tbuckley/cabot-search huggingface dataset:
Medical management of victims contaminated with radionuclides after a “dirty bomb” attack
Authors: Alexis Rump, Benjamin Becker, Stefan Eder, Andreas Lamkowski, Michael Abend, Matthias Port
Journal: Military Medical Research (2018)

A wide spectrum of scenarios may lead to radiation incidents and the liberation of radioactive material. In the case of a terrorist attack by a "dirty bomb", there is a risk of mechanical and thermal trauma, external irradiation, superficial contamination and incorporation of radioactive material. The first treatment priority must be given to the care of trauma patients with life-threatening injuries, as the health effects of radiation occur with latency. Radionuclide incorporation will lead to a longer-lasting irradiation from inside the body, associated with a higher risk of stochastic radiation effects (e.g., occurrence of tumors) in the long run. It must be expected that victims with potentially incorporated radionuclides will far outnumber trauma patients. The elimination of radionuclides can be enhanced by the administration of decorporation agents such as (Ca) Diethylenetriaminepentaacetic acid (DTPA) or Prussian blue, reducing the radiological burden of the body. There is still no consensus whether decorporation treatment should be started immediately based only on a suspicion of radionuclide incorporation ("urgent approach") or if the results of internal dosimetry confirming the necessity of a treatment should be awaited, accepting the delay caused by the measurements and computations ("precautionary approach"). As the therapeutic effectiveness may be substantially decreased if treatment initiation is delayed only by several days, depending on the radionuclide, the physicochemical properties of the compounds involved and the route of absorption, we favor an "urgent approach" from a medical point of view. In doubt, it seems justified to treat victims by precaution, as the adverse effects of the medication seem minimal. However, in the case of a high number of victims, an "urgent treatment approach" may require a large number of daily doses of antidotes, and therefore, adequate investments in preparedness and antidote stockpiling are necessary.
Regulatory T Cells in Ovarian Cancer Are Characterized by a Highly Activated Phenotype Distinct from that in Melanoma
Authors: Aras Toker, Linh T. Nguyen, Simone C. Stone, S.Y. Cindy Yang, Sarah Rachel Katz, Patricia A. Shaw, Blaise A. Clarke, Danny Ghazarian, Ayman Al-Habeeb, Alexandra Easson, Wey L. Leong, David R. McCready, Michael Reedijk, Cynthia J. Guidos, Trevor J. Pugh, Marcus Q. Bernardini, Pamela S. Ohashi
Journal: Clinical Cancer Research (2018)

Regulatory T (Treg) cells expressing the transcription factor FOXP3 are essential for the maintenance of immunologic self-tolerance but play a detrimental role in most cancers due to their ability to suppress antitumor immunity. The phenotype of human circulating Treg cells has been extensively studied, but less is known about tumor-infiltrating Treg cells. We studied the phenotype and function of tumor-infiltrating Treg cells in ovarian cancer and melanoma to identify potential Treg cell-associated molecules that can be targeted by tumor immunotherapies.
Macrophage-Derived Neuropilin-2 Exhibits Novel Tumor-Promoting Functions
Authors: Sohini Roy, Arup K. Bag, Samikshan Dutta, Navatha Shree Polavaram, Ridwan Islam, Samuel Schellenburg, Jasjit Banwait, Chittibabu Guda, Sophia Ran, Michael A. Hollingsworth, Rakesh K. Singh, James E. Talmadge, Michael H. Muders, Surinder K. Batra, Kaustubh Datta
Journal: Cancer Research (2018)

Abstract Tumor-associated macrophages (TAM) are causally associated with tumorigenesis as well as regulation of antitumor immune responses and have emerged as potential immunotherapeutic targets. Recent evidence suggests TAM phagocytose apoptotic tumor cells within the tumor microenvironment through efferocytosis in an immunologically silent manner, thus maintaining an immunosuppressed microenvironment. The signal transduction pathways coupling efferocytosis and immunosuppression are not well known. Neuropilin-2 (NRP2) is a member of the membrane-associated neuropilin family and has been reported in different immune cells but is poorly characterized. In this study, we show that NRP2 is expressed during macrophage differentiation, is induced by tumor cells, and regulates phagocytosis in macrophages. Furthermore, NRP2 in TAM promoted efferocytosis and facilitated tumor growth. Deletion of NRP2 from TAM impaired the clearance of apoptotic tumor cells and increased secondary necrosis within tumors. This resulted in a break in the immune tolerance and reinitiated antitumor immune responses, characterized by robust infiltration of CD8+ T and natural killer cells. This result suggests NRP2 may act as a molecular mediator that connects efferocytosis and immune suppression. Deletion of NRP2 in TAM downregulated several immunosuppressive and tumor-promoting genes and upregulated immunostimulatory genes in the myeloid compartment. Taken together, our study demonstrates that TAM-derived NRP2 plays a crucial role in tumor promotion through efferocytosis, opening the enticing option for the development of effective immunotherapy targeting TAM. Significance: Neuropilin-2 in macrophages promotes tumor growth by regulating efferocytosis of apoptotic tumor cells and orchestrating immune suppression. Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/19/5600/F1.large.jpg. Cancer Res; 78(19); 5600–17. ©2018 AACR.
Attainment of Functional and Social Independence in Adult Survivors of Pediatric CNS Tumors: A Report From the St Jude Lifetime Cohort Study
Authors: Tara M. Brinkman, Kirsten K. Ness, Zhenghong Li, I-Chan Huang, Kevin R. Krull, Amar Gajjar, Thomas E. Merchant, James L. Klosky, Robyn E. Partin, Ingrid Tonning Olsson, Frederick Boop, Paul Klimo, Wassim Chemaitilly, Raja B. Khan, Deokumar Srivastava, Leslie L. Robison, Melissa M. Hudson, Gregory T. Armstrong
Journal: Journal of Clinical Oncology (2018)

Purpose Beyond survival, achieving independence is a primary goal for adult survivors of pediatric CNS tumors. However, the prevalence of and risk factors for failure to achieve independence, assessed with multiple concurrent indicators, have not been examined. Patients and Methods Functional and social independence was assessed in 306 survivors (astrocytoma [n = 130], medulloblastoma [n = 77], ependymoma [n = 36], and other [n = 63]; median current age, 25.3 years [range, 18.9 to 53.1 years]; time since diagnosis, 16.8 years [range, 10.6 to 41.8 years]). Six observed indicators were used to identify latent classes of independence, which included employment, living independently, assistance with personal care, assistance with routine needs, obtaining a driver's license, and marital status. Physical performance impairments were defined as scores < 10th percentile on measures of aerobic capacity, strength, flexibility, balance, mobility, and adaptive function. Multinomial logistic regression estimated odds ratios (ORs) and 95% CIs were calculated for associations of disease/treatment exposures and impairments in physical performance with nonindependence. Results Three classes of independence were identified as independent (40%), moderately independent (34%), and nonindependent (26%). In multivariable models, craniospinal irradiation (OR, 4.20; 95% CI, 1.69 to 10.44) and younger age at diagnosis (OR, 1.24; 95% CI, 1.14 to 1.35) were associated with risk of nonindependence versus independence. Beyond impaired IQ, limitations in aerobic capacity (OR, 5.47; 95% CI, 1.78 to 16.76), flexibility (OR, 3.66; 95% CI, 1.11 to 12.03), and adaptive physical function (OR, 11.54; 95% CI, 3.57 to 37.27) were associated with nonindependence versus independence. Nonindependent survivors reported reduced physical but not mental health-related quality of life compared with independent survivors. Conclusion Sixty percent of survivors of pediatric CNS tumors do not achieve complete independence as adults. Reduction in intensity of primary therapies and interventions that target physical performance and adaptive deficits may help survivors to achieve greater independence.
Angiotensin Type 2 Receptors Are Reexpressed by Cardiac Fibroblasts From Failing Myopathic Hamster Hearts and Inhibit Cell Growth and Fibrillar Collagen Metabolism
Authors: NaohikoOhkubo, HiroakiMatsubara, YoshihisaNozawa, YasukiyoMori, SatoshiMurasawa, KazuhisaKijima, KatsuyaMaruyama, HiroyaMasaki, YoshiakiTsutumi, YoshinobuShibazaki, ToshijiIwasaka, MitsuoInada
Journal: Circulation (1997)

Background Angiotensin (Ang) II type 1 receptor (AT1-R) induces cardiomyocyte hypertrophy and fibroblast proliferation, whereas the physiological role of AT2-R in cardiac remodeling remains poorly defined. Methods and Results Using Bio14.6 cardiomyopathic (CM) hamsters, we found that AT2-R sites were increased by 153% during heart failure compared with F1B controls. AT1-R numbers were increased by 72% in the hypertrophy stage and then decreased to the control level during heart failure. Such differential regulation of AT2-R and AT1-R during heart failure was consistent with changes in the respective mRNA levels. Autoradiography and immunocytochemistry revealed that both AT2-R and AT1-R are localized at higher densities in fibroblasts present in fibrous regions. Surrounding myocardium predominantly expressed AT1-R, but the level of expression was less than that in fibrous regions. Cardiac fibroblasts isolated from CM hearts during heart failure but not from control hamsters expressed AT2-R (30 fmol/mg prot...
National Survey of Coronary Artery Bypass Grafting for Coronary Stenosis Caused by Kawasaki Disease in Japan
Authors: EtsukoTsuda, SoichiroKitamura
Journal: Circulation (2004)

Background— We surveyed the national experience of coronary artery bypass grafting (CABG) for coronary sequelae of Kawasaki disease (kDa) in 2002. Methods and Results— A questionnaire was returned from 323/552 (59%) institutions. Two hundred forty-four patients (188 male 56 female) since 1975 were identified. The mean number of grafts was 1.8 and the age at operation ranged from 1 to 44 years (median 11 years). The interval from the onset of kDa to operation ranged from 1 month to 42 years (median 8 years), whereas the follow-up period was from 7 days to 25 years (median 5 years). Previous myocardial infarction was found in 70 patients (28%). When the age at operation was older than 12 years, patency rates for internal thoracic artery grafts (ITA) at 1, 5, and 15 years were 95%, 91%, and 91%, respectively (n=156). When the age at operation was younger than 12 years, the corresponding values were significantly lower, with 1, 5, and 15 years being 93%, 73%, and 65%, respectively (n=146) (P<0.05). Reoperatio...
Abstract 682: The mechanism of PI3Kα activation by SH2 release
Authors: Mingzhen Zhang, Hyunbum Jang, Ruth Nussinov
Journal: Cancer Research (2018)

Abstract Phosphoinositide 3-kinase α (PI3Kα) is a ubiquitous kinase mediating signaling cascades important for cell survival, proliferation and protein synthesis. It phosphorylates PIP2 to PIP3, to which downstream Akt kinase binds to execute singling. PI3Kα dysfunction has been extensively implicated in cancers. The kinase activity of PI3Kα is controlled by the interactions between its catalytic p110 and regulatory p85 subunits. The interactions of the SH2 domains in the p85 subunit, particularly nSH2, with p110 are key factors in PI3Kα inhibition. Release of the SH2 domains from the p110 subunit, is promoted by factors including phosphotyrosine peptides (RTK), calmodulin (CaM), and oncogenic mutations, thereby activating PI3Kα. Our recent data show that both phosphorylated and unphosphorylated CaMs are capable of binding to the SH2 domains, nSH2 and cSH2, thus promoting the PI3K activation. Despite numerous seminal publications over the past two decades, the mechanism of PI3Kα activation is still a mystery. The large distance between the PIP2 binding sites and the ATP pocket in the crystal structure suggests that the solved PI3Kα structure represents the inactive conformation. What is the activated conformation of PI3Kα, and how PI3Kα switches from the inactive to the active conformation in response to stimulus are the significant mechanistic questions. We employ the large-scale molecular dynamics (MD) simulations to visualize the PI3Kα activation stimulated by the release of SH2 domains in the p85 subunit at the atomic resolution. Our trajectories show that release of the nSH2 domain initiates a “switch-like” conformational change of the iSH2 domain, extracting the ATP from its pocket to the PIP2 binding sites, eventually leading to an activated conformation. This dynamic process is initiated by the break of salt-bridges between iSH2 and helical domains induced by the nSH2 release, and further facilitated by the various residues in activation loop of p110 subunit including His-917, Lys-802 and Lys-776 and in iSH2 of p85 subunit including Arg-461 and Arg-465. The release of the cSH2 domain in PI3Kα has a minor effect. This work, which for the first time uncovers the mechanism of PI3Kα activation at atomic resolution, is expected to promote cancer drug design from a mechanistic dynamic standpoint view. Funded by Frederick National Laboratory for Cancer Research, National Institutes of Health, under contract HHSN261200800001E. Citation Format: Mingzhen Zhang, Hyunbum Jang, Ruth Nussinov. The mechanism of PI3Kα activation by SH2 release [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 682.
Biventricular Pacing Improves the Blunted Force–Frequency Relation Present During Univentricular Pacing in Patients With Heart Failure and Conduction Delay
Authors: DirkVollmann, LarsLüthje, PeterSchott, GerdHasenfuss, ChristinaUnterberg-Buchwald
Journal: Circulation (2006)

Background— In patients with chronic heart failure (CHF) and conduction delay, biventricular (BiV) and left ventricular (LV) pacing similarly improve systolic function at resting heart rates. We hypothesized that BiV and univentricular pacing differentially affect contractile function at increasing heart rates. Methods and Results— Twenty-two patients (aged 66±2 years, QRS 179±8 ms, LV ejection fraction 23±1%) underwent cardiac catheterization before device implantation to measure LV hemodynamics at baseline (rate 68±2 bpm; sinus rhythm n=18; atrial fibrillation n=4) and during BiV, LV, and right ventricular (RV) stimulation at 80, 100, 120, and 140 bpm. BiV and LV pacing at 80 bpm equally augmented dP/dtmax as compared with baseline and RV pacing (P<0.001). Stimulation rate significantly interacted with the effect of BiV, LV, and RV pacing on LV end-diastolic pressure (LVEDP), systolic pressure (LVSP), and dP/dtmax. Increasing the rate from 80 to 140 bpm enhanced dP/dtmax from 913±28 to 1119±50 mm Hg/s d...
Elastic Deformation in Orthotropic Vessels
Authors: Juliusmelbin, Abrahamnoordergraaf
Journal: Circulation Research (1971)

Excursions of the semiaxes were used to define the distortion and shape of the vessel cross section considered for conic and almost conic models. Some describing functions and mensuration expressions closely approximate, yet greatly simplify, calculations of perimeter and cross sections. Theory and experiments with models were in good agreement, but preliminary experiments showed the real case to be more complicated. Physical properties of the pulmonary trunk varied along its axis, growing stiffer toward the periphery. Furthermore, the dimension variations with transmural loading alter concepts of properties derived from measurements of a single diameter. The influence of the pericardium on the deformation of the main pulmonary artery under transmural stress was also explored. It was seen that the pericardium exerts significant restraint on the distortion and volume variations of this vessel. Over normal pressure ranges, removal of the pericardium can result in trunk volumes up to 100% greater than realiz...
Abstract SY40-01: In vivo genetic screens for genes that modulate tumor immunity
Authors: W Nicholas Haining
Journal: Cancer Research (2018)

Abstract Despite the dramatic clinical success of cancer immunotherapy with PD-1 checkpoint blockade, most patients do not experience sustained clinical benefit from treatment, suggesting that additional therapeutic strategies are needed. To discover new immunotherapy targets, we developed a pooled, loss-of-function in vivo genetic screening approach using CRISPR/Cas9 genome editing in mouse transplantable tumors treated with vaccination and PD-1 checkpoint blockade. We tested 2,400 genes expressed by melanoma cells for those that synergize with or cause resistance to checkpoint blockade, and recovered the known immune evasion molecules, PD-L1 and CD47. Loss of function of genes required to sense interferon-γ caused resistance to immunotherapy. Deletion of Ptpn2, a pleotropic protein tyrosine phosphatase, improved response to immunotherapy. Cellular, biochemical, transcriptional, and genetic epistasis experiments demonstrated that loss of function of Ptpn2 sensitizes tumors to immunotherapy by enhancing interferon-γ-mediated effects on antigen presentation and growth suppression. Thus, strategies that increase interferon-γ sensing by tumor cells could improve the efficacy of immunotherapy. More generally, in vivo genetic screens in tumor models can identify new immunotherapy targets, model resistance mechanisms, and may accelerate the rational selection of combination immunotherapy. Citation Format: W Nicholas Haining. In vivo genetic screens for genes that modulate tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr SY40-01.
ST-Segment Elevation in Acute Myocardial Infarction
Authors: Bent Lyagernielsen
Journal: Circulation (1973)

Four hundred and four patients who were admitted to the hospital with their first myocardial infarction within 24 hours of the onset of symptoms were studied. In 315 patients the ECG findings in 12 standards leads (I, II, aVF, aVR, aVL, V1-V6) showed the infarction to be in the anterior wall, the inferior wall, or in multiple areas. The patients in each of these three categories were further subdivided into two groups according to the magnitude of the ST-elevation; those with major ST-elevation and those with minor ST-elevation. Occurrence of the risk factors of diabetes, hypertension, hyperlipidemias, age, and complicating chronic pulmonary and renal diseases were comparable, but since women predominated in one group (anterior wall infarction/ minor ST-elevation) the clinical course of the disease in men and women was studied separately. The patients with major ST-elevation had a more unfavorable course: cardiac arrest (P < 0.0005), congestive heart failure (P < 0.0005), death (P < 0.001), atrial fibrill...
Abstract 13604: Integrated Area of Desaturation Index can Predict Three-Year Prognosis in Heart Failure Patients after Adaptive Servo Ventilation Therapy
Authors: NoriakiTakama, HiroshiHasegawa, KeitaGoto, KunikoMasuda, HidemiSorimachi, MakitoSato, MasaruObokata, YaeMatsuo, HirokazuSano, RyuichiFunada, SyuKasama, NorimichiKoitabashi, MasahikoKurabayashi
Journal: Circulation (2014)

Introduction: Adaptive servo ventilation (ASV) is used as a device for patients with heart failure. Previously, we reported that Integrated Area of Desaturation Index (IAD index) can estimate the efficacy of ASV therapy in acute phase. However, it is unclear that IAD index can estimate long-term prognosis after ASV therapy. Hypothesis: We hypothesize that IAD index can predict long-term prognosis after ASV therapy. Methods: The study group consisted of 57 HF patients. The mean age was 70 ± 11 years. After treating the underlying disease in the acute phase, patients were treated with ASV. To estimate short-term effects, we established the association between changes in brain natriuretic peptide ([[Unable to Display Character: ⊿]]BNP) and left ventricular ejection fraction ([[Unable to Display Character: ⊿]]LVEF). We also estimate several polysomnographic parameters including IAD index, which is new measurement for assessing the severity of sleep apnea, which is obtained by integrating nocturnal...
Abstract 5085: CXCR2 signaling in pancreatic cancer induces a tumor supporting inflammatory phenotype of the cancer-associated fibroblasts
Authors: Mohammad Awaji, Michelle Varney, Abhilasha Purohit, Surinder Batra, Rakesh Singh
Journal: Cancer Research (2018)

Abstract Pancreatic cancer (PC) remains one of the deadliest types of solid malignancies. Making progress in dealing with PC starts by understanding the complex interaction of cellular components in the tumor microenvironment and identifying the crucial checkpoints for tumor progression and metastasis. Desmoplasia and inflammation are two major hallmarks of PC. Cancer-associated fibroblasts (CAFs) are known for inducing fibrosis in several pathologies of the pancreas including PC. Recent reports have described that CAFs can assume the fibrosis-inducing phenotype, when close or have a direct contact with tumor cells, or a tumor-promoting inflammatory phenotype, through distant paracrine signaling. Known for their role in recruiting granulocytes and inducing angiogenesis, CXC chemokines (1-3 and 5-8) contain a conserved motif of Glutamic acid-Leucine-Arginine (ELR) and signal through CXCR1/2 chemokine receptors. In PC, ELR+ chemokines produced by malignant cells and stromal cells contribute to tumor growth, angiogenesis, and tumor-supporting immunosuppression. The deletion of CXCR2 in the genetically engineered PC mouse model (KC) promoted fibrosis and tumor metastasis. Taken together, we hypothesize that ELR+ chemokines signaling through CXCR2 may trigger the inflammatory phenotype of CAFs in PC that promotes tumor growth and progression. Utilizing unidirectional coculture studies, incubating CAFs in conditioned media of PC cells inhibited their growth, decreased the expression of the fibrotic CAFs-associated markers such as αSMA and collagen I, and increased the expression of immunosuppressive cytokines and tumor-promoting chemokines including IL-4, IL-10, IL-13, and CXCL7. Treating CAFs with exogenous ELR+ chemokines (CXCL1 and CXCL8) exhibited a similar phenotype. Furthermore, treating CAFs with exogenous ELR+ chemokines or PC cells conditioned media in the presence of pharmacological inhibitors of CXCR2 rescued this phenotype. In summary, we believe that ELR+ chemokine signaling through CXCR2 induces the inflammatory phenotype of CAFs that promotes immunosuppression, tumor growth, and tumor progression of PC. Citation Format: Mohammad Awaji, Michelle Varney, Abhilasha Purohit, Surinder Batra, Rakesh Singh. CXCR2 signaling in pancreatic cancer induces a tumor supporting inflammatory phenotype of the cancer-associated fibroblasts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5085.
Erratum: Corrigendum: Phosphatase SHP-1 promotes TLR- and RIG-I-activated production of type I interferon by inhibiting the kinase IRAK1
Authors: Huazhang An, Jin Hou, Jun Zhou, Wei Zhao, Hongmei Xu, Yuejuan Zheng, Yizhi Yu, Shuxun Liu, Xuetao Cao
Journal: Nature Immunology (2011)