tbuckley/cabot-search huggingface dataset:
Empirical Evidence for the Effect of Airline Travel on Inter-Regional Influenza Spread in the United States
Authors: John S Brownstein, Cecily J Wolfe, Kenneth D Mandl
Journal: PLoS Medicine (2006)

Background The influence of air travel on influenza spread has been the subject of numerous investigations using simulation, but very little empirical evidence has been provided. Understanding the role of airline travel in large-scale influenza spread is especially important given the mounting threat of an influenza pandemic. Several recent simulation studies have concluded that air travel restrictions may not have a significant impact on the course of a pandemic. Here, we assess, with empirical data, the role of airline volume on the yearly inter-regional spread of influenza in the United States. Methods and Findings We measured rate of inter-regional spread and timing of influenza in the United States for nine seasons, from 1996 to 2005 using weekly influenza and pneumonia mortality from the Centers for Disease Control and Prevention. Seasonality was characterized by band-pass filtering. We found that domestic airline travel volume in November (mostly surrounding the Thanksgiving holiday) predicts the rate of influenza spread (r2 = 0.60; p = 0.014). We also found that international airline travel influences the timing of influenza mortality (r2 = 0.59; p = 0.016). The flight ban in the US after the terrorist attack on September 11, 2001, and the subsequent depression of the air travel market, provided a natural experiment for the evaluation of flight restrictions; the decrease in air travel was associated with a delayed and prolonged influenza season. Conclusions We provide the first empirical evidence for the role of airline travel in long-range dissemination of influenza. Our results suggest an important influence of international air travel on the timing of influenza introduction, as well as an influence of domestic air travel on the rate of inter-regional influenza spread in the US. Pandemic preparedness strategies should account for a possible benefit of airline travel restrictions on influenza spread.
GENETIC APPROACHES TO THE STUDY OF ANXIETY
Authors: Joshua A. Gordon, Rene Hen
Journal: Annual Review of Neuroscience (2004)

Anxiety and its disorders have long been known to be familial. Recently, genetic approaches have been used to clarify the role of heredity in the development of anxiety and to probe its neurobiological underpinnings. Twin studies have shown that a significant proportion of the liability to develop any given anxiety disorder is due to genetic factors. Ongoing efforts to map anxiety-related loci in both animals and humans are underway with limited success to date. Animal models have played a large role in furthering our understanding of the genetic basis of anxiety, demonstrating that the genetic factors underlying anxiety are complex and varied. Recent advances in molecular genetic techniques have allowed increasing specificity in the manipulation of gene expression within the central nervous system of the mouse. With this increasing specificity has come the ability to ask and answer precise questions about the mechanisms of anxiety and its treatment.
The Importance of Protein Kinase A in Prostate Cancer: Relationship to Patient Outcome in Radiation Therapy Oncology Group Trial 92-02
Authors: Alan Pollack, Kyounghwa Bae, Li-Yan Khor, Tahseen Al-Saleem, M. Elizabeth Hammond, Varagur Venkatesan, Roger W. Byhardt, Sucha O. Asbell, William U. Shipley, Howard M. Sandler
Journal: Clinical Cancer Research (2009)

Abstract Purpose: We previously reported that protein kinase A type I (PKARIα) overexpression was predictive of outcome in prostate cancer patients treated with radiotherapy (RT) ± short-term androgen deprivation (STAD) on Radiation Therapy Oncology Group (RTOG) protocol 86-10. Here, we attempt to verify our prior findings and test the hypothesis that the relationship of the length of AD to patient outcome is affected by PKARIα overexpression. Experimental Design: There were 313 cases in the RTOG 92-02 study cohort with available tissue and suitable staining by immunohistochemistry. Median follow-up was 10.1 years. The intensity of PKARIα staining intensity was quantified manually and by image analysis. Multivariate analyses were done for overall mortality using Cox proportional hazards models and for local failure, biochemical failure, distant metastasis, and cause-specific mortality using Fine and Gray's regression models. Results: The expression levels of PKARIα, determined by manual and image analysis, were strongly correlated (P &amp;lt; 0.0001). In the multivariate analyses, manual-quantified and image analysis–quantified PKARIα staining intensities were independent predictors of distant metastasis (P &amp;lt; 0.01), local failure (P &amp;lt; 0.05), and biochemical failure (P ≤ 0.01). Furthermore, the benefit of long-term AD over STAD was much less when PKARIα expression was high. Conclusions: PKARIα overexpression has been shown in two RTOG trials to be associated with an increased risk of failure after AD + RT. In this series of contemporary high-risk patients, PKARIα overexpression was associated with diminished response to LTAD + RT relative to STAD + RT, suggesting that such patients would be ideal for a PKARIα knockdown strategy. (Clin Cancer Res 2009;15(17):5478–84)
The Role of Cell-Mediated Immune Responses in Resistance to Malaria, with Special Reference to Oxidant Stress
Authors: Anthony C. Allison, Elsie M. Eugui
Journal: Annual Review of Immunology (1983)

Asexual blood forms of malaria parasites are microaerophilic and sensitive to oxidant stress. Plasmodium falciparum and some other species of malaria parasites undergo schizogony attached to endothelial cells of postcapillary venules, where oxygen tensions are low. Acquired immune responses to all forms of malaria parasites so far investigated are thymus dependent. Animals deprived of T lymphocytes do not recover from the infections and cannot be immunized against malaria parasites. In contrast, animals unable to make antibodies recover normally from some primary infections, e.g. with Plasmodium chabaudi, and when rescued by chemotherapy from other species of malaria parasite develop lasting, nonsterile immunity. Immunity to malaria can be transferred in mice by T lymphocytes of the Ly1+ phenotype, but transfer of B lymphocytes together with this T-cell subset increases the effectiveness of immunity to Plasmodium yoelii. Thus, antibodies facilitate recovery from some primary malaria infections and increase the effectiveness of cell-mediated immune responses in these infections. Mice of the A strain are highly susceptible to malaria and are unable to increase the number of mononuclear cells in the spleen during the course of the infections. It is postulated that T lymphocytes responding to parasite antigens release factors that stimulate the proliferation of effector cell precursors and their recruitment into the red pulp of the spleen. In this site, the liver and probably the peripheral circulation, effector cells bind to the surface of parasitized erythrocytes and are activated to release superoxide (O2-). The consequent exposure to oxidant stress can lead to degeneration of parasites in erythrocytes. This effect on the parasites can be prevented by agents chelating metals, which suggests that iron-catalyzed lipid peroxidation and consequent K+ loss, or inactivation of metal-containing enzymes, may be the mechanism by which oxidant stress kills the intracellular parasites. Antibodies on the surface of schizont-infected cells could facilitate binding of effector cells and trigger O2- release, thereby acting synergistically with cell-mediated immunity. Inherited traits, such as abnormal hemoglobins and G-6-PD deficiency, and acquired cell-mediated immunity both subject malaria parasites to oxidant stress and may reinforce one another, increasing the chances of survival of children bearing these traits during the dangerous years of first exposure to malaria in areas where the disease is endemic.
Aggression, Mythology, and the College Student
Authors: JAMES B. RAYBIN
Journal: American Journal of Psychiatry (1971)

Conflicts about aggression are among the most significant problems that students encounter. They must face these conflicts within the framework of crucial developmental tasks such as the achievement of identity, intimacy, and maturity. The incorporation of conflicts about aggression into a complicated and distorted belief system or family mythology is a common phenomenon. An appreciation of this mythology is an important step in understanding the student's individual and family psychodynamics.
Important Roles for E Protein Binding Sites within the Immunoglobulin κ Chain Intronic Enhancer in Activating <i>V<b>κ</b> J<b>κ</b> </i> Rearrangement
Authors: Matthew A. Inlay, Hua Tian, Tongxiang Lin, Yang Xu
Journal: The Journal of Experimental Medicine (2004)

The immunoglobulin κ light chain intronic enhancer (iEκ) activates κ rearrangement and is required to maintain the earlier or more efficient rearrangement of κ versus lambda (λ). To understand the mechanism of how iEκ regulates κ rearrangement, we employed homologous recombination to mutate individual functional motifs within iEκ in the endogenous κ locus, including the NF-κB binding site (κB), as well as κE1, κE2, and κE3 E boxes. Analysis of the impacts of these mutations revealed that κE2 and to a lesser extent κE1, but not κE3, were important for activating κ rearrangement. Surprisingly, mutation of the κB site had no apparent effect on κ rearrangement. Comparable to the deletion of the entire iEκ, simultaneous mutation of κE1 and κE2 reduces the efficiency of κ rearrangement much more dramatically than either κE1 or κE2 mutation alone. Because E2A family proteins are the only known factors that bind to these E boxes, these findings provide unambiguous evidence that E2A is a key regulator of κ rearrangement.
Diastolic Blood Pressure as a Biomarker of Axitinib Efficacy in Solid Tumors
Authors: Brian I. Rini, Joan H. Schiller, John P. Fruehauf, Ezra E.W. Cohen, Jamal C. Tarazi, Brad Rosbrook, Angel H. Bair, Alejandro D. Ricart, Anthony J. Olszanski, Kristen J. Letrent, Sinil Kim, Olivier Rixe
Journal: Clinical Cancer Research (2011)

Abstract Purpose: To evaluate if diastolic blood pressure (dBP) ≥90 mm Hg during axitinib treatment is a marker of efficacy. Experimental Design: The relationship between dBP ≥90 mm Hg and efficacy was retrospectively explored across 5 phase II studies of single-agent axitinib for the treatment of 4 different tumor types. All patients had baseline BP ≤140/90 mm Hg and were stratified into 2 groups based on in-clinic BP measurements after initiating therapy: those with dBP &amp;lt;90 mm Hg throughout therapy and those with at least 1 dBP ≥90 mm Hg. Median overall survival (mOS), median progression-free survival (mPFS), objective response rate (ORR), and adverse events were evaluated by dBP group in individual and pooled analyses. Results: Two-hundred thirty patients were evaluated. Patients with dBP ≥90 mm Hg had a significantly lower relative risk of death than those with dBP &amp;lt;90 mm Hg [adjusted HR (95% CI) = 0.55 (0.39, 0.77); P &amp;lt; 0.001]. The relative risk of progression was also lower in patients with dBP ≥90 mm Hg [HR (95% CI) = 0.76 (0.54, 1.06), P = 0.107], and ORR was significantly higher (43.9% vs. 12.0%; P &amp;lt; 0.001). In an 8-week landmark analysis, mOS (25.8 vs. 14.9 months) and mPFS (10.2 vs. 7.1 months) were greater for patients in the ≥90 mm Hg group. Adverse events were similar between groups. Conclusions: Axitinib efficacy correlated with dBP ≥90 mm Hg. Further investigation of dBP as a predictive biomarker of efficacy in patients receiving axitinib is warranted. Clin Cancer Res; 17(11); 3841–9. ©2011 AACR.
Chemoprevention of Aerodigestive Tract Cancers
Authors: Edward S. Kim, Waun Ki Hong, Fadlo Raja Khuri
Journal: Annual Review of Medicine (2002)

▪ Abstract Epithelial cancers are a major worldwide health problem. Since the mid-1970s, advances in multidisciplinary cancer therapeutics have only slightly improved the mortality rate from epithelial malignancies. Chemoprevention is the use of specific natural or synthetic chemical agents to reverse, suppress, or prevent progression to invasive cancer. Chemopreventive medicine is based on translating basic biologic research into clinical chemical interventions, thus attempting to impede carcinogenesis. Its principles build on the concepts of field cancerization (diffuse epithelial injury that results from carcinogen exposure) and multistep carcinogenesis (a stepwise accumulation of cellular and genetic alterations that progress to cancer). Chemoprevention targets the carcinogenic process at earlier and potentially more reversible stages, focusing on the inhibition of one or many steps in the progression towards cancer. Strategies of chemoprevention include primary prevention in groups at high risk, reversal of premalignant lesions, and prevention of second primary tumors.
Persistent Activation of the Akt Pathway in Head and Neck Squamous Cell Carcinoma
Authors: Panomwat Amornphimoltham, Virote Sriuranpong, Vyomesh Patel, Fernando Benavides, Claudio J. Conti, John Sauk, Edward A. Sausville, Alfredo A. Molinolo, J. Silvio Gutkind
Journal: Clinical Cancer Research (2004)

Squamous carcinomas of the head and neck (HNSCC) represent the sixth most common cancer among men worldwide and a major cause of morbidity and mortality due to its relatively poor prognosis. As part of ongoing studies addressing the molecular events underlying tumor progression in HNSCC, we have explored the nature of the proliferative pathways in which dysregulation may promote aberrant cell growth in this tumor type. The serine/threonine protein kinase Akt is a downstream target of phosphatidylinositol 3-kinase and a key regulator of normal and cancerous growth and cell fate decisions. Therefore, in this study, we have examined the status of activation of Akt in different stages of squamous cell carcinoma development in mice and in clinical samples from HNSCC patients. By immunohistochemical analysis, using a recently developed phosphorylation state-specific antibody, we demonstrated that Akt activation correlates closely with the progression of mouse skin squamous cell carcinoma. We also observed that activation of Akt is a frequent event in human HNSCC because active Akt can be detected in these tumors with a pattern of expression and localization correlating with the progression of the lesions. In line with these observations, Akt was constitutively activated in a large fraction of HNSCC-derived cell lines. We also provide evidence that the Akt signaling pathway may represent a biologically relevant target for a novel antineoplastic agent, UCN-01, which recently has been shown to be active in cellular and xenograft models for HNSCC at concentrations safely achievable in clinically relevant situations.
Is Bone Mineral Composition Disrupted by Organochlorines in East Greenland Polar Bears ( <i>Ursus maritimus</i> )?
Authors: Christian Sonne, Rune Dietz, Erik W. Born, Frank F. Riget, Maja Kirkegaard, Lars Hyldstrup, Robert J. Letcher, Derek C. G. Muir
Journal: Environmental Health Perspectives (2004)

We analyzed bone mineral density (BMD) in skulls of polar bears (Ursus maritimus) (n = 139) from East Greenland sampled during 1892-2002. Our primary goal was to detect possible changes in bone mineral content (osteopenia) due to elevated exposure to organochlorine [polychlorinated biphenyls (PCBs), dichlorodiphenyl trichloroethane (DDT) and its metabolites, chlordanes (CHLs), dieldrin, hexacyclohexanes, hexachlorobenzene] and polybrominated diphenyl ether (PBDE) compounds. To ensure that the BMD value in skull represented the mineral status of the skeletal system in general, we compared BMD values in femur and three lumbar vertebrae with skull in a subsample. We detected highly significant correlations between BMD in skull and femur (r = 0.99; p < 0.001; n = 13) and skull and vertebrae (r = 0.97; p < 0.001; n = 8). BMD in skulls sampled in the supposed pre-organochlorine/PBDE period (1892-1932) was significantly higher than that in skulls sampled in the supposed pollution period (1966-2002) for subadult females, subadult males, and adult males (all, p < 0.05) but not adult females (p = 0.94). We found a negative correlation between organochlorines and skull BMD for the sum of PCBs (SigmaPCB; p < 0.04) and SigmaCHL (p < 0.03) in subadults and for dieldrin (p < 0.002) and SigmaDDT (p < 0.02) in adult males; indications for SigmaPBDE in subadults were also found (p = 0.06). In conclusion, the strong correlative relationships suggest that disruption of the bone mineral composition in East Greenland polar bears may have been caused by organochlorine exposure.
COLLABORATIVE STUDY OF VERY-LOW-BIRTHWEIGHT INFANTS: OUTCOME OF TWO-YEAR-OLD SURVIVORS
Authors: W.H Kitchen, A Orgill, A Rickards, M.M Ryan, J.V Lissenden, C.G Keith, V.Y.H Yu, G.W Ford, J Astbury, W Russo, B Bajuk, J.R.M Nave
Journal: The Lancet (1982)
Prognostic Significance of Allelic Imbalance at the <i>c-kit</i> Gene Locus and c-kit Overexpression by Immunohistochemistry in Pediatric Osteosarcomas
Authors: Natacha Entz-Werlé, Luc Marcellin, Marie-Pierre Gaub, Eric Guerin, Anne Schneider, Perrine Berard-Marec, Chantal Kalifa, Laurence Brugiere, Helène Pacquement, Claudine Schmitt, Marie-Dominique Tabone, Corinne Jeanne-Pasquier, Philippe Terrier, Frédérique Dijoud, Pierre Oudet, Patrick Lutz, Annie Babin-Boilletot
Journal: Journal of Clinical Oncology (2005)

Since the recent development of biologic agents targeting oncogenes, increasing attention has been focused on determining the role of tyrosine kinase receptors in the pathogenesis of tumors. Our study was designed to investigate the status of region 4q12, which contains the candidate gene c-kit, and the expression of c-kit by immunohistochemistry (IHC).Paired blood and biopsy specimens of 68 children treated for high-grade primary osteosarcomas were collected. Microsatellite analysis at two genomic sites containing c-kit gene was performed on paired DNA using a sensible fluorescent polymerase chain reaction technology. To confirm the DNA data, we studied c-kit protein expression by IHC in 56 available paraffin-embedded tumor tissues.The frequency of allelic imbalance (AI) at locus 4q12 was 39% in the overall population. In agreement with previous studies, we did not detect microsatellite instability, allowing us to hypothesize that this pathway is not implicated. Furthermore, the normal status at locus 4q12 was associated with a significantly better survival in the whole osteosarcoma population (P = .05). IHC overexpression of c-kit was concordant in all cases presenting an AI. However, normal status at locus 4q12 was correlated to an absence of c-kit protein expression in 19 (65.5%) of 29 informative cases.Allelotyping of locus 4q12, which contains the c-kit gene, could help pediatric osteosarcoma prognostic screening and showed a strong correlation with overexpression of c-kit protein. These results allowed us to hypothesize that, in some cases, a mutation of c-kit gene could lead to a protein overexpression.
TW-37, a Small-Molecule Inhibitor of Bcl-2, Inhibits Cell Growth and Induces Apoptosis in Pancreatic Cancer: Involvement of Notch-1 Signaling Pathway
Authors: Zhiwei Wang, Asfar Sohail Azmi, Aamir Ahmad, Sanjeev Banerjee, Shaomeng Wang, Fazlul H. Sarkar, Ramzi M. Mohammad
Journal: Cancer Research (2009)

Abstract Overexpression of Bcl-2 family proteins has been found in a variety of aggressive human carcinomas, including pancreatic cancer, suggesting that specific agents targeting Bcl-2 family proteins would be valuable for pancreatic cancer therapy. We have previously reported that TW-37, a small-molecule inhibitor of Bcl-2 family proteins, inhibited cell growth and induced apoptosis in pancreatic cancer. However, the precise role and the molecular mechanism of action of TW-37 have not been fully elucidated. In our current study, we found that TW-37 induces cell growth inhibition and S-phase cell cycle arrest, with regulation of several important cell cycle–related genes like p27, p57, E2F-1, cdc25A, CDK4, cyclin A, cyclin D1, and cyclin E. The cell growth inhibition was accompanied by increased apoptosis with concomitant attenuation of Notch-1, Jagged-1, and its downstream genes such as Hes-1 in vitro and in vivo. We also found that down-regulation of Notch-1 by small interfering RNA or γ-secretase inhibitors before TW-37 treatment resulted in enhanced cell growth inhibition and apoptosis. Our data suggest that the observed antitumor activity of TW-37 is mediated through a novel pathway involving inactivation of Notch-1 and Jagged-1. [Cancer Res 2009;69(7):2757–65]
Recombinant interleukin‐12, but not granulocyte‐colony stimulating factor, improves survival in lethally irradiated nonhuman primates in the absence of supportive care: Evidence for the development of a frontline radiation medical countermeasure
Authors: Zoya Gluzman‐Poltorak, Vladimir Vainstein, Lena A. Basile
Journal: American Journal of Hematology (2014)

Hematopoietic syndrome of acute radiation syndrome (HSARS) is a life-threatening condition with no approved treatment. We compared recombinant human interleukin-12 (rHuIL-12; 175 ng/kg × 1) with vehicle, granulocyte-colony-stimulating factor (G-CSF; 10 µg/kg/day × 18), or rHuIL-12+G-CSF after lethal irradiation in rhesus monkeys in a Good Laboratory Practice, randomized, blinded, placebo-controlled study. Fluids, antibiotics, and blood products were not used. Survival at day 60 was significantly increased for rHuIL-12 versus G-CSF or vehicle. rHuIL-12/G-CSF combination provided no additional survival benefit over rHuIL-12. Both rHuIL-12 and rHuIL-12+G-CSF increased blood cell nadirs, induced earlier recovery of all hematopoietic lineages, and significantly decreased frequencies of severe cytopenias versus vehicle or G-CSF. In bone marrow, rHuIL-12 alone increased erythroid, myeloid, and megakaryocyte counts relative to vehicle or G-CSF. Thus, a single injection of rHuIL-12, without supportive medical intervention, significantly improved survival and promoted multilineage hematopoietic recovery in a nonhuman primate model of HSARS.
Tyrosine phosphorylation of a human killer inhibitory receptor recruits protein tyrosine phosphatase 1C.
Authors: K S Campbell, M Dessing, M Lopez-Botet, M Cella, M Colonna
Journal: The Journal of Experimental Medicine (1996)

Natural killer (NK) cells express killer inhibitory receptors that mediate negative regulation of NK cell cytotoxicity upon binding to MHC class I molecules on target cells. Unrelated inhibitory receptors on B cells have recently been shown to function through recruitment of phosphotyrosine phosphatase 1C (PTP-1C). Here, we show that a human killer inhibitory receptor specific for HLA-C also recruits PTP-1C after phosphorylation induced either by the pharmacological agent phenylarsine oxide or by conjugation with target cells. This recruitment is mediated by the binding of specific cytoplasmic phosphotyrosine-containing sequences to PTP-1C. These results implicate PTP-1C as a cytosolic component of the negative signaling pathway through NK cell inhibitory receptors.