Guido Kroemer

Bio: Guido Kroemer is an academic researcher from Institut Gustave Roussy. The author has contributed to research in topics: Programmed cell death & Autophagy. The author has an hindex of 236, co-authored 1404 publications receiving 246571 citations. Previous affiliations of Guido Kroemer include Karolinska Institutet & Spanish National Research Council.

The Pharmacology of T Cell Apoptosis

Abstract: L’inferno dei viventi non e qualcosa che sara; se ce n’e uno, e quello che e gia qui, l’inferno che abitiamo tutti i giorni, che formiamo stando insieme. Due modi ci sono per non soffrirne. Il primo riesce facile a molti: accettare l’inferno e diventarne parte fino al punto di non verderlo piu. Il secondo e rischioso ed esige attenzione e apprendimento continui: cercare e saper riconoscere chi e cosa, in mezzo all’inferno, non e inferno, e farlo durare, e dargli spazio. Italo Calvino, Le citta invisibili The hell of the living is not something that will arrive in the future; if hell exists, then it is that we are already living in day by day, that we form being together. There are two ways for not suffering from hell. The first results easy for many people: accept hell and become part of it to the point that it you will not see it any more. The second way is risky and requires continuous attention and learning: find out and recognize what, in the middle of hell, does not belong to hell, and help it to last and give room to it. Italo Calvino, The invisible cities

A novel treatment of cystic fibrosis acting on-target: cysteamine plus epigallocatechin gallate for the autophagy-dependent rescue of class II-mutated CFTR.

Abstract: We previously reported that the combination of two safe proteostasis regulators, cysteamine and epigallocatechin gallate (EGCG), can be used to improve deficient expression of the cystic fibrosis transmembrane conductance regulator (CFTR) in patients homozygous for the CFTR Phe508del mutation. Here we provide the proof-of-concept that this combination treatment restored CFTR function and reduced lung inflammation (P<0.001) in Phe508del/Phe508del or Phe508del/null-Cftr (but not in Cftr-null mice), provided that such mice were autophagy-competent. Primary nasal cells from patients bearing different class II CFTR mutations, either in homozygous or compound heterozygous form, responded to the treatment in vitro. We assessed individual responses to cysteamine plus EGCG in a single-centre, open-label phase-2 trial. The combination treatment decreased sweat chloride from baseline, increased both CFTR protein and function in nasal cells, restored autophagy in such cells, decreased CXCL8 and TNF-α in the sputum, and tended to improve respiratory function. These positive effects were particularly strong in patients carrying Phe508del CFTR mutations in homozygosity or heterozygosity. However, a fraction of patients bearing other CFTR mutations failed to respond to therapy. Importantly, the same patients whose primary nasal brushed cells did not respond to cysteamine plus EGCG in vitro also exhibited deficient therapeutic responses in vivo. Altogether, these results suggest that the combination treatment of cysteamine plus EGCG acts 'on-target' because it can only rescue CFTR function when autophagy is functional (in mice) and improves CFTR function when a rescuable protein is expressed (in mice and men). These results should spur the further clinical development of the combination treatment.

Prerequisites for the antitumor vaccine-like effect of chemotherapy and radiotherapy.

Abstract: For a long time, anticancer therapies were believed to work (and hence convey a therapeutic benefit) either by killing cancer cells or by inducing a permanent arrest in their cell cycle (senescence). In both scenarios, the efficacy of anticancer regimens was thought to depend on cancer cellYintrinsic features only. More recently, the importance of the tumor microenvironment (including stromal and immune cells) has been recognized, along with the development of therapies that function by modulating tumor cellYextrinsic pathways. In particular , it has been shown that some chemotherapeutic and radiotherapeutic regimens trigger cancer cell death while stimulating an active immune response against the tumor. Such an immunogenic cell death relies on the coordinated emission of specific signals from dying cancer cells and their perception by the host immune system. The resulting tumor-specific immune response is critical for the eradication of tumor cells that may survive therapy. In this review, we discuss the molecular mechanisms that underlie the vaccine-like effects of some chemotherapeutic and radiotherapeutic regimens, with particular attention to the signaling pathways and genetic elements that constitute the prerequisites for immunogenic anticancer therapy.

Mechanisms of mitochondrial membrane permeabilization.

Abstract: devoted to the topic of mitochondria andtheir role in apoptosis. The reviews are provided by some ofthe world’s leading groups working on this importantsubject.An incontrovertable role for mitochondria in inducingapoptosis and controlling cell death commitment has beenestablished. However, for the past several years, con-troversy has abounded as to the precise mechanisms bywhich mitochondria control cell life/death decisions.Release of cytochrome c from mitochondria couplesthese organelles to a pathway for caspase activation andapoptosis induction. However, inhibiting caspases andpreventing apoptosis does not necessarily protect cellsfrom undergoing cell death via a non-apoptotic mechanismfollowing cytochrome c release. This observation raisesthe question: What is the cell death commitmentmechanism? Theories abound as to why cells sometimesstill die even when caspases are inhibited, and several ofthe competing ideas are reflected in the reviews providedin this issue.Another subject given considerable attention in thereview articles is the question of how cytochrome cescapes from mitochondria, and in particular, how Bcl-2family proteins regulate this event. Several different modelshave been proposed, some involving swelling and ruptureof mitochondria due to problems with inner membranepermeability barrier function and others envisioningselective loss of outer membrane barrier function withoutirreversible damage to these organelles. These differentpoints of view are also articulated in the reviews provided.As will become clear to the reader, the precise details ofthe cytochrome c release mechanism remain controversial,even within the swelling pro and con camps. Thus, nearlyas many opinions are voiced as there are articles on thesubject.Also found within the review articles in this issue isdiscussion of the role of Bcl-2 family proteins as pore-likemolecules, and competing theories about their mechanismsare entertained.Why has so much controversy haunted the field? Partly,the problem may be explained by the technical difficulties ofstudying mitochondria and the imprecise tools (probes)available for monitoring the status of these organelles –their respiratory activity, balances and imbalances of ion-fluxes, and integrity of membranes. In this regard, one ofthe reviews discusses a new technique for local monitoringof pH, using pH-sensitive mutants of the Green FluorescentProtein (GFP), and other contributions in this issue illustratethe diversity of traditional methods that can be brought totask for studying mechanism of mitochondrial participationin apoptosis and cell death. However, it seems probablethat at least some of the present controversy thatcharacterizes the field of apoptosis derives from thelikelihood that more than one mechanism can result inevents such as release of cytochrome c or mitochondrialmembrane depolarization. Thus, it could be argued thateveryone’s model is correct, but only in certain cellularcontexts and scenarios. Regardless, we hope thatapoptosis researchers will find the review articles con-tained in this issue informative, enlightening, and stimulat-ing. May the ideas shared by the authors encourage furtherdebate, and above all, further experimentation.

疟原虫var基因转换速率变化导致抗原变异[英]／Paul H, Robert P, Christodoulou Z, et al//Proc Natl Acad Sci U S A

Abstract: 抗原变异可使得多种致病微生物易于逃避宿主免疫应答。表达在感染红细胞表面的恶性疟原虫红细胞表面蛋白1（PfPMP1）与感染红细胞、内皮细胞、树突状细胞以及胎盘的单个或多个受体作用，在黏附及免疫逃避中起关键的作用。每个单倍体基因组var基因家族编码约60种成员，通过启动转录不同的var基因变异体为抗原变异提供了分子基础。

Apoptosis: A Review of Programmed Cell Death

Abstract: The process of programmed cell death, or apoptosis, is generally characterized by distinct morphological characteristics and energy-dependent biochemical mechanisms. Apoptosis is considered a vital component of various processes including normal cell turnover, proper development and functioning of the immune system, hormone-dependent atrophy, embryonic development and chemical-induced cell death. Inappropriate apoptosis (either too little or too much) is a factor in many human conditions including neurodegenerative diseases, ischemic damage, autoimmune disorders and many types of cancer. The ability to modulate the life or death of a cell is recognized for its immense therapeutic potential. Therefore, research continues to focus on the elucidation and analysis of the cell cycle machinery and signaling pathways that control cell cycle arrest and apoptosis. To that end, the field of apoptosis research has been moving forward at an alarmingly rapid rate. Although many of the key apoptotic proteins have been identified, the molecular mechanisms of action or inaction of these proteins remain to be elucidated. The goal of this review is to provide a general overview of current knowledge on the process of apoptosis including morphology, biochemistry, the role of apoptosis in health and disease, detection methods, as well as a discussion of potential alternative forms of apoptosis.

The blockade of immune checkpoints in cancer immunotherapy

Abstract: Immune checkpoints refer to the plethora of inhibitory pathways that are crucial to maintaining self-tolerance. Tumour cells induce immune checkpoints to evade immunosurveillance. This Review discusses the progress in targeting immune checkpoints, the considerations for combinatorial therapy and the potential for additional immune-checkpoint targets.