Preclinical models of idiosyncratic drug-induced liver injury (iDILI): Moving towards prediction

Idiosyncratic drug-induced liver injury (iDILI) encompasses the unexpected harms that prescription and non-prescription drugs, herbal and dietary supplements can cause to the liver. iDILI remains a major public health problem and a major cause of drug attrition. Given the lack of biomarkers for iDILI prediction, diagnosis and prognosis, searching new models to predict and study mechanisms of iDILI is necessary. One of the major limitations of iDILI preclinical assessment has been the lack of correlation between the markers of hepatotoxicity in animal toxicological studies and clinically significant iDILI. Thus, major advances in the understanding of iDILI susceptibility and pathogenesis have come from the study of well-phenotyped iDILI patients. However, there are many gaps for explaining all the complexity of iDILI susceptibility and mechanisms. Therefore, there is a need to optimize preclinical human

Minimum quality threshold in pre-clinical sepsis studies (MQTiPSS): quality thresholds for study design and humane modeling endpoints / 中华危重病急救医学

Preclinical animal studies are mandatory before new treatments can be tested in clinical trials. However, their use in developing new therapies for sepsis has been controversial because of limitations of the models and inconsistencies with the clinical conditions. In consideration of the revised definition for clinical sepsis and septic shock (Sepsis-3), a Wiggers-Bernard Conference was held in Vienna in May 2017 to propose standardized guidelines on preclinical sepsis modeling. The participants conducted a literature review of 260 most highly cited scientific articles on sepsis models published between 2003 and 2012. The review showed, for example, that mice were used in 79% and euthanasia criteria were defined in 9% of the studies. PartⅠof this report details the recommendations for study design and humane modeling endpoints that should be addressed in sepsis models. The first recommendation is that survival follow-up should reflect the clinical time course of the infectious agent used in the sepsis model. Furthermore, it is recommended that therapeutic interventions should be initiated after the septic insult replicating clinical care. To define an unbiased and reproducible association between a new treatment and outcome, a randomization and blinding of treatments as well as inclusion of all methodological details in scientific publications is essential. In all preclinical sepsis studies, the high standards of animal welfare must be implemented. Therefore, development and validation of specific criteria for monitoring pain and distress, and euthanasia of septic animals, as well as the use of analgesics are recommended. A set of four considerations is also proposed to enhance translation potential of sepsis models. Relevant biological variables and comorbidities should be included in the study design and sepsis modeling should be extended to mammalian species other than rodents. In addition, the need for source control (in case of a defined infection focus) should be considered. These recommendations and considerations are proposed as "best practices" for animal models of sepsis that should be implemented.

Minimum quality threshold in pre-clinical sepsis studies (MQTiPSS): quality thresholds for study design and humane modeling endpoints / 中华危重病急救医学

Preclinical animal studies are mandatory before new treatments can be tested in clinical trials. However, their use in developing new therapies for sepsis has been controversial because of limitations of the models and inconsistencies with the clinical conditions. In consideration of the revised definition for clinical sepsis and septic shock (Sepsis-3), a Wiggers-Bernard Conference was held in Vienna in May 2017 to propose standardized guidelines on preclinical sepsis modeling. The participants conducted a literature review of 260 most highly cited scientific articles on sepsis models published between 2003 and 2012. The review showed, for example, that mice were used in 79% and euthanasia criteria were defined in 9% of the studies. PartⅠof this report details the recommendations for study design and humane modeling endpoints that should be addressed in sepsis models. The first recommendation is that survival follow-up should reflect the clinical time course of the infectious agent used in the sepsis model. Furthermore, it is recommended that therapeutic interventions should be initiated after the septic insult replicating clinical care. To define an unbiased and reproducible association between a new treatment and outcome, a randomization and blinding of treatments as well as inclusion of all methodological details in scientific publications is essential. In all preclinical sepsis studies, the high standards of animal welfare must be implemented. Therefore, development and validation of specific criteria for monitoring pain and distress, and euthanasia of septic animals, as well as the use of analgesics are recommended. A set of four considerations is also proposed to enhance translation potential of sepsis models. Relevant biological variables and comorbidities should be included in the study design and sepsis modeling should be extended to mammalian species other than rodents. In addition, the need for source control (in case of a defined infection focus) should be considered. These recommendations and considerations are proposed as "best practices" for animal models of sepsis that should be implemented.

The Role of Invariant Natural Killer T Cells in Cancer.

Invariant natural killer T (iNKT) cells are a unique subset of T lymphocytes that recognize glycolipid antigens presented by the class I-like non-polymorphic histocompatibility complex (MHC) molecule, CD1d. They express both innate and adaptive immune cells’ surface receptors, but act more like cells of the innate immune system. Although iNKT cells represent a relatively small population of T lymphocytes, they can rapidly produce copious amounts of cytokines after activation which can polarize different axes of the immune response. Many glycolipid agonists have been discovered of which the marine sponge-derivative called α-Galactosylceramide (α-GalCer) is a potent ligand for iNKT cells. iNKT cells have been described by many researchers as a critical immunotherapeutic target characterized by having tumor-suppressive potential. However, their actual role in immune responses is still unclear. In addition, the need for appropriate preclinical models that mimic human diseases is important for better understanding the iNKT cell biology. This review describes the characteristics of iNKT cells and their role in immunotherapy in cancers such as multiple myeloma and how they can interact with the components of the neighbouring environment.

The development of preclinical safety evaluation models for microbicides / 中国艾滋病性病

Sexual transmission of HIV-1 has recently become the predominant route over the world.As an effective HIV vaccine has been elusive so far,microbicides,which are usually applied at topical mucosal sites to prevent vaginal or rectal mucosa from HIV-1 infection,have been paid ever increasing attentions.The failure of previous clinical trials have demonstrated that it is critical to ensure the safety and efficacy of microbicides before they move forward into clinical trials.In this review,we have summarized recent progress in preclinical models evaluating the safety and efficacy of microbicides,including cell culture in vitro,mucosal explant and animal models in vivo which are used at different phases during the preclinical development of microbicides,and have elaborated the characteristics of these models and their advantages.Finally,we emphasize the urgent need to establish effective evaluation systems at molecular levels for different models,which may serve as good surrogates to predict the inflammation and HIV infection in future clinical testing.