bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract IA007: The mutational landscape of normal human endometrial epithelium
Authors: Moore Luiza
Published: February 2021

Human endometrium is a highly dynamic tissue that undergoes numerous cycles of breakdown, rapid repair and remodelling in response to the oscillating levels of oestrogen and progesterone. The marked regenerative capacity of the tissue’s epithelial compartment is maintained by the intra-glandular adult stem cells (ASCs) that are retained during menstruation. Although the endometrial epithelial ASCs were first described over a decade ago, they remain poorly characterised in comparison to their counterparts in other tissues, such as the small and arge intestine. In particular, the size of the stem cell pool within individual glands, clonal dynamics and genomic landscape are largely unknown. In this study, we laser-capture microdissected 257 morphologically normal endometrial glands from pre- and post-menopausal women (aged 19 to 81). In selected donors, we also obtained samples of normal endocervical and Fallopian tubular epithelium. Isolated cellular material was subjected to our modified library preparation protocol and subsequent whole genome sequencing (WGS). Analysis of the WGS data identified that the majority of the glands were clonal cell populations sharing a recent common ancestor. Somatic mutations accumulated at a rate of 29 substitutions per year. Total mutation burden in the normal endometrial epithelium is higher than in other normal cells and manyfold lower than in endometrial cancers. Overall, despite the heterogeneity in age, reproductive history and BMI, we found relatively homogenous mutational processes to be operative in this tissue with only occasional outliers. Remarkably, we not only identify recurrent acquisitions of certain cancer-associated mutations, particularly those that are advantageous to cell growth, proliferation and migration, but also show that such events occur early in life, potentially even before adolescence. Using a generalised linear mixed effect model, we found that age has a positive association with the accumulation of driver mutations, while parity has a negative association. Over time, the mutant ASCs serve as a reservoir for the acquisition of further driver mutations to the extent that in some cases, the entire sampled endometrium becomes ‘neoplastic’ on the genomic level while still retaining the apparently normal phenotype. Our data identify a distinct mutational landscape in normal endometrium that is in keeping with the presence of early positive selection in this highly regenerative tissue.

Citation Format: Luiza Moore. The mutational landscape of normal human endometrial epithelium [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr IA007.
Abstract IA008: Mismatch repair deficiency and survival in stage I endometrial cancer
Authors: Broaddus Russell R.
Published: February 2021

The importance of testing for DNA mismatch repair defects and high levels of tumor microsatellite instability (MSI) is established for screening colorectal and endometrial cancers for Lynch Syndrome and advanced solid tumor malignancies for treatment with checkpoint inhibitors. Therefore, accurate clinical assays are necessary to identify DNA mismatch repair defects and patients with cancers with high levels of MSI. While defects in DNA mismatch repair identified by immunohistochemistry may often overlap with tumor microsatellite instability as identified by PCR-based assays, the two molecular events are not synonymous and can be discordant in individual cancers. Cancers outside of the GI tract may have loss of DNA mismatch repair proteins but may have more subtle microsatellite instability or even be microsatellite stable. The College of American Pathologists has established an expert guideline committee to help navigate some of the clinical testing issues when trying to detect defects in DNA mismatch repair and MSI in cancers. In addition to these established clinical uses of DNA mismatch repair and MSI, their use as a prognostic biomarker for endometrial cancer is emerging. Data suggest that specific environmental factors may interact with DNA mismatch repair, causing a more variable phenotype in cancers with loss of DNA mismatch repair.

Citation Format: Russell R. Broaddus. Mismatch repair deficiency and survival in stage I endometrial cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr IA008.
Abstract IA012: Recent progress with PTEN
Authors: Parsons Ramon E.
Published: February 2021

PTEN is one of the most frequently mutated genes in cancer and is frequently mutated in endometrial carcinoma. Recent progress on PTEN will be presented from our laboratory regarding its role in metabolism, RNA polymerase II transcription, and its expression in tumors with p53 mutations. I) Loss of PTEN activates metabolism of glutamine to pyrimidine and inactivates the ATR DNA damage checkpoint elicited when pyrimidine synthesis is interrupted, which leads to DNA damage and cell death suggesting a metabolic strategy for cancer treatment. II) PTEN in the nucleus binds to RNA polymerase II as wells as CDK7 and CDK9 on chromatin at promoters and regulates RNA Pol II transcription of genes involved in cellular metabolism. Mutation of PTEN increases RNA poly II levels and phosphorylation and increases sensitivity to inhibition of CDK7 and CDK9. III) Mutation of p53 is associated with reduced expression of PTEN and other tumor suppressor genes in many forms of cancer. p53 was found to bind to a dozen tumor suppressor genes in its wild type state and activates their expression under basal low stress conditions when the level of p53 is at a low level. All of these tumor suppressor genes had p53 binding elements in their promoters and enhancers and deletion of the element in a PTEN enhancer lowered its expression. These findings suggest that p53 mediates tumor suppression by maintaining the expression of other tumor suppressor genes including PTEN.

Citation Format: Ramon E. Parsons. Recent progress with PTEN [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr IA012.
Abstract IA015: Molecular stratification: Beyond TCGA
Authors: Church David
Published: February 2021

The molecular endometrial cancer (EC) classification defined by TCGA has improved both understanding of disease biology and clinical risk stratification. In my talk, I will review data for other biomarkers with proven or potential utility to further refine risk stratification in EC. I will also present results of analysis of whole genome sequence data from the large cohort of ECs recruited to the Genomics England 100,000 Genomes Project, and highlight the promise of this initiative to define new tumour subsets and therapeutic targets.

Citation Format: David Church. Molecular stratification: Beyond TCGA [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr IA015.
Abstract IA020: Chromatin regulation of the endometrium: What are our models telling us?
Authors: Wilson Mike R. , Reske Jake J. , Chandler Ronald L.
Published: February 2021

ARID1A and PI3-Kinase (PI3K) pathway alterations are common in neoplasms originating from the uterine endometrium. ARID1A is a SWI/SNF chromatin-remodeling complex subunit. ARID1A loss in the mouse endometrial epithelium leads vaginal bleeding when combined with PI3K pathway activation. Sorted mutant endometrial epithelial cells display gene expression and promoter chromatin signatures associated with epithelial-to-mesenchymal transition (EMT), inflammation and estrogen signaling in vivo. ARID1A loss leads to the expression of EMT genes, suggesting ARID1A normally maintains endometrial epithelial cell identity by repressing mesenchymal cell fates. In contrast to its repressive roles, ARID1A is required for the activation estrogen responsive genes, including the progesterone receptor (PGR). Estrogen responsive genes are marked by bivalent chromatin domains containing both histone H3 lysine 4 trimethylation (H3K4me3) and lysine 27 trimethylation (H3K27me3). High H3K27me3 correlates with low PGR expression, suggesting Polycomb Repressive Complex 2 (PRC2)-mediated H3K27me3 normally silences PGR. In support of this, pharmacological inhibition of PRC2 partially rescues PGR activation is estrogen treated, ARID1A-deficient cells. Given the known antagonistic relationship between SWI/SNF and PRC2 complexes, we propose that SWI/SNF normally opposes PRC2 mediated silencing of the PGR promoter in response to estrogen, leading to PGR expression. In the ARID1A mutant endometrium, PGR promoter silencing by PRC2 is maintained. In the absence of PGR, progesterone cannot oppose the actions estrogen in the endometrium, leading to unopposed estrogen signaling. Our data demonstrate ARID1A has both activating and repressive roles in the endometrium, and ARID1A loss contributes to multiple aspects of disease pathogenesis.

Citation Format: Mike R. Wilson, Jake J. Reske, Ronald L. Chandler. Chromatin regulation of the endometrium: What are our models telling us? [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr IA020.
Abstract PO002: Inducing homologous recombination deficiency in uterine serous cancer (USC) using AVB-500, a receptor tyrosine kinase AXL inhibitor
Authors: Toboni Michael D. , Blachut Barbara , Lomonosova Elena , Khabele Dineo , Kuroki Lindsay , Hagemann Andrea , McCourt Carolyn , Thaker Premal , Mutch David , Powell Matthew , Fuh Katherine
Published: February 2021

Background: Evidence suggests that inducing homologous recombination deficiency (HRD) can be a therapeutic target in endometrial cancer (EC). Given this, we determined whether AVB-500, an AXL inhibitor, could induce HRD measured by a reduction of RAD51 foci in response to DNA damage in a uterine serous cancer (USC). Methods: Baseline homologous recombination (HR) status was determined after inducing DNA damage by radiating USC cell lines (ARK1 and ARK4) with 10Gy radiation treatment (RT) and identifying RAD51 foci by immunofluorescence (IF). Both radiated and non-radiated cells were quantified in both cell lines. Cell lines were considered to be HR proficient if over 30% of the cells expressed RAD51 (>5 foci per cell). AVB-500 (Aravive Biologics, Houston, TX) was given prior to radiation after baseline HR status was established. IF was conducted using a Leica confocal microscope and foci were quantified using FociCounter. Results: Both ARK1 and ARK4, showed HR proficiency at baseline. After radiation, there was an increase in gamma-H2Ax indicative of DNA damage and an appropriate increase in RAD51 foci in response. However, when cells were treated with AVB-500 prior to radiation, there was a decrease in RAD51 foci when compared to radiation alone in both ARK1 (2.7 foci for AVB + RT vs 7.3 foci for RT only, p=0.0003) and ARK4 (6.3 foci for AVB + RT vs 13.0 foci for RT only, p=0.0054). Furthermore, after treatment with AVB-500 followed by RT, the proportion of ARK1 cells expressing RAD51 decreased to 21%, indicating HR deficiency. Conclusions: ARK1 and ARK4 are HR proficient at baseline. Pretreatment with AVB500 followed by RT led to a decrease in RAD51 foci suggestive of inducing HRD. Additional therapeutic and mechanistic experiments are ongoing.

Citation Format: Michael D. Toboni, Barbara Blachut, Elena Lomonosova, Dineo Khabele, Lindsay Kuroki, Andrea Hagemann, Carolyn McCourt, Premal Thaker, David Mutch, Matthew Powell, Katherine Fuh. Inducing homologous recombination deficiency in uterine serous cancer (USC) using AVB-500, a receptor tyrosine kinase AXL inhibitor [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO002.
Abstract PO005: A comprehensive analysis of the transcriptional effects of progesterone receptor isoforms A and B identifies VEGF, PDGF and STAT3 as therapeutic targets
Authors: Leslie Kimberly K. , Leiva Stephanie M. , Dai Donghai , Zhang Yuping , Thiel Kristina W.
Published: February 2021

Progesterone prevents development of endometrial cancers through its receptors A (PRA) and B (PRB) although the molecular mechanisms have yet to be fully characterized. In this study, we performed a global analysis of gene regulation by progesterone using human endometrial cancer cells that express heterologous progesterone receptors. Functional replicate Affymetrix microarrays encompassing 54,000 transcripts were performed for two independent experiments. Data suggest that progesterone exerts the growth-limiting effects in endometrium via down-regulation of several growth factors important in angiogenesis and cell proliferation. In particular, progesterone down-regulates the vascular endothelial growth factor (VEGF), platelet derived growth factor (PDGF), and signal transducer and activator of transcription 3 (STAT3) genes. Down-regulation of these pro-growth pathways required the co-expression of both PR isoforms A and B, whereas expression of either isoform alone resulted in unchanged or even elevated levels of PDGF and STAT3 transcripts. Our study identifies these pathways as central to the growth limiting effects of progesterone in endometrial cancer and suggests that these factors constitute important targets for future therapeutic interventions. We also provide a comprehensive catalogue of the transcriptional effects of PR isoforms in endometrial cancer for future reference.

Citation Format: Kimberly K. Leslie, Stephanie M. Leiva, Donghai Dai, Yuping Zhang, Kristina W. Thiel. A comprehensive analysis of the transcriptional effects of progesterone receptor isoforms A and B identifies VEGF, PDGF and STAT3 as therapeutic targets [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO005.
Abstract PO013: SNP rs1982 in the 3’UTR of placenta-specific protein 1 (PLAC1) is associated with endometrial cancer survival
Authors: Devor Eric J. , Gonzalez-Bosquet Jesus , Leslie Kimberly K.
Published: February 2021

Placenta-specific protein 1 (PLAC1) is a small (212aa) secreted protein normally only expressed on the apical surfaces of syncytiotrophoblasts. However, over the past two decades we and other investigators have shown that human cancers and, in particular, cancers of the human reproductive tract, induce PLAC1 expression. In gynecologic cancers, PLAC1 expression has been shown to be associated with risk, histology and TP53 mutation status. A previously unassessed informative SNP rs1982 (A>C) lies in the 3’ untranslated region of the PLAC1 gene. We have begun to explore the utility of this SNP by genotyping a panel of 75 endometrial cancers. The panel is composed of 29 endometrial adenocarcinomas, 10 papillary serous adenocarcinomas, 9 mixed Mullerian tumors, 6 mixed histologies, 2 tumors identified as displaying complex atypia and 1 neuroendocrine tumor. High molecular weight genomic DNA was extracted from these tumors and SNP genotypes determined by directly sequencing a 312bp PCR amplicon generated by the primers:

rs1982for: GAGGATTGGTCTCTTCACACAG; rs1982rev: ACAATGTCTGGCCCATACTAAA

SNP genotypes were then evaluated against a variety of clinical variables including age, BMI, tobacco use, Charlson Index, co-morbidities, stage, grade, myometrial invasion, recurrence, and death by cancer using both univariate and multivariate logistic regression. Progression-free and overall survival were assessed by Cox Proportional Hazard ratio. Results show that CC homozygotes have increased progression-free and overall survival though neither reached statistical significance. However, several clinical variables were statistically associated with different rs1982 genotypes. Charlson co-morbidity Index was positively associated with presence of the wild-type A allele (OR = 1.61; 1.06 - 2.69; p<0.05), while death from disease was negatively associated (OR = 0.15; 0.03 – 0.64; p<0.02). These differences hold when accounting for other co-variates in the multivariate analysis. These data support further exploration of this SNP in gynecologic cancers.

Citation Format: Eric J. Devor, Jesus Gonzalez-Bosquet, Kimberly K. Leslie. SNP rs1982 in the 3’UTR of placenta-specific protein 1 (PLAC1) is associated with endometrial cancer survival [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO013.
Abstract PO032: Bacterial, archaea and viral transcripts (BAVT) expression in endometrial cancer
Authors: Nobre Silvana Pedra , Cardillo Nicholas , Bender David , Goodheart Michael , Devor Eric , Bosquet Jesus Gonzalez
Published: February 2021

Objectives: Microbes are found virtually everywhere, including the human body. High-throughput sequencing of microbial genome, also known as metagenomic sequencing, may help to understand interactions between human and microbial processes. In this pilot study we aimed to determine differences of bacterial, archaea and viral expression between normal fallopian tube samples and ovarian and endometrial cancer samples. Then, we assessed these differentially expressed transcripts in endometrial and ovarian cancer from TCGA data. Methods: RNA was extracted and sequenced from 62 endometrial cancers, 104 high-grade serous ovarian cancers and 12 normal tubes specimens from our Biobank repository. Sequencing was performed using the Illumina HiSeq4000 platform that sequences 150 bp paired-end transcripts. Reads were processed with Centrifuge, a novel algorithm that classifies metagenomic sequences. We built our own index to differentiate between bacterial, archaea, viral and human transcripts. Resulting number of transcripts were normalized, log transformed and compared between tubal epithelium and ovarian and endometrial cancers (t-test). Lasso regression was used to identify significant independent transcripts between samples. TCGA ovarian and endometrial samples were processed as previously, and expression of significant probes were evaluated. Results: Bacterial, archaea and viral transcripts (BAVT) were 4.7% and 3,1% of all transcriptome in tubal and ovarian cancer respectively. 266 transcripts were differentially expressed between normal tubes and ovarian and endometrial cancer, with a p<0.005. 11 bacteria and 1 virus were independently significant in the multivariate regression model. These microbes were mapped close to genome regulatory areas. In general, there were more BVAT in normal tube samples. The amount of BAVT decreased in endometrial cancer and even more in ovarian cancer, supporting this regulatory role of BAVT. BAVTs in TCGA were 0.8% of all transcriptome. Conclusions: BAVT expression is different between normal tissues and cancers in the gynecologic tract. Cancer amount of BAVT seems to decrease in malignant tissues, supporting a regulatory role of BAVT. Further studies are needed to determine the significance of BAVT amount and change of expression.

Citation Format: Silvana Pedra Nobre, Nicholas Cardillo, David Bender, Michael Goodheart, Eric Devor, Jesus Gonzalez Bosquet. Bacterial, archaea and viral transcripts (BAVT) expression in endometrial cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference: Endometrial Cancer: New Biology Driving Research and Treatment; 2020 Nov 9-10. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(3_Suppl):Abstract nr PO032.
Nutrition Management of Gestational Diabetes Mellitus
Authors: Kapur Kavita , Kapur Anil , Hod Moshe
Published: February 2021

Medical nutrition therapy (MNT) is the bedrock for the management of gestational diabetes mellitus (GDM). Several different types of dietary approaches are used globally, and there is no consensus among the various professional groups as to what constitutes an ideal approach. The conventional approach of limiting carbohydrates at the cost of increasing energy from the fat source may not be most optimal. Instead, allowing higher levels of complex, low-to-medium glycaemic index carbohydrates and adequate fibre through higher consumption of vegetables and fruits seems more beneficial. No particular diet or dietary protocol is superior to another as shown in several comparative studies. However, in each of these studies, one thing was common – the intervention arm included more intensive diet counselling and more frequent visits to the dieticians. For MNT to work, it is imperative that diet advice and nutrition counselling is provided by a dietician, which is easy to understand and use and includes healthy food options, cooking methods, and practical guidance that empower and motivate to make changes towards a healthy eating pattern. Various simple tools to achieve these objectives are available, and in the absence of qualified dieticians, they can be used to train other health care professionals to provide nutrition counselling to women with GDM. Given the impact of GDM on the future health of the mother and offspring, dietary and lifestyle behaviour changes during pregnancy in women with GDM are not only relevant for immediate pregnancy outcomes, but continued adherence is also important for future health.
Cystic Pancreatic Neuroendocrine Tumor in a Patient with Neurofibromatosis Type 1
Authors: Shinozaki Hiroharu , Sasakura Yuuichi , Shinozaki Satoshi , Terauchi Toshiaki , Matsui Junichi , Kobayashi Kenji , Lefor Alan Kawarai , Ogata Yoshiro
Published: February 2021

Neurofibromatosis type 1 (NF-1) is strongly associated with neurofibromas and malignancies. Solid pancreatic neuroendocrine tumors (PanNETs) have been recently reported in patients with NF-1. PanNETs are always solid and rarely present with a cystic appearance due to central necrosis and hemorrhage caused by rapid growth. A 33-year-old female diagnosed with NF-1 at age 16 was referred for evaluation of a pelvic mass found on abdominal ultrasound. Magnetic resonance imaging showed a 6 cm solid pelvic mass adjacent to the left external iliac artery, and contrast-enhanced computed tomography scan showed a 3-cm solid para-aortic mass and a 3-cm cystic mass in the pancreatic tail. Endoscopic ultrasonography showed a cystic tumor with necrotic tissue and septa. Preoperative diagnosis was pancreatic cystic malignancy with para-aortic lymph node metastasis accompanied with a pelvic neurofibroma. These lesions were resected simultaneously. The specimen resected from the pancreas showed a necrotizing cystic tumor invading abutting lymph nodes. Immunohistochemical analysis showed positive chromogranin A and synaptophysin. The Ki-67 index was <1%, and the mitotic count was 1/10 in high power field. Therefore, a non-functional PanNET (grade G1) was diagnosed. The pelvic and para-aortic tumors were both neurofibromas. A cystic appearance is atypical for PanNET and makes preoperative diagnosis difficult. To the best of our knowledge, this is the first report of a cystic PanNET in a patient with NF-1.
Silodosin versus Tamsulosin as Medical Expulsive Therapy for Children with Lower-Third Ureteric Stones: Prospective Randomized Placebo-Controlled Study
Authors: Soliman Mohamed G. , El-Gamal Osama , El-Gamal Samir , Abdel Raheem Ali , Abou-Ramadan Ahmed , El-Abd Ahmed
Published: February 2021

Aim: To compare the efficacy and safety of silodosin versus tamsulosin as medical expulsive therapy for stones of lower-third ureter in children. Patients and Methods: This prospective single-blind placebo-controlled randomized study included 167 pediatric patients who presented with distal ureteric stone (DUS) less than 1 cm. Patients were randomized into 3 groups; group I received silodosin 4 mg once daily, and group II received tamsulosin 0.4 mg while those in group III had placebo. The side effects of the used drugs, both rate and time of stone expulsion, and number of pain episodes were compared among the study groups for a maximum of 4 weeks. Results: Follow-up data of our patients after treatment revealed that the stone expulsion rate was significantly higher and the time to stone expulsion was significantly shorter in group I (89.3%, 12.4 ± 2.3 days) and group II (74.5%, 16.2 ± 4.2 days) compared to group III (51.8%, 21.2 ± 5.6). However, a statistically significant difference between silodosin and tamsulosin groups in favor of the former one was reported regarding the 2 studied items. Meanwhile, pain episodes requiring analgesia were statistically fewer in group I and II in contrast to placebo group. Adverse events were comparable among all groups. Conclusion: Silodosin provides significantly better stone expulsion rate and shorter expulsion time than tamsulosin for treatment of DUS. Both medications showed good safety profiles in children. However, further studies are required on a larger scale to confirm our results. Assessment of drug safety on younger age-group is still needed.
Establishing Normative Data on Singing Voice Parameters of Children and Adolescents with Average Singing Activity Using the Voice Range Profile
Authors: Dienerowitz Tobias , Peschel Thomas , Vogel Mandy , Poulain Tanja , Engel Christoph , Kiess Wieland , Fuchs Michael , Berger Thomas
Published: February 2021

Purpose: The purpose of this study was to establish and characterize age- and gender-specific normative data of the singing voice using the voice range profile for clinical diagnostics. Furthermore, associations between the singing voice and the socioeconomic status were examined. Methods: Singing voice profiles of 1,578 mostly untrained children aged between 7.0 and 16.11 years were analyzed. Participants had to reproduce sung tones at defined pitches, resulting in maximum and minimum fundamental frequency and sound pressure level (SPL). In addition, maximum phonation time (MPT) was measured. Percentile curves of frequency, SPL and MPT were estimated. To examine the associations of socioeconomic status, multivariate analyses adjusted for age and sex were performed. Results: In boys, the mean of the highest frequency was 750.9 Hz and lowered to 397.1 Hz with increasing age. Similarly, the minimum frequency was 194.4 Hz and lowered to 91.9 Hz. In girls, the mean maximum frequency decreased from 754.9 to 725.3 Hz. The mean minimum frequency lowered from 202.4 to 175.0 Hz. For both sexes, the mean frequency range ∆f showed a constant range of roughly 24 semitones. The MPT increased with age, for boys and girls. There was neither an effect of age nor sex on SPLmin or SPLmax, ranging between 52.6 and 54.1 dBA and between 86.5 and 82.8 dBA, respectively. Socioeconomic status was not associated with the above-mentioned variables. Conclusion: To our knowledge, this study is the first to present large normative data on the singing voice in childhood and adolescence based on a high number of measurements. In addition, we provide percentile curves for practical application in clinic and vocal pedagogy which may be applied to distinguish between normal and pathological singing voice.
COVID-19: Empfehlung zur Behandlung alter Tumorpatienten in Zeiten der Pandemie
Authors: Kolb Gerald
Published: February 2021

The COVID-19 pandemic poses a barrier to equal and evidence-based management of cancer in older adults. The International Society of Geriatric Oncology (SIOG) formed a panel of experts to develop consensus recommendations on the implications of the pandemic on several aspects of cancer care in this age group including geriatric assessment (GA), surgery, radiotherapy, systemic treatment, palliative care and research. Age and cancer diagnosis are significant predictors of adverse outcomes of the COVID-19 infection. In this setting, GA is particularly valuable to drive decision-making. GA may aid estimating physiologic reserve and adaptive capability, assessing risk-benefits of either providing or temporarily withholding treatments, and determining patient preferences to help inform treatment decisions. In a resource-constrained setting, geriatric screening tools may be administered remotely to identify patients requiring comprehensive GA. Tele-health is also crucial to ensure adequate continuity of care and minimize the risk of infection exposure. In general, therapeutic decisions should favor the most effective and least invasive approach with the lowest risk of adverse outcomes. In selected cases, this might require deferring or omitting surgery, radiotherapy or systemic treatments especially where benefits are marginal and alternative safe therapeutic options are available. Ongoing research is necessary to expand knowledge of the management of cancer in older adults. However, the pandemic presents a significant barrier and efforts should be made to ensure equitable access to clinical trials and prospective data collection to elucidate the outcomes of COVID-19 in this population.
Karzinome des Magens und ösophagogastralen Übergangs: Leitlinienempfehlung für die palliative Erstlinientherapie bestätigt
Authors: Stahl Michael
Published: February 2021

Background: The observational study HerMES collected primary data on effectiveness and safety of trastuzumab in patients with human epidermal growth receptor 2 (HER2)-positive cancer of the stomach or gastroesophageal junction (GEJ) in routine clinical practice, exploring the treatment with trastuzumab, chemotherapy backbones used, and the HER2 testing in a real-world setting in Germany. Subjects, materials, and methods: This noninterventional study observed patients with histologically confirmed, HER2-positive metastatic adenocarcinoma of the stomach or GEJ, who were treated with trastuzumab according to the physicians’ judgement and clinical practice. The observation phase per patient took as long as the duration of the trastuzumab therapy, but for a maximum of 12 months. A subsequent extended follow-up phase lasted until the patient’s death or the end of the study, that is, 2 years from start of the follow-up phase of the last patient. All data were analyzed descriptively. Results: Between February 2010 and July 2016, 364 patients were observed at 171 sites throughout Germany. The median overall survival was 14.1 months and the median progression-free survival was 7.9 months. The overall response rate was 43%. Safety was in line with previous reports. This study observed a high diversity of chemotherapy regimens that were combined with trastuzumab. Post hoc subgroup analyses showed differences in outcomes according to the chemotherapy regimen used. Conclusion: Trastuzumab treatment in everyday practice as observed in HerMES confirmed the positive results of the pivotal study ToGA in an observational, real-world setting. Implications for practice: Real-world data of trastuzumab treatment of patients with gastroesophageal or gastric metastatic adenocarcinoma confirmed the positive results of the pivotal clinical trial. The observed median overall survival was 14.1 months and the median progression-free survival was 7.9 months. Although recommendations concerning administration of trastuzumab were well implemented, a high diversity of chemotherapy regimens were combined with trastuzumab. Regimens other than the in-label regimens, especially oxaliplatin-based doublets or 5-fluorouracil, leucovorin, oxaliplatin, taxane triplets, were used in 29% of patients. Observation of a second, marginal HER2-positivity population confirmed the benefit of trastuzumab predominantly for well-confirmed human epidermal growth receptor 2 (HER2)-positive tumors and the requirement of reliable HER2 testing.
Mineralocorticoid Receptor in Smooth Muscle Contributes to Pressure Overload–Induced Heart Failure
Authors: Kim Seung Kyum , Biwer Lauren A. , Moss M. Elizabeth , Man Joshua J. , Aronovitz Mark J. , Martin Gregory L. , Carrillo-Salinas Francisco J. , Salvador Ane M. , Alcaide Pilar , Jaffe Iris Z.
Published: February 2021

Background:

Mineralocorticoid receptor (MR) antagonists decrease heart failure (HF) hospitalization and mortality, but the mechanisms are unknown. Preclinical studies reveal that the benefits on cardiac remodeling and dysfunction are not completely explained by inhibition of MR in cardiomyocytes, fibroblasts, or endothelial cells. The role of MR in smooth muscle cells (SMCs) in HF has never been explored.

Methods:

Male mice with inducible deletion of MR from SMCs (SMC-MR-knockout) and their MR-intact littermates were exposed to HF induced by 27-gauge transverse aortic constriction versus sham surgery. HF phenotypes and mechanisms were measured 4 weeks later using cardiac ultrasound, intracardiac pressure measurements, exercise testing, histology, cardiac gene expression, and leukocyte flow cytometry.

Results:

Deletion of MR from SMC attenuated transverse aortic constriction-induced HF with statistically significant improvements in ejection fraction, cardiac stiffness, chamber dimensions, intracardiac pressure, pulmonary edema, and exercise capacity. Mechanistically, SMC-MR-knockout protected from adverse cardiac remodeling as evidenced by decreased cardiomyocyte hypertrophy and fetal gene expression, interstitial and perivascular fibrosis, and inflammatory and fibrotic gene expression. Exposure to pressure overload resulted in a statistically significant decline in cardiac capillary density and coronary flow reserve in MR-intact mice. These vascular parameters were improved in SMC-MR-knockout mice compared with MR-intact littermates exposed to transverse aortic constriction.

Conclusions:

These results provide a novel paradigm by which MR inhibition may be beneficial in HF by blocking MR in SMC, thereby improving cardiac blood supply in the setting of pressure overload–induced hypertrophy, which in turn mitigates the adverse cardiac remodeling that contributes to HF progression and symptoms.
Gestational Diabetes History and Glucose Tolerance After Pregnancy Associated With Coronary Artery Calcium in Women During Midlife
Authors: Gunderson Erica P. , Sun Baiyang , Catov Janet M. , Carnethon Mercedes , Lewis Cora E. , Allen Norrina B. , Sidney Stephen , Wellons Melissa , Rana Jamal S. , Hou Lifang , Carr John Jeffrey
Published: February 2021

Background:

Gestational diabetes (GD) leads to earlier onset and heightened risk of type 2 diabetes, a strong risk factor for cardiovascular disease (CVD). However, it is unclear whether attaining normoglycemia can ameliorate the excess CVD risk associated with GD history. This study sought to evaluate GD history and glucose tolerance after pregnancy associated with coronary artery calcification (CAC) in women, a manifestation of atherosclerotic CVD and a predictor of CVD clinical events.

Methods:

Data were obtained from the CARDIA study (Coronary Artery Risk Development in Young Adults), a US multicenter, community-based prospective cohort of young Black (50%) and White adults aged 18 to 30 years at baseline (1985–1986). The sample included 1133 women without diabetes at baseline, who had ≥1 singleton births (n=2066) during follow-up, glucose tolerance testing at baseline and up to 5 times during 25 years (1986–2011), GD status, and CAC measurements obtained from 1 or more follow up examinations at years 15, 20, and 25 (2001–2011). CAC was measured by noncontrast cardiac computed tomography; dichotomized as Any CAC (score>0) or No CAC (score=0). Complementary log-log models for interval-censored data estimated adjusted hazard ratios of CAC and 95% confidence intervals for GD history and subsequent glucose tolerance groups (normoglycemia, prediabetes, or incident diabetes) on average 14.7 years after the last birth adjusted for prepregnancy and follow-up covariates.

Results:

Of 1133 women, 139 (12.3%) reported GD and were 47.6 years of age (4.8 SD) at follow-up. CAC was present in 25% (34/139) of women with GD and 15% (149/994) of women with no GD. In comparison with no GD/normoglycemia, adjusted hazard ratios (95% CIs) were 1.54 (1.06–2.24) for no GD/prediabetes and 2.17 (1.30–3.62) for no GD/incident diabetes, and 2.34 (1.34–4.09), 2.13 (1.09–4.17), and 2.02 (0.98–4.19) for GD/normoglycemia, GD/prediabetes, and GD/incident diabetes, respectively (overall
P
=0.003).

Conclusions:

Women without previous GD showed a graded increase in the risk of CAC associated with worsening glucose tolerance. Women with a history of GD had a 2-fold higher risk of CAC across all subsequent levels of glucose tolerance. Midlife atherosclerotic CVD risk among women with previous GD is not diminished by attaining normoglycemia.
Association of Self-Reported Polycystic Ovary Syndrome, Obesity, and Weight Gain From Adolescence to Adulthood With Hypertensive Disorders of Pregnancy
Authors: Rantakallio Juhani S.S. , Nevalainen Jaana E. , West Sammeli I. , Ollila Meri-Maija , Puukka Katri , Bloigu Aini H. , Järvelin Marjo-Riitta , Tapanainen Juha S. , Franks Stephen , Dunkel Leo , Piltonen Terhi T. , Vääräsmäki Marja S. , Morin-Papunen Laure C.
Published: February 2021

The purpose of this prospective, population-based cohort study was to evaluate the roles of polycystic ovary syndrome (PCOS), obesity, weight gain, and hyperandrogenemia in the development of hypertensive disorders of pregnancy (HDP) through fertile age both in PCOS and in non-PCOS women. The study population—NFBC1966 (Northern Finland Birth Cohort 1966)—allowed a long-term follow-up of women from age 14 until 46 years who developed HDP (n=408) or did not (n=3373). HDP diagnosis was confirmed by combining hospital discharge records, data from Finnish Medical Birth Registers, and the questionnaire data at age 46. Women with self-reported PCOS (srPCOS; n=279), defined by both oligo-amenorrhea and hirsutism at age 31 or with PCOS diagnosis by age 46, were compared with women without reported PCOS (n=1577). Women with srPCOS had an increased HDP risk (odds ratio, 1.56 [95% CI, 1.03–2.37]), but the association disappeared after adjustment for body mass index. In women with srPCOS and HDP, body mass index increased from age 14 to 46 significantly more than in srPCOS women without HDP (median [interquartile range], 9.82 [6.23–14.6] and 7.21 [4.16–10.5] kg/m
2
, respectively;
P
<0.001). Also, in non-PCOS women, the increase was higher in women with (7.54 [5.32–11.62] kg/m
2
;
P
<0.001) than without HDP (6.33 [3.90–9.33] kg/m
2
;
P
<0.001). Increase in waist circumference between ages 31 and 46 years was associated with HDP but not with PCOS. Hyperandrogenemia at 31 or 46 years did not associate with HDP (1.44 [0.98–2.11]). In conclusion, obesity, especially abdominal obesity, and weight gain from adolescence to age 46, but not srPCOS or hyperandrogenemia, were associated with an increased risk of HDP.
The Benefits of Intensive Versus Standard Blood Pressure Treatment According to Fine Particulate Matter Air Pollution Exposure
Authors: Al-Kindi Sadeer G. , Brook Robert D. , Bhatt Udayan , Brauer Michael , Cushman William C. , Hanson Heidi A. , Kostis John , Lash James P. , Paine Robert , Raphael Kalani L. , Rapp Stephen , Tamariz Leonardo , Wright Jackson T. , Rajagopalan Sanjay ,   For the SPRINT Research Group
Published: February 2021

Fine particulate matter <2.5 µm (PM
2.5
) air pollution is implicated in global mortality, especially from cardiovascular causes. A large body of evidence suggests a link between PM
2.5
and elevation in blood pressure (BP), with the latter implicated as a potential mediator of cardiovascular events. We sought to determine if the outcomes of intensive BP lowering (systolic BP <120 mm Hg) on cardiovascular events are modified by PM
2.5
exposure in the SPRINT (Systolic BP Intervention Trial). We linked annual PM
2.5
exposure estimates derived from an integrated model to subjects participating in SPRINT. We evaluated the effect of intensive BP lowering by PM
2.5
exposure on the primary outcome in SPRINT using cox-proportional hazard models. A total of 9286 participants were linked to PM
2.5
levels (mean age 68±9 years). Intensive BP-lowering decreased risk of the primary outcome more among patients exposed to higher PM
2.5
(
P
interaction
=0.047). The estimate for lowering of primary outcome was numerically lower in the highest than in the lower quintiles. The benefits of intensive BP-lowering were larger among patients chronically exposed to PM
2.5
levels above US National Ambient Air Quality Standards of 12 µg/m
3
(hazard ratio, 0.47 [95% CI, 0.29–0.74]) compared with those living in cleaner locations (hazard ratio, 0.81 [95% CI, 0.68–0.97]),
P
interaction
=0.037. This exploratory nonprespecified post hoc analysis of SPRINT suggests that the benefits of intensive BP lowering on the primary outcome was greater in patients exposed to higher PM
2.5
, suggesting that the magnitude of benefit may depend upon the magnitude of antecedent PM
2.5
exposure.
Effects of Different High-Intensity Interval Training Regimens on Endurance and Neuroplasticity After Cerebral Ischemia
Authors: Pin-Barre Caroline , Hugues Nicolas , Constans Annabelle , Berton Eric , Pellegrino Christophe , Laurin Jérôme
Published: February 2021

Background and Purpose:

The objective is to compare the effects of high-intensity interval training (HIIT) with long versus short intervals on endurance and motor performance. Their influence on neuroplasticity markers is assessed in the ipsilesional and contralesional cortex and hippocampus since their remodeling could improve functional recovery.

Methods:

Rats performed work-matched HIIT4 (long intervals: 4 minutes) or HIIT1 (short intervals: 1 minute) on treadmill for 2 weeks following transient middle cerebral artery occlusion. Forelimb grip strength evaluated motor function while incremental exercise tests measured the endurance performance. Key neuroplasticity markers were assessed by Western blot.

Results:

Both regimens were effective in enhancing both the speed associated with the lactate threshold and maximal speed at D8 and D15. Neuroplasticity markers were upregulated in the contralesional hemisphere after training contrary to the ipsilesional side. Grip strength completely recovered but is faster with HIIT4.

Conclusions:

HIIT with short and long intervals induced early aerobic fitness and grip strength improvements. Our findings revealed that neuroplasticity markers were upregulated in the contralesional cortex and hippocampus to promote functional recovery.
It's a Beautiful Name for a Satellite: Paradoxical Art Objects Somewhere between Politics and Poetics
Authors: Bureaud Annick
Published: February 2021

Since the launch of Sputnik, artists have dreamt of putting artistic satellites into orbit. The dream came true in 2013–2014. This article compares a selection of projects by the pioneers in the 1980s and ’90s with some of the current ones developed by a new generation of artists. The article analyzes and discusses different approaches, discourses, techniques and aesthetics.
Cosmic Inspirations and Explorations by Soviet Nonconformist Artists
Authors: Kolodzei Natalia
Published: February 2021

The author explores diverse artistic trends and styles in works by Nonconformist artists Vyacheslav Koleychuk, Francisco Infante, Eduard Steinberg, Dmitri Plavinsky, Petr Belenok, Ilya Kabakov, Vitaly Komar and Alexander Melamid, and Konstantin Khudyakov, and their relationship to the ideas of the Russian cosmism movement. She traces historical and cultural contexts for Soviet Nonconformist art from the mid-1950s to the early 1980s and the artists’ interest in early twentieth-century Russian avant-garde practices. Elaborating on a long interdisciplinary tradition while balancing scientific and metaphysical views of art, their works allude to the multidimensional reality of our cosmos. Cosmism may offer an escape into one's own cosmos, fantasy and dreams.
The Status of Franchising Laws in the Arab Region
Authors: Mattar Mohammed Y.
Published: February 2021

There has been a vast and rapid growth in the franchising business in the countries of the Middle East. The purpose of this article is to examine the status of franchising laws in the Arab World with particular focus on the commercial relationship between a franchisor and a franchisee. Most Arab countries rely on the traditional commercial agency laws to regulate the franchising business. These are designed to protect the interest of the national franchisee. Saudi Arabia is the first Arab country to adopt a comprehensive and independent law in the Arab region, while other countries rely on a code of conduct, an application of the distribution trade law or the implementation of the general rule of commercial agency. Saudi Arabia provides a detailed account of the franchising business, its establishment and its operation in an attempt to balance the interest of both, the franchisor and the franchisee.
Hurricane Predictability Analysis with Singular Vectors in the Multiresolution Global Shallow Water Model
Authors: Tian Xiaoxu , Ide Kayo
Published: February 2021

In this study, the tangent linear and adjoint (TL/AD) models for the Model for Prediction Across Scales (MPAS) Shallow Water (SW) component are tested and demonstrated. Necessary verification check procedures of TL/AD are included to ensure that the models generate correct results. The TL/AD models are applied to calculate the singular vectors (SVs) with a 48-h optimization time interval (OTI) under both the quasi-uniform-resolution (UR) and smoothly variable-resolution (VR) meshes in the cases of Hurricanes Sandy (2012) and Joaquin (2015). For the global domain, the VR mesh with 30 210 grid cells uses slightly fewer computational resources than the UR mesh with 40 962 cells. It is found that at the points before Hurricanes Sandy and Joaquin made sharp turns, the leading SV from the VR experiment show sensitivities in both areas surrounding the hurricane and those relatively far away, indicating the significant impacts from the environmental flows. The leading SVs from the UR experiments are sensitive to only areas near the storm. Forecasts by the nonlinear SW model demonstrate that in the VR experiment, Hurricane Sandy has a northwest turn similar to the case in the real world while the storm gradually disappeared in the UR experiment. In the case of Hurricane Joaquin, the nonlinear forecast with the VR mesh can generate a track similar to the best track, while the storm became falsely dissipated in the forecast with the UR mesh. These experiments demonstrate, in the context of SW dynamics with a single layer and no physics, the track forecasts in the cases of Hurricanes Sandy and Joaquin with the VR mesh are more realistic than the UR mesh. The SV analyses shed light on the key features that can have significant impacts on the forecast performances.