Inhibition of DDAH1, but not DDAH2, results in apoptosis of a human trophoblast cell line in response to TRAIL.

STUDY QUESTION: Does inhibition of dimethylarginine dimethylaminohydrolase (DDAH) increase the sensitivity of trophoblasts to TRAIL-induced apoptosis? SUMMARY ANSWER: Inhibition of DDAH1, but not DDAH2, increases the sensitivity of trophoblasts to TRAIL-induced apoptosis. WHAT IS KNOWN ALREADY: Successful human pregnancy is dependent on adequate trophoblast invasion and remodelling of the maternal spiral arteries. Increased trophoblast apoptosis is seen in pregnancies complicated by pre-eclampsia. The mechanism underlying this increase is unknown. We have previously shown that nitric oxide (NO) is involved in regulating trophoblast motility and invasion, and have also demonstrated an important role for NO in regulating trophoblast sensitivity to apoptotic stimuli. DDAH is an enzyme that metabolizes asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthesis, previously shown to be elevated in the plasma of pre-eclamptic mothers. STUDY DESIGN, SIZE, DURATION: This study used the human extravillous trophoblast-derived cell line SGHPL-4 cells. All experiments were performed at least three times. PARTICIPANTS/MATERIALS, SETTING, METHODS: The effect of DDAH on trophoblast apoptosis was examined using siRNA and time-lapse microscopy. Changes in the expression of DDAH were followed by PCR and western blot analysis. Receptor expression was followed by flow cytometry. MAIN RESULTS AND THE ROLE OF CHANCE: Inhibiting the expression of DDAH1, but not DDAH2, resulted in a significant increase in the sensitivity of the EVT cell line SGHPL-4 to tumour necrosis factor related apoptosis inducing ligand (TRAIL) induced apoptosis (P < 0.01). This response could be mimicked by the addition of Asymmetric Dimethylarginine (ADMA), an endogenous inhibitor of NO synthesis and the substrate for both isoforms of DDAH. We further showed that this increased sensitivity to apoptosis is accompanied by a significant increase in the expression of TRAIL receptor 2 (TR2; P < 0.05) but not TRAIL receptor 1 (TR1). LIMITATIONS, REASONS FOR CAUTION: This study was performed only in vitro using a well characterized trophoblast cell line, SGHPL-4, derived from first trimester extravillous trophoblasts. WIDER IMPLICATIONS OF THE FINDINGS: This study provides new insight into the role of the DDAH/ADMA pathway in the regulation of trophoblast function. Both dysregulation of DDAH and the accumulation of ADMA have been associated with the development of pre-eclampsia. This is the first study to implicate the DDAH/ADMA pathway as a mechanism that might underlie the poor trophoblast invasion seen in this common pregnancy disorder. STUDY FUNDING/COMPETING INTERESTS: B.A.L. was supported by a grant from Action Medical Research UK (SP4577). A.E.W. was supported by a grant from the Wellcome Trust (091550). There are no competing interests and the authors have no conflict interest to declare

Artificial intelligence for the management of pancreatic diseases

Novel artificial intelligence techniques are emerging in all fields of healthcare, including gastroenterology. The aim of this review is to give an overview of artificial intelligence applications in the management of pancreatic diseases. We performed a systematic literature search in PubMed and Medline up to May 2020 to identify relevant articles. Our results showed that the development of machine-learning based applications is rapidly evolving in the management of pancreatic diseases, guiding precision medicine in clinical, endoscopic and radiologic settings. Before implementation into clinical practice, further research should focus on the external validation of novel techniques, clarifying the accuracy and robustness of these models.Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Prevalence, features, and explanations of missed and misinterpreted pancreatic cancer on imaging: a matched case-control study

Purpose To characterize the prevalence of missed pancreatic masses and pancreatic ductal adenocarcinoma (PDAC)-related findings on CT and MRI between pre-diagnostic patients and healthy individuals.Materials and methods Patients diagnosed with PDAC (2010-2016) were retrospectively reviewed for abdominal CT- or MRI-examinations 1 month-3 years prior to their diagnosis, and subsequently matched to controls in a 1:4 ratio. Two blinded radiologists scored each imaging exam on the presence of a pancreatic mass and secondary features of PDAC. Additionally, original radiology reports were graded based on the revised RADPEER criteria.Results The cohort of 595 PDAC patients contained 60 patients with a pre-diagnostic CT and 27 with an MRI. A pancreatic mass was suspected in hindsight on CT in 51.7% and 50% of cases and in 1.3% and 0.9% of controls by reviewer 1 (p < .001) and reviewer 2 (p < .001), respectively. On MRI, a mass was suspected in 70.4% and 55.6% of cases and 2.9% and 0% of the controls by reviewer 1 (p < .001) and reviewer 2 (p < .001), respectively. Pancreatic duct dilation, duct interruption, focal atrophy, and features of acute pancreatitis is strongly associated with PDAC (p < .001). In cases, a RADPEER-score of 2 or 3 was assigned to 56.3% of the CT-reports and 71.4% of MRI-reports.Conclusion Radiological features as pancreatic duct dilation and interruption, and focal atrophy are common first signs of PDAC and are often missed or unrecognized. Further investigation with dedicated pancreas imaging is warranted in patients with PDAC-related radiological findings.Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Elastic electron deuteron scattering with consistent meson exchange and relativistic contributions of leading order

The influence of relativistic contributions to elastic electron deuteron scattering is studied systematically at low and intermediate momentum transfers ($Q^2\leq 30$ fm$^{-2}$). In a $(p/M)$-expansion, all leading order relativistic $\pi$-exchange contributions consistent with the Bonn OBEPQ models are included. In addition, static heavy meson exchange currents including boost terms and lowest order $\rho\pi\gamma$-currents are considered. Sizeable effects from the various relativistic two-body contributions, mainly from $\pi$-exchange, have been found in form factors, structure functions and the tensor polarization $T_{20}$. Furthermore, static properties, viz. magnetic dipole and charge quadrupole moments and the mean square charge radius are evaluated.Comment: 15 pages Latex including 5 figures, final version accepted for publication in Phys.Rev.C Details of changes: (i) The notation of the curves in Figs. 1 and 2 have been clarified with respect to left and right panels. (ii) In Figs. 3 and 4 an experimental point for T_20 has been added and a corresponding reference [48] (iii) At the end of the text we have added a paragraph concerning the quality of the Bonn OBEPQ potential

Macrophage polarisation affects their regulation of trophoblast behaviour

Introduction During the first trimester of human pregnancy, fetally-derived extravillous trophoblast (EVT) cells invade into uterine decidua and remodel the uterine spiral arteries to ensure that sufficient blood reaches the maternal-fetal interface. Decidual macrophages have been implicated in the regulation of decidual remodelling and aberrant activation of these immune cells is associated with pre-eclampsia. Methods The monocytic cell line THP-1 was activated to induce an M1 or M2 phenotype and the conditioned media was used to treat the EVT cell line SGHPL-4 in order to determine the effect of macrophage polarisation on trophoblast behaviour in-vitro. SGHPL-4 cell functions were assessed using time-lapse microscopy, endothelial-like tube formation assays and western blot. Results The polarisation state of the THP-1 cells was found to differentially alter the behaviour of trophoblast cells in-vitro with pro-inflammatory M1 conditioned media significantly inhibiting trophoblast motility, impeding trophoblast tube formation, and inducing trophoblast expression of caspase 3, when compared to anti-inflammatory M2 conditioned media. Discussion Macrophages can regulate trophoblast functions that are critical during decidual remodelling in early pregnancy. Importantly, there is differential regulation of trophoblast function in response to the polarisation state of these cells. Our studies indicate that the balance between a pro- and anti-inflammatory environment is important in regulating the cellular interactions at the maternal-fetal interface and that disturbances in this balance likely contribute to pregnancy disorders associated with poor trophoblast invasion and vessel remodelling

Artificial intelligence in gastroenterology: a state-of-the-art review

The development of artificial intelligence (AI) has increased dramatically in the last 20 years, with clinical applications progressively being explored for most of the medical specialties. The field of gastroenterology and hepatology, substantially reliant on vast amounts of imaging studies, is not an exception. The clinical applications of AI systems in this field include the identification of premalignant or malignant lesions (e.g., identification of dysplasia or esophageal adenocarcinoma in Barrett's esophagus, pancreatic malignancies), detection of lesions (e.g., polyp identification and classification, small-bowel bleeding lesion on capsule endoscopy, pancreatic cystic lesions), development of objective scoring systems for risk stratification, predicting disease prognosis or treatment response [e.g., determining survival in patients post-resection of hepatocellular carcinoma), determining which patients with inflammatory bowel disease (IBD) will benefit from biologic therapy], or evaluation of metrics such as bowel preparation score or quality of endoscopic examination. The objective of this comprehensive review is to analyze the available AI-related studies pertaining to the entirety of the gastrointestinal tract, including the upper, middle and lower tracts; IBD; the hepatobiliary system; and the pancreas, discussing the findings and clinical applications, as well as outlining the current limitations and future directions in this field.Cellular mechanisms in basic and clinical gastroenterology and hepatolog

Investigating Predictors of Preserved Cognitive Function in Older Women Using Machine Learning: Women's Health Initiative Memory Study

Background: Identification of factors that may help to preserve cognitive function in late life could elucidate mechanisms and facilitate interventions to improve the lives of millions of people. However, the large number of potential factors associated with cognitive function poses an analytical challenge. Objective: We used data from the longitudinal Women's Health Initiative Memory Study (WHIMS) and machine learning to investigate 50 demographic, biomedical, behavioral, social, and psychological predictors of preserved cognitive function in later life. Methods: Participants in WHIMS and two consecutive follow up studies who were at least 80 years old and had at least one cognitive assessment following their 80th birthday were classified as cognitively preserved. Preserved cognitive function was defined as having a score ≥39 on the most recent administration of the modified Telephone Interview for Cognitive Status (TICSm) and a mean score across all assessments ≥39. Cognitively impaired participants were those adjudicated by experts to have probable dementia or at least two adjudications of mild cognitive impairment within the 14 years of follow-up and a last TICSm score < 31. Random Forests was used to rank the predictors of preserved cognitive function. Results: Discrimination between groups based on area under the curve was 0.80 (95%-CI-0.76-0.85). Women with preserved cognitive function were younger, better educated, and less forgetful, less depressed, and more optimistic at study enrollment. They also reported better physical function and less sleep disturbance, and had lower systolic blood pressure, hemoglobin, and blood glucose levels. Conclusion: The predictors of preserved cognitive function include demographic, psychological, physical, metabolic, and vascular factors suggesting a complex mix of potential contributors

Cognitive Function and Changes in Cognitive Function as Predictors of Incident Cardiovascular Disease: The Women's Health Initiative Memory Study

Background Cognitive impairment and decline may signal the increased risk of incident cardiovascular disease (CVD). We examined associations of global cognitive function, as measured by the Modified Mini-Mental State Examination (3MS) and changes in 3MS over time, with incident CVD, individual CVD outcomes, CVD death, and all-cause mortality. Methods A total of 5,596 women (≥ 60) from the Women's Health Initiative Memory Study free of CVD at baseline were followed for an average of 7.1 years. The 3MS was measured at baseline and annually thereafter. Cox proportional hazards regressions were used to model associations between baseline 3MS and changes in 3MS and time to events. Results In the fully-adjusted models for every 5-point lower baseline 3MS score, the risk was 12% greater for incident CVD, 37% for HF, 35% for CVD death, and 24% for all-cause mortality. No significant relationships were found for coronary heart disease (CHD), angina, stroke/transient ischemic attack (TIA), or coronary revascularization. When change in 3MS was added as a time-varying covariate in the fully-adjusted models, for every 1-point/year greater decline in 3MS, the risk was 4% greater for incident CVD, 10% for CHD, 9% for Stroke/TIA, 17% for CVD death, and 13% for all-cause mortality. Conclusions In older women free of prevalent CVD at baseline, lower baseline global cognitive function or decline in global cognitive function over time, increased risk of incident CVD, CVD death, and all-cause mortality