Signaling pathways and stem cells in uterus and fallopian tubes

During her fertile years, the endometrium of fertile women undergoes regular cycles of regeneration, differentiation and shedding, driven by changing concentrations of the steroid hormones estradiol and progesterone. In the present study, the role of Wnt/β-catenin signaling in relation to steroid hormone signaling and the balance between proliferation and differentiation was investigated. Furthermore, since the consequence of hormone signaling in the endometrium is tissue degradation followed by regeneration, the role of stem cells was also investigated. Chapter 1, the introductory chapter, reviews what is known about a functional link between steroid hormone signaling, Wnt/β-catenin signaling, and endometrial physiology. In the normal human menstrual cycle, estradiol induces proliferation during the first two weeks, whereas during the third and fourth week of the cycle progesterone inhibits this estradiol-induced proliferation thus stimulating cellular differentiation. The two steroid hormones also play a role in oncogenesis of the endometrium: unbalanced hormone signaling can induce endometrial hyperplasia which may continue to develop into endometrial cancer. Elevated estrogen receptor signaling, caused for example by overweight or use of the synthetic analog tamoxifen, significantly increases the risk of endometrial carcinogenesis. The role of Wnt signaling in initiation, development and function of the female reproductive tract, investigated, in particular for mouse, is significant. There are good indications that hormonal regulation of the human menstrual cycle during reproductive life is also mediated by estrogen-induced activation and progesterone-induced inhibition of Wnt/β-catenin signaling. Similar to elevated estradiol signaling, constitutive activation of canonical Wnt signaling has been associated with the development of human endometrial cancer. Activation of Wnt/β-catenin signaling can be caused by mutations that affect β-catenin degradation, in women and in mouse models. These mutations result in β-catenin protein stabilization which, upon translocation to the nucleus, can activate transcription of Wnt/β-catenin target genes. Chapter 2 describes the role of constitutive activation of Wnt/β-catenin signaling during uterine development using a novel mouse model (Amhr2Cre/+;Apc15lox/15lox). It was observed that the promoter of Amhr2 was mainly active in myometrial cells. Furthermore, PCR results confirmed that recombination of the Apc15lox allele occurred exclusively in the myometrial region of the uterus. Consequently, the main phenotype in these Apc conditional knock-down mice was loss and aberrant organization of the myometrial muscle fibers. As a result, endometrial tissue was sometimes observed in the myometrial layer, a phenomenon which in our opinion is a passive rather than an active invasion process. A mouse model to activate Wnt/β-catenin signaling specifically in the epithelial cells of the developing Mϋllerian ducts, unfortunately is not available. Hence, we cannot exclude that there might be an additional role for this signaling pathway, directly targeting the epithelial cells and their derivatives. As described in Chapter 3, it was investigated how progesterone regulates Wnt/β-catenin signaling. Among the genes regulated by progesterone in patients, DKK1 and FOXO1 as well as genes encoding other known inhibitors of Wnt/β-catenin signaling, were identified and selected for further investigations. First, it was established that during progesterone-driven inhibition of Wnt/β-catenin signaling, both DKK1 and FOXO1 gene expression were induced. Secondly, it was observed that progesterone could not inhibit Wnt/β-catenin signaling in the endometrial cancer cell lines in the absence of DKK1 and FOXO1 (by the use of lentiviral sequence-specific shRNAs). To put the observed results in a clinical perspective, patient samples (hormone treated endometria, hyperplasia and endometrial cancers) were evaluated for Wnt signaling activation using a histochemical approach. On the basis of these results it was concluded that the Wnt inhibitory effect of progesterone action is likely to play a rate-limiting role in the maintenance of endometrial homeostasis and, upon loss of progesterone signaling, in tumor onset and progression towards malignancy. In Chapter 4, the research focused on the identification, characterization and isolation of stem cells of the female reproductive tract is presented. The initial observations were well in line with those published in several papers by the group of Gargett et al. (2004, 2006, 2009), where they reported short-term label-retaining cells in the uterus. In subsequent experiments, we found a new population of long-term label-retaining cells at the distal oviduct. These cells were isolated and were shown to be able to form undifferentiated spheroids in stem cell medium, to self-renew upon re-culture of spheroid cells, and to differentiate into glandular structures which expressed markers of mature Műllerian epithelial cells. Based on these findings, it is suggested that these quiescent, stem-like cells located within the distal oviduct might contribute to the homeostasis of at least part of the female genital tract, in particular concerning the cyclic regeneration of the epithelial lining of the endometrium and the maintenance of the oviduct. Chapter 5 provides a general discussion, where the significance of the current findings is put into a broader perspective

Numerical weather prediction wind correction methods and its impact on computational fluid dynamics based wind power forecasting

Numerical weather prediction (NWP) of wind speed (WS) is an important input to wind power forecasting (WPF), which its accuracy will limit the WPF performance. This paper proposes three NWP correcting methods based on the multiple linear regression, a radial basis function neural network, and an Elman neural network. The proposed correction methods exhibit small sample learning and efficient computational ability. So, they are in favour of forecasting the performance of planned large-scale wind farms. To this end, a physical WPF model based on computational fluid dynamics is used to demonstrate the impact of improving the NWP WS data based forecasting. A certain wind farm located in China is selected as the case study, and the measured and NWP WS forecasts before and after correction are taken as inputs to the WPF model. Results show that all three correction methods improve the precision of the NWP WS forecasts, with the nonlinear correction models performing a little better than the linear one. Compared with the original NWP, the three corrected NWP WS have higher annual, single point, and short-term prediction accuracy. As expected, the accuracy of wind power forecasting will increase with the accuracy of the input NWP WS forecast. Moreover, the WS correction enhances the consistency of error variation trends between input WS and output wind power. The proposed WS correction methods greatly improve the accuracy of both original NWP WS and the WPF derived from them

Impact of wind farm wake steering control on blade root load

Yaw misalignment is known to affect blade root loads on wind turbines. Most of previous studies concentrate on yaw misalignment in the context of wake steering control, aiming at increasing the total output power of the wind farm. There, wake steering is compared with greedy control, in which yaw misalignment is considered to be 0. In reality, yaw misalignment also occurs in greedy control due to changes in wind direction arising from varying inflow conditions (e.g. turbulence). This paper aims at comparing these two sources of yaw misalignment-naturally changing wind direction versus active yaw in wake steering-in terms of blade root loads. To this end, SCADA data from a real wind farm is used to get yaw misalignment statistics in actual greedy control conditions. FAST.Farm is used to simulate three wind turbines arranged in series, to study maximum and damage-equivalent loads corresponding to in-plane and out-of-plane bending moments on the blades. The results show that compared with actual greedy control, wake steering control reduces the maximum load from the upstream wind turbine, but increases it from other wind turbines. Concerning the damage-equivalent loads from all wind turbines, the blade's in-plane moment is reduced, but the blade's out-of-plane moment is increased.Impact of wind farm wake steering control on blade root loadacceptedVersio

Pre- and post-diagnosis diabetes as a risk factor for all-cause and cancer-specific mortality in breast, prostate, and colorectal cancer survivors: a prospective cohort study

Objective: The relationship between diabetes and all- and cause-specific mortality in individuals with common cancers (breast, colorectal, and prostate) remains both under-researched and poorly understood. Methods: Cancer survivors (N = 37,993) from the National Health Interview Survey with linked data retrieved from the National Death Index served as our study participants. Cox proportional-hazards models were used to assess associations between pre- and post-diabetes and all-cause and cause-specific mortality. Results: Over a median follow-up period of 13 years, 2,350 all-cause, 698 cancer, and 506 CVD deaths occurred. Among all cancer survivors, patients with diabetes had greater risk of: all-cause mortality [hazard ratio (HR) 1.35, 95% CI = 1.27–1.43], cancer-specific mortality (HR: 1.14, 95% CI = 1.03–1.27), CVD mortality (HR: 1.36, 95% CI = 1.18–1.55), diabetes related mortality (HR: 17.18, 95% CI = 11.51–25.64), and kidney disease mortality (HR: 2.51, 95% CI = 1.65–3.82), compared with individuals without diabetes. The risk of all-cause mortality was also higher amongst those with diabetes and specific types of cancer: breast cancer (HR: 1.28, 95% CI = 1.12–1.48), prostate cancer (HR: 1.20, 95% CI = 1.03–1.39), and colorectal cancer (HR: 1.29, 95% CI = 1.10–1.50). Diabetes increased the risk of cancer-specific mortality among colorectal cancer survivors (HR: 1.36, 95% CI = 1.04–1.78) compared to those without diabetes. Diabetes was associated with higher risk of diabetes-related mortality when compared to non-diabetic breast (HR: 9.20, 95% CI = 3.60–23.53), prostate (HR: 18.36, 95% CI = 6.01–56.11), and colorectal cancer survivors (HR: 12.18, 95% CI = 4.17–35.58). Both pre- and post-diagnosis diabetes increased the risk of all-cause mortality among all cancer survivors. Cancer survivors with diabetes had similar risk of all-cause and CVD mortality during the second 5 years of diabetes and above 10 years of diabetes as compared to non-diabetic patients. Conclusions: Diabetes increased the risk of all-cause mortality among breast, prostate, and colorectal cancer survivors, not for pre- or post-diagnosis diabetes. Greater attention on diabetes management is warranted in cancer survivors with diabetes

One Possible Mechanism of Pulsed Dye Laser Treatment on Infantile Hemangioma: Induction of Endothelial Apoptosis and Serum vascular endothelial growth factor (VEGF) Level Changes

Introduction: Pulsed dye laser (PDL) is an important treatment for superficial infantile hemangioma, but few studies report on its cellular mechanism. The aim of this study was to evaluate alterations of serum vascular endothelial growth factor (VEGF) level in infantile hemangioma (IH) patients after laser treatment and effects of PDL irradiation on human umbilical vein endothelial cells (HUVECs) in vitro, as well as to explore the biomolecular mechanisms and ultrastructure changes of the PDL effect.Methods: 74 children with infant hemangioma including 45 patients in proliferating phase, 18 patients in involuting phase, 11 patients in involuted phase and 10 healthy children were engaged in this study. The plasma VEGF levels of children were measured with the enzyme-linked immunosorbent assay (ELISA). 24 hours after, HUVECs cultured in vitro were irradiated with PDL, cell apoptosis, mRNA levels of VEGF, and changes of ultrastructure were evaluated using flow cytometry, real-time reverse transcriptase polymerase chain reaction (RT-PCR), and transmission electron microscopy, respectively.Results: The serum VEGF concentrations in children with proliferating hemangiomas were significantly higher than in patients with involuting / involved hemangiomas and healthy patients. After receiving 3 laser treatments, the plasma VEGF levels of IH patients in proliferating hemangiomas decreased significantly. PDL irradiation could down-regulate VEGF mRNA expression of HUVECs, and increase cell apoptosis rate. Conclusion: The present study demonstrates that PDL irradiation imparts apoptosis induction effects on HUVECs in vitro. Furthermore, our results suggest that vascular endothelial growth factor may be of particular importance in pathophysiology and PDL treatment of hemangiomas, also serum VEGF levels may be used as an aid in the follow up of IH. This provides valuable evidence of the PDL effect on infantile hemangioma

Improving the Predictability of Severe Convective Weather Processes by Using Wind Vectors and Potential Temperature Changes: A Case Study of a Severe Thunderstorm

Strong, local convective weather events are capable of causing extensive damage, but weather observation systems with limited resolution and radar monitoring can typically provide only a few minutes to hours of prior warning time. This paper presents a comprehensive case study of the cumulative evolution of several characteristic quantities during one extremely severe convective weather process. The research results indicate that the main feature of strong convective weather is the uneven distribution of thermal energy in the atmosphere, and the structure of this heat distribution determines the level of instability in the atmosphere. A vertical “clockwise rolling current” occurs in the wind field structure at the beginning of the process, and this is accompanied by a rapid drop in temperature at the top of the troposphere. When these signs occurred in the case study, radar technology was used to refine the precipitation region and spatial characteristics of the approaching storm. The height and vertical evolution of radar echoes were indicative of the characteristics of the system’s movement through space. Such findings may be useful for improving the forecasting times for strong convective weather

Similarity and Potential Relation Between Periimplantitis and Rheumatoid Arthritis on Transcriptomic Level: Results of a Bioinformatics Study

Background: This bioinformatics study aimed to reveal potential cross-talk genes, related pathways, and transcription factors between periimplantitis and rheumatoid arthritis (RA). Methods: The datasets GSE33774 (seven periimplantitis and eight control samples) and GSE106090 (six periimplantitis and six control samples) were included from the National Center for Biotechnology Information (NCBI) Gene Expression Omnibus (GEO). A differential expression analysis (p < 0.05 and |logFC (fold change)| ≥ 1) and a functional enrichment analysis (p < 0.05) were performed. Based on this, a protein–protein interaction (PPI) network was constructed by Cytoscape. RA-related genes were extracted from DisGeNET database, and an overlap between periimplantitis-related genes and these RA-related genes was examined to identify potential cross-talk genes. Gene expression was merged between two datasets, and feature selection was performed by Recursive Feature Elimination (RFE) algorithm. For the feature selection cross-talk genes, support vector machine (SVM) models were constructed. The expression of these feature genes was determined from GSE93272 for RA. Finally, a network including cross-talk genes, related pathways, and transcription factors was constructed. Results: Periimplantitis datasets included 138 common differentially expressed genes (DEGs) including 101 up- and 37 downregulated DEGs. The PPI interwork of periimplantitis comprised 1,818 nodes and 2,517 edges. The RFE method selected six features, i.e., MERTK, CD14, MAPT, CCR1, C3AR1, and FCGR2B, which had the highest prediction. Out of these feature genes, CD14 and FCGR2B were most highly expressed in periimplantitis and RA. The final activated pathway–gene network contained 181 nodes and 360 edges. Nuclear factor (NF) kappa B signaling pathway and osteoclast differentiation were identified as potentially relevant pathways. Conclusions: This current study revealed FCGR2B and CD14 as the most relevant potential cross-talk genes between RA and periimplantitis, which suggests a similarity between RA and periimplantitis and can serve as a theoretical basis for future research

Dissecting the Immunological Profiles in NSD3-Amplified LUSC through Integrative Multi-Scale Analyses.

The histone H3 lysine 36 (H3K36) methyltransferase NSD3, a neighboring gene of FGFR1, has been identified as a critical genetic driver of lung squamous cell carcinoma (LUSC). However, the molecular characteristics, especially the immunological roles of NSD3 in driving carcinogenesis, are poorly understood. In this study, we systematically integrated multi-omics data (e.g., genome, transcriptome, proteome, and TMA array) to dissect the immunological profiles in NSD3-amplified LUSC. Next, pharmaco-transcriptomic correlation analysis was implemented to identify the molecular underpinnings and therapeutic vulnerabilities in LUSC. We revealed that NSD3-amplified LUSC presents a non-inflamed tumor immune microenvironment (TIME) state in multiple independent LUSC patient cohorts. Predictably, elevated NSD3 expression was correlated with a worse immunotherapy outcome. Further molecular characterizations revealed that the high activity of unfolded protein response (UPR) signaling might be a pivotal mediator for the non-immunogenic phenotype of NSD3-amplified LUSC. Concordantly, we showed that NSD3-amplified LUSCs exhibited a more sensitive phenotype to compounds targeting UPR branches than the wild-type group. In brief, our multi-level analyses point to a previously unappreciated immunological role for NSD3 and provide therapeutic rationales for NSD3-amplified squamous lung cancer