tbuckley/cabot-search huggingface dataset:
Adenovirally Delivered Tumor Necrosis Factor-α Improves the Antiglioma Efficacy of Concomitant Radiation and Temozolomide Therapy
Authors: Bakhtiar Yamini, Xiaohong Yu, Peter Pytel, Nicholas Galanopoulos, Vinay Rawlani, Jula Veerapong, Kai Bickenbach, Ralph R. Weichselbaum
Journal: Clinical Cancer Research (2007)

Abstract Purpose: Treatment of malignant glioma involves concomitant temozolomide and ionizing radiation (IR). Nevertheless, overall patient survival remains poor. This study was designed to evaluate if addition of Ad.Egr–tumor necrosis factor (TNF), a replication defective adenovector encoding a cDNA for TNF-α, to temozolomide and IR can improve overall antiglioma effect. Experimental Design: The efficacy of combination treatment with Ad.Egr-TNF, IR, and temozolomide was assessed in two glioma xenograft models. Animal toxicity and brain histopathology after treatment were also examined. In addition, in an attempt to explain the antitumor interaction between these treatments, the activation status of the transcription factor nuclear factor-κB was examined. Results: Triple therapy (Ad.Egr-TNF, IR, and temozolomide) leads to significantly increased survival in mice bearing glioma xenografts compared with dual treatment. Fifty percent of animals treated with the triple regimen survive for &amp;gt;130 days. Pathologic examination shows that triple therapy leads to a complete response with formation of a collagenous scar. No significant change in myelination pattern is noted after triple therapy, compared with any double treatment. Treatment of intracranial glioma bearing mice with Ad.Egr-TNF and IR leads to cachexia and poor feeding that does not improve, whereas triple therapy results in less toxicity, which improves over 21 days. Both Ad.Egr-TNF and IR activate nuclear factor-κB, and temozolomide inhibits this activity in an inhibitor of κBα (IκBα)–independent manner. Conclusion: This work shows that the addition of adenoviral TNF-α gene delivery to temozolomide and IR significantly improves antiglioma efficacy and illustrates a potential new treatment regimen for use in patients with malignant glioma.
Bosutinib inhibits migration and invasion via ack1 in kras mutant non-small cell lung cancer
Authors: Daniel SW Tan, Benjamin Haaland, Jia Min Gan, Su Chin Tham, Indrajit Sinha, Eng Huat Tan, Kiat Hon Lim, Angela Takano, Sai Sakktee Krisna, Minn Minn Myint Thu, Hoe Peng Liew, Axel Ullrich, Wan-Teck Lim, Boon Tin Chua
Journal: Molecular Cancer (2014)

The advent of effective targeted therapeutics has led to increasing emphasis on precise biomarkers for accurate patient stratification. Here, we describe the role of ACK1, a non-receptor tyrosine kinase in abrogating migration and invasion in KRAS mutant lung adenocarcinoma. Bosutinib, which inhibits ACK1 at 2.7 nM IC50, was found to inhibit cell migration and invasion but not viability in a panel of non-small cell lung cancer (NSCLC) cell lines. Knockdown of ACK1 abrogated bosutinib-induced inhibition of cell migration and invasion specifically in KRAS mutant cells. This finding was further confirmed in an in vivo zebrafish metastatic model. Tissue microarray data on 210 Singaporean lung adenocarcinomas indicate that cytoplasmic ACK1 was significantly over-expressed relative to paired adjacent non-tumor tissue. Interestingly, ACK1 expression in "normal" tissue adjacent to tumour, but not tumour, was independently associated with poor overall and relapse-free survival. In conclusion, inhibition of ACK1 with bosutinib attenuates migration and invasion in the context of KRAS mutant NSCLC and may fulfil a therapeutic niche through combinatorial treatment approaches.
Host B cells produce IL-10 following TBI and attenuate acute GVHD after allogeneic bone marrow transplantation
Authors: Vanessa Rowe, Tatjana Banovic, Kelli P. MacDonald, Rachel Kuns, Alistair L. Don, Edward S. Morris, Angela C. Burman, Helen M. Bofinger, Andrew D. Clouston, Geoffrey R. Hill
Journal: Blood (2006)
Clinical response, pharmacokinetics, development of human anti-chimaeric antibodies, and synovial tissue response to rituximab treatment in patients with rheumatoid arthritis
Authors: R M Thurlings, O Teng, K Vos, D M Gerlag, L Aarden, S O Stapel, J M van Laar, P P Tak, G J Wolbink
Journal: Annals of the Rheumatic Diseases (2009)

Objectives: To analyse whether persistence of synovial B lineage cells and lack of clinical response to rituximab treatment in patients with rheumatoid arthritis (RA) are associated with low rituximab serum levels and anti-rituximab antibody (ARA) formation. Methods: Fifty-eight patients with RA were treated with rituximab. The clinical response was determined 24 weeks after each treatment course using the Disease Activity Score evaluated in 28 joints (DAS28) and EULAR response criteria. Rituximab serum levels, ARAs and synovial B lineage cell numbers were determined before and after treatment. Results: Four weeks after treatment rituximab serum levels were highly variable. Low rituximab levels were associated with ARA formation (in five patients (8.6%)) and high baseline erythrocyte sedimentation rate. Interestingly, serum rituximab levels were not related to persistence of synovial B lineage cells or clinical response. Furthermore, response to treatment and re-treatment was similar in ARA-positive and ARA-negative patients. Conclusion: There is clear variability in serum levels after rituximab treatment, but rituximab levels are not lower in patients with persistence of synovial B lineage cells or lack of clinical response. The current treatment schedule suffices to induce and maintain a clinical response, even when ARAs are formed.
Influence of Na <sup>+</sup> -Independent Cl <sup>−</sup> -HCO <sub>3</sub> <sup>−</sup> Exchange on the Slow Force Response to Myocardial Stretch
Authors: Horacio E. Cingolani, Gladys E. Chiappe, Irene L. Ennis, Patricio G. Morgan, Bernardo V. Alvarez, Joseph R. Casey, Raúl A. Dulce, Néstor G. Pérez, María C. Camilión de Hurtado
Journal: Circulation Research (2003)

Previous work demonstrated that the slow force response (SFR) to stretch is due to the increase in calcium transients (Ca2+T) produced by an autocrine-paracrine mechanism of locally produced angiotensin II/endothelin activating Na+-H+ exchange. Although a rise in pHi is presumed to follow stretch, it was observed only in the absence of extracellular bicarbonate, suggesting pHi compensation through the Na+-independent Cl--HCO3- exchange (AE) mechanism. Because available AE inhibitors do not distinguish between different bicarbonate-dependent mechanisms or even between AE isoforms, we developed a functional inhibitory antibody against both the AE3c and AE3fl isoforms (anti-AE3Loop III) that was used to explore if pHi would rise in stretched cat papillary muscles superfused with bicarbonate after AE3 inhibition. In addition, the influence of this potential increase in pHi on the SFR was analyzed. In this study, we present evidence that cancellation of AE3 isoforms activity (either by superfusion with bicarbonate-free buffer or with anti-AE3Loop III) results in pHi increase after stretch and the magnitude of the SFR was larger than when AE was operative, despite of similar increases in [Na+]i and Ca2+T under both conditions. Inhibition of reverse mode Na+-Ca2+ exchange reduced the SFR to the half when the AE was inactive and totally suppressed it when AE3 was active. The difference in the SFR magnitude and response to inhibition of reverse mode Na+-Ca2+ exchange can be ascribed to a pHi-induced increase in myofilament Ca2+ responsiveness.
Use of a magnified cardiac airflow oscillation to classify neonatal apnea.
Authors: R P Lemke, S A Al-Saedi, R E Alvaro, N E Wiseman, D B Cates, K Kwiatkowski, H Rigatto
Journal: American Journal of Respiratory and Critical Care Medicine (1996)

Currently the classification of neonatal apnea relies upon an inference of airway closure based upon the presence of breathing efforts against such an obstruction. In this study we evaluate a new method of classification which utilizes the presence or absence of cardiac airflow oscillation to detect airway closure. Specifically, this evaluation consisted of an examination of the transmission characteristics of an artificially produced airflow oscillation through discrete airway narrowing in a model system; a confirmation that voluntary upper airway occlusion in adult volunteers uniformly induces complete loss of the oscillation; and a comparison of the cardiac oscillation method with the traditional method of apnea classification in a cohort of 4,309 apneas in 32 infants. We determined that the amplitude of the oscillation is negatively correlated with resistance (r = 0.97) and positively with the radius (r = 0.98) of narrowing in a model system, and that voluntary airway obstruction in adult subjects uniformly results in loss of transmitted cardiac oscillations. Moreover, although there was similarity in the frequency distribution of central, obstructive, and mixed apneas in our infants, there were statistically significantly greater obstructive events detected by the cardiac oscillation method. In addition, the cardiac oscillation method had the additional advantage of providing information regarding the timing of airway obstruction during apnea.
On-Target Effect of FK866, a Nicotinamide Phosphoribosyl Transferase Inhibitor, by Apoptosis-Mediated Death in Chronic Lymphocytic Leukemia Cells
Authors: Iris Gehrke, Eric D.J. Bouchard, Sara Beiggi, Armando G. Poeppl, James B. Johnston, Spencer B. Gibson, Versha Banerji
Journal: Clinical Cancer Research (2014)

Chronic lymphocytic leukemia (CLL) remains incurable despite advances in therapy. In this study, we characterize the effect of nicotinamide phosphoribosyltransferase (NAMPT) inhibition by FK866 in primary CLL cells from patients with various clinical prognostic markers.CLL cells were treated with FK866 to assess viability by Annexin V/PI staining. Functional analysis of FK866 included time- and concentration-dependent evaluation of cellular NAD, ATP, mitochondrial membrane potential (MMP), reactive oxygen species (ROS), and apoptotic signaling. Chemosensitization potential by FK866 to fludarabine was also assessed. Prognostic markers were correlated with drug response.FK866 induced CLL cell death by depleting cellular NAD content by day 1, followed by a drop in ATP on day 2. We observed loss of MMP, ROS increase, and induction of apoptotic signaling at day 3. On-target activity of FK866 was confirmed by NAD-mediated rescue of NAD and ATP loss, apoptotic signaling, and viability. The response to FK866 was independent of most prognostic markers. Higher doses were required with short lymphocyte doubling time and positive CD38 status, whereas CLL cells resistant to fludarabine in vitro and from patients with del17p13.1 were equally sensitive to FK866. FK866 did not upregulate the p53-target p21, nor did the p53 activator Nutlin improve FK866-mediated cell death. Furthermore, fludarabine and FK866 were synergistic at clinically relevant concentrations.NAMPT inhibition by FK866 may be a potential treatment for CLL, including patients with del17p13.1 or other high-risk features. FK866 may complement standard agents to enhance their efficacy and/or allow dose reduction for improved tolerability.
Cancer-Specific Requirement for BUB1B/BUBR1 in Human Brain Tumor Isolates and Genetically Transformed Cells
Authors: Yu Ding, Christopher G. Hubert, Jacob Herman, Philip Corrin, Chad M. Toledo, Kyobi Skutt-Kakaria, Julio Vazquez, Ryan Basom, Bin Zhang, Jennifer K. Risler, Steven M. Pollard, Do-Hyun Nam, Jeffery J. Delrow, Jun Zhu, Jeongwu Lee, Jennifer DeLuca, James M. Olson, Patrick J. Paddison
Journal: Cancer Discovery (2012)

Abstract To identify new candidate therapeutic targets for glioblastoma multiforme, we combined functional genetics and glioblastoma network modeling to identify kinases required for the growth of patient-derived brain tumor–initiating cells (BTIC) but that are dispensable to proliferating human neural stem cells (NSC). This approach yielded BUB1B/BUBR1, a critical mitotic spindle checkpoint player, as the top-scoring glioblastoma lethal kinase. Knockdown of BUB1B inhibited expansion of BTIC isolates, both in vitro and in vivo, without affecting proliferation of NSCs or astrocytes. Mechanistic studies revealed that BUB1B's GLE2p-binding sequence (GLEBS) domain activity is required to suppress lethal kinetochore–microtubule (KT–MT) attachment defects in glioblastoma isolates and genetically transformed cells with altered sister KT dynamics, which likely favor KT–MT instability. These results indicate that glioblastoma tumors have an added requirement for BUB1B to suppress lethal consequences of altered KT function and further suggest that sister KT measurements may predict cancer-specific sensitivity to BUB1B inhibition and perhaps other mitotic targets that affect KT–MT stability. Significance: Currently, no effective therapies are available for glioblastoma, the most frequent and aggressive brain tumor. Our results suggest that targeting the GLEBS domain activity of BUB1B may provide a therapeutic window for glioblastoma, as the GLEBS domain is nonessential in untransformed cells. Moreover, the results further suggest that sister KT distances at metaphase may predict sensitivity to anticancer therapeutics targeting KT function. Cancer Discov; 3(2); 198–211. ©2012 AACR. See related commentary by Venere et al., p. 141 This article is highlighted in the In This Issue feature, p. 125
Endogenous Sex Hormones, Prolactin, and Breast Cancer in Premenopausal Women2
Authors: François Meyer, James B. Brown, Alan S. Morrison, Brian MacMahon
Journal: JNCI Journal of the National Cancer Institute (1986)

Forty-one women with breast cancer and 119 controls participated in a case-control study of the relation of endogenous sex hormones to breast carcinoma in premenopausal women. During the follicular phase of the menstrual cycle, one overnight urine specimen was collected. During the luteal phase, urine and blood specimens were obtained. 17 beta-Estradiol, sex hormone-binding globulin, progesterone, and prolactin were measured in plasma, whereas estrogen metabolites (estrone, estradiol, and estriol) and pregnanediol were assessed in the urine. Breast cancer was associated with high-plasma estradiol and prolactin and with low progesterone. Similar but weaker associations were observed for urinary estrogens and pregnanediol in the luteal phase.
RETRACTED: The first tissue-engineered airway transplantation: 5-year follow-up results
Authors: Alessandro Gonfiotti, Massimo O Jaus, Daniel Barale, Silvia Baiguera, Camilla Comin, Federico Lavorini, Giovanni Fontana, Oriol Sibila, Giovanni Rombolà, Philipp Jungebluth, Paolo Macchiarini
Journal: The Lancet (2013)
A guide to creating your own patient-oriented website
Authors: W A Clement, S Wilson, B J Bingham
Journal: Journal of the Royal Society of Medicine (2002)

This paper is designed to help clinicians or allied health professionals to construct their own patient-oriented website. Our website for Glaswegian patients, on ear, nose and throat problems [www.glasgowent.com ], was awarded four stars for both content and construction by the Internet Magazine1.
A recessive genetic screen for host factors required for retroviral infection in a library of insertionally mutated Blm-deficient embryonic stem cells
Authors: Wei Wang, Allan Bradley
Journal: Genome biology (2007)

Abstract Background Host factors required for retroviral infection are potential targets for the modulation of diseases caused by retroviruses. During the retroviral life cycle, numerous cellular factors interact with the virus and play an essential role in infection. Cultured embryonic stem (ES) cells are susceptible to retroviral infection, therefore providing access to all of the genes required for this process to take place. In order to identify the host factors involved in retroviral infection, we designed and implemented a scheme for identifying ES cells that are resistant to retroviral infection and subsequent cloning of the mutated gene. Results A library of mutant ES cells was established by genome-wide insertional mutagenesis in Blm -deficient ES cells, and a screen was performed by superinfection of the library at high multiplicity with a recombinant retrovirus carrying a positive and negative selection cassette. Stringent negative selection was then used to exclude the infected ES cells. We successfully recovered five independent clones of ES cells that are resistant to retroviral infection. Analysis of the mutations in these clones revealed four different homozygous and one compound heterozygous mutation in the mCat-1 locus, which confirms that mCat-1 is the ecotropic murine leukemia virus receptor in ES cells. Conclusion We have demonstrated the feasibility and reliability of this recessive genetic approach to identifying critical genes required for retroviral infection in ES cells; the approach provides a unique opportunity to recover other cellular factors required for retroviral infection. The resulting insertionally mutated Blm -deficient ES cell library might also provide access to essential host cell components that are required for infection and replication for other types of virus.
Apolipoprotein E2/E5 Variants in Lipoprotein Glomerulopathy Recurred in Transplanted Kidney
Authors: TOSHIO MIYATA, SATOSHI SUGIYAMA, MASAOMI NANGAKU, DAISUKE SUZUKI, KEN-ICHI URAGAMI, REIKO INAGI, HIDETO SAKAI, KIYOSHI KUROKAWA
Journal: Journal of the American Society of Nephrology (1999)

Abstract. Lipid abnormalities are associated with various disorders ranging from generalized atherosclerosis to renal diseases, including lipoprotein glomerulopathy that is characterized by glomerular lipoprotein thrombi and causes type III hyperlipoproteinemia, proteinuria, and renal failure. This study examines lipoprotein glomerulopathy, which recurred in a transplanted kidney. Molecular biologic analysis of the patient's apolipoprotein (apo) E gene demonstrated E2/E5 type variants. Immunohistochemical analysis of the diseased kidney demonstrated various lipid peroxidation-specific protein adducts, suggesting a potential role of oxidative stress in this disorder. Recurrence in the transplanted kidney suggested a pathogenic role of extraglomerular humoral component(s) resulting from abnormal lipoprotein metabolism, presumably linked to apo E and other genetic or acquired factor(s). Furthermore, the finding that the patient showed pathologic abnormalities in the transplanted kidney with no clinical signs or symptoms of renal disease indicated that lipoprotein glomerular damage progresses early before any clinical manifestations.
CLINICAL TRIALS IN PULMONARY HYPERTENSION
Authors: David B. Badesch, MD
Journal: Annual Review of Medicine (1997)

▪ Abstract Progress in treatment of pulmonary hypertension has been impaired by the lack of formal clinical trials. This is now beginning to change, and the impact on our approach to treating patients with pulmonary hypertension is substantial. As with other relatively uncommon medical disorders, randomized, controlled, multi-center trials are needed to assess the safety and efficacy of potential therapeutic modalities. Treatments showing promise at the level of small pilot studies within a single center should be studied more rigorously.
Regulation of Dendritic Cell Migration to the Draining Lymph Node
Authors: Alfonso Martín-Fontecha, Silvia Sebastiani, Uta E. Höpken, Mariagrazia Uguccioni, Martin Lipp, Antonio Lanzavecchia, Federica Sallusto
Journal: The Journal of Experimental Medicine (2003)

Antigen-pulsed dendritic cells (DCs) are used as natural adjuvants for vaccination, but the factors that influence the efficacy of this treatment are poorly understood. We investigated the parameters that affect the migration of subcutaneously injected mouse-mature DCs to the draining lymph node. We found that the efficiency of DC migration varied with the number of injected DCs and that CCR7+/+ DCs migrating to the draining lymph node, but not CCR7-/- DCs that failed to do so, efficiently induced a rapid increase in lymph node cellularity, which was observed before the onset of T cell proliferation. We also report that DC migration could be increased up to 10-fold by preinjection of inflammatory cytokines that increased the expression of the CCR7 ligand CCL21 in lymphatic endothelial cells. The magnitude and quality of CD4+ T cell response was proportional to the number of antigen-carrying DCs that reached the lymph node and could be boosted up to 40-fold by preinjection of tumor necrosis factor that conditioned the tissue for increased DC migration. These results indicate that DC number and tissue inflammation are critical parameters for DC-based vaccination.
Long-term follow-up of a phase III study comparing radiotherapy with or without weekly oxaliplatin for locoregionally advanced nasopharyngeal carcinoma
Authors: X. Wu, P.Y. Huang, P.J. Peng, L.X. Lu, F. Han, S.X. Wu, X. Hou, H.Y. Zhao, Y. Huang, W.F. Fang, Y.Y. Zhao, C. Xue, Z.H. Hu, J. Zhang, J.W. Zhang, Y.X. Ma, W.H. Liang, C. Zhao, L. Zhang
Journal: Annals of Oncology (2013)
Controlling Urban Epidemics of West Nile Virus Infection
Authors: Robert W. Haley
Journal: JAMA (2012)

THE CENTER of its worst-ever regional epidemic of West Nile virus (WNV) infection, with one-quarter of the nation's cases identified in Dallas County. 1 With a record high number of trapped mosquitoes testing positive for WNV, from June 20 to August 21 WNV infections have been confirmed in 270 county residents; 160 have been hospitalized, 51 have required intensive care unit admission, and 11 have died. 2 Given this epidemic in Dallas, which has spilled over into Fort Worth and the 14 surrounding counties, and similar WNV activity in Louisiana, Alabama, Oklahoma, and the Midwest, 2 physicians and the public should be aware of key information about WNV infection 3 to enable informed decision making in countering urban WNV epidemics.
Dopamine Blocks Stress-Mediated Ovarian Carcinoma Growth
Authors: Myrthala Moreno-Smith, Chunhua Lu, Mian M.K. Shahzad, Guillermo N. Armaiz Pena, Julie K. Allen, Rebecca L. Stone, Lingegowda S. Mangala, Hee Dong Han, Hye Sun Kim, Donna Farley, Gabriel Lopez Berestein, Steve W. Cole, Susan K. Lutgendorf, Anil K. Sood
Journal: Clinical Cancer Research (2011)

Increased adrenergic activity in response to chronic stress is known to promote tumor growth by stimulating the tumor microenvironment. The focus of the current study was to determine whether dopamine, an inhibitory catecholamine, could block the effects of chronic stress on tumor growth.Expression of dopamine receptors (DR1-DR5) was analyzed by reverse transcriptase-PCR and by Western blotting. In vitro effects of dopamine on cell viability, apoptosis, and migration were examined. For in vivo therapy, murine and human DR2-siRNAs were incorporated into chitosan nanoparticles (CH-NP).In this model of chronic stress, tumoral norepinephrine levels remained elevated whereas dopamine levels were significantly decreased compared with nonstressed animals. Daily restraint stress resulted in significantly increased tumor growth in both immunodeficient (SKOV3ip1 and HeyA8) and immunocompetent (ID8) ovarian cancer models. This increase was completely blocked with daily dopamine treatment. Dopamine treatment also blocked the stress-induced increase in angiogenesis. Endothelial and ovarian cancer cells expressed all dopamine receptors except for the lack of DR3 expression in ovarian cancer cells. DR2 was responsible for the inhibitory effects of dopamine on tumor growth and microvessel density as well as the stimulatory effect on apoptosis, as the DR2 antagonist eticlopride reversed these effects. Dopamine significantly inhibited cell viability and stimulated apoptosis in vitro. Moreover, dopamine reduced cyclic AMP levels and inhibited norepinephrine and vascular permeability factor/VEGF-induced Src kinase activation.Dopamine depletion under chronic stress conditions creates a permissive microenvironment for tumor growth that can be reversed by dopamine replacement.