Dynamic transcriptome analysis reveals signatures of paradoxical effect of vemurafenib on human dermal fibroblasts

Background Vemurafenib (PLX4032) is one of the most frequently used treatments for late-stage melanoma patients with the BRAFV600E mutation; however, acquired resistance to the drug poses as a major challenge. It remains to be determined whether off-target effects of vemurafenib on normal stroma components could reshape the tumor microenvironment in a way that contributes to cancer progression and drug resistance. Methods By using temporally-resolved RNA- and ATAC-seq, we studied the early molecular changes induced by vemurafenib in human dermal fibroblast (HDF), a main stromal component in melanoma and other tumors with high prevalence of BRAFV600 mutations. Results Transcriptomics analyses revealed a stepwise up-regulation of proliferation signatures, together with a down-regulation of autophagy and proteolytic processes. The gene expression changes in HDF strongly correlated in an inverse way with those in BRAFV600E mutant malignant melanoma (MaMel) cell lines, consistent with the observation of a paradoxical effect of vemurafenib, leading to hyperphosphorylation of MEK1/2 and ERK1/2. The transcriptional changes in HDF were not strongly determined by alterations in chromatin accessibility; rather, an already permissive chromatin landscape seemed to facilitate the early accessibility to MAPK/ERK-regulated transcription factor binding sites. Combinatorial treatment with the MEK inhibitor trametinib did not preclude the paradoxical activation of MAPK/ERK signaling in HDF. When administered together, vemurafenib partially compensated for the reduction of cell viability and proliferation induced by trametinib. These paradoxical changes were restrained by using the third generation BRAF inhibitor PLX8394, a so-called paradox breaker compound. However, the advantageous effects on HDF during combination therapies were also lost. Conclusions Vemurafenib induces paradoxical changes in HDF, enabled by a permissive chromatin landscape. These changes might provide an advantage during combination therapies, by compensating for the toxicity induced in stromal cells by less specific MAPK/ERK inhibitors. Our results highlight the relevance of evaluating the effects of the drugs on non-transformed stromal components, carefully considering the implications of their administration either as mono- or combination therapies.

The COVID-19 Crisis in Romania: A Hypothesis around Penal Populism and Legal Culture

In this paper I seek to present a working hypothesis to be eventually developed in a future contribution, namely that the COVID-19 crisis exposed some problematic behaviours evocative of an authoritarian ethos on the part of both public authorities and citizens which suggest that a penal populist attitude might now be part or even embedded in the Romanian legal culture. Specifically, I will organize this contribution as follows: in the first part, I will briefly describe Romania’s reaction (as evidenced both in the official measures taken and the attitude of citizens) to the first wave of the pandemic focusing on the role of penal and military means; I shall qualify this reaction as containing some traces of penal populism. In the second part I shall offer a tentative mapping of the factors that can explain this problematic cultural reaction. Importantly, among these I include the successful fight against corruption with the consequence that what appears to have very much consolidated the rule of law in post-1989 Romania could be shown to have had the unintended and paradoxical effect of undermining the very same ideal.

The Paradoxical Effect Hypothesis of Abused Drugs in a Rat Model of Chronic Morphine Administration

A growing body of studies has recently shown that abused drugs could simultaneously induce the paradoxical effect in reward and aversion to influence drug addiction. However, whether morphine induces reward and aversion, and which neural substrates are involved in morphine’s reward and aversion remains unclear. The present study first examined which doses of morphine can simultaneously produce reward in conditioned place preference (CPP) and aversion in conditioned taste aversion (CTA) in rats. Furthermore, the aversive dose of morphine was determined. Moreover, using the aversive dose of 10 mg/kg morphine tested plasma corticosterone (CORT) levels and examined which neural substrates were involved in the aversive morphine-induced CTA on conditioning, extinction, and reinstatement. Further, we analyzed c-Fos and p-ERK expression to demonstrate the paradoxical effect—reward and aversion and nonhomeostasis or disturbance by morphine-induced CTA. The results showed that a dose of more than 20 mg/kg morphine simultaneously induced reward in CPP and aversion in CTA. A dose of 10 mg/kg morphine only induced the aversive CTA, and it produced higher plasma CORT levels in conditioning and reacquisition but not extinction. High plasma CORT secretions by 10 mg/kg morphine-induced CTA most likely resulted from stress-related aversion but were not a rewarding property of morphine. For assessments of c-Fos and p-ERK expression, the cingulate cortex 1 (Cg1), prelimbic cortex (PrL), infralimbic cortex (IL), basolateral amygdala (BLA), nucleus accumbens (NAc), and dentate gyrus (DG) were involved in the morphine-induced CTA, and resulted from the aversive effect of morphine on conditioning and reinstatement. The c-Fos data showed fewer neural substrates (e.g., PrL, IL, and LH) on extinction to be hyperactive. In the context of previous drug addiction data, the evidence suggests that morphine injections may induce hyperactivity in many neural substrates, which mediate reward and/or aversion due to disturbance and nonhomeostasis in the brain. The results support the paradoxical effect hypothesis of abused drugs. Insight from the findings could be used in the clinical treatment of drug addiction.

Atopic Dermatitis as a Paradoxical Effect of Secukinumab for the Treatment of Psoriasis

In the therapeutic arsenal to treat moderate to severe psoriasis, the new agents are secukinumab and ustekinumab, which are fully human monoclonal antibodies, directed against IL-17A and IL-12/23, respectively, which have been shown to be effective and safe in several studies. Their side effects are rare, and the most frequently reported side effects were infection, especially nasopharyngitis, headache, pruritus, high blood pressure, and low back pain. Unlike the side effects, the paradoxical reaction can be defined by the appearance or exacerbation of a pathological condition that usually responds to a certain class of drug. The appearance of this reaction in patients using anti-interleukins is poorly described; however, as they are new drugs, they may be more common than the literature reports. We describe a case of a paradoxical reaction, with the appearance of atopic dermatitis, after using secukinumab to treat psoriasis.

The Paradoxical Effect of Social Media Usage on Developer Creativity and the Moderating Role of Openness to Experience

Developer creativity is vital for software companies to innovate and survive. Studies on social media have yielded mixed results about its impact on creativity due to the ubiquitous nature of social media. This research differentiates the effects of informational and socializing social media usage on both incremental and radical creativity and explore the moderating role of a developer's openness to experience. Based on a survey of software developers, the authors show that openness positively moderates the impact of informational social media usage on incremental and radical creativity and negatively moderates the impact of socializing social media usage on both types of creativity. There is a stronger positive moderation for the relationship between informational social media usage and radical creativity compared to incremental creativity. The results provide a foundation for understanding explanations of the paradoxical effect of social media usage on creativity.