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In his Scroogenomics, Joel Waldfogel argues that gifting creates enormous deadweight loss, as individuals give one another gifts that they do not want or cannot use. He views efficiency as static, calculating the gains from trade (or gifting) at the moment of transaction. A puzzle arises, however, when one realizes that gifting has been a nearly ubiquitous institution throughout history. If gifting wastes valuable resources, why does it persist? We argue that gift giving is dynamically efficient despite the possibility of generating short-term deadweight loss. A well-functioning market economy requires expanded social networks and trustworthiness among anonymous and quasi-anonymous exchange partners. Gifting allows individuals to signal trustworthiness by offering ‘burnt sacrifices’. Gifting practices that include a willingness to sacrifice via reciprocity norms, public visibility and ritual will tend to promote generalized trust. We consider these four elements – sacrifice, reciprocity, publicness, and ritual – to be critical institutional design principles for fostering dynamic efficiency. Our essay contributes to the literature on institutional economics by prompting scholars to think about the long-term (dynamic) efficiencies generated by cultural practices that appear inexplicably inefficient.

Cancer immunoediting1is a hallmark of cancer2that predicts that lymphocytes kill more immunogenic cancer cells to cause less immunogenic clones to dominate a population. Although proven in mice1,3, whether immunoediting occurs naturally in human cancers remains unclear. Here, to address this, we investigate how 70 human pancreatic cancers evolved over 10 years. We find that, despite having more time to accumulate mutations, rare long-term survivors of pancreatic cancer who have stronger T cell activity in primary tumours develop genetically less heterogeneous recurrent tumours with fewer immunogenic mutations (neoantigens). To quantify whether immunoediting underlies these observations, we infer that a neoantigen is immunogenic (high-quality) by two features—‘non-selfness’ based on neoantigen similarity to known antigens4,5, and ‘selfness’ based on the antigenic distance required for a neoantigen to differentially bind to the MHC or activate a T cell compared with its wild-type peptide. Using these features, we estimate cancer clone fitness as the aggregate cost of T cells recognizing high-quality neoantigens offset by gains from oncogenic mutations. With this model, we predict the clonal evolution of tumours to reveal that long-term survivors of pancreatic cancer develop recurrent tumours with fewer high-quality neoantigens. Thus, we submit evidence that that the human immune system naturally edits neoantigens. Furthermore, we present a model to predict how immune pressure induces cancer cell populations to evolve over time. More broadly, our results argue that the immune system fundamentally surveils host genetic changes to suppress cancer.

Previously regarded as a subgenus of Pseudanthias Bleeker, Mirolabrichthys is rediagnosed and restricted to three species, the type species, M. tuka Herre & Montalban, along with M. pascalus (Jordan & Tanaka) and M. evansi (Smith). Five other species previously classified in Mirolabrichthys are reallocated to Nemanthias Smith, which beforehand had included only the type species, N. carberryi Smith: N. bartlettorum (Randall & Lubbock), N. bicolor (Randall), N. dispar (Herre), N. ignitus (Randall & Lubbock), and N. regalis (Randall & Lubbock). The remaining nine species previously placed in Mirolabrichthys are classified in a new genus, Pyronotanthias: P. lori (Lubbock & Randall), P. aurulentus (Randall & McCosker), P. bimarginatus (Randall), P. flavoguttatus (Katayama & Masuda), P. parvirostris (Randall & Lubbock), P. privitera (Randall & Pyle), P. smithvanizi (Randall & Lubbock), P. timanoa (Victor, Teitelbaum & Randall) and P. unimarginatus (Randall). Synapomorphies supporting monophyly of each genus are provided, along with generic descriptions and character summaries for included species. Characters supporting relationships of the three genera to each other and to other anthiadines are discussed.

Genomic deletions in medullary thyroid cancer (MTC) are rare. Selpercatinib is a highly selective RET inhibitor for treatment of metastatic RET-altered MTC. We report a case of a 35 year old male with an aggressive metastatic MTC harboring p.632_633del RET poorly responsive to RET kinase inhibitor selpercatinib. Objective Understand the clinical phenotype of p.632_633del RET in MTC in context of novel RET kinase inhibitor treatment.Wild-type and p.632_633del RET sequences were modeled using a lighter version of the AlphaFold2 (AF2) software. Functional studies were performed on transfected HEK 293 cells (pCMV6-Entry, pCMV6-RET or pCMV6-RET(p.632_633del) treated with inhibitors for 24 hours and analysed on luciferase assays.Structural modeling revealed the paucity of disulfide bridge between Cys630-Cys634 in p.632_633del RET sequences, apparent in wild-type, while forming an intermolecular disulfide bridge between two Cys656. Proximity of juxtamembrane segments of each dimer may impede Tyr687 phosphorylation and stable conformation of intracellular RET that hosts selpercatinib. In vitro experiments confirmed a reduction in efficacy of selpercatinib upon p.632_633del RET compared with wild-type RET control.Clinical presentation together with structural modeling and functional studies suggest p.632_633del RET results inpoor response to selpercatinib.

There is no effective treatment for methamphetamine withdrawal. This study aimed to determine the feasibility and safety of a tapering dose of lisdexamfetamine for the treatment of acute methamphetamine (MA) withdrawal.Open-label, single-arm pilot study, in an inpatient drug and alcohol withdrawal unit assessing a tapering dose of oral lisdexamfetamine dimesylate commencing at 250 mg once daily, reducing by 50 mg per day to 50 mg on Day 5. Measures were assessed daily (days 0-7) with 21-day telephone follow-up. Feasibility was measured by the time taken to enrol the sample. Safety was the number of adverse events (AEs) by system organ class. Retention was the proportion to complete treatment. Other measures included the Treatment Satisfaction Questionnaire for Medication (TSQM), the Amphetamine Withdrawal Questionnaire and craving (Visual Analogue Scale).Ten adults seeking inpatient treatment for MA withdrawal (9 male, median age 37.1 years [IQR 31.7-41.9]), diagnosed with MA use disorder were recruited. The trial was open for 126 days; enroling one participant every 12.6 days. Eight of ten participants completed treatment (Day 5). Two participants left treatment early. There were no treatment-related serious adverse events (SAEs). Forty-seven AEs were recorded, 17 (36%) of which were potentially causally related, all graded as mild severity. Acceptability of the study drug by TSQM was rated at 100% at treatment completion. Withdrawal severity and craving reduced through the admission.A tapering dose regimen of lisdexamfetamine was safe and feasible for the treatment of acute methamphetamine withdrawal in an inpatient setting.

All of the major religious confessions existing today have outlasted every single secular ruling regime known in human history. That observation poses an interesting puzzle for social scientists interested in institutional durability. If religions can be seen as governance institutions that organize and coordinate people’s lives, why have they outlasted secular states? Despite claims regarding the inevitability of secularization, religious institutions refuse to fade from the social landscape and in many places are thriving and expanding. I argue that the durability of religious institutions relative to secular governing regimes is related to the unique ability of religions to avoid the public choice “paradox of government” as laid out by James Buchanan. More precisely, religious institutions are more resilient because they effectively provide vital public goods, involve “citizens” in the process of governance at the local level, and provide a credible neutral arbitrator for violations of the governing covenant. A further argument is made for the efficiency of religious institutions relative to states based on the smaller deadweight losses associated with participatory governance. Finally, state-sponsored confessions expose themselves to the paradox of government and become less effective in pursuing their missions.

Context Metastatic medullary thyroid carcinoma (MTC) and radioactive iodine–refractory differentiated thyroid carcinoma (RAI-R DTC) have poor prognosis and limited treatment options. Selpercatinib (LOXO-292), a selective kinase inhibitor targeting the RET gene, has shown a 69% to 79% objective response rate in this cohort with benefits in other tumors including lung cancer harboring the same oncogenic driver. Published reports describe only 17% of patients experiencing gastrointestinal (GI) adverse effects (AEs), which is in contrast to our local experience. Objective Here we characterize the AEs and correlate them with radiological and histopathological findings. Methods Sequential patients enrolled in LIBRETTO-001 at Royal North Shore Hospital, Sydney, Australia, with available imaging (n = 22) were recruited. Patients had regular visits with AEs documented and computed tomography (CT) scans every 3 months. CT at screening, at time of GI AE, and at most recent follow-up were reviewed and scored. Endoscopic examination was performed in 5 patients. Results Of 22 patients in this cohort, the majority had somatic RET alterations (n = 18), most commonly p.Met918Thr (n = 14). Ten patients (50%) developed GI AEs. Dose reduction was required in 8 of the 10 patients, but none discontinued therapy. The majority had stable disease (n = 17). Gastric and small-bowel edema was evident in symptomatic patients after a median time of 67 weeks’ treatment. Histological correlation in 5 patients revealed mucosal edema correlating with radiological evidence of congestion and edema. Conclusion GI AEs with selpercatinib may be more common than previously described. Most are self-limiting but often require dose adjustments. Histological evidence of mucosal edema observed in conjunction with the radiological findings of congestion and wall thickening suggest bowel-wall edema is a predominant mechanism of abdominal pain in these patients.

The 2022 WHO classification reflects increases in the knowledge of the underlying pathogenesis of parathyroid disease. In addition to the classic characteristic features of parathyroid neoplasms, subtleties in histologic features which may indicate an underlying genetic abnormality reflect increased understanding of the clinical manifestations, histologic, and genetic correlation in parathyroid disease. The importance of underlying genetic aberrancies is emphasized due to their significance to the care of the patient. Traditionally, the term "parathyroid hyperplasia" has been applied to multiglandular parathyroid disease; however, the concept of hyperplasia is generally no longer supported in the context of primary hyperparathyroidism since affected glands are usually composed of multiple "clonal" neoplastic proliferations. In light of these findings and management implications for patient care, the 2022 WHO classification endorses primary hyperparathyroidism-related multiglandular parathyroid disease (multiglandular multiple parathyroid adenomas) as a germline susceptibility-driven multiglandular parathyroid neoplasia. From such a perspective, pathologists can provide additional value to genetic triaging by recognizing morphological and immunohistochemical harbingers of MEN1, CDKN1B, MAX, and CDC73-related manifestations. In the current WHO classification, the term "parathyroid hyperplasia" is now used primarily in the setting of secondary hyperplasia which is most often caused by chronic renal failure. In addition to expansion in the histological features, including those that may be suggestive of an underlying genetic abnormality, there are additional nomenclature changes in the 2022 WHO classification reflecting increased understanding of the underlying pathogenesis of parathyroid disease. The new classification no longer endorses the use of "atypical parathyroid adenoma". This entity is now being replaced with the term of "atypical parathyroid tumor" to reflect a parathyroid neoplasm of uncertain malignant potential. The differential diagnoses of atypical parathyroid tumor are discussed along with the details of worrisome clinical and laboratory findings, and also features that define atypical histological and immunohistochemical findings to qualify for this diagnosis. The histological definition of parathyroid carcinoma still requires one of the following findings: (i) angioinvasion (vascular invasion) characterized by tumor invading through a vessel wall and associated thrombus, or intravascular tumor cells admixed with thrombus, (ii) lymphatic invasion, (iii) perineural (intraneural) invasion, (iv) local malignant invasion into adjacent anatomic structures, or (v) histologically/cytologically documented metastatic disease. In parathyroid carcinomas, the documentation of mitotic activity (e.g., mitoses per 10mm

This review of the familial tumor syndromes involving the endocrine organs is focused on discussing the main updates on the upcoming fifth edition of the WHO Classification of Endocrine and Neuroendocrine Tumors. This review emphasizes updates on histopathological and molecular genetics aspects of the most important syndromes involving the endocrine organs. We describe the newly defined Familial Cancer Syndromes as MAFA-related, MEN4, and MEN5 as well as the newly reported pathological findings in DICER1 syndrome. We also describe the updates done at the new WHO on the syndromic and non-syndromic familial thyroid diseases. We emphasize the problem of diagnostic criteria, mention the new genes that are possibly involved in this group, and at the same time, touching upon the role of some immunohistochemical studies that could support the diagnosis of some of these conditions. As pathologists play an important role in identifying tumors within a familial cancer syndrome, we highlight the most important clues for raising the suspicious of a syndrome. Finally, we highlight the challenges in defining these entities as well as determining their clinical outcome in comparison with sporadic tumors. Instead of the usual subject review, we present the highlights of the updates on familial cancer syndromes by answering select questions relevant to practicing pathologists.

Background Whole-genome sequencing data from wild-caught individuals of closely related North American killifish species (Fundulus xenicus, Fundulus catenatus, Fundulus nottii, and Fundulus olivaceus) were obtained using long-read Oxford Nanopore Technology (ONT) PromethION and short-read Illumina platforms. Findings Draft de novo reference genome assemblies were generated using a combination of long and short sequencing reads. For each species, the PromethION platform was used to generate 30–45× sequence coverage, and the Illumina platform was used to generate 50–160× sequence coverage. Illumina-only assemblies were fragmented with high numbers of contigs, while ONT-only assemblies were error prone with low BUSCO scores. The highest N50 values, ranging from 0.4 to 2.7 Mb, were from assemblies generated using a combination of short- and long-read data. BUSCO scores were consistently >90% complete using the Eukaryota database. Conclusions High-quality genomes can be obtained from a combination of using short-read Illumina data to polish assemblies generated with long-read ONT data. Draft assemblies and raw sequencing data are available for public use. We encourage use and reuse of these data for assembly benchmarking and other analyses.

Hereditary leiomyomatosis and renal cell carcinoma-associated renal cell carcinoma (HLRCC)/ fumarate hydratase deficient renal cell carcinoma (FHRCC) is an aggressive tumor defined by molecular genetic changes - alteration in fumarate hydratase (FH) gene. The morphologic spectrum of HLRCC/FHDRCC is remarkably variable. The presence of large nuclei and prominent dark red inclusion-like nucleoli and perinucleolar clearing are considered as helpful morphologic clue. We selected 23 renal neoplasms primarily based on their morphologic features suspicious for HLRCC/FHDRCC. Morphological, basic immunohistochemical, and genetic analysis was performed. The tumors were divided in two groups according to the molecular genetic findings. The first group included 13 tumors with detected FH mutation/LOH (compatible with diagnosis FHRCC), and the second group included 10 tumors without FH mutation/LOH (FH-like RCCs). In the FHRCC group, the vast majority of cases (9/13) had mixed morphology with different architectural growth patterns. All cases showed prominent macronucleoli, and perinucleolar clearing was found in 10/13 cases. Immunohistochemically, 6/7 FHRCC cases were negative for FH antibody, while one case showed strong diffuse FH reactivity. The FH-like RCC group showed more uniform architectural growth pattern. All 10 tumors had prominent macronucleoli, and perinucleolar clearing was present in 8/10 cases. Eight FH-like RCC cases showed diffuse strong positivity for FH, although 2 cases were completely negative for FH. It is evident that neither morphologic feature nor immunohistochemical analysis can be reliably used in routine practice for the diagnosis of HLRCC/FHRCC. In suspected cases, the diagnosis of HLRCC/FHRCC can be confirmed by molecular-genetic testing for FH mutation. It should be noted that the traditionally described morphologic features of HLRCC/FHRCC (prominent eosinophilic macronuclei with perinucleolar halos) can frequently be seen in other renal neoplasms.

Ever since the dawn of civilization, human beings have been mixing religion and politics. And irrespective of various attempts to “separate church and state” or “secularize” society by confining matters of spiritual belief to the private sphere, the realms of religion and politics have remained intertwined and will, in all likelihood, continue to be. Indeed, speaking of “separate realms” may be misleading given that people with religious convictions take their beliefs and values into the political arena as a way of informing their choices and behavior. Political authorities, irrespective of their own faith, must factor the existence of people with religious beliefs. Even self-proclaimed atheistic rulers such as Vladimir Lenin and Josef Stalin had to devise policies of how to deal with the remnants of the Orthodox Church that they could not extinguish. Even in North Korea, history’s most-recent paragon of secular totalitarianism, President Kim Jong-Un must repeatedly enforce restrictions on Christians who refuse to vanish. Religion and politics will continue to mix and it behooves social scientists to understand why and how.

Religion long has been the neglected child of the social sciences thanks to the stranglehold secularization theory has had on the field. Despite ignoring religious institutions as major actors, the fact remains that all the world's largest faith traditions -- Hinduism, Judaism, Buddhism, Christianity, and Islam -- have outlasted every single secular institution, government, or dynasty. The Catholic Church holds the record for the longest-surviving formal hierarchy in human history and boasts over one billion members. This paper examines why the major faith traditions have been more enduring than secular institutions, states, and social movements. Using a public choice framework, and spring-boarding the argument from the thought of James Buchanan, this paper argues that religious institutions tend to be more enduring than their secular counterparts for three reasons. First, religious institutions provide valuable public goods, namely the ability to coordinate human behavior around a set of cultural expectations that reduce uncertainty and promote transactions. Second, federalist forms of organization within these institutions helps to leverage local information and supports an ongoing renewal of a "social contract." Finally, ultimate authority for judgement regarding adherence to rules of social order exists outside the temporal whims of individuals who write and execute the laws of the religious society. In other words, "God" serves as Buchanan's ideal neutral arbitrator in his contract theory of government. A case is also made that this form of institutional design is efficient for society, including non-believers in the particular faith.

Christian Democracy is often championed as a romantic means of bringing ethical considerations for the common good into the daily life of politics. Public choice theory, on the other hand, reveals that the search for the common good is quixotic amidst divergent policy preferences within a nation. While there may be a handful of values that are accepted by nearly all citizens (e.g., prohibitions on murder), more mundane policy choices will likely promote differences of opinion. Given the often arbitrary nature of voting procedures, the ability of one faction to manipulate the vote choice, and the self-interested behavior of politicians to be re-elected, political parties will inevitably alienate some portion of the citizenry. Attaching Christianity to short-term political outcomes serves to undermine its long-term goal of promoting God's mission. Nonetheless, the Catholic concept of subsidiarity is congruent with many of the findings of public choice theory and offers a way for Christians to engage...

Religious liberty is generally thought to apply to rights of conscience. However, acting upon one’s beliefs also involves numerous other civil liberties including the right to assemble, as well as the right to own and use real estate. I assert that the successful operation and growth of religious movements requires well-specified and protected private property rights. However, in recent decades, one of the major threats to religious freedom has been an attack on the property rights of religious denominations, particularly smaller and less organized ones. In addition to common Not in my backyard complaints, I assert two additional reasons for this phenomenon: (1) the tax-exempt status of religious groups dis-incentivizes politicians from giving out building permits to congregations; and (2) the growth of private and homeschooling incentivizes politicians concerned with protecting public school funding from granting land use permits that could facilitate alternative educational facilities.

Background There is no available evidence providing detailed and valid accounts of how people with schizophrenia construct meaning in their lives. Aim To explore the lived experiences of people with schizophrenia who had been prescribed atypical antipsychotic medications. Methods Adopting a phenomenological approach, a purposive sample of 19 adults with schizophrenia provided data using a combination of daily diaries and individual face-to-face interviews. Findings Five core themes were evident in the data: social isolation, stigma, quality of life, confidence and social networks. The findings provide a distinctive, enlightening and encouraging insight into how people diagnosed with schizophrenia live their lives. Conclusion Participants reported a loss of identity and control over their lives and they said that stigma continues to have a detrimental effect on their lived experiences. However, despite these impairments, many of the participants managed to integrate themselves into the community and participate in meaningful activities associated with everyday living.

The potential bioavailability of toxic chemicals from oil spills to water column organisms such as fish embryos may be influenced by physical dispersion along an energy gradient. For example, a surface slick with minimal wave action (low energy) could potentially produce different toxic effects from high energy situations such as pressurized discharge from a blown wellhead. Here we directly compared the toxicity of water accommodated fractions (WAFs) of oil prepared with low and high mixing energy (LEWAFs and HEWAFs, respectively) using surface oil samples collected during the 2010 Deepwater Horizon spill, and embryos of a representative nearshore species, red drum (Sciaenops ocellatus). Biological effects of each WAF type was quantified with several functional and morphological indices of developmental cardiotoxicity, providing additional insight into species-specific responses to oil exposure. Although the two WAF preparations yielded different profiles of polycyclic aromatic hydrocarbons (PAHs), cardiotoxic phenotypes were essentially identical. Based on benchmark thresholds for both morphological and functional cardiotoxicity, in general LEWAFs had lower thresholds for these phenotypes than HEWAFs based on total PAH measures. However, HEWAF and LEWAF toxicity thresholds were more similar when calculated based on estimates of dissolved PAHs only. Differences in thresholds were attributable to the weathering state of the oil samples.

This chapter explores how political economists have tried to answer the questions of economic growth and distribution. "Political economy" can often be a menacing subject area for many students. It convinces students that political economy is not only an important field of inquiry, central to most questions in comparative politics, but it is an accessible topic as well. Understanding why modern colleges maintain separate departments of government and economics reveals a great deal about where political economy has been as a field, and it explains why the topic is considered a "new direction" in comparative politics today. Two factors account for the reemergence of political economy in the latter part of the twentieth century First, by mid-century, economists began realizing that ignoring political factors left them with only partial explanations of economic behavior. The second motivation to resurrect political economy resulted from the Cold War.

Metabolic disease is a leading cause of death worldwide, and obesity, a central risk factor, is reaching epidemic proportions. Energy expenditure and brown adipose tissue (BAT) thermogenesis are implicated in metabolic disease, and it is becoming evident that impaired BAT activity is regulated by gene/environment interactions. Peroxisome proliferator-activated receptor γ coactivator 1α (Pgc-1α) is a critical regulator of BAT thermogenesis, which is highly inducible by environmental stimuli such as cold and diet. This review focuses on the environmentally mediated epigenetic and transcriptional regulation of Pgc-1α gene expression during BAT thermogenesis. We illustrate interactions between histone modifications and transcription factors at the Pgc-1α promoter that cause BAT Pgc-1α transcription in response to cold. Histone modifications also modulate BAT Pgc-1α transcription in response to nutrients though diet has been less characterized than cold with respect to regulation of Pgc-1α transcription. Pgc-1α DNA methylation and RNA expression were also correlated to indicators of adiposity and glucose homeostasis across numerous human tissues. Although post-translational modification of Pgc-1α protein has been well-characterized across diverse tissues and environments, comparatively little is known of the epigenetic mechanisms regulating Pgc-1α transcription, particularly in BAT thermogenesis.

A few upscale restaurants in the United States recently have ended the practice of tipping their wait staff, preferring a fixed labor cost method of compensation. This attempt to change this long-standing cultural practice presents a fascinating opportunity to explore a variety of economic concepts including principal-agent problems, gains-from-trade, price discrimination, and cultural institutions designed to build trust. I argue that tipping remains an economically efficient means of providing quality service wherein restaurant owners, wait staff, and customers all benefit in what can be a win-win-win situation. The norm of tipping also provides an excellent example to teach basic economic principles and foster classroom discussion.

The Convention on Biological Diversity (CBD) commits its 196 nation parties to conserve biological diversity, use its components sustainably, and share fairly and equitably the benefits from the utilization of genetic resources. The last of these objectives was further codified in the Convention's Nagoya Protocol (NP), which came into effect in 2014. Although these aspirations are laudable, the NP and resulting national ambitions on Access and Benefit Sharing (ABS) of genetic resources have generated several national regulatory regimes fraught with unintended consequences (1). Anticipated benefits from the commercial use of genetic resources, especially those that might flow to local or indigenous communities because of regulated access to those resources, have largely been exaggerated and not yet realized. Instead, national regulations created in anticipation of commercial benefits, particularly in many countries that are rich in biodiversity, have curtailed biodiversity research by in-country scientists as well as international collaboration (1). This weakens the first and foremost objective of the CBD—conservation of biological diversity. We suggest ways that the Conference of the Parties (CoP) of the CBD may proactively engage scientists to create a regulatory environment conducive to advancing biodiversity science. Fil: Divakaran Prathapan, K.. Kerala Agricultural University; India Fil: Pethiyagoda, Rohan. Australian Museum; Australia Fil: Bawa, Kamaljit S.. University of Massachussets; Estados Unidos Fil: Raven, Peter H.. Missouri Botanical Garden; Estados Unidos Fil: Rajan, Priyadarsanan Dharma. Ashoka Trust For Research In Ecology And The Environment; India Fil: Acosta, Luis Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Diversidad y Ecología Animal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto de Diversidad y Ecología Animal; Argentina Fil: Avila, Luciano Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Centro Nacional Patagónico. Instituto Patagónico para el Estudio de los Ecosistemas Continentales; Argentina Fil: Baldo, Juan Diego. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Nordeste. Instituto de Biología Subtropical. Instituto de Biología Subtropical - Nodo Posadas | Universidad Nacional de Misiones. Instituto de Biología Subtropical. Instituto de Biología Subtropical - Nodo Posadas; Argentina Fil: Crespo, Francisco Antonio. Dirección Nacional de Institutos de Investigación. Administración Nacional de Laboratorios e Institutos de Salud. Centro Nacional de Diagnóstico e Investigaciones Endemo-epidémicas; Argentina Fil: Pérez González, Abel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Museo Argentino de Ciencias Naturales “Bernardino Rivadavia”; Argentina Fil: Ramirez, Martin Javier. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Museo Argentino de Ciencias Naturales “Bernardino Rivadavia”; Argentina Fil: Sidorchuk, Ekaterina. Russian Academy of Sciences; Rusia Fil: Svavarsson, Jörundur. University of Iceland; Islandia Fil: Twomey, Evan. Pontificia Universidade Católica do Rio Grande do Sul; Brasil Fil: Vasudevan, Karthikeyan. Centre For Cellular And Molecular Biology India; India Fil: Vences, Miguel. Technische Universität Braunschweig; Alemania Fil: de Voogd, Nicole. Naturalis Biodiversity Center; Países Bajos Fil: Wang, Qiao. Massey University; Nueva Zelanda Fil: Watson, Gillian W.. California Department of Food and Agriculture; Estados Unidos Fil: Weiner, Wanda M.. Polish Academy of Sciences; Argentina Fil: Wesener, Thomas. Zoological Research Museum A. Koenig; Alemania. Institute for Terrestrial Biodiversity; Alemania Fil: Whitmore, Daniel. Natural History Museum; Reino Unido Fil: Wiklund, Helena. Natural History Museum; Reino Unido Fil: Williams, Paul H.. Natural History Museum; Reino Unido Fil: Winterton, Shaun L.. California Department of Food and Agriculture; Estados Unidos Fil: Wood, Timothy S.. Wright State University; Estados Unidos Fil: Yen, Shen Horn. National Sun Yat-sen University Taiwan; República de China Fil: Zaher, Hussam. Universidade de Sao Paulo; Brasil Fil: Zhang, Z. Q.. Manaaki Whenua - Landcare Research; Nueva Zelanda Fil: Zhou, Hong Zhang. Chinese Academy of Sciences; República de China

A free exercise of Religion is so valuable a branch of true liberty, and so essential to the enriching and improving of a Trading Nation, it should ever be held sacred in His Majesty's Colonies. —T...

BACKGROUND: Papillary thyroid cancer (PTC) persistence or recurrence and the need for long-term surveillance can cause significant inconvenience and morbidity in patients. Currently, recurrence risk stratification is accomplished by using clinicopathologic factors, and serum thyroglobulin is the only commercially available marker for persistent or recurrent disease. The objective of this study was to determine microRNA (miRNA) expression in PTC and determine whether 1 or more miRNAs could be measured in plasma as a biomarker for recurrence. METHODS: Patients with recurrent PTC (Rc-PTC) and those without recurrence (NR-PTC) were retrospectively recruited for a comparison of their tumor miRNA profiles. Patients with either newly diagnosed PTC or multinodular goiter who were undergoing total thyroidectomy were prospectively recruited for an analysis of preoperative and postoperative circulating miRNA levels. Healthy volunteers were recruited as the control group. RESULTS: MicroRNA-222 and miR-146b were over-expressed 10.8-fold and 8.9-fold, respectively, in Rc-PTC tumors compared with NR-PTC tumors (P 5.014 and P 5.038, respectively). In plasma from preoperative PTC patients, levels of miR-222 and miR-146b were higher compared with the levels in plasma from healthy volunteers (P

The human apolipoprotein E (APOE) gene plays an important role in lipid metabolism. It has three common genetic variants, alleles ɛ2/ɛ3/ɛ4, which translate into three protein isoforms of apoE2, E3 and E4. These isoforms can differentially influence total serum cholesterol levels; therefore, APOE has been linked with cardiovascular disease. Additionally, its ɛ4 allele is strongly associated with the risk of Alzheimer's disease (AD), whereas the ɛ2 allele appears to have a modest protective effect for AD. Despite decades of research having illuminated multiple functional differences among the three apoE isoforms, the precise mechanisms through which different APOE alleles modify diseases risk remain incompletely understood. In this study, we examined the genomic structure of APOE in search for properties that may contribute novel biological consequences to the risk of disease. We identify one such element in the ɛ2/ɛ3/ɛ4 allele-carrying 3′-exon of APOE. We show that this exon is imbedded in a well-defined CpG island (CGI) that is highly methylated in the human postmortem brain. We demonstrate that this APOE CGI exhibits transcriptional enhancer/silencer activity. We provide evidence that this APOE CGI differentially modulates expression of genes at the APOE locus in a cell type-, DNA methylation- and ɛ2/ɛ3/ɛ4 allele-specific manner. These findings implicate a novel functional role for a 3′-exon CGI and support a modified mechanism of action for APOE in disease risk, involving not only the protein isoforms but also an epigenetically regulated transcriptional program at the APOE locus driven by the APOE CGI.

Testicular germ cell tumors (TGCTs) are the most common malignancy in young men. However, there are few in vivo animal models that have been developed to study this disease. We have used the pufferfish (fugu) lymphocyte-specific protein tyrosine kinase (flck) promoter, which has been shown to enforce high-level expression in the testes of transgenic mice, to express Simian virus 40 large T-antigen in zebrafish testes. Zebrafish that express T-antigen develop TGCTs after a long latency of >1 year. Although overt TGCTs are only evident in 20% of the fish, occult TGCTs can be detected in 90% of the transgenic fish by 36 month of age. The TGCTs resemble the human disease in terms of morphology and gene expression pattern, and can be transplanted to healthy wild-type recipient fish. In addition, enforced expression of the zebrafish stem cell leukemia (scl) gene in the zebrafish testes also generated TGCTs in transgenic fish. These results demonstrate the feasibility of studying TGCTs in a model organism.

Background Medullary thyroid carcinoma (MTC), which comprises 3-5% of all thyroid cancers, originates from a small population of neuroendocrine calcitonin C-cells of thyroid gland. Gain-of-function mutations of the human Rearranged during Transfection (RET) proto-oncogene have been recognized as the key driver of MTC tumorigenesis. RET has been targeted by tyrosine kinase inhibitors (TKIs), however with modest efficacy. Many of the microRNAs (miRNAs) identified in human genome have been associated with cancer and have prompted interest in the establishment of miRNA-based therapeutics. However miRNA studies in MTC has been hampered due to the lack of normal C-cell tissue as a differential expression comparator. Aims We aimed to characterize differentially expressed miRNAs, which play fundamental roles in MTC tumorigenesis and in modulation of TKI responses. Methods RET of human MTC cells were silenced using TKI, Cabozantinib, or siRNA. Small RNA sequencing was performed (AGRF) to identify differentially expressed miRNAs before and after RET inhibition. MiRNA effects on cell proliferation (MTS assay), cell cycle and apoptosis (flow cytometry, Western blot) were investigated with gain-of-function studies. For in vivo study, MTC xenografts were established and miRNAs were intravenously delivered using nanoparticle delivery vehicles invented by biotechnology company - EnGeneIC Ltd. Results miR-153-3p was identified to be under-expressed in MTC following RET inhibition. Restoration of miR-153-3p significantly reduced cell proliferation, induced G2 cell arrest and increased cell apoptosis. Furthermore, combined treatment of miR-153-3p and Cabozantinib caused greater cell proliferation inhibition compared to individual treatment. miR-153-3p targets ribosomal protein S6 kinase B1 (RPS6KB1) and reduced phosphorylation of Bcl-2 associated death promoter (BAD) protein. In vivo delivery of miR-153-3p significantly impeded tumor growth compared to scrambled sequence. Combination of miR-153-3p delivery and oral administration of Cabozantinib resulted in further tumor stabilization effect. Conclusion miR-153-3p reveals a significant tumor suppressive role in MTC via S6K signaling, demonstrating its important therapeutic potential for MTC patients. Citation Format: Lauren Jin Suk Joo, Jocelyn Weiss, Anthony J. Gill, Roderick Clifton-Bligh, Himanshu Brahmbhatt, Jennifer A. MacDiarmid, Matti L. Gild, Bruce G. Robinson, Stan B. Sidhu, Jing Ting Zhao. A RET-related microRNA, miR-153-3p, acts as a tumor suppressor in medullary thyroid carcinoma (MTC) via S6K signaling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 501.