tbuckley/cabot-search huggingface dataset:
Abstract 16304: Manipulation of the Sphingolipid Rheostat Alters the Mediator of Flow-Induced Dilation in the Human Microcirculation
Authors: Julie K Freed, Joseph C Hockenberry, David D Gutterman
Journal: Circulation (2014)

Flow-induced dilation (FID) maintains vascular homeostasis and is inversely related to future cardiovascular events. Our laboratory has recently discovered that ceramide, a bioactive signaling lipid elevated in patients with CAD, initiates a switch in the mediator of FID from NO to mitochondrial-derived H2O2, the same transition that occurs between health and disease. Intracellular levels of ceramide are tightly controlled by neutral ceramidases, enzymes that degrade ceramide to sphingosine, a pathologically less active sphingolipid. We tested the hypothesis that inhibition of neutral ceramidase will alter the sphingolipid rheostat and trigger the change in mediator of FID. Small adipose arterioles (100-200μm) from patients without CAD were prepared for videomicroscopy and constricted with endothelin-1. Changes in internal diameter to flow were recorded. L-NAME (100μM) did not affect FID in healthy arterioles pre-treated with the neutral ceramidase inhibitor, Ceranib-1 (10μM, 16-20hrs), (83.6%±4.1 of maximal dilator capacity, n=7) compared to vehicle-treated control (76.9%±5.0, n=10), however dilation was abolished in the presence of PEG-Catalase (500 Units) (1.9%±4.9, n=7, p
An Old Story Retold: Loss of G1 Control Defines a Distinct Genomic Subtype of Esophageal Squamous Cell Carcinoma
Authors: Qiyan Wang, Jian Bai, Amir Abliz, Ying Liu, Kenan Gong, Jingjing Li, Wenjie Shi, Yaqi Pan, Fangfang Liu, Shujuan Lai, Haijun Yang, Changdong Lu, Lixin Zhang, Wei Chen, Ruiping Xu, Hong Cai, Yang Ke, Changqing Zeng
Journal: Genomics Proteomics & Bioinformatics (2015)

Esophageal squamous cell carcinoma (ESCC) has a high mortality rate. To determine the molecular basis of ESCC development, this study sought to identify characteristic genome-wide alterations in ESCC, including exonic mutations and structural alterations. The clinical implications of these genetic alterations were also analyzed. Exome sequencing and verification were performed for nine pairs of ESCC and the matched blood samples, followed by validation with additional samples using Sanger sequencing. Whole-genome SNP arrays were employed to detect copy number alteration (CNA) and loss of heterozygosity (LOH) in 55 cases, including the nine ESCC samples subjected to exome sequencing. A total of 108 non-synonymous somatic mutations (NSSMs) in 102 genes were verified in nine patients. The chromatin modification process was found to be enriched in our gene ontology (GO) analysis. Tumor genomes with TP53 mutations were significantly more unstable than those without TP53 mutations. In terms of the landscape of genomic alterations, deletion of 9p21.3 covering CDKN2A/2B (30.9%), amplification of 11q13.3 covering CCND1 (30.9%), and TP53 point mutation (50.9%) occurred in two-thirds of the cases. These results suggest that the deregulation of the G1 phase during the cell cycle is a key event in ESCC. Furthermore, six minimal common regions were found to be significantly altered in ESCC samples and three of them, 9p21.3, 7p11.2, and 3p12.1, were associated with lymph node metastasis. With the high correlation of TP53 mutation and genomic instability in ESCC, the amplification of CCND1, the deletion of CDKN2A/2B, and the somatic mutation of TP53 appear to play pivotal roles via G1 deregulation and therefore helps to classify this cancer into different genomic subtypes. These findings provide clinical significance that could be useful in future molecular diagnoses and therapeutic targeting.
Abstract 17076: Attenuating Endoplasmic Reticulum (ER) Stress as a Novel Therapeutic Strategy in Pulmonary Arterial Hypertension
Authors: Peter Dromparis, Roxanne Paulin, Gopinath Sutendra, Adam S Kinnaird, Trevor H Stenson, Alois Haromy, Evangelos Michelakis
Journal: Circulation (2011)

The poor prognosis associated with pulmonary arterial hypertension (PAH) is in part, due to the complex and poorly understood pathogenesis. ER stress is a potential common denominator among many of the seemingly unrelated molecular triggers of PAH, including BMPRII mutations and the misfolded protein response that follows, viruses, inflammation, Notch signaling and hypoxia. The ER forms a functional unit with the mitochondria (the ER-mito unit), allowing exchange of Ca2+, lipids and ATP between the organelles. Recently, we showed that disruption of the ER-mito unit was critical in PAH pathogenesis. ER stress-regulated induction of the reticulon protein Nogo caused structural/functional disruption of the ER-mito unit resulting in PAH. Chemical chaperones including the clinically studied 4-phenylbutyrate (PBA) can attenuate ER-stress and have been used in animals and patients to treat metabolic diseases and cancer. We hypothesized that attenuation of ER stress with PBA will prevent the disruption of the ER-mito unit and prevent/reverse PAH. We used two models of PAH associated with ER stress: hypoxia and monocrotaline (MCT). Mice exposed to chronic hypoxia and treated with PBA in the drinking water (~750mg/kg/day) in both prevention and reversal protocols had less distal pulmonary artery remodeling, improved hemodynamics, decreased right ventricular hypertrophy and better functional capacity (see table; data presented as mean±SEM). MCT-animals responded similarly. Mechanistic studies were performed in human cell lines and tissues from these animals. We showed that 2mM PBA decreased ER stress (decrease in the marker grp78), decreased Nogo and normalized the ER-mito unit (mitochondrial calcium and membrane potential). Both in vivo and in vitro, PBA suppressed proliferation (Ki67/PCNA) and induced apoptosis (TUNEL) in SMA+ cells. Metabolism and ER stress may be a common downstream effect of many diverse triggers of PAH and may expose a new therapeutic window.
A family-genetic study of girls with DSM-III attention deficit disorder
Authors: S V Faraone, J Biederman, K Keenan, M T Tsuang
Journal: American Journal of Psychiatry (1991)

The authors evaluated family-genetic risk factors in girls with attention deficit disorder and compared these results to findings in the authors' previous study of boys with attention deficit disorder.Twenty-one girls with attention deficit disorder and 20 normal comparison girls were consecutively ascertained from a pool of existing and new referrals from a pediatric psychopharmacology unit and a medical pediatric unit of the same urban hospital. First-degree relatives of the attention deficit disordered girls (N = 69) and of the normal girls (N = 71) were also assessed. Both groups of girls and their relatives were evaluated on the basis of structured diagnostic interviews conducted by raters who were blind to the clinical status of the probands.The relatives of the girls with attention deficit disorder had higher risks for attention deficit disorder, antisocial disorders, major depression, and anxiety disorders. The higher risk for attention deficit disorder could not be accounted for by gender or generation of relative, age of proband, social class, or family intactness. These findings are highly consistent with the findings in the authors' previous study of boys with attention deficit disorder, which was conducted with identical methods.This study provides further support for the validity of the diagnosis of attention deficit disorder in girls and suggests that the genders share a common biological substrate.
New algorithm using chest computed tomographic imaging characteristics for the differential diagnosis in female patients with pneumothorax
Authors: Yuki Ko, Keisuke Anan, Kazunori Tobino, Takahiro Haga, Masatoshi Kurihara, Takeshi Johkoh, Kuniaki Seyama
Journal: European Respiratory Journal (2014)

RATIONALE: In female patients, the etiologies of spontaneous pneumothorax are more various than those in male, because diseases specific to females exist. To our knowledge, there have been no reports concerning the usefulness of the chest computed tomographic (CT) findings in female pneumothorax patients in differentiation of potential causes.  AIMS: To make a useful diagnostic algorithm for potential causes of female pneumothorax.  METHODS: First, we retrospectively reviewed the characteristics of the chest CT findings in 123 consecutive female pneumothorax patients in whom the definitive diagnosis was obtained by pathological analysis or genetic testing. Second, using the clinical and CT imaging characteristics obtained by the first examination, we made a diagnostic algorithm for potential causes of pneumothorax. Finally, the algorithm was validated in another 141 female pneumothorax patients.  RESULTS: On the first examination, the number of patients with primary spontaneous pneumothorax, catamenial pneumothorax, Birt-Hogg-Dube syndrome, and lymphangioleiomyomatosis were 47, 42, 19 and 15, respectively. The important CT findings for differentiation of these diseases were; side of pneumothorax, number or extent of pulmonary cysts, dependent zone of pulmonary cysts, and the presence of pulmonary cysts abutting the proximal portions pulmonary blood vessels, and we made a diagnostic algorithm using those four findings. The validation study of the algorithm with another 141 female pneumothorax revealed high diagnostic accuracy (84.4%).  CONCLUSION: In female pneumothorax patients, our new diagnostic algorithm for potential causes may be useful.
Brivanib as adjuvant therapy to transarterial chemoembolization in patients with hepatocellular carcinoma: A randomized phase III trial
Authors: Masatoshi Kudo, Guohong Han, Richard S. Finn, Ronnie T.P. Poon, Jean-Frederic Blanc, Lunan Yan, Jijin Yang, Ligong Lu, Won-Young Tak, Xiaoping Yu, Joon-Hyeok Lee, Shi-Ming Lin, Changping Wu, Tawesak Tanwandee, Guoliang Shao, Ian B. Walters, Christine Dela Cruz, Valerie Poulart, Jian-Hua Wang
Journal: Hepatology (2014)

Transarterial chemoembolization (TACE) is the current standard of treatment for unresectable intermediate-stage hepatocellular carcinoma (HCC). Brivanib, a selective dual inhibitor of vascular endothelial growth factor and fibroblast growth factor signaling, may improve the effectiveness of TACE when given as an adjuvant to TACE. In this multinational, randomized, double-blind, placebo-controlled, phase III study, 870 patients with TACE-eligible HCC were planned to be randomly assigned (1:1) after the first TACE to receive either brivanib 800 mg or placebo orally once-daily. The primary endpoint was overall survival (OS). Secondary endpoints included time to disease progression (TTDP; a composite endpoint based on development of extrahepatic spread or vascular invasion, deterioration of liver function or performance status, or death), time to extrahepatic spread or vascular invasion (TTES/VI), rate of TACE, and safety. Time to radiographic progression (TTP) and objective response rate were exploratory endpoints. The trial was terminated after randomization of 502 patients (brivanib, 249; placebo, 253) when two other phase III studies of brivanib in advanced HCC patients failed to meet OS objectives. At termination, median follow-up was approximately 16 months. Intention-to-treat analysis showed no improvement in OS with brivanib versus placebo (median, 26.4 [95% confidence interval {CI}: 19.1 to not reached] vs. 26.1 months [19.0-30.9]; hazard ratio [HR]: 0.90 [95% CI: 0.66-1.23]; log-rank P = 0.5280). Brivanib improved TTES/VI (HR, 0.64 [95% CI: 0.45-0.90]), TTP (0.61 [0.48-0.77]), and rate of TACE (0.72 [0.61-0.86]), but not TTDP (0.94 [0.72-1.22]) versus placebo. Most frequent grade 3-4 adverse events included hyponatremia (brivanib, 18% vs. placebo, 5%) and hypertension (13% vs. 3%). Conclusions : In this study, brivanib as adjuvant therapy to TACE did not improve OS. (Hepatology 2014;60:1697–1707)
Abstract 4845: Microarray analysis of melanoma autologous tumor cell lines used as the source of tumor associated antigens in patient-specific dendritic cell immunotherapy phase II trial in patients with metastatic melanoma
Authors: Andrew N. Cornforth, Gary Fogel, Denysha Carbonell, Robert O. Dillman
Journal: Cancer Research (2015)

Abstract Melanoma cells that are proliferating and self-renewing in short-term cell culture, have the phenotypic and functional characteristics of tumor stem cells, and they express unique patient-specific neoantigens, as well as numerous common melanoma associated antigens. Patient-specific therapeutic vaccines, produced by Incubating autologous dendritic cells with autologous tumor cells from such cell lines (DC-TC), have yielded promising results in phase II trials in metastatic melanoma. In this study we examined the expression of genes on the tumor cell lines which had served as the sources of tumor associated antigens loaded onto autologous dendritic cells as part of a phase II trial in which there was an observed 5-year survival rate of 50%.[Dillman 2009] There was sufficient melanoma tumor cells to analyze for 50 of the 54 patients enrolled in the phase II trial. Microarray analysis was performed by Response Genetics, Inc. (Los Angeles) for 54,000 genes. The Excel data file was entered into an Affymetrix data processing algorithm using the R programming language. Gene ranking was performed using prediction analysis of microarrays.[Tibshirani 2002] Correlation with overall survival was done for 26 patients who survived 5 years or longer, and 24 patients who survived less than 5 years. Hierarchical clustering for over and under expression yielded 9 genes, VEPH1, ZNF280B, FGF13, ST6GALNAC3, QPCT, ZNF280B, BST, PBRM1 and C21orf91 which identified 11/11 patients who had a survival greater than 5 years, and 17/18 patients who died in less than 2 years. Using the top six genes, overall survival greater than 5 years was correctly predicted for 80.3% of patients, and survival less than 5 years was correctly predicted for 74.2% of patients. Gene array data obtained from self-renewing, proliferating, autologous tumor cells was prognostic for survival. It is unclear whether these genes are predictive of an effective immune response after repeated injections of a therapeutic dendritic cell-tumor cell vaccine. Citation Format: Andrew N. Cornforth, Gary Fogel, Denysha Carbonell, Robert O. Dillman. Microarray analysis of melanoma autologous tumor cell lines used as the source of tumor associated antigens in patient-specific dendritic cell immunotherapy phase II trial in patients with metastatic melanoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4845. doi:10.1158/1538-7445.AM2015-4845
Abstract 18289: Cardiac Macrophages Adopt Profibrotic/M2 Phenotype in Ischemic Hearts
Authors: Signe Carlson, Deri Helterline, Sarah Dupras, Elina Minami, April Stempien-Otero
Journal: Circulation (2013)

Background: Macrophages (macs) that over express urokinase plasminogen activator(uPA) adapt a profibrotic M2 phenotype in the heart in association with cardiac fibrosis. We tested the hypothesis that cardiac macs are M2 polarized in ischemic mouse and human hearts and that polarization is dependent on mac derived uPA. Methods: Mouse cardiac macs were isolated from hearts of infarcted (MI) and uninjured(UI) wild-type (WT) , uPA overexpressing (SR-uPA), or uPA null mice. RNA was extracted after isolation or culture with vehicle, IL-4 or plasmin. M2 markers Arg1, YM1, and Fizz1 measured with qrtPCR. Human cardiac macs were isolated from tissue at time of LVAD placement or transplantation. Peripheral blood was collected at the same time and monocyte-derived macs (PMDM) generated. Expression of CD206 was measured in isolated and IL-4 treated macs. All values were normalized to GAPDH. Values are meanSEM Results: Macs from WT mice had increased expression of Arg1 and Ym1 following MI (41.36.5 and 70.336, fold change vs UI, n=8, p &lt; 0.007). ANOVA analysis of UI vs MI in WT, SR-uPA, and uPA null showed significant upregulation of Arg1 and Ym1 with MI in all genotypes (n=4-9 per genotype and condition). There was no increase in Fizz1 in any group. Treatment with IL-4 increased expression of Arg1 and YM1, to a greater degree in cardiac macs from SR-uPA versus WT mice. Human cardiac macs expressed increased levels of CD206 in comparison to PMDM (4.91.3). Conclusions: Cardiac macs in mouse and human hearts adapt a M2 phenotype in association with cardiac fibrosis. uPA is not necessary for M2 phenotype development. Altering mac phenotype in the heart is a potential target to modify cardiac fibrosis.
A retrovirus in human breast cancer: Isolation and characterization of human mammary tumor virus (HMTV)
Authors: Stella M. Melana, Irene Nepomnaschy, Samuel Dales, Helen Rojowsky, Andrea Abbott, Jian-Dong Jiang, James F. Holland, Beatriz G-T Pogo
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

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We have previously reported sequences homologous to the env gene of Mouse Mammary Tumor Virus (MMTV) but not to human endogenous retroviruses in 38% of the human breast cancers studied, yet they were absent from others human tissues (Wang et al, Cancer Research 1995, 55: 5173). We have also found that normal breast tissue from env positive breast cancer patients was negative, suggesting that the sequences are of exogenous origin (Melana et al, Cl. Cancer Research 2001, 7:283). The sequences were also expressed in most of the positive breast cancer specimens as detected by RT PCR (Wang et al, Cl. Cancer Research 1998, 4:2565).Finally, the complete 9.9 Kb proviral sequence of an MMTV-like agent has been amplified and sequenced in two breast cancers (Liu, B. et al, Cancer Res 2001, 61:1754). Structural features of this provirus suggest that it is functional. We have now looked for the presence of viral particles in primary cultures (MSSM cells) of env sequence positive tumors. The cells expressed Env proteins as shown by immunofluorescence and western blot. FACS analysis indicated that between 10 to 20 % of the cells expressed the surface protein. Retroviral particles budding from cells as well as in particulate fractions from culture media were observed by electron microscopy. Particulate fractions also display reverse transcriptase (RT) activity and the presence of all viral genes as detected by RT-PCR. The RT activity peaked at densities characteristic of retroviruses in sucrose gradients. None of these properties were observed in similar studies with normal Human Mammary Epithelial Cells (HMEC) primary cultures or established normal breast cell line (MCF10F). Co-culture of MSSM virus-producing cells with HMEC, MCF10F, and B cells (Ramos) demonstrated transfer of viral sequences, as detected by PCR, and expression of Env proteins by western blot and FACS analysis in the recipient cells. Taken together, these findings support the identification of a human mammary tumor virus (HMTV) similar to MMTV in human breast cancer, which is able to infect human cells. Morphological cell transformation and tumorigenesis experiments are being performed.
Low CSF 5-HIAA concentrations and severe aggression and impaired impulse control in nonhuman primates
Authors: P T Mehlman, J D Higley, I Faucher, A A Lilly, D M Taub, J Vickers, S J Suomi, M Linnoila
Journal: American Journal of Psychiatry (1994)

The purpose of this study was to examine the relationship between behavior and serotonin by using a nonhuman primate model of aggression and impulse control.During a routine capture and medical examination, 26 adolescent male rhesus macaques (Macaca mulatta) were selected as subjects from a free-ranging population of 4,500 rhesus monkeys inhabiting a 475-acre sea island. Physiological data were obtained from 22-23 of the subjects. Blood and CSF samples were obtained, and each subject was fitted with a radio transmitter collar for rapid location. The subjects were released into their social groups, and quantitative behavioral observations were made over a 3-month period.CSF 5-hydroxyindoleacetic acid (5-HIAA) concentrations were inversely correlated with "escalated" aggression, i.e., a measure of more intense or severe aggression as defined by the ratio of chases and physical assaults to all aggressive acts. CSF 5-HIAA concentrations were significantly lower in those subjects who showed evidence of physical wounding than in subjects with no wounds. Low CSF 5-HIAA concentrations were also correlated with greater risk-taking as determined by an analysis of leaping behaviors in the forest canopy. The ratio of long leaps (leaps that traversed the longest distances at dangerous heights) to all leaps was negatively correlated with CSF 5-HIAA concentrations.Adolescent male rhesus macaques with low CSF 5-HIAA concentrations are at risk for 1) exhibiting more violent forms of aggressive behavior and 2) loss of impulse control as evidenced by greater risk taking during movement through the forest canopy.
Services for elderly and disabled people face collapse
Authors: Jacqui Wise
Journal: BMJ (2001)

Social care services in Britain are in danger of collapsing unless the government allocates an extra £700m ($980m) each year, an inquiry by the King's Fund has concluded.

The report, from the healthcare charity based in London, warns that without urgent improvements care and support services could face recruitment and retention crises as bad as those currently seen in nursing and medicine. The report says that the one million care and support workers in Britain exist on low pay, are poorly trained, …
Progesterone-Induced Erythema Multiforme
Authors: F Wojnarowska, M W Greaves, R D G Peachey, P L Drury, G M Besser
Journal: Journal of the Royal Society of Medicine (1985)

This paper presents the 1st reported case of progesterone-induced cyclical erythema multiforme. The patient, 33 years of age, suffered from recurrent pruritic annular and target lesions on the hands, feet, and trunk and oral laceration from 1977-83. She had taken oral contraceptives in 1972 without adverse effects. The eruptions began in the 2nd half of the menstrual cycle, worsened through the luteal phase, and were at their most florid on days 2-4 of menstrution. There was no relationship to estrogen levels; however, the postovulatory progesterone peak, as indicated by serial serum progesterone levels, corresponded to the initiation of eruptions. Erythema multiforme was induced within 48 hours by intramuscular injection of 10 mg progesterone or 10 mg medroxyprogesterone; this further evoked a rise in circulating immune complexes for 48 hours. There was no indication that the erythema multiforme was associated with menstrual-linked herpes simplex or the use of analgesics during menstruation. Autoimmune progesterone dermatitis is often associated with prior exposure to synthetic progesterones, as in this case. It has been suggested that the synthetic progesterone acts as a stimulus for antibodies which cross-react with natural progesterone. The antiestrogen tamoxifern was used successfully in this case and is a valuable alternative to treatment with oophorectomy.