ENDOCRINE TUMOURS: Advances in the molecular pathogenesis of thyroid cancer: lessons from the cancer genome

Thyroid cancer is the most common endocrine malignancy giving rise to one of the most indolent solid cancers, but also one of the most lethal. In recent years, systematic studies of the cancer genome, most importantly those derived from The Cancer Genome Altas (TCGA), have catalogued aberrations in the DNA, chromatin, and RNA of the genomes of thousands of tumors relative to matched normal cellular genomes and have analyzed their epigenetic and protein consequences. Cancer genomics is therefore providing new information on cancer development and behavior, as well as new insights into genetic alterations and molecular pathways. From this genomic perspective, we will review the main advances concerning some essential aspects of the molecular pathogenesis of thyroid cancer such as mutational mechanisms, new cancer genes implicated in tumor initiation and progression, the role of non-coding RNA, and the advent of new susceptibility genes in thyroid cancer predisposition. This look across these genomic and cellular alterations results in the reshaping of the multistep development of thyroid tumors and offers new tools and opportunities for further research and clinical development of novel treatment strategies.

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Disease activity and lifestyle influence comorbidities and cardiovascular events in patients with acromegaly

Objective

The primary objective of this study is to identify the predictors of comorbidities and major adverse cardiovascular events (MACE) that can develop after diagnosis of acromegaly. The role of therapy for acromegaly in the event of such complications was also evaluated.

Design and methods

Retrospective cohort study was conducted on 200 consecutive acromegalic patients in a tertiary referral center. The following outcomes were evaluated: diabetes, hypertension and MACE. Each patient was included in the analysis of a specific outcome, unless they were affected when acromegaly was diagnosed, and further classified as follows: (i) in remission after adenomectomy (Hx), (ii) controlled by somatostatin analogues (SSA) (SSAc) or (iii) not controlled by SSA (SSAnc). Data were evaluated using Cox regression analysis.

Results

After diagnosis of acromegaly, diabetes occurred in 40.8% of patients. The SSAnc group had a three-fold higher risk of diabetes (HR: 3.32, P = 0.006), whereas the SSAc group had a 1.4-fold higher risk of diabetes (HR: 1.43, P = 0.38) compared with the Hx group. Hypertension occurred in 35.5% of patients, after diagnosis. The determinants of hypertension were age (HR: 1.06, P = 0.01) and BMI (HR: 1.05, P = 0.01). MACE occurred in 11.8% of patients, after diagnosis. Age (HR: 1.09, P = 0.005) and smoking habit (HR: 5.95, P = 0.01) were predictors of MACE. Conversely, therapy for acromegaly did not influence hypertension or MACE.

Conclusion

After diagnosis of acromegaly, control of the disease (irrespective of the type of treatment) and lifestyle are predictors of comorbidities and major adverse cardiovascular events.

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ENDOCRINE TUMOURS: Imaging in the follow-up of differentiated thyroid cancer: current evidence and future perspectives for a risk-adapted approach

The clinical and epidemiological profiles of differentiated thyroid cancers (DTCs) have changed in the last three decades. Today's DTCs are more likely to be small, localized, asymptomatic papillary forms. Current practice is, though, moving toward more conservative approaches (e.g. lobectomy instead of total thyroidectomy, selective use of radioiodine). This evolution has been paralleled and partly driven by rapid technological advances in the field of diagnostic imaging. The challenge of contemporary DTCs follow-up is to tailor a risk-of-recurrence-based management, taking into account the dynamic nature of these risks, which evolve over time, spontaneously and in response to treatments. This review provides a closer look at the evolving evidence-based views on the use and utility of imaging technology in the post-treatment staging and the short- and long-term surveillance of patients with DTCs. The studies considered range from cervical US with Doppler flow analysis to an expanding palette of increasingly sophisticated second-line studies (cross-sectional, functional, combined-modality approaches), which can be used to detect disease that has spread beyond the neck and, in some cases, shed light on its probable outcome.

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Impact of proton pump inhibitor treatment on pancreatic beta-cell area and beta-cell proliferation in humans

Introduction

Gastrin has been shown to promote beta-cell proliferation in rodents, but its effects in adult humans are largely unclear. Proton pump inhibitors (PPIs) lead to endogenous hypergastrinaemia, and improved glucose control during PPI therapy has been reported in patients with diabetes. Therefore, we addressed whether PPI treatment is associated with improved glucose homoeostasis, islet cell hyperplasia or increased new beta-cell formation in humans.

Patients and methods

Pancreatic tissue specimens from 60 patients with and 33 patients without previous PPI therapy were examined. The group was subdivided into patients without diabetes (n = 27), pre-diabetic patients (n = 31) and patients with diabetes (n = 35).

Results

Fasting glucose and HbA_1c levels were not different between patients with and without PPI therapy (P = 0.34 and P = 0.30 respectively). Beta-cell area was higher in patients without diabetes than in patients with pre-diabetes or diabetes (1.33 ± 0.12%, 1.05 ± 0.09% and 0.66 ± 0.07% respectively; P < 0.0001). There was no difference in beta-cell area between patients with and without PPI treatment (1.05 ± 0.08% vs 0.87 ± 0.08%, respectively; P = 0.16). Beta-cell replication was rare and not different between patients with and without PPI therapy (P = 0.20). PPI treatment was not associated with increased duct-cell replication (P = 0.18), insulin expression in ducts (P = 0.28) or beta-cell size (P = 0.63).

Conclusions

These results suggest that in adult humans, chronic PPI treatment does not enhance beta-cell mass or beta-cell function to a relevant extent.

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Hypothyroidism incidence in and around pregnancy: a Danish nationwide study

Objective

Immunological changes in and after a pregnancy may influence the onset of autoimmune diseases. An increased incidence of hyperthyroidism has been observed both in early pregnancy and postpartum, but it remains to be studied if the incidence of hypothyroidism varies in a similar way.

Design

Population-based cohort study using Danish nationwide registers.

Method

All women who gave birth to a singleton live-born child in Denmark from 1999 to 2008 (n = 403 958) were identified, and data on hospital diagnosis of hypothyroidism and redeemed prescriptions of thyroid hormone were extracted. The overall incidence rate (IR) of hypothyroidism during 1997–2010 and the IR in three-month intervals before, during and after the woman's first pregnancy in the study period were calculated and compared with the IR of hyperthyroidism.

Results

Altogether 5220 women were identified with onset of hypothyroidism from 1997 to 2010 (overall IR 92.3/100 000/year) and 1572 women developed hypothyroidism in the period from 2 years before to 2 years after birth of the first child in the study period. The incidence of hypothyroidism decreased during the pregnancy (incidence rate ratio (IRR) vs overall IR in the rest of the study period: first trimester: 0.89 (95% CI: 0.66–1.19), second trimester: 0.71 (0.52–0.97), third trimester: 0.29 (0.19–0.45)) and increased after birth with the highest level at 4–6 months postpartum (IRR 3.62 (2.85–4.60)).

Conclusion

These are the first population-based data on the incidence of hypothyroidism in and around pregnancy. The incidence declined during pregnancy followed by a sharp increase postpartum. Notably, hypothyroidism as opposed to hyperthyroidism showed no early pregnancy increase.

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Congenital hypothyroidism with delayed TSH elevation in low-birth-weight infants: incidence, diagnosis and management

Objective

To evaluate the incidence of congenital hypothyroidism (CH) with delayed TSH elevation among low-birth-weight (LBW) newborns in North-Eastern Italy and to verify if they need a second or third screening.

Design

Analysis of clinical and biochemical data of newborns affected by CH with delayed TSH elevation identified by neonatal screening.

Methods

Data of all newborns with birth weight (BW) <2500 g and evidence of delayed TSH elevation at newborn screening were collected between 2011 and 2014. Confirmatory tests were based on serum TSH and FT₄ levels. All their clinical signs at diagnosis were reported.

Results

57.5% of LBW newborns with delayed TSH increase at neonatal screening presented a CH with delayed TSH elevation and began a treatment with l-thyroxine. The incidence of this condition in North-Eastern Italy is therefore 1:908. The remaining infants presented a subclinical hypothyroidism (21.25%) or a complete normal serum thyroid function (21.25%). These data could be drawn only from a retesting strategy of neonatal screening.

Conclusions

Our report describes the incidence of CH with delayed TSH rise in North-Eastern Italy and differentiates this clinical condition from other thyroid dysfunctions of preterm or LBW newborns. The second-screening strategy for CH in neonates with BW < 2500 g proved useful in detecting newborns who otherwise would not be identified at the first screening.

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IFC (Ed. Board)

Publication date: September 2016
Source:Brain Research Bulletin, Volume 126, Part 2





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Live imaging of inhibitory axons: Synapse formation as a dynamic trial-and-error process

Publication date: Available online 5 October 2016
Source:Brain Research Bulletin
Author(s): Corette J. Wierenga
In this review I discuss recent live imaging studies that demonstrate that synapses, and in particular inhibitory synapses, are highly dynamic structures. The ongoing changes of presynaptic boutons within axons emphasize the stochastic aspect of inhibitory synapse formation and paint a picture of a dynamic trial-and-error process. Furthermore, I discuss recent and previous insights in the molecular and mechanistic pathways that underlie synapse formation, with a specific focus on the formation of inhibitory presynaptic boutons.



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Pathology of Human Pheochromocytoma and Paraganglioma Xenografts in NSG Mice

Abstract

A major impediment to the development of effective treatments for metastatic or unresectable pheochromocytomas and paragangliomas has been the absence of valid models for pre-clinical testing. Attempts to establish cell lines or xenografts from human pheochromocytomas and paragangliomas have previously been unsuccessful. NOD-scid gamma (NSG) mice are a recently developed strain lacking functional B-cells, T-cells, and NK cells. We report here that xenografts of primary human paragangliomas will take in NSG mice while maintaining their architectural and immunophenotypic characteristics as expressed in the patients. In contrast to grafts of cell lines and of most common types of primary tumors, the growth rate of grafted paragangliomas is very slow, accurately representing the growth rate of most pheochromocytomas and paragangliomas even in metastases in humans. Although the model is therefore technically challenging, primary patient-derived xenografts of paragangliomas in NSG mice provide a potentially valuable new tool that could prove especially valuable for testing treatments aimed at eradicating the small tumor deposits that are often numerous in patients with metastatic paraganglioma.

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Neuronal SOCE: Myth or Reality?

Publication date: Available online 6 October 2016
Source:Trends in Cell Biology
Author(s): Bo Lu, Marc Fivaz
Store-operated Ca²⁺ entry (SOCE) is the primary Ca²⁺ influx pathway in non-excitable cells. Long thought to be absent in nerve cells, neuronal SOCE is gaining popularity. We argue here that the evidence for SOCE in neurons remains contentious, mostly because SOCE imaging assays are inadequate in these cells.



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Effect of Gabapentin on Postoperative Pain Control Among Head and Neck Cancer Patients

Conditions:   Head and Neck Cancer;   Acute Pain;   Postoperative Pain
Interventions:   Drug: Gabapentin;   Drug: Placebo
Sponsor:   Washington University School of Medicine
Recruiting - verified September 2016

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Anxiety Sensitivity and Racial Differences in Sleep Duration: Results from a National Survey of Adults with Cardiovascular Disease

Publication date: Available online 5 October 2016
Source:Journal of Anxiety Disorders
Author(s): Carmela Alcántara, Luciana Andrea Giorgio Cosenzo, Weijia Fan, David Matthew Doyle, Jonathan A. Shaffer
Although Blacks sleep between 37–75minutes less per night than non-Hispanic Whites, research into what drives racial differences in sleep duration is limited. We examined the association of anxiety sensitivity, a cognitive vulnerability, and race (Blacks vs. White) with short sleep duration (<7hours of sleep/night), and whether anxiety sensitivity mediated race differences in sleep duration in a nationally representative sample of adults with cardiovascular disease. Overall, 1289 adults (115 Black, 1174 White) with a self-reported physician/health professional diagnosis of ≥1 myocardial infarction completed an online survey. Weighted multivariable logistic regressions and mediation analyses with bootstrapping and case resampling were conducted. Anxiety sensitivity and Black vs. White race were associated with 4%–84% increased odds, respectively, of short sleep duration. Anxiety sensitivity mediated Black–White differences in sleep duration. Each anxiety sensitivity subscale was also a significant mediator. Implications for future intervention science to address sleep disparities are discussed.



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Obsessive-Compulsive Symptoms and Negative Affect During Tobacco Withdrawal in a Non-Clinical Sample of African American Smokers

Publication date: Available online 5 October 2016
Source:Journal of Anxiety Disorders
Author(s): Mariel S. Bello, Raina D. Pang, Gregory S. Chasson, Lara A. Ray, Adam M. Leventhal
The association between obsessive-compulsive (OC) symptomatology and smoking is poorly understood, particularly in African Americans—a group subject to smoking- and OC-related health disparities. In a non-clinical sample of 253 African American smokers, we tested the negative reinforcement model of OC-smoking comorbidity, purporting that smokers with higher OC symptoms experience greater negative affect (NA) and urge to smoke for NA suppression upon acute tobacco abstinence. Following a baseline visit involving OC assessment, participants completed two counterbalanced experimental visits (non-abstinent vs. 16-hr tobacco abstinence) involving affect, smoking urge, and nicotine withdrawal assessment. OC symptom severity predicted larger abstinence-provoked increases in overall NA, anger, anxiety, depression, fatigue, urge to smoke to suppress NA, and composite nicotine withdrawal symptom index. African American smokers with elevated OC symptoms appear to be vulnerable to negative reinforcement-mediated smoking motivation and may benefit from cessation treatments that diminish NA or the urge to quell NA via smoking.



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Fear Conditioning and Stimulus Generalization in Patients with Social Anxiety Disorder

Publication date: Available online 5 October 2016
Source:Journal of Anxiety Disorders
Author(s): Lea M. Ahrens, Paul Pauli, Andreas Reif, Andreas Mühlberger, Gernot Langs, Tim Aalderink, Matthias J. Wieser
Although overgeneralization seems to be a hallmark of several anxiety disorders, this until now has not been investigated in social anxiety disorder (SAD). Therefore, we examined fear generalization in 26 SAD patients and 29 healthy controls (HC) using two faces as conditioned stimuli (CS+, CS-), and a loud scream and a fearful face as unconditioned stimulus (US). Generalization was tested by presenting both CS and four morphs of the two faces (generalization stimuli [GSs]), while ratings, heart rate (HR) and skin conductance responses (SCR) were recorded. Results revealed that SAD patients rated all stimuli as less pleasant and more arousing compared to HC. Moreover, ratings and SCR indicated that both groups generalized their acquired fear from the CS+ to GSs. Remarkably, only SAD patients showed generalization in HR responses (fear bradycardia). Overall, SAD seems not to be characterized by strong overgeneralization but discrepancies in fear responses to both conditioned and generalized threat stimuli.



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Panic Attacks and Panic Disorder in the American Indian Community

Publication date: Available online 5 October 2016
Source:Journal of Anxiety Disorders
Author(s): Craig N. Sawchuk, Peter Roy-Byrne, Carolyn Noonan, Julia R. Craner, Jack Goldberg, Spero Manson, Dedra Buchwald
Panic disorder is a common mental health condition, but little is known about panic disorder in non-Caucasian populations. The purpose of this study is to describe the epidemiology, clinical features, and comorbidities of panic attacks and panic disorder in two large American Indian (AI) tribes (N=3,084). A culturally-adapted version of the Composite International Diagnostic Interview assessed panic attacks, panic disorder, and various psychiatric comorbidities. After adjusting for age, gender, and tribe, linear and logistic regression analyses were conducted to compare AIs with panic disorder to those with panic attacks only on clinical characteristics and panic symptoms. Approximately 8.5% (N=234) of American Indians reported a lifetime history of panic attacks. Among individuals with panic attacks, comorbid posttraumatic stress disorder was higher in females (p=0.03) and comorbid alcohol-related disorders were higher in males (p≤0.001). The prevalence and clinical features of panic attacks and panic disorder in American Indians were similar to epidemiologic studies with majority populations. However, in contrast to earlier research, panic symptoms were similar in both males and females, and different patterns of comorbidity emerged. Future research should examine the availability and accessibility of evidence-based panic treatments for this traditionally underserved population.



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Pyridineimdamide derivatives - Efficient zinc(II) extractants

Publication date: 1 February 2017
Source:Separation and Purification Technology, Volume 173
Author(s): Irmina Wojciechowska, Karolina Wieszczycka, Aleksandra Wojciechowska
Novel extractants, hydrophobic N′-alkyloxypyridine-2-, -3- and -4-carboximidamides, were proposed as the efficient zinc(II) extractants from acidic chloride solutions. In this study various factors affecting zinc(II) extraction, such as concentration of chloride ions, mineral acid and zinc in the aqueous feed solution, structure and concentration of the extractant and type of the organic diluent were studied. It was found that the extraction of Zn(II) was observed for the pyridine-3- and 4-carboximidamides with 2-ethylhexyl group and the extraction abilities increased with the increase of chloride ions concentration. N′-(2-ethylhexyloxy)pyridine-4-carboximidamide appeared to be the most efficient extractant, as well as, it was the most suitable in terms of loading capacity. It was also found that 4-EH enabled a complete transfer of Zn(II) from the concentrated aqueous solution by using a two-stage counter-current extraction at an O/A ratio of 7.5 or at O/A=8 by using a one-stage cross-flow extraction.



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Structural, magnetic and electrical properties of nickel doped Mn-Zn spinel ferrite synthesized by sol-gel method

Publication date: 1 February 2017
Source:Journal of Magnetism and Magnetic Materials, Volume 423
Author(s): K. Jalaiah, K. Vijaya Babu
Manganese ferrites (MnFe2O4) have been of great interest for their remarkable and soft-magnetic properties (low coercivity, moderate saturation magnetization) accompanied by good chemical stability and mechanical hardness. X-ray diffraction analysis confirmed the presence of single phase cubic spinel ferrite with space group Fm3m for all prepared samples. Structural parameters such as lattice constant, crystallite size were calculated from the studies of X-ray diffraction. The morphological analysis of all the compounds is studied using scanning electron microscope. The magnetic properties were measured using electron spin resonance (ESR) and vibrating sample magnetometer (VSM). The results obtained showed the formation of manganese ferrites with an average particle size are in good agreement with previous results and displayed good magnetic properties. The dielectric and impedance properties are studied over a frequency range 20Hz–1MHz at room temperature.



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Commentary on ‘Gender related Outcome Inequalities in Endovascular Aneurysm Repair’. Please still take good care of the ladies

Publication date: October 2016
Source:European Journal of Vascular and Endovascular Surgery, Volume 52, Issue 4
Author(s): J.S. Lindholt




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Selected Abstracts from the October Issues of the Journal of Vascular Surgery and the Journal of Vascular Surgery: Venous and Lymphatic Disorders

Publication date: October 2016
Source:European Journal of Vascular and Endovascular Surgery, Volume 52, Issue 4





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Editorial Board

Publication date: October 2016
Source:European Journal of Vascular and Endovascular Surgery, Volume 52, Issue 4





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