Délégation Ile-de-France Villejuif

DC-derived exosomes (Dex) are nanometer-sized membrane vesicles that are secreted by the sentinel antigen-presenting cells of the immune system: DCs. Like DCs, the molecular composition of Dex includes surface expression of functional MHC-peptide complexes, costimulatory molecules, and other components that interact with immune cells. Dex have the potential to facilitate immune cell-dependent tumor rejection and have distinct advantages over cell-based immunotherapies involving DCs. Accordingly, Dex-based phase I and II clinical trials have been conducted in advanced malignancies, showing the feasibility and safety of the approach, as well as the propensity of these nanovesicles to mediate T and NK cell-based immune responses in patients. This Review will evaluate the interactions of Dex with immune cells, their clinical progress, and the future of Dex immunotherapy for cancer.

Despite current developments in therapeutics focusing on biotechnologically-oriented species, the unflagging utility of small molecules or peptides in medicine is still producing strong results. In 2014 for example, of the 41 new medicines authorized for sale, 33 belonged to the category of small molecules, while in 2013 they represented 24 of 27, according to the FDA. This can be explained as the result of recent forays into new or long-neglected areas of chemistry. Medicinal organometallic chemistry can provide us with an antimalarial against resistant parasitic strains, as attested by the phase II clinical development of ferroquine, with a new framework for conceptual advances based on three-dimensional space-filling, and with redox or indeed catalytic intracellular properties. In this context, bioferrocene species with antiproliferative potential have for several years been the subject of sustained effort, based on some initial successes and on the nature of ferrocene as a stable aromatic, with low toxicity, low cost, and possessing reversible redox properties. We show here the different antitumoral approaches offered by ferrocifen derivatives, originally simple derivatives of tamoxifen, which over the course of their development have proved to possess remarkable structural and mechanistic diversity. These entities act via various targets, some of which have been identified, that are triggered according to the concentration of the products. They also act according to the nature of the cancer cells and their functionality, by mechanistic pathways that can operate either synergistically or not, in successive, concomitant or sequential ways, depending for example on newly identified signaling pathways inducing senescence or apoptosis. Here we present a first attempt to rationalize the behavior of these entities with various anticancer targets.

The European Liver Transplant Registry (ELTR) currently allows for the analysis of 44,286 liver transplantations (LTs) performed on 39,196 patients in a 13-year period. After an exponential increase, the number of LTs is plateauing due to a lack of organs. To cope with this, alternatives to cadaveric LT, such as split LT, domino LT, or living-related LT (LRLT) are being used increasingly. They now account for 11% of all procedures. One of the most important findings in the evolution of LT is the considerable improvement of results along time with, for the mean time, a one-year survival of 83%, all indications confounded. The improvement is particularly significant for cancers. This improvement is mainly represented by hepatocellular carcinoma, with a gain of 17% for 5-year survival rate from 1990 to 2000. Increasingly, older donors are used to augment the donor pool and older recipients are transplanted due to improved results and a better selection of patients. More than two thirds of deaths and three quarters of retransplantations occurred within the first year of transplantation. Retransplantation is associated with much less optimal results than first LT. One of the prominent features of recent years is the development of LRLT. LRLT is now performed by almost half of the European centers. As with split LT or domino LT, LRLT aims to provide more patients to be transplanted. Special attention is paid to reducing the risk for the donor, which is now estimated to be 0.5% mortality and 21% postoperative morbidity.

Since the discovery that mitochondrial membrane permeabilization represents a critical step in the regulation of intrinsic apoptosis, mitochondria have been viewed as pluripotent organelles, controlling cell death as well as several aspects of cell survival. Mitochondria constitute the most prominent source of ATP and are implicated in multiple anabolic and catabolic circuitries. In addition, mitochondria coordinate cell-wide stress responses, such as autophagy, and control nonapoptotic cell death routines, such as regulated necrosis. Thus, mitochondria seem to regulate a continuum of cellular functions, spanning from physiological metabolism to stress responses and death. The involvement of mitochondria in both vital and lethal processes is crucial for both embryonic and postembryonic development, as well as for the maintenance of adult tissue homeostasis. In line with this notion, primary mitochondrial defects or alterations in the signaling pathways that converge on or emanate from mitochondria underpin a large number of human diseases, including premature aging, neurodegenerative disorders, cardiovascular disorders, and cancer. Here, we provide an overview of the molecular mechanisms that enable mitochondria to sustain cell survival, coordinate stress responses, and mediate cell death, linking these pathways—whenever relevant—to cardiovascular health and disease.

Programmed cell death, or apoptosis, has in the past few years undoubtedly become one of the most intensively investigated biological processes. However, fundamental questions concerning the molecular and biochemical mechanisms remain to be elucidated. The central question concerns the biochemical steps shared by the numerous death induction pathways elicited by different stimuli. Heterogeneous death signals precede a common effector phase during which cells pass a threshold of 'no return' and are engaged in a degradation phase where they acquire the typical onset of late apoptosis. Alterations in mitochondrial permeability transition linked to membrane potential disruption precede nuclear and plasma membrane changes. In vitro induction of permeability transition in isolated mitochondria provokes the release of a protein factor capable of inducing nuclear chromatin condensation and fragmentation. This permeability transition is regulated by multiple endogenous effectors, including members of the bcl-2 gene family. Inhibition of these effects prevents apoptosis.

Chronic kidney disease (CKD) guidelines recommend evaluating patients with GFR <60 ml/min per 1.73 m(2) for complications, but little evidence supports the use of a single GFR threshold for all metabolic disorders. We used data from the NephroTest cohort, including 1038 adult patients who had stages 2 through 5 CKD and were not on dialysis, to study the occurrence of metabolic complications. GFR was measured using renal clearance of (51)Cr-EDTA (mGFR) and estimated using two equations derived from the Modification of Diet in Renal Disease study. As mGFR decreased from 60 to 90 to <20 ml/min per 1.73 m(2), the prevalence of hyperparathyroidism increased from 17 to 85%, anemia from 8 to 41%, hyperphosphatemia from 1 to 30%, metabolic acidosis from 2 to 39%, and hyperkalemia from 2 to 42%. Factors most strongly associated with metabolic complications, independent of mGFR, were younger age for acidosis and hyperphosphatemia, presence of diabetes for acidosis, diabetic kidney disease for anemia, and both male gender and the use of inhibitors of the renin-angiotensin system for hyperkalemia. mGFR thresholds for detecting complications with 90% sensitivity were 50, 44, 40, 39, and 37 ml/min per 1.73 m(2) for hyperparathyroidism, anemia, acidosis, hyperkalemia, and hyperphosphatemia, respectively. Analysis using estimated GFR produced similar results. In summary, this study describes the onset of CKD-related complications at different levels of GFR; anemia and hyperparathyroidism occur earlier than acidosis, hyperkalemia, and hyperphosphatemia.

In this perspective, we present an overview of the determination of excited-state properties of "real-life" dyes, and notably of their optical absorption and emission spectra, performed during the last decade with time-dependent density functional theory (TD-DFT). We discuss the results obtained with both vertical and adiabatic (vibronic) approximations, choosing relevant examples for several series of dyes. These examples include reproducing absorption wavelengths of numerous families of coloured molecules, understanding the specific band shape of amino-anthraquinones, optimising the properties of dyes used in solar cells, mimicking the fluorescence wavelengths of fluorescent brighteners and BODIPY dyes, studying optically active biomolecules and photo-induced proton transfer, as well as improving the properties of photochromes.

Earth-abundant Fe, Ni, and Co aza macrocyclic and polypyridine complexes have been thoroughly investigated for CO2 electrochemical and visible-light-driven reduction. Since the first reports in the 1970s, an enormous body of work has been accumulated regarding the two-electron two-proton reduction of the gas, along with mechanistic and spectroscopic efforts to rationalize the reactivity and establish guidelines for structure-reactivity relationships. The ability to fine tune the ligand structure and the almost unlimited possibilities of designing new complexes have led to highly selective and efficient catalysts. Recent efforts toward developing hybrid systems upon combining molecular catalysts with conductive or semi-conductive materials have converged to high catalytic performances in water solutions, to the inclusion of these catalysts into CO2 electrolyzers and photo-electrochemical devices, and to the discovery of catalytic pathways beyond two electrons. Combined with the continuous mechanistic efforts and new developments for in situ and in operando spectroscopic studies, molecular catalysis of CO2 reduction remains a highly creative approach.

Different classes of anticancer drugs may trigger apoptosis by acting on different subcellular targets and by activating distinct signaling pathways. Here, we report that betulinic acid (BetA) is a prototype cytotoxic agent that triggers apoptosis by a direct effect on mitochondria. In isolated mitochondria, BetA directly induces loss of transmembrane potential independent of a benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone-inhibitable caspase. This is inhibited by bongkrekic acid, an agent that stabilizes the permeability transition pore complex. Mitochondria undergoing BetA-induced permeability transition mediate cleavage of caspase-8 (FLICE/MACH/Mch5) and caspase-3 (CPP32/Yama) in a cell-free system. Soluble factors such as cytochrome c or apoptosis-inducing factor released from BetA-treated mitochondria are sufficient for cleavage of caspases and nuclear fragmentation. Addition of cytochromec to cytosolic extracts results in cleavage of caspase-3, but not of caspase-8. However, supernatants of mitochondria, which have undergone permeability transition, and partially purified apoptosis-inducing factor activate both caspase-8 and caspase-3 in cytosolic extracts and suffice to activate recombinant caspase-8. These findings show that induction of mitochondrial permeability transition alone is sufficient to trigger the full apoptosis program and that some cytotoxic drugs such as BetA may induce apoptosis via a direct effect on mitochondria. Different classes of anticancer drugs may trigger apoptosis by acting on different subcellular targets and by activating distinct signaling pathways. Here, we report that betulinic acid (BetA) is a prototype cytotoxic agent that triggers apoptosis by a direct effect on mitochondria. In isolated mitochondria, BetA directly induces loss of transmembrane potential independent of a benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone-inhibitable caspase. This is inhibited by bongkrekic acid, an agent that stabilizes the permeability transition pore complex. Mitochondria undergoing BetA-induced permeability transition mediate cleavage of caspase-8 (FLICE/MACH/Mch5) and caspase-3 (CPP32/Yama) in a cell-free system. Soluble factors such as cytochrome c or apoptosis-inducing factor released from BetA-treated mitochondria are sufficient for cleavage of caspases and nuclear fragmentation. Addition of cytochromec to cytosolic extracts results in cleavage of caspase-3, but not of caspase-8. However, supernatants of mitochondria, which have undergone permeability transition, and partially purified apoptosis-inducing factor activate both caspase-8 and caspase-3 in cytosolic extracts and suffice to activate recombinant caspase-8. These findings show that induction of mitochondrial permeability transition alone is sufficient to trigger the full apoptosis program and that some cytotoxic drugs such as BetA may induce apoptosis via a direct effect on mitochondria. permeability transition apoptosis-inducing factor betulinic acid fluorescence-activated cell sorting benzyloxycarbonyl-Val-Ala-Asp-fluoromethyl ketone bongkrekic acid phosphate-buffered saline polyacrylamide gel electrophoresis bovine serum albumin poly(ADP-ribose) polymerase monoclonal antibody 1,4-piperazinediethanesulfonic acid mitochondrial transmembrane potential. Anticancer agents with different modes of action have been reported to trigger apoptosis in chemosensitive cells (1Fisher D.E. Cell. 1994; 78: 539-542Abstract Full Text PDF PubMed Scopus (1368) Google Scholar). Alterations of mitochondrial functions such as permeability transition (PT)1 have been found to play a major role in the apoptotic process including cell death induced by chemotherapeutic agents (2Kroemer G. Zamzami N. Susin S.A. Immunol. Today. 1997; 18: 44-51Abstract Full Text PDF PubMed Scopus (1379) Google Scholar, 3Susin S.A. Zamzami N. Castedo M. Daugas E. Wang H.G. Geley S. Fassy F. Reed J.C. Kroemer G. J. Exp. Med. 1997; 186: 5-37Crossref Scopus (587) Google Scholar, 4Marchetti P. Castedo M. Susin S.A. Zamzami N. Hirsch T. Macho A. Haeffner A. Hirsch T. Geuskens M. Kroemer G. J. Exp. Med. 1996; 184: 1155-1160Crossref PubMed Scopus (779) Google Scholar, 5Zamzami N. Susin S.A. Marchetti P. Hirsch T. Gomez-Monterrey I. Castedo M. Kroemer G. J. Exp. Med. 1996; 183: 1533-1544Crossref PubMed Scopus (1262) Google Scholar, 6Susin S.A. Zamzami N. Castedo M. Hirsch T. Marchetti P. Macho A. Daugas E. Geuskens M. Kroemer G. J. Exp. Med. 1996; 184: 1331-1341Crossref PubMed Scopus (1028) Google Scholar, 7Decaudin D. Geley S. Hirsch T. Castedo M. Marchetti P. Macho A. Kofler R. Kroemer G. Cancer Res. 1997; 57: 62-67PubMed Google Scholar). Mitochondria undergoing PT release apoptogenic proteins such as cytochrome c or apoptosis-inducing factor (AIF) from the mitochondrial intermembrane space into the cytosol, where they can activate caspases and endonucleases (2Kroemer G. Zamzami N. Susin S.A. Immunol. Today. 1997; 18: 44-51Abstract Full Text PDF PubMed Scopus (1379) Google Scholar, 3Susin S.A. Zamzami N. Castedo M. Daugas E. Wang H.G. Geley S. Fassy F. Reed J.C. Kroemer G. J. Exp. Med. 1997; 186: 5-37Crossref Scopus (587) Google Scholar, 6Susin S.A. Zamzami N. Castedo M. Hirsch T. Marchetti P. Macho A. Daugas E. Geuskens M. Kroemer G. J. Exp. Med. 1996; 184: 1331-1341Crossref PubMed Scopus (1028) Google Scholar, 8Kluck R.M. Bossy-Wetzel E. Green D.R. Newmeyer D.D. Science. 1997; 275: 1132-1136Crossref PubMed Scopus (4256) Google Scholar, 9Yang J. Liu X. Bhalla K. Kim C.N. Ibrado A.M. Cai J. Peng T.I. Jones D.P. Wang X. Science. 1997; 275: 1129-1132Crossref PubMed Scopus (4384) Google Scholar, 10Liu X. Kim C.N. Yang J. Jemmerson R. Wang X. Cell. 1996; 86: 147-157Abstract Full Text Full Text PDF PubMed Scopus (4435) Google Scholar, 11Li P. Nijhawan D. Budihardjo I. Srinivasula S. Ahmad M. Alnemri A.S. Wang X. Cell. 1997; 91: 479-489Abstract Full Text Full Text PDF PubMed Scopus (6183) Google Scholar). However, activated caspases can also induce PT, probably via a direct effect on the PT pore complex (3Susin S.A. Zamzami N. Castedo M. Daugas E. Wang H.G. Geley S. Fassy F. Reed J.C. Kroemer G. J. Exp. Med. 1997; 186: 5-37Crossref Scopus (587) Google Scholar, 12Marzo I. Brenner C. Zamzami N. Susin S.A. Beutner G. Brdiczka D. Remy R. Xie Z.-H. Reed J.C. Kroemer G. J. Exp. Med. 1998; 187: 1261-1271Crossref PubMed Scopus (614) Google Scholar). These findings suggest that caspases can act upstream and downstream of mitochondria. Mitochondrial function during apoptosis is controlled by the Bcl-2 family of proteins localized to intracellular membranes including the mitochondrial membrane (13Kroemer G. Nat. Med. 1997; 3: 614-620Crossref PubMed Scopus (1706) Google Scholar). Overexpression of the anti-apoptotic molecules Bcl-2 and Bcl-XL has been found to confer resistance to anticancer treatment (14Kim C.N. Wang X. Huang Y. Ibrado A.M. Liu L. Fang G. Bhalla K. Cancer Res. 1997; 57: 3115-3120PubMed Google Scholar, 15Dole M. Nuñez G. Merchant A.K. Maybaum J. Rode C.K. Bloch C.A. Castle V.P. Cancer Res. 1994; 54: 3253-3259PubMed Google Scholar, 16Dole M.G. Jasty R. Cooper M.J. Thompson C.B. Nuñez G. Castle V.P. Cancer Res. 1995; 55: 2576-2582PubMed Google Scholar). Bcl-2 and Bcl-XL may inhibit apoptosis through the capacity to prevent PT and/or to stabilize the barrier function of the outer mitochondrial membrane (5Zamzami N. Susin S.A. Marchetti P. Hirsch T. Gomez-Monterrey I. Castedo M. Kroemer G. J. Exp. Med. 1996; 183: 1533-1544Crossref PubMed Scopus (1262) Google Scholar, 6Susin S.A. Zamzami N. Castedo M. Hirsch T. Marchetti P. Macho A. Daugas E. Geuskens M. Kroemer G. J. Exp. Med. 1996; 184: 1331-1341Crossref PubMed Scopus (1028) Google Scholar, 13Kroemer G. Nat. Med. 1997; 3: 614-620Crossref PubMed Scopus (1706) Google Scholar, 17Vander Heiden M.G. Chandel N.S. Williamson E.K. Schumacker P.T. Thompson C.B. Cell. 1997; 91: 627-637Abstract Full Text Full Text PDF PubMed Scopus (1233) Google Scholar, 18Bossy-Wetzel E. Newmeyer D.D. Green D.R. EMBO J. 1998; 17: 37-49Crossref PubMed Scopus (1105) Google Scholar).Cytotoxic drugs such as doxorubicin can activate apoptosis pathways by such as the C. I. Nat. Med. 1996; PubMed Scopus Google Scholar, S. C. I. Cancer Res. 1997; 57: Google Scholar, S. M. C. J. 1998; PubMed Scopus Google Scholar, S. C. T. 1998; PubMed Scopus Google Scholar, M. I. C. S. K. 1997; PubMed Google Scholar, C. S. 1997; Scopus Google Scholar, J. Cancer 1997; PubMed Scopus Google Scholar, M. S. J. 1997; PubMed Scopus Google Scholar). caspase-8 (FLICE/MACH/Mch5) is in of a downstream including caspase-3 (CPP32/Yama) A. I. M. G. C. M. S. J. J. Full Text PDF PubMed Google Scholar, C. S. P. Science. PubMed Scopus Google Scholar, 1996; 3: Google Scholar, S. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, S. A.M. 1996; 3: Google Scholar, M. A.M. K. C. M. R. M. Cell. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, A.M. K. S. J. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, S. I. M. M. EMBO J. 1995; PubMed Scopus Google Scholar, C. M. EMBO J. 1997; PubMed Scopus Google Scholar). of the and of treatment with cytotoxic drugs such as doxorubicin have been in a of and of by has been found to inhibit cell death C. I. Nat. Med. 1996; PubMed Scopus Google Scholar, S. C. I. Cancer Res. 1997; 57: Google Scholar, S. M. C. J. 1998; PubMed Scopus Google Scholar, S. C. T. 1998; PubMed Scopus Google Scholar, M. I. C. S. K. 1997; PubMed Google Scholar, C. S. 1997; Scopus Google Scholar, J. Cancer 1997; PubMed Scopus Google Scholar, M. S. J. 1997; PubMed Scopus Google acid (BetA) is a anticancer with for E. Nat. Med. 1995; PubMed Scopus Google Scholar, S. C. M. C. M. Nuñez G. Cancer Res. 1997; 57: Google Scholar). found that BetA-induced apoptosis from anticancer agents such as doxorubicin S. C. M. C. M. Nuñez G. Cancer Res. 1997; 57: Google Scholar). BetA-induced apoptosis is not with of such as and not of mitochondrial function including loss of mitochondrial permeability transition of apoptosis such as of the and nuclear S. C. M. C. M. Nuñez G. Cancer Res. 1997; 57: Google Scholar). This that BetA may have a direct effect on mitochondria. BetA directly activate mitochondria and the of the apoptosis drugs have been reported to act by apoptosis in cells (1Fisher D.E. Cell. 1994; 78: 539-542Abstract Full Text PDF PubMed Scopus (1368) Google Scholar). of apoptosis by anticancer drugs or of death of mitochondrial and of the death molecules of apoptosis J. Cancer 1997; PubMed Scopus Google Scholar). the cell death may and drugs may the have not been in Here, we report that of anticancer agents by BetA may act by directly mitochondria, in downstream of a cell-free we found that BetA directly PT in isolated mitochondria, and induction of PT to the in of PT by of Bcl-2 or Bcl-XL or by the of apoptosis in cells and in a cell-free such as of of cleavage of and nuclear fragmentation. In to cytotoxic drugs such as or not induce mitochondrial in isolated mitochondria, that mitochondrial PT, which in cells during apoptosis by S. C. I. Cancer Res. 1997; 57: Google the of a of pathways or BetA cells S. C. M. C. M. Nuñez G. Cancer Res. 1997; 57: Google Scholar). to BetA induced mitochondrial in but not in cell not However, BetA-treated mitochondria isolated from the cell mitochondrial PT and nuclear to mitochondria from the of BetA for may by and/or of the to the mitochondrial by in mitochondria BetA-treated of different caspases and nuclear found in cells with mitochondrial and BetA-induced loss of not inhibited by the This that downstream of mitochondria and that of mitochondria is sufficient to trigger downstream to In in loss of inhibited by that of mitochondria is by upstream S. and Cancer Res. BetA to a of cytotoxic agents apoptosis-inducing effect is by of on BetA-induced apoptosis a of the of different caspases and mitochondrial death the caspase-8 which in full of the cleavage of and of mitochondrial PT C. S. F. C. A. EMBO J. 1998; 17: PubMed Scopus Google Scholar, C. J. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, A. F. A. L. R. J.C. J. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, Thompson C.B. S. A. 1997; PubMed Scopus Google Scholar). of caspase-8 in cells in which mitochondrial PT and of downstream caspases are by of Bcl-2 or Bcl-XL (2Kroemer G. Zamzami N. Susin S.A. Immunol. Today. 1997; 18: 44-51Abstract Full Text PDF PubMed Scopus (1379) Google Scholar). In in BetA-treated of both caspase-8 and caspase-3 to mitochondrial proteins such as cytochromec and released from mitochondria permeability transition have been to directly induce cleavage of caspases (2Kroemer G. Zamzami N. Susin S.A. Immunol. Today. 1997; 18: 44-51Abstract Full Text PDF PubMed Scopus (1379) Google S.A. Zamzami N. Castedo M. Daugas E. Wang H.G. Geley S. Fassy F. Reed J.C. Kroemer G. J. Exp. Med. 1997; 186: 5-37Crossref Scopus (587) Google Scholar, 6Susin S.A. Zamzami N. Castedo M. Hirsch T. Marchetti P. Macho A. Daugas E. Geuskens M. Kroemer G. J. Exp. Med. 1996; 184: 1331-1341Crossref PubMed Scopus (1028) Google Scholar). mitochondrial PT and apoptosis cleavage of caspase-8 and caspase-3 independent of in BetA-treated caspase-8 activated by mitochondria undergoing PT in the of signaling complex released from mitochondria may mediate caspase-8 cleavage BetA treatment partially purified recombinant caspase-8. In cytochromec not induce of induced caspase-3 that the of caspase-8 downstream of mitochondria from that of to for partially purified has been to induce and we found of with isolated mitochondria. However, may of cytosolic that may mediate of downstream targets such as or X. C. Wang X. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, M. K. A. S. 1997; Scopus Google classes of anticancer drugs may the apoptotic distinct they induce a that the of a of findings may have for of apoptosis of mitochondrial PT, as by cytotoxic drugs such as may sufficient for induction of apoptosis in cells and may the for upstream drugs cells that have a in upstream apoptosis pathways. In that cells with a in the C. S. 1997; Scopus Google which to to chemotherapeutic are to BetA-induced cell death S. C. M. C. M. Nuñez G. Cancer Res. 1997; 57: Google Scholar). findings may to and a of cytotoxic agents with direct mitochondrial that some of of Anticancer agents with different modes of action have been reported to trigger apoptosis in chemosensitive cells (1Fisher D.E. Cell. 1994; 78: 539-542Abstract Full Text PDF PubMed Scopus (1368) Google Scholar). Alterations of mitochondrial functions such as permeability transition (PT)1 have been found to play a major role in the apoptotic process including cell death induced by chemotherapeutic agents (2Kroemer G. Zamzami N. Susin S.A. Immunol. Today. 1997; 18: 44-51Abstract Full Text PDF PubMed Scopus (1379) Google Scholar, 3Susin S.A. Zamzami N. Castedo M. Daugas E. Wang H.G. Geley S. Fassy F. Reed J.C. Kroemer G. J. Exp. Med. 1997; 186: 5-37Crossref Scopus (587) Google Scholar, 4Marchetti P. Castedo M. Susin S.A. Zamzami N. Hirsch T. Macho A. Haeffner A. Hirsch T. Geuskens M. Kroemer G. J. Exp. Med. 1996; 184: 1155-1160Crossref PubMed Scopus (779) Google Scholar, 5Zamzami N. Susin S.A. Marchetti P. Hirsch T. Gomez-Monterrey I. Castedo M. Kroemer G. J. Exp. Med. 1996; 183: 1533-1544Crossref PubMed Scopus (1262) Google Scholar, 6Susin S.A. Zamzami N. Castedo M. Hirsch T. Marchetti P. Macho A. Daugas E. Geuskens M. Kroemer G. J. Exp. Med. 1996; 184: 1331-1341Crossref PubMed Scopus (1028) Google Scholar, 7Decaudin D. Geley S. Hirsch T. Castedo M. Marchetti P. Macho A. Kofler R. Kroemer G. Cancer Res. 1997; 57: 62-67PubMed Google Scholar). Mitochondria undergoing PT release apoptogenic proteins such as cytochrome c or apoptosis-inducing factor (AIF) from the mitochondrial intermembrane space into the cytosol, where they can activate caspases and endonucleases (2Kroemer G. Zamzami N. Susin S.A. Immunol. Today. 1997; 18: 44-51Abstract Full Text PDF PubMed Scopus (1379) Google Scholar, 3Susin S.A. Zamzami N. Castedo M. Daugas E. Wang H.G. Geley S. Fassy F. Reed J.C. Kroemer G. J. Exp. Med. 1997; 186: 5-37Crossref Scopus (587) Google Scholar, 6Susin S.A. Zamzami N. Castedo M. Hirsch T. Marchetti P. Macho A. Daugas E. Geuskens M. Kroemer G. J. Exp. Med. 1996; 184: 1331-1341Crossref PubMed Scopus (1028) Google Scholar, 8Kluck R.M. Bossy-Wetzel E. Green D.R. Newmeyer D.D. Science. 1997; 275: 1132-1136Crossref PubMed Scopus (4256) Google Scholar, 9Yang J. Liu X. Bhalla K. Kim C.N. Ibrado A.M. Cai J. Peng T.I. Jones D.P. Wang X. Science. 1997; 275: 1129-1132Crossref PubMed Scopus (4384) Google Scholar, 10Liu X. Kim C.N. Yang J. Jemmerson R. Wang X. Cell. 1996; 86: 147-157Abstract Full Text Full Text PDF PubMed Scopus (4435) Google Scholar, 11Li P. Nijhawan D. Budihardjo I. Srinivasula S. Ahmad M. Alnemri A.S. Wang X. Cell. 1997; 91: 479-489Abstract Full Text Full Text PDF PubMed Scopus (6183) Google Scholar). However, activated caspases can also induce PT, probably via a direct effect on the PT pore complex (3Susin S.A. Zamzami N. Castedo M. Daugas E. Wang H.G. Geley S. Fassy F. Reed J.C. Kroemer G. J. Exp. Med. 1997; 186: 5-37Crossref Scopus (587) Google Scholar, 12Marzo I. Brenner C. Zamzami N. Susin S.A. Beutner G. Brdiczka D. Remy R. Xie Z.-H. Reed J.C. Kroemer G. J. Exp. Med. 1998; 187: 1261-1271Crossref PubMed Scopus (614) Google Scholar). These findings suggest that caspases can act upstream and downstream of mitochondria. Mitochondrial function during apoptosis is controlled by the Bcl-2 family of proteins localized to intracellular membranes including the mitochondrial membrane (13Kroemer G. Nat. Med. 1997; 3: 614-620Crossref PubMed Scopus (1706) Google Scholar). Overexpression of the anti-apoptotic molecules Bcl-2 and Bcl-XL has been found to confer resistance to anticancer treatment (14Kim C.N. Wang X. Huang Y. Ibrado A.M. Liu L. Fang G. Bhalla K. Cancer Res. 1997; 57: 3115-3120PubMed Google Scholar, 15Dole M. Nuñez G. Merchant A.K. Maybaum J. Rode C.K. Bloch C.A. Castle V.P. Cancer Res. 1994; 54: 3253-3259PubMed Google Scholar, 16Dole M.G. Jasty R. Cooper M.J. Thompson C.B. Nuñez G. Castle V.P. Cancer Res. 1995; 55: 2576-2582PubMed Google Scholar). Bcl-2 and Bcl-XL may inhibit apoptosis through the capacity to prevent PT and/or to stabilize the barrier function of the outer mitochondrial membrane (5Zamzami N. Susin S.A. Marchetti P. Hirsch T. Gomez-Monterrey I. Castedo M. Kroemer G. J. Exp. Med. 1996; 183: 1533-1544Crossref PubMed Scopus (1262) Google Scholar, 6Susin S.A. Zamzami N. Castedo M. Hirsch T. Marchetti P. Macho A. Daugas E. Geuskens M. Kroemer G. J. Exp. Med. 1996; 184: 1331-1341Crossref PubMed Scopus (1028) Google Scholar, 13Kroemer G. Nat. Med. 1997; 3: 614-620Crossref PubMed Scopus (1706) Google Scholar, 17Vander Heiden M.G. Chandel N.S. Williamson E.K. Schumacker P.T. Thompson C.B. Cell. 1997; 91: 627-637Abstract Full Text Full Text PDF PubMed Scopus (1233) Google Scholar, 18Bossy-Wetzel E. Newmeyer D.D. Green D.R. EMBO J. 1998; 17: 37-49Crossref PubMed Scopus (1105) Google Scholar). drugs such as doxorubicin can activate apoptosis pathways by such as the C. I. Nat. Med. 1996; PubMed Scopus Google Scholar, S. C. I. Cancer Res. 1997; 57: Google Scholar, S. M. C. J. 1998; PubMed Scopus Google Scholar, S. C. T. 1998; PubMed Scopus Google Scholar, M. I. C. S. K. 1997; PubMed Google Scholar, C. S. 1997; Scopus Google Scholar, J. Cancer 1997; PubMed Scopus Google Scholar, M. S. J. 1997; PubMed Scopus Google Scholar). caspase-8 (FLICE/MACH/Mch5) is in of a downstream including caspase-3 (CPP32/Yama) A. I. M. G. C. M. S. J. J. Full Text PDF PubMed Google Scholar, C. S. P. Science. PubMed Scopus Google Scholar, 1996; 3: Google Scholar, S. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, S. A.M. 1996; 3: Google Scholar, M. A.M. K. C. M. R. M. Cell. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, A.M. K. S. J. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, S. I. M. M. EMBO J. 1995; PubMed Scopus Google Scholar, C. M. EMBO J. 1997; PubMed Scopus Google Scholar). of the and of treatment with cytotoxic drugs such as doxorubicin have been in a of and of by has been found to inhibit cell death C. I. Nat. Med. 1996; PubMed Scopus Google Scholar, S. C. I. Cancer Res. 1997; 57: Google Scholar, S. M. C. J. 1998; PubMed Scopus Google Scholar, S. C. T. 1998; PubMed Scopus Google Scholar, M. I. C. S. K. 1997; PubMed Google Scholar, C. S. 1997; Scopus Google Scholar, J. Cancer 1997; PubMed Scopus Google Scholar, M. S. J. 1997; PubMed Scopus Google Scholar). acid (BetA) is a anticancer with for E. Nat. Med. 1995; PubMed Scopus Google Scholar, S. C. M. C. M. Nuñez G. Cancer Res. 1997; 57: Google Scholar). found that BetA-induced apoptosis from anticancer agents such as doxorubicin S. C. M. C. M. Nuñez G. Cancer Res. 1997; 57: Google Scholar). BetA-induced apoptosis is not with of such as and not of mitochondrial function including loss of mitochondrial permeability transition of apoptosis such as of the and nuclear S. C. M. C. M. Nuñez G. Cancer Res. 1997; 57: Google Scholar). This that BetA may have a direct effect on mitochondria. BetA directly activate mitochondria and the of the apoptosis drugs have been reported to act by apoptosis in cells (1Fisher D.E. Cell. 1994; 78: 539-542Abstract Full Text PDF PubMed Scopus (1368) Google Scholar). of apoptosis by anticancer drugs or of death of mitochondrial and of the death molecules of apoptosis J. Cancer 1997; PubMed Scopus Google Scholar). the cell death may and drugs may the have not been in Here, we report that of anticancer agents by BetA may act by directly mitochondria, in downstream of a cell-free we found that BetA directly PT in isolated mitochondria, and induction of PT to the in of PT by of Bcl-2 or Bcl-XL or by the of apoptosis in cells and in a cell-free such as of of cleavage of and nuclear fragmentation. In to cytotoxic drugs such as or not induce mitochondrial in isolated mitochondria, that mitochondrial PT, which in cells during apoptosis by S. C. I. Cancer Res. 1997; 57: Google the of a of pathways or BetA cells S. C. M. C. M. Nuñez G. Cancer Res. 1997; 57: Google Scholar). to BetA induced mitochondrial in but not in cell not However, BetA-treated mitochondria isolated from the cell mitochondrial PT and nuclear to mitochondria from the of BetA for may by and/or of the to the mitochondrial by in mitochondria BetA-treated of different caspases and nuclear found in cells with mitochondrial and BetA-induced loss of not inhibited by the This that downstream of mitochondria and that of mitochondria is sufficient to trigger downstream to In in loss of inhibited by that of mitochondria is by upstream S. and Cancer Res. BetA to a of cytotoxic agents apoptosis-inducing effect is by of on BetA-induced apoptosis a of the of different caspases and mitochondrial death the caspase-8 which in full of the cleavage of and of mitochondrial PT C. S. F. C. A. EMBO J. 1998; 17: PubMed Scopus Google Scholar, C. J. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, A. F. A. L. R. J.C. J. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, Thompson C.B. S. A. 1997; PubMed Scopus Google Scholar). of caspase-8 in cells in which mitochondrial PT and of downstream caspases are by of Bcl-2 or Bcl-XL (2Kroemer G. Zamzami N. Susin S.A. Immunol. Today. 1997; 18: 44-51Abstract Full Text PDF PubMed Scopus (1379) Google Scholar). In in BetA-treated of both caspase-8 and caspase-3 to mitochondrial proteins such as cytochromec and released from mitochondria permeability transition have been to directly induce cleavage of caspases (2Kroemer G. Zamzami N. Susin S.A. Immunol. Today. 1997; 18: 44-51Abstract Full Text PDF PubMed Scopus (1379) Google S.A. Zamzami N. Castedo M. Daugas E. Wang H.G. Geley S. Fassy F. Reed J.C. Kroemer G. J. Exp. Med. 1997; 186: 5-37Crossref Scopus (587) Google Scholar, 6Susin S.A. Zamzami N. Castedo M. Hirsch T. Marchetti P. Macho A. Daugas E. Geuskens M. Kroemer G. J. Exp. Med. 1996; 184: 1331-1341Crossref PubMed Scopus (1028) Google Scholar). mitochondrial PT and apoptosis cleavage of caspase-8 and caspase-3 independent of in BetA-treated caspase-8 activated by mitochondria undergoing PT in the of signaling complex released from mitochondria may mediate caspase-8 cleavage BetA treatment partially purified recombinant caspase-8. In cytochromec not induce of induced caspase-3 that the of caspase-8 downstream of mitochondria from that of to for partially purified has been to induce and we found of with isolated mitochondria. However, may of cytosolic that may mediate of downstream targets such as or X. C. Wang X. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, M. K. A. S. 1997; Scopus Google classes of anticancer drugs may the apoptotic distinct they induce a that the of a of findings may have for of apoptosis of mitochondrial PT, as by cytotoxic drugs such as may sufficient for induction of apoptosis in cells and may the for upstream drugs cells that have a in upstream apoptosis pathways. In that cells with a in the C. S. 1997; Scopus Google which to to chemotherapeutic are to BetA-induced cell death S. C. M. C. M. Nuñez G. Cancer Res. 1997; 57: Google Scholar). findings may to and a of cytotoxic agents with direct mitochondrial that some of of drugs have been reported to act by apoptosis in cells (1Fisher D.E. Cell. 1994; 78: 539-542Abstract Full Text PDF PubMed Scopus (1368) Google Scholar). of apoptosis by anticancer drugs or of death of mitochondrial and of the death molecules of apoptosis J. Cancer 1997; PubMed Scopus Google Scholar). the cell death may and drugs may the have not been in Here, we report that of anticancer agents by BetA may act by directly mitochondria, in downstream of mitochondria. a cell-free we found that BetA directly PT in isolated mitochondria, and induction of PT to the in of PT by of Bcl-2 or Bcl-XL or by the of apoptosis in cells and in a cell-free such as of of cleavage of and nuclear fragmentation. In to cytotoxic drugs such as or not induce mitochondrial in isolated mitochondria, that mitochondrial PT, which in cells during apoptosis by S. C. I. Cancer Res. 1997; 57: Google the of a of pathways or BetA cells S. C. M. C. M. Nuñez G. Cancer Res. 1997; 57: Google Scholar). to BetA induced mitochondrial in but not in cell not However, BetA-treated mitochondria isolated from the cell mitochondrial PT and nuclear to mitochondria from the of BetA for may by and/or of the to the mitochondrial by in mitochondria In BetA-treated of different caspases and nuclear found in cells with mitochondrial and BetA-induced loss of not inhibited by the This that downstream of mitochondria and that of mitochondria is sufficient to trigger downstream to In in loss of inhibited by that of mitochondria is by upstream S. and Cancer Res. BetA to a of cytotoxic agents apoptosis-inducing effect is by of mitochondria. on BetA-induced apoptosis a of the of different caspases and mitochondrial death the caspase-8 which in full of the cleavage of and of mitochondrial PT C. S. F. C. A. EMBO J. 1998; 17: PubMed Scopus Google Scholar, C. J. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, A. F. A. L. R. J.C. J. 1998; Full Text Full Text PDF PubMed Scopus Google Scholar, Thompson C.B. S. A. 1997; PubMed Scopus Google Scholar). of caspase-8 in cells in which mitochondrial PT and of downstream caspases are by of Bcl-2 or Bcl-XL (2Kroemer G. Zamzami N. Susin S.A. Immunol. Today. 1997; 18: 44-51Abstract Full Text PDF PubMed Scopus (1379) Google Scholar). In in BetA-treated of both caspase-8 and caspase-3 to mitochondrial proteins such as cytochromec and released from mitochondria permeability transition have been to directly induce cleavage of caspases (2Kroemer G. Zamzami N. Susin S.A. Immunol. Today. 1997; 18: 44-51Abstract Full Text PDF PubMed Scopus (1379) Google S.A. Zamzami N. Castedo M. Daugas E. Wang H.G. Geley S. Fassy F. Reed J.C. Kroemer G. J. Exp. Med. 1997; 186: 5-37Crossref Scopus (587) Google Scholar, 6Susin S.A. Zamzami N. Castedo M. Hirsch T. Marchetti P. Macho A. Daugas E. Geuskens M. Kroemer G. J. Exp. Med. 1996; 184: 1331-1341Crossref PubMed Scopus (1028) Google Scholar). mitochondrial PT and apoptosis cleavage of caspase-8 and caspase-3 independent of in BetA-treated caspase-8 activated by mitochondria undergoing PT in the of signaling complex released from mitochondria may mediate caspase-8 cleavage BetA treatment partially purified recombinant caspase-8. In cytochromec not induce of induced caspase-3 that the of caspase-8 downstream of mitochondria from that of to for partially purified has been to induce and we found of with isolated mitochondria. However, may of cytosolic that may mediate of downstream targets such as or X. C. Wang X. Cell. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar, M. K. A. S. 1997; Scopus Google Scholar). Different classes of anticancer drugs may the apoptotic distinct they induce a that the of a of findings may have for of apoptosis of mitochondrial PT, as by cytotoxic drugs such as may sufficient for induction of apoptosis in cells and may the for upstream drugs cells that have a in upstream apoptosis pathways. In that cells with a in the C. S. 1997; Scopus Google which to to chemotherapeutic are to BetA-induced cell death S. C. M. C. M. Nuñez G. Cancer Res. 1997; 57: Google Scholar). findings may to and a of cytotoxic agents with direct mitochondrial that some of of for and Nuñez and of for and

We assessed the prevalence of overt and latent primary myeloproliferative disorders in hepatic vein thrombosis. Cultures of bone marrow or peripheral blood mononuclear cells were done in 20 patients with Budd-Chiari syndrome. Erythroid colony formation in the absence of erythropoietin, which is a reliable indicator for a primary myeloproliferative disorder, was seen in 16 patients in whom Budd-Chiari syndrome was due to hepatic vein thrombosis, including 13 women aged 18 to 45 years. Among these 16 patients, the conventional criteria for the diagnosis of a primary myeloproliferative disorder were met in only 2. Primary myeloproliferative disorder, often without peripheral blood changes, is a major cause of hepatic vein thrombosis in young women.

STUDY OBJECTIVES: Previous studies have reported that insomnia and excessive daytime sleepiness (EDS) may predict depression in adults. However, these associations have not been investigated in community-dwelling elderly taking into account insomnia symptoms, EDS, and sleep medication. DESIGN: Four-year longitudinal study. SETTING: The French Three-City Study. PARTICIPANTS: 3824 subjects aged ≥ 65 years and free of depressive symptoms at baseline. MEASUREMENTS AND RESULTS: Questionnaires were used to evaluate "insomnia symptoms", EDS, and sleep medication at baseline. Depressive symptoms (DEP-s) were assessed using the Center for Epidemiologic Studies-Depression scale at baseline, and at 2-year and 4-year follow-up. Logistic regression models controlling for potential confounders were generated to determine whether sleep disturbances were associated with incident DEP-s and to determine the effect of individual insomnia symptoms. Insomnia symptoms and EDS independently increased the risk of incident DEP-s (OR=1.23, 95% CI=1.01-1.49 and OR=2.05, 95% CI=1.30-3.23, respectively). Poor sleep quality and difficulty in initiating and in maintaining sleep-but not early morning awakening-were identified as risk factors of DEP-s, with risk increasing with the frequency of insomnia symptoms. Sleep medication was not only a risk factor for DEP-s independent of insomnia symptoms (OR=1.62, 95% CI=1.26-2.09), but also independent of EDS (OR=1.71 95%=1.33-2.20). CONCLUSIONS: Insomnia symptoms, EDS, and the use of medication independently increase the risk of subsequent depression in the elderly. In clinical practice, disturbed sleep and prolonged use of sleep medication may be early indicators or potentially reversible risk factors for depression, suggesting the need for further clinical interventional research.

OBJECTIVE: We hypothesized that specific mutations in the β-glucocerebrosidase gene (GBA) causing neuropathic Gaucher's disease (GD) in homozygotes lead to aggressive cognitive decline in heterozygous Parkinson's disease (PD) patients, whereas non-neuropathic GD mutations confer intermediate progression rates. METHODS: A total of 2,304 patients with PD and 20,868 longitudinal visits for up to 12.8 years (median, 4.1) from seven cohorts were analyzed. Differential effects of four types of genetic variation in GBA on longitudinal cognitive decline were evaluated using mixed random and fixed effects and Cox proportional hazards models. RESULTS: Overall, 10.3% of patients with PD and GBA sequencing carried a mutation. Carriers of neuropathic GD mutations (1.4% of patients) had hazard ratios (HRs) for global cognitive impairment of 3.17 (95% confidence interval [CI], 1.60-6.25) and a hastened decline in Mini-Mental State Exam scores compared to noncarriers (p = 0.0009). Carriers of complex GBA alleles (0.7%) had an HR of 3.22 (95% CI, 1.18-8.73; p = 0.022). By contrast, the common, non-neuropathic N370S mutation (1.5% of patients; HR, 1.96; 95% CI, 0.92-4.18) or nonpathogenic risk variants (6.6% of patients; HR, 1.36; 95% CI, 0.89-2.05) did not reach significance. INTERPRETATION: Mutations in the GBA gene pathogenic for neuropathic GD and complex alleles shift longitudinal cognitive decline in PD into "high gear." These findings suggest a relationship between specific types of GBA mutations and aggressive cognitive decline and have direct implications for improving the design of clinical trials. Ann Neurol 2016;80:674-685.

Nonalcoholic steatohepatitis (NASH) is a condition which can progress to cirrhosis and hepatocellular carcinoma. Markers for NASH diagnosis are still lacking. We performed a comprehensive lipidomic analysis on human liver biopsies including normal liver, nonalcoholic fatty liver and NASH. Random forests-based machine learning approach allowed characterizing a signature of 32 lipids discriminating NASH with 100% sensitivity and specificity. Furthermore, we validated this signature in an independent group of NASH patients. Then, metabolism dysregulations were investigated in both patients and murine models. Alterations of elongase and desaturase activities were observed along the fatty acid synthesis pathway. The decreased activity of the desaturase FADS1 appeared as a bottleneck, leading upstream to an accumulation of fatty acids and downstream to a deficiency of long-chain fatty acids resulting to impaired phospholipid synthesis. In NASH, mass spectrometry imaging on tissue section revealed the spreading into the hepatic parenchyma of selectively accumulated fatty acids. Such lipids constituted a highly toxic mixture to human hepatocytes. In conclusion, this study characterized a specific and sensitive lipid signature of NASH and positioned FADS1 as a significant player in accumulating toxic lipids during NASH progression.

DNA hypomethylation in certain genes is associated with tobacco exposure but it is unknown whether these methylation changes translate into increased lung cancer risk. In an epigenome-wide study of DNA from pre-diagnostic blood samples from 132 case-control pairs in the NOWAC cohort, we observe that the most significant associations with lung cancer risk are for cg05575921 in AHRR (OR for 1 s.d.=0.37, 95% CI: 0.31-0.54, P-value=3.3 × 10(-11)) and cg03636183 in F2RL3 (OR for 1 s.d.=0.40, 95% CI: 0.31-0.56, P-value=3.9 × 10(-10)), previously shown to be strongly hypomethylated in smokers. These associations remain significant after adjustment for smoking and are confirmed in additional 664 case-control pairs tightly matched for smoking from the MCCS, NSHDS and EPIC HD cohorts. The replication and mediation analyses suggest that residual confounding is unlikely to explain the observed associations and that hypomethylation of these CpG sites may mediate the effect of tobacco on lung cancer risk.

STUDY OBJECTIVES: To examine the association of sleep complaints reported at baseline (insomnia complaints and excessive daytime sleepiness (EDS)) and medication, with cognitive decline in community-dwelling elderly. DESIGN: An 8-yr longitudinal study. SETTING: The French Three-City Study. PARTICIPANTS: There were 4,894 patients without dementia recruited from 3 French cities and having a Mini-Mental Status Examination (MMSE) score ≥ 24 points at baseline. MEASUREMENTS AND RESULTS: Questionnaires were used to evaluate insomnia complaints (poor sleep quality (SQ), difficulty in initiating sleep (DIS), difficulty in maintaining sleep (DMS), early morning awakening (EMA)), EDS, and sleep medication at baseline. Cognitive decline was defined as a 4-point reduction in MMSE score during follow-up at 2, 4, and 8 yr. Logistic regression models were adjusted for sociodemographic, behavioral, physical, and mental health variables, and apolipoprotein E genotype. EDS independently increased the risk of cognitive decline (odds ratio (OR) = 1.26, 95% confidence interval (CI) = 1.02-1.56), especially for those patients who also developed dementia during the follow-up period (OR = 1.39, 95% CI = 1.00-1.97). The number of insomnia complaints and DMS were negatively associated with MMSE cognitive decline (OR = 0.77, 95% CI = 0.60-0.98 for 3-4 complaints, OR = 0.81, 95% CI = 0.68-0.96, respectively). The 3 other components of insomnia (SQ, DIS, EMA) were not significantly associated with MMSE cognitive decline. CONCLUSIONS: Our results suggest that EDS may be associated independently with the risk of cognitive decline in the elderly population. Such results could have important public health implications because EDS may be an early marker and potentially reversible risk factor of cognitive decline and onset of dementia.

UNLABELLED: Breast, ovarian, and prostate cancers are hormone-related and may have a shared genetic basis, but this has not been investigated systematically by genome-wide association (GWA) studies. Meta-analyses combining the largest GWA meta-analysis data sets for these cancers totaling 112,349 cases and 116,421 controls of European ancestry, all together and in pairs, identified at P < 10(-8) seven new cross-cancer loci: three associated with susceptibility to all three cancers (rs17041869/2q13/BCL2L11; rs7937840/11q12/INCENP; rs1469713/19p13/GATAD2A), two breast and ovarian cancer risk loci (rs200182588/9q31/SMC2; rs8037137/15q26/RCCD1), and two breast and prostate cancer risk loci (rs5013329/1p34/NSUN4; rs9375701/6q23/L3MBTL3). Index variants in five additional regions previously associated with only one cancer also showed clear association with a second cancer type. Cell-type-specific expression quantitative trait locus and enhancer-gene interaction annotations suggested target genes with potential cross-cancer roles at the new loci. Pathway analysis revealed significant enrichment of death receptor signaling genes near loci with P < 10(-5) in the three-cancer meta-analysis. SIGNIFICANCE: We demonstrate that combining large-scale GWA meta-analysis findings across cancer types can identify completely new risk loci common to breast, ovarian, and prostate cancers. We show that the identification of such cross-cancer risk loci has the potential to shed new light on the shared biology underlying these hormone-related cancers. Cancer Discov; 6(9); 1052-67. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 932.

Due to the increasing impact of cancer on worldwide mortality, more and more attention is being devoted to the investigation of novel anticancer strategies. Among these, chemotherapy plays a key role in fighting cancer. This explains the increasing engagement of both the pharmaceutical industry and academia towards the discovery of new chemotherapeutic agents. In recent years, metal-based drugs have attracted much attention due to their atypical physico-chemical properties compared to organic molecules. After the approval of cisplatin as a chemotherapeutic agent in 1978, several types of metal-based drugs have been explored. Among them, Ru-based anticancer drug candidates have become a central subject in this research field. However, most of the Ru-based compounds investigated over the last two decades express their cytotoxicity with a mechanism of action involving, among others, a ligand-exchange mechanism. In this Review, we give a complete overview of a specific class of antiproliferative ruthenium complexes, namely coordinatively saturated and substitutionally inert Ru(ii) polypyridyl complexes. This implies that the cytotoxicity observed comes from the entire complex and not from ligand-exchange. In this Review, we present monomeric and dimeric Ru(ii) polypyridyl complexes, which have been found to be toxic to cancer cells. More specifically, monomeric Ru(ii) polypyridyl complexes are analysed considering their direct interaction or not with DNA as the cause of cell death, while dimeric Ru(ii) polypyridyl complexes are classified according to their biological targets. Very importantly, the cellular targets of these complexes are discussed in detail. Indeed, several targets were identified and different mechanisms of action were suggested.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is one of the most common chronic diseases worldwide. In high-income countries, low socioeconomic status seems to be related to a high incidence of T2DM, but very little is known about the intermediate factors of this relationship. Method We performed a case-cohort study in eight Western European countries nested in the EPIC study (n = 340, 234, 3.99 million person-years of follow-up). A random sub-cohort of 16,835 individuals and a total of 12,403 incident cases of T2DM were identified. Crude and multivariate-adjusted hazard ratios (HR) were estimated for each country and pooled across countries using meta-analytical methods. Age-, gender- and country-specific relative indices of inequality (RII) were used as the measure of educational level and RII tertiles were analysed. RESULTS: Compared with participants with a high educational level (RII tertile 1), participants with a low educational level (RII tertile 3) had a higher risk of T2DM [HR: 1.77, 95% confidence interval (CI): 1.69-1.85; P-trend < 0.01]. The HRs adjusted for physical activity, smoking status and propensity score according to macronutrient intake were very similar to the crude HR (adjusted HR: 1.67, 95% CI: 1.52-1.83 in men; HR: 1.88, 95% CI: 1.73-2.05 in women). The HRs were attenuated only when they were further adjusted for BMI (BMI-adjusted HR: 1.36, 95% CI: 1.23-1.51 in men; HR: 1.32, 95% CI: 1.20-1.45 in women). CONCLUSION: This study demonstrates the inequalities in the risk of T2DM in Western European countries, with an inverse relationship between educational level and risk of T2DM that is only partially explained by variations in BMI.

Fasting glucose and insulin are intermediate traits for type 2 diabetes. Here we explore the role of coding variation on these traits by analysis of variants on the HumanExome BeadChip in 60,564 non-diabetic individuals and in 16,491 T2D cases and 81,877 controls. We identify a novel association of a low-frequency nonsynonymous SNV in GLP1R (A316T; rs10305492; MAF=1.4%) with lower FG (β=-0.09±0.01 mmol l(-1), P=3.4 × 10(-12)), T2D risk (OR[95%CI]=0.86[0.76-0.96], P=0.010), early insulin secretion (β=-0.07±0.035 pmolinsulin mmolglucose(-1), P=0.048), but higher 2-h glucose (β=0.16±0.05 mmol l(-1), P=4.3 × 10(-4)). We identify a gene-based association with FG at G6PC2 (pSKAT=6.8 × 10(-6)) driven by four rare protein-coding SNVs (H177Y, Y207S, R283X and S324P). We identify rs651007 (MAF=20%) in the first intron of ABO at the putative promoter of an antisense lncRNA, associating with higher FG (β=0.02±0.004 mmol l(-1), P=1.3 × 10(-8)). Our approach identifies novel coding variant associations and extends the allelic spectrum of variation underlying diabetes-related quantitative traits and T2D susceptibility.

Transthyretin (TTR) familial amyloid polyneuropathies (FAP) are autosomal dominant devastating afflictions. They were first described in Portugal, later in Japan and Sweden and are now recognized worldwide. The TTR Val30Met mutation is the most common, and depending on the geographic origin, a wide variation in age at onset of the disease is observed. In Europe, northern Sweden is the second most prevalent area of the disease, and a late age of onset of 56 years has been reported. The present study aims to estimate the penetrance in TTR Val30Met Swedish families. Genealogical investigations, clinical data and genotyping were obtained in 77 TTR-Val30Met Swedish families. The penetrance in Val30Met carriers and variation within the endemic area, according to gender and transmitting parents were calculated by a newly developed bias-free method. The penetrance estimates were low, i.e. 1.7% and 22% at age 30 and 60 years, respectively, and far from complete (69%) by age 90 years. Differences between Piteå and Skellefteå regions were observed. Moreover, penetrance was significantly higher when the mutation was inherited from the mother than from the father. The low penetrance observed in TTR FAP kindreds and its variations is important information for the genetic counseling and treatment of Swedish FAP patients and their families.