mainly because of the absence of the requirement for blood testing. Most of the complaints concerned the pain/discomfort dimension in the VKA group and anxiety/depression dimension in the DOAC group. CONCLUSION: Patients were satisfied with their anticoagulant treatment, especially when they were involved in choosing the anticoagulant, and the treatment suited them. Quality of life of patients in the DOAC group was better than in the VKA group, but adherence remains to be improved. This study highlights the importance of the physician-patient relationship, pretreatment initiation, and follow-up of any anticoagulation therapy throughout.

Synergistic induction of the MUC4 mucin gene by interferon-gamma and retinoic acid in human pancreatic tumour cells involves a reprogramming of signalling pathways.

The transmembrane mucin, MUC4, is aberrantly expressed with a high incidence in human pancreatic adenocarcinomas and plays an important role in the pathogenesis of the disease. Our recent studies have shown that interferon-gamma (IFNgamma) and retinoic acid (RA) are important regulators of MUC4 in pancreatic tumour cells. Induction of MUC4 by IFNgamma occurs via a novel pathway involving upregulation of the signal transducer and activator of transcription 1 (STAT-1), whereas its stimulation by RA requires mediation by the transforming growth factor beta-2 (TGFbeta-2). In this study, we have investigated the molecular mechanisms underlying the interaction of IFNgamma and RA in MUC4 regulation in pancreatic tumour cells. We demonstrate that these reagents exert a synergistic induction of MUC4. Interestingly, while the upregulation of STAT-1 by IFNgamma is partially inhibited by RA, IFNgamma is shown to repress RA-driven TGFbeta-2 induction, pointing to the involvement of alternative mechanism(s) in IFNgamma-RA synergism. Moreover, a dose-dependent and cooperative induction of MUC4 promoter activity suggests a regulation at the transcriptional level, most likely by STAT-1 and RAR/RXR (RA receptor/retinoic X receptor) or other IFNgamma/RA-induced secondary intermediate effectors. Our findings provide potential mechanisms that may account for the aberrant expression of MUC4 in pancreatic tumour cells and expose a novel molecular mechanism of gene induction, whereby a reprogramming of signalling pathway through alternative route(s) operates during a synergistic interaction of biological modifiers.

Immunohistochemical analysis of MUC5B apomucin expression in breast cancer and non-malignant breast tissues.

A deregulation of several MUC genes (MUC1, MUC2, MUC3, MUC5AC, and MUC6) was previously demonstrated in breast carcinomas. Considering that recently we found the "non-mammary" MUC5B mRNA in primary breast tumors (Berois et al. 2003), we undertook the present study to evaluate the expression profile of MUC5B protein product in breast tissues, using LUM5B-2 antisera raised against sequences within the non-glycosylated regions of this apomucin. Expression of MUC5B by breast cancer cells was confirmed by immunocytochemistry, in situ hybridization, and Western blot on MCF-7 cancer cells. Using an immunohistochemical procedure, MUC5B apomucin was detected in 34/42 (81%) primary breast tumors, in 13/14 (92.8%) samples of non-malignant breast diseases, in 8/19 (42.1%) samples of normal-appearing breast epithelia adjacent to cancer, and in 0/5 normal control breast samples. The staining pattern of MUC5B was very different when comparing breast cancer cells (cytoplasmic) and non-malignant breast cells (predominantly apical and in the secretory material). We analyzed MUC5B mRNA expression using RT-PCR in bone marrow aspirates from 22/42 patients with breast cancer to compare with MUC5B protein expression in the primary tumors. Good correlation was observed because the six MUC5B-positive bone marrow samples also displayed MUC5B expression in the tumor. Our results show, for the first time at the protein level, that MUC5B apomucin is upregulated in breast cancer. Its characterization could provide new insights about the glycobiology of breast cancer cells.

Relationships between mucinous gastric carcinoma, MUC2 expression and survival.

AIM: To investigate the expression of the four secreted gel-forming mucins (MUC2, MUC5AC, MUC5B and MUC6) in a series of gastric carcinomas, classified according Lauren's, Mulligan's, WHO and Goseki's classifications, with special attention to all the different components (major and minor) present in tumors and to follow up clinical data. METHODS: Expression of MUC2, MUC5AC, MUC5B and MUC6 was investigated using immunohistochemistry and in situ hybridization. RESULTS: Expression of secreted gel-forming mucins in gastric carcinoma was particularly complex, each mucin being not restricted to any histopathological type even considering all components (major and minor) present in a given tumor. There was a worst survival in patients with a higher content of mucus (Goseki II or IV) and high positive MUC2 expression. CONCLUSION: Complexity of mucin gene expression patterns in gastric cancer may reflect a precise state of differentiation at the cell level not recognized in used morphologic classification systems. High expression of MUC2 was nevertheless associated with mucinous subtype of the WHO classification and with group II of Goseki's classification identified by the major component of a particular tumor. The quantity and quality of mucus were related to survival.

The antagonistic regulation of human MUC4 and ErbB-2 genes by the Ets protein PEA3 in pancreatic cancer cells: implications for the proliferation/differentiation balance in the cells.

The human transmembrane mucin MUC4 is aberrantly expressed in 75% of pancreatic ductal adenocarcinomas, whereas no expression is found in normal pancreas. Therefore MUC4 appears as a useful biological marker for the diagnosis of ductal adenocarcinomas. Since rat Muc4 was shown to interact with ErbB-2 tyrosine kinase receptor and to either promote cell survival and differentiation or cell proliferation, it is postulated that MUC4 may also participate in pancreatic carcinogenesis. Our aim was to investigate in parallel the role of the Ets factor PEA3 in MUC4 and ErbB-2 transcriptional regulation in pancreatic cancer cells. Two MUC4-expressing WD (well-differentiated) (CAPAN-1 and -2) and one MUC4-non-expressing poorly differentiated (PANC-1) cell lines were used. The three cell lines express ErbB-2 at different levels. By co-transfection and site-directed mutagenesis, we show that PEA3 is a transactivator of the MUC4 promoter and that the -216 and -2368 PEA3 binding sites of the MUC4 promoter are essential. We also demonstrate that PEA3 acts in synergy with c-Jun and specificity protein 1 to transactivate the proximal region of the MUC4 promoter and increase MUC4 mRNA levels in WD cells. These results suggest that MUC4 is a new target gene of the Ets factor PEA3 in pancreatic cancer cells. In contrast, PEA3 represses the transcriptional activity of two fragments of the ErbB-2 promoter in a dose-dependent manner and decreases the endogenous ErbB-2 mRNA levels in WD cell lines. Thus, PEA3, by its capacity to up-regulate the epithelial marker MUC4 and to down-regulate the ErbB-2 oncogene, appears as a key regulator of the differentiation/proliferation balance in pancreatic cancer cells.

GOSPEL 2 - Colchicine for the treatment of gout flares in France - a GOSPEL survey subgroup analysis. Doses used in common practices regardless of renal impairment and age.

OBJECTIVES: The objective of this sub-study was to assess the use of colchicine for the treatment of gout flares in real life conditions in the GOSPEL cohort following the 2006 EULAR recommendations for gout management. METHODS: This national cross-sectional epidemiologic survey included outpatients with gout suffering from acute flare followed by randomly selected primary care physicians (n=398) and private practice rheumatologists (n=109) between October 2008 and September 2009 in France. Data regarding patient characteristics and treatment prescription was collected by each physician. Glomerular filtration rate (eGFR) was estimated using the Cockroft-Gault formula. Patients included in the survey for a gout flare filled in a specific self-questionnaire including colchicine effective intake and pain relief (numeric scale). RESULTS: This analysis focused on the 349 patients presenting with gout flare and treated with colchicine. Mean (±SD) prescribed dose of colchicine was 2.8 (±0.7) mg within the first 24hours and the cumulative dose over the first three days of treatment was 6.9 (±1.8) mg. Patients with mild decline in eGFR (eDFG 60-80mL/min) were prescribed an average initial dose of 2.8mg (±0.8) mg (n=58), 2.7 (±0.8) mg in chronic kidney disease (CKD) stage 3 (n=43) and 2.5 (±0.7) mg in CKD stage 4 (n=2). Cumulative doses of colchicine did not take into account either renal impairment or age. CONCLUSIONS: This study draws attention to some misuse of colchicine in daily practice and the prescription of excessive doses especially in case of renal impairment. eGFR should be enforced in daily practice.

A role for human MUC4 mucin gene, the ErbB2 ligand, as a target of TGF-beta in pancreatic carcinogenesis.

MUC4: encodes a large transmembrane mucin that is overexpressed in pancreatic adenocarcinomas. The molecular mechanisms responsible for that altered pattern of expression are unknown. TGF-beta, a pleiotropic cytokine, regulates numerous genes involved in pancreatic carcinogenesis via activation of the Smads proteins and MUC4 promoter is rich in Smad-binding elements. Our aim was to study whether the regulation of MUC4 expression by TGF-beta in pancreatic cancer cells was strictly dependent on Smad4 activity. Three pancreatic cancer cell lines, CAPAN-1 (MUC4+/Smad4-), CAPAN-2 (MUC4+/Smad4+) and PANC-1 (MUC4-/Smad4+), were used. By RT-PCR, transfection assays and immunohistochemistry, we show that (i) both MUC4 mRNA and apomucin expression are upregulated by TGF-beta, (ii) Smad2 positively cooperates with Smad4 to activate the promoter, (iii) activation of Smad4 by exogenous TGF-beta induces Smad4 binding to the promoter, (iv) Smad7 and c-ski both inhibit activation by Smad4. When Smad4 is mutated and inactive, TGF-beta activates MUC4 expression via MAPK, PI3K and PKA signaling pathways. Absence of expression in PANC-1 cells is due to histone deacetylation. Altogether, these results indicate that upregulation of MUC4 by TGF-beta is restricted to well-differentiated pancreatic cancer cells, and point out a novel mechanism for TGF-beta as a key molecule in targeting MUC4 overexpression in pancreatic adenocarcinomas.

The mouse secreted gel-forming mucin gene cluster.

Using genomic cosmid and BAC clones and genome shotgun supercontigs available in GenBank, we determined the complete gene structure of the four mouse secreted gel-forming mucin genes Muc2, Muc5ac, Muc5b and Muc6 and the organization of the genomic locus harboring these genes. The mouse secreted gel-forming mucin gene is 215 kb on distal chromosome 7 to 69.0 cM from the centromere and organized as: Muc6-Muc2-Muc5ac-Muc5b with Muc2, Muc5ac and Muc5b arranged in the same orientation and Muc6 in opposite. Mouse mucin genes have highly similar genomic organization to each other and to their respective human homologues indicating that they have been well conserved through evolution. Deduced peptides showed striking sequence similarities in their N- and C-terminal regions whereas the threonine/serine/proline-rich central region is specific for each other and for species. Expression studies also showed that they have expression patterns similar to human mucin genes with Muc2 expressed in small and large intestines, Muc5ac and Muc6 in stomach, and Muc5b in laryngo-tracheal tract. These data constitute an important initial step for investigation of mucin gene regulation and mucin function through the use of animal models.