Genomic Heterogeneity as a Barrier to Precision Medicine in Gastroesophageal Adenocarcinoma

Pectasides, Eirini,Stachler, Matthew D.,Derks, Sarah,Liu, Yang,Maron, Steven,Islam, Mirazul,Alpert, Lindsay,Kwak, Heewon,Kindler, Hedy,Polite, Blase,Sharma, Manish R.,Allen, Kenisha,O'Day, Emily,Lomni American Association for Cancer Research 2018 Cancer discovery Vol.8 No.1

<P>Heterogeneity of actionable genomic alterations among primary and metastatic lesions suggests that biomarker profiling of a single primary tumor site may limit the success of targeted therapy in gastroesophageal adenocarcinoma.</P><P>Gastroesophageal adenocarcinoma (GEA) is a lethal disease where targeted therapies, even when guided by genomic biomarkers, have had limited efficacy. A potential reason for the failure of such therapies is that genomic profiling results could commonly differ between the primary and metastatic tumors. To evaluate genomic heterogeneity, we sequenced paired primary GEA and synchronous metastatic lesions across multiple cohorts, finding extensive differences in genomic alterations, including discrepancies in potentially clinically relevant alterations. Multiregion sequencing showed significant discrepancy within the primary tumor (PT) and between the PT and disseminated disease, with oncogene amplification profiles commonly discordant. In addition, a pilot analysis of cell-free DNA (cfDNA) sequencing demonstrated the feasibility of detecting genomic amplifications not detected in PT sampling. Lastly, we profiled paired primary tumors, metastatic tumors, and cfDNA from patients enrolled in the personalized antibodies for GEA (PANGEA) trial of targeted therapies in GEA and found that genomic biomarkers were recurrently discrepant between the PT and untreated metastases. Divergent primary and metastatic tissue profiling led to treatment reassignment in 32% (9/28) of patients. In discordant primary and metastatic lesions, we found 87.5% concordance for targetable alterations in metastatic tissue and cfDNA, suggesting the potential for cfDNA profiling to enhance selection of therapy.</P><P><B>Significance:</B> We demonstrate frequent baseline heterogeneity in targetable genomic alterations in GEA, indicating that current tissue sampling practices for biomarker testing do not effectively guide precision medicine in this disease and that routine profiling of metastatic lesions and/or cfDNA should be systematically evaluated. <I>Cancer Discov; 8(1); 37–48. ©2017 AACR.</I></P><P><I>See related commentary by Sundar and Tan, p. 14</I>.</P><P><I>See related article by Janjigian et al., p. 49</I>.</P><P><I>This article is highlighted in the In This Issue feature, p. 1</I></P>

The Relationship between Depression and Insomnia Symptoms Amongst a Sample of UK University Students

Umair Akram,asha akram,Maria Gardani,Antonia Ypsilanti,Kristofor McCarty,Sarah Allen,Lambros Lazuras 대한수면학회 2019 sleep medicine research Vol.10 No.1

Research exploring the relationship between mental health difficulties and insomnia amongst stu- dents in the UK remains limited. This study further examined the extent of potential relationships between insomnia, anxiety and depression symptoms amongst university students in the UK. A sample of 487 students from four northern universities completed The Insomnia Severity Index, SLEEP-50, and Hospital Anxiety and Depression Scales. Approximately one fifth of students expe- rienced mild to severe levels of depressive symptoms, and two thirds reported anxious symptoms. One quarter of students indicated insomnia symptoms in the clinical range, however the preva- lence of sleep-disorders other than insomnia remained low (< 5%). Finally, symptoms of insomnia and apnoea were significantly related to depression, after controlling for co-morbid anxiety. The current outcomes highlight the high prevalence of depressive and insomnia symptoms amongst university students in the UK. Considering the relationship between insomnia and depression, stu- dent-focused mental health services should explore the possibility of treating insomnia to circum- vent depression.

THE SAMI GALAXY SURVEY: GALAXY INTERACTIONS AND KINEMATIC ANOMALIES IN ABELL 119

Oh, Sree,Yi, Sukyoung K.,Cortese, Luca,Sande, Jesse van de,Mahajan, Smriti,Jeong, Hyunjin,Sheen, Yun-Kyeong,Allen, James T.,Bekki, Kenji,Bland-Hawthorn, Joss,Bloom, Jessica V.,Brough, Sarah,Bryant, Ju American Astronomical Society 2016 The Astrophysical journal Vol.832 No.1

<P>Galaxy mergers are important events that can determine the fate of a galaxy by changing its morphology, star formation activity and mass growth. Merger systems have commonly been identified from their disturbed morphologies, and we now can employ integral field spectroscopy to detect and analyze the impact of mergers on stellar kinematics as well. We visually classified galaxy morphology using deep images (mu(r) = 28 mag arcsec(-2)) taken by the Blanco 4 m telescope at the Cerro Tololo Inter-American Observatory. In this paper we investigate 63 bright (M-r < - 19.3) spectroscopically selected galaxies in Abell 119, of which 53 are early type and 20 show a disturbed morphology by visual inspection. A misalignment between the major axes in the photometric image and the kinematic map is conspicuous in morphologically disturbed galaxies. Our sample is dominated by early-type galaxies, yet it shows a surprisingly tight Tully-Fisher relation except for the morphologically disturbed galaxies which show large deviations. Three out of the eight slow rotators in our sample are morphologically disturbed. The morphologically disturbed galaxies are generally more asymmetric, visually as well as kinematically. Our findings suggest that galaxy interactions, including mergers and perhaps fly-bys, play an important role in determining the orientation and magnitude of a galaxy's angular momentum.</P>

THE SAMI GALAXY SURVEY: REVISITING GALAXY CLASSIFICATION THROUGH HIGH-ORDER STELLAR KINEMATICS

Sande, Jesse van de,Bland-Hawthorn, Joss,Fogarty, Lisa M. R.,Cortese, Luca,d’Eugenio, Francesco,Croom, Scott M.,Scott, Nicholas,Allen, James T.,Brough, Sarah,Bryant, Julia J.,Cecil, Gerald,Colless, Ma American Astronomical Society 2017 The Astrophysical journal Vol.835 No.1

<P>Recent cosmological hydrodynamical simulations suggest that integral field spectroscopy can connect the high-order stellar kinematic moments h(3) (similar to skewness) and h(4) (similar to kurtosis) in galaxies to their cosmological assembly history. Here, we assess these results by measuring the stellar kinematics on a sample of 315 galaxies, without a morphological selection, using two-dimensional integral field data from the SAMI Galaxy Survey. Proxies for the spin parameter (lambda(Re)) and ellipticity (epsilon(e)) are used to separate fast and slow rotators; there exists a good correspondence to regular and non-regular rotators, respectively, as also seen in earlier studies. We confirm that regular rotators show a strong h(3) versus V/sigma s anti-correlation, whereas quasi-regular and non-regular rotators show a more vertical relation in h(3) and V/sigma. Motivated by recent cosmological simulations, we develop an alternative approach to kinematically classify galaxies from their individual h(3) versus V/sigma signatures. Within the SAMI Galaxy Survey, we identify five classes of high-order stellar kinematic signatures using Gaussian mixture models. Class 1 corresponds to slow rotators, whereas Classes 2-5 correspond to fast rotators. We find that galaxies with similar lambda(Re)-epsilon(e) -values can show distinctly different h(3)-V/sigma signatures. Class 5 objects are previously unidentified fast rotators that show a weak h(3) versus V/sigma anti-correlation. From simulations, these objects are predicted to be disk-less galaxies formed by gas-poor mergers. From morphological examination, however, there is evidence for large stellar disks. Instead, Class 5 objects are more likely disturbed galaxies, have counter-rotating bulges, or bars in edge-on galaxies. Finally, we interpret the strong anti-correlation in h(3) versus V/sigma as evidence for disks in most fast rotators, suggesting a dearth of gas-poor mergers among fast rotators.</P>