bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase II Trial of Response-Based Radiation Therapy for Patients With Localized CNS Nongerminomatous Germ Cell Tumors: A Children's Oncology Group Study
Authors: Fangusaro Jason , Wu Shengjie , MacDonald Shannon , Murphy Erin , Shaw Dennis , Bartels Ute , Khatua Soumen , Souweidane Mark , Lu Hsiao-Ming , Morris David , Panigrahy Ashok , Onar-Thomas Arzu , Fouladi Maryam , Gajjar Amar , Dhall Girish 
Published: September 2019

PURPOSE Stratum 1 of ACNS1123 (ClinicalTrials.gov identifier: NCT01602666 ), a Children’s Oncology Group phase II trial, evaluated efficacy of reduced-dose and volume of radiotherapy (RT) in children and adolescents with localized nongerminomatous germ cell tumors (NGGCTs). The primary objective was to evaluate the impact of reduced RT on progression-free survival (PFS) with a goal of preserving neurocognitive function. PATIENTS AND METHODS Patients received six cycles of chemotherapy with carboplatin and etoposide alternating with ifosfamide and etoposide, as used in the Children’s Oncology Group predecessor study (ACNS0122; ClinicalTrials.gov identifier: NCT00047320 ). Patients who achieved a complete response (CR) or partial response (PR) with or without second-look surgery were eligible for reduced RT, defined as 30.6 Gy whole ventricular field and 54 Gy tumor-bed boost, compared with 36 Gy craniospinal irradiation plus 54 Gy tumor-bed boost used in ACNS0122. RESULTS A total of 107 eligible patients were enrolled. Median age was 10.98 years (range, 3.68 to 21.63) and 75% were male. Sixty-six of 107 (61.7%) achieved a CR or PR and proceeded to reduced RT. The 3-year PFS and overall survival and standard error values were 87.8% ± 4.04% and 92.4% ± 3.3% compared with 92% and 94.1%, respectively, in ACNS0122. There were 10 recurrences, prompting early study closure; however, after a retrospective central review, only disease in eight of 66 (12.1%) patients eligible for reduced RT subsequently progressed; six patients had distant spinal relapse alone and two had disease with combined local plus distant relapse. Serum and CSF α-fetoprotein and β-human chorionic gonadotropin levels were not associated with PFS. CONCLUSION Patients with localized NGGCT who achieved a CR or PR to chemotherapy and received reduced RT had encouraging PFS similar to patients in ACNS0122 who received full-dose craniospinal irradiation. However, the patterns of failure were distinct, with all patients having treatment failure in the spine.
Pioglitazone Exposure Reduced the Risk of All-Cause Mortality in Insulin-Treated Patients with Type 2 Diabetes Mellitus
Authors: Yen Fu-Shun , Wang Hsiang-Chi , Pan Chun-Wei , Wei James Cheng-Chung , Hsu Chih-Cheng , Hwu Chii-Min 
Published: September 2019

AbstractContextThe long-term safety and benefit of pioglitazone use in combination with insulin are still uncertain.ObjectiveThis study compared the risks of all-cause mortality and major cardiovascular (CV) events between pioglitazone users and nonusers receiving insulin therapy.Design, Setting and PatientsWe conducted a 13-year retrospective cohort study by using data from the population-based National Health Insurance Research Database in Taiwan. A total of 20 376 patients with type 2 diabetes mellitus (T2DM) receiving insulin therapy were enrolled during 2000 to 2012. Overall, the incidence rates of all-cause mortality and CV events were compared between 2579 pioglitazone users and 2579 matched nonusers.ResultsAfter adjustment for age, sex, comorbidities, Diabetes Complications Severity Index scores, and drugs used, mortality rates were 30.26 and 15.02 per 1000 person-years for pioglitazone nonusers and users, respectively. The adjusted hazard ratio (aHR) of mortality was 0.47 (95% confidence interval [CI]: 0.38–0.58, P &lt; 0.001) for pioglitazone users compared with nonusers. The aHRs of CV and non-CV deaths were 0.78 (95% CI: 0.51–1.19) and 0.50 (95% CI: 0.38–0.66), respectively. The aHRs of hospitalized coronary artery disease, hospitalized stroke, and incident heart failure were not significantly different between pioglitazone users and nonusers.ConclusionsThis nationwide cohort study demonstrated that pioglitazone use reduced the risks of all-cause mortality and non-CV death for patients with T2DM undergoing insulin therapy.
Body Composition and Markers of Cardiometabolic Health in Transgender Youth Compared With Cisgender Youth
Authors: Nokoff Natalie J , Scarbro Sharon L , Moreau Kerrie L , Zeitler Philip , Nadeau Kristen J , Juarez-Colunga Elizabeth , Kelsey Megan M 
Published: September 2019

Abstract

Context
As many as 1.8% of adolescents identify as transgender and many more seek care, yet the impact of gender-affirming hormone therapy (GAHT) on cardiometabolic health is unknown.

Objective
To determine insulin sensitivity and body composition among transgender females (TF) and males (TM) on estradiol or testosterone, compared with cisgender females (CF) and males (CM).

Design
Pilot, cross-sectional study conducted from 2016–2018.

Setting
Academic regional transgender referral center.

Participants
Transgender adolescents on either testosterone or estradiol for at least 3 months were recruited. Nineteen TM were matched to 19 CM and 42 CF on pubertal stage and body mass index (BMI). Eleven TF were matched to 23 CF and 13 TF to 24 CM on age and BMI.

Main Outcome Measures
1/[fasting insulin] and body composition (dual-energy x-ray absorptiometry).

Results
Total body fat was lower in TM than CF mean ± SD: (29% ± 7% vs 33% ± 7%; P = 0.002) and higher than in CM (28% ± 7% vs 24% ± 9%; P = 0.047). TM had higher lean mass than CF (68% ± 7% vs 64% ± 7%, P = 0.002) and lower than CM (69% ± 7% vs 73% ± 8%; P = 0.029). Insulin sensitivity was not different between the groups.
TF had lower body fat than CF (31% ± 7% vs 35% ± 8%; P = 0.033) and higher than CM (28% ± 6% vs 20% ± 10%; P = 0.001). TF had higher lean mass than CF (66% ± 6% vs 62% ± 7%; P = 0.032) and lower than CM (69% ± 5% vs 77% ± 9%; P = 0.001). TF were more insulin resistant than CM (0.078 ± 0.025 vs 0.142 ± 0.064 mL/μU; P = 0.011).

Conclusions
Transgender adolescents on GAHT have significant differences in body composition compared with cisgender controls, with a body composition intermediate between BMI-matched CMs and CFs. These changes in body composition may have consequences for the cardiometabolic health of transgender adolescents.

ClinicalTrials.gov
NCT02550431
Fibroblast Activation Protein is a GH Target: A Prospective Study of Patients with Acromegaly Before and After Treatment
Authors: Arlien-Søborg Mai C , Grøndahl Camilla , Bæk Amanda , Dal Jakob , Madsen Michael , Høgild Morten Lyng , Pedersen Steen B , Bjerre Mette , Jørgensen Jens O L 
Published: September 2019

Abstract

Background
Fibroblast growth factor 21 (FGF21) is a circulating hormone with pleiotropic metabolic effects, which is inactivated by fibroblast activation protein (FAP). Data regarding interaction between FGF21, FAP, and growth hormone (GH) are limited, but it is noteworthy that collagens are also FAP substrates, since GH potently stimulates collagen turnover.

Aim
To measure circulating FGF21 components, including FAP, in patients with acromegaly before and after disease control.

Methods
Eighteen patients with active acromegaly were studied at the time of diagnosis and ≥ 6 months after disease control by either surgery or medical treatment. Serum levels of total and active FGF21, β-klotho, FAP, and collagen turnover markers were measured by immunoassays. Expression of putative FGF21-dependent genes were measured in adipose tissue by reverse transcriptase-polymerase chain reaction, body composition assessed by dual-energy x-ray absorptiometry scan, and insulin sensitivity estimated with homeostatic model assessment of insulin resistance (HOMA-IR).

Results
Total FGF21, active FGF21 and β-klotho remained unchanged. Insulin sensitivity and body fat mass increased after disease control but neither correlated with active FGF21. Expression of FGF21-dependent genes did not change after treatment. FAP levels (µg/L) were markedly reduced after treatment [105.6 ± 29.4 vs 62.2 ± 32.4, P &lt; 0.000]. Collagen turnover markers also declined significantly after treatment and ΔFAP correlated positively with ΔProcollagen Type I (P &lt; 0.000) and Type III (P &lt; 0.000).

Conclusion
1) Circulating FGF21 and β-klotho do not change in response to acromegaly treatment, 2) FAP concentrations in serum decrease after disease control and correlate positively with collagen turnover markers, and 3) FAP is a hitherto unrecognized GH target linked to collagen turnover.

Clinical Trials Registration
NCT00647179
IGF2 Mutations
Authors: Masunaga Yohei , Inoue Takanobu , Yamoto Kaori , Fujisawa Yasuko , Sato Yasuhiro , Kawashima-Sonoyama Yuki , Morisada Naoya , Iijima Kazumoto , Ohata Yasuhisa , Namba Noriyuki , Suzumura Hiroshi , Kuribayashi Ryota , Yamaguchi Yu , Yoshihashi Hiroshi , Fukami Maki , Saitsu Hirotomo , Kagami Masayo , Ogata Tsutomu 
Published: September 2019

Abstract

Objective
IGF2 is a paternally expressed growth-promoting gene. Here, we report five cases with IGF2 mutations and review IGF2 mutation-positive patients described in the literature. We also compare clinical features between patients with IGF2 mutations and those with H19/IGF2:IG-DMR epimutations.

Results
We recruited five cases with IGF2 mutations: case 1 with a splice site mutation (c.–6–1G&gt;C) leading to skipping of exon 2 and cases 2–5 with different missense mutations (p.(Cys70Tyr), p.(Cys71Arg), p.(Cys33Ser), and p.(Cys45Ser)) affecting cysteine residues involved in the S-S bindings. All the mutations resided on the paternally inherited allele, and the mutation of case 5 was present in a mosaic condition. Clinical assessment revealed Silver–Russell syndrome (SRS) phenotype with Netchine–Harbison scores of ≥5/6 in all the apparently nonmosaic 14 patients with IGF2 mutations (cases 1–4 described in this study and 10 patients reported in the literature). Furthermore, compared with H19/IGF2:IG-DMR epimutations, IGF2 mutations were associated with low frequency of hemihypoplasia, high frequency of feeding difficulty and/or reduced body mass index, and mild degree of relative macrocephaly, together with occasional development of severe limb malformations, high frequency of cardiovascular anomalies and developmental delay, and low serum IGF-II values.

Conclusions
This study indicates that IGF2 mutations constitute a rare but important cause of SRS. Furthermore, while both IGF2 mutations and H19/IGF2:IG-DMR epimutations lead to SRS, a certain degree of phenotypic difference is observed between the two groups, probably due to the different IGF2 expression pattern in target tissues.
Nonconventional Doses of Somatostatin Analogs in Patients With Progressing Well-Differentiated Neuroendocrine Tumor
Authors: Lamberti Giuseppe , Faggiano Antongiulio , Brighi Nicole , Tafuto Salvatore , Ibrahim Toni , Brizzi Maria Pia , Pusceddu Sara , Albertelli Manuela , Massironi Sara , Panzuto Francesco , Badalamenti Giuseppe , Riccardi Ferdinando , Butturini Giovanni , Gelsomino Fabio , De Divitiis Chiara , Modica Roberta , Bongiovanni Alberto , La Salvia Anna , Torchio Martina , Colao Annamaria , Ferone Diego , Campana Davide 
Published: September 2019

Abstract

Purpose
To evaluate the antiproliferative activity and safety of nonconventional high doses of somatostatin analogs (HD-SSA) in patients with well-differentiated gastroenteropancreatic (GEP) neuroendocrine tumors (NET) with radiological disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria on a previous treatment.

Methods
A retrospective analysis of prospectively maintained databases from 13 Italian NET-dedicated centers was performed. Main inclusion criteria were: well-differentiated G1 or G2 GEP-NET, progressive disease on a previous treatment, and subsequent treatment with HD-SSA (either by increased administered dose [dose intensity] or shortened interval between administrations [dose density]). Main endpoints were progression-free survival (PFS) and safety.

Results
Of 198 patients, 140 matched inclusion criteria and were included in the analysis. Overall, median PFS was 31 months. Use of HD-SSA as second-line treatment was associated with reduced risk for progression or death compared with third- or further-line treatment (HR: 2.12; P = 0.004). There was no difference in PFS between HD-SSA by increased dose density (N = 133; 95%) or intensity (N = 7; 5%). Partial response according to RECIST criteria was observed in 12 patients (8.6%), and stable disease was achieved in 106 (75.7%) patients. Adverse events occurred in 21 patients (15.0%), 2 of whom had grade 3 biliary stone disease. No patients discontinued HD-SSA treatment due to adverse events.

Conclusions
HD-SSA is an active and safe treatment option in patients with progressive well-differentiated GEP-NET. The high rate of objective responses observed deserves prospective validation in ad hoc clinical trials.
Comparison Between Total Thyroidectomy and Medical Therapy for Amiodarone-Induced Thyrotoxicosis
Authors: Cappellani Daniele , Papini Piermarco , Pingitore Alessandro , Tomisti Luca , Mantuano Michele , Di Certo Agostino M , Manetti Luca , Marconcini Giulia , Scattina Ilaria , Urbani Claudio , Morganti Riccardo , Marcocci Claudio , Materazzi Gabriele , Iervasi Giorgio , Martino Enio , Bartalena Luigi , Bogazzi Fausto 
Published: September 2019

Abstract

Context
It is not known whether total thyroidectomy is more favorable than medical therapy for patients with amiodarone-induced thyrotoxicosis (AIT).

Objective
To compare total thyroidectomy with medical therapy on survival and cardiac function in AIT patients.

Methods
Observational longitudinal cohort study involving 207 AIT patients that had received total thyroidectomy (surgery group, n = 51) or medical therapy (medical therapy group, n = 156) over a 20-year period. AIT types and left ventricular ejection fraction (LVEF) classes were determined at diagnosis of AIT. Cardiac and thyroid function were reevaluated during the study period. Survival was estimated using the Kaplan-Meier method.

Results
Overall mortality and cardiac-specific mortality at 10 and 5 years, respectively, were lower in the surgery group than in the medical therapy group (P = 0.04 and P = 0.01, respectively). The lower mortality rate of the surgery group was due to patients with moderate to severely compromised LVEF (P = 0.005 vs medical therapy group). In contrast, mortality of patients with normal or mildly reduced LVEF did not differ between the 2 groups (P = 0.281 and P = 0.135, respectively). Death of patients with moderate to severe LV systolic dysfunction in the medical therapy group occurred after 82 days (interquartile range, 56–99), a period longer than that necessary to restore euthyroidism in the surgery group (26 days; interquartile range, 15–95; P = 0.038). Risk factors for mortality were age (hazard ratio [HR] = 1.036) and LVEF (HR = 0.964), whereas total thyroidectomy was shown to be a protective factor (HR = 0.210). LVEF increased in both groups after restoration of euthyroidism, above all in the most compromised patients in the surgery group.

Conclusions
Total thyroidectomy could be considered the therapeutic choice for AIT patients with severe systolic dysfunction, whereas it is not superior to medical therapy in those with normal or mildly reduced LVEF.
The Role of Sex and Sex Hormones in Neurodegenerative Diseases
Authors: Vegeto Elisabetta , Villa Alessandro , Della Torre Sara , Crippa Valeria , Rusmini Paola , Cristofani Riccardo , Galbiati Mariarita , Maggi Adriana , Poletti Angelo 
Published: September 2019

AbstractNeurodegenerative diseases (NDs) are a wide class of disorders of the central nervous system (CNS) with unknown etiology. Several factors were hypothesized to be involved in the pathogenesis of these diseases, including genetic and environmental factors. Many of these diseases show a sex prevalence and sex steroids were shown to have a role in the progression of specific forms of neurodegeneration. Estrogens were reported to be neuroprotective through their action on cognate nuclear and membrane receptors, while adverse effects of male hormones have been described on neuronal cells, although some data also suggest neuroprotective activities. The response of the CNS to sex steroids is a complex and integrated process that depends on (i) the type and amount of the cognate steroid receptor and (ii) the target cell type—either neurons, glia, or microglia. Moreover, the levels of sex steroids in the CNS fluctuate due to gonadal activities and to local metabolism and synthesis. Importantly, biochemical processes involved in the pathogenesis of NDs are increasingly being recognized as different between the two sexes and as influenced by sex steroids. The aim of this review is to present current state-of-the-art understanding on the potential role of sex steroids and their receptors on the onset and progression of major neurodegenerative disorders, namely, Alzheimer’s disease, Parkinson’s diseases, amyotrophic lateral sclerosis, and the peculiar motoneuron disease spinal and bulbar muscular atrophy, in which hormonal therapy is potentially useful as disease modifier.
Ossified and Materialized Selves in Three Manuscripts of Colonial Guatemala: Connections with the Sacred Instrumentality of Bone
Authors: Hinojosa Servando Z. 
Published: September 2019

AbstractGuatemalan colonial-period documents have proven valuable for revealing Maya thinking about bone, especially how Mayas imbued bones with personal identity. At key moments in the narratives of three Guatemalan manuscripts, the Rabinal Achi, Xpantzay Cartulary, and Pop Wuj, Mayas materialized the self of important individuals through their bones, treating the bones at times like captives. By doing this, colonial-era Mayas were revealing their ideational linkages with Mayas from the Classic and Postclassic periods who practiced ancestor veneration using bones. In this network of practices, Classic-, Postclassic-, and colonial-era Mayas linked human bones to enduring personal forces and used bones to support claims of ancestry to specific people. This study explores this feature of Maya life, and then analyzes how Mayas of the last hundred years now value bone more for other, non-ancestral ritual utilities. They have shifted from treating certain bones as a materialization of self to viewing bones in terms of the practical potentialities the bones encase, employing a mode of engagement exemplified by Tz’utujiil Maya bonesetters who treat broken bones with sacralized bones and bone surrogates. This work examines how bone use has oscillated between these two modes, contrasting how Mayas of the Classic, Postclassic, and colonial periods treated certain bones as a materialization of self against how Mayas of more recent decades have come to emphasize the sacred instrumentality of bone and put it to active use.
Two distinct actin filament populations have effects on mitochondria, with differences in stimuli and assembly factors
Authors: Fung Tak Shun , Ji Wei-Ke , Higgs Henry N. , Chakrabarti Rajarshi 
Published: September 2019

ABSTRACT
Recent studies show that mitochondria and actin filaments work together in two contexts: (1) increased cytoplasmic calcium induces cytoplasmic actin polymerization that stimulates mitochondrial fission and (2) mitochondrial depolarization causes actin assembly around mitochondria, with roles in mitophagy. It is unclear whether these two processes utilize similar actin assembly mechanisms. Here, we show that these are distinct actin assembly mechanisms in the acute phase after treatment (&lt;10 min). Calcium-induced actin assembly is INF2 dependent and Arp2/3 complex independent, whereas depolarization-induced actin assembly is Arp2/3 complex dependent and INF2 independent. The two types of actin polymerization are morphologically distinct, with calcium-induced filaments throughout the cytosol and depolarization-induced filaments as ‘clouds’ around depolarized mitochondria. We have previously shown that calcium-induced actin stimulates increases in both mitochondrial calcium and recruitment of the dynamin GTPase Drp1 (also known as DNM1L). In contrast, depolarization-induced actin is temporally associated with extensive mitochondrial dynamics that do not result in mitochondrial fission, but in circularization of the inner mitochondrial membrane (IMM). These dynamics are dependent on the protease OMA1 and independent of Drp1. Actin cloud inhibition causes increased IMM circularization, suggesting that actin clouds limit these dynamics.
This article has an associated First Person interview with the first author of the paper.
Drosophila emerins control LINC complex localization and transcription to regulate myonuclear position
Authors: Mandigo Torrey R. , Turcich Blake D. , Anderson Alyssa J. , Hussey Michael R. , Folker Eric S. 
Published: September 2019

ABSTRACT
Mispositioned nuclei are a hallmark of skeletal muscle disease. Many of the genes that are linked to Emery–Dreifuss muscular dystrophy (EDMD) encode proteins that are critical for nuclear movement in various cells, suggesting that disruptions in nuclear movement and position may contribute to disease progression. However, how these genes are coordinated to move nuclei is not known. Here, we focussed on two different emerin proteins in Drosophila, Bocksbeutel and Otefin, and their effects on nuclear movement. Although nuclear position was dependent on both, elimination of either Bocksbeutel or Otefin produced distinct phenotypes that were based in differential effects on the KASH-domain protein Klarsicht. Specifically, loss of Bocksbeutel reduced Klarsicht localization to the nucleus and resulted in a disruption in nuclear separation. Loss of Otefin increased the transcription of Klarsicht and led to premature separation of nuclei and their positioning closer to the edge of the muscle. Consistent with opposing functions, nuclear position is normal in otefin; bocksbeutel double mutants. These data indicate emerin-dependent regulation of Klarsicht levels in the nuclear envelope is a critical determinant of nuclear position.