tbuckley/cabot-search huggingface dataset:
Causes and Circumstances of Death in Pulmonary Arterial Hypertension
Authors: Adriano R. Tonelli, Vineesha Arelli, Omar A. Minai, Jennie Newman, Nancy Bair, Gustavo A. Heresi, Raed A. Dweik
Journal: American Journal of Respiratory and Critical Care Medicine (2013)

The causes and circumstances surrounding death are understudied in patients with pulmonary arterial hypertension (PAH).We sought to determine the specific reasons and characteristics surrounding the death of patients with PAH.All deaths of patients with pulmonary hypertension (PH) followed in the Cleveland Clinic Pulmonary Vascular Program were prospectively reviewed by the PH team. A total of 84 patients with PAH (age 58 ± 14 yr; 73% females) who died between June 2008 and May 2012 were included.PH was determined to be the direct cause of death (right heart failure or sudden death) in 37 (44%) patients; PH contributed to but did not directly cause death in 37 (44%) patients; and the death was not related to PH in the remaining cases (n = 7; 8.3%). In three (3.6%) patients the final cause of death could not be adequately assessed. Most patients died in a healthcare environment and most received PH-specific therapies. In our cohort, 50% of all patients with PAH and 75.7% of those who died of right heart failure received parenteral prostanoid therapy. Less than half of patients had advanced healthcare directives.Most patients with PAH in our cohort died of their disease; however, right ventricular failure or sudden death was the sole cause of death in less than half of patients.
Comparative sequencing analysis reveals high genomic concordance between matched primary and metastatic colorectal cancer lesions
Authors: A Rose Brannon, Efsevia Vakiani, Brooke E Sylvester, Sasinya N Scott, Gregory McDermott, Ronak H Shah, Krishan Kania, Agnes Viale, Dayna M Oschwald, Vladimir Vacic, Anne-Katrin Emde, Andrea Cercek, Rona Yaeger, Nancy E Kemeny, Leonard B Saltz, Jinru Shia, Michael I D’Angelica, Martin R Weiser, David B Solit, Michael F Berger
Journal: Genome biology (2014)

Colorectal cancer is the second leading cause of cancer death in the United States, with over 50,000 deaths estimated in 2014. Molecular profiling for somatic mutations that predict absence of response to anti-EGFR therapy has become standard practice in the treatment of metastatic colorectal cancer; however, the quantity and type of tissue available for testing is frequently limited. Further, the degree to which the primary tumor is a faithful representation of metastatic disease has been questioned. As next-generation sequencing technology becomes more widely available for clinical use and additional molecularly targeted agents are considered as treatment options in colorectal cancer, it is important to characterize the extent of tumor heterogeneity between primary and metastatic tumors. We performed deep coverage, targeted next-generation sequencing of 230 key cancer-associated genes for 69 matched primary and metastatic tumors and normal tissue. Mutation profiles were 100% concordant for KRAS, NRAS, and BRAF, and were highly concordant for recurrent alterations in colorectal cancer. Additionally, whole genome sequencing of four patient trios did not reveal any additional site-specific targetable alterations. Colorectal cancer primary tumors and metastases exhibit high genomic concordance. As current clinical practices in colorectal cancer revolve around KRAS, NRAS, and BRAF mutation status, diagnostic sequencing of either primary or metastatic tissue as available is acceptable for most patients. Additionally, consistency between targeted sequencing and whole genome sequencing results suggests that targeted sequencing may be a suitable strategy for clinical diagnostic applications.
Morbid Obesity: Effects on the Marital System of Weight Loss after Gastric Restriction
Authors: Julian Hafner
Journal: Psychotherapy and Psychosomatics (1991)

Eighty morbidly obese married women and 69 of their husbands completed a self-report measure of personal and marital adjustment before the women proceeded to gastric restriction surgery. Fifty-five women and 41 husbands repeated the measure 12 months after surgery, at which time the women had lost a mean of 35.4 kg. Women rated themselves as significantly more attractive and sociable, and rated their husbands as significantly less sociable and interesting, than before surgery. Husbands rated their wives as excessively sociable after surgery, the reverse of their previous view. The data offered some support for a family systems view of morbid obesity, but the systemic effect appeared weak, and is probably not a major contributor to wives' morbid obesity in most cases.
Assessing Potential Glycemic Overtreatment in Persons at Hypoglycemic Risk
Authors: Chin-Lin Tseng, Orysya Soroka, Miriam Maney, David C. Aron, Leonard M. Pogach
Journal: JAMA Internal Medicine (2013)

Although serious hypoglycemia is a common adverse drug event in ambulatory care, current performance measures do not assess potential overtreatment.To identify high-risk patients who had evidence of intensive glycemic management and thus were at risk for serious hypoglycemia.Cross-sectional study of patients in the Veterans Health Administration receiving insulin and/or sulfonylureas in 2009.Intensive control was defined as the last hemoglobin A1c (HbA1c) measured in 2009 that was less than 6.0%, less than 6.5%, or less than 7.0%. The primary outcome measure was an HbA1c less than 7.0% in patients who were aged 75 years or older who had a serum creatinine value greater than 2.0 mg/dL or had a diagnosis of cognitive impairment or dementia. We also assessed the rates in patients with other significant medical, neurologic, or mental comorbid illness. Variation in rates of possible glycemic overtreatment was evaluated among 139 Veterans Health Administration facilities grouped within 21 Veteran Integrated Service Networks.There were 652,378 patients who received insulin and/or a sulfonylurea with an HbA1c test result. Fifty percent received sulfonylurea therapy without insulin; the remainder received insulin therapy. We identified 205,857 patients (31.5%) as the denominator for the primary outcome measure; 11.3% had a last HbA1c value less than 6.0%, 28.6% less than 6.5%, and 50.0% less than 7.0%. Variation in rates by Veterans Integrated Service Network facility ranged 8.5% to 14.3%, 24.7% to 32.7%, and 46.2% to 53.4% for HbA1c less than 6.0%, less than 6.5%, and less than 7.0%, respectively. The magnitude of variation by facility was larger, with overtreatment rates ranging from 6.1% to 23.0%, 20.4% to 45.9%, and 39.7% to 65.0% for HbA1c less than 6.0%, less than 6.5%, and less than 7.0%, respectively. The maximum rate was nearly 4-fold compared with the minimum rates for HbA1c less than 6.0%, followed by 2.25-fold for HbA1c less than 6.5% and less than 2-fold for HbA1c less than 7.0%. When comorbid conditions were included, 430,178 patients (65.9%) were identified as high risk. Rates of overtreatment were 10.1% for HbA1c less than 6.0%, 25.2% for less than 6.5%, and 44.3% for less than 7.0%.Patients with risk factors for serious hypoglycemia represent a large subset of individuals receiving hypoglycemic agents; approximately one-half had evidence of intensive treatment. A patient safety indicator derived from administrative data can identify high-risk patients for whom reevaluation of glycemic management may be appropriate, consistent with meaningful use criteria for electronic medical records.
Theranostic Nanoparticles Carrying Doxorubicin Attenuate Targeting Ligand Specific Antibody Responses Following Systemic Delivery
Authors: Emmy Yang, Weiping Qian, Zehong Cao, Liya Wang, Erica N. Bozeman, Christina Ward, Bin Yang, Periasamy Selvaraj, Malgorzata Lipowska, Y. Andrew Wang, Hui Mao, Lily Yang
Journal: Theranostics (2014)

Understanding the effects of immune responses on targeted delivery of nanoparticles is important for clinical translations of new cancer imaging and therapeutic nanoparticles.In this study, we found that repeated administrations of magnetic iron oxide nanoparticles (IONPs) conjugated with mouse or human derived targeting ligands induced high levels of ligand specific antibody responses in normal and tumor bearing mice while injections of unconjugated mouse ligands were weakly immunogenic and induced a very low level of antibody response in mice.Mice that received intravenous injections of targeted and polyethylene glycol (PEG)-coated IONPs further increased the ligand specific antibody production due to differential uptake of PEG-coated nanoparticles by macrophages and dendritic cells.However, the production of ligand specific antibodies was markedly inhibited following systemic delivery of theranostic nanoparticles carrying a chemotherapy drug, doxorubicin.Targeted imaging and histological analysis revealed that lack of the ligand specific antibodies led to an increase in intratumoral delivery of targeted nanoparticles.Results of this study support the potential of further development of targeted theranostic nanoparticles for the treatment of human cancers.
Improvement of criteria for refractory cytopenia with multilineage dysplasia according to the WHO classification based on prognostic significance of morphological features in patients with refractory anemia according to the FAB classification
Authors: A Matsuda, U Germing, I Jinnai, M Iwanaga, M Misumi, A Kuendgen, C Strupp, Y Miyazaki, H Tsushima, M Sakai, M Bessho, N Gattermann, C Aul, M Tomonaga
Journal: Leukemia (2007)
Protective Role of Nitric Oxide in a Model of Thrombotic Microangiopathy in Rats
Authors: JING SHAO, TOSHIO MIYATA, KOEI YAMADA, NORIO HANAFUSA, TAKEHIKO WADA, KATHERINE L. GORDON, REIKO INAGI, KIYOSHI KUROKAWA, TOSHIRO FUJITA, RICHARD J. JOHNSON, MASAOMI NANGAKU
Journal: Journal of the American Society of Nephrology (2001)

A new model of thrombotic microangiopathy (TMA) was previously developed, and it was demonstrated that endothelial nitric oxide (NO) synthase (NOS) is upregulated in glomeruli in this model. It was hypothesized that the synthesis of NO, a potent vasodilator and platelet inhibitory factor, is induced as a defense mechanism. The goal of this study was to clarify the role of NO in this model. Ex vivo experiments using Western blotting and functional assays demonstrated upregulation of endothelial NOS in isolated glomeruli from TMA rats. In in vivo experiments, five groups of rats were studied, including rats with TMA treated with vehicle, NG-nitro-L-arginine methyl ester (L-NAME) (a NOS inhibitor), or L-N6-(1-iminoethyl)lysine (L-NIL) (a specific inducible NOS inhibitor) and normal control rats treated with vehicle or L-NAME. Blood urea nitrogen levels, BP, urinary nitrate/nitrite excretion, and proteinuria were measured. Histologic assessments using periodic acid-Schiff staining and immunohistologic studies with markers for endothelium, platelets, fibrin, cell proliferation, and apoptosis were also performed. L-NAME inhibition of NO synthesis in rats with TMA resulted in more severe glomerular and tubulointerstitial injury, which was accompanied by thrombus formation and a marked loss of endothelial cells, with more apoptotic cells. These changes were associated with severe renal function deterioration. In contrast, these features were less pronounced in the vehicle- or L-NIL-treated rats with TMA and were absent in the control animals. In conclusion, inhibition of NO production in this model of TMA markedly exacerbated renal injury. The absence of effects with L-NIL treatment suggests a minor role for inducible NOS in this model. These results suggest that production of NO, most likely by endothelial cells, is an important protective mechanism in TMA.
Endogenous Surfactant Turnover in Preterm Infants Measured with Stable Isotopes
Authors: JAN ERIK H. BUNT, LUC J. ZIMMERMANN, J. L. DARCOS WATTIMENA, RON H. van BEEK, PIETER J. SAUER, VIRGILIO P. CARNIELLI
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

We studied surfactant synthesis and turnover in vivo in preterm infants using the stable isotope [U-13C]glucose, as a precursor for the synthesis of palmitic acid in surfactant phosphatidylcholine (PC). Six preterm infants (birth weight, 916 ± 244 g; gestational age, 27.7 ± 1.7 wk) received a 24-h [U-13C]glucose infusion on the first day of life. The 13C-enrichment of palmitic acid in surfactant PC, obtained from tracheal aspirates, was measured by gas chromatography-combustion interface-isotope ratio mass spectrometry. We observed a significant incorporation of carbon-13 from glucose into surfactant PC palmitate. PC palmitate became enriched after 19.4 ± 2.3 (16.5 to 22.3) h and reached maximum enrichment at 70 ± 18 (48 to 96) h after the start of the label infusion. The fractional synthesis rate (FSR) of surfactant PC palmitate from glucose was 2.7 ± 1.3%/d. We calculated the absolute production rate of surfactant PC to be 4.2 mg/kg/d, and the half-life to be 113 ± 25 (87 to 144) h. Data on endogenous surfactant production and turnover were obtained for the first time in human infants with the use of stable isotopes. This novel and safe method could be applied to address many important issues concerning surfactant metabolism in preterm infants, children, and adults.
Direct vasoconstriction evoked by A1-adenosine receptor stimulation in the cutaneous microcirculation.
Authors: K G Proctor, I Stojanov
Journal: Circulation Research (1991)

To determine whether the vasoconstriction evoked by A1-adenosine receptor stimulation in the skin circulation caused the release of other substances or whether A1 stimulation modulated the vasoconstriction evoked by other compounds, a potent A1-selective, synthetic agonist, cyclohexyladenosine (CHA), was topically applied simultaneously with several different vasoconstrictor agonists or antagonists. CHA was chosen instead of adenosine because the parent compound is metabolized quickly and also does not discriminate between A1 or A2 receptors. Blood flow was calculated from measurements of arteriolar diameter (40-60 microns) and red blood cell velocity using intravital videomicroscopy. Responses were recorded only in a steady state. The dose-related vasoconstriction evoked by CHA (ED50, 2.07 +/- 0.80 nM; half-minimal response, 93 +/- 1%) was not attenuated by antagonists to norepinephrine (phentolamine [11 microM] or prazosin [10 microM]), serotonin (methysergide [11 microM]), angiotensin II (saralasin [0.11 microM]), thromboxane (SK&amp;F 88046 [13 microM]), or leukotrienes (SK&amp;F 102922 [2.1 microM]). The vasoconstriction evoked by 2 nM CHA was attenuated by a subthreshold concentration (1 nM) of norepinephrine, whereas the vasoconstriction evoked by 0.1-1 microM norepinephrine was attenuated by a threshold concentration (1 nM) of CHA. Higher concentrations (10-100 nM) of CHA had no additional inhibitory effect. In contrast, CHA had no effect on the vasoconstrictions evoked by angiotensin II (10 nM or 1 microM) or serotonin (100 or 500 nM). Therefore, it is unlikely that A1-receptor stimulation causes the release of norepinephrine, serotonin, angiotensin, thromboxane, or leukotrienes in the skin microcirculation. Because norepinephrine attenuated the vasoconstriction evoked by CHA while CHA attenuated that evoked by norepinephrine, there appears to be a negative interaction between alpha-adrenergic and A1-adenosinergic receptors.
First-in-Human Trial of a STAT3 Decoy Oligonucleotide in Head and Neck Tumors: Implications for Cancer Therapy
Authors: Malabika Sen, Sufi M. Thomas, Seungwon Kim, Joanne I. Yeh, Robert L. Ferris, Jonas T. Johnson, Umamaheswar Duvvuri, Jessica Lee, Nivedita Sahu, Sonali Joyce, Maria L. Freilino, Haibin Shi, Changyou Li, Danith Ly, Srinivas Rapireddy, Jonathan P. Etter, Pui-Kai Li, Lin Wang, Simion Chiosea, Raja R. Seethala, William E. Gooding, Xiaomin Chen, Naftali Kaminski, Kusum Pandit, Daniel E. Johnson, Jennifer R. Grandis
Journal: Cancer Discovery (2012)

Despite evidence implicating transcription factors, including STAT3, in oncogenesis, these proteins have been regarded as "undruggable." We developed a decoy targeting STAT3 and conducted a phase 0 trial. Expression levels of STAT3 target genes were decreased in head and neck cancers following injection with the STAT3 decoy compared with tumors receiving saline control. Decoys have not been amenable to systemic administration due to instability. To overcome this barrier, we linked the oligonucleotide strands using hexaethylene glycol spacers. This cyclic STAT3 decoy bound with high affinity to STAT3 protein, reduced cellular viability, and suppressed STAT3 target gene expression in cancer cells. Intravenous injection of the cyclic STAT3 decoy inhibited xenograft growth and downregulated STAT3 target genes in the tumors. These results provide the first demonstration of a successful strategy to inhibit tumor STAT3 signaling via systemic administration of a selective STAT3 inhibitor, thereby paving the way for broad clinical development.This is the fi rst study of a STAT3-selective inhibitor in humans and the fi rst evidence that a transcription factor decoy can be modifi ed to enable systemic delivery. These findings have therapeutic implications beyond STAT3 to other “undruggable” targets in human cancers.
Electrical Restitution and Spatiotemporal Organization During Ventricular Fibrillation
Authors: Mark L. Riccio, Marcus L. Koller, Robert F. Gilmour
Journal: Circulation Research (1999)

Abstract —Despite recent advances in our understanding of the mechanism for ventricular fibrillation (VF), important electrophysiological aspects of the development of VF still are poorly defined. It has been suggested that the onset of VF involves the disintegration of a single spiral wave into many self-perpetuating waves. It has been further suggested that such a process requires that the slope of the electrical restitution relation be ≥1. The same theory anticipates that a single spiral wave will be stable (not disintegrate) if the maximum slope of the restitution relation is &lt;1. We have shown previously that the slope of the restitution relation during rapid pacing and during VF is ≥1 in canine ventricle. We now show that drugs that reduce the slope of the restitution relation (diacetyl monoxime and verapamil) prevent the induction of VF and convert existing VF into a periodic rhythm. In contrast, a drug that does not reduce the slope of the restitution relation (procainamide) does not prevent the induction of VF, nor does it regularize VF. These results indicate that the kinetics of electrical restitution is a key determinant of VF. Moreover, they suggest novel approaches to preventing the induction or maintenance of VF.
Abstract 1463: Detection of cancer before distant metastasis.
Authors: Frank AW Coumans, Sabine Siesling, Leon WMM Terstappen
Journal: Cancer Research (2013)

Abstract Introduction: The majority of deaths from cancer are due to disseminated disease rather than the primary tumor. As metastases are often discovered years after surgical removal of the primary tumor, probably at least one metastasis was already present at the time of surgery. To establish a distant metastasis cells must disseminate from the primary tumor and overcome a series of obstacles, the metastatic cascade. In this study we develop a mathematical model for this cascade to estimate the technology requirements for detection of a primary tumor before the first metastasis has been formed. Methods: The metastatic cascade is described in discrete steps: 1. local tumor growth; 2. dissemination into circulation; 3. survival in circulation; 4. extravasation into tissue; and 5. growth into a metastasis. The model was built using data and relationships described in the literature to predict the relationship between tumor size and probability of distant metastasis for 38715 patients with surgically removed TxNxM0 primary breast cancer from the Netherlands Cancer Registry. The model was calibrated using primary tumor size, probability of distant metastasis and time to distant metastasis for 1489 patients with stage T1bNxM0 (25% of total patients with T1bNxM0). Validation of the model was done with data for all patients. Results: From the time to distant metastasis of these 38715 breast cancer patients, we determined a tumor doubling time of 1.7 ± 0.9 months. Fitting the data for 25% of T1b patients estimates a metastatic efficiency of 1 metastasis formed per 60 million disseminated tumor cells. Validation of the model to data of patients in all T-stages shows good agreement between model and epidemiological data. To reduce the 5-year risk of distant metastasis for TxNxM0 from 9.2% to 1.0%, the primary tumor needs to be detected and removed before it reaches a diameter of 2.7 ± 1.6 mm. At this size, the model predicts that there will be 9 ± 6 CTC/L blood. Conclusions: To reduce the rate of distant metastasis in surgically treated TxNxM0 breast cancer to 1%, imaging technology will need to be able to detect lesions of 2.7 mm in diameter or smaller. Before CTC detection can be applied in the early disease setting, sensitivity will need to be improved by at least 15-fold and combined with technology that minimizes false positives. Citation Format: Frank AW Coumans, Sabine Siesling, Leon WMM Terstappen. Detection of cancer before distant metastasis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1463. doi:10.1158/1538-7445.AM2013-1463
Resting-State Functional Connectivity in Treatment-Resistant Depression
Authors: Su Lui, Qizhu Wu, Lihua Qiu, Xun Yang, Weihong Kuang, Raymond C.K. Chan, Xiaoqi Huang, Graham J. Kemp, Andrea Mechelli, Qiyong Gong
Journal: American Journal of Psychiatry (2011)

Objective: The authors used resting-state functional connectivity MRI to evaluate brain networks in patients with refractory and nonrefractory major depressive disorder. Method: In a cross-sectional study, 28 patients with refractory major depression, 32 patients with nonrefractory major depression, and 48 healthy comparison subjects underwent scanning using a gradient-echo echo-planar imaging sequence on a 3-T MR system. Thirteen regions of interest that have been identified in the literature as relevant to mood regulation were selected as seed areas. A reference time series was extracted for each seed and used for voxel-wise correlation analysis with the rest of the brain. Voxel-based comparisons of z-value maps among the three groups were performed using one-way analysis of variance followed by post hoc t tests with age and duration of illness as covariates of no interest. Results: Relative to healthy comparison subjects, both patient groups showed significantly reduced connectivity in prefrontal-limbic-thalamic areas bilaterally. However, the nonrefractory group showed a more distributed decrease in connectivity than the refractory group, especially in the anterior cingulate cortex and in the amygdala, hippocampus, and insula bilaterally; in contrast, the refractory group showed disrupted functional connectivity mainly in prefrontal areas and in thalamus areas bilaterally. Conclusions: Refractory depression is associated with disrupted functional connectivity mainly in thalamo-cortical circuits, while nonrefractory depression is associated with more distributed decreased connectivity in the limbic-striatal-pallidal-thalamic circuit. These results suggest that nonrefractory and refractory depression are characterized by distinct functional deficits in distributed brain networks.