tbuckley/cabot-search huggingface dataset:
Abstract 21: Years of Life Lost from Cardiovascular Disease Mortality Among Hispanics
Authors: Fatima Rodriguez, Katherine Hastings, Jiaqi Hu, Latha Palaniappan
Journal: Circulation (2017)

Background: Hispanics face a disproportionate burden of cardiovascular disease (CVD) risk factors yet paradoxically experience lower death rates as compared to their non-Hispanic white (NHW) counterparts. Years of life lost (YLL) is a more precise measure of premature mortality. Hypothesis: We hypothesize there will be heterogeneity in the YLL due to CVD between Hispanic subgroups. Methods: We used data from the National Center for Health Statistics Mortality file to compare deaths for Hispanic (n=832,550) subgroups and NHWs (n=7,770,145) &lt;75 years of age from 2003 to 2012. We identified all CVD deaths and by subtype (i.e. ischemic, cerebrovascular, hypertensive and heart failure) using the underlying cause of death (ICD-10: I00-I78, I20-I25, I60-I69, I11, I13 and I50, respectively). YLL was calculated by age categories standardizing with 2000 U.S. Census population. Population estimates were calculated using linear interpolation from 2000 and 2010 U.S. Census. Results: After standardization, 11.4 year-losses per 1000 people due to CVD for NHWs and 8.2 per 1000 for Hispanics. Overall, Hispanics had lower YLL compared to NHWs and Puerto Ricans had higher losses among Hispanic subgroups. Most Hispanics had higher YLL for cerebrovascular disease than NHWs (Hispanics 1.1 times higher, Puerto Rican 1.2 times higher and Mexican 1.3 times higher) (Figure). Conclusions: Premature mortality from CVD varies greatly by Hispanic subgroups. These findings suggest the importance of disaggregating CVD mortality by Hispanic subgroup and using more sensitive measures of premature death in public health analyses.
Oscillation-specific nodal alterations in early to middle stages Parkinson’s disease
Authors: Xiaojun Guan, Tao Guo, Qiaoling Zeng, Jiaqiu Wang, Cheng Zhou, Chunlei Liu, Hongjiang Wei, Yuyao Zhang, Min Xuan, Quanquan Gu, Xiaojun Xu, Peiyu Huang, Jiali Pu, Baorong Zhang, Min-Ming Zhang
Journal: Translational Neurodegeneration (2019)

Abstract Background Different oscillations of brain networks could carry different dimensions of brain integration. We aimed to investigate oscillation-specific nodal alterations in patients with Parkinson’s disease (PD) across early stage to middle stage by using graph theory-based analysis. Methods Eighty-eight PD patients including 39 PD patients in the early stage (EPD) and 49 patients in the middle stage (MPD) and 36 controls were recruited in the present study. Graph theory-based network analyses from three oscillation frequencies (slow-5: 0.01–0.027 Hz; slow-4: 0.027–0.073 Hz; slow-3: 0.073–0.198 Hz) were analyzed. Nodal metrics (e.g. nodal degree centrality, betweenness centrality and nodal efficiency) were calculated. Results Our results showed that (1) a divergent effect of oscillation frequencies on nodal metrics, especially on nodal degree centrality and nodal efficiency, that the anteroventral neocortex and subcortex had high nodal metrics within low oscillation frequencies while the posterolateral neocortex had high values within the relative high oscillation frequency was observed, which visually showed that network was perturbed in PD; (2) PD patients in early stage relatively preserved nodal properties while MPD patients showed widespread abnormalities, which was consistently detected within all three oscillation frequencies; (3) the involvement of basal ganglia could be specifically observed within slow-5 oscillation frequency in MPD patients; (4) logistic regression and receiver operating characteristic curve analyses demonstrated that some of those oscillation-specific nodal alterations had the ability to well discriminate PD patients from controls or MPD from EPD patients at the individual level; (5) occipital disruption within high frequency (slow-3) made a significant influence on motor impairment which was dominated by akinesia and rigidity. Conclusions Coupling various oscillations could provide potentially useful information for large-scale network and progressive oscillation-specific nodal alterations were observed in PD patients across early to middle stages.
TMOD-41. ORTHOTOPIC PATIENT-DERIVED XENOGRAFT MODELS OF BRAIN METASTASIS: PLATFORMS FOR PRECISION ONCOLOGY AND UNDERSTANDING TUMOR BIOLOGY
Authors: Matthew Dankner, Paul Savage, April Rose, Mathieu Lajoie, Roberto Diaz, Morag Park, Ian Watson, Marie-Christine Guiot, Kevin Petrecca, Peter Siegel
Journal: Neuro-Oncology (2019)

Abstract RATIONALE Brain metastasis (BrM) occurs in 10–20% of cancer patients and results in median survival times of less than 1 year. In order to accurately develop novel treatment strategies, there is an urgent need to establish animal models of BrM that resemble the human disease. OBJECTIVES: We sought to establish orthotopic patient-derived xenografts (PDX) models of BrM from diverse solid cancers to understand biological characteristics of BrM and to test novel drug candidates in their ability to treat BrM. METHODS 35 PDXs were established by subcutaneous or mammary fat pad implantation and by intracranial injection. PDXs were validated by immunohistochemistry of routine pathological markers in patient specimens and matched primary and intracranial PDXs. PDXs were applied for precision medicine in class II BRAF mutant tumours treated with targeted therapy and in the pre-clinical development of a novel therapeutic agent, DZ-2384, which may have applications in treating BrM. They were also used to understand the underlying biology of leptomeningeal dissemination from parenchymal BrM. RESULTS PDXs reveal strong similarity to patient specimens by IHC staining. Class II BRAF mutant PDXs are optimally sensitive to BRAF and MEK inhibitors compared to either agent alone. DZ-2384 is effective in slowing the progression of breast cancer BrM. PDXs that most efficiently invade the leptomeninges display loss of E-Cadherin expression, suggesting the role of an epithelial-mesenchymal transition in this process. CONCLUSIONS PDXs of BrM represent important models that can be employed to test novel therapeutics and to improve understanding of molecular mechanisms engaged by BrM.
NIMG-44. NON-INVASIVE ADVANCED IMAGING METRICS PROVIDE POTENTIAL BIOMARKERS FOR GBM BIOLOGICAL HETEROGENEITY AND IMMUNE LANDSCAPE VARIANCE
Authors: Cymon Kersch, Leslie Muldoon, Rochelle Fu, Cheryl Claunch, Edward Neuwelt, Ramon Barajas
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Treatment of glioblastoma multiforme (GBM) is complicated by extensive tumor heterogeneity. We hypothesize that transcriptomic analysis of brain tumor regions with different magnetic resonance imaging (MRI) characteristics will define specific biological processes, providing a non-invasive method for tumor characterization and stratification. METHODS Previously at the University of California San Francisco, treatment naïve GBM tissue from gadolinium contrast enhancing lesion (CEL) and non-enhancing lesion (NCEL) regions were stereotactically sampled; prior to resection, relative cerebral blood volume (rCBV) and apparent diffusion coefficient (ADC) were determined. The tissue samples were characterized by immunohistochemistry and assessed for gene expression by microarray analysis. We correlated gene expression patterns in the CEL, NCEL, and non-tumor gliotic brain samples with multimodal physiological imaging metrics and immunohistochemical phenotypes. Gene expression networks were probed using Gene Set Enrichment Analysis. Key immunologic genes were examined individually. RESULTS Samples with differing MRI and histological phenotypes demonstrated transcriptomic variance reflecting distinct biological networks. We found significant differences in immune pathways, with immune gene signature prominent in CEL areas, moderate in NCEL and low in gliotic non-tumor brain. Within homogenously enhancing areas of CEL and NCEL there was underlying heterogeneity detectable by variable rCBV, ADC and histological phenotypes, which correlate with differing gene expression profiles indicative of biological and immunological tumor microenvironments. Increasing rCBV was correlated with an anti-inflammatory immune response in the CEL and a pro-inflammatory immune response in the NCEL. ADC was negatively correlated with cell cycle and immune networks in CEL, while NCEL ADC was positively correlated with immune processes. GBM samples with the mesenchymal molecular subtype had the greatest immune response. CONCLUSIONS Multimodal MRI features identify regionally diverse transcriptomic-based biological and immunological phenotypes in GBM. We propose that imaging genomics provides a technique for localizing biological processes and tumor immune microenvironments across space and time in GBM.
Neoplastic Diseases (Cancer)
Authors: D Laszlo, H Spencer, A Weiss
Journal: Annual Review of Medicine (1956)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), emerged in China in December 2019 and quickly spread around the globe, killing more than 4 million people and causing a severe economic crisis. ...Read More
New safeguarding arrangements: identifying children outside the system
Authors: Adhnan Omar
Journal: BMJ (2019)

Ambitions to safeguard children and promote their welfare rightfully demand national impetus. Recent legislative changes represent purposeful strides in that direction and must facilitate improvements in child wellbeing.1 Redefining social care structures and responsible persons gives us scope to progress care for children under social and safeguarding services. But questions remain around children that need care …
A Functional Analysis of SNP on Anthracycline-Induced Cardiotoxicity in a Uniform Genetic Background Using CRISPR/Cas9 Mediated Single-Base-Edited iPSCs
Authors: Takayuki Nakamura, Shinichi Mizuno, Hidetoshi Ozawa, Yoshitaka Yamasaki, Shuki Oya, Satoshi Morishige, Kazutoshi Aoyama, Maki Ymaguchi, Ritsuko Seki, Fumihiko Mouri, Koichi Osaki, Koji Nagafuji
Journal: Blood (2019)
Trends in the prevalence of chronic liver disease in the Korean adult population, 1998–2017
Authors: Seung Ha Park, Lindsay D. Plank, Ki Tae Suk, Yong Eun Park, Jin Lee, Joon Hyuk Choi, Nae Yun Heo, Jongha Park, Tae Oh Kim, Young Soo Moon, Hyun Kuk Kim, Hang Jea Jang, Ha Young Park, Dong Joon Kim
Journal: Clinical and Molecular Hepatology (2019)

Data on the trends in the prevalence of chronic liver disease (CLD) in Korea are scarce. This study aimed to evaluate whether the CLD prevalence changed between 1998–2001 and 2016–2017. Data were extracted from the Korea National Health and Nutrition Examination Survey (1998–2001 to 2016–2017; n=25,893). Non-alcoholic fatty liver disease (NAFLD) was defined as a hepatic steatosis index &gt;36 in the absence of any other evidence of CLD. The definition of alcoholrelated liver disease (ALD) was excessive alcohol consumption (≥210 g/week for men and ≥140 g/week for women) and an ALD/NAFLD index &gt;0. The prevalence of NAFLD increased from 18.6% (95% confidence interval [CI], 17.8–19.5%) in 1998–2001 to 21.5% (95% CI, 20.6–22.6%) in 2016–2017. During the same time period, increases were observed in the prevalence of obesity (27.0 vs. 35.1%), central obesity (29.4 vs. 36.0%), diabetes (7.5 vs. 10.6%), and excessive drinking (7.3 vs. 10.5%). ALD prevalence also increased from 3.8% (95% CI, 3.4–4.2%) to 7.0% (95% CI, 6.4–7.6%). In contrast, chronic hepatitis B decreased from 5.1% (95% CI, 4.6–5.5%) to 3.4% (95% CI, 3.0–3.8%). The prevalence of chronic hepatitis C was approximately 0.3% in 2016–2017. The prevalence of NAFLD and ALD increase among Korean adults. Our results suggest potential targets for interventions to reduce the future burden of CLD.
NIMG-09. NONINVASIVE PERFUSION IMAGING BIOMARKER OF MALIGNANT GENOTYPE IN ISOCITRATE DEHYDROGENASE MUTANT GLIOMAS
Authors: Monica Mureb, Rajan Jain, Laila Poisson, Ingrid Aguiar Littig, Lucidio Nunes Neto, Chih-Chin Wu, Victor Ng, Sohil Patel, Seema Patel, Jonathan Serrano, Sylvia Kurz, Daniel Cahill, Martin Bendszus, Andreas von Deimling, Dimitris Placantonakis, John Golfinos, Philipp Kickingereder, Matija Snuderl, Andrew Chi
Journal: Neuro-Oncology (2019)

Abstract OBJECTIVE A small subset of IDHmut astrocytomas behave aggressively, similarly to IDHwt glioblastoma. Genomic correlates of poor prognosis IDHmut astrocytomas include global relative DNA hypomethylation, MYCN amplification copy number variation (CNV) abundance, and CDKN2A/B homozygous deletion. We sought to identify a non-invasive imaging correlate of poor prognosis IDHmut astrocytomas. METHODS 30 IDHmut astrocytomas (NYU=18, TCGA=12) were included. Relative cerebral blood volume was obtained from 4 regions of interest within the highest perfusion areas. Genomic CNV analysis and CDKN2A/B copy number status was obtained using Illumina Infinium 450k or Illumina EPIC methylation array data. Associations between rCBV, survival, and genomic alterations were evaluated. An additional 22 IDHmut astrocytomas were obtained from another institution for validation. RESULTS CNV stable (CNV-S, n=14) astrocytomas demonstrated significantly lower mean rCBV than and CNV unstable (CNV-U, n=16) (P=0.0.0155) ones. IDHmut astrocytomas with CDKN2A/B homozygous deletion (n=7) had higher rCBV (3.9 ± 2.3, mean ± SD) compared to those without this alteration (n=22; 1.8 ± 1.9, mean ± SD; P=0.0489). In the validation set, there was no significant evidence in rCBV between CNV-S and CNV-U tumors (P=0.3976). These results were sensitive to a single outlier in the CNV-S group. Excluding this case with rCBV=7.15, the CNV-S tumors demonstrated significantly lower mean rCBV (P=0.0279). IDHmut astrocytomas with CDKN2A/B homozygous deletion (n=9) tended to have higher rCBV (4.2 ± 1.8, mean ± SD) compared to those without this alteration (n=16; 2.5 ± 1.5, mean ± SD; P=0.0757, t-test). This led to significant discrimination (P=0.0328, Wilcoxon). CONCLUSION Our study is the first to identify a non-invasive imaging biomarker for prognostic genomic alterations in IDHmut astrocytomas. Greater CNV abundance and/or CDKN2A/B homozygous deletion have higher rCBV and worse prognosis. Our methods can be applied to standard clinical practice and may enhance informed treatment decisions in the preoperative and immediate postoperative settings.
Automation in Hemopoietic Stem Cell Gene Therapy: Results of a Head-to-Head Comparison of a Manual Vs an Automated Procedure
Authors: Eleni Papanikolaou, Ute Bissels, Ian Johnston, Sarah Reinartz, Dominik Brams, Faidra Aivazidou, Dariusz Krenz, Inga von Bomhard, Sebastian Knöbel, Andreas Bosio
Journal: Blood (2019)
Incidence of Late-Diagnosed Hip Dislocation After Universal Clinical Screening in Sweden
Authors: Daniel Wenger, Henrik Düppe, Jan-Åke Nilsson, Carl Johan Tiderius
Journal: JAMA Network Open (2019)

<h3>Importance</h3> Developmental dysplasia of the hip, including late-diagnosed hip dislocation, is the leading cause of hip arthroplasties in young adults. Early treatment is essential for a good prognosis. Before the institution of a national screening program, a minimum of 0.9 per 1000 Swedish children were affected. <h3>Objectives</h3> To evaluate the incidence of late-diagnosed hip dislocation among children who undergo clinical screening as neonates and to study antenatal and perinatal risk factors for late-diagnosed hip dislocation. <h3>Design, Setting, and Participants</h3> This nested case-control study included children born in Sweden from January 1, 2000, through December 31, 2009. All maternity wards, maternal health units, and orthopedic departments in Sweden participated. Children with a late-diagnosed hip dislocation were matched by sex and birth year to randomly selected controls in a 1:10 ratio. Potential risk factors in pregnant women and newborns were recorded, and cases of hip dislocation were registered. Observation time ranged from 8 to 18 years, with the last data analysis in January 2019. <h3>Exposures</h3> Clinical hip examinations neonatally and at 6 to 8 weeks, 6 months, and 10 to 12 months. <h3>Main Outcomes and Measures</h3> Hip dislocation diagnosed more than 14 days after birth, age at diagnosis, and severity of dislocation. <h3>Results</h3> Among 1 013 589 live births (521 728 [51.5%] boys), 126 children (0.12 [95% CI, 0.10-0.15] per 1000 live births) had a late-diagnosed hip dislocation at a median age of 31.4 weeks (interquartile range, 16.1-67.1 weeks; 95% CI, 27.4-44.1 weeks). The incidence of late-diagnosed hip dislocation was 9 times higher among girls (113 of 491 861; 0.23 [95% CI, 0.19-0.28] per 1000 live births) than among boys (13 of 521 728; 0.02 [95% CI, 0.01-0.04] per 1000 live births). Twenty-one children (0.02 per 1000 live births) had high (severe) dislocations. Breech delivery (adjusted odds ratio, 3.07; 95% CI, 1.34-7.02), short body length at birth (adjusted odds ratio, 0.86; 95% CI, 0.76-0.98, per additional 1 cm), and being large for gestational age (adjusted odds ratio, 3.59; 95% CI, 1.30-9.95) were independent risk factors. Maternal smoking at the first visit to the maternal health care center was less common among children with hip dislocation (adjusted odds ratio, 0.16; 95% CI, 0.04-0.70). <h3>Conclusions and Relevance</h3> Compared with historical data, the incidence of late-diagnosed hip dislocation in Swedish-born children appears to have decreased substantially since the screening program was initiated, as have the age at detection and disease severity. Similar screening programs should also be possible to institute in upper-middle- and lower-middle-income countries.
IMGN632, a CD123-Alkylating ADC Bearing a DNA-Alkylating IGN Payload, Combines Effectively with Azacitidine and Venetoclax In Vivo, Prolonging Survival in Preclinical Models of Human Acute Myeloid Leukemia (AML)
Authors: Vinitha Mary Kuruvilla, Rebecca McCarthy, Qi Zhang, Callum M. Sloss, Patrick A. Zweidler-McKay, Angela Romanelli, Sharlene Adams, Marina Y Konopleva
Journal: Blood (2019)
De Novo and Therapy-Related Acute Myeloid Leukemia and Myelodysplastic Syndrome: Similarities and Differences in SNP-Array Detected Chromosomal Aberrations in Pre-Transplant Blood Samples
Authors: Youjin Wang, Weiyin Zhou, Lisa J. McReynolds, Elizabeth A. Griffiths, Swapna Thota, Mitchell Machiela, Stephen J Chanock, Meredith Yeager, Philip L. McCarthy, Marcelo C. Pasquini, Junke Wang, Ezgi Karaesmen, Abbas A. Rizvi, Leah Preus, Hancong Tang, Yiwen Wang, Daniel Stram, Loreall Pooler, Xin Sheng, Christopher Haiman, David Van Den Berg, Stephen R. Spellman, Tao Wang, Michelle Kuxhausen, Stephanie J. Lee, Theresa E. Hahn, Lara E. Sucheston-Campbell, Shahinaz M Gadalla
Journal: Blood (2019)
2019 American Heart Association and American Red Cross Focused Update for First Aid: Presyncope: An Update to the American Heart Association and American Red Cross Guidelines for First Aid
Authors: Nathan P. Charlton, Jeffrey L. Pellegrino, Amy Kule, Tammy M. Slater, Jonathan L. Epstein, Gustavo E. Flores, Craig A. Goolsby, Aaron M. Orkin, Eunice M. Singletary, Janel M. Swain
Journal: Circulation (2019)

This 2019 focused update to the American Heart Association and American Red Cross first aid guidelines follows the completion of a systematic review of treatments for presyncope of vasovagal or orthostatic origin. This review was commissioned by the International Liaison Committee on Resuscitation and resulted in the development of an international summary statement of the International Liaison Committee on Resuscitation First Aid Task Force Consensus on Science With Treatment Recommendations. This focused update highlights the evidence supporting specific interventions for presyncope of orthostatic or vasovagal origin and recommends the use of physical counterpressure maneuvers. These maneuvers include the contraction of muscles of the body such as the legs, arms, abdomen, or neck, with the goal of elevating blood pressure and alleviating symptoms. Although lower-body counterpressure maneuvers are favored over upper-body counterpressure maneuvers, multiple methods can be beneficial, depending on the situation.
HIF-2 Complex Dissociation, Target Inhibition, and Acquired Resistance with PT2385, a First-in-Class HIF-2 Inhibitor, in Patients with Clear Cell Renal Cell Carcinoma
Authors: Kevin D. Courtney, Yuanqing Ma, Alberto Diaz de Leon, Alana Christie, Zhiqun Xie, Layton Woolford, Nirmish Singla, Allison Joyce, Haley Hill, Ananth J. Madhuranthakam, Qing Yuan, Yin Xi, Yue Zhang, Jenny Chang, Oluwatomilade Fatunde, Yull Arriaga, Arthur E. Frankel, Sanjeeva Kalva, Song Zhang, Tiffani McKenzie, Oscar Reig Torras, Robert A. Figlin, Brian I. Rini, Renée M. McKay, Payal Kapur, Tao Wang, Ivan Pedrosa, James Brugarolas
Journal: Clinical Cancer Research (2019)

Abstract Purpose: The heterodimeric transcription factor HIF-2 is arguably the most important driver of clear cell renal cell carcinoma (ccRCC). Although considered undruggable, structural analyses at the University of Texas Southwestern Medical Center (UTSW, Dallas, TX) identified a vulnerability in the α subunit, which heterodimerizes with HIF1β, ultimately leading to the development of PT2385, a first-in-class inhibitor. PT2385 was safe and active in a first-in-human phase I clinical trial of patients with extensively pretreated ccRCC at UTSW and elsewhere. There were no dose-limiting toxicities, and disease control ≥4 months was achieved in 42% of patients. Patients and Methods: We conducted a prospective companion substudy involving a subset of patients enrolled in the phase I clinical trial at UTSW (n = 10), who were treated at the phase II dose or above, involving multiparametric MRI, blood draws, and serial biopsies for biochemical, whole exome, and RNA-sequencing studies. Results: PT2385 inhibited HIF-2 in nontumor tissues, as determined by a reduction in erythropoietin levels (a pharmacodynamic marker), in all but one patient, who had the lowest drug concentrations. PT2385 dissociated HIF-2 complexes in ccRCC metastases, and inhibited HIF-2 target gene expression. In contrast, HIF-1 complexes were unaffected. Prolonged PT2385 treatment resulted in the acquisition of resistance, and we identified a gatekeeper mutation (G323E) in HIF2α, which interferes with drug binding and precluded HIF-2 complex dissociation. In addition, we identified an acquired TP53 mutation elsewhere, suggesting a possible alternate mechanism of resistance. Conclusions: These findings demonstrate a core dependency on HIF-2 in metastatic ccRCC and establish PT2385 as a highly specific HIF-2 inhibitor in humans. New approaches will be required to target mutant HIF-2 beyond PT2385 or the closely related PT2977 (MK-6482).