tbuckley/cabot-search huggingface dataset:
An unusual cause of superior vena cava obstruction
Authors: S L Chan
Journal: Thorax (2006)

An unusual cause of superior vena cava obstruction S uperior vena cava (SVC) obstruction is commonly seen in patients with intrathoracic malignancies.Most cases are due to extrinsic compression by tumour masses.We present the case history of a man with SVC obstruction due instead to an intraluminal tumour which turned out to be adenocarcinoma of an unknown primary.A 54 year old chronic smoker presented with a 2 week history of progressive facial swelling and dyspnoea.Physical examination revealed signs of SVC obstruction.A CT scan of the thorax showed an expansile tumour mass located within and obstructing the lumen of the SVC lumen (fig 1).Neither CT scanning nor ultrasonography of the abdomen and pelvis showed any evidence of malignancy.Thoracotomy revealed an intracaval tumour obstructing the SVC and invading up to the level of the innominate veins.No primary or secondary tumours could be found.Subtotal tumour resection under extracorporeal circulatory bypass was performed followed by construction of a vascular bypass between the left brachiocephalic vein and right atrium.Histological examination confirmed adenocarcinoma (fig 2) without any features pointing to a specific primary origin.Immunohistochemical analysis showed positive staining for cytokeratin 7 (CK7) but not for CK20, CEA, thyroid transcription factor-1 (TTF-1), thyroglobulin, and hepatocyte paraffin antibody 1 (HepPar-1), suggesting that the primary tumour might have originated from the lungs or pancreaticobiliary tract.The patient received postoperative radiotherapy to the residual mass followed by platinum based chemotherapy.While SVC obstruction is not an uncommon presenting feature of certain cancers, 1 2 most cases are due to extrinsic compression.Primary or metastatic cancer presenting as an obstructive mass within the SVC is very rare.Reported histology in the literature include thymic carcinoma, primary leiomyosarcoma of the SVC, invasive thymoma, paraganglioma, follicular carcinoma of the thyroid, renal cell carcinoma, and lymphoma.
Lymphokines Enhance the Capacity of Human Monocytes to Secrete Reactive Oxygen Intermediates
Authors: Akira Nakagawara, Nancy M. Desantis, Nadia Nogueira, Carl F. Nathan
Journal: Journal of Clinical Investigation (1982)

Supernatants from mitogen- or antigen-stimulated human blood mononuclear cells enhanced the capacity of human monocytes or monocyte-derived macrophages (MDM) to release H2O2 or O2̇̄ in response to phorbol myristate acetate or zymosan. The stimulatory effect of lymphokines (LK) lasted ∼5 d, regardless of the time of their addition. However, the magnitude of stimulation depended on whether LK were added to freshly explanted monocytes or to MDM. When LK were added on day 0 of culture, they enhanced MDM H2O2-releasing capacity ∼40% measured on day 3, when H2O2-releasing capacity in the controls was maximal. Addition of LK on day 2 retarded the decline in H2O2-releasing capacity normally seen by day 5, so that LK-treated cells released about twice as much H2O2 as the controls. Addition of LK to MDM that had already lost most of their H2O2-releasing capacity (e.g., on day 4-6) restored it to an average of 60% of the values seen with freshly explanted monocytes. In this case, LK-treated cells were about 12 times more active than cells incubated in medium alone. The effects of LK were dose- and time-dependent, with maximal effects requiring 3 d of exposure. The specific activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, and myeloperoxidase, and the specific content of glutathione were not diminished in LK-treated MDM, suggesting that increased synthesis of H2O2 rather than decreased catabolism probably explained the greater release of H2O2 from LK-treated cells. In contrast, release of H2O2 was suppressed 93±4% by exposing monocytes for 4 d to hydrocortisone (50%-inhibitory concentration, 1.9±0.3 × 10−7 M). Thus, the oxidative metabolism of human mononuclear phagocytes can be markedly modulated in vitro: augmented by mediators released from lymphocytes during an immune response, and suppressed by antiinflammatory corticosteroids.
Efficacy of targeted FasL in nasopharyngeal carcinoma
Authors: Jian-Hua Li, Wei Shi, Marie Chia, Otto Sanchez-Sweatman, Christopher Siatskas, Dolly Huang, Pierre Busson, Henry Klamut, Wen-Chen Yeh, Chris Richardson, Brian O'Sullivan, Pat Gullane, Peter Neligan, Jeff Medin, Fei-Fei Liu
Journal: Molecular Therapy (2003)

We have successfully achieved selective gene expression in human nasopharyngeal carcinoma (NPC) by exploiting the presence of the Epstein-Barr virus (EBV), utilizing a transcriptional targeting strategy (J. H. Li et al., 2002, Cancer Res. 62: 171). Building on this platform, we have generated a novel DeltaE1 adenoviral vector mediating the expression of a mutant noncleavable form of the FasL gene (HUGO-approved symbol TNFSF6) (ad5oriP.ncFasL). We observe that this therapy induces significant cytotoxicity in the EBV-positive NPC cell line C666-1, mediated by the induction of caspase-dependent apoptosis. The addition of ionizing radiation therapy (RT) causes additional cytotoxicity. Ex vivo infection of C666-1 cells with adv.oriP.ncFasL completely prevents tumor formation in SCID mice followed for up to 100 days. The combination of intratumoral adv.oriP.ncFasL with RT causes regression of established nasopharyngeal xenograft tumors for 2 weeks' duration. Systemic delivery of this targeted strategy achieves 50-fold higher gene expression in nasopharyngeal tumors than in normal organs. Intravenously injected adv.oriP.ncFasL results in mild perturbation of liver function that returns to normal 2 weeks after initial therapy. These results demonstrate the efficacy of our EBV-specific targeting strategy, which allows the potentially safe and effective utilization of a highly potent membrane-based apoptotic gene.
Antidrug antibodies (ADAb) to tumour necrosis factor (TNF)-specific neutralising agents in chronic inflammatory diseases: a real issue, a clinical perspective
Authors: Fabien B Vincent, Eric F Morand, Kim Murphy, Fabienne Mackay, Xavier Mariette, Christian Marcelli
Journal: Annals of the Rheumatic Diseases (2012)

The introduction of biologics, especially tumour necrosis factor (TNF) inhibitors, has revolutionized the management of chronic inflammatory diseases. However, at least one third of patients with these diseases, receiving TNF inhibitors either do not respond to treatment, or lose initial responsiveness. For a significant proportion, improvement of clinical response is achieved after switching to another anti-TNF drug, suggesting a basis for failure unrelated to the therapeutic target itself. A likely explanation for this is immunogenicity, as all biologics are potentially immunogenic, and the resulting anti-drug antibodies (ADAb) can theoretically decrease the efficacy of biologics and/or induce adverse events. Indeed, in these chronic inflammatory diseases, many studies have now established correlations between ADAb formation, low serum drug levels, and the failure or loss of response to anti-TNF antibodies. This article will review key findings related to ADAb, and propose a model wherein monitoring of drug levels and ADAb may be a predictive tool leading to a better choice of biologics. Such an approach could improve chronic inflammatory disease management toward a personalized and more cost-effective approach.
Lead poisoning. Further observations on erythrocyte pyrimidine-nucleotidase deficiency and intracellular accumulation of pyrimidine nucleotides.
Authors: D E Paglia, W N Valentine, K Fink
Journal: Journal of Clinical Investigation (1977)

Pyrimidine nucleotides, detectable in normal erythrocytes only in trace quantities if at all, were found to comprise 7-80% of the intracellular nucleotide pools in nine subjects with severe lead over-burden. Blood lead concentrations ranged from approximately equal to 200- to 400-microgram/dl packed cells, and the greatest accumulations of pyrimidine-containing nucleotides occurred in the two subjects with the highest blood lead levels. Most of the patients had mild or moderate anemia and moderate basophilic stippling evident in Wright's-stained peripheral smears. Pyrimidine nucleotidase activities were inhibited to 13-28% of the mean activity in normal control erythrocytes and even more so (5-15%) when compared to specimens with increased reticulocytes and young cells. Reticulocytosis was absent in two subjects and modest to moderate in the remainder, but erythrocyte assays revealed the substantial elevations in populations of young mean cell age. Inappropriately low reticulocyttial elevations in glucose-6-phosphate dehydrogenase expected in populations of young mean cell age. Inappropriately low reticulocyte responses may reflect hematopoietic suppressive effects of lead at a variety of metabolic loci.
Clinical Features and Outcomes of Takotsubo (Stress) Cardiomyopathy
Authors: Christian Templin, Jelena R. Ghadri, Johanna Diekmann, L. Christian Napp, Dana R. Bataiosu, Milosz Jaguszewski, Victoria L. Cammann, Annahita Sarcon, Verena Geyer, Catharina A. Neumann, Burkhardt Seifert, Jens Hellermann, Moritz Schwyzer, Katharina Eisenhardt, Josef Jenewein, Jennifer Franke, Hugo A. Katus, Christof Burgdorf, Heribert Schunkert, Christian Moeller, Holger Thiele, Johann Bauersachs, Carsten Tschöpe, Heinz Peter Schultheiss, Charles A. Laney, Lawrence Rajan, Guido Michels, Roman Pfister, Christian Ukena, Michael Böhm, Raimund Erbel, Alessandro Cuneo, Karl Heinz Kuck, Claudius Jacobshagen, Gerd Hasenfuss, Mahir Karakas, Wolfgang Koenig, Wolfgang Rottbauer, Samir M. Said, Ruediger C. Braun-Dullaeus, Florim Cuculi, Adrian Banning, Thomas A. Fischer, Tuija Vasankari, K. E Juhani Airaksinen, Marcin Fijalkowski, Andrzej Rynkiewicz, Maciej Pawlak, Grzegorz Opolski, Rafal Dworakowski, Philip MacCarthy, Christoph Kaiser, Stefan Osswald, Leonarda Galiuto, Filippo Crea, Wolfgang Dichtl, Wolfgang M. Franz, Klaus Empen, Stephan B. Felix, Clément Delmas, Olivier Lairez, Paul Erne, Jeroen J. Bax, Ian Ford, Frank Ruschitzka, Abhiram Prasad, Thomas F. Lüscher
Journal: New England Journal of Medicine (2015)

The natural history, management, and outcome of takotsubo (stress) cardiomyopathy are incompletely understood.The International Takotsubo Registry, a consortium of 26 centers in Europe and the United States, was established to investigate clinical features, prognostic predictors, and outcome of takotsubo cardiomyopathy. Patients were compared with age- and sex-matched patients who had an acute coronary syndrome.Of 1750 patients with takotsubo cardiomyopathy, 89.8% were women (mean age, 66.8 years). Emotional triggers were not as common as physical triggers (27.7% vs. 36.0%), and 28.5% of patients had no evident trigger. Among patients with takotsubo cardiomyopathy, as compared with an acute coronary syndrome, rates of neurologic or psychiatric disorders were higher (55.8% vs. 25.7%) and the mean left ventricular ejection fraction was markedly lower (40.7±11.2% vs. 51.5±12.3%) (P<0.001 for both comparisons). Rates of severe in-hospital complications including shock and death were similar in the two groups (P=0.93). Physical triggers, acute neurologic or psychiatric diseases, high troponin levels, and a low ejection fraction on admission were independent predictors for in-hospital complications. During long-term follow-up, the rate of major adverse cardiac and cerebrovascular events was 9.9% per patient-year, and the rate of death was 5.6% per patient-year.Patients with takotsubo cardiomyopathy had a higher prevalence of neurologic or psychiatric disorders than did those with an acute coronary syndrome. This condition represents an acute heart failure syndrome with substantial morbidity and mortality. (Funded by the Mach-Gaensslen Foundation and others; ClinicalTrials.gov number, NCT01947621.).
Risks for Nonaffective Psychotic Disorder and Bipolar Disorder in Young People With Autism Spectrum Disorder
Authors: Jean-Paul Selten, Michael Lundberg, Dheeraj Rai, Cecilia Magnusson
Journal: JAMA Psychiatry (2015)

Whether individuals with autism spectrum disorder (ASD) are at increased risk for nonaffective psychotic disorder (NAPD) or bipolar disorder (BD) is unknown.To test whether the risks for NAPD and BD in individuals with ASD are increased and whether these risks are higher than those of their siblings not diagnosed as having ASD.We performed a nested case-control study of all individuals 17 years or younger who ever resided in Stockholm County, Sweden, from January 1, 2001, through December 31, 2011 (Stockholm Youth Cohort). We included cohort members ever diagnosed as having ASD (n = 9062) and their full siblings never diagnosed as having ASD. Each case was matched with 10 control individuals of the same sex born during the same month and year. Using Swedish registers, cases, siblings, and controls were followed up until December 31, 2011. By then, the oldest individuals had reached the age of 27 years.Autism spectrum disorder, registered before age 16 or 28 years. We distinguished between ASD with and without intellectual disability (ID).We calculated odds ratios (ORs) for NAPD and BD adjusted for age, sex, population density of place of birth, personal or parental history of migration, hearing impairment, parental age, parental income, parental educational level, and parental history of psychiatric disorder.The adjusted ORs for NAPD and BD for cases with non-ID ASD registered before age 16 years were 5.6 (95% CI, 3.3-8.5) and 5.8 (95% CI, 3.9-8.7), respectively; the adjusted ORs for cases with ID ASD were 3.5 (95% CI, 2.0-6.0) and 1.8 (95% CI, 0.8-4.1). The adjusted ORs for NAPD and BD in cases with non-ID ASD registered before age 28 years were 12.3 (95% CI, 9.5-15.9) and 8.5 (95% CI, 6.5-11.2), respectively; for cases with ID ASD, these ORs were 6.4 (95% CI, 4.2-9.8) and 2.0 (95% CI, 1.0-3.9), respectively. The ORs for NAPD and BD for the nonautistic full siblings of cases for whom ASD was registered before age 16 years, adjusted for hearing loss, were 1.8 (95% CI, 1.1-2.7) and 1.7 (95% CI, 1.1-2.6), respectively.A diagnosis of ASD is associated with a substantially increased risk for NAPD and BD. This finding contributes to our understanding of these disorders and has implications for the management of ASD.
Development of hypertrophic cardiomyopathy in perilipin-1 null mice with adipose tissue dysfunction
Authors: Shangxin Liu, Bin Geng, Liangqiang Zou, Suning Wei, Weiyi Wang, Jingna Deng, Chong Xu, Xiaojing Zhao, Ying Lyu, Xueying Su, Guoheng Xu
Journal: Cardiovascular Research (2014)

Perilipin-1 (Plin1), exclusively located on the surface of lipid droplets in adipocytes, regulates the storage and hydrolysis of adipose triglycerides. Plin1 deficiency primarily causes low adiposity and aberrant lipolysis in rodents and humans. Here, we investigated whether adipose tissue dysfunction in perilipin-1 null (Plin1−/−) mice has maladaptive consequences for the heart and an association with hypertrophic cardiomyopathy. Perilipin-1 was expressed specifically in adipocytes but was undetectable in cardiomyocytes. Plin1−/− mice were histologically lipodystrophic, with reduced body fat. Paradoxically, the adipocytes of Plin1−/− mice, like those of obese and diabetic mammals, showed robust basal lipolysis and fatty acid efflux to the plasma. Such adipose tissue dysfunctions accounted for the ectopic lipid accumulation and enhanced fatty acid transport and oxidation in Plin1−/− mouse hearts. Excessive fatty acid β-oxidation and lipotoxicity induced excessive production of reactive oxygen species and oxidative stress because antioxidative capacity was reduced in cardiomyocytes, These malefactors injured the myocardial structure and function, as evidenced by disorganized myofilaments as well as irregular and swollen mitochondria with disrupted cristae. Finally, Plin1−/− mice showed grossly visible cardiac hypertrophy, with progressively up-regulated expression of hypertrophy and dysfunction marker genes, leading to heart failure, particularly with left ventricular diastolic dysfunction at 20 weeks of age. Adipose tissue dysfunction may have deleterious effects on the heart and contribute to the development of hypertrophic cardiomyopathy. Hypertrophic cardiomyopathy in Plin1−/− mice with adipose tissue dysfunction may mimic and mechanistically explain the cardiomyopathies occurring in two typical adipose tissue disorders in humans, lipodystrophy and obesity.
Natural course of sleep-disordered breathing after acute myocardial infarction
Authors: Stefan Buchner, Tanja Greimel, Andrea Hetzenecker, Andreas Luchner, Okka W. Hamer, Kurt Debl, Florian Poschenrieder, Claudia Fellner, Günter A.J. Riegger, Michael Pfeifer, Michael Arzt
Journal: European Respiratory Journal (2012)

The aim of this study was to test whether an improvement of left ventricular ejection fraction (EF) in the early phase after acute myocardial infarction is associated with a reduction of the severity of central and obstructive sleep apnoea. 40 consecutive patients with acute myocardial infarction underwent polysomnography and cardiovascular magnetic resonance imaging within 5 days and 12 weeks after the event to assess sleep apnoea and cardiac function. We stratified the sample in patients who improved their left ventricular EF within 12 weeks by ≥5% (improved EF group, ΔEF 9±1%, n=16) and in those who did not (unchanged EF group, ΔEF -1±1%, n=24). Prevalence of sleep apnoea (≥15 apnoea and hypopnoea events·h −1 ) within ≤5 days after myocardial infarction was 55%. Apnoea and hypopnoea events·h −1 were significantly more reduced in the improved EF group compared with the unchanged EF group (-10±3 versus 1±3 events·h −1 ; p=0.036). This reduction was based on a significant alleviation of obstructive events (-7±2 versus 4±3 events·h −1 ; p=0.009), while the reduction of central events was similar between groups (p=0.906). An improvement of cardiac function early after myocardial infarction is associated with an alleviation of sleep apnoea. This finding suggests that re-evaluation of treatment indication for sleep apnoea is needed when a change in cardiac function occurs.
Recent Retrotransposon Insertions Are Methylated and Phylogenetically Clustered in Japonica Rice (Oryza sativa spp. japonica)
Authors: Bridgett M. vonHoldt, Shohei Takuno, Brandon S. Gaut
Journal: Molecular Biology and Evolution (2012)

In plants, the genome of the host responds to the amplification of transposable elements (TEs) with DNA methylation. However, neither the factors involved in TE methylation nor the dynamics of the host–TE interaction are well resolved. Here, we identify 5,522 long terminal repeat retrotransposons (LTR-RT) in the genome of Oryza sativa ssp. japonica and then assess methylation for individual elements. Our analyses uncover three strong trends: long LTR-RTs are more highly methylated, the insertion times of LTR-RTs are negatively correlated with methylation, and young LTR-RTs tend to be closer to genes than older insertions. Additionally, a phylogenetic examination of the gypsy-like LTR-RT superfamily revealed that methylation is phylogenetically correlated. Given these observations, we present a model suggesting that the phylogenetic correlation among related LTR-RTs is a primary mechanism driving methylation. In this model, bursts of transposition produce new elements with high sequence similarity. The host machinery identifies proliferating elements as well as closely related LTR-RTs through cross-homology. In addition, our data are consistent with previous hypotheses that methylated LTR-RT elements are removed preferentially from regions near genes, explaining some of the observed age distribution.
Androgen Receptor Signaling in Circulating Tumor Cells as a Marker of Hormonally Responsive Prostate Cancer
Authors: David T. Miyamoto, Richard J. Lee, Shannon L. Stott, David T. Ting, Ben S. Wittner, Matthew Ulman, Malgorzata E. Smas, Jenna B. Lord, Brian W. Brannigan, Julie Trautwein, Neil H. Bander, Chin-Lee Wu, Lecia V. Sequist, Matthew R. Smith, Sridhar Ramaswamy, Mehmet Toner, Shyamala Maheswaran, Daniel A. Haber
Journal: Cancer Discovery (2012)

Abstract Androgen deprivation therapy (ADT) is initially effective in treating metastatic prostate cancer, and secondary hormonal therapies are being tested to suppress androgen receptor (AR) reactivation in castration-resistant prostate cancer (CRPC). Despite variable responses to AR pathway inhibitors in CRPC, there are no reliable biomarkers to guide their application. Here, we used microfluidic capture of circulating tumor cells (CTC) to measure AR signaling readouts before and after therapeutic interventions. Single-cell immunofluorescence analysis revealed predominantly “AR-on” CTC signatures in untreated patients, compared with heterogeneous (“AR-on, AR-off, and AR-mixed”) CTC populations in patients with CRPC. Initiation of first-line ADT induced a profound switch from “AR-on” to “AR-off” CTCs, whereas secondary hormonal therapy in CRPC resulted in variable responses. Presence of “AR-mixed” CTCs and increasing “AR-on” cells despite treatment with abiraterone acetate were associated with an adverse treatment outcome. Measuring treatment-induced signaling responses within CTCs may help guide therapy in prostate cancer. Significance: Acquired resistance to first-line hormonal therapy in prostate cancer is heterogeneous in the extent of AR pathway reactivation. Measurement of pre- and posttreatment AR signaling within CTCs may help target such treatments to patients most likely to respond to second-line therapies. Cancer Discov; 2(11); 995–1003. ©2012 AACR. Read the Commentary on this article by Pantel and Alix-Panabières, p. 974. This article is highlighted in the In This Issue feature, p. 961
Deposition of idiotype-anti-idiotype immune complexes in renal glomeruli after polyclonal B cell activation.
Authors: M Goldman, L M Rose, A Hochmann, P H Lambert
Journal: The Journal of Experimental Medicine (1982)

We investigated the possible role of idiotypic interactions in the pathogenesis of the glomerular lesions observed in mice undergoing polyclonal B cell activation. BALB/c mice were studied for the presence of renal deposits of T15 idiotype-anti-T15 idiotype-immune complexes (IC) after injection of bacterial lipopolysaccharides (LPS). The T15 idiotype is the major idiotype of BALB/c mice anti-phosphorylcholine (PC) antibodies, which are cross-reactive with the idiotype of the TEPC-15 myeloma protein. This model was used because T15 idiotype-anti-T15 idiotype IC have been detected in the circulation of BALB/c mice after polyclonal B cell activation. First, an idiotype-specific immunofluorescence technique allowed us to detect T15 idiotype-bearing immunoglobulins in glomeruli from day 6 to day 28 after LPS injection. Second, fluorescein isothiocyanate-conjugated TEPC-15 myeloma protein was found to localize in the glomeruli after in vivo injection 18 d after LPS administration. This renal localization was shown to be idiotype-specific and could be quantified in a trace-labeling experiment. Third, kidney-deposited immunoglobulins of mice injected with LPS were eluted, radiolabeled, and analyzed by radioimmunoassay. Both T15 idiotype-bearing immunoglobulins and anti-T15 idiotype antibodies were detected in the eluates, providing further evidence for a renal deposition of T15 idiotype-anti-T15 idiotype IC. Polyclonal B cell activation is likely to result in a simultaneous triggering of many idiotypic clones and of corresponding anti-idiotypic clones represented in the B cell repertoire. This could lead to the formation of a variety of idiotype-anti-idiotype IC that could participate in the development of glomerular lesions.