Phase 0 clinical trials in cancer drug development: from FDA guidance to clinical practice

The Food and Drug Administration (FDA) recently introduced the Exploratory Investigational New Drug Guidance to expedite the clinical evaluation of new therapeutic and imaging agents. Early clinical studies performed under the auspices of this guidance, so-called "Phase 0" trials, have been initiated at the National Cancer Institute to integrate qualified pharmacodynamic biomarker assays into first-in-human cancer clinical trials of molecularly targeted agents. The goal of this integration is to perform molecular proof-of-concept investigations at the earliest stage of cancer drug development. Phase 0 trials do not offer any possibility of patient benefit; instead, intensive, real-time pharmacodynamic and pharmacokinetic analyses of patient tumor samples and/or surrogate tissues are performed to inform subsequent trials. Phase 0 studies do not replace formal Phase I drug safety testing and require a substantial investment of resources in assay development early on; however, they offer the promise of more rational selection of agents for further, large-scale development as well as the molecular identification of potential therapeutic failures early in the development process.     

Seasonal habitat use of three predatory fishes in a freshwater ecosystem

Hydrobiologia - To understand the spatiotemporal overlap in the habitat use of sympatric predators, we studied longitudinal activity and reservoir section and depth use of pike (Esox lucius),...     

Plant Hormone Metabolome and Transcriptome Analysis of Dwarf and Wild-type Banana

Journal of Plant Growth Regulation - Gibberellin (GA), auxin (IAA) and brassinosteroid (BR) are indispensable in the process of plant growth and development. Currently, research on the regulatory...     

Comparative analysis of the gut microbiota composition between two sea snakes,Hydrophis curtus,and Hydrophis cyanocinctus

Coral Reefs - Gut microbiota plays an important role in host nutrition, metabolism, immune, and homeostasis. Although there has been extensive research on gut microbiota over the past decade, few...     

Acacetin antagonized lipotoxicity in pancreatic β-cells via ameliorating oxidative stress and endoplasmic reticulum stress

Molecular Biology Reports - During the pathogenesis and progression of diabetes, lipotoxicity is a major threat to the function and survival of pancreatic β-cells. To battle against the...     

Hyperhomocysteinemia Induces Rat Memory Impairment Via Injuring Hippocampal CA3 Neurons and Downregulating cAMP Response Element-Binding Protein (CREB) Phosphorylation

Accumulated evidence demonstrated that an elevated plasma homocysteine level, hyperhomocysteinemia, induced cognitive impairment in animals, elderly and the patients with neurodegenerative diseases. To date, the underlying cellular and molecular mechanisms by which hyperhomocysteinemia induces cognitive impairment has not been clearly defined. The purpose of this study was to investigate the possible cellular and molecular mechanisms behind hyperhomocysteinemia signaling in rat memory impairment. The results from this study demonstrated that hyperhomocysteinemia induced neuronal damage and loss in hippocampal CA3 region and downregulated the cAMP response element-binding protein (CREB) phosphorylation. The findings of this study provide evidence that hyperhomocysteinemia induces rat memory impairment via injuring hippocampal CA3 neurons and downregulating CREB phosphorylation.

     

MiR-674-5p Suppresses the Proliferation and Migration of Glioma Cells by Targeting Cul4b

Neurochemical Research - Glioma multiforme (GBM) is the most common malignant primary brain tumors. Despite the considerable advances in GBM treatment, it is still one of the most lethal forms of...     

MsSAMS,a cold stress-responsive gene,provides resistance to environmental stress in T2-generation transgenic plants

The SAMS (S-adenosylmethionine synthetase) gene is known to play an important role in the mechanism of cold resistance, as overexpression of this gene results in phenotypic changes in T₁-generation transgenic plants. Accordingly, this study was conducted to test the expression of the MsSAMS gene in T₂-generation transgenic plants and to investigate the resistance of these plants and the function of the transgene in response to various environmental stresses. For the morphological analysis of T₂-generation transgenic plants overexpressing the MsSAMS gene, observations using scanning electron microscopy (SEM) were performed. T₂-generation transgenic plants were obtained by planting a total of 5 lines, and their characteristics were tested by comparisons with those of the control. SEM revealed that the thickest leaves were produced by the T6 transgenic line—161.24?±?8.05 µm. The number of stomata ranged from 20.00?±?2.65 to 34.00?±?1.00 in the T₂-generation transgenic plants, but the control had more stomata. Resistance to various factors, such as low temperature, drought, and oxidative stress, in the T₂-generation transgenic plants was also confirmed. Under cold-stress conditions, the T6 transgenic line presented the lowest value (22.73%) of ion leakage, and under drought-stress conditions, compared with the control, the transgenic lines presented lower ion leakage after being treated with various concentrations of mannitol. Even under oxidative-stress conditions, the T₂-generation transgenic plants presented ion leakage levels that were 32.91?±?4.24 to 48.33?±?3.54% lower than those of the control after treatment with various concentrations of methyl viologen. Regarding SAMS enzyme activity, as the duration of cold treatment increased, the activity in the transgenic plants tended to decrease and then increase. During 48 h of cold treatment, the control showed a decrease in SAM content, while the T₂-generation transgenic plants presented an increase in SAM content, from 13.58?±?1.04 to 22.75?±?1.95 mg protein/g FW. The results suggest that the MsSAMS gene may be important to the mechanisms of resistance to oxidative and drought stresses in addition to its previously known association with cold resistance. Based on these results, it was suggested that the MsSAMS gene, whose expression is induced by cold stress, can serve as a marker of various responses to environmental stresses, because resistance to cold damage and various environmental stresses are stably inherited in the T₂ generation.

     

黄土丘陵区坡耕地与撂荒地土壤水分对降雨的响应特征

为了揭示黄土丘陵区不同土地覆被方式下土壤含水量对不同强度降雨的响应过程,选取山西省冯家沟小流域农耕地和撂荒地为研究对象,基于2019年4—10月降雨和土壤含水量以小时为单位的观测数据,分析了土壤含水量对不同强度降雨的响应规律。结果表明:(1)小雨、中雨、大雨和暴雨对土层的影响深度分别为20、20、60 cm和60 cm,研究区降雨最主要的形式—小雨对土壤水分的补给作用较小。(2)各强度降雨过程中,除0—10 cm土层外,农耕地土壤含水量均大于撂荒地,且大雨条件下农耕地各土层土壤含水量变化较显著,而撂荒地仅0—10 cm和10—20 cm土层土壤含水量有所增加。(3)不同土层土壤含水量对降雨的响应不同,表层响应相对明显而深层相对减弱;农耕地土壤平均含水量最大值出现在50—60 cm土层,而撂荒地出现在30—40 cm土层。(4)本地区农耕地土壤含水量高于撂荒地,表明在该地区适当的作物种植有较好的储存土壤水分的作用。本研究的结果对地区水资源的高效利用和水土流失防控提供了一定的科学依据。