tbuckley/cabot-search huggingface dataset:
Localized Oncolytic Virotherapy Overcomes Systemic Tumor Resistance to Immune Checkpoint Blockade Immunotherapy
Authors: Dmitriy Zamarin, Rikke B. Holmgaard, Sumit K. Subudhi, Joon Seok Park, Mena Mansour, Peter Palese, Taha Merghoub, Jedd D. Wolchok, James P. Allison
Journal: Science Translational Medicine (2014)

Preexisting lymphocytic infiltration of tumors is associated with superior prognostic outcomes in a variety of cancers. Recent studies also suggest that lymphocytic responses may identify patients more likely to benefit from therapies targeting immune checkpoints, suggesting that therapeutic efficacy of immune checkpoint blockade can be enhanced through strategies that induce tumor inflammation. To achieve this effect, we explored the immunotherapeutic potential of oncolytic Newcastle disease virus (NDV). We find that localized intratumoral therapy of B16 melanoma with NDV induces inflammatory responses, leading to lymphocytic infiltrates and antitumor effect in distant (nonvirally injected) tumors without distant virus spread. The inflammatory effect coincided with distant tumor infiltration with tumor-specific CD4(+) and CD8(+) T cells, which was dependent on the identity of the virus-injected tumor. Combination therapy with localized NDV and systemic CTLA-4 blockade led to rejection of preestablished distant tumors and protection from tumor rechallenge in poorly immunogenic tumor models, irrespective of tumor cell line sensitivity to NDV-mediated lysis. Therapeutic effect was associated with marked distant tumor infiltration with activated CD8(+) and CD4(+) effector but not regulatory T cells, and was dependent on CD8(+) cells, natural killer cells, and type I interferon. Our findings demonstrate that localized therapy with oncolytic NDV induces inflammatory immune infiltrates in distant tumors, making them susceptible to systemic therapy with immunomodulatory antibodies, which provides a strong rationale for investigation of such combination therapies in the clinic.
Suppressive effect of aspirin on aberrant crypt foci in patients with colorectal cancer
Authors: B Shpitz
Journal: Gut (2003)

<b>Background and aims:</b> Aspirin and other non-steroidal anti-inflammatory drugs have been shown to reduce the risk of colorectal cancer (CRC). Animal models have shown that aspirin is also effective in reducing the density of aberrant crypt foci (ACF). The aim of the study was to evaluate the effect of chronic administration of aspirin on the distribution pattern and histological characteristics of ACF in patients with CRC. <b>Methods:</b> Our study compared the distribution patterns and histomorphological characteristics of ACF between a group of CRC patients treated with low dose aspirin (n=59) and a control group without aspirin (n=135). ACF were visualised on methylene blue stained macroscopically normal mucosa, microdissected, and serially cut. <b>Results:</b> ACF were found in 75.8% of mucosal samples from the control group and in 36% of mucosal samples from the aspirin treated group, indicating a 47% decline in prevalence of ACF in colonic samples of patients treated with aspirin. A significant reduction from 92.5% to 40% (p&lt;0.0001) was found in distal large bowel samples containing one or more ACF. Similarly, the aspirin treated group showed a reduction in ACF density of 64% and 82%, respectively, in both proximal and distal parts of the colon, indicating a significant reduction in ACF/cm<sup>2</sup> in distal colon samples (p&lt;0.01). The aspirin treated group displayed a 52% reduction in dysplastic ACF although this difference was not statistically significant. <b>Conclusions:</b> Our study has provided evidence of the effective chemopreventive action of low dose aspirin on ACF in humans.
Monoclonal T-cell expansions in asymptomatic individuals and in patients with large granular leukemia consist of cytotoxic effector T cells expressing the activating CD94:NKG2C/E and NKD2D killer cell receptors
Authors: Valérie Bigouret, Till Hoffmann, Lionel Arlettaz, Jean Villard, Marco Colonna, André Ticheli, Alois Gratwohl, Kaveh Samii, Bernard Chapuis, Nathalie Rufer, Eddy Roosnek
Journal: Blood (2003)
Chromosomal imbalances and partial uniparental disomies in primary central nervous system lymphoma
Authors: H Schwindt, I Vater, M Kreuz, M Montesinos-Rongen, A Brunn, J Richter, S Gesk, O Ammerpohl, O D Wiestler, D Hasenclever, M Deckert, R Siebert
Journal: Leukemia (2009)
Heparin-Binding Epidermal Growth Factor–Like Growth Factor Signaling in Flow-Induced Arterial Remodeling
Authors: Hua Zhang, Susan W. Sunnarborg, K. Kirk McNaughton, Terrance G. Johns, David C. Lee, James E. Faber
Journal: Circulation Research (2008)

Heparin-binding epidermal growth factor (EGF)-like growth factor (HB-EGF) is activated by reduced endothelial shear stress and stimulates smooth muscle cell proliferation in vitro. Moreover, HB-EGF is augmented at sites of intimal hyperplasia and atherosclerosis, conditions favored by low/disturbed shear stress. We thus tested whether HB-EGF contributes to low flow-induced negative hypertrophic remodeling (FINR) of a mouse carotid artery. Blood flow was surgically decreased in the left and increased in the right common carotid arteries. After 21 days, the left carotid artery exhibited lumen narrowing, thickening of intima–media and adventitia, and increased circumference that were inhibited by ≈50% in HB-EGF +/− and ≈90% in HB-EGF −/− mice. FINR was also inhibited by the EGF receptor inhibitor AG1478. In contrast, eutrophic outward remodeling of the right carotid artery was unaffected in HB-EGF +/− and HB-EGF −/− mice, nor by AG1478. FINR-induced proliferation and leukocyte accumulation were reduced in HB-EGF −/− . FINR was associated with increased reactive oxygen species, increased expression of pro-HB-EGF and tumor necrosis factor α–converting enzyme (pro-HB-EGF sheddase), increased phosphorylation of EGF receptor and extracellular signal-regulated kinase 1/2, and increased nuclear factor κB activity. Apocynin and deletion of p47 phox inhibited FINR, whereas deletion of HB-EGF abolished nuclear factor κB activation in smooth muscle cells. These findings suggest that HB-EGF signaling is required for low flow-induced hypertrophic remodeling and may participate in vascular wall disease and remodeling.
A mixed treatment of categoricity and regularity: Solutions that don't do justice to a well-exposed complexity
Authors: René Joseph Lavie
Journal: Behavioral and Brain Sciences (2003)

Jackendoff's position with respect to categories (for lexical items and larger constituents) is unclear. Positing categories is (1) implausible in several respects; (2) it makes the binding problem in language seem more massive than it actually is; and (3) it makes it difficult to explain language acquisition. Waiting for connectionism to fulfill its promise, a different track is sketched which is residually symbolic, exemplarist, and analogy-based.
Anaplastic large cell lymphoma Hodgkin's-like: a randomized trial of ABVD versus MACOP-B with and without radiation therapy.
Authors: Pl Zinzani, M Martelli, M Magagnoli, A Zaccaria, F Ronconi, M Cantonetti, Monica Bocchia, R Marra, M Gobbi, B Falini, F Gherlinzoni, L Moretti, A De Renzo, P Mazza, E Pavone, E Sabattini, A Amendola, M Bendandi, Sa Pileri, F Mandelli, S. Tura
Journal: Blood (1998)
Panic Attacks and Perception of Inspiratory Resistive Loads in Chronic Obstructive Pulmonary Disease
Authors: Nicole Livermore, Jane E Butler, Louise Sharpe, Rachel A McBain, Simon C Gandevia, David K McKenzie
Journal: American Journal of Respiratory and Critical Care Medicine (2008)

Panic attacks are common in chronic obstructive pulmonary disease (COPD), and the prevalence of panic disorder is at least 10 times higher than in the general population. In the current study, we examined resistive load perception in patients with COPD with and without panic attacks.We tested competing hypotheses, based on conflicting results of earlier studies, that those patients with COPD with panic attacks or panic disorder would show either heightened or blunted perception of dyspnea as the magnitude of inspiratory resistive loads increased.We compared 20 patients with COPD with panic attacks or panic disorder, 20 patients without panic, and 20 healthy, age-matched subjects using an inspiratory resistive load-testing protocol.We administered a diagnostic interview for panic attacks and panic disorder. We measured perceived dyspnea in response to increasing inspiratory resistive loads (modified Borg scale) and several respiratory variables. Dyspnea ratings increased linearly for all groups as the size of resistive loads increased. No significant differences were found between groups on the respiratory variables. Patients with COPD with panic attacks or panic disorder rated their level of dyspnea significantly higher than did other subjects.Patients with COPD with panic attacks showed heightened sensitivity to inspiratory loads. The result reinforces the influence of psychological factors on symptom perception in this disease.
Downregulation of HtrA1 Promotes Resistance to Anoikis and Peritoneal Dissemination of Ovarian Cancer Cells
Authors: Xiaoping He, Takayo Ota, Peng Liu, Changqing Su, Jeremy Chien, Viji Shridhar
Journal: Cancer Research (2010)

Abstract We previously identified serine protease HtrA1 as a downregulated gene in epithelial ovarian cancer (EOC), but the functional consequence of loss of HtrA1 in EOC remains largely unclear. Here, we report that loss of HtrA1 attenuates anoikis—a critical physiologic barrier for tumor metastasis. In response to loss of anchorage, HtrA1 expression was upregulated in SKOV3 cells, resulting in autocatalytic activation of HtrA1. Stable knockdown of HtrA1 in SKOV3 and TOV21G cells resulted in resistance to anoikis due to enhanced activation of epidermal growth factor receptor (EGFR)/AKT pathway. In suspended SKOV3 cells, enhanced expression of HtrA1 inhibited EGFR/AKT pathway, leading to increased cell death, whereas protease-inactive mutant HtrA1 failed to result in either the inhibition of EGFR/AKT pathway or increased cell death, suggesting the requirement of HtrA1 protease activity in regulating anoikis. Immunoprecipitation and immunofluorescence assays revealed that HtrA1 interacted with EGFR not only on the cell membrane but also in the nucleus. Most importantly, downregulation of HtrA1 significantly enhanced the peritoneal dissemination of SKOV3ip1 cells in nonobese diabetic/severe combined immunodeficient mice, with increased phospho-EGFR level in corresponding tumor nodules compared with that in xenografts originated from the control cells. Taken together, these data reveal for the first time a novel function of HtrA1 in promoting anoikis by attenuating activation of EGFR/AKT pathway that may contribute to its metastasis suppression capacity, thus providing a possible explanation for the aggressive nature of human ovarian tumors with downregulated HtrA1. Cancer Res; 70(8); 3109–18. ©2010 AACR.
Earliest Holozoan Expansion of Phosphotyrosine Signaling
Authors: Hiroshi Suga, Guifré Torruella, Gertraud Burger, Matthew W. Brown, Iñaki Ruiz-Trillo
Journal: Molecular Biology and Evolution (2013)

Phosphotyrosine (pTyr) signaling is involved in development and maintenance of metazoans' multicellular body through cell-to-cell communication. Tyrosine kinases (TKs), tyrosine phosphatases, and other proteins relaying the signal compose the cascade. Domain architectures of the pTyr signaling proteins are diverse in metazoans, reflecting their complex intercellular communication. Previous studies had shown that the metazoan-type TKs, as well as other pTyr signaling proteins, were already diversified in the common ancestor of metazoans, choanoflagellates, and filastereans (which are together included in the clade Holozoa) whereas they are absent in fungi and other nonholozoan lineages. However, the earliest-branching holozoans Ichthyosporea and Corallochytrea, as well as the two fungi-related amoebae Fonticula and Nuclearia, have not been studied. Here, we analyze the complete genome sequences of two ichthyosporeans and Fonticula, and RNAseq data of three additional ichthyosporeans, one corallochytrean, and Nuclearia. Both the ichthyosporean and corallochytrean genomes encode a large variety of receptor TKs (RTKs) and cytoplasmic TKs (CTKs), as well as other pTyr signaling components showing highly complex domain architectures. However, Nuclearia and Fonticula have no TK, and show much less diversity in other pTyr signaling components. The CTK repertoires of both Ichthyosporea and Corallochytrea are similar to those of Metazoa, Choanoflagellida, and Filasterea, but the RTK sets are totally different from each other. The complex pTyr signaling equipped with positive/negative feedback mechanism likely emerged already at an early stage of holozoan evolution, yet keeping a high evolutionary plasticity in extracellular signal reception until the co-option of the system for cell-to-cell communication in metazoans.
Sustained Hyperglycemia Among Patients With Diabetes: What matters when action is needed?
Authors: Jennifer E. Lafata, Elizabeth A. Dobie, George W. Divine, Marianne E. Ulcickas Yood, Bruce D. McCarthy
Journal: Diabetes Care (2009)

OBJECTIVE To estimate prevalence of, and factors associated with, sustained periods of hyperglycemia among patients with diabetes and factors associated with receipt of appropriate care once A1C values are persistently elevated. RESEARCH DESIGN AND METHODS Among patients initiating oral monotherapy (n = 5,070), Kaplan-Meier and Cox proportional hazards methods were used to estimate time to, and factors associated with, sustained hyperglycemia (defined by two A1cs >8% and no recent medication intensification), and among those experiencing sustained hyperglycemia, time to, and factors associated with, appropriate receipt of care (i.e., medication intensification or achieving A1C < or =7%). RESULTS Within 1 year, 8% experienced sustained hyperglycemia, with the proportion rising to 38% within 5 years. Patients using sulfonylurea had greater risk of hyperglycemia (hazard ratio [HR] 1.47 [95% CI 1.30-1.66]) compared with those initiating metformin. Risk increased with age (1.89 [1.27-2.83]), was greater for African Americans (1.19 [1.05-1.36]), and increased with A1C levels >7%. Among individuals with sustained hyperglycemia (n = 1,386), mean time to appropriate care was 9.7 months, with 25% not receiving appropriate care within 1 year. Shorter delays to appropriate care receipt were associated with increasing income (1.03 [1.00-1.07]), A1C >9% (1.38 [1.06-1.79]) and >11% (1.65 [1.25-2.18]), increasing medication adherence (1.03 [1.01-1.04]), and visits to primary care (4.22 [3.65-4.88]) or endocrinology (3.89 [2.26-6.70]). Longer delays were associated with increasing drug copayments (0.96 [0.93-0.98]). CONCLUSIONS Patients incurring sustained hyperglycemia are at risk of further delays in appropriate management. Barriers to appropriate care include prescription drug copayments, few physician contacts, and other factors that are likely amenable to intervention.
Sepsis depresses the metabolic oxygen reserve of the coronary circulation in mature sheep.
Authors: F M Bloos, H M Morisaki, A M Neal, C M Martin, C G Ellis, W J Sibbald, M L Pitt
Journal: American Journal of Respiratory and Critical Care Medicine (1996)

This study was undertaken to describe the metabolic O2 reserve of the coronary circulation in an awake sheep model of hyperdynamic sepsis. Forty-eight hours after sheep were randomized to either a SHAM group (n = 8) or a cecal ligation and perforation (CLP) group (n = 8), we measured hemodynamics, organ blood flows, and systemic and myocardial O2 metabolism variables at baseline and through four stages of progressive hypoxia. A significant elevation in arterial lactate levels occurred at a higher O2 delivery in the CLP group (527 +/- 55 ml/min/m2) than in the SHAM group (357 +/- 29 ml/min/m2, p < 0.05). The heart's metabolic O2 reserve (difference in circulatory determinants of O2 availability between baseline and where O2 uptake could not be sustained) was exhausted at an O2 content of 56.9 +/- 4.2 ml O2/L in SHAM sheep and 79.6 +/- 7.2 ml O2/L (p < 0.05) in CLP sheep. An increase in coronary blood flow was three times greater in SHAM than in CLP animals. Myocardial O2 extraction increased in hypoxia in SHAM sheep (0.78 +/- 0.03 to 0.88 +/- 0.02, p < 0.05), but not in CLP sheep (0.79 +/- 0.02 to 0.80 +/- 0.04). We conclude that the metabolic O2 reserve of the coronary circulation is depressed in this model of hyperdynamic sepsis as the ability to increase both coronary blood flows and myocardial O2 extraction was significantly limited.
Clarifying the Spectrum of Driver Oncogene Mutations in Biomarker-Verified Squamous Carcinoma of Lung: Lack of <i>EGFR</i>/<i>KRA</i>S and Presence of <i>PIK3CA</i>/<i>AKT1</i> Mutations
Authors: Natasha Rekhtman, Paul K. Paik, Maria E. Arcila, Laura J. Tafe, Geoffrey R. Oxnard, Andre L. Moreira, William D. Travis, Maureen F. Zakowski, Mark G. Kris, Marc Ladanyi
Journal: Clinical Cancer Research (2012)

Abstract Purpose: There is persistent controversy as to whether EGFR and KRAS mutations occur in pulmonary squamous cell carcinoma (SQCC). We hypothesized that the reported variability may reflect difficulties in the pathologic distinction of true SQCC from adenosquamous carcinoma (AD-SQC) and poorly differentiated adenocarcinoma due to incomplete sampling or morphologic overlap. The recent development of a robust immunohistochemical approach for distinguishing squamous versus glandular differentiation provides an opportunity to reassess EGFR/KRAS and other targetable kinase mutation frequencies in a pathologically homogeneous series of SQCC. Experimental Design: Ninety-five resected SQCCs, verified by immunohistochemistry as ΔNp63+/TTF-1−, were tested for activating mutations in EGFR, KRAS, BRAF, PIK3CA, NRAS, AKT1, ERBB2/HER2, and MAP2K1/MEK1. In addition, all tissue samples from rare patients with the diagnosis of EGFR/KRAS-mutant “SQCC” encountered during 5 years of routine clinical genotyping were reassessed pathologically. Results: The screen of 95 biomarker-verified SQCCs revealed no EGFR/KRAS [0%; 95% confidence interval (CI), 0%–3.8%], four PIK3CA (4%; 95% CI, 1%–10%), and one AKT1 (1%; 95% CI, 0%–5.7%) mutations. Detailed morphologic and immunohistochemical reevaluation of EGFR/KRAS-mutant “SQCC” identified during clinical genotyping (n = 16) resulted in reclassification of 10 (63%) cases as AD-SQC and five (31%) cases as poorly differentiated adenocarcinoma morphologically mimicking SQCC (i.e., adenocarcinoma with “squamoid” morphology). One (6%) case had no follow-up. Conclusions: Our findings suggest that EGFR/KRAS mutations do not occur in pure pulmonary SQCC, and occasional detection of these mutations in samples diagnosed as “SQCC” is due to challenges with the diagnosis of AD-SQC and adenocarcinoma, which can be largely resolved by comprehensive pathologic assessment incorporating immunohistochemical biomarkers. Clin Cancer Res; 18(4); 1167–76. ©2012 AACR.
Estrogen Receptor-β Affects the Prognosis of Human Malignant Mesothelioma
Authors: Giulia Pinton, Elisa Brunelli, Bruno Murer, Riccardo Puntoni, Matteo Puntoni, Dean A. Fennell, Giovanni Gaudino, Luciano Mutti, Laura Moro
Journal: Cancer Research (2009)

Malignant pleural mesothelioma is an asbestos-related neoplasm with poor prognosis, refractory to current therapies, the incidence of which is expected to increase in the next decades. Female gender was identified as a positive prognostic factor among other clinical and biological prognostic markers for malignant mesothelioma, yet a role of estrogen receptors (ERs) has not been studied. Our goal was to investigate ERs expression in malignant mesothelioma and to assess whether their expression correlates with prognosis. Immunohistochemical analysis revealed intense nuclear ERbeta staining in normal pleura that was reduced in tumor tissues. Conversely, neither tumors nor normal pleura stained positive for ERalpha. Multivariate analysis of 78 malignant mesothelioma patients with pathologic stage, histologic type, therapy, sex, and age at diagnosis indicated that ERbeta expression is an independent prognostic factor of better survival. Moreover, studies in vitro confirmed that treatment with 17beta-estradiol led to an ERbeta-mediated inhibition of malignant mesothelioma cell proliferation as well as p21(CIP1) and p27(KIP1) up-regulation. Consistently cell growth was suppressed by ERbeta overexpression, causing a G(2)-M-phase cell cycle arrest, paralleled by cyclin B1 and survivin down-regulation. Our data support the notion that ERbeta acting as a tumor suppressor is of high potential relevance to prediction of disease progression and to therapeutic response of malignant mesothelioma patients.
Lessons Learned from Radiation Oncology Clinical Trials
Authors: Fei-Fei Liu, Paul Okunieff, Eric J. Bernhard, Helen B. Stone, Stephen Yoo, C. Norman Coleman, Bhadrasain Vikram, Martin Brown, John Buatti, Chandan Guha
Journal: Clinical Cancer Research (2013)

Abstract A workshop entitled “Lessons Learned from Radiation Oncology Trials” was held on December 7–8, 2011, in Bethesda, MD, to present and discuss some of the recently conducted radiation oncology clinical trials with a focus on those that failed to refute the null hypothesis. The objectives of this workshop were to summarize and examine the questions that these trials provoked, to assess the quality and limitations of the preclinical data that supported the hypotheses underlying these trials, and to consider possible solutions to these challenges for the design of future clinical trials. Several themes emerged from the discussions: (i) opportunities to learn from null-hypothesis trials through tissue and imaging studies; (ii) value of preclinical data supporting the design of combinatorial therapies; (iii) significance of validated biomarkers; (iv) necessity of quality assurance in radiotherapy delivery; (v) conduct of sufficiently powered studies to address the central hypotheses; and (vi) importance of publishing results of the trials regardless of the outcome. The fact that well-designed hypothesis-driven clinical trials produce null or negative results is expected given the limitations of trial design and complexities of cancer biology. It is important to understand the reasons underlying such null results, however, to effectively merge the technologic innovations with the rapidly evolving biology for maximal patient benefit through the design of future clinical trials. Clin Cancer Res; 19(22); 6089–100. ©2013 AACR.