Identification of novel membrane markers in circulating tumor cells of mesenchymal state in breast cancer.

Cancer metastasis is a major cause of cancer-related deaths worldwide. The ability to detect and monitor circulating tumor cells (CTCs) offers a promising approach to early detection and management of metastasis. Although studies on epithelial markers for CTC detection are actively underway, the discovery of mesenchymal markers has not been studied sufficiently. In this study, we developed a new pipeline to identify membrane markers in CTCs of mesenchymal state in breast cancer based on expression profiles of the 310 CTC samples. From the total CTC samples, only CTC samples in the mesenchymal state were collected by employing hierarchical clustering. In samples belonging to the mesenchymal state, we calculated the correlation coefficients between 1995 membrane genes and ZEB2, which was determined as the key mesenchymal signature, allowing the 84 positively correlated genes. Furthermore, to ensure clinical significance, Kaplan-Meier analysis were performed on the 124 breast cancer patients, resulting in the 14 genes predicting prognosis. By exploring genes commonly identified in the both analyses, F11R and PTGIR were characterized as membrane markers in CTCs of mesenchymal state in breast cancer, which were evaluated by enriched terms, literature evidence, and relevant molecular pathways. We expect that the results will be helpful to more effective strategies for metastasis management.

[4+2]-Cycloaddition of 2-Aminophenyl Enones with Cyclic N-Sulfimines to Access Enantioenriched Ring-Fused Aminals.

Ring-fused aminal is an interesting structural skeleton in biologically active and pharmaceutically relevant compounds. A novel and efficient method for synthesizing benzosulfamidate-fused tetrahydroquinazolines is described. By employing the [4+2]-cycloaddition of 2-aminophenyl enones with cyclic N-sulfimines in the presence of DMAP as a base, the desired benzosulfamidate-fused tetrahydroquinazolines were obtained in good yields with high diastereoselectivities. Furthermore, an organocatalytic asymmetric [4+2]-cycloaddition was successfully achieved using a squaramide-based catalyst, enabling the enantioselective synthesis of chiral ring-fused tetrahydroquinazolines with high yields and enantio- as well as diastereoselectivities (up to 89 % yield, 94 % ee, and >30 : 1 dr).

Enantioselective effect of trifloxystrobin in early-stage zebrafish (Danio rerio) embryos: Cardiac abnormalities impacted by E,E-trifloxystrobin enantiomer.

Trifloxystrobin (TFS) is one of the extensively used strobilurin fungicides, which is composed of four enantiomers and its active form is E,E-TFS. In this study, we assess the acute toxicity of four enantiomers, E,E-, E,Z-, Z,E-, and Z,Z-TFS in zebrafish (Danio rerio) embryos. Among the four enantiomers, only E,E-TFS was found to be acutely toxic, with an estimated LC50 value of 0.68 mg/L. Treatment with E,E-TFS resulted in various phenotypic changes in the embryos, including pericardial and yolk-sac edema, spine curvature, and blood pooling. And it shortened the whole body length in the treated embryos by increasing the total intersegmental vessel numbers using a Tg(fli1a:EGFP) zebrafish line. Further study using Tg(cmlc2:EGFP) zebrafish line revealed that E,E-TFS treatment was associated with cardiac malformations, a failure of heart function, and a lowered heartbeat rate at the concentration of 0.25 mg/L. Also, the differential gene expression analysis identified significant down-regulation of vmhc and cacna1c genes encoding ventricular myosin heavy chain and calcium voltage-gated channel subunit alpha 1C, which are crucial for heart development. These results suggest the need for regular monitoring of E,E-TFS enantiomers after field application and further research into their potential chronic effects on environmental organisms.

Heart Rate Variability as a Potential Indicator of Cancer Pain in a Mouse Model of Peritoneal Metastasis.

Heart rate variability (HRV) is closely related to changes in the autonomic nervous system (ANS) associated with stress and pain. In this study, we investigated whether HRV could be used to assess cancer pain in mice with peritoneal metastases. At 12 days after cancer induction, positive indicators of pain such as physiological characteristics, appearance, posture, and activity were observed, and time- and frequency-domain HRV parameters such as mean R-R interval, square root of the mean squared differences of successive R-R intervals, and percentage of successive R-R interval differences greater than 5 ms, low frequency (LF), high frequency (HF), and ratio of LF and HF power, were found to be significantly decreased. These parameters returned to normal after analgesic administration. Our results indicate that overall ANS activity was decreased by cancer pain and that HRV could be a useful tool for assessing pain.

Acute and developmental toxic effects of mono-halogenated and halomethyl naphthalenes on zebrafish (Danio rerio) embryos: Cardiac malformation after 2-bromomethyl naphthalene exposure.

Polyhalogenated polycyclic aromatic hydrocarbons (HPAHs) represent a major environmental concern due to their persistency and toxicity. Among them, mono-halogenated (HNs) and halomethyl naphthalenes (HMNs) are not well-studied, and the toxicity of many HNs to fishes has not been reported. In this study, we exposed zebrafish (Danio rerio) embryos to naphthalene and five HNs at concentrations ranging from 0.25 to 2.0 mg L-1 to assess acute toxicities and developmental effects. Among them, 2-bromomethyl naphthalene (2-BMN) produced moderate lethal effects (96-h LC50 = 1.4 mg L-1) and significantly reduced hatchability. Abnormal phenotypes, including pericardial edema, spine curvature, and shortened body length, were also induced by 2-BMN (96-h EC50 = 0.45 mg L-1). Treatments of 0.5-2.0 mg L-1 2-BMN evoked cardiac malformations via significant down-regulation of the cacna1c gene, which codes the voltage-dependent calcium channel, at 72 hpf and up-regulation of the nppa gene, responsible for the expression of natriuretic peptides, at 96 hpf in zebrafish. One presumable toxic photo-dissociated metabolite of 2-BMN, the 2-naphthylmethyl radical, may be responsible for the toxic effect on zebrafish embryos. HPAHs must be monitored and managed due to their adverse effects on living organisms at low concentrations.

The Rho/Rac Guanine Nucleotide Exchange Factor Vav1 Regulates Hif-1α and Glut-1 Expression and Glucose Uptake in the Brain.

Vav1 is a Rho/Rac (Ras-related C3 botulinum toxin substrate) guanine nucleotide exchange factor expressed in hematopoietic and endothelial cells that are involved in a wide range of cellular functions. It is also stabilized under hypoxic conditions when it regulates the accumulation of the transcription factor HIF (Hypoxia Inducible Factor)-1α, which activates the transcription of target genes to orchestrate a cellular response to low oxygen. One of the genes induced by HIF-1α is GLUT (Glucose Transporter)-1, which is the major glucose transporter expressed in vessels that supply energy to the brain. Here, we identify a role for Vav1 in providing glucose to the brain. We found that Vav1 deficiency downregulates HIF-1α and GLUT-1 levels in endothelial cells, including blood-brain barrier cells. This downregulation of GLUT-1, in turn, reduced glucose uptake to endothelial cells both in vitro and in vivo, and reduced glucose levels in the brain. Furthermore, endothelial cell-specific Vav1 knock-out in mice, which caused glucose uptake deficiency, also led to a learning delay in fear conditioning experiments. Our results suggest that Vav1 promotes learning by activating HIF-1α and GLUT-1 and thereby distributing glucose to the brain. We further demonstrate the importance of glucose transport by endothelial cells in brain functioning and reveal a potential new axis for targeting GLUT-1 deficiency syndromes and other related brain diseases.

Use of complementary and alternative medicine in pregnancy: a cross-sectional survey on Iraqi women.

BACKGROUND: Due to the lack of strong evidence on safety and efficacy of complementary and alternative medicine (CAM) approaches, the use of CAM in women during pregnancy could be hazardous for mother and fetus. Meanwhile, little is known regarding the patterns, the reasons and the factors affecting use of CAM among pregnant women in Iraq. METHODS: A cross sectional survey design was used to carry out face-to-face interviews with 335 consecutive pregnant women. The questionnaire comprised of three sections: socio-demographic characteristics, pregnancy-related aspects and the patterns and attitudes towards use of CAM. Determinants of CAM use were assessed through the logistic regression analysis. RESULTS: Three hundred thirty-five pregnant women completed the questionnaire. 56.7 % reported using at least one form of CAM modalities. In total, 24 different types of CAM were used; with herbal medicine (53.7 %) and multivitamins (36.3 %) the most commonly used modalities. From the logistic regression analysis, the variables positively associated with CAM use were: rural residence (odds ratio (OR) 2.0, p < 0.01), no occupation (OR 2.7, p < 0.05), high income (OR 2.0, p < 0.05), perceived healthy status (OR 2.6, p < 0.05) and ever use of contraception (OR 2.0, p < 0.01). Only 0.5 % of CAM users disclosed their CAM use to physicians. CONCLUSIONS: The proportion of CAM users among pregnant women is relatively high and it is important to learn what types of CAM they use. However, disclosure of CAM use was extraordinarily low. Given the low rate of disclosure, it should be ensured that physicians establish good level of communication with pregnant women and have adequate knowledge of CAM.

A diastereoselective carbocyclisation of allene-hydrazones through the intramolecular allylic transfer reaction.

A diastereoselective synthesis of cyclic hydrazines was achieved from a carbocyclisation of allene-hydrazones by the Pd-catalyzed distannylation of an allene moiety, followed by the transmetallation of allylic stannane intermediates with TiCl4.

Gliotoxin reduces the severity of trinitrobenzene sulfonic acid-induced colitis in mice: evidence of the connection between heme oxygenase-1 and the nuclear factor-kappaB pathway in vitro and in vivo.

BACKGROUND: Gliotoxin, a fungal metabolite, has been known to show strong immunosuppressive properties, although its mechanisms are not completely understood. In this report, the authors investigated the mechanism whereby gliotoxin has anti-inflammatory properties in vitro and in trinitrobenzene sulfonic acid-induced colitis. MATERIALS AND METHODS: Body weight, histological scores, and myeloperoxidase activity were evaluated in trinitrobenzene sulfonic acid colitis. Nuclear factor-kappaB (NF-kappaB) p65, tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-12, and intercellular adhesion molecule-1 were detected by immunohistochemical staining. IL-8 secretion was measured by an enzyme-linked immunosorbent assay. Heme oxygenase-1 (HO-1) expression and I-kappaB degradation were analyzed by Western blot. RESULTS: Pretreatment of human epithelial HT-29 cells with gliotoxin significantly blocked the I-kappaB degradation and NF-kappaB p65 nuclear translocation induced by tumor necrosis factor-alpha or IL-1beta; these were parallel with the inhibition of IL-8 secretion and intercellular adhesion molecule-1 expression in the same cells. Interestingly, gliotoxin induced HO-1 in HT-29 cells and, in turn, inhibition of HO-1 activity by a zinc protoporphyrin IX reversed the effects of gliotoxin in terms of I-kappaB degradation, intercellular adhesion molecule-1 expression, and IL-8 production. In trinitrobenzene sulfonic acid colitis, gliotoxin administration significantly improved the clinical and histopathological symptoms. Notably, gliotoxin also induced HO-1 in the colonic mucosa and zinc protoporphyrin IX reversed the protective effects of gliotoxin in trinitrobenzene sulfonic acid colitis. CONCLUSIONS: These results demonstrate for the first time that the anti-inflammatory actions mediated by gliotoxin include HO-1 induction and the subsequent blockade of NF-kappaB-dependent signaling pathways in vitro and in vivo. The current results also demonstrate that gliotoxin may be an effective agent for the treatment of diseases characterized by mucosal inflammation.