tbuckley/cabot-search huggingface dataset:
Imaging, Biodistribution, and Dosimetry of Radionuclide-Labeled PD-L1 Antibody in an Immunocompetent Mouse Model of Breast Cancer
Authors: Anders Josefsson, Jessie R. Nedrow, Sunju Park, Sangeeta Ray Banerjee, Andrew Rittenbach, Fabien Jammes, Benjamin Tsui, George Sgouros
Journal: Cancer Research (2015)

The programmed cell death ligand 1 (PD-L1) participates in an immune checkpoint system involved in preventing autoimmunity. PD-L1 is expressed on tumor cells, tumor-associated macrophages, and other cells in the tumor microenvironment. Anti-PD-L1 antibodies are active against a variety of cancers, and combined anti-PD-L1 therapy with external beam radiotherapy has been shown to increase therapeutic efficacy. PD-L1 expression status is an important indicator of prognosis and therapy responsiveness, but methods to precisely capture the dynamics of PD-L1 expression in the tumor microenvironment are still limited. In this study, we developed a murine anti-PD-L1 antibody conjugated to the radionuclide Indium-111 ((111)In) for imaging and biodistribution studies in an immune-intact mouse model of breast cancer. The distribution of (111)In-DTPA-anti-PD-L1 in tumors as well as the spleen, liver, thymus, heart, and lungs peaked 72 hours after injection. Coinjection of labeled and 100-fold unlabeled antibody significantly reduced spleen uptake at 24 hours, indicating that an excess of unlabeled antibody effectively blocked PD-L1 sites in the spleen, thus shifting the concentration of (111)In-DTPA-anti-PD-L1 into the blood stream and potentially increasing tumor uptake. Clearance of (111)In-DTPA-anti-PD-L1 from all organs occurred at 144 hours. Moreover, dosimetry calculations revealed that radionuclide-labeled anti-PD-L1 antibody yielded tolerable projected marrow doses, further supporting its use for radiopharmaceutical therapy. Taken together, these studies demonstrate the feasibility of using anti-PD-L1 antibody for radionuclide imaging and radioimmunotherapy and highlight a new opportunity to optimize and monitor the efficacy of immune checkpoint inhibition therapy.
Tocilizumab in early progressive rheumatoid arthritis: FUNCTION, a randomised controlled trial
Authors: Gerd R Burmester, William F Rigby, Ronald F van Vollenhoven, Jonathan Kay, Andrea Rubbert-Roth, Ariella Kelman, Sophie Dimonaco, Nina Mitchell
Journal: Annals of the Rheumatic Diseases (2015)

The efficacy of tocilizumab (TCZ), an anti-interleukin-6 receptor antibody, has not previously been evaluated in a population consisting exclusively of patients with early rheumatoid arthritis (RA).In a double-blind randomised controlled trial (FUNCTION), 1162 methotrexate (MTX)-naive patients with early progressive RA were randomly assigned (1:1:1:1) to one of four treatment groups: 4 mg/kg TCZ+MTX, 8 mg/kg TCZ+MTX, 8 mg/kg TCZ+placebo and placebo+MTX (comparator group). The primary outcome was remission according to Disease Activity Score using 28 joints (DAS28-erythrocyte sedimentation rate (ESR) <2.6) at week 24. Radiographic and physical function outcomes were also evaluated. We report results through week 52.The intent-to-treat population included 1157 patients. Significantly more patients receiving 8 mg/kg TCZ+MTX and 8 mg/kg TCZ+placebo than receiving placebo+MTX achieved DAS28-ESR remission at week 24 (45% and 39% vs 15%; p<0.0001). The 8 mg/kg TCZ+MTX group also achieved significantly greater improvement in radiographic disease progression and physical function at week 52 than did patients treated with placebo+MTX (mean change from baseline in van der Heijde-modified total Sharp score, 0.08 vs 1.14 (p=0.0001); mean reduction in Health Assessment Disability Index, -0.81 vs -0.64 (p=0.0024)). In addition, the 8 mg/kg TCZ+placebo and 4 mg/kg TCZ+MTX groups demonstrated clinical efficacy that was at least as effective as MTX for these key secondary endpoints. Serious adverse events were similar among treatment groups. Adverse events resulting in premature withdrawal occurred in 20% of patients in the 8 mg/kg TCZ+MTX group.TCZ is effective in combination with MTX and as monotherapy for the treatment of patients with early RA.ClinicalTrials.gov, number NCT01007435.
Abstract 14406: Rho-kinase Mediates Myocardial Ischemia Reperfusion Injury by Regulating Leukocyte Responses in Mice
Authors: Soichiro Usui, Katsunori Kitano, Shuichi Kaneko, Masayuki Takamura
Journal: Circulation (2011)

Background: Rho-kinase has been implicated in pathogenesis of cardiovascular diseases. We examine the role of Rho-kinase in acute myocardial ischemia/reperfusion (I/R) injury and the protective eff...
Membrane and Capillary Components of Lung Diffusion in Infants with Bronchopulmonary Dysplasia
Authors: Daniel V. Chang, Santiago J. Assaf, Christina J. Tiller, Jeffrey A. Kisling, Robert S. Tepper
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Autopsied lungs of infants with bronchopulmonary dysplasia (BPD) demonstrate impaired alveolar development with larger and fewer alveoli, which is consistent with our previous physiologic findings of lower pulmonary diffusing capacity of the lung for carbon monoxide (DL(CO)) in infants and toddlers with BPD compared with healthy controls born at full term (FT). However, it is not known whether the decreased DL(CO) in infants with BPD results from a reduction in both components of DL(CO): pulmonary membrane diffusing capacity (D(M)) and Vc.We hypothesized that impairment of alveolar development in BPD results in a decrease in both D(M) and Vc components of DlCO but that the D(M)/Vc ratio would not differ between the BPD and FT groups.DL(CO) was measured under conditions of room air and high inspired oxygen (90%), which enabled D(M) and Vc to be calculated.D(M) and Vc increased with increasing body length; however, infants with BPD had significantly lower D(M) and Vc than FT subjects after adjustment for race, sex, body length, and corrected age. In contrast to D(M) and Vc, the D(M)/Vc ratio remained constant with increasing body length and did not differ for infants with BPD and FT subjects.Our findings are consistent with infants with BPD having impaired alveolar development with fewer but larger alveoli, as well as a reduced Vc.
Lymph node aspiration in the management of Hodgkin's disease.
Authors: E Dmitrovsky, S E Martin, A G Krudy, E W Chu, E S Jaffe, D L Longo, R C Young
Journal: Journal of Clinical Oncology (1986)

Diagnosing recurrent Hodgkin's disease is an important oncologic problem. When relapse does not occur in peripheral nodal sites, then a major surgical exploration is often considered. Lymph node aspiration is proposed as a less invasive approach capable of establishing a diagnosis in some instances. In this retrospective study, 19 patients with Hodgkin's disease underwent 64 lymph node aspirations. Of these patients, 17 had suspected Hodgkin's disease with involvement at an inaccessible site. Two patients with a primary diagnosis of Hodgkin's disease underwent aspiration of a peripheral site. Of these 19 patients, five (26.3%) had a positive aspirate and only two (10.5%) had an unsatisfactory aspirate. No patient had a false-positive aspirate. Of 15 patients with a negative aspirate, five (33%) had a false-negative aspirate. In no case did a false-negative aspirate delay appropriate therapy. In those patients with a positive aspirate, surgical exploration was avoided. We conclude that lymph node aspiration cytology is useful as an initial step to document clinical relapse of Hodgkin's disease at a site that might require a major surgical procedure for diagnosis.
Anemia of Prematurity
Authors: P R Dallman
Journal: Annual Review of Medicine (1981)

During the first two months after birth, the concentration of hemoglobin declines rapidly from the highest to the lowest values that occur at any period of development (1-6). The low point is termed the physiologic anemia of infancy. It is considered physiologic because it is characteristic of healthy infants, it occurs in the absence of any recognized nutritional deficiency, and there is no sustained response to blood transfusion. If the fall in hemoglobin concentration were an isolated phenomenon, it would significantly diminish the availability of oxygen to the tissues. However, while hemoglobin concentration is decreasing, there are other changes that lead to a progressive rightward shift of the oxygen equilibrium curve, permitting more oxygen to be released by hemoglobin at any given oxygen tension (7-9). While these modifications in oxygen delivery are taking place, there are concurrent changes in oxygen requirements. As the newborn adapts to an extrauterine environment, his oxygen needs progressively in­ crease (10-12), and he becomes less able to withstand oxygen lack (13). Therefore, if tissue oxygenation is to remain adequate, oxygen extraction and/or cardiac output must increase. In the otherwise healthy term infant, the adaptations in oxygen delivery during the first two months after birth are rarely associated with clinical evidence of hypoxia. However, in the premature infant, the fall in hemo­ globin concentration is more profound, and in some infants clinical evi­ dence suggests that O2 delivery is compromised and that a blood transfusion is required ( 1 416). Nevertheless, the rapidity of developmental changes that affect oxygen delivery and the complexity of their interactions has been an impediment to developing clear-cut criteria for transfusion. Conse­ quently, this is an area in which clinical practices vary widely. Regardless
<i>CARD14</i> alterations in Tunisian patients with psoriasis and further characterization in European cohorts
Authors: M. Ammar, C.T. Jordan, L. Cao, E. Lim, C. Bouchlaka Souissi, A. Jrad, I. Omrane, S. Kouidhi, I. Zaraa, H. Anbunathan, M. Mokni, N. Doss, E. Guttman-Yassky, A. B. El Gaaied, A. Menter, A.M. Bowcock
Journal: British Journal of Dermatology (2015)

Rare highly penetrant gain-of-function mutations in caspase recruitment domain family, member 14 (CARD14) can lead to psoriasis, a chronic inflammatory disease of the skin and other organs.To investigate the contribution of rare CARD14 variants to psoriasis in the Tunisian population and to expand knowledge of CARD14 variants in the European population.CARD14 coding exons were resequenced in patients with psoriasis and controls from Tunisia and Europe, including 16 European cases with generalized pustular psoriasis (GPP). Novel variants were evaluated for their effect on nuclear factor (NF)-κB signalling.Rare variants in CARD14 were significantly enriched in Tunisian cases compared with controls. Three were collectively found in 5% of Tunisian cases, and all affected the N-terminal region of the protein harbouring its caspase recruitment domain or coiled-coil domain. These variants were c.349G>A (p.Gly117Ser), c.205C>T (p.Arg69Trp) and c.589G>A (p.Glu197Lys). c.589G>A (p.Glu197Lys) led to upregulation of NF-κB activity in a similar manner to that of previously described psoriasis-associated mutations. p.Arg69Trp led to sevenfold downregulation of NF-κB activity. One Tunisian case harboured a c.1356+5G>A splice alteration that is predicted to lead to loss of exon 9, which encodes part of the coiled-coil domain. No cases of GPP harboured an interleukin-36RN mutation, but one of 16 cases of GPP with a family history of psoriasis vulgaris harboured a c.1805C>T (p.Ser602Leu) mutation in CARD14.These observations provide further insights into the genetic basis of psoriasis in the Tunisian population and provide functional information on novel CARD14 variants seen in cases from Tunisia and other populations.
Penetrance of monogenetic cardiac conduction diseases. A matter of conduction reserve?
Authors: H VANRIJEN, J DEBAKKER
Journal: Cardiovascular Research (2007)

See article by Tan et al.  [3]  (pages 409–417) in this issue. 

Loss-of-function mutations in the SCN5a gene coding for the human Nav1.5 cardiac sodium channel, which lead to decreased peak sodium current, are associated with cardiac conduction defects (CCD), progressive cardiac conduction disease [1] or Brugada syndrome [2]. However, despite the strong linkage of sodium channel mutations to the disease in probands, the same mutation is often found in non-affected family members. The study by Tan and coworkers in this issue describes a SCN5a mutation leading to a C-terminal truncation (L1821fs/10) that was found in a patient with sick sinus syndrome, CCD and ventricular tachycardia [3]. This particular mutation was shown to lead to an almost complete loss of channel function and thus to haploinsufficiency of the peak sodium current. Interestingly, the same mutation was found in 6 family members of which 2 had very mild symptoms and … 

*Corresponding author. Department of Medical Physiology, Division Heart and Lungs, University Medical Center Utrecht, The Netherlands. Tel.: +31 30 253 8900; fax: +31 30 253 9036. h.v.m.vanrijen{at}med.uu.nl
Consequences of Comorbidity of Elevated Stress and/or Depressive Symptoms and Incident Cardiovascular Outcomes in Diabetes: Results From the REasons for Geographic And Racial Differences in Stroke (REGARDS) Study
Authors: Doyle M. Cummings, Kari Kirian, George Howard, Virginia Howard, Ya Yuan, Paul Muntner, Brett Kissela, Nicole Redmond, Suzanne E. Judd, Monika M. Safford
Journal: Diabetes Care (2015)

To evaluate the impact of comorbid depressive symptoms and/or stress on adverse cardiovascular (CV) outcomes in individuals with diabetes compared with those without diabetes.
<i>CDKN2B</i> Regulates <i>TGF</i> β Signaling and Smooth Muscle Cell Investment of Hypoxic Neovessels
Authors: Vivek Nanda, Kelly P. Downing, Jianqin Ye, Sophia Xiao, Yoko Kojima, Joshua M. Spin, Daniel DiRenzo, Kevin T. Nead, Andrew J. Connolly, Sonny Dandona, Ljubica Perisic, Ulf Hedin, Lars Maegdefessel, Jessie Dalman, Liang Guo, XiaoQing Zhao, Frank D. Kolodgie, Renu Virmani, Harry R. Davis, Nicholas J. Leeper
Journal: Circulation Research (2015)

Genetic variation at the chromosome 9p21 cardiovascular risk locus has been associated with peripheral artery disease, but its mechanism remains unknown.To determine whether this association is secondary to an increase in atherosclerosis, or it is the result of a separate angiogenesis-related mechanism.Quantitative evaluation of human vascular samples revealed that carriers of the 9p21 risk allele possess a significantly higher burden of immature intraplaque microvessels than carriers of the ancestral allele, irrespective of lesion size or patient comorbidity. To determine whether aberrant angiogenesis also occurs under nonatherosclerotic conditions, we performed femoral artery ligation surgery in mice lacking the 9p21 candidate gene, Cdkn2b. These animals developed advanced hindlimb ischemia and digital autoamputation, secondary to a defect in the capacity of the Cdkn2b-deficient smooth muscle cell to support the developing neovessel. Microarray studies identified impaired transforming growth factor β (TGFβ) signaling in cultured cyclin-dependent kinase inhibitor 2B (CDKN2B)-deficient cells, as well as TGFβ1 upregulation in the vasculature of 9p21 risk allele carriers. Molecular signaling studies indicated that loss of CDKN2B impairs the expression of the inhibitory factor, SMAD-7, which promotes downstream TGFβ activation. Ultimately, this manifests in the upregulation of a poorly studied effector molecule, TGFβ1-induced-1, which is a TGFβ-rheostat known to have antagonistic effects on the endothelial cell and smooth muscle cell. Dual knockdown studies confirmed the reversibility of the proposed mechanism, in vitro.These results suggest that loss of CDKN2B may not only promote cardiovascular disease through the development of atherosclerosis but may also impair TGFβ signaling and hypoxic neovessel maturation.
Immunotargeting of Antigen xCT Attenuates Stem-like Cell Behavior and Metastatic Progression in Breast Cancer
Authors: Stefania Lanzardo, Laura Conti, Ronald Rooke, Roberto Ruiu, Nathalie Accart, Elisabetta Bolli, Maddalena Arigoni, Marco Macagno, Giuseppina Barrera, Stefania Pizzimenti, Luigi Aurisicchio, Raffaele Adolfo Calogero, Federica Cavallo
Journal: Cancer Research (2015)

Abstract Resistance to therapy and lack of curative treatments for metastatic breast cancer suggest that current therapies may be missing the subpopulation of chemoresistant and radioresistant cancer stem cells (CSC). The ultimate success of any treatment may well rest on CSC eradication, but specific anti-CSC therapies are still limited. A comparison of the transcriptional profiles of murine Her2+ breast tumor TUBO cells and their derived CSC-enriched tumorspheres has identified xCT, the functional subunit of the cystine/glutamate antiporter system xc−, as a surface protein that is upregulated specifically in tumorspheres. We validated this finding by cytofluorimetric analysis and immunofluorescence in TUBO-derived tumorspheres and in a panel of mouse and human triple negative breast cancer cell-derived tumorspheres. We further show that downregulation of xCT impaired tumorsphere generation and altered CSC intracellular redox balance in vitro, suggesting that xCT plays a functional role in CSC biology. DNA vaccination based immunotargeting of xCT in mice challenged with syngeneic tumorsphere-derived cells delayed established subcutaneous tumor growth and strongly impaired pulmonary metastasis formation by generating anti-xCT antibodies able to alter CSC self-renewal and redox balance. Finally, anti-xCT vaccination increased CSC chemosensitivity to doxorubicin in vivo, indicating that xCT immunotargeting may be an effective adjuvant to chemotherapy. Cancer Res; 76(1); 62–72. ©2015 AACR.
The First Use of the Global Oral Cholera Vaccine Emergency Stockpile: Lessons from South Sudan
Authors: Abdinasir Abubakar, Andrew S. Azman, John Rumunu, Iza Ciglenecki, Trina Helderman, Haley West, Justin Lessler, David A. Sack, Stephen Martin, William Perea, Dominique Legros, Francisco J. Luquero
Journal: PLoS Medicine (2015)

Points• A global oral cholera vaccine (OCV) stockpile was established in 2013 to improve rapid access to the vaccine in outbreaks and emergencies in which cholera risk is high.The first deployment from the global OCV stockpile was to South Sudan in 2014 because of high cholera risk from massive population displacements within the civil war.• 256,700 doses of OCV were delivered, with high coverage, throughout the country as part of a comprehensive cholera prevention strategy by multiple agencies, some of which had little to no previous experience with this vaccine.• A cholera epidemic began during vaccination, and a basic comparison of epidemic curves in vaccinated and unvaccinated areas suggests little to no transmission occurred in vaccinated areas, though more in depth analysis is needed.• This deployment highlights the feasibility of effective deployments from the OCV stockpile and the importance of strong coordination between governmental and nongovernmental agencies in cholera prevention and control planning from the assessment of cholera risk to the deployment of the vaccines.• A larger global supply of OCV is urgently needed to cover those most in need.With limited vaccine availability now and likely in the upcoming years, more work is needed on deciding how to most efficiently use the vaccine, which may include alternative dosing regimens and targeting specific subpopulations.
Phase I study of docetaxel dose escalation in combination with fixed weekly gemcitabine in patients with advanced malignancies.
Authors: C H Spiridonidis, L R Laufman, J Jones, V A Rhodes, K Wallace, S Nicol
Journal: Journal of Clinical Oncology (1998)

PURPOSE To determine the maximum-tolerated dose of monthly docetaxel combined with fixed-dose weekly gemcitabine and describe the dose-limiting toxicities (DLTs) of the combination. PATIENTS AND METHODS Patients with refractory solid tumors were treated with gemcitabine days 1, 8, and 15 every 4 weeks at a fixed dose of 800 mg/m2. Two docetaxel administration schedules were studied, with the drug administered either day 1 or day 15 at doses of 45, 60, 75, and 100 mg/m2 per cycle. RESULTS Forty patients received 132 cycles of chemotherapy. On the day-1 schedule, the maximum-tolerated docetaxel dose was the highest planned dose of 100 mg/m2 with two DLT episodes among 12 patients treated with 34 cycles at this dose level. On the day-15 schedule, delivery of the planned docetaxel doses was not feasible because of thrombocytopenia and hepatic dysfunction. Hematologic toxicities included grade 4 neutropenia in 16 patients, with three episodes of febrile neutropenia; grades 3 to 4 thrombocytopenia in nine patients; and anemia that required RBC transfusions in 10 patients. For patients treated at the highest docetaxel dose level, myelosuppression was not dose limiting and only one of 34 cycles was complicated by febrile neutropenia. The most common nonhematologic toxicities were asthenia, flu-like symptoms, and fluid retention. Antineoplastic activity was noteworthy, with partial responses in nine of 21 patients with pretreated non-small-cell lung cancer (NSCLC; 43%; 95% confidence interval, 22 to 66), in four of seven patients with breast cancer, and in one patient with esophageal adenocarcinoma. CONCLUSION Gemcitabine 800 mg/m2 days 1,8, and 15 can be safely combined with docetaxel 100 mg/m2 day 1 of a 28-day cycle. The observed antitumor activity warrants phase II evaluation.
Whole-exome sequencing identifies novel MPL and JAK2 mutations in triple-negative myeloproliferative neoplasms
Authors: Jelena D. Milosevic Feenstra, Harini Nivarthi, Heinz Gisslinger, Emilie Leroy, Elisa Rumi, Ilyas Chachoua, Klaudia Bagienski, Blanka Kubesova, Daniela Pietra, Bettina Gisslinger, Chiara Milanesi, Roland Jäger, Doris Chen, Tiina Berg, Martin Schalling, Michael Schuster, Christoph Bock, Stefan N. Constantinescu, Mario Cazzola, Robert Kralovics
Journal: Blood (2015)
Outcome Disparities in Pancreatic Cancer
Authors: Daniel A. Anaya, Mokenge Malafa
Journal: JAMA Surgery (2015)

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Visualising childhood vaccination schedules across G8 countries
Authors: P. Doshi, W. Stahl-Timmins, J. G. Merino, C. Simpkins
Journal: BMJ (2015)

Peter Doshi and colleagues compare the approaches to routine childhood vaccination 

The interactive infographic above presents childhood vaccination schedules across the G8 nations. By selecting and deselecting individual vaccines, readers can visually explore similarities and differences in official recommendations. Data are displayed in two graphs simultaneously. The top indicates the cumulative doses over time, while the bottom adds detail: which vaccines at what times.

The data present an overarching message of variations on a theme: substantial similarity but interesting differences. Some countries start vaccinating at birth, others after a month, and some wait longer.

We …