tbuckley/cabot-search huggingface dataset:
Hereditary Patent Ductus Arteriosus and Its Sequelae in the Dog
Authors: D. F. Patterson, R. L. Pyle, J. W. Buchanan, E. Trautvetter, D. A. Abt
Journal: Circulation Research (1971)

Further studies of hereditary patent ductus arteriosus (PDA) in the dog show the defect to have a graded phenotypic expression. A high proportion of offspring of test matings had a fully patent ductus arteriosus, while a smaller proportion had a blind diverticulum of the ductus arteriosus which communicated with the aorta. This is considered to be a forme fruste of PDA, representing incomplete closure. Approximately 50% of pups with fully patent ductus arteriosus developed signs of left heart failure, and about 15% developed severe pulmonary hypertension with right-to-left or bidirectional shunts. Genetic analysis indicated that hereditary PDA in the dog is not a simple mendelian trait, Rather, it resembles a quasi-continuous or threshold trait with a high degree of heritability. Results were analyzed using a polygenic model with two developmental thresholds. Liability to defective closure of the ductus arteriosus increased with the proportion of the genome received from dogs with PDA. Moreover, in pups which had PDA, the incidence of serious sequelae (left heart failure and severe pulmonary hypertension) increased in a parallel fashion, suggesting that an increased liability to PDA was accompanied by an increase in the severity of the lesion.
Genetic influences modulating the radiological severity of rheumatoid arthritis: Table 1
Authors: I Marinou, J R Maxwell, A G Wilson
Journal: Annals of the Rheumatic Diseases (2010)

This review focuses on the contribution of genetic markers to the severity of radiological damage in rheumatoid arthritis (RA). Currently available biomarkers of more severe disease include elevated erythrocyte sedimentation rates or C-reactive protein levels and rheumatoid factor (RF) or anticyclic citrullinated protein antibodies positivity; however, these biomarkers explain a relatively modest proportion of the variance in radiological damage. An important role of genetic factors on RA severity has recently emerged but studies to date have generally been of low statistical power and many have not been replicated. Genetic markers have a number of advantages over conventional biomarkers; genotypes are stable, measurable at disease onset, remain unchanged by treatment and are amenable to high-throughput assays. The recent advances in genome-wide genetic analysis should lead to a more comprehensive understanding of RA severity genes. This knowledge could be used, along with existing biomarkers, to therapeutically target subjects at risk of poor radiological outcome.
<b><i>In Vitro</i></b>and<b><i>in Vivo</i></b>Activity of the Maytansinoid Immunoconjugate huN901-<b><i>N</i></b>2′-Deacetyl-<b><i>N</i></b>2′-(3-Mercapto-1-Oxopropyl)-Maytansine against CD56+ Multiple Myeloma Cells
Authors: Pierfrancesco Tassone, Antonella Gozzini, Victor Goldmacher, Masood A. Shammas, Kathleen R. Whiteman, Daniel R. Carrasco, Cheng Li, Charles K. Allam, Salvatore Venuta, Kenneth C. Anderson, Nikhil C. Munshi
Journal: Cancer Research (2004)

HuN901 is a humanized monoclonal antibody that binds with high affinity to CD56, the neuronal cell adhesion molecule. HuN901 conjugated with the maytansinoid N(2')-deacetyl-N(2')-(3-mercapto-1-oxopropyl)-maytansine (DM1), a potent antimicrotubular cytotoxic agent, may provide targeted delivery of the drug to CD56 expressing tumors. Based on gene expression profiles of primary multiple myeloma (MM) cells showing expression of CD56 in 10 out of 15 patients (66.6%) and flow cytometric profiles of MM (CD38(bright)CD45(lo)) cells showing CD56 expression in 22 out of 28 patients (79%), we assessed the efficacy of huN901-DM1 for the treatment of MM. We first examined the in vitro cytotoxicity and specificity of huN901-DM1 on a panel of CD56(+) and CD56(-) MM cell lines, as well as a CD56(-) Waldenstrom's macroglobulinemia cell line. HuN901-DM1 treatment selectively decreased survival of CD56(+) MM cell lines and depleted CD56(+) MM cells from mixed cultures with a CD56(-) cell line or adherent bone marrow stromal cells. In vivo antitumor activity of huN901-DM1 was then studied in a tumor xenograft model using a CD56(+) OPM2 human MM cell line in SCID mice. We observed inhibition of serum paraprotein secretion, inhibition of tumor growth, and increase in survival of mice treated with huN901-DM1. Our data therefore demonstrate that huN901-DM1 has significant in vitro and in vivo antimyeloma activity at doses that are well tolerated in a murine model. Taken together, these data provide the framework for clinical trials of this agent to improve patient outcome in MM.
Too close for comfort: Accidental burn following subcutaneous mastectomy and immediate implant reconstruction
Authors: R Seth, Mj Lamyman, A Athanassopoulos, M Tyler
Journal: Journal of the Royal Society of Medicine (2008)

We report a case of an accidental burn from a self-applied heat pack following subcutaneous mastectomy and implant reconstruction. Such patients are at increased risk of accidental burns not only due to loss of protective sensation, but also because of the thinner, less vascular overlying skin. We have changed our practice so that all patients undergoing breast reconstructive surgery are warned postoperatively to protect the skin from externally applied heat sources.
Desquamative interstitial pneumonia: relationship to interstitial fibrosis
Authors: A. S. Patchefsky, H. L. Israel, W. S. Hoch, G. Gordon
Journal: Thorax (1973)

<b>Patchefsky, A. S., Israel, H. L., Hoch, W. S., and Gordon, Gloria (1973).</b><i>Thorax</i>, <b>28</b>, 680-693. <b>Desquamative interstitial pneumonia: relationship to interstitial fibrosis.</b> The clinical course and radiographic and pathological findings in 14 patients having the histological pattern of desquamative interstitial pneumonia (DIP) have been studied. Four deaths occurred from cardiorespiratory failure and two from other diseases, and one patient has severe pulmonary insufficiency. Seven patients had altered immunological reactivity or arthritis. Necropsy of three patients, one who died of respiratory insufficiency and two of other diseases, revealed diffuse pulmonary fibrosis with loss of the desquamative features noted on biopsy. One patient had had industrial exposure to tungsten carbide dust and <i>x</i>-ray diffraction analysis of the post-mortem lung showed high concentrations of this substance. Ultrastructural observation and direct immunofluorescent staining of one specimen demonstrated fibrin in the alveolar space, a feature usually regarded as distinguishing DIP from chronic fibrosing interstitial pneumonia. Our clinical and pathological observations suggest that the histological pattern recognized as DIP may be a non-specific reaction to diverse forms of injury, which is not clearly separable from the usual type of diffuse interstitial fibrosis.
Systemic Inhibition of Transforming Growth Factor-β in Glioma-Bearing Mice Improves the Therapeutic Efficacy of Glioma-Associated Antigen Peptide Vaccines
Authors: Ryo Ueda, Mitsugu Fujita, Xinmei Zhu, Kotaro Sasaki, Edward R. Kastenhuber, Gary Kohanbash, Heather A. McDonald, Jay Harper, Scott Lonning, Hideho Okada
Journal: Clinical Cancer Research (2009)

Abstract Purpose: A variety of cancers, including malignant gliomas, overexpress transforming growth factor-β (TGF-β), which helps tumors evade effective immune surveillance through a variety of mechanisms, including inhibition of CD8+ CTLs and enhancing the generation of regulatory T (Treg) cells. We hypothesized that inhibition of TGF-β would improve the efficacy of vaccines targeting glioma-associated antigen (GAA)–derived CTL epitopes by reversal of immunosuppression. Experimental Design: Mice bearing orthotopic GL261 gliomas were treated systemically with a TGF-β–neutralizing monoclonal antibody, 1D11, with or without s.c. vaccinations of synthetic peptides for GAA-derived CTL epitopes, GARC-1 (77-85) and EphA2 (671-679), emulsified in incomplete Freund's adjuvant. Results: Mice receiving the combination regimen exhibited significantly prolonged survival compared with mice receiving either 1D11 alone, GAA vaccines alone, or mock treatments alone. TGF-β neutralization enhanced the systemic induction of antigen-specific CTLs in glioma-bearing mice. Flow cytometric analyses of brain-infiltrating lymphocytes revealed that 1D11 treatment suppressed phosphorylation of Smad2, increased GAA-reactive/IFN-γ–producing CD8+ T cells, and reduced CD4+/FoxP3+ Treg cells in the glioma microenvironment. Neutralization of TGF-β also upregulated plasma levels of interleukin-12, macrophage inflammatory protein-1α, and IFN-inducible protein-10, suggesting a systemic promotion of type-1 cytokine/chemokine production. Furthermore, 1D11 treatment upregulated plasma interleukin-15 levels and promoted the persistence of GAA-reactive CD8+ T cells in glioma-bearing mice. Conclusions: These data suggest that systemic inhibition of TGF-β by 1D11 can reverse the suppressive immunologic environment of orthotopic tumor-bearing mice both systemically and locally, thereby enhancing the therapeutic efficacy of GAA vaccines. (Clin Cancer Res 2009;15(21):6551–9)
Underestimating Cardiac Toxicity in Cancer Trials: Lessons Learned?
Authors: Ronald M. Witteles, Melinda Telli
Journal: Journal of Clinical Oncology (2012)

Sunitinib (Sutent; Pfizer, New York, NY) represents one of the most successful cancer therapies, with US Food and Drug Administration (FDA) approval for three malignancies and ongoing trials in more than 30 tumor types. It also represents an instructive example revealing how adverse events can be vastly underestimated. The purpose of this article is to critically evaluate the history of the underrecognition of the cardiac toxicity of sunitinib and to propose solutions to improve adverse event monitoring for future therapies.
Incomplete Behcet's syndrome with unusual manifestations.
Authors: T Akoglu, S Paydas, S Sarpel, N Tunali, I Tuncer
Journal: Annals of the Rheumatic Diseases (1987)

We report a case of incomplete Behçet9s syndrome with two major criteria plus interstitial pneumonia. The patient had also hypoplastic bone marrow and disseminated intravascular coagulation developed during the terminal stage.
Understanding Surgical Decision Making in Early Hepatocellular Carcinoma
Authors: Hari Nathan, John F.P. Bridges, Richard D. Schulick, Andrew M. Cameron, Kenzo Hirose, Barish H. Edil, Christopher L. Wolfgang, Dorry L. Segev, Michael A. Choti, Timothy M. Pawlik
Journal: Journal of Clinical Oncology (2011)

Purpose The choice between liver transplantation (LT), liver resection (LR), and radiofrequency ablation (RFA) as initial therapy for early hepatocellular carcinoma (HCC) is controversial, yet little is known about how surgeons choose therapy for individual patients. We sought to quantify the impact of both clinical factors and surgeon specialty on surgical decision making in early HCC by using conjoint analysis. Methods Surgeons with an interest in liver surgery were invited to complete a Web-based survey including 10 case scenarios. Choice of therapy was then analyzed by using regression models that included both clinical factors and surgeon specialty (non-LT v LT). Results When assessing early HCC occurrences, non-LT surgeons (50% LR; 41% LT; 9% RFA) made significantly different recommendations compared with LT surgeons (63% LT; 31% LR; 6% RFA; P &lt; .001). Clinical factors, including tumor number and size, type of resection required, and platelet count, had significant effects on the choice between LR, LT, and RFA. After adjusting for clinical factors, non-LT surgeons remained more likely than LT surgeons to choose LR compared with LT (relative risk ratio [RRR], 2.67). When the weight of each clinical factor was allowed to vary by surgeon specialty, the residual independent effect of surgeon specialty on the decision between LR and LT was negligible (RRR, 0.93). Conclusion The impact of surgeon specialty on choice of therapy for early HCC is stronger than that of some clinical factors. However, the influence of surgeon specialty does not merely reflect an across-the-board preference for one therapy over another. Rather, certain clinical factors are weighed differently by surgeons in different specialties.
Reduced mRNA abundance of the main enzymes involved in methionine metabolism in human liver cirrhosis and hepatocellular carcinoma
Authors: Matías A Avila, Carmen Berasain, Luis Torres, Antonio Martín-Duce, Fernando J Corrales, Heping Yang, Jesús Prieto, Shelly C Lu, Juan Caballería, Juan Rodés, José M Mato
Journal: Journal of Hepatology (2000)
Vitamin D Insufficiency and Prognosis in Non-Hodgkin's Lymphoma
Authors: Matthew T. Drake, Matthew J. Maurer, Brian K. Link, Thomas M. Habermann, Stephen M. Ansell, Ivana N. Micallef, Jennifer L. Kelly, William R. Macon, Grzegorz S. Nowakowski, David J. Inwards, Patrick B. Johnston, Ravinder J. Singh, Cristine Allmer, Susan L. Slager, George J. Weiner, Thomas E. Witzig, James R. Cerhan
Journal: Journal of Clinical Oncology (2010)

Vitamin D insufficiency is common in the United States, with low levels linked in some studies to higher cancer incidence, including non-Hodgkin's lymphoma (NHL). Recent data also suggest that vitamin D insufficiency is related to inferior prognosis in some cancers, although there are no data for NHL.We tested the hypothesis that circulating 25-hydroxyvitamin D [25(OH)D] levels are predictive of event-free survival (EFS) and overall survival (OS) in a prospective cohort of 983 newly diagnosed patients with NHL. 25(OH)D and 1,25-dihydroxyvitamin D [1,25(OH)(2)D] levels were measured by liquid chromatography-tandem mass spectrometry.Mean age at diagnosis was 62 years (range, 19 to 94 years); 44% of patients had insufficient 25(OH)D levels (< 25 ng/mL) within 120 days of diagnosis. Median follow-up was 34.8 months; 404 events and 193 deaths (168 from lymphoma) occurred. After adjusting for known prognostic factors and treatment, 25(OH)D insufficient patients with diffuse large B-cell lymphoma (DLBCL) had inferior EFS (hazard ratio [HR], 1.41; 95% CI, 0.98 to 2.04) and OS (HR, 1.99; 95% CI, 1.27 to 3.13); 25(OH)D insufficient patients with T-cell lymphoma also had inferior EFS (HR, 1.94; 95% CI, 1.04 to 3.61) and OS (HR, 2.38; 95% CI, 1.04 to 5.41). There were no associations with EFS for the other NHL subtypes. Among patients with DLBCL and T-cell lymphoma, higher 1,25(OH)(2)D levels were associated with better EFS and OS, suggesting that any putative tumor 1-α-hydroxylase activity did not explain the 25(OH)D associations.25(OH)D insufficiency was associated with inferior EFS and OS in DLBCL and T-cell lymphoma. Whether normalizing vitamin D levels in these patients improves outcomes will require testing in future trials.
Cyclophosphamide Metabolism in Children with Non-Hodgkin’s Lymphoma
Authors: S. Murray Yule, Lisa Price, Alex D. McMahon, Andrew D. J. Pearson, Alan V. Boddy
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The purpose of our study was to determine whether variation in cyclophosphamide metabolism influences the incidence of recurrence among children receiving chemotherapy for B-cell non-Hodgkin’s lymphoma. Experimental Design: The pharmacokinetics and metabolism of cyclophosphamide were studied during a single course of treatment in 36 children receiving a uniform chemotherapy regimen for B-cell non-Hodgkin’s lymphoma and were analyzed in terms of disease recurrence and hematological toxicity. Results: At a median follow-up of 43 months (range, 17–98 months), six children had developed recurrent disease, giving an overall disease-free survival of 83%. The median clearance of cyclophosphamide in patients who remain free of B-cell non-Hodgkin’s lymphoma was 3.7 liter/h/m2 (range, 2.3–5.0 liter/h/m2), compared with 2.2 (range, 1.5–2.5 liter/h/m2) in those with disease recurrence. Likelihood of recurrence was higher in patients with low clearance (&amp;lt;3.5 liter/h/m2) of cyclophosphamide (P &amp;lt; 0.01) and positively related to detection of the inactive metabolites carboxyphosphamide and dechloroethylcyclophosphamide in plasma (P = 0.01). There was no correlation between cyclophosphamide metabolism and hematological toxicity. Conclusions: Inadequate clearance of cyclophosphamide to active metabolites is associated with increased risk of recurrence of B-cell non-Hodgkin’s lymphoma in children. Modified chemotherapy strategies should be considered in patients who exhibit low rates of clearance of the parent drug and/or extensive production of inactive metabolites.
Peptide-siRNA nanocomplexes targeting NF-κB subunit p65 suppress nascent experimental arthritis
Authors: Hui-fang Zhou, Huimin Yan, Hua Pan, Kirk K. Hou, Antonina Akk, Luke E. Springer, Ying Hu, J. Stacy Allen, Samuel A. Wickline, Christine T.N. Pham
Journal: Journal of Clinical Investigation (2014)

The NF-κB signaling pathway is implicated in various inflammatory diseases, including rheumatoid arthritis (RA); therefore, inhibition of this pathway has the potential to ameliorate an array of inflammatory diseases. Given that NF-κB signaling is critical for many immune cell functions, systemic blockade of this pathway may lead to detrimental side effects. siRNAs coupled with a safe and effective delivery nanoplatform may afford the specificity lacking in systemic administration of small-molecule inhibitors. Here we demonstrated that a melittin-derived cationic amphipathic peptide combined with siRNA targeting the p65 subunit of NF-κB (p5RHH-p65) noncovalently self-assemble into stable nanocomplexes that home to the inflamed joints in a murine model of RA. Specifically, administration of p5RHH-p65 siRNA nanocomplexes abrogated inflammatory cytokine expression and cellular influx into the joints, protected against bone erosions, and preserved cartilage integrity. The p5RHH-p65 siRNA nanocomplexes potently suppressed early inflammatory arthritis without affecting p65 expression in off-target organs or eliciting a humoral response after serial injections. These data suggest that this self-assembling, largely nontoxic platform may have broad utility for the specific delivery of siRNA to target and limit inflammatory processes for the treatment of a variety of diseases.
Blockage of transdifferentiation from fibroblast to myofibroblast in experimental ovarian cancer models
Authors: Qin Yao, Xun Qu, Qifeng Yang, David A Good, Shuzhen Dai, Beihua Kong, Ming Q Wei
Journal: Molecular Cancer (2009)

Abstract Background Tumour stromal myofibroblasts can promote tumour invasion. As these cells are genetically more stable than cancer cells, there has been enormous interest in developing targeted molecular therapies against them. Chloride intracellular channel 4 (CLIC4) and reactive oxygen species (ROS) have been linked with promoting stromal cell transdifferentiation in various cancers, but little is known of their roles in ovarian cancer. In this study, we examined the functional roles that both CLIC4 and ROS play in the process of ovarian cancer cell-stimulated or TGF-β1 induced fibroblast-to-myofibroblast transdifferentiation. We also examine whether it is possible to reverse such a process, with the aim of developing novel therapies against ovarian cancer by targeting activated transdifferentiated myofibroblasts. Results We demonstrate that TGF-β1 induced or CM SKOV3 activate transdifferentiated myofibroblasts (fibroblasts). These fibroblasts mimic "reactive" stromal myofibroblasts and demonstrate significant up-regulation of CLIC4 expression and increased level of ROS production. Blocking the production of ROS with an antioxidant consequently reduces the expression of CLIC4, and is accompanied by disappearance of α -smooth-muscle actin (α-SMA), a myofibroblast marker, suggesting ROS acts as a signalling molecule that promotes and enhances CLIC4 activities in the myofibroblast transdifferentiaton process. Down-regulation of CLIC4 with a generic agent or specific siRNA both significantly reduces the expression of factors related to the phenotypes and functions of myofibroblasts, such as α-SMA, hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF), thus reversing the myofibroblast phenotype back to fibroblasts. These results convincingly show that ROS and CLIC4 are responsible for TGF-β1 induced fibroblast-to-myofibroblast transdifferentiaton and down-regulation of both is sufficient to block transdifferentiated myofibroblasts. Conclusion Molecular targeting of ROS and CLIC4 has the potential to develop novel therapies for ovarian cancer.
Granulocyte-macrophage colony-stimulating factor (GM-CSF)–secreting cellular immunotherapy in combination with autologous stem cell transplantation (ASCT) as postremission therapy for acute myeloid leukemia (AML)
Authors: Ivan M. Borrello, Hyam I. Levitsky, Wendy Stock, Dorie Sher, Lu Qin, Daniel J. DeAngelo, Edwin P. Alyea, Richard M. Stone, Lloyd E. Damon, Charles A. Linker, Daniel J. Maslyar, Kristen M. Hege
Journal: Blood (2009)
Resistance of Cultured Lewis Lung Carcinoma Cell Lines to Tiazofurin&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: G J Finlay, L M Ching, W R Wilson, B C Baguley
Journal: JNCI Journal of the National Cancer Institute (1987)

An established in vitro cell line (LLTC), originally derived from the Lewis lung carcinoma (LL), was found to have lost sensitivity to the C-nucleoside antitumor agent tiazofurin (NSC-286193; 2-beta-D-ribofuranosylthiazole-4-carboxamide) both in vitro and in vivo. A new in vitro cell line (LLAK) was derived from LL and compared to LLTC in its growth properties and sensitivity to tiazofurin. LLAK resembled the in vivo tumor in having both a high S-phase fraction and a high rate of cell death at high cell density. In continuous drug exposure growth inhibition assays, the concentration of tiazofurin required to reduce the number of cells in a culture by 50% with respect to control cultures was 0.51 microM for LLAK, 2.6 microM for LLTC, and greater than 10 microM for a range of human cancer cell lines. In cytotoxicity assays involving a 2-hour drug exposure followed by clonogenic assay, tiazofurin was more toxic to LLAK cells than to LLTC cells or L1210 murine leukemia cells, consistent with its high in vivo activity against LL. MM-96 human melanoma cells were highly resistant. Flow cytometry studies indicated that tiazofurin selectively depleted the LLAK cell population of S- and G2-phase cells. In one experiment involving 16 consecutive in vitro passages of LLAK in the absence of tiazofurin, a new line emerged that was resistant to tiazofurin in the clonogenic assay. The results demonstrate the spontaneous emergence of resistance from a tiazofurin-sensitive cell line. If similar processes occur during adaptation of human tumor cells to culture, this may explain the finding of low activity of tiazofurin toward a range of human tumor cell lines.
Basic human rights of older people are abused in home care
Authors: A. O'Dowd
Journal: BMJ (2011)

The needs of older people receiving home care in England are often unmet and there are too many examples of physical and financial abuse, claims a report.

A highly critical report from a year long inquiry into the home care system in England has found evidence of “serious, systemic threats to the basic human rights of older people” who receive home care services.

The final report of the Equality and Human Rights Commission’s inquiry says the poor treatment of many older people breaches their human rights and too many find it difficult to voice concerns about their care.

Poor standards of care and little support have also led to some …