Centre de recherche Translationnelle en Médecine moléculaire

Excess body weight, as defined by the body mass index (BMI), has been associated with several diseases and includes subjects who are overweight (BMI ≥ 25-29.9 kg/m(2)) or obese (BMI ≥ 30 kg/m(2)). Overweight and obesity constitute the fifth leading risk for overall mortality, accounting for at least 2.8 million adult deaths each year. In addition around 11% of colorectal cancer (CRC) cases have been attributed to overweight and obesity in Europe. Epidemiological data suggest that obesity is associated with a 30-70% increased risk of colon cancer in men, whereas the association is less consistent in women. Similar trends exist for colorectal adenoma, although the risk appears lower. Visceral fat, or abdominal obesity, seems to be of greater concern than subcutaneous fat obesity, and any 1 kg/m(2) increase in BMI confers additional risk (HR 1.03). Obesity might be associated with worse cancer outcomes, such as recurrence of the primary cancer or mortality. Several factors, including reduced sensitivity to antiangiogenic-therapeutic regimens, might explain these differences. Except for wound infection, obesity has no significant impact on surgical procedures. The underlying mechanisms linking obesity to CRC are still a matter of debate, but metabolic syndrome, insulin resistance and modifications in levels of adipocytokines seem to be of great importance. Other biological factors such as the gut microbiota or bile acids are emerging. Many questions still remain unanswered: should preventive strategies specifically target obese patients? Is the risk of cancer great enough to propose prophylactic bariatric surgery in certain patients with obesity?

PURPOSE: Complete resection of liver metastases of colorectal origin is the only potentially curative treatment. In order to decrease recurrences, the use of adjuvant systemic chemotherapy after liver resection is controversial because no randomized study demonstrated its benefit. PATIENTS AND METHODS: In a multicenter trial, we randomly assigned 173 patients with completely resected (R0) hepatic metastases from colorectal cancer to surgery alone and observation (87 patients) or to surgery followed by 6 months of systemic adjuvant chemotherapy with a fluorouracil and folinic acid monthly regimen (86 patients). The main outcome criterion was disease-free survival. Secondary outcome measures were overall survival and treatment-related toxicity. RESULTS: The intention-to-treat analysis was based on 171 patients, after a median follow-up of 87 months (SE = 5.8). The 5-year disease-free survival rate, after adjustment for major prognostic factors, was 33.5% for patients in the chemotherapy group and 26.7% for patients in the control group (Cox multivariate analysis: odds ratio for recurrence or death = 0.66; 95% CI, 0.46 to 0.96; P = .028). With regard to secondary outcome measures, a trend towards increased overall survival was observed but did not reach statistical significance (5-year overall survival: chemotherapy group, 51.1% v control group, 41.1%; odds ratio for death, 0.73; 95% CI, 0.48 to 1.10; P = .13). CONCLUSION: Despite a suboptimal regimen, which was the standard at the beginning of the study, adjuvant intravenous systemic chemotherapy provided a significant disease-free survival benefit for patients with resected liver metastases from colorectal cancer.

Point-of-care ultrasound is increasingly used at the bedside to integrate the clinical assessment of the critically ill; in particular, lung ultrasound has greatly developed in the last decade. This review describes basic lung ultrasound signs and focuses on their applications in critical care. Lung semiotics are composed of artifacts (derived by air/tissue interface) and real images (i.e., effusions and consolidations), both providing significant information to identify the main acute respiratory disorders. Lung ultrasound signs, either alone or combined with other point-of-care ultrasound techniques, are helpful in the diagnostic approach to patients with acute respiratory failure, circulatory shock, or cardiac arrest. Moreover, a semiquantification of lung aeration can be performed at the bedside and used in mechanically ventilated patients to guide positive end-expiratory pressure setting, assess the efficacy of treatments, monitor the evolution of the respiratory disorder, and help the weaning process. Finally, lung ultrasound can be used for early detection and management of respiratory complications under mechanical ventilation, such as pneumothorax, ventilator-associated pneumonia, atelectasis, and pleural effusions. Lung ultrasound is a useful diagnostic and monitoring tool that might in the near future become part of the basic knowledge of physicians caring for the critically ill patient.

We have previously shown that the small heat shock protein HSP27 inhibited apoptotic pathways triggered by a variety of stimuli in mammalian cells. The present study demonstrates that HSP27 overexpression decreases U937 human leukemic cell sensitivity to etoposide-induced cytotoxicity by preventing apoptosis. As observed for Bcl-2, HSP27 overexpression delays poly(ADP-ribose)polymerase cleavage and procaspase-3 activation. In contrast with Bcl-2, HSP27 overexpression does not prevent etoposide-induced cytochrome c release from the mitochondria. In a cell-free system, addition of cytochrome c and dATP to cytosolic extracts from untreated cells induces the proteolytic activation of procaspase-3 in both control and bcl-2-transfected U937 cells but fails to activate procaspase-3 in HSP27-overexpressing cells. Immunodepletion of HSP27 from cytosolic extracts increases cytochrome c/dATP-mediated activation of procaspase-3. Overexpression of HSP27 also prevents procaspase-9 activation. In the cell-free system, immunodepletion of HSP27 increases LEDH-AFC peptide cleavage activity triggered by cytochrome c/dATP treatment. We conclude that HSP27 inhibits etoposide-induced apoptosis by preventing cytochrome c and dATP-triggered activity of caspase-9, downstream of cytochrome c release.

Poly(ADP-ribose)-1 (PARP-1) is a key mediator of cell death in excitotoxicity, ischemia, and oxidative stress. PARP-1 activation leads to cytosolic NAD(+) depletion and mitochondrial release of apoptosis-inducing factor (AIF), but the causal relationships between these two events have been difficult to resolve. Here, we examined this issue by using extracellular NAD(+) to restore neuronal NAD(+) levels after PARP-1 activation. Exogenous NAD(+) was found to enter neurons through P2X(7)-gated channels. Restoration of cytosolic NAD(+) by this means prevented the glycolytic inhibition, mitochondrial failure, AIF translocation, and neuron death that otherwise results from extensive PARP-1 activation. Bypassing the glycolytic inhibition with the metabolic substrates pyruvate, acetoacetate, or hydroxybutyrate also prevented mitochondrial failure and neuron death. Conversely, depletion of cytosolic NAD(+) with NAD(+) glycohydrolase produced a block in glycolysis inhibition, mitochondrial depolarization, AIF translocation, and neuron death, independent of PARP-1 activation. These results establish NAD(+) depletion as a causal event in PARP-1-mediated cell death and place NAD(+) depletion and glycolytic failure upstream of mitochondrial AIF release.

Resveratrol (3,4',5 tri-hydroxystilbene) is a phytoalexin produced in hudge amount in grapevine skin in response to infection by Bothrytis cinerea. This production of resveratrol blocks the proliferation of the pathogen, thereby acting as a natural antibiotic. Numerous studies have reported interesting properties of trans-resveratrol as a preventive agent against important pathologies i.e. vascular diseases, cancers, viral infection or neurodegenerative processes. Moreover, several epidemiological studies have revealed that resveratrol is probably one of the main microcomponents of wine responsible for its health benefits such as prevention of vaso-coronary diseases and cancer. Resveratrol acts on the process of carcinogenesis by affecting the three phases: tumor initiation, promotion and progression phases and suppresses the final steps of carcinogenesis, i.e. angiogenesis and metastasis. It is also able to activate apoptosis, to arrest the cell cycle or to inhibit kinase pathways. Interestingly, resveratrol does not present any cytotoxicity in animal models. Moreover, concentrations of resveratrol in blood seem to be sufficient for anti-invasive activity. The enterohepatic recirculation may contribute to a delayed elimination of the drug from the body and bring about a prolonged effect. By its binding to plasmatic proteins, resveratrol also exhibits a prolonged effect. Interestingly, low doses of resveratrol can sensitize to low doses of cytotoxic drugs and so provide an innovative strategy to enhance the efficacy of anticancer therapy in various human cancers. By these properties, resveratrol appears to be a good candidate in chemopreventive or chemotherapeutic strategies and is believed to be a novel weapon for new therapeutic strategies.

Macrophage internalization of modified lipoproteins is thought to play a critical role in the initiation of atherogenesis. Two scavenger receptors, scavenger receptor A (SR-A) and CD36, have been centrally implicated in this lipid uptake process. Previous studies showed that these receptors mediated the majority of cholesterol ester accumulation in macrophages exposed to oxidized LDL and that mice with deletions of either receptor exhibited marked reductions in atherosclerosis. This work has contributed to an atherosclerosis paradigm: scavenger receptor-mediated oxidized lipoprotein uptake is required for foam cell formation and atherogenesis. In this study, Apoe-/- mice lacking SR-A or CD36, backcrossed into the C57BL/6 strain for 7 generations, were fed an atherogenic diet for 8 weeks. Hyperlipidemic Cd36-/-Apoe-/- and Msr1-/-Apoe-/- mice showed significant reductions in peritoneal macrophage lipid accumulation in vivo; however, in contrast with previous reports, this was associated with increased aortic sinus lesion areas. Characterization of aortic sinus lesions by electron microscopy and immunohistochemistry showed abundant macrophage foam cells, indicating that lipid uptake by intimal macrophages occurs in the absence of CD36 or SR-A. These data show that alternative lipid uptake mechanisms may contribute to macrophage cholesterol ester accumulation in vivo and suggest that the roles of SR-A and CD36 as proatherosclerotic mediators of modified LDL uptake in vivo need to be reassessed.

Abstract Lipid droplet (LD) accumulation is a now well-recognised hallmark of cancer. However, the significance of LD accumulation in colorectal cancer (CRC) biology is incompletely understood under chemotherapeutic conditions. Since drug resistance is a major obstacle to treatment success, we sought to determine the contribution of LD accumulation to chemotherapy resistance in CRC. Here we show that LD content of CRC cells positively correlates with the expression of lysophosphatidylcholine acyltransferase 2 (LPCAT2), an LD-localised enzyme supporting phosphatidylcholine synthesis. We also demonstrate that LD accumulation drives cell-death resistance to 5-fluorouracil and oxaliplatin treatments both in vitro and in vivo. Mechanistically, LD accumulation impairs caspase cascade activation and ER stress responses. Notably, droplet accumulation is associated with a reduction in immunogenic cell death and CD8 + T cell infiltration in mouse tumour grafts and metastatic tumours of CRC patients. Collectively our findings highlight LPCAT2-mediated LD accumulation as a druggable mechanism to restore CRC cell sensitivity.

β-Amyloid accumulation is associated with pathologic changes in the brain in Alzheimer's disease and has recently been identified in plaques of another chronic inflammatory disorder, atherosclerosis. The class B scavenger receptor, CD36, mediates binding of fibrillar β-amyloid to cells of the monocyte/macrophage lineage, including brain macrophages (microglia). In this study, we demonstrate that in microglia and other tissue macrophages, β-amyloid initiates a CD36-dependent signaling cascade involving the Src kinase family members, Lyn and Fyn, and the mitogen-activated protein kinase, p44/42. Interruption of this signaling cascade, through targeted disruption of Src kinases downstream of CD36, inhibits macrophage inflammatory responses to β-amyloid, including reactive oxygen and chemokine production, and results in decreased recruitment of microglia to sites of amyloid deposition in vivo. The finding that engagement of CD36 by β-amyloid initiates a Src kinase-dependent production of inflammatory mediators in cells of the macrophage lineage reveals a novel receptor-mediated pro-inflammatory signaling pathway of potential therapeutic importance. β-Amyloid accumulation is associated with pathologic changes in the brain in Alzheimer's disease and has recently been identified in plaques of another chronic inflammatory disorder, atherosclerosis. The class B scavenger receptor, CD36, mediates binding of fibrillar β-amyloid to cells of the monocyte/macrophage lineage, including brain macrophages (microglia). In this study, we demonstrate that in microglia and other tissue macrophages, β-amyloid initiates a CD36-dependent signaling cascade involving the Src kinase family members, Lyn and Fyn, and the mitogen-activated protein kinase, p44/42. Interruption of this signaling cascade, through targeted disruption of Src kinases downstream of CD36, inhibits macrophage inflammatory responses to β-amyloid, including reactive oxygen and chemokine production, and results in decreased recruitment of microglia to sites of amyloid deposition in vivo. The finding that engagement of CD36 by β-amyloid initiates a Src kinase-dependent production of inflammatory mediators in cells of the macrophage lineage reveals a novel receptor-mediated pro-inflammatory signaling pathway of potential therapeutic importance. The observation that activated microglia and astrocytes surround fibrillar β-amyloid (fAβ) 1The abbreviations used are: fAβ, fibrillar β-amyloid; MAP, mitogen-activated protein; MAPK, MAP kinase; revAβ, reverse β-amyloid peptide 42–1; ROS, reactive oxygen species; LPS, lipopolysaccharide; PTK, phosphotyrosine kinase; DMEM, Dulbecco's modified Eagle's medium; FCS, fetal calf serum; PBS, phosphate-buffered saline; Ab, antibody(s); FITC, fluorescein isothiocyanate; DAPI, 4′,6-diamidino-2-phenylindole; MCP-1, monocyte chemoattractant protein-1 1The abbreviations used are: fAβ, fibrillar β-amyloid; MAP, mitogen-activated protein; MAPK, MAP kinase; revAβ, reverse β-amyloid peptide 42–1; ROS, reactive oxygen species; LPS, lipopolysaccharide; PTK, phosphotyrosine kinase; DMEM, Dulbecco's modified Eagle's medium; FCS, fetal calf serum; PBS, phosphate-buffered saline; Ab, antibody(s); FITC, fluorescein isothiocyanate; DAPI, 4′,6-diamidino-2-phenylindole; MCP-1, monocyte chemoattractant protein-1 aggregates in senile plaques has led to the hypothesis that a chronic inflammatory reaction by glia may underlie the neurodegenerative events in the brains of Alzheimer's disease patients (1Akiyama H. Barger S. Barnum S. Bradt B. Bauer J. Cole G.M. Cooper N.R. Eikelenboom P. Emmerling M. Fiebich B.L. Finch C.E. Frautschy S. Griffin W.S. Hampel H. Hull M. Landreth G. Lue L. Mrak R. Mackenzie I.R. McGeer P.L. O'Banion M.K. Pachter J. Pasinetti G. Plata-Salaman C. Rogers J. Rydel R. Shen Y. Streit W. Strohmeyer R. Tooyoma I. Van Muiswinkel F.L. Veerhuis R. Walker D. Webster S. Wegrzyniak B. Wenk G. Wyss-Coray T. Neurobiol. Aging. 2000; 21: 383-421Google Scholar). Central to this “inflammatory response to Aβ” hypothesis is the recruitment and activation of microglia, which, like other tissue macrophages, represent a reservoir of pro-inflammatory cytokines and chemokines capable of inciting chronic inflammation and tissue damage (2Gonzalez-Scarano F. Baltuch G. Annu. Rev. Neurosci. 1999; 22: 219-240Google Scholar). The identification of a receptor-associated signal transduction pathway that mediates the inflammatory response to β-amyloid could contribute substantially to an understanding of the etiology of Alzheimer's disease and the development of novel approaches to its treatment. We have recently reported that the class B scavenger receptor, CD36, is expressed on microglia and vascular endothelial cells in the brains of normal and Alzheimer's disease patients and can mediate binding to fibrillar β-amyloid (3Coraci I.S. Husemann J. Berman J.W. Hulette C. Dufour J.H. Campanella G.K. Luster A.D. Silverstein S.C. El Khoury J. Am. J. Pathol. 2002; 160: 101-112Google Scholar). Indeed, in microglia and macrophages, β-amyloid stimulated H2O2 production could be blocked substantially by antibodies to CD36, suggesting a potential role for CD36 in mediating the inflammatory response of mononuclear phagocytes to fibrillar β-amyloid. CD36 has previously been shown to play a substantive role in the pathogenesis of atherosclerosis (4Febbraio M. Hajjar D.P. Silverstein R.L. J. Clin. Invest. 2001; 108: 785-791Google Scholar). Atherosclerosis, like Alzheimer's disease, has been postulated to result from a chronic inflammatory state (5Ross R. N. Engl. J. Med. 1999; 340: 115-126Google Scholar). CD36 is believed to play a critical role in the initiation of atherosclerotic lesions through its ability to bind and internalize modified low density lipoprotein trapped in the artery wall, facilitating the formation of lipid-engorged macrophage “foam cells” (4Febbraio M. Hajjar D.P. Silverstein R.L. J. Clin. Invest. 2001; 108: 785-791Google Scholar). Interestingly, β-amyloid was recently identified in advanced human atherosclerotic lesions, raising the possibility that non-lipid ligands of CD36 might contribute to atherogenesis through a pathway that diverges from that involved in lipid uptake (6De Meyer G.R. De Cleen D.M. Cooper S. Knaapen M.W. Jans D.M. Martinet W. Herman A.G. Bult H. Kockx M.M. Circ. Res. 2002; 90: 1197-1204Google Scholar, 7Tedgui A. Mallat Z. Circ. Res. 2002; 90: 1145-1146Google Scholar). Although a CD36 signaling pathway has been identified in endothelial cells, where its stimulation by thrombospondin results in kinase activation and programmed cell death (8Jimenez B. Volpert O.V. Crawford S.E. Febbraio M. Silverstein R.L. Bouck N. Nat. Med. 2000; 6: 41-48Google Scholar), a corresponding signaling cascade in mononuclear cells has not been identified. In this article, we report that β-amyloid initiates a pro-inflammatory CD36 signaling cascade in mononuclear cells. We show that β-amyloid induces association of CD36 with the Src phosphotyrosine kinase (PTK) Lyn and activates a signaling cascade involving another Src kinase family member, Fyn, and p44/42 mitogen-activated protein kinase (MAPK). Interruption of this signaling cascade, via chemical inhibitors or targeted disruption of the Src kinases downstream of CD36, results in inhibition of macrophage inflammatory responses to β-amyloid and decreased recruitment of microglia to sites of amyloid injection in vivo. These studies reveal a macrophage activation program initiated by a non-lipid ligand of CD36 that promotes inflammatory changes in response to amyloid proteins that accumulate in Alzheimer's disease and atherosclerosis. A P1 clone containing the murine CD36 locus was obtained from Genome Systems (St. Louis, MO) and used to generate a CD36 targeting vector KO3CD36tm1 (Fig.1 A). The linearized vector was electroporated into 129/SvEv embryonic stem cells. G418-resistant clones were selected and screened for homologous recombination by Southern blot analysis ofEcoRI-digested DNA. Using a probe corresponding to the exon 10 sequence, a clone containing the targeted allele was identified. This embryonic stem cell clone was microinjected into C57BL/6J blastocysts to generate chimeras, which were bred to C57BL/6J female mice to obtain offspring heterozygous for the CD36 targeted allele. F1 CD36 heterozygotes were intercrossed to obtain CD36−/− and wild type littermate control mice. CD14/CD36 double null mice (CD14−/−/CD36−/−) were generated by crossing the CD14−/− mice we had generated previously (9Moore K.J. Andersson L.P. Ingalls R.R. Monks B.G. Li R. Arnaout M.A. Golenbock D.T. Freeman M.W. J. Immunol. 2000; 165: 4272-4280Google Scholar) with CD36−/− mice. Lyn−/− and Fyn−/− mice were obtained from the Jackson Laboratories (Bar Harbor, ME). For inhibitor studies, cells were treated with the general Src kinase inhibitor PP1 (5 μm, 45 min; Biomol, Plymouth Meeting, PA). Aβ1–42 and reverse Aβ42–1 (revAβ) peptides were obtained from American Peptide Company (Sunnyvale, CA). To induce fibril formation, Aβ1–42 was resuspended in H2O at 1 mg/ml and incubated for 1 week at 37 °C (10El Khoury J. Hickman S.E. Thomas C.A. Loike J.D. Silverstein S.C. Neurobiol. Aging. 1998; 19: S81-S84Google Scholar, 11El Khoury J. Hickman S.E. Thomas C.A. Cao L. Silverstein S.C. Loike J.D. Nature. 1996; 382: 716-719Google Scholar). Fibril formation was confirmed by thioflavine S (Sigma) fluorescent staining as described previously (3Coraci I.S. Husemann J. Berman J.W. Hulette C. Dufour J.H. Campanella G.K. Luster A.D. Silverstein S.C. El Khoury J. Am. J. Pathol. 2002; 160: 101-112Google Scholar). fAβ and revAβ were used at 40 μm in all studies unless otherwise stated. Elicited peritoneal macrophages were collected from mice 4 days after intraperitoneal injection of 3% thioglycollate as we described previously (9Moore K.J. Andersson L.P. Ingalls R.R. Monks B.G. Li R. Arnaout M.A. Golenbock D.T. Freeman M.W. J. Immunol. 2000; 165: 4272-4280Google Scholar). Cells adherent after 2 h of culture (>97% F4/80+) were incubated in DMEM with 1% FCS overnight prior to use. Primary microglia were prepared from mixed brain cultures of post-natal day 2 mice as previously described (10El Khoury J. Hickman S.E. Thomas C.A. Loike J.D. Silverstein S.C. Neurobiol. Aging. 1998; 19: S81-S84Google Scholar, 11El Khoury J. Hickman S.E. Thomas C.A. Cao L. Silverstein S.C. Loike J.D. Nature. 1996; 382: 716-719Google Scholar). Briefly, whole brains were incubated in 0.25% trypsin and 1 mm EDTA (10 min, 25 °C) and dissociated to obtain a single-cell suspension. Cells were washed in Hanks' balanced salt solution (four times, 10 min) and cultured in DMEM containing 10% FCS for 10–12 days. Microglia accumulating above astrocyte monolayers were collected after gentle agitation and were routinely >95% CR3+ by flow cytometric analysis. Primary microglia were cultured for 48 h in DMEM containing 0.5% FBS prior to use. Following stimulation, microglia were fixed in 3% paraformaldehyde and stained for phospho-p44/42 according to the manufacturer's protocol (New England Biolabs). Immunoreactivity was detected using the Vectastain Avidin/Biotin ABC kit (Vector Laboratories, Burlingame, CA) and 3,3′-diaminobenzidine. Staining was recorded on a Nikon Eclipse E600 microscope at a fixed exposure setting. Cells were washed in ice-cold PBS and lysed in radioimmune precipitation buffer containing protease and phosphatase inhibitors, and 40 μg of protein was run on 10% denaturing SDS-polyacrylamide gels. Blotted proteins were blocked in 5% nonfat dry milk in Tris-buffered saline containing 0.1% Tween 20, incubated overnight at 4 °C with primary antibody (4G10, mouse anti-phosphotyrosine Ab (Upstate Biotechnology Inc., Lake Placid, and and Ab (New England washed in Tris-buffered saline containing 0.1% Tween 20, incubated with and with were to and were using a μg of protein prepared as described above was incubated with or Ab Biotechnology Inc., CA) overnight at 4 and were with proteins were washed in radioimmune precipitation buffer and resuspended in of of was run on an denaturing SDS-polyacrylamide for of CD36 using a Ab K.J. F. Andersson L.P. D. Freeman M.W. Nat. Med. 2001; Scholar), and 10 was run on a 10% denaturing SDS-polyacrylamide for of Lyn or using a or Ab as described oxygen production was by as we described previously (3Coraci I.S. Husemann J. Berman J.W. Hulette C. Dufour J.H. Campanella G.K. Luster A.D. Silverstein S.C. El Khoury J. Am. J. Pathol. 2002; 160: 101-112Google Scholar). Cells were incubated on in DMEM containing 1% FCS for 1 h and stimulated with 10 μg or 1 mg/ml in Hanks' balanced salt solution containing 1 mg/ml for 10 at 37 of 1 mg/ml was and cells were incubated at 37 °C for 1 production with the formation of a the of which was by microscope (10 and analysis Cells were incubated in DMEM containing 1% FCS for 1 h prior to and stimulated with 10 μg of fAβ, 10 μg of or for were collected and to cell and in was by injection or revAβ was on wild type and Lyn−/− mice as described previously C. D. A. M. Nat. Med. 1998; Scholar). Briefly, mice were with and and in a A was in the 1 mm to and 2 mm to the 2 of fAβ was into the mm from the on the and 2 of revAβ was at the on the of the The mice and The of fAβ and revAβ injection were 48 h mice were by of ice-cold PBS containing The brains were in paraformaldehyde 1 and to 1 The brains were and stained for microglia using a antibody (10 and with to The were washed in PBS, and were using (Vector and at 4 The of microglia at sites of was on by and and of the and staining were at exposure and staining at the of was using analysis To stimulated signal transduction we generated CD36 null mice by targeted in embryonic stem cells as described previously (9Moore K.J. Andersson L.P. Ingalls R.R. Monks B.G. Li R. Arnaout M.A. Golenbock D.T. Freeman M.W. J. Immunol. 2000; 165: 4272-4280Google Scholar). of the mice CD36 null offspring at the of 1 with or on or We confirmed the of CD36 protein in peritoneal macrophages and primary cultures used in signaling from CD36−/− mice by blot analysis 1 kinases activated in macrophages in response to inflammatory and a critical of the signaling In cultured microglia and macrophages, β-amyloid induces protein of activated signal transduction Landreth J. Neurosci. Scholar). microglia senile plaques for suggesting that signaling events in P. Neurosci. Scholar, F. M. B. Cole G.M. Am. J. Pathol. 1998; Scholar). We β-amyloid stimulation of peritoneal macrophages in the of proteins via engagement of fAβ the accumulation of proteins in wild type macrophages, this was in the peritoneal macrophages from CD36−/− mice 1 These detected by with an anti-phosphotyrosine with of and and were detected at proteins represent potential mediators of a CD36-dependent signaling the of the of proteins was with that of MAP kinase p44/42 as the possibility that β-amyloid of macrophages of in a CD36-dependent was of wild type macrophages with fAβ the activation of p44/42 MAPK, as detected by an antibody for the of the protein A). In phospho-p44/42 protein was detected in treated CD36−/− macrophages, the of of p44/42 2 A). In wild type macrophages, p44/42 by fAβ was and at which that activation of p44/42 MAP kinase is a primary signaling activation of p44/42 was detected in wild type or CD36−/− macrophages stimulated with revAβ the of the response 2 of of p44/42 in wild type and CD36−/− macrophages treated with that p44/42 could be activated by signaling that of CD36 2 To possibility that signaling in wild type macrophages from with LPS, mice the were used as a of cells (9Moore K.J. Andersson L.P. Ingalls R.R. Monks B.G. Li R. Arnaout M.A. Golenbock D.T. Freeman M.W. J. Immunol. 2000; 165: 4272-4280Google Scholar). was in wild type macrophages, phospho-p44/42 in treated with fAβ of stimulation 2 of macrophages null for and CD36 or accumulation of that this signaling response is via We have recently that microglia pro-inflammatory cells to play a role in the pathogenesis of Alzheimer's CD36, and that this can mediate to fAβ (3Coraci I.S. Husemann J. Berman J.W. Hulette C. Dufour J.H. Campanella G.K. Luster A.D. Silverstein S.C. El Khoury J. Am. J. Pathol. 2002; 160: 101-112Google Scholar). To activation of p44/42 by fAβ was CD36-dependent in microglia, was for phospho-p44/42 accumulation in primary microglia from wild type and CD36−/− mice. type microglia staining for phospho-p44/42 at and 10 with fAβ 2 In accumulation of phospho-p44/42 was not in the of treated CD36−/− microglia 2 that β-amyloid initiates p44/42 signaling via CD36 in macrophages and of the Src family of have previously been reported to with CD36 (8Jimenez B. Volpert O.V. Crawford S.E. Febbraio M. Silverstein R.L. Bouck N. Nat. Med. 2000; 6: 41-48Google Scholar), and to be of involved in the activation of MAP we of this family of might previously reported S.C. Landreth J. Neurosci. 2001; 21: Scholar), we that of wild type macrophages with a general inhibitor of Src p44/42 activation by fAβ A). To of the Src family involved in we obtained mice null for or Lyn We on the expressed had previously been reported to with CD36 in endothelial cells (8Jimenez B. Volpert O.V. Crawford S.E. Febbraio M. Silverstein R.L. Bouck N. Nat. Med. 2000; 6: 41-48Google Scholar), Lyn is expressed in cells Annu. Rev. Scholar). The accumulation of phospho-p44/42 was in Fyn−/− and Lyn−/− macrophages as with wild type cells macrophage were shown to of p44/42 protein and to of phospho-p44/42 in response to LPS, that p44/42 is activated by signaling of Lyn and in cells not These that of the Src kinase family may signaling and that the of Lyn or the downstream activation of this signaling To β-amyloid induces the association of Lyn or with CD36, we were generated from macrophages treated with fAβ and used for with antibodies to Lyn or The were and for of of wild type macrophages initiated the recruitment of CD36 to containing Lyn not CD36 was to with Lyn of fAβ suggesting a association of proteins exposure to β-amyloid To that the that was detected in was in CD36 we in treated CD36−/− was detected in from CD36−/− macrophages studies, to the association of CD36 with kinase, to show of CD36 and not These that fAβ initiates the association of CD36 to containing Lyn in a with the downstream activation of p44/42 signaling in β-Amyloid has been reported to the of in and microglia Landreth J. Neurosci. Scholar, J.W. T. J. J. 2001; Scholar), and we have that this is blocked by antibodies to CD36 (3Coraci I.S. Husemann J. Berman J.W. Hulette C. Dufour J.H. Campanella G.K. Luster A.D. Silverstein S.C. El Khoury J. Am. J. Pathol. 2002; 160: 101-112Google Scholar). the role of Lyn and kinase in activation of p44/42 MAPK, we kinases for macrophage production was by and in Lyn−/− and Fyn−/− macrophages, as with wild type macrophages A). A was in CD36−/− macrophages stimulated El J. T. J. M. W. and A. D. for that of proteins is an of signaling pathway to macrophage the of by Lyn−/− and Fyn−/− macrophages in response to another inflammatory was to that in wild type macrophages 4 A). These results that Lyn−/− and Fyn−/− macrophages have a in production in response to fAβ the ability to generate reactive oxygen in response to other β-amyloid induces production of MCP-1, a chemokine that to sites of To production is by a signaling cascade, production in wild and Fyn−/− macrophages was In the of Lyn kinase, production was by 4 This in Lyn−/− macrophages was to that in macrophages CD36 Interestingly, in production was in treated Fyn−/− macrophages, that this kinase is not an in the signaling pathway to production 4 type and Lyn−/− macrophages of in response to and revAβ suggesting that the in production in stimulated with fAβ is to that These the of CD36 and Lyn as a novel signal transduction pathway mediating the production of of Lyn kinase signaling chemokine production in response to fAβ, we used an in to of this signaling pathway recruitment to sites injection has previously been shown to induce the of Alzheimer's disease in and including the recruitment and activation of microglia and of C. D. A. M. Nat. Med. 1998; Scholar, N. Y. 1999; D.T. Rogers J. Neurosci. 1998; Scholar). Using wild type and Lyn−/− we the response to fAβ injection to that of revAβ injection in the as an In wild type injection of fAβ the accumulation of cells with a of microglia 48 h A). the response to fAβ was to revAβ injection in wild type mice as by of at the injection analysis A and in treated Lyn−/− the recruitment of microglia to sites of fAβ was not to sites of revAβ injection and of the of cells at the sites of injection a accumulation of microglia to fAβ in wild type mice in Lyn−/− mice to In in of Lyn signaling not macrophage to wild type microglia not This that the decreased accumulation at sites injection in Lyn−/− brains is to of chemokine production a in the ability of cells to to These that Lyn kinase signaling a role in the response to fAβ in vivo. The activation of microglia at sites of β-amyloid deposition is believed to result in a chronic inflammation that the of Alzheimer's The of pro-inflammatory mediators by macrophages and microglia has been studies have identified signaling events activated by β-amyloid in this cell type Landreth J. Neurosci. Scholar, S.C. Landreth J. Neurosci. 2001; 21: Scholar, J.W. T. J. J. 2001; Scholar, Landreth J. Neurosci. 1999; 19: Scholar, Landreth J. Neurosci. 2000; Scholar, Landreth J. Neurosci. 1998; Scholar), the of a receptor-mediated signaling pathway that responses has been We have identified a pro-inflammatory signaling cascade, by β-amyloid, that mediates the recruitment and activation of mononuclear The CD36 signaling cascade initiated by β-amyloid is in The signaling identified was the association of CD36 with Lyn Although CD36 has been shown to with Lyn in this had not previously been to response M.M. J.W. S. A. Scholar). A role for Lyn in β-amyloid signaling has previously been Landreth J. Neurosci. S.C. Landreth J. Neurosci. 2001; 21: Scholar), the via which Lyn activation at the was not We have that the of CD36 and Lyn in macrophages is for the of downstream p44/42 activation and pro-inflammatory responses to β-amyloid. In we that another of the Src kinase Fyn, to p44/42 activation by β-amyloid. has previously been shown to with CD36 in endothelial cells and is an of the CD36 signaling cascade that thrombospondin inhibition of (8Jimenez B. Volpert O.V. Crawford S.E. Febbraio M. Silverstein R.L. Bouck N. Nat. Med. 2000; 6: 41-48Google Scholar). In endothelial cells, the activation of another family member, and this signaling initiates programmed cell we were to a association of CD36 with in is that in macrophages, a cell type in which Lyn is CD36 with Although an of this signaling its with CD36 may be We show that of Lyn or kinase signaling inhibits macrophage inflammatory responses in the of Lyn kinase signaling results in accumulation of microglia at sites of β-amyloid accumulation in the Using the of injection of fAβ, we have in accumulation in the brains of mice In that signal transduction an role in the inflammatory response to this Atherosclerosis, like Alzheimer's disease, is associated with pathologic changes in chronic inflammatory CD36 has been postulated to play a critical role in the initiation of atherosclerotic lesions through its ability to bind and internalize modified low density lipoprotein trapped in the artery wall, facilitating the formation of lipid-engorged macrophage cells G. J. Scholar, Febbraio M. N. D. Silverstein R.L. Hajjar D.P. J. Clin. Invest. 2000; Scholar) (5Ross R. N. Engl. J. Med. 1999; 340: 115-126Google Scholar). studies in mice CD36 a role for this in In its atherosclerotic formation was by as as M. J.D. Hajjar D.P. Silverstein R.L. J. Clin. Invest. 2000; Scholar). is the in atherosclerosis in the CD36 null mouse was a of macrophage lipid accumulation or of signaling events might have to the the finding that β-amyloid is in advanced human atherosclerotic lesions, an or pathway for CD36 activation in atherosclerotic plaques is (6De Meyer G.R. De Cleen D.M. Cooper S. Knaapen M.W. Jans D.M. Martinet W. Herman A.G. Bult H. Kockx M.M. Circ. Res. 2002; 90: 1197-1204Google Scholar, 7Tedgui A. Mallat Z. Circ. Res. 2002; 90: 1145-1146Google Scholar). Although other scavenger including and have been to be involved in atherosclerosis and Alzheimer's disease Khoury J. Hickman S.E. Thomas C.A. Cao L. Silverstein S.C. Loike J.D. Nature. 1996; 382: 716-719Google H. M. H. H. T. S. S. G. S. N. Invest. 1998; Scholar, H. Y. M. N. M. H. T. T. Y. Y. Y. M. H. H. T. A. S. T. Y. H. Y. T. Scholar), ligand engagement of CD36 may be of its ability to a pro-inflammatory signaling pathway (8Jimenez B. Volpert O.V. Crawford S.E. Febbraio M. Silverstein R.L. Bouck N. Nat. Med. 2000; 6: 41-48Google Scholar). CD36 is a of the scavenger family of These proteins that the of binding of with This that other proteins that fibrillar might this pathway and responses that contribute to chronic the we report with β-amyloid the possibility that CD36 engagement by non-lipid ligands could play a role in Alzheimer's disease and via the chronic activation of mononuclear We from the for the of and from the for with of

Most of diurnal time is spent in a postprandial state due to successive meal intakes during the day. As long as the meals contain enough fat, a transient increase in triacylglycerolaemia and a change in lipoprotein pattern occurs. The extent and kinetics of such postprandial changes are highly variable and are modulated by numerous factors. This review focuses on factors affecting postprandial lipoprotein metabolism and genes, their variability and their relationship with intermediate phenotypes and risk of CHD. Postprandial lipoprotein metabolism is modulated by background dietary pattern as well as meal composition (fat amount and type, carbohydrate, protein, fibre, alcohol) and several lifestyle conditions (physical activity, tobacco use), physiological factors (age, gender, menopausal status) and pathological conditions (obesity, insulin resistance, diabetes mellitus). The roles of many genes have been explored in order to establish the possible implications of their variability in lipid metabolism and CHD risk. The postprandial lipid response has been shown to be modified by polymorphisms within the genes for apo A-I, A-IV, A-V, E, B, C-I and C-III, lipoprotein lipase, hepatic lipase, fatty acid binding and transport proteins, microsomal triglyceride transfer protein and scavenger receptor class B type I. Overall, the variability in postprandial response is important and complex, and the interactions between nutrients or dietary or meal compositions and gene variants need further investigation. The extent of present knowledge and needs for future studies are discussed in light of ongoing developments in nutrigenetics.

Trimerization of the Fas receptor (CD95, APO-1), a membrane bound protein, triggers cell death by apoptosis. The main death pathway activated by Fas receptor involves the adaptor protein FADD (for Fas-associated deathdomain) that connects Fas receptor to the caspase cascade. Anticancer drugs have been shown to enhance both Fas receptor and Fas ligand expression on tumor cells. The contribution of Fas ligand-Fas receptor interactions to the cytotoxic activity of these drugs remains controversial. Here, we show that neither the antagonistic anti-Fas antibody ZB4 nor the Fas-IgG molecule inhibit drug-induced apoptosis in three different cell lines. The expression of Fas ligand on the plasma membrane, which is identified in untreated U937 human leukemic cells but remains undetectable in untreated HT29 and HCT116 human colon cancer cell lines, is not modified by exposure to various cytotoxic agents. These drugs induce the clustering of Fas receptor, as observed by confocal laser scanning microscopy, and its interaction with FADD, as demonstrated by co-immunoprecipitation. Overexpression of FADD by stable transfection sensitizes tumor cells to drug-induced cell death and cytotoxicity, whereas down-regulation of FADD by transient transfection of an antisense construct decreases tumor cell sensitivity to drug-induced apoptosis. These results were confirmed by transient transfection of constructs encoding either a FADD dominant negative mutant or MC159 or E8 viral proteins that inhibit the FADD/caspase-8 pathway. These results suggest that drug-induced cell death involves the Fas/FADD pathway in a Fas ligand-independent fashion. Trimerization of the Fas receptor (CD95, APO-1), a membrane bound protein, triggers cell death by apoptosis. The main death pathway activated by Fas receptor involves the adaptor protein FADD (for Fas-associated deathdomain) that connects Fas receptor to the caspase cascade. Anticancer drugs have been shown to enhance both Fas receptor and Fas ligand expression on tumor cells. The contribution of Fas ligand-Fas receptor interactions to the cytotoxic activity of these drugs remains controversial. Here, we show that neither the antagonistic anti-Fas antibody ZB4 nor the Fas-IgG molecule inhibit drug-induced apoptosis in three different cell lines. The expression of Fas ligand on the plasma membrane, which is identified in untreated U937 human leukemic cells but remains undetectable in untreated HT29 and HCT116 human colon cancer cell lines, is not modified by exposure to various cytotoxic agents. These drugs induce the clustering of Fas receptor, as observed by confocal laser scanning microscopy, and its interaction with FADD, as demonstrated by co-immunoprecipitation. Overexpression of FADD by stable transfection sensitizes tumor cells to drug-induced cell death and cytotoxicity, whereas down-regulation of FADD by transient transfection of an antisense construct decreases tumor cell sensitivity to drug-induced apoptosis. These results were confirmed by transient transfection of constructs encoding either a FADD dominant negative mutant or MC159 or E8 viral proteins that inhibit the FADD/caspase-8 pathway. These results suggest that drug-induced cell death involves the Fas/FADD pathway in a Fas ligand-independent fashion. tumor necrosis factor Fas ligand soluble Fas-L cisplatin vinblastine arbitrary unit phosphate-buffered saline etoposide Fas is a 45-kDa membrane protein that belongs to the tumor necrosis factor (TNF)1/nerve growth factor receptor family (1Itoh N. Yonehara S. Ishii A. Yonehara M. Mizushima S. Sameshima M. Hase A. Seto Y. Nagata S. Cell. 1991; 66: 233-243Abstract Full Text PDF PubMed Scopus (2663) Google Scholar). Engagement of Fas by agonistic anti-Fas antibodies triggers programmed cell death in a variety of cell types (2Trauth B.C. Klas C. Peters A.M.J. Matzuku S. Möller P. Falk W. Debatin K.M. Krammer P.H. Science. 1989; 245: 301-305Crossref PubMed Scopus (1655) Google Scholar, 3Yonehara S. Ishii A. Yonehara M.A. J. Exp. Med. 1989; 169: 1747-1756Crossref PubMed Scopus (1422) Google Scholar). Its natural ligand, Fas ligand (Fas-L), belongs to the TNF family (4Suda T. Takahashi T. Golstein P. Nagata S. Cell. 1993; 75: 1169-1178Abstract Full Text PDF PubMed Scopus (2431) Google Scholar) and can be found as a 40-kDa membrane-bound or a 26-kDa soluble cytokine (5Tanaka M. Suda T. Takahashi T. Nagata S. EMBO J. 1995; 14: 1129-1135Crossref PubMed Scopus (604) Google Scholar). Similarly to agonistic anti-Fas antibodies, binding of membrane-bound or soluble Fas-L to Fas receptor can induce apoptosis in Fas-bearing cells (1Itoh N. Yonehara S. Ishii A. Yonehara M. Mizushima S. Sameshima M. Hase A. Seto Y. Nagata S. Cell. 1991; 66: 233-243Abstract Full Text PDF PubMed Scopus (2663) Google Scholar, 4Suda T. Takahashi T. Golstein P. Nagata S. Cell. 1993; 75: 1169-1178Abstract Full Text PDF PubMed Scopus (2431) Google Scholar). The main death pathway initiated from Fas activation involves a series of death-associated molecules (6Cock J.G. DeVries E. Williams G.T. Borst J. Apoptosis. 1998; 3: 17-25Crossref PubMed Scopus (26) Google Scholar), including FADD (Fas-associateddeath domain-containing protein), which is an adaptor protein that is recruited to Fas receptor upon its engagement (7Chinnaiyan A.M. Tepper C.G. Seldin M.F. O'Rourke K. Kischkel F.C. Hellbardt S. Krammer P.H. Peter M.E. Dixit V.M. J. Biol. Chem. 1996; 271: 4961-4965Abstract Full Text Full Text PDF PubMed Scopus (705) Google Scholar, 8Boldin M.P. Goncharov T.M. Goltsev Y.V. Wallach D. Cell. 1996; 85: 803-815Abstract Full Text Full Text PDF PubMed Scopus (2100) Google Scholar, 9Chinnaiyan A.M. O'Rourke K. Tewari M. Dixit V.M. Cell. 1995; 81: 505-512Abstract Full Text PDF PubMed Scopus (2150) Google Scholar). FADD then binds to and activates procaspase-8 (also called FLICE or MACH) (8Boldin M.P. Goncharov T.M. Goltsev Y.V. Wallach D. Cell. 1996; 85: 803-815Abstract Full Text Full Text PDF PubMed Scopus (2100) Google Scholar, 9Chinnaiyan A.M. O'Rourke K. Tewari M. Dixit V.M. Cell. 1995; 81: 505-512Abstract Full Text PDF PubMed Scopus (2150) Google Scholar, 10Muzio M. Chinnaiyan A.M. Kischkel F.C. O'Rourke K. Shevchenko A. Ni J.N. Scaffidi C. Bretz J.D. Zhang M. Gentz R. Mann M. Krammer P.H. Peter M.E. Dixit V.M. Cell. 1996; 85: 817-827Abstract Full Text Full Text PDF PubMed Scopus (2723) Google Scholar), which is believed to be the first step of a proteolytic cascade that triggers activation of other caspases such as caspases-7, -3, and -6 (11Hirata H. Takahashi A. Kobayashi S. Yonehara S. Sawai H. Okazaki T. Yamamoto K. Sasada M. J. Exp. Med. 1998; 187: 587-600Crossref PubMed Scopus (398) Google Scholar). Although other cell death pathways could be initiated from Fas activation (12Yang X. Khosravi-Far R. Chang H.Y. Baltimore D. Cell. 1997; 89: 1067-1076Abstract Full Text Full Text PDF PubMed Scopus (823) Google Scholar, 13Sillence D.J. Allan D. Biochem. J. 1997; 324: 29-32Crossref PubMed Scopus (54) Google Scholar), analysis of lymphocytes from FADD −/− mice has recently demonstrated the prominent role of the FADD/procaspase-8 pathway in Fas-mediated cell death (14Zhang J.K. Cado D. Chen A. Kabra N.H. Winoto A. Nature. 1998; 392: 296-300Crossref PubMed Scopus (635) Google Scholar).Cytotoxic drugs commonly used in cancer therapy can induce tumor cell death by apoptosis (15Bose R. Verheij M. Haimovitz-Friedman A. Scotto K. Fuks Z. Kolesnick R. Cell. 1995; 82: 405-414Abstract Full Text PDF PubMed Scopus (782) Google Scholar, 16Barry M.A. Behnke C.A. Eastman A. Biochem. Pharmacol. 1990; 40: 2353-2362Crossref PubMed Scopus (909) Google Scholar, 17Hannun Y.A. Blood. 1997; 89: 1845-1853Crossref PubMed Google Scholar). These drugs were shown to enhance the expression of Fas (18Micheau O. Solary E. Hammann A. Martin F. Dimanche-Boitrel M.T. J. Natl. Cancer Inst. 1997; 89: 783-789Crossref PubMed Scopus (271) Google Scholar) and Fas-L (19Friesen C. Herr I. Krammer P.H. Debatin K.M. Nat. Med. 1996; 2: 574-577Crossref PubMed Scopus (951) Google Scholar, 20Herr I. Wilhelm D. Böhler T. Angel P. Debatin K.M. EMBO J. 1997; 16: 6200-6208Crossref PubMed Scopus (277) Google Scholar) on the surface of certain malignant cells. It has been proposed that the molecular process leading from specific cellular damage induced by the drugs to apoptosis might involve an interaction between Fas ligand and Fas (19Friesen C. Herr I. Krammer P.H. Debatin K.M. Nat. Med. 1996; 2: 574-577Crossref PubMed Scopus (951) Google Scholar). However, this issue remains controversial because antagonistic anti-Fas antibodies that block Fas-L-mediated apoptosis do not always inhibit drug-induced cell death (21Eischen C.M. Kottke T.J. Martins L.M. Basi G.S. Tung J.S. Earnshaw W.C. Leibson P.J. Kaufmann S.H. Blood. 1997; 90: 935-943Crossref PubMed Google Scholar, 22McGahon A.J. Costa Pereira A.P. Daly L. Cotter T.G. Br. J. Haematol. 1998; 101: 539-547Crossref PubMed Scopus (81) Google Scholar). In the present study, we further addressed the role played by the Fas/FADD pathway in drug-induced cell death. We show that anticancer drugs can induce Fas receptor clustering and FADD recruitment to Fas receptor in a Fas ligand-independent fashion. By modulating FADD expression, we also demonstrate the role of this adaptor molecule in drug-induced apoptosis.DISCUSSIONThe molecular mechanisms involved during the course of apoptosis upon exposure to anticancer drugs are still poorly understood but are of major importance for the understanding of tumor cell killing. Induction of apoptosis pathways and on the We have shown that anticancer could Fas receptor the tumor cell surface by Fas The in Fas receptor and tumor cells were to Fas-mediated apoptosis (18Micheau O. Solary E. Hammann A. Martin F. Dimanche-Boitrel M.T. J. Natl. Cancer Inst. 1997; 89: 783-789Crossref PubMed Scopus (271) Google Scholar). interaction of Fas receptor with its ligand a role in anticancer remains a controversial issue (21Eischen C.M. Kottke T.J. Martins L.M. Basi G.S. Tung J.S. Earnshaw W.C. Leibson P.J. Kaufmann S.H. Blood. 1997; 90: 935-943Crossref PubMed Google Scholar). Here, we show that the antagonistic anti-Fas antibody ZB4 and the Fas-IgG used a that Fas-mediated and apoptosis C. P. W. K. F. E. M. 1998; PubMed Scopus Google Scholar), have on anticancer drug-induced apoptosis in three different cell lines. we to of Fas-L expression on the plasma membrane of tumor cells to cytotoxic C. P. W. K. F. E. M. 1998; PubMed Scopus Google Scholar, D. S. D. J. 1998; Google Scholar). In with in other cell (21Eischen C.M. Kottke T.J. Martins L.M. Basi G.S. Tung J.S. Earnshaw W.C. Leibson P.J. Kaufmann S.H. Blood. 1997; 90: 935-943Crossref PubMed Google Scholar, 22McGahon A.J. Costa Pereira A.P. Daly L. Cotter T.G. Br. J. Haematol. 1998; 101: 539-547Crossref PubMed Scopus (81) Google Scholar, A. A. M. S. R. R. Cancer 1997; Google Scholar), these results a role for a Fas interaction in drug-induced cell pathway has been shown to be by Fas in the of Fas-L in cells to Y. D. D. T. J. Biol. 1998; PubMed Scopus Google Scholar, A. C.A. Chinnaiyan A.M. Dixit V.M. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). In this the adaptor protein FADD is recruited to Fas receptor its death (7Chinnaiyan A.M. Tepper C.G. Seldin M.F. O'Rourke K. Kischkel F.C. Hellbardt S. Krammer P.H. Peter M.E. Dixit V.M. J. Biol. Chem. 1996; 271: 4961-4965Abstract Full Text Full Text PDF PubMed Scopus (705) Google Scholar, 8Boldin M.P. Goncharov T.M. Goltsev Y.V. Wallach D. Cell. 1996; 85: 803-815Abstract Full Text Full Text PDF PubMed Scopus (2100) Google Scholar, 9Chinnaiyan A.M. O'Rourke K. Tewari M. Dixit V.M. Cell. 1995; 81: 505-512Abstract Full Text PDF PubMed Scopus (2150) Google Scholar, 10Muzio M. Chinnaiyan A.M. Kischkel F.C. O'Rourke K. Shevchenko A. Ni J.N. Scaffidi C. Bretz J.D. Zhang M. Gentz R. Mann M. Krammer P.H. Peter M.E. Dixit V.M. Cell. 1996; 85: 817-827Abstract Full Text Full Text PDF PubMed Scopus (2723) Google Scholar), by an interaction of the death receptor of FADD with the of procaspase-8 leading to the activation of the proteolytic cascade of caspases (11Hirata H. Takahashi A. Kobayashi S. Yonehara S. Sawai H. Okazaki T. Yamamoto K. Sasada M. J. Exp. Med. 1998; 187: 587-600Crossref PubMed Scopus (398) Google Scholar). laser scanning and that anticancer drugs could induce Fas receptor and FADD to of lymphocytes from FADD −/− mice have recently demonstrated the prominent role of the FADD/procaspase-8 pathway in cell death by either Fas-L or agonistic anti-Fas antibodies (14Zhang J.K. Cado D. Chen A. Kabra N.H. Winoto A. Nature. 1998; 392: 296-300Crossref PubMed Scopus (635) Google Scholar). The of FADD on the cell on the cell and the FADD a activity in cells A.M. O'Rourke K. Tewari M. Dixit V.M. Cell. 1995; 81: 505-512Abstract Full Text PDF PubMed Scopus (2150) Google Scholar), whereas its the growth of cells K. A. EMBO J. 1998; PubMed Scopus Google Scholar). We show that FADD a role in drug-induced apoptosis. We HT29 cell that FADD, that a in FADD protein expression not to apoptosis in these cells. These FADD were to drug-induced apoptosis and cells. role for FADD in drug-induced cell death further demonstrated by the of cytotoxic in HT29 cells in which FADD expression by transient expression of an antisense results were by the FADD/procaspase-8 pathway different transient expression of viral proteins J. S. Martin Y. S. T.G. Natl. S. A. 1997; PubMed Scopus Google Scholar) and dominant negative construct J. C.M. J. 1998; Google Scholar). that anticancer drugs can induce Fas receptor clustering in a and FADD to Fas receptor in the cytotoxic process leading to apoptosis. Fas is a 45-kDa membrane protein that belongs to the tumor necrosis factor (TNF)1/nerve growth factor receptor family (1Itoh N. Yonehara S. Ishii A. Yonehara M. Mizushima S. Sameshima M. Hase A. Seto Y. Nagata S. Cell. 1991; 66: 233-243Abstract Full Text PDF PubMed Scopus (2663) Google Scholar). Engagement of Fas by agonistic anti-Fas antibodies triggers programmed cell death in a variety of cell types (2Trauth B.C. Klas C. Peters A.M.J. Matzuku S. Möller P. Falk W. Debatin K.M. Krammer P.H. Science. 1989; 245: 301-305Crossref PubMed Scopus (1655) Google Scholar, 3Yonehara S. Ishii A. Yonehara M.A. J. Exp. Med. 1989; 169: 1747-1756Crossref PubMed Scopus (1422) Google Scholar). Its natural ligand, Fas ligand (Fas-L), belongs to the TNF family (4Suda T. Takahashi T. Golstein P. Nagata S. Cell. 1993; 75: 1169-1178Abstract Full Text PDF PubMed Scopus (2431) Google Scholar) and can be found as a 40-kDa membrane-bound or a 26-kDa soluble cytokine (5Tanaka M. Suda T. Takahashi T. Nagata S. EMBO J. 1995; 14: 1129-1135Crossref PubMed Scopus (604) Google Scholar). Similarly to agonistic anti-Fas antibodies, binding of membrane-bound or soluble Fas-L to Fas receptor can induce apoptosis in Fas-bearing cells (1Itoh N. Yonehara S. Ishii A. Yonehara M. Mizushima S. Sameshima M. Hase A. Seto Y. Nagata S. Cell. 1991; 66: 233-243Abstract Full Text PDF PubMed Scopus (2663) Google Scholar, 4Suda T. Takahashi T. Golstein P. Nagata S. Cell. 1993; 75: 1169-1178Abstract Full Text PDF PubMed Scopus (2431) Google Scholar). The main death pathway initiated from Fas activation involves a series of death-associated molecules (6Cock J.G. DeVries E. Williams G.T. Borst J. Apoptosis. 1998; 3: 17-25Crossref PubMed Scopus (26) Google Scholar), including FADD (Fas-associateddeath domain-containing protein), which is an adaptor protein that is recruited to Fas receptor upon its engagement (7Chinnaiyan A.M. Tepper C.G. Seldin M.F. O'Rourke K. Kischkel F.C. Hellbardt S. Krammer P.H. Peter M.E. Dixit V.M. J. Biol. Chem. 1996; 271: 4961-4965Abstract Full Text Full Text PDF PubMed Scopus (705) Google Scholar, 8Boldin M.P. Goncharov T.M. Goltsev Y.V. Wallach D. Cell. 1996; 85: 803-815Abstract Full Text Full Text PDF PubMed Scopus (2100) Google Scholar, 9Chinnaiyan A.M. O'Rourke K. Tewari M. Dixit V.M. Cell. 1995; 81: 505-512Abstract Full Text PDF PubMed Scopus (2150) Google Scholar). FADD then binds to and activates procaspase-8 (also called FLICE or MACH) (8Boldin M.P. Goncharov T.M. Goltsev Y.V. Wallach D. Cell. 1996; 85: 803-815Abstract Full Text Full Text PDF PubMed Scopus (2100) Google Scholar, 9Chinnaiyan A.M. O'Rourke K. Tewari M. Dixit V.M. Cell. 1995; 81: 505-512Abstract Full Text PDF PubMed Scopus (2150) Google Scholar, 10Muzio M. Chinnaiyan A.M. Kischkel F.C. O'Rourke K. Shevchenko A. Ni J.N. Scaffidi C. Bretz J.D. Zhang M. Gentz R. Mann M. Krammer P.H. Peter M.E. Dixit V.M. Cell. 1996; 85: 817-827Abstract Full Text Full Text PDF PubMed Scopus (2723) Google Scholar), which is believed to be the first step of a proteolytic cascade that triggers activation of other caspases such as caspases-7, -3, and -6 (11Hirata H. Takahashi A. Kobayashi S. Yonehara S. Sawai H. Okazaki T. Yamamoto K. Sasada M. J. Exp. Med. 1998; 187: 587-600Crossref PubMed Scopus (398) Google Scholar). Although other cell death pathways could be initiated from Fas activation (12Yang X. Khosravi-Far R. Chang H.Y. Baltimore D. Cell. 1997; 89: 1067-1076Abstract Full Text Full Text PDF PubMed Scopus (823) Google Scholar, 13Sillence D.J. Allan D. Biochem. J. 1997; 324: 29-32Crossref PubMed Scopus (54) Google Scholar), analysis of lymphocytes from FADD −/− mice has recently demonstrated the prominent role of the FADD/procaspase-8 pathway in Fas-mediated cell death (14Zhang J.K. Cado D. Chen A. Kabra N.H. Winoto A. Nature. 1998; 392: 296-300Crossref PubMed Scopus (635) Google Scholar). drugs commonly used in cancer therapy can induce tumor cell death by apoptosis (15Bose R. Verheij M. Haimovitz-Friedman A. Scotto K. Fuks Z. Kolesnick R. Cell. 1995; 82: 405-414Abstract Full Text PDF PubMed Scopus (782) Google Scholar, 16Barry M.A. Behnke C.A. Eastman A. Biochem. Pharmacol. 1990; 40: 2353-2362Crossref PubMed Scopus (909) Google Scholar, 17Hannun Y.A. Blood. 1997; 89: 1845-1853Crossref PubMed Google Scholar). These drugs were shown to enhance the expression of Fas (18Micheau O. Solary E. Hammann A. Martin F. Dimanche-Boitrel M.T. J. Natl. Cancer Inst. 1997; 89: 783-789Crossref PubMed Scopus (271) Google Scholar) and Fas-L (19Friesen C. Herr I. Krammer P.H. Debatin K.M. Nat. Med. 1996; 2: 574-577Crossref PubMed Scopus (951) Google Scholar, 20Herr I. Wilhelm D. Böhler T. Angel P. Debatin K.M. EMBO J. 1997; 16: 6200-6208Crossref PubMed Scopus (277) Google Scholar) on the surface of certain malignant cells. It has been proposed that the molecular process leading from specific cellular damage induced by the drugs to apoptosis might involve an interaction between Fas ligand and Fas (19Friesen C. Herr I. Krammer P.H. Debatin K.M. Nat. Med. 1996; 2: 574-577Crossref PubMed Scopus (951) Google Scholar). However, this issue remains controversial because antagonistic anti-Fas antibodies that block Fas-L-mediated apoptosis do not always inhibit drug-induced cell death (21Eischen C.M. Kottke T.J. Martins L.M. Basi G.S. Tung J.S. Earnshaw W.C. Leibson P.J. Kaufmann S.H. Blood. 1997; 90: 935-943Crossref PubMed Google Scholar, 22McGahon A.J. Costa Pereira A.P. Daly L. Cotter T.G. Br. J. Haematol. 1998; 101: 539-547Crossref PubMed Scopus (81) Google Scholar). In the present study, we further addressed the role played by the Fas/FADD pathway in drug-induced cell death. We show that anticancer drugs can induce Fas receptor clustering and FADD recruitment to Fas receptor in a Fas ligand-independent fashion. By modulating FADD expression, we also demonstrate the role of this adaptor molecule in drug-induced apoptosis. molecular mechanisms involved during the course of apoptosis upon exposure to anticancer drugs are still poorly understood but are of major importance for the understanding of tumor cell killing. Induction of apoptosis pathways and on the We have shown that anticancer could Fas receptor the tumor cell surface by Fas The in Fas receptor and tumor cells were to Fas-mediated apoptosis (18Micheau O. Solary E. Hammann A. Martin F. Dimanche-Boitrel M.T. J. Natl. Cancer Inst. 1997; 89: 783-789Crossref PubMed Scopus (271) Google Scholar). interaction of Fas receptor with its ligand a role in anticancer remains a controversial issue (21Eischen C.M. Kottke T.J. Martins L.M. Basi G.S. Tung J.S. Earnshaw W.C. Leibson P.J. Kaufmann S.H. Blood. 1997; 90: 935-943Crossref PubMed Google Scholar). Here, we show that the antagonistic anti-Fas antibody ZB4 and the Fas-IgG used a that Fas-mediated and apoptosis C. P. W. K. F. E. M. 1998; PubMed Scopus Google Scholar), have on anticancer drug-induced apoptosis in three different cell lines. we to of Fas-L expression on the plasma membrane of tumor cells to cytotoxic C. P. W. K. F. E. M. 1998; PubMed Scopus Google Scholar, D. S. D. J. 1998; Google Scholar). In with in other cell (21Eischen C.M. Kottke T.J. Martins L.M. Basi G.S. Tung J.S. Earnshaw W.C. Leibson P.J. Kaufmann S.H. Blood. 1997; 90: 935-943Crossref PubMed Google Scholar, 22McGahon A.J. Costa Pereira A.P. Daly L. Cotter T.G. Br. J. Haematol. 1998; 101: 539-547Crossref PubMed Scopus (81) Google Scholar, A. A. M. S. R. R. Cancer 1997; Google Scholar), these results a role for a Fas interaction in drug-induced cell pathway has been shown to be by Fas in the of Fas-L in cells to Y. D. D. T. J. Biol. 1998; PubMed Scopus Google Scholar, A. C.A. Chinnaiyan A.M. Dixit V.M. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). In this the adaptor protein FADD is recruited to Fas receptor its death (7Chinnaiyan A.M. Tepper C.G. Seldin M.F. O'Rourke K. Kischkel F.C. Hellbardt S. Krammer P.H. Peter M.E. Dixit V.M. J. Biol. Chem. 1996; 271: 4961-4965Abstract Full Text Full Text PDF PubMed Scopus (705) Google Scholar, 8Boldin M.P. Goncharov T.M. Goltsev Y.V. Wallach D. Cell. 1996; 85: 803-815Abstract Full Text Full Text PDF PubMed Scopus (2100) Google Scholar, 9Chinnaiyan A.M. O'Rourke K. Tewari M. Dixit V.M. Cell. 1995; 81: 505-512Abstract Full Text PDF PubMed Scopus (2150) Google Scholar, 10Muzio M. Chinnaiyan A.M. Kischkel F.C. O'Rourke K. Shevchenko A. Ni J.N. Scaffidi C. Bretz J.D. Zhang M. Gentz R. Mann M. Krammer P.H. Peter M.E. Dixit V.M. Cell. 1996; 85: 817-827Abstract Full Text Full Text PDF PubMed Scopus (2723) Google Scholar), by an interaction of the death receptor of FADD with the of procaspase-8 leading to the activation of the proteolytic cascade of caspases (11Hirata H. Takahashi A. Kobayashi S. Yonehara S. Sawai H. Okazaki T. Yamamoto K. Sasada M. J. Exp. Med. 1998; 187: 587-600Crossref PubMed Scopus (398) Google Scholar). laser scanning and that anticancer drugs could induce Fas receptor and FADD to of lymphocytes from FADD −/− mice have recently demonstrated the prominent role of the FADD/procaspase-8 pathway in cell death by either Fas-L or agonistic anti-Fas antibodies (14Zhang J.K. Cado D. Chen A. Kabra N.H. Winoto A. Nature. 1998; 392: 296-300Crossref PubMed Scopus (635) Google Scholar). The of FADD on the cell on the cell and the FADD a activity in cells A.M. O'Rourke K. Tewari M. Dixit V.M. Cell. 1995; 81: 505-512Abstract Full Text PDF PubMed Scopus (2150) Google Scholar), whereas its the growth of cells K. A. EMBO J. 1998; PubMed Scopus Google Scholar). We show that FADD a role in drug-induced apoptosis. We HT29 cell that FADD, that a in FADD protein expression not to apoptosis in these cells. These FADD were to drug-induced apoptosis and cells. role for FADD in drug-induced cell death further demonstrated by the of cytotoxic in HT29 cells in which FADD expression by transient expression of an antisense results were by the FADD/procaspase-8 pathway different transient expression of viral proteins J. S. Martin Y. S. T.G. Natl. S. A. 1997; PubMed Scopus Google Scholar) and dominant negative construct J. C.M. J. 1998; Google Scholar). that anticancer drugs can induce Fas receptor clustering in a and FADD to Fas receptor in the cytotoxic process leading to apoptosis. The molecular mechanisms involved during the course of apoptosis upon exposure to anticancer drugs are still poorly understood but are of major importance for the understanding of tumor cell killing. Induction of apoptosis pathways and on the We have shown that anticancer could Fas receptor the tumor cell surface by Fas The in Fas receptor and tumor cells were to Fas-mediated apoptosis (18Micheau O. Solary E. Hammann A. Martin F. Dimanche-Boitrel M.T. J. Natl. Cancer Inst. 1997; 89: 783-789Crossref PubMed Scopus (271) Google Scholar). interaction of Fas receptor with its ligand a role in anticancer remains a controversial issue (21Eischen C.M. Kottke T.J. Martins L.M. Basi G.S. Tung J.S. Earnshaw W.C. Leibson P.J. Kaufmann S.H. Blood. 1997; 90: 935-943Crossref PubMed Google Scholar). Here, we show that the antagonistic anti-Fas antibody ZB4 and the Fas-IgG used a that Fas-mediated and apoptosis C. P. W. K. F. E. M. 1998; PubMed Scopus Google Scholar), have on anticancer drug-induced apoptosis in three different cell lines. we to of Fas-L expression on the plasma membrane of tumor cells to cytotoxic C. P. W. K. F. E. M. 1998; PubMed Scopus Google Scholar, D. S. D. J. 1998; Google Scholar). In with in other cell (21Eischen C.M. Kottke T.J. Martins L.M. Basi G.S. Tung J.S. Earnshaw W.C. Leibson P.J. Kaufmann S.H. Blood. 1997; 90: 935-943Crossref PubMed Google Scholar, 22McGahon A.J. Costa Pereira A.P. Daly L. Cotter T.G. Br. J. Haematol. 1998; 101: 539-547Crossref PubMed Scopus (81) Google Scholar, A. A. M. S. R. R. Cancer 1997; Google Scholar), these results a role for a Fas interaction in drug-induced cell death. Fas pathway has been shown to be by Fas in the of Fas-L in cells to Y. D. D. T. J. Biol. 1998; PubMed Scopus Google Scholar, A. C.A. Chinnaiyan A.M. Dixit V.M. J. Biol. Chem. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). In this the adaptor protein FADD is recruited to Fas receptor its death (7Chinnaiyan A.M. Tepper C.G. Seldin M.F. O'Rourke K. Kischkel F.C. Hellbardt S. Krammer P.H. Peter M.E. Dixit V.M. J. Biol. Chem. 1996; 271: 4961-4965Abstract Full Text Full Text PDF PubMed Scopus (705) Google Scholar, 8Boldin M.P. Goncharov T.M. Goltsev Y.V. Wallach D. Cell. 1996; 85: 803-815Abstract Full Text Full Text PDF PubMed Scopus (2100) Google Scholar, 9Chinnaiyan A.M. O'Rourke K. Tewari M. Dixit V.M. Cell. 1995; 81: 505-512Abstract Full Text PDF PubMed Scopus (2150) Google Scholar, 10Muzio M. Chinnaiyan A.M. Kischkel F.C. O'Rourke K. Shevchenko A. Ni J.N. Scaffidi C. Bretz J.D. Zhang M. Gentz R. Mann M. Krammer P.H. Peter M.E. Dixit V.M. Cell. 1996; 85: 817-827Abstract Full Text Full Text PDF PubMed Scopus (2723) Google Scholar), by an interaction of the death receptor of FADD with the of procaspase-8 leading to the activation of the proteolytic cascade of caspases (11Hirata H. Takahashi A. Kobayashi S. Yonehara S. Sawai H. Okazaki T. Yamamoto K. Sasada M. J. Exp. Med. 1998; 187: 587-600Crossref PubMed Scopus (398) Google Scholar). laser scanning and that anticancer drugs could induce Fas receptor and FADD to of lymphocytes from FADD −/− mice have recently demonstrated the prominent role of the FADD/procaspase-8 pathway in cell death by either Fas-L or agonistic anti-Fas antibodies (14Zhang J.K. Cado D. Chen A. Kabra N.H. Winoto A. Nature. 1998; 392: 296-300Crossref PubMed Scopus (635) Google Scholar). The of FADD on the cell on the cell and the FADD a activity in cells A.M. O'Rourke K. Tewari M. Dixit V.M. Cell. 1995; 81: 505-512Abstract Full Text PDF PubMed Scopus (2150) Google Scholar), whereas its the growth of cells K. A. EMBO J. 1998; PubMed Scopus Google Scholar). We show that FADD a role in drug-induced apoptosis. We HT29 cell that FADD, that a in FADD protein expression not to apoptosis in these cells. These FADD were to drug-induced apoptosis and cells. role for FADD in drug-induced cell death further demonstrated by the of cytotoxic in HT29 cells in which FADD expression by transient expression of an antisense results were by the FADD/procaspase-8 pathway different transient expression of viral proteins J. S. Martin Y. S. T.G. Natl. S. A. 1997; PubMed Scopus Google Scholar) and dominant negative construct J. C.M. J. 1998; Google Scholar). that anticancer drugs can induce Fas receptor clustering in a and FADD to Fas receptor in the cytotoxic process leading to apoptosis. We are to C. for on confocal laser We are to A. for Fas J. I. for and M. Dixit of for C. M. for and S. Nagata for Fas-IgG

. We showed that following their uptake by NK cells, hypoxic TD-MVs transfer TGF-β1 to NK cells, decreasing the cell surface expression of the activating receptor NKG2D, thereby inhibiting NK cell function. MicroRNA profiling revealed the presence of high levels of miR-210 and miR-23a in hypoxic TD-MVs. We demonstrated that miR-23a in hypoxic TD-MVs operates as an additional immunomosuppressive factor, since it directly targets the expression of CD107a in NK cells. To our knowledge, this is the first study to show that hypoxic tumor cells by secreting MVs can educate NK cells and decrease their antitumor immune response. This study highlights the existence of a novel mechanism of immune suppression mediated by hypoxic TD-MVs and further improves our understanding of the immunosuppressive mechanisms prevailing in the hypoxic tumor microenvironment.

Abstract Immunogenic cell death (ICD) converts dying cancer cells into a therapeutic vaccine and stimulates antitumor immune responses. Here we unravel the results of an unbiased screen identifying high-dose (10 µM) crizotinib as an ICD-inducing tyrosine kinase inhibitor that has exceptional antineoplastic activity when combined with non-ICD inducing chemotherapeutics like cisplatin. The combination of cisplatin and high-dose crizotinib induces ICD in non-small cell lung carcinoma (NSCLC) cells and effectively controls the growth of distinct (transplantable, carcinogen- or oncogene induced) orthotopic NSCLC models. These anticancer effects are linked to increased T lymphocyte infiltration and are abolished by T cell depletion or interferon-γ neutralization. Crizotinib plus cisplatin leads to an increase in the expression of PD-1 and PD-L1 in tumors, coupled to a strong sensitization of NSCLC to immunotherapy with PD-1 antibodies. Hence, a sequential combination treatment consisting in conventional chemotherapy together with crizotinib, followed by immune checkpoint blockade may be active against NSCLC.

Cardiovascular diseases are the leading cause of death in developed countries where the common pathological substrate underlying this process is atherosclerosis. Several new concepts have emerged in relation to mechanisms that contribute to the regulation of the vascular diseases and associated inflammatory effects. Recently, potential antioxidants (vitamin E, polyphenols) have received much attention as potential anti-atherosclerotic agents. Among the polyphenols with health benefic properties, resveratrol, a phytoalexin of grape, seem to be a good candidate protecting the vascular walls from oxidation, inflammation, platelet aggregation, and thrombus formation. In this review, we focus on the mechanism of resveratrol cardiovascular benefic effects. We analyze, in relation with the different steps of atherosclerotic process, the resveratrol properties at multiple levels, such as cellular signaling, enzymatic pathways, apoptosis, and gene expression. We show and discuss the relationship with reactive oxygen species, regulation of pro-inflammatory genes including cycloxygenases and cytokines in molecular inflammatory and aging processes, and how the regulation of these activites by resveratrol can lead to a prevention of vascular diseases.

Host immunity controls the development of colorectal cancer, and chemotherapy used to treat colorectal cancer is likely to recruit the host immune system at some level. Athough preclinical studies have argued that colorectal cancer drugs, such as 5-fluorouracil (5-FU) and oxaliplatin, exert such effects, their combination as employed in the oncology clinic has not been evaluated. Here, we report the results of prospective immunomonitoring of 25 metastatic colorectal cancer (mCRC) patients treated with a first-line combination regimen of 5-FU, oxaliplatin, and bevacizumab (FOLFOX-bevacizumab), as compared with 20 healthy volunteers. Before this therapy was initiated, T regulatory cells (Treg), Th17, and granulocytic myeloid-derived suppressor cells (gMDSC) were increased significantly in mCRC, but only a high level of gMDSC was associated with a poor prognosis. Chemotherapy modulated the Treg/Th17 balance by decreasing Treg and increasing Th17 cell frequency by 15 days after the start of treatment. Increased Th17 frequency was associated with a poor prognosis. FOLFOX-bevacizumab treatment elicited a decrease in gMDSC in 15 of 25 patients and was associated with a better survival outcome. Notably, the gMDSCs that expressed high levels of PD-L1, CD39, and CD73 exerted a robust immunosuppressive activity, relative to other myeloid cells present in blood, which could be reversed by blocking the CD39/CD73 and PD-1/PD-L1 axes. Our work underscores the critical prognostic impact of early modifications in Th17 and gMDSC frequency in mCRC. Furthermore, it provides a clinical rationale to combine FOLFOX-bevacizumab chemotherapy with inhibitors of ATP ectonucleotidases and/or anti-PD-1/PD-L1 antibodies to more effectively treat this disease. Cancer Res; 76(18); 5241-52. ©2016 AACR.

BACKGROUND: Since 2009, IPF patients across Europe are recruited into the eurIPFreg, providing epidemiological data and biomaterials for translational research. METHODS: The registry data are based on patient and physician baseline and follow-up questionnaires, comprising 1700 parameters. The mid- to long-term objectives of the registry are to provide clues for a better understanding of IPF phenotype sub-clusters, triggering factors and aggravating conditions, regional and environmental characteristics, and of disease behavior and management. RESULTS: This paper describes baseline data of 525 IPF subjects recruited from 11/2009 until 10/2016. IPF patients had a mean age of 68.1 years, and seeked medical advice due to insidious dyspnea (90.1%), fatigue (69.2%), and dry coughing (53.2%). A surgical lung biopsy was performed in 32% in 2009, but in only 8% of the cases in 2016, possibly due to increased numbers of cryobiopsy. At the time of inclusion in the eurIPFreg, FVC was 68.4% ± 22.6% of predicted value, DLco ranged at 42.1% ± 17.8% of predicted value (mean value ± SD). Signs of pulmonary hypertension were found in 16.8%. Steroids, immunosuppressants and N-Acetylcysteine declined since 2009, and were replaced by antifibrotics, under which patients showed improved survival (p = 0.001). CONCLUSIONS: Our data provide important insights into baseline characteristics, diagnostic and management changes as well as outcome data in European IPF patients over time. TRIAL REGISTRATION: The eurIPFreg and eurIPFbank are listed in ClinicalTrials.gov( NCT02951416 ).

Stress or heat shock proteins (HSPs) such as HSP27 and HSP70 are expressed in response to a wide variety of physiological and environmental insults including heat, reactive oxygen species or anticancer drugs. Their overexpression allows cells to survive to otherwise lethal conditions. Several different mechanisms may account for the cytoprotective activity of HSP27 and HSP70. First, both proteins are powerful chaperones. Second, both inhibit key effectors of the apoptotic machinery including the apoptosome, the caspase activation complex (both HSP27 and HSP70), and apoptosis inducing factor (only HSP70). Third, they both play a role in the proteasome-mediated degradation of apoptosis-regulatory proteins. HSP27 and HSP70 may participate in oncogenesis, as suggested by the fact that overexpression of heat shock proteins can increase the tumorigenic potential of tumor cells. The down-regulation or selective inhibition of HSP70 might constitute a valuable strategy for the treatment of cancer.

The French Society of Intensive Care Medicine (SRLF), jointly with the French-Speaking Group of Paediatric Emergency Rooms and Intensive Care Units (GFRUP) and the French-Speaking Association of Paediatric Surgical Intensivists (ADARPEF), worked out guidelines for the management of central venous catheters (CVC), arterial catheters and dialysis catheters in intensive care unit. For adult patients: Using GRADE methodology, 36 recommendations for an improved catheter management were produced by the 22 experts. Recommendations regarding catheter-related infections' prevention included the preferential use of subclavian central vein (GRADE 1), a one-step skin disinfection(GRADE 1) using 2% chlorhexidine (CHG)-alcohol (GRADE 1), and the implementation of a quality of care improvement program. Antiseptic- or antibiotic-impregnated CVC should likely not be used (GRADE 2, for children and adults). Catheter dressings should likely not be changed before the 7th day, except when the dressing gets detached, soiled or impregnated with blood (GRADE 2- adults). CHG dressings should likely be used (GRADE 2+). For adults and children, ultrasound guidance should be used to reduce mechanical complications in case of internal jugular access (GRADE 1), subclavian access (Grade 2) and femoral venous, arterial radial and femoral access (Expert opinion). For children, an ultrasound-guided supraclavicular approach of the brachiocephalic vein was recommended to reduce the number of attempts for cannulation and mechanical complications. Based on scarce publications on diagnostic and therapeutic strategies and on their experience (expert opinion), the panel proposed definitions, and therapeutic strategies.

― Essential fatty acids (EFA), which are not synthesized in animal and human tissues, belong to the n-6 and n-3 families of polyunsaturated fatty acids (PUFA), derived from linoleic acid (LA, 18:2n-6) and a-linolenic acid (LNA, 18:3n-3). Optimal requirements are 3-6% of ingested energy for LA and 0.5-1% for LNA in adults. Requirements in LNA are higher in development. Dietary sources of LA and LNA are principally plants, while arachidonic acid (AA, 20:4n-6) is found in products from terrestrian animals, and eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are found in products from marine animals. EFA are principally present in dietary triacylglycerols, which should be hydrolyzed by lipases in gastric and intestinal lumen. DHA seems to be released more slowly than the others. Its intestinal absorption is delayed but not decreased. Long-chain PUFAs are incorporated in noticeable amounts in chylomicron phospholipids. However, their uptake by tissues is no more rapid than uptake of shorter chain PUFA. In tissues, LA and LNA, which constitute the major part of dietary EFA, should be converted into fatty acids of longer and more unsaturated chain by alternate desaturation (A6, A5, A4)-elongation reactions. Animal tissues are more active in this biosynthesis than human tissues. Liver is one of the most active organs and its role is critical in providing less active tissues, particularly the brain, with long-chain PUFA secreted in VLDL (very low density lipoprotein). In liver, many nutritional, hormonal and physiological factors act on the PUFA biosynthesis. Dietary fatty acids exert a great influence and are often inhibitory. Dietary LNA inhibits A6 desaturation of LA. The desaturation products AA, EPA, and DHA inhibit A6 desaturation of LA and A5 desaturation of DGLA (dihomo-y-linolenic acid). With regard to hormones, insulin and thyroxin are necessary to A6 and A5 desaturation activities, whereas other hormones (glucagon, epinephrine, ACTH, glucocorticoids) inhibit desaturation. Concerning the physiological factors, the age of individuals is critical. In the fetus, the liver and the brain are capable of converting LA and LNA into longer-chain EFA, but these are also delivered by the mother, after synthesis in the maternal liver and placenta. Just after birth, in animals, the A6 desaturation activity increases in the liver and decreases in the brain. In aging, the capacity of the whole liver to desaturate LA and DGLA is equal at 1.5 and 25 months of age in rats fed a balanced diet throughout their life and the AA and DHA content of tissue phospholipids is unchanged in aging. Fatty acid oxidation in the liver is also likely to decrease the availability of EFA in tissues, in particular oxidation of long-chain PUFAs which is high in peroxisomes. However, in healthy individuals, despite the numerous factors likely to influence the availability of EFA, in most cases a regular and balanced diet meets the tissue requirements in n-6 and n-3 EFA essential fatty acids / dietary sources / desaturation / oxidation / nutritional factors / hormonal factors / physiological factors Rsum ― Mtabolisme et disponibilit des acides gras indispensables dans les tissus animaux et humains. Les acides gras indispensables (EFA), qui ne sont pas synthtiss dans les tissus animaux et humains, appartiennent aux 2 familles d'acides gras polyinsaturs (PUFA) n-6 et n-3, drivant de l'acide linolique (LA, 18:2n-6) et de l'acide a-linolnique (LNA, 18:3n-3). Les besoins optima sont de 3-6 % de l'nergie ingre pour LA et de 0,5-1 % pour LNA chez les adultes. Les besoins en LNA sont suprieurs au cours du dveloppement. Les sources alimentaires de LA et de LNA sont principalement vgtales, tandis que l'acide arachidonique (AA, 20:4n-6) est prsent dans les produits des animaux terrestres et les acides eicosapentanoique (EPA) et docosahexanoi'que (DHA) sont prsents dans les produits des animaux marins. Ces acides gras sont prsents principalement dans les tri- acylglycrols, qui doivent tre hydrolyss par des lipases dans la lumire gastrique et intestinale. Le DHA parat libr plus lentement que les autres. Son absorption intestinale est retarde mais non diminue. Les PUFA longue chane sont incorpors dans les phospholipides des chylomicrons en pro- portion notable. Toutefois, ils ne sont pas capts par les tissus plus rapidement que les PUFA plus courts. Dans les tissus, LA et LNA, qui constituent la majeure partie des EFA fournis par l'alimentation, doivent tre convertis en acides gras plus longue chane et plus insaturs par une srie alterne de dsa- turations (A6, A5 et A4 dsaturations) et d'longations. Dans cette biosynthse, les tissus animaux sont plus actifs que les tissus humains. Le foie est un des organes les plus actifs et son rle est primordial pour l'approvisionnement des autres organes moins actifs, comme le cerveau, en PUFA longue chane scrts avec les VLDL (very low density lipoprotein). Dans le foie, de nombreux facteurs nutritionnels, hormonaux et physiologiques interviennent sur la biosynthse des PUFA. Les acides gras du rgime ont une grande influence et sont souvent inhibiteurs. Ainsi LNA alimentaire inhibe la A6 dsa- turation de LA. De mme, AA, EPA et DHA, produits des dsaturations, inhibent la A6 dsaturation de LA et la A5 dsaturation de DGLA (dihomo-y linolnique). Parmi les hormones, l'insuline et la thy- roxine sont ncessaires l'activit des A6 et A5 dsaturation tandis que d'autres hormones (glucagon, adrnaline, ACTH, glucocorticoides) les inhibent. Concernant les facteurs physiologiques, l'ge est un facteur important. Chez le foetus, le foie et le cerveau sont capables de convertir LA et LNA en EFA plus longs mais ceux-ci sont aussi apports par la mre, synthtiss dans le foie et le placenta maternels. Juste aprs la naissance, chez l'animal, l'activit de A6 dsaturation augmente dans le foie et diminue dans le cerveau. Au cours du vieillissement, les capacits du foie entier dsaturer LA et DGLA sont les mmes 1,5 et 24 mois chez le rat recevant un rgime quilibr toute sa vie, et les contenus en AA et DHA des phospholipides tissulaires ne sont pas modifis avec l'ge. L'oxydation des acides gras dans le foie peut aussi diminuer la disponibilit en EFA dans les tissus en particulier l'oxydation des PUFA longue chane qui est leve dans les peroxisomes. Toutefois, chez les individus sains, en dpit des nombreux facteurs susceptibles d'influencer la biodisponibilit en EFA, un rgime rgulier et quilibr permet, dans la plupart des cas, de satisfaire les besoins des tissus en EFA n-6 et n-3. acides gras indispensables / sources alimentaires / dsaturations / oxydation / facteurs nutri- tionnels, hormonaux et physiologiques

The sense of taste informs the body about the quality of ingested foods. Tastant‐mediated signals are generated by a rise in free intracellular calcium levels ([Ca 2+ ]i) in the taste bud cells and then are transferred to the gustatory area of brain via connections between the gustatory nerves (chorda tym‐ pani and glossopharyngeal nerves) and the nucleus of solitary tract in the brain stem. We have recently shown that lingual CD36 contributes to fat preference and early digestive secretions in the mouse. We show here that 1 ) the induction of an increase in [Ca 2+ ]i by linoleic acid is CD36‐dependent in taste receptor cells, 2) the spontaneous preference for or conversely con ditioned aversion to linoleic acid requires intact gusta tory nerves, and 3) the activation of gustatory neurons in the nucleus of the solitary tract elicited by a linoleic acid deposition on the tongue in wild‐type mice cannot be reproduced in CD36‐null animals. We conclude that the CD36‐mediated perception of long‐chain fatty acids involves the gustatory pathway, suggesting that the mouse may have a “taste“ for fatty foods. This system would constitute a potential physiological advantage under conditions of food scarcity by leading the mouse to select and absorb fatty foods. However, it might also lead to a risk of obesity and associated diseases in a context of constantly abundant food.—Gaillard, D., Laugerette, F., Darcel, N., El‐Yassimi, A., Passilly‐De grace, P., Hichami, A., Khan, N. A., Montmayeur, J.‐P., Besnard, P. The gustatory pathway is involved in CD36‐ mediated orosensory perception of long‐chain fatty acids in the mouse. FASEB J . 22, 1458–1468 (2008)