Angiogenesis requires co-ordination of multiple signalling inputs to regulate the behaviour of endothelial cells (ECs) as they form vascular networks. Vascular endothelial growth factor (VEGF) is essential for angiogenesis and induces downstream signalling pathways including increased cytosolic calcium levels. Here we show that transmembrane protein 33 (tmem33), which has no known function in multicellular organisms, is essential to mediate effects of VEGF in both zebrafish and human ECs. We find that tmem33 localises to the endoplasmic reticulum in zebrafish ECs and is required for cytosolic calcium oscillations in response to Vegfa. tmem33-mediated endothelial calcium oscillations are critical for formation of endothelial tip cell filopodia and EC migration. Global or endothelial-cell-specific knockdown of tmem33 impairs multiple downstream effects of VEGF including ERK phosphorylation, Notch signalling and embryonic vascular development. These studies reveal a hitherto unsuspected role for tmem33 and calcium oscillations in the regulation of vascular development.

The present study aims to test two different doses of aqueous extract of black maca on learning and memory in ovariectomized (OVX) mice and their relation with malonalehyde (MDA), acetylcholinesterase (Ache) and monoamine oxidase (MAO) brain levels. Female mice were divided into five groups: (i) naive (control), (ii) sham, (iii) OVX mice and OVX mice treated with (iv) 0.50 g kg−1 and (v) 2.00 g kg−1 black maca. Mice were orally treated with distilled water or black maca during 35 days starting 7 days after surgery. Memory and learning were assessed using the water Morris maze (from day 23–27) and the step-down avoidance test (days 34 and 35). At the end of each treatment, mice were sacrificed by decapitation and brains were dissected out for MDA, Ache and MAO determinations. Black maca (0.5 and 2.0 g/kg) increased step-down latency when compared to OVX control mice. Black maca decreased MDA and Ache levels in OVX mice; whereas, no differences were observed in MAO levels. Finally, black maca improved experimental memory impairment induced by ovariectomy, due in part, by its antioxidant and Ache inhibitory activities.

The higher calcium retention in boys than in girls was attained through higher net calcium absorption and lower urinary excretion than in girls.

ObjectiveTo present the surgical outcomes of advanced epithelial ovarian cancer (AEOC) since the implementation of a personalized approach and to validate multiple predictive models for R0 resection.MethodsPersonalized strategies included: 1) Non-invasive model: preoperative clinico-radiological assessment according to Suidan criteria with a predictive score for all individuals. Patients with a score 0–2 were recommended for primary debulking surgery (PDS, group A), or otherwise were counseled on the choices of PDS, neoadjuvant chemotherapy (NAC, group B) or staging laparoscopy (S-LPS). 2) Minimally invasive model: S-LPS with a predictive index value (PIV) according to Fagotti. Individuals with a PIV <8 underwent PDS (group C) or otherwise received NAC (group D). Intraoperative assessment (with Eisenkop, peritoneal cancer index [PCI], and Aletti scores) and surgical results were prospectively collected.ResultsBetween September 2015 and August 2017, 161 pathologically confirmed epithelial ovarian cancer patients were included. A total of 52 (32.3%) patients had a predictive score of 0–2, and 109 (67.7%) patients had a score ≥3. Among these individuals, 41 (25.5%) patients received S-LPS. Finally, 110 (68.3%) patients underwent PDS (A+C), and 51 (31.7%) patients received NAC (B+D). The R0 resection rates in PDS and NAC patients were 56.4% and 60.8%, respectively. The area under the curve (AUC) of Suidan criteria was 0.548 for group (A+C). The AUC of Fagotti score was 0.702 for group C. The AUC of Eisenkop, PCI, and Aletti scores were 0.808, 0.797, and 0.524, respectively.ConclusionThe Suidan criteria were not effective in these AEOC patients. S-LPS was helpful in decision-making for PDS and should be endorsed in the future.

Transforming growth factor-β1 (TGF-β1)-induced epithelial-mesenchymal transition (EMT) of non-small-cell carcinoma (NSCLC) may contribute to tumor metastasis. TGF-β1-induced EMT in H1975 cells (a human NSCLC cell line) resulted in the adoption of mesenchymal responses that were predominantly mediated via the TGF-β1-integrin signaling pathway. Ursolic acid has been previously reported to inhibit tumor growth and metastasis in several cancers. However, whether ursolic acid can attenuate TGF-β1-induced EMT in H1975 cells and its underlying mechanisms remains unknown. In this study, ursolic acid significantly attenuated the TGF-β1-induced decrease in E-cadherin level and elevated the level of N-cadherin. Furthermore, ursolic acid inhibited the mesenchymal-like responses in H1975 cells, including cell migration, invasion and activity of matrix metallopeptidase (MMP)-2 and -9. Finally, our new findings provided evidence that, ursolic acid could inhibit EMT in NSCLC through TGF-β1 signaling pathway mediated integrinαVβ5 expression, and this might the potential mechanism of resveratrol on the inhibition of invasion and metastases in NSCLC. We conclude that ursolic acid attenuated TGF-β1-induced EMT in H1975 cells and might be a promising therapeutic agent for treating NSCLC.

Angiopoietin/TIE signalling plays a major role in blood and lymphatic vessel development. In mouse, Tek/Tie2 mutants die prenatally due to a severely underdeveloped cardiovascular system. In contrast, in zebrafish, previous studies have reported that while embryos injected with tek morpholinos (MOs) exhibit severe vascular defects, tek mutants display no obvious vascular malformations. To further investigate the function of zebrafish Tek, we generated a panel of loss-of-function tek mutants, including RNA-less alleles, an allele lacking the MO-binding site, an in-frame deletion allele, and a premature termination codon-containing allele. Our data show that all these mutants survive to adulthood with no obvious cardiovascular defects. MO injections into tek mutants lacking the MO-binding site or the entire tek locus cause similar vascular defects as those observed in MO-injected +/+ siblings, indicating off-target effects of the MOs. Surprisingly, comprehensive phylogenetic profiling and synteny analyses reveal that Tek was lost in the largest teleost clade, suggesting a lineage-specific shift in the function of TEK during vertebrate evolution. Altogether, these data show that Tek is dispensable for zebrafish development, and probably dispensable in most teleost species.

Transgenerational epigenetic inheritance (TEI) is mostly discussed in the context of physiological or environmental factors. Here, we show intergenerational and transgenerational inheritance of transcriptional adaptation (TA), a process whereby mutant messenger RNA (mRNA) degradation affects gene expression, in nematodes and zebrafish. Wild-type offspring of animals heterozygous for mRNA-destabilizing alleles display increased expression of adapting genes. Notably, offspring of animals heterozygous for nontranscribing alleles do not display this response. Germline-specific mutations are sufficient to induce TA in wild-type offspring, indicating that, at least for some genes, mutations in somatic tissues are not necessary for this process. Microinjecting total RNA from germ cells of TA-displaying heterozygous zebrafish can trigger TA in wild-type embryos and in their progeny, suggesting a model whereby mutant mRNAs in the germline trigger a TA response that can be epigenetically inherited. In sum, this previously unidentified mode of TEI reveals a means by which parental mutations can modulate the offspring’s transcriptome.

BackgroundTo assess the effect of visceral adiposity on clinical and pathological characteristics in patients with endometrial cancer.MethodsA retrospective review of medical documentation was performed in surgically treated endometrial cancer patients from January to November 2015 in our institution. The visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) were measured at the level of umbilicus on single-slice computerized tomography. Visceral adiposity (VAT%) was calculated as VAT/(VAT + SAT).ResultsA total of 200 cases were included in the study. Median age at diagnosis was 54 years old. Most patients presented with early-stage tumor (86.0 % for I + II) and endometrioid histology (90.5 %). Positive lymph node occurred in 11.0 % (22/200) of the patients with the median number of retrieved nodes as 25 (range, 4–56). The entire population had a median body mass index (BMI) of 24.7 kg/m2 and median VAT% of 31.89 %. BMI correlated with total adipose tissue (correlation coefficient = 0.667, P < 0.001), but not with VAT% (P = 0.495). Viscerally obese patients tended to be old and post-menopausal (P < 0.001; P = 0.003). Nodal metastasis and extrauterine disease were more commonly reported in patients with high VAT% (6.0 % vs. 16.0 %, P = 0.024; 9.0 % vs. 19.0 %, P = 0.042, respectively). Univariate and multivariate logistic regressions were performed to discern the contribution of variable factors on the lymph node metastasis. Grade (HR = 15.41, 95 % CI = 1.60–148.76; P = 0.018), lympho-vascular invasion (HR = 449.61, 95 % CI = 31.27–6463.93; P < 0.001) and high VAT% (HR = 6.37, 95 % CI = 1.42–28.69; P = 0.016) retained statistical significance for predicting lymph node metastasis.ConclusionsViscerally obese patients were more likely to be old and have positive lymph node as well as extrauterine disease. Grade, lympho-vascular invasion presence and visceral adiposity were predictors of nodal disease.