Nuclear factor erythroid-2 related factor 2 (Nrf2) is a transcription factor that regulates protection against a wide variety of toxic insults to cells, including cytotoxic cancer chemotherapeutic ...drugs. Many lung cancer cells harbor a mutation in either Nrf2 or its inhibitor Keap1 resulting in permanent activation of Nrf2 and chemoresistance. In this study, we sought to examine whether this attribute could be exploited in cancer suicide gene therapy by using a lentiviral (LV) vector expressing herpes simplex virus thymidine kinase (HSV-TK/GCV) under the regulation of antioxidant response element (ARE), a cis-acting enhancer sequence that binds Nrf2. In human lung adenocarcinoma cells in which Nrf2 is constitutively overexpressed, ARE activity was found to be high under basal conditions. In this setting, ARE-HSV-TK was more effective than a vector in which HSV-TK expression was driven by a constitutively active promoter. In a mouse xenograft model of lung cancer, suicide gene therapy with LV-ARE-TK/GCV was effective compared with LV-PGK-TK/GCV in reducing tumor size. We conclude that ARE-regulated HSV-TK/GCV therapy offers a promising approach for suicide cancer gene therapy in cells with high constitutive ARE activity, permitting a greater degree of therapeutic targeting to those cells.
Retinoic acid receptor-related orphan receptor γ (RORc, RORγ, or NR1F3) is the nuclear receptor master transcription factor that drives the function and development of IL-17-producing T helper cells ...(Th17), cytotoxic T cells (Tc17), and subsets of innate lymphoid cells. Activation of RORγ+ T cells in the tumor microenvironment is hypothesized to render immune infiltrates more effective at countering tumor growth. To test this hypothesis, a family of benzoxazines was optimized to provide LYC-55716 (37c), a potent, selective, and orally bioavailable small-molecule RORγ agonist. LYC-55716 decreases tumor growth and enhances survival in preclinical tumor models and was nominated as a clinical development candidate for evaluation in patients with solid tumors.
Randomness of functional Magnetic Resonance Imaging (fMRI) resting-state time-series has recently been used as a biomarker for numerous disorders including Alzheimer's and Parkinson's disease as well ...as autism. To date, however, it remains unknown whether and to what degree personality traits are associated with the randomness of resting-state temporal dynamics. To investigate this question, we estimated the Hurst exponent – a measure of the randomness of a time-series – during resting-state fMRI in brain areas previously associated with trait Impulsivity as defined in Gray's Reinforcement Sensitivity Theory of Personality in 15 healthy individuals. The Hurst exponent in the ventral striatum as well as in the orbitofrontal cortex (OFC) was significantly associated with the measure of Gray's trait Impulsivity. Specifically, more random resting-state neural dynamics corresponded to higher Impulsivity scores both in the ventral striatum (r(15)=−.71; p=.003) and the OFC (r(15)=−.81; p<.001). In summary, we provide evidence for an association between individual differences in Gray's Impulsivity and randomness in key areas of the reward system which have previously been associated with this personality trait. Based on evidence from fMRI and electroencephalographical studies, we suggest that this association might arise from resting-state fluctuations constraining task-related neural responsiveness. Thereby, we outline a potential mechanism linking randomness of resting-state dynamics and personality.
► Randomness of resting-state fMRI predicts personality trait. ► Fractal properties of the time-series in the ventral striatum and the orbitofrontal. ► Cortex are associated with Gray's Impulsivity. ► We suggest a mechanism by which neurodynamics randomness might impact personality.
The therapeutic efficacy of a lentiviral vector (LV) expressing the herpes simplex virus thymidine kinase (HSV-TK) was studied in an immunocompetent rat glioblastoma model. Intraperitoneal ...ganciclovir injections (50 mg/kg/day) were administered for 14 consecutive days, resulting in reduced tumor volumes as monitored by MRI. Survival analyses revealed a significant improvement among the LV-expressing HSV-TK (LV-TK)/ganciclovir-treated animals when compared to non-treated control rats. However, a limiting factor in the use of LV has been the suboptimal small-scale production in flasks. Our aim during the translation phase, prior to entering the final pre-clinical and early clinical phases, was to develop a scalable, robust, and disposable manufacturing process for LV-TKs. We also aimed to minimize future process changes and enable production upscaling to make the process suitable for larger patient populations. The upstream process relies on fixed-bed iCELLis technology and transient plasmid transfection. This is the first time iCELLis 500 commercial-scale bioreactor was used for LV production. A testing strategy to determine the pharmacological activity of LV-TK drug product by measuring cell viability was developed, and the specificity of the potency assay was also proven. In this paper we focus on upstream process development while showing analytical development and the proof-of-concept of LV-TK functionality.
The cell-cell signaling gene
is associated with a wide spectrum of neuropsychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD), autism, and major depression.
regulates ...axonal outgrowth and synapse formation, substantiating its relevance for neurodevelopmental processes. Several studies support the influence of
on personality traits, behavior, and executive functions. However, evidence for functional effects of common gene variation in the
gene in humans is sparse. Therefore, we tested for association of a functional intronic
SNP rs2199430 with ADHD in a sample of 998 adult patients and 884 healthy controls. The Big Five personality traits were assessed by the NEO-PI-R questionnaire. Assuming that altered neural correlates of working memory and cognitive response inhibition show genotype-dependent alterations, task performance and electroencephalographic event-related potentials were measured by n-back and continuous performance (Go/NoGo) tasks. The rs2199430 genotype was not associated with adult ADHD on the categorical diagnosis level. However, rs2199430 was significantly associated with agreeableness, with minor G allele homozygotes scoring lower than A allele carriers. Whereas task performance was not affected by genotype, a significant heterosis effect limited to the ADHD group was identified for the n-back task. Heterozygotes (AG) exhibited significantly higher N200 amplitudes during both the 1-back and 2-back condition in the central electrode position Cz. Consequently, the common genetic variation of
is associated with personality traits and impacts neural processing during working memory tasks. Thus,
might contribute to symptomatic core dysfunctions of social and cognitive impairment in ADHD.
Yezid Sayigh's encylopedic history focuses on the role that the idea of armed struggle played in the Palestinian national movement as it evolved over the past half-century. His central thesis is that ...“armed struggle provided the political impulse and organisational dynamic in the evolution of Palestinian national identity and in the formation of parastatal institutions and a bureaucratic elite, the nucleus of government” (p. vii). The concept of armed struggle reforged Palestinian national identity, mobilized Palestinians, provided political legitimization to the Palestinian movement, made the Palestinians a distinct political actor in relation to the Arab states, helped to create institutions that could form the basis of a government, and established a well-defined political elite. Thus, even though Palestinian leaders never transformed the armed struggle into a people's war along the lines of Algeria or Vietnam, and never liberated any part of Palestine by force, armed struggle served other important, statist functions.
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