Moeglichkeiten der systemischen Therapie im metastasierten Stadium [Treatment options for chemotherapy in metastatic gastric cancer]

Die Ergebnisse mehrerer, in letzter Zeit publizierter Phase-III-Studien haben die therapeutischen Möglichkeiten in der Behandlung des metastasierten Magenkarzinoms deutlich erweitert. Die Dauerinfusion von 5-Fluorouracil (5-FU) kann ohne Verlust an Wirkung durch Capecitabin ersetzt werden, ebenso wie Cisplatin durch Oxaliplatin. Nach den Ergebnissen der REAL-2-Studie zeigt die Kombination aus Epirubicin, Oxaliplatin und Capecitabin (EOX) eine Verbesserung des Gesamtüberlebens (9,9 vs. 11,2 Monate; HR 0,8) im Vergleich zu Epirubicin, Cisplatin und 5-FU (ECF). Die Frage, ob in der First-Line-Therapie eine Dreifachkombination oder eine Zweifachkombination eingesetzt werden sollte, ist allerdings weiterhin umstritten. Die Kombination aus Irinotecan und 5-FU stellt für solche Patienten, bei denen aufgrund von Komorbiditäten eine platinfreie Therapie bevorzugt wird, eine Alternative zur Kombination Cisplatin/5-FU dar. Docetaxel, 5-FU und Cisplatin (DCF) hat sich bezüglich des Überlebens in einer randomisierten Phase-III-Studie als statistisch signifikant überlegen erwiesen, allerdings besteht eine ausgeprägte hämatologische Toxizität, welche die Anwendbarkeit insbesondere bei den häufig älteren Patienten mit einem Magenkarzinom limitiert. Randomisierte Phase-III-Studien zum Vergleich von DCF mit anderen Dreierkombinationen, wie z. B. EOX, stehen aus. Recently published results from several phase III trials have significantly increased the therapeutic options in the treatment of metastatic stomach cancer: The continuous infusion of 5-FU can be replaced by capecitabine, and cisplatin can be replaced by oxaliplatin in both cases without impairing efficacy. According to the results of the REAL-2 trial, the combination of epirubicin, oxaliplatin and capecitabine (EOX) achieved superior results for overall survival compared to epirubicin, cisplatin und 5-FU (ECF) (9.9 versus 11.2 months, HR 0.8). However, the question of whether an optimal first line therapy should include a triplet regimen or the sequential use of doublets is a matter of debate. The combination of irinotecan and 5-FU may serve as an alternative to platinum-containing regimens in patients where, due to co-morbidity, a platinum-free regimen is preferred. The 3-drug combination of docetaxel, 5-FU and cisplatin (DCF) demonstrated a statistically significant survival benefit compared to the 2-drug combination of 5-FU and cisplatin in a randomized phase III trial, although results were limited by a particularly significant hematological toxicity, which prevents its application in the large group of elderly patients with gastric cancer. Direct randomized phase III comparisons of DCF with other 3-drug combinations, such as EOX are still missing.

Comparison of molecular signatures from multiple skin diseases identifies mechanisms of immunopathogenesis.

The ability to obtain gene expression profiles from human disease specimens provides an opportunity to identify relevant gene pathways, but is limited by the absence of data sets spanning a broad range of conditions. Here, we analyzed publicly available microarray data from 16 diverse skin conditions in order to gain insight into disease pathogenesis. Unsupervised hierarchical clustering separated samples by disease as well as common cellular and molecular pathways. Disease-specific signatures were leveraged to build a multi-disease classifier, which predicted the diagnosis of publicly and prospectively collected expression profiles with 93% accuracy. In one sample, the molecular classifier differed from the initial clinical diagnosis and correctly predicted the eventual diagnosis as the clinical presentation evolved. Finally, integration of IFN-regulated gene programs with the skin database revealed a significant inverse correlation between IFN-β and IFN-γ programs across all conditions. Our study provides an integrative approach to the study of gene signatures from multiple skin conditions, elucidating mechanisms of disease pathogenesis. In addition, these studies provide a framework for developing tools for personalized medicine toward the precise prediction, prevention, and treatment of disease on an individual level.

Dosimetric comparison of different treatment modalities for stereotactic radiosurgery of meningioma.

BACKGROUND: The objective of this study was to compare the three most prominent systems for stereotactic radiosurgery in terms of dosimetric characteristics: the Cyberknife system, the Gamma Knife Perfexion and the Novalis system. METHODS: Ten patients treated for recurrent grade I meningioma after surgery using the Cyberknife system were identified; the Cyberknife contours were exported and comparative treatment plans were generated for the Novalis system and Gamma Knife Perfexion. Dosimetric values were compared with respect to coverage, conformity index (CI), gradient index (GI) and beam-on time (BOT). RESULTS: All three systems showed comparable results in terms of coverage. The Gamma Knife and the Cyberknife system showed significantly higher levels of conformity than the Novalis system (Cyberknife vs Novalis, p = 0.002; Gamma Knife vs Novalis, p = 0.002). The Gamma Knife showed significantly steeper gradients compared with the Novalis and the Cyberknife system (Gamma Knife vs Novalis, p = 0.014; Gamma Knife vs Cyberknife, p = 0.002) and significantly longer beam-on times than the other two systems (BOT = 66 ± 21.3 min, Gamma Knife vs Novalis, p = 0.002; Gamma Knife vs Cyberknife, p = 0.002). CONCLUSIONS: The multiple focal entry systems (Gamma Knife and Cyberknife) achieve higher conformity than the Novalis system. The Gamma Knife delivers the steepest dose gradient of all examined systems. However, the Gamma Knife is known to require long beam-on times, and despite worse dose gradients, LINAC-based systems (Novalis and Cyberknife) offer image verification at the time of treatment delivery.

Up-regulated 14-3-3β and 14-3-3ζ proteins in prefrontal cortex of subjects with schizophrenia: effect of psychotropic treatment.

14-3-3 is a family of conserved regulatory proteins that bind to a multitude of functionally diverse signalling proteins. Various genetic studies and gene expression and proteomic analyses have involved 14-3-3 proteins in schizophrenia (SZ). On the other hand, studies about the status of these proteins in major depressive disorder (MD) are still missing. Immunoreactivity values of cytosolic 14-3-3β and 14-3-3ζ proteins were evaluated by Western blot in prefrontal cortex (PFC) of subjects with schizophrenia (SZ; n=22), subjects with major depressive disorder (MD; n=21) and age-, gender- and postmortem delay-matched control subjects (n=52). The modulation of 14-3-3β and 14-3-3ζ proteins by psychotropic medication was also assessed. The analysis of both proteins in SZ subjects with respect to matched control subjects showed increased 14-3-3β (Δ=33±10%, p<0.05) and 14-3-3ζ (Δ=29±6%, p<0.05) immunoreactivity in antipsychotic-free but not in antipsychotic-treated SZ subjects. Immunoreactivity values of 14-3-3β and 14-3-3ζ were not altered in MD subjects. These results show the specific up-regulation of 14-3-3β and 14-3-3ζ proteins in PFC of SZ subjects and suggest a possible down-regulation of both proteins by antipsychotic treatment.

Patients' satisfaction with community treatment: a pilot cross-sectional survey adopting multiple perspectives.

ACCESSIBLE SUMMARY: Patients' satisfaction is scarcely studied within the context of community treatment for adolescents. Thus, this study adopts a multiple perspective on patients' satisfaction (including service users as well as staff members). The results highlighted that all informants (patients, foster carers in foster homes and professional caregivers from community treatment teams) perceived the patients to be satisfied, with foster carers reporting the highest patient satisfaction rate. Considering the patient satisfaction rate from multiple perspectives provides complementary understandings. Clinical outcomes and, specifically, a reduction in emotional difficulties were related to patient's satisfaction, but only from the patients' perspective. ABSTRACT: Community treatment (CT) teams in Switzerland provide care to patients who are unable to use regular child and adolescent mental health services (i.e. inpatient and outpatients facilities). No study has considered patients' self-rated satisfaction alongside with staff members' perspectives on patient satisfaction. Thus, adopting a cross-sectional survey design, we collected patients' satisfaction using the Client Satisfaction Questionnaire (CSQ-8), rated by multiple informants (patients, foster carers in foster homes and professional caregivers from CT teams). Professional caregivers assessed clinical outcomes using the Health of the Nation Outcome Scale for Children and Adolescents. The results indicated that all informants were satisfied with the community treatment teams. The satisfaction scores were not correlated across informants; however, the alleviation of emotional symptoms was correlated with patients' satisfaction. This study indicated that the use of a combined approach including the views of service users and professionals gives important complementary information. Finally, in our sample, lower emotional symptoms were linked to enhanced patient satisfaction. This study demonstrated the importance of considering multiple perspectives to obtain the most accurate picture of patients' satisfaction. Second, focusing on the reduction of emotional symptoms might lead to a higher degree of patients' satisfaction.

Patients' satisfaction with community treatment: a pilot cross-sectional survey adopting multiple perspectives.

ACCESSIBLE SUMMARY: Patients' satisfaction is scarcely studied within the context of community treatment for adolescents. Thus, this study adopts a multiple perspective on patients' satisfaction (including service users as well as staff members). The results highlighted that all informants (patients, foster carers in foster homes and professional caregivers from community treatment teams) perceived the patients to be satisfied, with foster carers reporting the highest patient satisfaction rate. Considering the patient satisfaction rate from multiple perspectives provides complementary understandings. Clinical outcomes and, specifically, a reduction in emotional difficulties were related to patient's satisfaction, but only from the patients' perspective. ABSTRACT: Community treatment (CT) teams in Switzerland provide care to patients who are unable to use regular child and adolescent mental health services (i.e. inpatient and outpatients facilities). No study has considered patients' self-rated satisfaction alongside with staff members' perspectives on patient satisfaction. Thus, adopting a cross-sectional survey design, we collected patients' satisfaction using the Client Satisfaction Questionnaire (CSQ-8), rated by multiple informants (patients, foster carers in foster homes and professional caregivers from CT teams). Professional caregivers assessed clinical outcomes using the Health of the Nation Outcome Scale for Children and Adolescents. The results indicated that all informants were satisfied with the community treatment teams. The satisfaction scores were not correlated across informants; however, the alleviation of emotional symptoms was correlated with patients' satisfaction. This study indicated that the use of a combined approach including the views of service users and professionals gives important complementary information. Finally, in our sample, lower emotional symptoms were linked to enhanced patient satisfaction. This study demonstrated the importance of considering multiple perspectives to obtain the most accurate picture of patients' satisfaction. Second, focusing on the reduction of emotional symptoms might lead to a higher degree of patients' satisfaction.

Comparisons between two economically valuable forest species (Eucalyptus grandis and Pinus taeda) in relation to seed behaviour under controlled deterioration

The objectives of this work were to analyze seed behaviour under controlled deterioration and estimate viability equations for forest species Eucalyptus grandis and Pinus taeda. Desired moisture content levels were achieved from initial values after either rehydration over water or drying over silica gel, both at 25 ºC. Seed sub samples with 8 moisture contents each for E. grandis (1.2 to 18.1%, initial value of 11.3%) and P. taeda (1.5 to 19.5%, initial value of 12.9%) were sealed in laminate aluminium-foil packets and stored in incubators maintained at 40, 50 and 65 ºC. The seeds from these species exhibited true orthodox and sub-orthodox storage behaviour, respectively, however E. grandis showed higher seed storability, probably due to a different seed chemical composition. Lowest moisture content limits estimated for application of the viability equations at 65 ºC were 4.9 and 4.1 mc for E. grandis and P. taeda, on equilibrium with ±20% RH. The viability equation estimated quantified the response of seed longevity to storage environment well with K E = 9.661 and 8.838; C W = 6.467 and 5.981; C H = 0.03498 and 0.10340; C Q = 0.0002330 and 0.0005476, for E. grandis and P. taeda, respectively.

Establishment of anammox process in sludge samples collected from swine wastewater treatment system

The high load of nitrogen present in swine wastewater is one of the biggest management challenges of the activity. The Anammox process emerges as a good alternative for biological removal of nitrogen. This study aims to acclimate sludge collected from swine effluent treatment systems to establish the Anammox process. Two sludge samples were collected at Embrapa Swine and Poultry, Concordia - SC, Brazil, one from the bottom of an inactive anaerobic pond (inoculum A) and another from an aeration tank (inoculum B). Both were acclimated until the depletion of NO3-N, being subsequently inoculated in two reactors (Reactor A - Inoculum A and Reactor B - Inoculum B). The Reactor A showed activity after 110 days of operation, while the Reactor B needed 170 days. The difference in the start-up time could be explained by the different environmental conditions to which each sludge was submitted. FISH and PCR analyses confirmed the presence of microorganisms with Anammox activity, demonstrating that the sludge of swine wastewater treatment systems is a good source of inoculum for the development of the Anammox process.

Reference values for lung function tests: II. Maximal respiratory pressures and voluntary ventilation

The strength of the respiratory muscles can be evaluated from static measurements (maximal inspiratory and expiratory pressures, MIP and MEP) or inferred from dynamic maneuvers (maximal voluntary ventilation, MVV). Although these data could be suitable for a number of clinical and research applications, no previous studies have provided reference values for such tests using a healthy, randomly selected sample of the adult Brazilian population. With this main purpose, we prospectively evaluated 100 non-smoking subjects (50 males and 50 females), 20 to 80 years old, selected from more than 8,000 individuals. Gender-specific linear prediction equations for MIP, MEP and MVV were developed by multiple regression analysis: age and, secondarily, anthropometric measurements explained up to 56% of the variability of the dependent variables. The most cited previous studies using either Caucasian or non-Caucasian samples systematically underestimated the observed values of MIP (P<0.05). Interestingly, the self-reported level of regular physical activity and maximum aerobic power correlates strongly with both respiratory and peripheral muscular strength (knee extensor peak torque) (P<0.01). Our results, therefore, provide a new frame of reference to evaluate the normalcy of some useful indexes of respiratory muscle strength in Brazilian males and females aged 20 to 80.

Reference values for lung function tests: III. Carbon monoxide diffusing capacity (transfer factor)

Carbon monoxide diffusing capacity (DLCO) or transfer factor (TLCO) is a particularly useful test of the appropriateness of gas exchange across the lung alveolocapillary membrane. With the purpose of establishing predictive equations for DLCO using a non-smoking sample of the adult Brazilian population, we prospectively evaluated 100 subjects (50 males and 50 females aged 20 to 80 years), randomly selected from more than 8,000 individuals. Gender-specific linear prediction equations were developed by multiple regression analysis with single breath (SB) absolute and volume-corrected (VA) DLCO values as dependent variables. In the prediction equations, age (years) and height (cm) had opposite effects on DLCOSB (ml min-1 mmHg-1), independent of gender (-0.13 (age) + 0.32 (height) - 13.07 in males and -0.075 (age) + 0.18 (height) + 0.20 in females). On the other hand, height had a positive effect on DLCOSB but a negative one on DLCOSB/VA (P<0.01). We found that the predictive values from the most cited studies using predominantly Caucasian samples were significantly different from the actually measured values (P<0.05). Furthermore, oxygen uptake at maximal exercise (VO2max) correlated highly to DLCOSB (R = 0.71, P<0.001); this variable, however, did not maintain an independent role to explain the VO2max variability in the multiple regression analysis (P>0.05). Our results therefore provide an original frame of reference for either DLCOSB or DLCOSB/VA in Brazilian males and females aged 20 to 80 years, obtained from the standardized single-breath technique.

Pharmacokinetic and parasitological evaluation of the bone marrow of dogs with visceral leishmaniasis submitted to multiple dose treatment with liposome-encapsulated meglumine antimoniate

The aim of the present study was to evaluate the impact of a multiple dose regimen of a liposomal formulation of meglumine antimoniate (LMA) on the pharmacokinetics of antimony in the bone marrow of dogs with visceral leishmaniasis and on the ability of LMA to eliminate parasites from this tissue. Dogs naturally infected with Leishmania chagasi received 4 intravenous doses of either LMA (6.5 mg antimony/kg body weight, N = 9), or empty liposomes (at the same lipid dose as LMA, N = 9) at 4-day intervals. A third group of animals was untreated (N = 8). Before each administration and at different times after treatment, bone marrow was obtained and analyzed for antimony level (LMA group) by electrothermal atomic absorption spectrometry, and for the presence of Leishmania parasites (all groups). There was a significant increase of antimony concentration from 0.76 µg/kg wet organ (4 days after the first dose) to 2.07 µg/kg (4 days after the fourth dose) and a half-life of 4 days for antimony elimination from the bone marrow. Treatment with LMA significantly reduced the number of dogs positive for parasites (with at least one amastigote per 1000 host cells) compared to controls (positive dogs 30 days after treatment: 0 of 9 in the LMA group, 3 of 9 in the group treated with empty liposomes and 3 of 8 in the untreated group). However, complete elimination of parasites was not achieved. In conclusion, the present study showed that multiple dose treatment with LMA was effective in improving antimony levels in the bone marrow of dogs with visceral leishmaniasis and in reducing the number of positive animals, even though it was not sufficient to achieve complete elimination of parasites.

Imaging Neuroinflammation in Progressive Multiple Sclerosis

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system CNS), where inflammation and neurodegeneration lead to irreversible neuronal damage. In MS, a dysfunctional immune system causes auto‐reactive lymphocytes to migrate into CNS where they initiate an inflammatory cascade leading to focal demyelination, axonal degeneration and neuronal loss. One of the hallmarks of neuronal injury and neuroinflammation is the activation of microglia. Activated microglia are found not only in the focal inflammatory lesions, but also diffusely in the normal‐appearing white matter (NAWM), especially in progressive MS. The purine base, adenosine is a ubiquitous neuromodulator in the CNS and also participates in the regulation of inflammation. The effect of adenosine mediated via adenosine A2A receptors has been linked to microglial activation, whereas modulating A2A receptors may exert neuroprotective effects. In the majority of patients, MS presents with a relapsing disease course, later advancing to a progressive phase characterised by a worsening, irreversible disability. Disease modifying treatments can reduce the severity and progression in relapsing MS, but no efficient treatment exists for progressive MS. The aim of this research was to investigate the prevalence of adenosine A2A receptors and activated microglia in progressive MS by using in vivo positron emission tomography (PET) imaging and [11C]TMSX and [11C](R)‐PK11195 radioligands. Magnetic resonance imaging (MRI) with diffusion tensor imaging (DTI) was performed to evaluate structural brain damage. Non‐invasive input function methods were also developed for the analyses of [11C]TMSX PET data. Finally, histopathological correlates of [11C](R)‐PK11195 radioligand binding related to chronic MS lesions were investigated in post‐mortem samples of progressive MS brain using autoradiography and immunohistochemistry. [11C]TMSX binding to A2A receptors was increased in NAWM of secondary progressive MS (SPMS) patients when compared to healthy controls, and this correlated to more severe atrophy in MRI and white matter disintegration (reduced fractional anisotropy, FA) in DTI. The non‐invasive input function methods appeared as feasible options for brain [11C]TMSX images obviating arterial blood sampling. [11C](R)‐PK11195 uptake was increased in the NAWM of SPMS patients when compared to patients with relapsing MS and healthy controls. Higher [11C](R)‐PK11195 binding in NAWM and total perilesional area of T1 hypointense lesions was associated with more severe clinical disability, increased brain atrophy, higher lesion load and reduced FA in NAWM in the MS patients. In autoradiography, increased perilesional [11C](R)‐PK11195 uptake was associated with increased microglial activation identified using immunohistochemistry. In conclusion, brain [11C]TMSX PET imaging holds promise in the evaluation of diffuse neuroinflammation in progressive MS. Being a marker of microglial activation, [11C](R)‐ PK11195 PET imaging could possibly be used as a surrogate biomarker in the evaluation of the neuroinflammatory burden and clinical disease severity in progressive MS.

Changes in circulating endothelial progenitor cells predict responses of multiple myeloma patients to treatment with bortezomib and dexamethasone

Four cycles of chemotherapy are required to assess responses of multiple myeloma (MM) patients. We investigated whether circulating endothelial progenitor cells (cEPCs) could be a biomarker for predicting patient response in the first cycle of chemotherapy with bortezomib and dexamethasone, so patients might avoid ineffective and costly treatments and reduce exposure to unwanted side effects. We measured cEPCs and stromal cell-derived factor-1α (SDF-1α) in 46 MM patients in the first cycle of treatment with bortezomib and dexamethasone, and investigated clinical relevance based on patient response after four 21-day cycles. The mononuclear cell fraction was analyzed for cEPC by FACS analysis, and SDF-1α was analyzed by ELISA. The study population was divided into 3 groups according to the response to chemotherapy: good responders (n=16), common responders (n=12), and non-responders (n=18). There were no significant differences among these groups at baseline day 1 (P>0.05). cEPC levels decreased slightly at day 21 (8.2±3.3 cEPCs/μL) vs day 1 (8.4±2.9 cEPCs/μL) in good responders (P>0.05). In contrast, cEPC levels increased significantly in the other two groups (P<0.05). SDF-1α changes were closely related to changes in cEPCs. These findings indicate that change in cEPCs at day 21 in the first cycle might be considered a noninvasive biomarker for predicting a later response, and extent of change could help decide whether to continue this costly chemotherapy. cEPCs and the SDF-1α/CXCR4 axis are potential therapeutic targets for improved response and outcomes in MM patients.

Vulnerability to adverse consequences of drinking and problem drinker status as predicted by risky drinking behaviours, drug use, sex differences and affect : a test of multiple models /

Although alcohol problems and alcohol consumption are related, consumption does not fully account for differences in vulnerability to alcohol problems. Therefore, other factors should account for these differences. Based on previous research, it was hypothesized that risky drinking behaviours, illicit and prescription drug use, affect and sex differences would account for differences in vulnerability to alcohol problems while statistically controlling for overall alcohol consumption. Four models were developed that were intended to test the predictive ability of these factors, three of which tested the predictor sets separately and a fourth which tested them in a combined model. In addition, two distinct criterion variables were regressed on the predictors. One was a measure of the frequency that participants experienced negative consequences that they attributed to their drinking and the other was a measure of the extent to which participants perceived themselves to be problem drinkers. Each of the models was tested on four samples from different populations, including fIrst year university students, university students in their graduating year, a clinical sample of people in treatment for addiction, and a community sample of young adults randomly selected from the general population. Overall, support was found for each of the models and each of the predictors in accounting for differences in vulnerability to alcohol problems. In particular, the frequency with which people become intoxicated, frequency of illicit drug use and high levels of negative affect were strong and consistent predictors of vulnerability to alcohol problems across samples and criterion variables. With the exception of the clinical sample, the combined models predicted vulnerability to negative consequences better than vulnerability to problem drinker status. Among the clinical and community samples the combined model predicted problem drinker status better than in the student samples.

La PCSK9 humaine, une molécule aux multiples facettes métaboliques et une cible thérapeutique prometteuse : études de régulation in vitro et in vivo

La proprotéine convertase subtilisine/kexine-9 (PCSK9) a été identifiée comme le troisième locus impliqué dans l’hypercholestérolémie autosome dominante (ADH). Les deux autres gènes impliqués dans l’ADH encodent le récepteur des lipoprotéines de faible densité (LDLR) et l’apolipoprotéine B. La PCSK9 est une convertase qui favorise la dégradation du LDLR dans les hépatocytes et augmente le niveau plasmatique de cholestérol des LDL (LDL-C). Les mutations « gain de fonction » de la PCSK9 sont associées à un phénotype d’hypercholestérolémie familiale, tandis que les variantes « perte de fonction » sont associées à un LDL-C réduit et à un risque coronarien plus faible. Pour élucider le rôle physiologique de la PCSK9, nous avons étudié sa régulation génique. En utilisant le RT-PCR quantitatif dans des hépatocytes humains, nous avons analysé la régulation de PCSK9 sous différentes conditions modulant l’expression des gènes impliqués dans le métabolisme du cholestérol. Nous avons démontré que l’expression de la PCSK9 était induite par les statines de manière dose-dépendante et que cette induction était abolie par le mévalonate. De plus, le promoteur de PCSK9 contenait deux motifs conservés pour la régulation par le cholestérol : le sterol regulatory element (SRE) et un site Sp1. La PCSK9 circule dans le plasma sous des formes mature et clivée par la furine. Grâce à notre anticorps polyclonal, nous avons mis au point un test ELISA mesurant la PCSK9 plasmatique totale. Une étude transversale a évalué les concentrations plasmatiques de PCSK9 chez des sujets sains et hypercholestérolémiques, traités ou non par des statines ou une combinaison statine/ezetimibe. Chez 254 sujets sains, la valeur moyenne de PCSK9 (écart-type) était de 89,5 (31,9) µg/L. La concentration plasmatique de la PCSK9 corrélait avec celle de cholestérol total, du LDL-C, des triglycérides (TG), de la glycémie à jeun, l’âge et l’indice de masse corporelle. Le séquençage de PCSK9 chez des sujets aux extrêmes de la distribution des concentrations de PCSK9 de notre cohorte a révélé la présence d’une nouvelle variation « perte de fonction » : R434W. Chez 200 patients hypercholestérolémiques, la concentration de PCSK9 était plus élevée que chez les sujets sains (P<0,04). Elle a augmenté avec une dose croissante de statine (P<0,001), et a augmenté encore plus suite à l’ajout d’ezetimibe (P<0,001). Chez les patients traités, ceux présentant une hypercholestérolémie familiale (HF; due à une mutation du LDLR) avaient des concentrations plus élevées de PCSK9 que les non-HF (P<0,005), et la réduction de LDL-C corrélait positivement avec la concentration de PCSK9 atteinte de la même manière dans les deux sous-catégories (P<0,02 et P<0,005, respectivement). Par ailleurs, une incubation des cellules HepG2 (hépatocytes) et Caco-2 (entérocytes) avec de l’ezetimibe a provoqué une augmentation de l’ARNm de PCSK9 et de NPC1L1 de 1,5 à 2 fois (P<0,05), mais aucune variation significative de PCSK9 sécrétée n’a été observée, suggérant que ces lignées cellulaires ne sont pas un modèle idéal. Nous avons également mesuré le niveau de PCSK9 chez 1 739 Canadiens-français âgés de 9, 13 et 16 ans. La valeur moyenne (écart-type) de PCSK9 dans cette cohorte était de 84,7 (24,7) µg/L, légèrement plus basse que dans la cohorte d’adultes (89,5 (31,9) µg/L). Chez les garçons, la PCSK9 circulante diminuait avec l’âge, tandis que c’était l’inverse chez les filles. Il y avait des associations positives et significatives entre la PCSK9 et la glycémie à jeun, l’insulinémie, le HOMA-IR, et les paramètres lipidiques (TC, LDL-C, TG, HDL-C, apoAI et apoB). Dans l’analyse multivariée, une hausse de 10% de l’insulinémie à jeun était associée à une augmentation de 1 à 2% de PCSK9. La régulation de PCSK9 est typique de celle d’un gène impliqué dans le métabolisme des lipoprotéines et est probablement la cible du facteur de transcription «sterol regulatory element-binding protein » (SREBP-2). La concentration plasmatique de la PCSK9 est associée avec l’âge, le sexe, et de multiples marqueurs métaboliques chez les enfants et les adultes. La détection de la PCSK9 circulante chez les sujets HF et non-HF signifie que ce test ELISA spécifique à PCSK9 pourrait servir à suivre la réponse à la thérapie chez un grand éventail de sujets. PCSK9 semble être une cible thérapeutique prometteuse dans le traitement de l’hypercholestérolémie et de la maladie cardiovasculaire.