Exosomes transferring long non-coding RNA FAL1 to regulate ovarian cancer metastasis through the PTEN/AKT signaling pathway.

The article "Exosomes transferring long non-coding RNA FAL1 to regulate ovarian cancer metastasis through the PTEN/AKT signaling pathway, by Q. Zhang, T.-Y. Len, S.-X. Zhang, Q.-H. Zhao, L.-H. Yang, published in Eur Rev Med Pharmacol Sci 2020; 24 (1): 43-54-DOI: 10.26355/eurrev_202001_19894-PMID: 31957817" has been withdrawn from the authors stating that "after the manuscript has been accepted, we are ready to continue to study the exosomes and their mechanism of action. Before the research, we read the latest guideline of exosomes research, MISEV2018. This guideline first suggests that extracellular vesicles should be used to refer to these cell-derived noncellular membrane structures, while exosomes are only applicable to those vesicles released from intracellular sources to extracellular cells by special means. Secondly, the guidelines suggest that when performing key functional verification experiments with extracellular vesicles, methods such as density gradient centrifugation should be used to purify the vesicles. Thirdly, strict negative control should be set up in the functional study of cells, such as cell-conditioned medium treated with extracellular vesicle production inhibitor (GW4869), so as to exclude the false positive of other non-extracellular vesicle components in functional analysis. In our published manuscripts, we called extracellular vesicles as exosomes, and used exosomes separation kit with low purity to separate the exosomes. No appropriate negative control is used in the functional analysis. Most importantly, the conclusion we made in our study is "SKOV3-secreted exosomes inhibited the PTEN/AKT signaling pathway by transferring lncRNA FAL1, thus inhibiting OC cell metastasis in vitro and in vivo". However, the study did not confirm whether lncRNA FAL1 was encapsulated by extracellular vesicles and transferred to OC cells or induced by extracellular vesicles to upregulate its expression in OC cells. Based on the above reasons, we believe that our understanding of extracellular vesicles is not deep enough, which leads to the inaccuracy and over-interpretation of the experimental results. In order to avoid the readers' misunderstanding of extracellular vesicles and ensure the preciseness of scientific research, all of our authors decided to withdraw this article. We will conduct our research again according to MISEV2018, interpret the experimental results and write articles again, and will submit to ERMPS in the near future". The Publisher apologizes for any inconvenience this may cause. https://www.europeanreview.org/article/19894.

Exosomes transferring long non-coding RNA FAL1 to regulate ovarian cancer metastasis through the PTEN/AKT signaling pathway.

OBJECTIVE: Tumor-derived exosomes have been repeatedly studied as tumor antigens, suppressing T-cell signaling molecules and promoting apoptosis in ovarian cancer (OC). Long non-coding RNAs (lncRNAs) have been recognized as major regulators in tumorigenesis, including OC. For this study, we try to find out the mechanism of exosomes and lncRNA FAL1 in OC. MATERIALS AND METHODS: After the extraction and identification of exosomes, the internalization of exosomes was observed. Invasion and migration experiments were conducted to investigate the effect of SKOV3 cells-secreted exosomes on OC tumorigenesis and metastasis. Furthermore, the in vivo findings were verified via xenograft tumors in nude mice. FAL1 was knocked out on exosomes. OC cells treated with exosomes were co-cultured with lncRNA FAL1 or/and PTEN to measure cell invasion and migration. RESULTS: SKOV3-secreted exosomes were absorbed and internalized by OC cells. After exosome treatment, the migration and invasion of OC cells were enhanced, tumors in nude mice were larger and heavier, metastasis was increased, and lncRNA FAL1 expression was increased. When lncRNA FAL1 was knocked out, the promoting effects of SKOV3 cells-secreted exosomes on OC cell metastasis were weakened, along with increased PTEN level and decreased AKT phosphorylation level. In HO-8910PM cells treated with siRNA-FAL1 exosomes and siRNA-PTEN, cell invasion and migration, and AKT phosphorylation were restored. CONCLUSIONS: SKOV3-secreted exosomes inhibited the PTEN/AKT signaling pathway by transferring lncRNA FAL1, thus inhibiting OC cell metastasis in vitro and in vivo.

Cerebrovascular pathophysiology following mild traumatic brain injury.

Mild traumatic brain injury (mTBI) or sport-induced concussion has recently become a prominent concern not only in the athletic setting (i.e. sports venue) but also in the general population. The majority of research to date has aimed at understanding the neurological and neuropsychological outcomes of injury as well as return-to-play guidelines. Remaining relatively unexamined has been the pathophysiological aspect of mTBI. Recent technological advances including transcranial Doppler ultrasound and near infrared spectroscopy have allowed researchers to examine the systemic effects of mTBI from rest to exercise, and during both asymptomatic and symptomatic conditions. In this review, we focus on the current research available from both human and experimental (animal) studies surrounding the pathophysiology of mTBI. First, the quest for a unified definition of mTBI, its historical development and implications for future research is discussed. Finally, the impact of mTBI on the control and regulation of cerebral blood flow, cerebrovascular reactivity, cerebral oxygenation and neuroautonomic cardiovascular regulation, all of which may be compromised with mTBI, is discussed.

Bexarotene: a clinical review.

Bexarotene (Targretin, Ligand Pharmaceuticals Inc.) is a synthetic retinoid analog with specific affinity for the retinoid X receptor and belongs to a group of compounds called rexinoids. Early clinical trials of this drug demonstrated activity in cutaneous T-cell lymphoma. Subsequent Phase II/III trials have demonstrated a greater than 50% response rate in patients with all stages of cutaneous T-cell lymphoma who were refractory or intolerant to the previous therapy. The principal toxicities of bexarotene include central hypothyroidism, xeroderma and elevation of cholesterol and triglycerides. These toxicities can be managed with dose attenuation or addition of atorvastatin (Lipitor, Pfizer) or fenofibrate (TriCor, Abbott Laboratories). Since bexarotene has little bone marrow toxicity, it is an excellent candidate for combination therapy with other modalities useful in the treatment of cutaneous T-cell lymphoma. These include ultraviolet B irradiation, psoralen and ultraviolet A photochemotherapy, interferons, denileukin diftitox (Ontak, Ligand Pharmaceuticals Inc.) and cytotoxic chemotherapy. Bexarotene has also been investigated in the treatment of breast cancer and non-small cell carcinoma of the lung with promising early results.

Orally active oxime derivatives of the dopaminergic prodrug 6-(N,N-di-n-propylamino)-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one. Synthesis and pharmacological activity.

A series of racemic and enantiomerically pure oxime derivatives of the potential anti-Parkinson prodrug 6-(N,N-di-n-propylamino)-3,4,5,6,7,8-hexahydro-2H-naphthalen-1-one (1) were synthesized and pharmacologically evaluated. The oximes induced rotational behavior in the Ungerstedt rat rotation model for Parkinson's disease after oral administration. Especially the unsubstituted oxime ((-)-3) and the acetyl-oxime ((-)-10) induced a pronounced and long lasting effect. In this model, large individual differences were observed in responsiveness to treatment between rats. Though less potent than the parent prodrug, the oxime derivatives of (+/-)-1 and (-)-1 can be orally active, acting as cascade prodrugs.

Plant species diversity as a driver of early succession in abandoned fields: a multi-site approach.

Succession is one of the most studied processes in ecology and succession theory provides strong predictability. However, few attempts have been made to influence the course of succession thereby testing the hypothesis that passing through one stage is essential before entering the next one. At each stage of succession ecosystem processes may be affected by the diversity of species present, but there is little empirical evidence showing that plant species diversity may affect succession. On ex-arable land, a major constraint of vegetation succession is the dominance of perennial early-successional (arable weed) species. Our aim was to change the initial vegetation succession by the direct sowing of later-successional plant species. The hypothesis was tested that a diverse plant species mixture would be more successful in weed suppression than species-poor mixtures. In order to provide a robust test including a wide range of environmental conditions and plant species, experiments were carried out at five sites across Europe. At each site, an identical experiment was set up, albeit that the plant species composition of the sown mixtures differed from site to site. Results of the 2-year study showed that diverse plant species mixtures were more effective at reducing the number of natural colonisers (mainly weeds from the seed bank) than the average low-diversity treatment. However, the effect of the low-diversity treatment depended on the composition of the species mixture. Thus, the effect of enhanced species diversity strongly depended on the species composition of the low-diversity treatments used for comparison. The effects of high-diversity plant species mixtures on weed suppression differed between sites. Low-productivity sites gave the weakest response to the diversity treatments. These differences among sites did not change the general pattern. The present results have implications for understanding biological invasions. It has been hypothesised that alien species are more likely to invade species-poor communities than communities with high diversity. However, our results show that the identity of the local species matters. This may explain, at least partly, controversial results of studies on the relation between local diversity and the probability of being invaded by aliens.

Ketamine blocks a conditioned taste aversion (CTA) in neonatal rats.

These experiments explored the effects of glutamate, N-methyl-D-aspartate (NMDA) receptor blockade on the formation, retention, and expression of conditioned taste aversion (CTA) in young rats. Previous data from our laboratory suggested that ketamine administration potentiates a CTA in E18 rat fetuses. The current studies investigated this phenomenon in neonates. High-pressure liquid chromatography (HPLC) methods were used to determine the amount of ketamine that must be injected intraperitoneally (i.p.) to achieve brain ketamine levels in neonates comparable to those found in the fetuses from our previous experiments. Then, on their day of birth, Sprague-Dawley rat pups received injections of either 0.1, 10, or 70 mg/kg of ketamine HCI, i.p. or a Sal control injection. One-half hour later, pups were injected orally with either Saccharin (Sac; 10 microL of 0.3%) or water followed by an injection of either lithium chloride (LiCl; 81 mg/kg) or Sal (i.p.). The CTA was evaluated in two different tests. Two weeks after conditioning, the dam was anesthetized and the frequency with which pups attached to Sac-painted nipples versus nipples painted with water was measured (i.e., the nipple taste test, NTT). Controls for state-dependent learning were run in which 10 mg/kg of ketamine or saline (Sal) was administered before both taste aversion conditioning and the NTT. After weaning, the CTA was also evaluated by measuring the amount of Sac (0.3%) or water consumed during a two-bottle test. Neonates that received Sal control injections before the Sac + LiCl pairing acquired CTAs and avoided Sac-painted nipples. However, the pups injected with ketamine on the conditioning day only (P0) did not avoid Sac-painted nipples (as compared to controls). Pups that had ketamine both at the time of CTA training and testing, or just before the NTT, also failed to avoid Sac-painted nipples. Ketamine's acute effects apparently influenced the outcome of the NTT of state-dependent control subjects. Rat pups that received the highest doses of ketamine (10 or 70 mg/kg) and tasted Sac on P0 later failed to show a neophobia for Sac-painted nipples. Whereas, rat pups that received the high dose of ketamine and water on P0, later exhibited a neophobic response. These data suggest that ketamine did not impair the animal's ability to taste Sac. These data reflecting a ketamine-induced blockade of neonatal CTAs may be contrasted with our previous findings in which ketamine potentiated fetal CTAs. However, they are in consonance with data from adult rats suggesting that ketamine can cause an amnesia for CTAs. NMDA receptor blockade may shape memory formation in a manner that is dependent on the stage of brain development.