tbuckley/cabot-search huggingface dataset:
Rates and Patterns of Clonal Oncogenic Mutations in the Normal Human Brain
Authors: Javier Ganz, Eduardo A. Maury, Basheer Becerra, Sara Bizzotto, Ryan N. Doan, Connor J. Kenny, Taehwan Shin, Junho Kim, Zinan Zhou, Keith L. Ligon, Eunjung Alice Lee, Christopher A. Walsh
Journal: Cancer Discovery (2021)

Abstract Although oncogenic mutations have been found in nondiseased, proliferative nonneural tissues, their prevalence in the human brain is unknown. Targeted sequencing of genes implicated in brain tumors in 418 samples derived from 110 individuals of varying ages, without tumor diagnoses, detected oncogenic somatic single-nucleotide variants (sSNV) in 5.4% of the brains, including IDH1R132H. These mutations were largely present in subcortical white matter and enriched in glial cells and, surprisingly, were less common in older individuals. A depletion of high-allele frequency sSNVs representing macroscopic clones with age was replicated by analysis of bulk RNA sequencing data from 1,816 nondiseased brain samples ranging from fetal to old age. We also describe large clonal copy number variants and that sSNVs show mutational signatures resembling those found in gliomas, suggesting that mutational processes of the normal brain drive early glial oncogenesis. This study helps understand the origin and early evolution of brain tumors. Significance: In the nondiseased brain, clonal oncogenic mutations are enriched in white matter and are less common in older individuals. We revealed early steps in acquiring oncogenic variants, which are essential to understanding brain tumor origins and building new mutational baselines for diagnostics. This article is highlighted in the In This Issue feature, p. 1
Reply to Roesler et al. concerning the MEVITEM trial
Authors: Didier Frappaz, Marc Barritault
Journal: Neuro-Oncology (2022)

We thank Dr. Rafael Roesler and colleagues for their meaningful comments on our recent paper entitled “MEVITEM—a phase I/II of vismodegib + temozolomide vs temozolomide in patients with recurrent/refractory medulloblastoma with Sonic Hedgehog pathway activation.” 1 Dr. Roesler and colleagues argue that relapse samples should be evaluated for resistance markers as medulloblastomas may change their mutational landscape in between primary diagnosis and relapse. As mentioned in our discussion, this represents an obvious limitation of our study. Due to the rarity of patients with Sonic Hedgehog (SHH) activated medulloblastoma who relapse and are fit enough to enter a trial, and due to reluctance to impose a potentially dangerous biopsy at time of relapse, the authors had to enlarge the criteria for inclusion. The protocol allowed any site (including extra central nervous system locations) and timing (including biopsies performed at diagnosis) of tumor sampling. Our study included mostly biopsies obtained at diagnosis.
Global, regional, and country estimates of metabolic syndrome burden in children and adolescents in 2020: a systematic review and modelling analysis
Authors: Jean Jacques Noubiap, Jobert Richie Nansseu, Eric Lontchi-Yimagou, Jan René Nkeck, Ulrich Flore Nyaga, Anderson T Ngouo, Dahlia Noelle Tounouga, Franck Leonel Tianyi, Audrey Joyce Foka, Aude Laetitia Ndoadoumgue, Jean Joel Bigna
Journal: The Lancet Child & Adolescent Health (2022)
Abstract 11492: Relationship Between Coronary Artery Calcium and Thoracic Spine Bone Mineral Density: The Multi-Ethnic Study of Atherosclerosis
Authors: Venkat Sanjay Manubolu, Song Mao, April Kinninger, Yanlin Gao, Jeffrey Carr, Christopher Dailing, Sion Roy, Matthew Budoff
Journal: Circulation (2021)

Background: Traditionally, osteoporosis and coronary artery disease were considered unrelated. Beyond age, these two conditions appear to share common etiologies that are not yet fully understood. Objective: We sought to evaluate the relationship between thoracic spine bone mineral density (BMD) and severity of coronary artery calcium (CAC) score. Methods: MESA is a cohort study of 6,814 men and women from six U.S. cities between the ages of 45 and 84 years, who were free of clinical CVD. Included participants had thoracic spine BMD and CAC that was assessed by non-contrast chest CT, using methods previously described by Budoff et al 2010. Multivariate regression analysis was performed to examine the association of thoracic spine BMD and CAC score after adjusting for conventional risk factors of atherosclerosis including age, gender, BMI, race/ethnicity, diabetes, hypertension medications, lipid lowering medications, smoking history and family history of CAD. Results: Correlation coefficient, r, was -0.29 (p&lt;0.0001), indicating inverse relationship between CAC and BMD. BMD was categorized as normal (T-score&gt;-1), osteopenia (-2.5&lt;T-score=&lt;-1) or osteoporosis (T-score&lt;=-2.5). Prevalence of CAC &gt;0 was 36% in normal group, 49% in the osteopenia group and 68% in the osteoporosis group. In adjusted regression models, the odds of CAC were significantly higher in those with osteoporosis (OR: 1.57 95% CI: 1.31,1.88) p&lt;0.0001 and trending higher in those with osteopenia (OR: 1.15; 95% CI:1.00,1.32) p=0.049. Analysis stratified based on gender, the odds of CAC in men with osteoporosis is higher (OR: 1.61; 95% CI: 1.24,2.09) p=0.0004 compared to women with osteoporosis (OR: 1.48; 95% CI: 1.15,1.90) p=0.002. Conclusion: The prevalence of CAC was significantly higher in osteoporosis group compared to normal BMD. There is an inverse relationship between BMD and CAC independent of cardiovascular risk factors.
The use of bimekizumab for the treatment of psoriasis
Journal: British Journal of Dermatology (2022)

Increasingly a major tool for the treatment of severe psoriasis has been the selective use of biologic agents that are antibodies, known as monoclonal antibodies. These are given by injection and block the action of a specific target such as an immunological reaction involved in the development of psoriasis. One potential target for these medicines is, for instance, an immunological product known as interleukin‐17 (IL‐17).
Cost-effectiveness of universal screening for chronic hepatitis B virus infection in China: an economic evaluation
Authors: Shu Su, William CW Wong, Zhuoru Zou, Dan Dan Cheng, Jason J Ong, Polin Chan, Fanpu Ji, Man-Fung Yuen, Guihua Zhuang, Wai-Kay Seto, Lei Zhang
Journal: The Lancet Global Health (2022)
Transvenous Diaphragm Neurostimulation Mitigates Ventilation-associated Brain Injury
Authors: Thiago G. Bassi, Elizabeth C. Rohrs, Karl C. Fernandez, Marlena Ornowska, Michelle Nicholas, Matt Gani, Doug Evans, Steven C. Reynolds
Journal: American Journal of Respiratory and Critical Care Medicine (2021)

Mechanical ventilation (MV) is associated with hippocampal apoptosis and inflammation, and it is important to study strategies to mitigate them.
Projecting Temperature-Attributable Mortality and Hospital Admissions due to Enteric Infections in the Philippines
Authors: Paul L.C. Chua, Chris Fook Sheng Ng, Lina Madaniyazi, Xerxes Seposo, Miguel Antonio Salazar, Veronika Huber, Masahiro Hashizume
Journal: Environmental Health Perspectives (2022)

Background: Enteric infections cause significant deaths, and global projection studies suggest that mortality from enteric infections will increase in the future with warmer climate. However, a major limitation of these projection studies is the use of risk estimates derived from nonmortality data to project excess enteric infection mortality associated with temperature because of the lack of studies that used actual deaths. Objective: We quantified the associations of daily temperature with both mortality and hospital admissions due to enteric infections in the Philippines. These associations were applied to projections under various climate and population change scenarios. Methods: We modeled nonlinear temperature associations of mortality and hospital admissions due to enteric infections in 17 administrative regions of the Philippines using a two-stage time-series approach. First, we quantified nonlinear temperature associations of enteric infections by fitting generalized linear models with distributed lag nonlinear models. Second, we combined regional estimates using a meta-regression model. We projected the excess future enteric infections due to nonoptimal temperatures using regional temperature–enteric infection associations under various combinations of climate change scenarios according to representative concentration pathways (RCPs) and population change scenarios according to shared socioeconomic pathways (SSPs) for 2010–2099. Results: Regional estimates for mortality and hospital admissions were significantly heterogeneous and had varying shapes in association with temperature. Generally, mortality risks were greater in high temperatures, whereas hospital admission risks were greater in low temperatures. Temperature-attributable excess deaths in 2090–2099 were projected to increase over 2010–2019 by as little as 1.3% [95% empirical confidence intervals (eCI): −3.1%, 6.5%] under a low greenhouse gas emission scenario (RCP 2.6) or as much as 25.5% (95% eCI: −3.5%, 48.2%) under a high greenhouse gas emission scenario (RCP 8.5). A moderate increase was projected for temperature-attributable excess hospital admissions, from 0.02% (95% eCI: −2.0%, 1.9%) under RCP 2.6 to 5.2% (95% eCI: −12.7%, 21.8%) under RCP 8.5 in the same period. High temperature-attributable deaths and hospital admissions due to enteric infections may occur under scenarios with high population growth in 2090–2099. Discussion: In the Philippines, futures with hotter temperatures and high population growth may lead to a greater increase in temperature-related excess deaths than hospital admissions due to enteric infections. Our results highlight the need to strengthen existing primary health care interventions for diarrhea and support health adaptation policies to help reduce future enteric infections. https://doi.org/10.1289/EHP9324
24P Tepotinib in patients with MET exon 14 skipping NSCLC: Efficacy and safety by line of therapy
Authors: F. Griesinger, E. Felip, E.F. Smit, R. Veillon, J. Raskin, M. Thomas, P. Conte, D. Kowalski, L. Paz-Ares, G. Garcia Ledo, F. de Marinis, A. Scherz, K. Berghoff, R. Bruns, G. Otto, P. Paik
Journal: Annals of Oncology (2022)
Searching in the wrong place: Might consciousness reside in the brainstem?
Authors: Marshall Devor, Mary Koukoui, Mark Baron
Journal: Behavioral and Brain Sciences (2022)

Abstract Doubtless, the conscious brain integrates masses of information. But declaring that consciousness simply “emerges” when enough has accumulated, doesn't really explain how first person experience is implemented by neurons. Moreover, empirical observations challenge integrated information theory's (IIT) reliance on thalamo–cortical interactions as the information integrator. More likely, the cortex streams processed information to a still-enigmatic consciousness generator, one perhaps located in the brainstem.
Increased 68Ga-FAPI Activity in Malignant Melanoma of the Nasal Cavity
Authors: Lei Ou, Xiao Yang, Huipan Liu, Weidong Gong, Chunyin Zhang
Journal: Clinical Nuclear Medicine (2021)

We report the case of a 56-year-old man who presented with a 1-month history of recurrent right-sided epistaxis. Nasal endoscopy revealed a mass in the right nasal cavity, and CT scans showed a nasal space-occupying lesion. 68Ga-FAPI PET/CT demonstrated a high FAPI uptake of the mass in the right nasal cavity. Biopsy revealed a malignant melanoma.
Mechanistic modeling for the masses
Authors: Matthew A Turner, Paul E Smaldino
Journal: Behavioral and Brain Sciences (2022)

The generalizability crisis is compounded, or even partially caused, by a lack of specificity in psychological theories. Expanding the use of mechanistic models among psychologists is therefore important, but faces numerous hurdles. A cultural evolutionary approach can help guide and evaluate interventions to improve modeling efforts in psychology, such as developing standards and implementing them at the institutional level.
85P Adjuvant osimertinib in patients (pts) with stage IB–IIIA EGFR mutation-positive (EGFRm) NSCLC after complete tumour resection: ADAURA China subgroup analysis
Authors: W. Jie, Y-L. Wu, S. Lu, Q. Wang, S. Li, W. Zhong, Q. Wang, W. Li, B. Wang, J. Chen, Y. Cheng, H. Duan, G. Li, L. Shan, Y. Liu, X. Huang, A. Atasoy, J. He
Journal: Annals of Oncology (2022)
Abstract 10538: Differences in Oxygen Uptake Kinetics Across Ejection Fraction Phenotypes in Heart Failure
Authors: Shane M Hammer, Katlyn E Koepp, Joshua R Smith, Eric J Bruhn, Barry A Borlaug, Thomas P Olson
Journal: Circulation (2021)

Introduction: Peripheral factors contribute to exercise limitations in heart failure (HF) with preserved ejection fraction (HFpEF) and may be related to excess regional adiposity. Slowed oxygen uptake (VO 2 ) kinetics are common in HF with reduced ejection fraction (HFrEF) and reflect peripheral O 2 transport impairments and abnormal muscle metabolic control. Differences in VO 2 kinetics between HFpEF and HFrEF may reveal phenotype-specific impairments in peripheral O 2 transport but remain unknown. Hypothesis: We hypothesized that VO 2 kinetics are slower in HFpEF (compared to HFrEF) and associated with greater leg adiposity. Methods: Patients with HFpEF (n=12; 3 women; 66±6 yrs; 29±3 kg/m 2 ; ejection fraction: 59±5%), HFrEF (n=12; 3 women; 62±9 yrs; 28±4 kg/m 2 ; ejection fraction: 37±8%), and controls (n=12; 3 women; 65±5 yrs; 28±3 kg/m 2 ) cycled at 20 W for 5 minutes prior to a maximal exercise test to determine VO 2peak . Age, sex, and BMI were matched by design and were not different among groups (p&gt;0.05). A monoexponential function with a time delay was used to describe the VO 2 transition from rest to 20 W and calculate the O 2 deficit. Leg fat mass was measured via dual energy X-ray absorptiometry. Results: VO 2peak was lower in HFpEF (18.6±6.2 mL/kg/min) and HFrEF (19.0±3.7 mL/kg/min) compared to controls (26.0±3.1; both p&lt;0.05). Amplitude (HFpEF: 507±97 mL/min; HFrEF: 443±91 mL/min; controls: 477±117 mL/min) and time delay (HFpEF: 16±9 s; HFrEF: 11±7 s; controls: 11±6 s) were not different among groups (p&gt;0.05). The time constant was slower in HFrEF compared to controls (45±9 s vs. 32±6 s; p=0.03) and further slowed in HFpEF (66±18 s; p&lt;0.001). The O 2 deficit was significantly greater in HFpEF (895±201 mL) and HFrEF (649±131 mL) compared to controls (590±125 mL; both p&lt;0.05). There were no differences in percent leg fat mass among groups (HFpEF: 33±8%; HFrEF: 31±6%; controls: 34±9%) and no associations were detected between percent leg fat mass and any VO 2 parameters (all p&gt;0.05). Conclusions: Patients with HFpEF exhibited slower VO 2 kinetics compared to HFrEF with no association to leg adiposity. These data suggest differences in peripheral O 2 transport and intramuscular metabolic control abnormalities between HF phenotypes.
Single-cell characterization of CRISPR-modified transcript isoforms with nanopore sequencing
Authors: Heon Seok Kim, Susan M. Grimes, Anna C. Hooker, Billy T. Lau, Hanlee P. Ji
Journal: Genome biology (2021)

Abstract We developed a single-cell approach to detect CRISPR-modified mRNA transcript structures. This method assesses how genetic variants at splicing sites and splicing factors contribute to alternative mRNA isoforms. We determine how alternative splicing is regulated by editing target exon-intron segments or splicing factors by CRISPR-Cas9 and their consequences on transcriptome profile. Our method combines long-read sequencing to characterize the transcript structure and short-read sequencing to match the single-cell gene expression profiles and gRNA sequence and therefore provides targeted genomic edits and transcript isoform structure detection at single-cell resolution.
Abstract P140: Short-chain Fatty Acids Levels Are Lower In Women With Preeclampsia
Authors: Jianbo H Zhao, Tiange Liu, Kristen McArthur, Noel T Mueller
Journal: Circulation (2022)

Introduction: Preeclampsia (PE) is a pregnancy-associated hypertension disorder with high morbidity and mortality. Short-chain fatty acids (SCFAs)—molecules produced by gut microbes—have been associated with hypertension, yet their relation to PE remains uncertain. Objectives: To review existing human studies that have examined associations of the major SCFAs (acetate, propionate, and butyrate) in pregnancy with the development of PE. Methods: Two reviewers independently searched online databases (EMBASE, PubMed, Web of Science, and Cochrane Database of Systematic Reviews) in January 2021 using the following terms: “short-chain fatty acids”, “acetic acid”, “butyric acid”, “propionic acid”, and “preeclampsia”. The final set of included studies had to: report associations of SCFAs with PE, be peer-reviewed, be written in English, and be in humans. Results: We screened the abstracts of 723 studies; 19 underwent full-text screening and 7 (980 total participants, 186 with PE) were included in the final review. All studies used a case-control design, but measured SCFAs from a range of bio-specimens (e.g., serum, plasma, feces, amniotic fluid) collected at distinct time points in pregnancy. Four studies showed that acetate was significantly (P&lt;0.05) lower in women with PE compared to healthy women; the other three studies also found acetate was lower in PE cases, albeit the association was non-significant. All three studies that investigated butyrate found it was lower in PE cases vs. controls. The same three studies also reported lower propionate among PE cases vs. controls, though only one of them was statistically significant. Results did not materially differ by bio-specimen or time-point in pregnancy. Conclusions: Current evidence, which derives only from case-control studies, indicates that lower SCFA levels in pregnancy (measured in amniotic fluid, blood, and feces) may be related to the development of PE. Large cohort studies are warranted to further investigate this association.
Pulmonary and Neurologic Effects of Mesenchymal Stromal Cell Extracellular Vesicles in a Multifactorial Lung Injury Model
Authors: Marissa A. Lithopoulos, Lannae Strueby, Megan O’Reilly, Shumei Zhong, Marius A. Möbius, Farah Eaton, Moses Fung, Maria Hurskainen, Chanèle Cyr-Depauw, Colin Suen, Liqun Xu, Jennifer J. P. Collins, Arul Vadivel, Duncan J. Stewart, Dylan Burger, Bernard Thébaud
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Rationale: Bronchopulmonary dysplasia, a chronic respiratory condition originating from preterm birth, is associated with abnormal neurodevelopment. Currently, there is an absence of effective therapies for bronchopulmonary dysplasia and its associated brain injury. In preclinical trials, mesenchymal stromal cell therapies demonstrate promise as a therapeutic alternative for bronchopulmonary dysplasia. Objectives: To investigate whether a multifactorial neonatal mouse model of lung injury perturbs neural progenitor cell function and to assess the ability of human umbilical cord-derived mesenchymal stromal cell extracellular vesicles to mitigate pulmonary and neurologic injury. Methods: Mice at Postnatal Day 7 or 8 were injected intraperitoneally with LPS and ventilated with 40% oxygen at Postnatal Day 9 or 10 for 8 hours. Treated animals received umbilical cord-mesenchymal stromal cell-derived extracellular vesicles intratracheally preceding ventilation. Lung morphology, vascularity, and inflammation were quantified. Neural progenitor cells were isolated from the subventricular zone and hippocampus and assessed for self-renewal, in vitro differentiation ability, and transcriptional profiles. Measurements and Main Results: The multifactorial lung injury model produced alveolar and vascular rarefaction mimicking bronchopulmonary dysplasia. Neural progenitor cells from lung injury mice showed reduced neurosphere and oligodendrocyte formation, as well as inflammatory transcriptional signatures. Mice treated with mesenchymal stromal cell extracellular vesicles showed significant improvement in lung architecture, vessel formation, and inflammatory modulation. In addition, we observed significantly increased in vitro neurosphere formation and altered neural progenitor cell transcriptional signatures. Conclusions: Our multifactorial lung injury model impairs neural progenitor cell function. Observed pulmonary and neurologic alterations are mitigated by intratracheal treatment with mesenchymal stromal cell-derived extracellular vesicles.
Abstract P090: Utility Of High-sensitivity Cardiac Troponin T For Short-term Cardiovascular Risk Monitoring In The General Population
Authors: Olive Tang, Dan Wang, Kunihiro Matsushita, Josef Coresh, Ron C Hoogeveen, John William McEvoy, Chiadi E Ndumele, Christie M Ballantyne, Elizabeth Selvin
Journal: Circulation (2022)

Background: Cardiac troponins are the cornerstone for the detection of heart attacks. Beyond the acute setting, there is growing evidence that high-sensitivity cardiac troponin T (hs-cTnT) is associated with long-term cardiovascular disease (CVD) risk. The implications of minute elevations in hs-cTnT on short-term CVD risk in the general population has not been investigated. Methods: We included 12,632 adults (43% men, 25% black, mean age: 57 years) in the Atherosclerosis Risk in Communities (ARIC) study who had at least one measurement of hs-cTnT (Roche) across visits 2 (1990-1992), 3 (1996-1998), and 4 (2011-2013) without diagnosed CVD, defined as coronary heart disease, heart failure, or stroke. We used bootstrapping to generate confidence intervals for the cumulative incidence of CVD and generalized estimating equation log-binomial models to quantify the short-term relative rates of incident CVD. Results: Overall, 3.8% (n=479) had elevated hs-cTnT ≥ 14ng/L at their earliest visit; of whom 65% (n=311) had intermediate or lower predicted 10-year risk by the Pooled Cohort Equation. The cumulative 1-year incidence of CVD among those with hs-cTnT ≥ 14ng/L was 5.7% (95% CI: 4.0%, 7.4%) compared to 1.0% (0.9%, 1.1%) among those with hs-cTnT &lt; 6 ng/L and 1.7% (1.3%, 2.2%) among those with hs-cTnT between 6 to 14 ng/L. Among those with hs-cTnT ≥ 14ng/L, the cumulative incidence of CVD at 2 years was 9.6% (7.3%, 11.8%) and at 3-years was 12.7% (10.0%, 15/3%) (Figure 1A). After accounting for traditional CVD risk factors, hs-cTnT ≥ 14ng/L was associated with 2.9 (2.0, 4.1) times higher incidence of CVD at 1-year compared to 1.9 (1.5, 2.4) times incidence at 3-years (Figure 1B). Conclusions: Middle-aged adults in the general population without CVD who had an elevated hs-cTnT experienced a 5.7% 1-year risk of CVD compared to 1% among those with low hs-cTnT. The relative risk associated with elevations in hs-cTnT was most pronounced within the first year, supporting its use for short-term risk monitoring as part of annual preventive visits.