tbuckley/cabot-search huggingface dataset:
Decreases in Young Children Who Received Blood Lead Level Testing During COVID-19 — 34 Jurisdictions, January–May <i>2</i>020
Authors: Joseph G. Courtney, Stella O. Chuke, Kelly Dyke, Kimball Credle, Carolina Lecours, Kathryn B. Egan, Monica Leonard
Journal: MMWR Morbidity and Mortality Weekly Report (2021)

Exposure to lead, a toxic metal, can result in severe effects in children, including decreased ability to learn, permanent neurologic damage, organ failure, and death.CDC and other health care organizations recommend routine blood lead level (BLL) testing among children as part of well-child examinations to facilitate prompt identification of elevated BLL, eliminate source exposure, and provide medical and other services (1).To describe BLL testing trends among young children during the coronavirus disease 2019 (COVID-19) pandemic, CDC analyzed data reported from 34 state and local health departments about BLL testing among children aged <6 years conducted during January-May 2019 and January-May 2020.Compared with testing in 2019, testing during January-May 2020 decreased by 34%, with 480,172 fewer children tested.An estimated 9,603 children with elevated BLL were missed because of decreased BLL testing.Despite geographic variability, all health departments reported fewer children tested for BLL after the national COVID-19 emergency declaration (March-May 2020).In addition, health departments reported difficulty conducting medical follow-up and environmental investigations for children with elevated BLLs because of staffing shortages and constraints on home visits associated with the pandemic.Providers and public health agencies need to take action to ensure that children who missed their scheduled blood lead screening test, or who required follow-up on an earlier high BLL, be tested as soon as possible and receive appropriate care.CDC identifies no safe BLL in children and considers a blood lead reference value (BLRV) of 5.0 µg/dL* sufficient to prompt clinical and public health intervention (1,2).Among children aged <6 years, very high BLL (>70 µg/dL) can cause neurologic problems (e.g., seizures or coma), organ failure, and death.Lower, but still elevated, BLL can affect the nervous system, causing permanent neurologic damage, behavioral disorders, and cognitive impairment (1).In the United States, the most common childhood lead exposures are from lead-based paint * CDC uses a BLRV of 5.0 µg/dL to identify children with blood lead levels that are higher than those of most children.The BLRV is based on the 97.5th percentile of the NHANES blood lead distribution in children aged 1-5 years.The current BLRV is based on NHANES data from 2007-2008 and 2009-2010.
Stress Echocardiography in Known or Suspected Coronary Artery Disease: An Exercise in Good Clinical Practice⁎⁎Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: Frank A. Flachskampf, Christian Rost
Journal: Journal of the American College of Cardiology (2009)
Yap1 Mediates Trametinib Resistance in Head and Neck Squamous Cell Carcinomas
Authors: Tenny Mudianto, Katie M. Campbell, Jason Webb, Paul Zolkind, Zachary L. Skidmore, Rachel Riley, Erica K. Barnell, Ibrahim Ozgenc, Tusar Giri, Gavin P. Dunn, Douglas R. Adkins, Malachi Griffith, Ann Marie Egloff, Obi L. Griffith, Ravindra Uppaluri
Journal: Clinical Cancer Research (2021)

In a head and neck squamous cell carcinoma (HNSCC) "window of opportunity" clinical trial, we reported that trametinib reduced MEK-Erk1/2 activation and resulted in tumor responses in a subset of patients. Here, we investigated resistance to trametinib and molecular correlates in HNSCC cell lines and patient samples.HNSCC cell lines were treated with trametinib to generate resistant lines. Candidate bypass pathways were assessed using immunoblotting, CRISPR knockout, and survival assays. Effectiveness of combined trametinib and verteporfin targeting was evaluated. Patient-derived xenografts (PDXs) from responder patients were treated with trametinib and resistant tumors were analyzed. Window trial clinical samples were subjected to whole-exome and RNA sequencing.HNSCC cell lines developed resistance (CAL27-TR and HSC3-TR) after prolonged trametinib exposure. Downstream effectors of the Hippo pathway were activated in CAL27-TR and HSC3-TR, and combined trametinib and verteporfin treatment resulted in synergistic treatment response. We defined the Hippo pathway effector Yap1 as an induced survival pathway promoting resistance to trametinib in HSC3-TR. Yap1 was necessary for HSC3-TR trametinib resistance, and constitutively active Yap1 was sufficient to confer resistance in parental HSC3. Analysis of trametinib neoadjuvant trial patient tumors indicated canonical MEK-Erk1/2 pathway activating mutations were infrequent, and Yap1 activity increased following trametinib treatment. Trametinib treatment of a PDX from a responder patient resulted in evolution of resistance with increased Yap1 expression and activity.These studies identify a Yap1-dependent resistance to trametinib therapy in HNSCCs. Combined Yap1 and MEK targeting may represent a strategy to enhance HNSCC response.
Macrophage AXL receptor tyrosine kinase inflames the heart after reperfused myocardial infarction
Authors: Matthew DeBerge, Kristofor Glinton, Manikandan Subramanian, Lisa D. Wilsbacher, Carla V. Rothlin, Ira Tabas, Edward B. Thorp
Journal: Journal of Clinical Investigation (2021)

Tyro3, AXL, and MerTK (TAM) receptors are activated in macrophages in response to tissue injury and as such have been proposed as therapeutic targets to promote inflammation resolution during sterile wound healing, including myocardial infarction. Although the role of MerTK in cardioprotection is well characterized, the unique role of the other structurally similar TAMs, and particularly AXL, in clinically relevant models of myocardial ischemia/reperfusion infarction (IRI) is comparatively unknown. Utilizing complementary approaches, validated by flow cytometric analysis of human and murine macrophage subsets and conditional genetic loss and gain of function, we uncover a maladaptive role for myeloid AXL during IRI in the heart. Cross signaling between AXL and TLR4 in cardiac macrophages directed a switch to glycolytic metabolism and secretion of proinflammatory IL-1β, leading to increased intramyocardial inflammation, adverse ventricular remodeling, and impaired contractile function. AXL functioned independently of cardioprotective MerTK to reduce the efficacy of cardiac repair, but like MerTK, was proteolytically cleaved. Administration of a selective small molecule AXL inhibitor alone improved cardiac healing, which was further enhanced in combination with blockade of MerTK cleavage. These data support further exploration of macrophage TAM receptors as therapeutic targets for myocardial infarction.
Short-term response to immune-chemotherapy and immune features of a ceritinib-resistant patient with <i>ROS1</i>-rearranged lung adenocarcinoma
Authors: Dongsheng Yue, Juanjuan Qian, Zhipeng Chen, Bin Zhang, Peng Chen, Lei Zhang, Jingjing Li, Henghui Zhang, Changli Wang
Journal: Journal for ImmunoTherapy of Cancer (2021)

Patients with ROS1 -rearranged non-small cell lung cancer (NSCLC) inevitably relapse after first-line targeted therapy with tyrosine kinase inhibitors. Efficacy of checkpoint inhibitor-based therapy on ROS1 -positive NSCLC in second-line setting and change of immune factors during treatment are rarely studied. We report a ROS1 -rearranged stage ⅢB lung adenocarcinoma patient who was resistant to ceritinib after developing a secondary ROS1 F2004L mutation. He received eight cycles of nivolumab plus chemotherapy and had an initial partial response, but brain metastases appeared in the seventh cycle. Lorlatinib was confirmed to have activity against CD74–ROS1 with F2004L in vitro, and was administered to this patient as the third-line therapy. The patient responded well to lorlatinib and had no relapse. We explored the tumor immune microenvironment (TIME) during immune-chemotherapy by multiplex immunohistochemistry, RNA sequencing, and multiplex plasma protein immunoassay. The results show that the TIME was active and plasma inflammatory factors were increased when the patient responded to immune-chemotherapy, while the plasma inhibitory checkpoint proteins, lymphocyte-activation gene 3, B and T lymphocyte attenuator, programmed cell death ligand 1 (PD-L1), and PD-1, were increased when the disease progressed. Moreover, the PD-L1 expression on tumor tissue was upregulated during treatment, predicting the limited benefit from immune-chemotherapy. This case report suggests that lorlatinib is a better choice than immune-chemotherapy in second-line setting for patients with similar genomic characteristics, and that monitoring the immune components during immunotherapy may help to predict disease response.
Vitamin C sensitizes triple negative breast cancer to PI3K inhibition therapy
Authors: Sushmita Mustafi, Vladimir Camarena, Rehana Qureshi, David W. Sant, Zachary Wilkes, Daniel Bilbao, Joyce Slingerland, Susan B. Kesmodel, Gaofeng Wang
Journal: Theranostics (2021)

Rationale: The clinical use of PI3K inhibitors, such as buparlisib, has been plagued with toxicity at effective doses. The aim of this study is to determine if vitamin C, a potent epigenetic regulator, can improve the therapeutic outcome and reduce the dose of buparlisib in treating PIK3CA-mutated triple negative breast cancer (TNBC). Methods: The response of TNBC cells to buparlisib was assessed by EC50 measurements, apoptosis assay, clonogenic assay, and xenograft assay in mice. Molecular approaches including Western blot, immunofluorescence, RNA sequencing, and gene silencing were utilized as experimental tools. Results: Treatment with buparlisib at lower doses, along with vitamin C, induced apoptosis and inhibited the growth of TNBC cells in vitro. Vitamin C via oral delivery rendered a sub-therapeutic dose of buparlisib able to inhibit TNBC xenograft growth and to markedly block metastasis in mice. We discovered that buparlisib and vitamin C coordinately reduced histone H3K4 methylation by enhancing the nuclear translocation of demethylase, KDM5, and by serving as a cofactor to promote KDM5-mediated H3K4 demethylation. The expression of genes in the PI3K pathway, such as AKT2 and mTOR, was suppressed by vitamin C in a KDM5-dependent manner. Vitamin C and buparlisib cooperatively blocked AKT phosphorylation. Inhibition of KDM5 largely abolished the effect of vitamin C on the response of TNBC cells to buparlisib. Additionally, vitamin C and buparlisib co-treatment changed the expression of genes, including PCNA and FILIP1L, which are critical to cancer growth and metastasis. Conclusion: Vitamin C can be used to reduce the dosage of buparlisib needed to produce a therapeutic effect, which could potentially ease the dose-dependent side effects in patients.
Taste Perception and Sweet Taste Preference in Type-2 Diabetic Subjects: Genomic And Metabolomic Factors Involved
Authors: Rebeca Fernandez-Carrion, Ignacio M. Gimenez-Alba, Jose V. Sorli, Eva C. Pascual, Carolina Ortega-Azorin, Olga Portoles, Raul Martinez-Lacruz, Andrea Alvarez-Sala, Rocio Barragan, Oscar Coltell, Dolores Corella
Journal: Metabolism (2021)
Descriptive study of selective reactions to NSAIDs in a referral Hospital
Authors: Ana MarÃa Prieto-Moreno Pfeifer, Isabel Torres-Rojas, Maria Desamparados Cervera, Diana Pérez-Alzate, Francisco J. Ruano, Maria Luisa Somoza Álvarez, Paula López-González, María Vázquez De La Torre, Elisa Haroun-Díaz, Natalia Blanca-López, Gabriela Canto
Journal: Journal of Allergy and Clinical Immunology (2021)
Abstract IA020: Chromatin regulation of the endometrium: What are our models telling us?
Authors: Mike R. Wilson, Jake J. Reske, Ronald L. Chandler
Journal: Clinical Cancer Research (2021)

Abstract 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 14512: The Mediator of Coronary Dilation Switch in Metabolic Syndrome
Authors: Zhiyuan Wang, Cody Juguilon, Molly Enrick, Anurag Jamaiyar, Tao Wang, Chris Kolz, William M Chilian, Liya Yin
Journal: Circulation (2019)

Patients with diabetes mellitus have a higher risk for cardiovascular disease. Endothelial dysfunction caused by reduced bioavailability of nitric oxide (NO) and oxidative stress has been identifie...
Abstract IA008: Mismatch repair deficiency and survival in stage I endometrial cancer
Authors: Russell R. Broaddus
Journal: Clinical Cancer Research (2021)

Abstract 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.
Genomic and evolutionary portraits of disease relapse in acute myeloid leukemia
Authors: Franck Rapaport, Yaseswini Neelamraju, Timour Baslan, Duane Hassane, Agata Gruszczynska, Marc Robert de Massy, Noushin Farnoud, Samuel Haddox, Tak Lee, Juan Medina-Martinez, Caroline Sheridan, Alexis Thurmond, Michael Becker, Stefan Bekiranov, Martin Carroll, Heardly Moses Murdock, Peter J. M. Valk, Lars Bullinger, Richard D’Andrea, Scott W. Lowe, Donna Neuberg, Ross L. Levine, Ari Melnick, Francine E. Garrett-Bakelman
Journal: Leukemia (2021)
CCR5-edited CD4+ T cells augment HIV-specific immunity to enable post-rebound control of HIV replication
Authors: Pablo Tebas, Julie K. Jadlowsky, Pamela A. Shaw, Lifeng Tian, Erin Esparza, Andrea L. Brennan, Sukyung Kim, Soe Yu Naing, Max W. Richardson, Ashley N. Vogel, Colby R. Maldini, Hong Kong, Xiaojun Liu, Simon F. Lacey, Anya M. Bauer, Felicity Mampe, Lee P. Richman, Gary Lee, Dale Ando, Bruce L. Levine, David L. Porter, Yangbing Zhao, Don L. Siegel, Katharine J. Bar, Carl H. June, James L. Riley
Journal: Journal of Clinical Investigation (2021)

BackgroundWe conducted a phase I clinical trial that infused CCR5 gene-edited CD4+ T cells to determine how these T cells can better enable HIV cure strategies.MethodsThe aim of trial was to develop RNA-based approaches to deliver zinc finger nuclease (ZFN), evaluate the effect of CCR5 gene-edited CD4+ T cells on the HIV-specific T cell response, test the ability of infused CCR5 gene-edited T cells to delay viral rebound during analytical treatment interruption, and determine whether individuals heterozygous for CCR5 Δ32 preferentially benefit. We enrolled 14 individuals living with HIV whose viral load was well controlled by antiretroviral therapy (ART). We measured the time to viral rebound after ART withdrawal, the persistence of CCR5-edited CD4+ T cells, and whether infusion of 10 billion CCR5-edited CD4+ T cells augmented the HIV-specific immune response.ResultsInfusion of the CD4+ T cells was well tolerated, with no serious adverse events. We observed a modest delay in the time to viral rebound relative to historical controls; however, 3 of the 14 individuals, 2 of whom were heterozygous for CCR5 Δ32, showed post-viral rebound control of viremia, before ultimately losing control of viral replication. Interestingly, only these individuals had substantial restoration of HIV-specific CD8+ T cell responses. We observed immune escape for 1 of these reinvigorated responses at viral recrudescence, illustrating a direct link between viral control and enhanced CD8+ T cell responses.ConclusionThese findings demonstrate how CCR5 gene-edited CD4+ T cell infusion could aid HIV cure strategies by augmenting preexisting HIV-specific immune responses.REGISTRATIONClinicalTrials.gov NCT02388594.FundingNIH funding (R01AI104400, UM1AI126620, U19AI149680, T32AI007632) was provided by the National Institute of Allergy and Infectious Diseases (NIAID), the National Institute on Drug Abuse (NIDA), the National Institute of Mental Health (NIMH), and the National Institute of Neurological Disorders and Stroke (NINDS). Sangamo Therapeutics also provided funding for these studies.
National perinatal survey demonstrates a decreasing seroprevalence of Toxoplasma gondii infection among pregnant women in France, 1995 to 2016: impact for screening policy
Authors: Eve Robinson, Henriette de Valk, Isabelle Villena, Yann Le Strat, Mathieu Tourdjman
Journal: Eurosurveillance (2021)

Background Toxoplasmosis during pregnancy can result in congenital anomalies or fetal death. Universal antenatal screening is recommended in France, a strategy in place since the 1970s. Aim We determined the seroprevalence of toxoplasmosis among pregnant women participating in the 2016 national perinatal survey (ENP), compared results with previous ENPs, and investigated factors associated with Toxoplasma gondii infection. Methods Using the 2016 ENP data, which contain sociodemographic and clinical information from all women giving birth during a one week period, we calculated adjusted prevalence ratios (aPR) by sociodemographic factors. Using available data from prior ENPs (1995, 2003 and 2010), we calculated age-standardised seroprevalences and aPRs for French women. Results In 2016, seroprevalence was 31.3% overall. Among French women, associations with increasing age (aPR: 1.54; 95% CI: 1.39–1.70), residence in Paris (aPR: 1.19; 95% CI: 1.08–1.31) or south-western regions (aPR: 1.19; 95% CI: 1.08–1.31), and higher professional status (aPR: 1.12; 95%CI 1.04–1.21) were observed. An association with increasing age was also evident among women from North Africa and sub-Saharan Africa. Age-standardised seroprevalence decreased from 55.0% in 1995 to 33.7% in 2016. Among French women, significant associations with age, Paris and south-west regions persisted across all ENPs. Conclusion Higher prevalences in older women may reflect a higher past risk of exposure while persistent geographical differences may reflect dietary or environmental differences. Toxoplasma seroprevalence among pregnant women continues to fall and will impact screening effectiveness. This warrants a comprehensive review to determine the appropriate future of prevention in France.
Efficacy and safety of ramucirumab containing chemotherapy in patients with pretreated metastatic gastric neuroendocrine carcinoma.
Authors: Saori Mishima, Akihito Kawazoe, Hiroshi Matsumoto, Yasutoshi Kuboki, Hideaki Bando, Takashi Kojima, Toshihiko Doi, Atsushi Ohtsu, Takayuki Yoshino, Elizabeth M Nonte, Sudhakar Chintharlapalli, Aejaz Nasir, Takeshi Kuwata, Kohei Shitara
Journal: Journal of Clinical Oncology (2018)

157 Background: Gastric neuroendocrine carcinoma (G-NEC) is associated with poor prognosis. Most patients (pts) present with advanced disease and have short survival. Ramucirumab (RAM), a monoclonal antibody for VEGFR-2, has been effective for advanced gastric adenocarcinoma (AC). However, little is known about efficacy of RAM containing chemotherapy in G-NEC. Methods: We retrospectively analyzed and compared the efficacy and safety of RAM containing chemotherapy in pretreated G-NEC and AC pts in our hospital (March 2015- January 2017). G-NEC was defined by NEC features, regardless of the proportion, based on histology and neuroendocrine markers (synaptophysin, chromogranin A or CD56). VEGFR-2 expression in tumor vessels was evaluated in archival primary G-NEC tissues by immunohistochemistry using the same anti-VEGFR2 primary antibody and scoring scheme (vascular VEGFR2 H-score) as in REGARD trial (Fuchs CS, et al. BJC. 2016). Results: Seventeen G-NEC and 173 AC pts were analyzed. Therapy for G-NEC included RAM + paclitaxel (n = 13), RAM + irinotecan (n = 2), and RAM monotherapy (n = 2). The overall response rate was significantly better in pts with G-NEC than AC (59 vs. 22%, p = 0.001). Progression-free survival was significantly longer in pts with G-NEC than AC (median 6.8 vs. 3.2 months, HR 0.38 [95%CI 0.22-0.66]; p &lt; 0.001). Overall survival was significantly longer in pts with G-NEC than AC (median 16.2 vs. 9.6 months, HR 0.4 [95%CI 0.19-0.86]; p = 0.014). No severe or unexpected adverse event occurred. Median vascular VEGFR2 H-score, based on available G-NEC tissues from 12 pts, was 220 (range 150-260) which was markedly higher than that reported on AC tissues from REGARD trial as historical control (median 35, range 0-240). Conclusions: Compared to AC patients, RAM containing chemotherapy showed a promising activity without severe or unexpected safety profile in G-NEC patients. This may in part be explained by higher vascular VEGFR-2 expression in G-NEC tissues. These data, though preliminary, support further clinical evaluation of RAM and biomarker investigation in this subset of gastric cancer.