Structure-function relationship between a natural cosmetic active ingredient and the olfactory receptor OR2AT4.

OBJECTIVE: Although the olfactory receptor OR2AT4 was described as involved in epidermal renewal, there is no data about a cosmetic active ingredient activating this receptor. The aim of this research work was thus to identify a natural molecule binding to this receptor in order to stimulate keratinocyte migration. METHODS: For this purpose, natural molecules were extracted from Cocos nucifera flour. Then, efficacy of this natural extract was evaluated on keratinocyte migration in vitro. Molecules of the Cocos nucifera flour extract were then identified by UPLC-MS/MS. Molecular docking was finally conducted to investigate the potential interaction between identified molecules and the olfactory receptor OR2AT4. RESULTS: The Cocos nucifera flour extract significantly increased keratinocyte migration and results demonstrated that this effect was mediated by the olfactory receptor OR2AT4. Metabolomic analysis revealed two molecules, nonioside D and butyl 4-O-alpha-D-glucopyranosyl-beta-D-glucopyranoside, as significantly present in the Cocos nucifera flour extract compared to both Cocos nucifera oil and water. Finally, molecular docking revealed that butyl 4-O-alpha-D-glucopyranosyl-beta-D-glucopyranoside could interact with the extracellular domain 2 of the OR2AT4. CONCLUSION: This study highlighted for the first time a natural molecule, extracted from Cocos nucifera flour, able to interact with the olfactory receptor OR2AT4 and promote the keratinocyte migration and thus the epithelialization.

OBJECTIF: Bien que le récepteur olfactif OR2AT4 a été décrit comme étant impliqué dans le renouvellement de l'épiderme, il n'y a à ce jour aucune donnée concernant un ingrédient actif cosmétique activant ce récepteur. Le but de cette étude est donc d'identifier une molécule naturelle capable de se fixer au récepteur OR2AT4 afin de stimuler la migration des kératinocytes. METHODE: L'efficacité de cet extrait naturel sur la migration des kératinocytes in vitro a ensuite été évaluée. Les molécules présentes dans l'extrait de farine de Cocos nucifera ont ensuite été identifées par UPLC-MS/MS. Enfin, des expérimentations de docking moléculaire ont été réalisées afin d'identifier une potentielle interaction entre les molécules précédemment identifiées et le récepteur olfactif OR2AT4. RESULTATS: L'extrait de farine de Cocos nucifera augmente significativement la migration des kératinocytes via l'activation du récepteur olfactif OR2AT4. Les analyses métabolomiques ont révélées deux molécules, le nonioside D et le butyl 4-O-alpha-D-glucopyranosyl-beta-D-glucopyranoside, comme étant significativement présentes dans l'extrait de farine de Cocos nucifera en comparaison avec l'huile et l'eau de coco. Enfin, le docking moléculaire révèle que le butyl 4-O-alpha-D-glucopyranosyl-beta-D-glucopyranoside, présent dans l'extrait de farine de Cocos nucifera peut interagir avec le domaine extracellulaire 2 du récepteur olfactif OR2AT4. CONCLUSION: Cette étude a identifié pour la première fois une molécule naturelle, extraite de la farine de Cocos nucifera, capable d'interagir avec le récepteur olfactif OR2AT4, afin de stimuler la migration kératinocytaire et ainsi favoriser le processus de ré-épithélialisation.

Prostate cancer screening: contrasting trends.

PURPOSE: Our previously published data showed rapidly increasing rates of prostate cancer screening in men aged 50-74, which rose from 36% in 2005 to 48% in 2008. Based on men's reported intentions at that time, this was expected to rise to 70% in 2011. Here we report the actual rate of prostate cancer screening. METHOD: Three nationwide observational telephone surveys (EDIFICE opinion polls) were conducted in 2005, 2008, and 2011. The overall target was a representative sample of > 1,500 individuals living in France and aged 40-75 years, including 481 men aged 50-74 years. RESULTS: Within this male population, the rate of screening reported remained stable between 2008 and 2011 (48 and 49%, respectively). However, comparison of privileged versus disadvantaged populations showed significant differences, with a relative decrease in screening among those of higher socioprofessional status (p = 0.03) and from higher-income groups (p = 0.02). For households with a monthly income above 2,500€, the screening rate decreased from 61% in 2008 to 51% in 2011 (p = 0.05), while for those with an income below 2,500€, it increased from 36% in 2008 to 44 % in 2011 (p = 0.18). CONCLUSION: A plateau or even a reduction in prostate cancer screening is currently being observed; this is possibly due to progressive recognition among the population at large of the controversy surrounding prostate cancer screening, whereas this speculation was formerly limited to health-care professionals. After previously being more likely to undergo prostate cancer screening, it is the younger, wealthier populations that are currently showing the most noteworthy step backwards.

Melanoma risk-takers: fathers and sons.

OBJECTIVES: The incidence of skin cancers, melanoma in particular, is increasing rapidly. Consequently, specific recommendations for sun-protection measures now exist. This survey set out to assess the compliance of the general population with these guidelines. METHODS: The French nationwide observational survey, EDIFICE Melanoma, was conducted (28 September to 20 October 2011) through phone interviews of a representative sample of 1502 subjects aged ≥ 18 years, using the quota method. Sun-protection was defined as frequent or systematic use of clothes or sunscreen. The group of individuals who declared exposure to the sun (N = 1172) was subdivided: risk-takers (N = 442), and those who used sun protection (N = 730). RESULTS: Risk-takers were significantly more often male (62% vs. 44%, P < 0.01), had a lower level of education (40% vs. 26%, P < 0.01), lower incomes (2587 euros vs. 2948 euros/month) and were more often smokers (42% vs. 31%, P < 0.01). In contrast, age, marital status and use of sunbeds were not significantly different between the two groups. Interestingly, risk-takers had less risk factors for melanoma. However, they were less well-informed about high-risk exposure and optimal use of sunscreen. Sun-protection measures for their children were less stringent than those of the group who used sun protection: systematic/frequent use of sunglasses (42% vs. 59%, P < 0.01), systematic use of sunscreen (77% vs. 86%, P < 0.01), and frequent renewal (69% vs. 82%, P < 0.01), high sun protection factors (SPF) (46% vs. 56%, P < 0.01), use of clothing (84% vs. 92%, P < 0.01) and hats (88% vs. 94%, P < 0.01). CONCLUSIONS: Risk-takers are characterized by a lesser understanding of sun-protection measures and behaviours. Their children benefit less from protective measures than those of people who use sun protection themselves. Improved understanding may well improve behaviours; one can therefore legitimately predict a considerable impact on parents' attitude to their own protection and that of their children.

Accuracy of dry vaginal self-sampling for detecting high-risk human papillomavirus infection in cervical cancer screening: a cross-sectional study.

OBJECTIVE: Cervical cancer screening coverage remains insufficient in most countries. Testing self-collected samples for high-risk human papillomavirus (HR-HPV) could be an alternative to the Pap smear, but costs, sampling methods and transport issues hamper its wide use. Our objective was to compare diagnostic accuracy of 2 vaginal self-collection methods, a dry swab (vsc-DRY) or swab in liquid medium (vsc-LIQ), for detecting HR-HPV cervical infection assessed by a cervical clinician-collected sample in liquid medium (ccc-LIQ). METHODS: Women 20 to 65 years attending a Pap smear were recruited between September, 2009 and March, 2011. Each sample (3 per woman) underwent HPV DNA testing. Samples were classified as HR-HPV+ with detection of at least one HR-HPV or probable HR-HPV type. RESULTS: Of 734 women included, 722 had complete HPV data. HR-HPV was detected in 20.9% of ccc-LIQ samples. Estimated sensitivity and specificity to detect HR-HPV in vsc-DRY samples were 88.7% and 92.5%, respectively, and in vsc-LIQ samples, 87.4% and 90.9%. Cytology findings were abnormal for 79 women (10.9%): among 27 samples of low-grade squamous intraepithelial lesions, 25 were HR-HPV+ in vsc-DRY, vsc-LIQ and ccc-LIQ samples. Among 6 samples of high-grade squamous intraepithelial lesions, all were HR-HPV+ in vsc-DRY samples, 1 was HR-HPV- in vsc-LIQ samples and 1 was HR-HPV- in ccc-LIQ samples. CONCLUSIONS: Vaginal self-sampling with a dry swab is accurate to detect HR-HPV infection as compared with cervical clinician-collection and accurate as compared with cytology results. This cheap and easy-to-ship sampling method could be widely used in a cervical cancer screening program.

[Breast cancer screening program in France: for optimization of the information]. / Dépistage organisé du cancer du sein en France : pour une optimisation de l'information.

BACKGROUND: Based on international and national recommendations, organized breast cancer screening in France raises questions of medical ethics built around the key concepts of individual autonomy and public health policy. Because of the evolving knowledge, professionals and institutions involved in the program must review the ethical values associated with this medical practice. METHODS: The ethical aspects of organized breast cancer screening were studied. In response to newly acquired knowledge highlighted by a review of texts governing this practice in France, proposals for changes resulting from reflections of a working group coordinated by the National Cancer Institute are presented. RESULTS: Ethical issues raised by screening must find expression in the general principles of the program's organization: acceptability of screening, efficiency, adverse effects, equity of access, free care…, but also at different stages of the procedure: information delivery, first and second invitations, refusal of further diagnostic investigation… CONCLUSION: A better match between breast cancer screening and recently developed knowledge requires optimal information delivery to women targeted by the program as well as a stronger role for the referring healthcare professional.

The KRAS mutation detection within the initial management of patients with metastatic colorectal cancer: a status report in France in 2011.

BACKGROUND: The detection of KRAS mutations is mandatory to initiate an anti-epidermal growth factor receptor (EGFR) antibody in the treatment of metastatic colorectal carcinoma (mCRC). PATIENTS AND METHODS: This observational retrospective study was performed in 160 French centres during a 2-week period in 2011. Its main objective was to evaluate the rate of KRAS testing in patients with mCRC having initiated their first-line therapy. Secondary objectives included time of process, techniques used and reasons for non-prescription. RESULTS: Five hundred and thirty eight mCRC patients (67.1 ± 11.3 years, synchronous metastases: 69.9%) were enrolled in the study. KRAS testing was prescribed in 81.1% of patients, in a median of 15 days after the diagnosis of metastases, and of 15 days prior to the initiation of the first-line metastatic chemotherapy. KRAS status was available for 87% of patients, after 23.6 ± 28.2 days, but after the choice of the first-line therapy in 56.6% of patients. Heterogeneity of reception time was noteworthy within regions (8.3 ± 7 days to 38.8 ± 101 days). KRAS testing was not prescribed mainly due to the planned non-prescription of an anti-EGFR antibody. CONCLUSION: This study confirmed that KRAS testing is definitely part of the management of most of mCRC patients, despite discrepancies observed in the rate of prescription and the time of results.

Comparison between a guaiac and three immunochemical faecal occult blood tests in screening for colorectal cancer.

BACKGROUND: The aim of this study was to compare the performance of the guaiac-based faecal occult blood test (G-FOBT), with that of three immunochemical faecal occult blood tests (I-FOBT) which allow automatic interpretation. PATIENTS AND METHODS: Under the French organised screening programme, 85,149 average-risk individuals aged 50-74 participating in the third screening round, performed both the G-FOBT (Hemoccult-II test) and one of the I-FOBTs: FOB-Gold, Magstream and OC-Sensor. RESULTS: Given the chosen threshold, the positivity ratio between the different I-FOBTs and the G-FOBT was 2.4 for FOB-Gold, 2.0 for Magstream and 2.2 for OC-Sensor (P=0.17). The three I-FOBTs were superior to the G-FOBT for colorectal cancer (CRC) detection. The ratios for detection rates were 1.6 (FOB-Gold), 1.7 (Magstream) and 2.1 (OC-Sensor) (P=0.74). For non-invasive CRC they were, respectively, 2.5, 3.0 and 4.0 (P=0.83) and for advanced adenomas 3.6, 3.1 and 4.0 (P=0.39). CONCLUSIONS: This study provides further evidence that I-FOBT is superior to G-FOBT. None of the three I-FOBTs studied appeared to be significantly better than the others.

Pre-treatment lymphopenia as a prognostic biomarker in colorectal cancer patients receiving chemotherapy.

BACKGROUND: Lymphopenia is a predictor of the efficacy and hematological toxicity of chemotherapy in various advanced cancers. There is little data about this relationship in colorectal cancer. In this retrospective study, the influence of pretreatment lymphopenia on hematological toxicity and the efficacy of chemotherapy was investigated in colorectal cancer patients. PATIENTS AND METHODS: In total, 260 patients were included in the study. Correlations between pre-treatment lymphopenia (lymphocyte count < 1,000/µl) and the occurrence of hematological toxicity and efficacy of first-line palliative chemotherapy were investigated. RESULTS: Lymphopenia was found in 49/260 (19%) patients. Ten of these patients with lymphopenia (20.4%) experienced severe hematological toxicity compared with 17 of the remaining 211 (8%) patients (P = 0.01). Lymphopenia was identified as an independent factor for hematological toxicity. Among patients who received palliative chemotherapy, the objective response rate was significantly lower in lymphopenic patients than in the other patients (12.5% vs. 40.2%; P = 0.004). Lymphopenia was strongly associated with shorter progression-free survival (median 4 vs. 7 months; P = 0.033) and shorter overall survival (median 16 vs. 24 months, P = 0.024). Multivariate analysis revealed that lymphopenia had an independent effect on survival. CONCLUSIONS: Our findings show that lymphopenia is an independent predictive factor for both hematological toxicity and efficacy of chemotherapy in colorectal cancer. Pre-treatment lymphocyte count may represent a simple and new predictive biomarker of chemotherapy effects in colorectal cancer patients.

[Digital ischemia in two patients treated with gemcitabine]. / Ischémie digitale sous gemcitabine, à propos de deux cas.

A 73-year-old man with an urothelial carcinoma treated with gemcitabine and carboplatinium and an 84-year-old man with a mesothelioma treated with gemcitabine alone developed digital ischemia. In the first patient, the ischemia involved all fingers except the thumbs during the second cycle of treatment. The ischemia developed during the first cycle in the second patient and involved the right major and ring fingers. In the literature, gemcitabine vascular toxicity is probably potentialized by platinium salts. Several nosological entities occur simultaneously. The most widely described involve isolated digital ischemia for doses to the order of 3000mg, and a hemolytic and uremic thrombotic microangiopathy for gemcitabine doses above 10,000mg. The vascular toxicity of platinium salts is not dose-dependent. In these two patients, the clinical course was favorable with interruption of the chemotherapy, treatment by iloprost and aspirin.

[Colorectal cancer: from diagnosis to screening]. / Cancer colorectal: du diagnostic au dépistage.

Colorectal cancer fulfils the conditions required for mass screening. Data from controlled studies indicate that it is possible to reduce colorectal cancer mortality at a population level using faecal occult blood testing. Screenings rely on biennial testing in between 50 and 74average risk subjects. Compliance must be over 50%. Colorectal cancer mortality decrease in this case between 15 and 18% in the general population, 33 and 39% among participants to screening. The European Commission, on the basis of available data recommended to organise colorectal cancer screening in the European Union. Generalisation of screening has become a reality in France. Epidemiological studies allow us to define subjects at very high risk (genetic origin) and high risk for colorectal cancer. Colonoscopy screening is recommended in first degree relatives of patients with colorectal cancer or large adenoma diagnosed before 60years or with two affected first-degree relatives, in subjects with an extended inflammatory bowel disease, or with a personal history of large bowel cancer or large adenoma. Promising research strategies are arising: immunochemical tests in the short term, stool-based DNA tests in stools and proteome-based approach in the long term.

Frequent alteration of DNA damage signalling and repair pathways in human colorectal cancers with microsatellite instability.

Accumulation of frameshift mutations at genes containing coding mononucleotide repeats is thought to be the major molecular mechanism by which mismatch repair-deficient cells accumulate functional alterations. These mutations resulting from microsatellite instability (MSI) can affect genes involved in pathways with a putative oncogenic role, but may also arise in genes without any expected role in MSI carcinogenesis because of the high mutation background of these tumours. We here screened 39 MSI colorectal tumours for the presence of mutations in 25 genes involved in DNA damage signalling and repair pathways. Using a maximum likelihood statistical method, these genes were divided into two different groups that differed significantly in their mutation frequencies, and likely represent mutations that do or do not provide selective pressure during MSI tumour progression. Interestingly, the so-called real-target mutational events were found to be distributed among genes involved in different functional pathways of the DNA metabolism, for example, DNA damage signalling (DNA-PKcs, ATR), double-strand break (DSB) repair (DNA-PKcs, RAD50), mismatch repair (MSH3, MSH6, MBD4) and replication (POLD3). In particular, mutations in MRE11 and/or RAD50 were observed in the vast majority of the tumours and resulted in the concomitant loss of immunohistochemical expression of both proteins. These data might explain why MSI colorectal cancers (CRC) behave differently in response to a wide variety of chemotherapeutic agents, notably those targeting DNA. More generally, they give further insights into how MSI leads to functional changes with synergistic effects in oncogenic pathways.

[Gastric stromal tumor with osteoclast-like multinucleated giant cells during Lynch II syndrome]. / Tumeur stromale gastrique à cellules géantes multinucléées de type ostéoclastique au cours d'un syndrome de Lynch II.

We report an unusual case of gastric tumor: a stromal tumor with osteoclast-like giant cells. This type of cells has been described in epithelial tumors, especially in adenocarcinoma of the pancreas, lung, thyroid and breast. It has also been reported in smooth cell tumors such as uterine leiomyosarcoma and malignant fibrous histiocytoma. In our patient, this gastric stromal tumor with osteoclast-like giant cells was diagnosed in a man with adenocarcinoma of the colon in the context of a familial cancer syndrome. This is the first report of stromal tumor with osteoclast-like giant cells associated with Lynch syndrome.

[Hepatic artery ligation for liver metastasis of a acinar cell carcinoma of the pancreas revealed by a nodular panniculitis]. / Ligature de l'artère hépatique pour métastases hépatiques d'un carcinome à cellules acineuses du pancréas révélé par une panniculite nodulaire.

We report the case of a 67-year-old-man presenting with pancreatic acinar cell carcinoma revealed by dermatological manifestations of cytosteatonecrosis and treated by hepatic artery ligation. The pancreatic etiology of these lesions was suspected due to hyperlipasemia, and was confirmed by abdominal computerized tomography showing a pancreatic tumor and multiple liver nodules, and by histological examination of one of these lesions. Because of symptomatic treatment failure, rapid impairment of patient's general condition, and by analogy with the treatment of hepatic metastases of neuroendocrine tumors, hepatic artery ligation was performed. Lipasemia decreased markedly and symptoms disappeared for 45 days. Hepatic artery obstruction may be used for emergency treatment of secreting liver metastases.

[Myotomy for esophageal muscular hypertrophy with eosinophil infiltration of the esophagus associated with toxocariasis revealed by esophageal motor disorder]. / Myotomie pour hypertrophie musculaire avec infiltration à éosinophiles de l'oesophage associée à une toxocarose et révélée par un trouble moteur oesophagien.

We report the case of a 61-year-old-man with an eosinophilic esophagitis with esophageal motor disorder associated with toxocariasis. He complained of non cardiac chest pain and had eosinophilia leading to the detection of Toxocara canis infection. Pain persisted despite treatment of toxocariasis. Basal manometry was normal but ambulatory 24-hour manometry-pHmetry showed diffuse esophageal spasm. Ultrasonography showed a thickening of the esophageal musculature in the two inferior thirds of the esophagus. After failure of treatment with sodium cromoglycate steroids and esophageal dilatation, calcium antagonists were partially effective. A long esophageal myotomy was performed permiting the disappearance of symptoms. The histological examination of a side myotomy biopsy showed an eosinophilic infiltration of the esophageal muscle layer. This observation leads to discuss the possible relation between toxocariasis, the esophageal motor disorder and the eosinophilic infiltration of the esophageal muscle layer.

Efficacy of heat and moisture exchangers after changing every 48 hours rather than 24 hours.

OBJECTIVE: To determine whether changing heat and moisture exchangers every 48 hrs rather than 24 hrs would affect their efficacy to preserve heat and moisture of expiratory gases. DESIGN: Prospective, controlled, randomized, not blinded, study. SETTING: Intensive care unit of a university hospital. PATIENTS: Twenty-nine patients requiring controlled mechanical ventilation and paralysis for >2 days. INTERVENTIONS: After randomization, the patients were allocated to one of the three following groups: a) group 1, ventilated for 24 hrs with a heat and moisture exchanger; b) group 2, ventilated for 48 hrs with the same heat and moisture exchanger; and c) group 3, ventilated for 48 hrs with a heated humidifier system. MEASUREMENTS AND MAIN RESULTS: In each patient, during the inspiration phase, the following measurements were performed: a) peak and mean airway pressures; b) mean values of temperature; c) relative and absolute humidity of inspired gases. In each patient, measurements were performed after 24 hrs and after 48 hrs, where appropriate. After 24 hrs, patients in groups 1 and 2 had similar levels of temperature (30.1 +/- 2.7 degrees C and 29.2 +/- 2.3 degrees C), relative humidity (98.3 +/- 3.6% and 99.3 +/- 3.4%), and absolute humidity (29.1 +/- 2.1 and 29.3 +/- 2.4 mg H2O/L). Using the same heat and moisture exchanger for 48 hrs rather than 24 hrs did not affect its technical performance. Results showed the following: a) temperature, 24 hrs, 29.2 +/- 2.3 degrees C, 48 hrs, 28.7 +/- 1.9 degrees C; b) relative humidity, 24 hrs, 99.3 +/- 3.4%, 48 hrs, 99.2 +/- 1.7%; and c) absolute humidity, 24 hrs, 29.3 +/- 2.4 mg H2O/L, 48 hrs, 28.7 +/- 3.1 mg H2O/L. Peak and mean airway pressures did not change over the 48-hr study period, with identical tidal and minute volumes in the study patients. Higher levels of temperature and absolute humidity of inspired gases were observed in group 3, compared with groups 1 and 2 (p< .02). CONCLUSIONS: Changing the heat and moisture exchanger after 48 hrs rather than 24 hrs did not affect its technical performance in terms of heat and water preservation of ventilatory gases. There is also some indirect evidence of very few, if any, changes in heat and moisture exchanger resistance. However, other large clinical trials should be undertaken to confirm the safety of extending the time between heat and moisture exchanger change. The heated humidifier, supplied with electric energy maintained high levels of humidification and temperature over the 48-hr study period.