tbuckley/cabot-search huggingface dataset:
Cross-linking of membrane immunoglobulin D, in the absence of T cell help, kills mature B cells in vivo.
Authors: F D Finkelman, J M Holmes, O I Dukhanina, S C Morris
Journal: The Journal of Experimental Medicine (1995)

In vivo experiments were performed to determine whether the cross-linking of membrane immunoglobulin (mIg) D on mature B cells, in the absence of T cell help, leads to B cell death. Mice were injected with either a monoclonal antibody (mAb) that cross-links mIgD effectively or a mAb that binds to mIgD avidly but cross-links it to a limited extent, and effects on B cell number and B cell Ia, mIgM, and mIgD expression were observed. In most experiments, mice were pretreated with anti-interleukin 7 mAb to prevent the generation of new bone marrow B cells, and with anti-CD4 mAb to prevent the generation of T cell help. In some experiments, mice also received anti-Fc gamma RII mAb to prevent cross-linking of mIgD with Fc gamma RII, and cobra venom factor to prevent possible mIg-complement receptor interactions and complement-mediated killing of B cells. The results of these studies demonstrate that (a) even limited cross-linking of mIgD on mature B cells can lead to B cell death; (b) increased cross-linking of mIgD leads to increased B cell death; (c) the loss of B cells is first detected 2 d after anti-IgD mAb injection and increases during the subsequent 3 d; (d) sustained modulation of mIgD may be necessary to cause B cell death; (e) mIgMdull but not mIgMbright B cells are lost in mice injected with anti-IgD mAbs; and (f) T cell help prevents or minimizes B cell death.
Double dissociations never license simple inferences about underlying brain organization, especially in developmental cases
Authors: James L. McClelland, Gary Lupyan
Journal: Behavioral and Brain Sciences (2002)

Different developmental anomalies produce contrasting deficits in a single, integrated system. In a network that inflects regular and exception verbs correctly, a disproportionate deficit with exceptions occurs if connections are deleted, whereas a disproportionate deficit with regulars occurs when an auditory deficit impairs perception of the regular inflection. In general, contrasting deficits do not license the inference of underlying modularity.
Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): prospective observational study
Authors: A. I Adler
Journal: BMJ (2000)

<h3>Abstract</h3> <b>Objective:</b> To determine the relation between systolic blood pressure over time and the risk of macrovascular or microvascular complications in patients with type 2 diabetes. <b>Design:</b> Prospective observational study. <b>Setting:</b> 23 hospital based clinics in England, Scotland, and Northern Ireland. <b>Participants:</b> 4801 white, Asian Indian, and Afro-Caribbean UKPDS patients, whether randomised or not to treatment, were included in analyses of incidence; of these, 3642 were included in analyses of relative risk. <b>Outcome measures:</b> Primary predefined aggregate clinical outcomes: any complications or deaths related to diabetes and all cause mortality. Secondary aggregate outcomes: myocardial infarction, stroke, lower extremity amputation (including death from peripheral vascular disease), and microvascular disease (predominantly retinal photocoagulation). Single end points: non-fatal heart failure and cataract extraction. Risk reduction associated with a 10 mm Hg decrease in updated mean systolic blood pressure adjusted for specific confounders <b>Results:</b> The incidence of clinical complications was significantly associated with systolic blood pressure, except for cataract extraction. Each 10 mm Hg decrease in updated mean systolic blood pressure was associated with reductions in risk of 12% for any complication related to diabetes (95% confidence interval 10% to 14%, P&lt;0.0001), 15% for deaths related to diabetes (12% to 18%, P&lt;0.0001), 11% for myocardial infarction (7% to 14%, P&lt;0.0001), and 13% for microvascular complications (10% to 16%, P&lt;0.0001). No threshold of risk was observed for any end point. <b>Conclusions:</b> In patients with type 2 diabetes the risk of diabetic complications was strongly associated with raised blood pressure. Any reduction in blood pressure is likely to reduce the risk of complications, with the lowest risk being in those with systolic blood pressure less than 120 mm Hg.
YM155, a Novel Small-Molecule Survivin Suppressant, Induces Regression of Established Human Hormone-Refractory Prostate Tumor Xenografts
Authors: Takahito Nakahara, Masahiro Takeuchi, Isao Kinoyama, Tsuyoshi Minematsu, Kenna Shirasuna, Akira Matsuhisa, Aya Kita, Fumiko Tominaga, Kentaro Yamanaka, Masafumi Kudoh, Masao Sasamata
Journal: Cancer Research (2007)

Various accumulating evidence suggests that survivin, a member of the inhibitor of apoptosis (IAP) family, plays an important role in drug resistance and cancer cell survival in many types of cancer, including hormone-refractory prostate cancer (HRPC). Here, we characterized YM155, a novel small-molecule survivin suppressant, using a survivin gene promoter activity assay. YM155 suppressed expression of survivin and induced apoptosis in PC-3 and PPC-1 human HRPC cell lines at 10 nmol/L. In contrast, YM155 up to 100 nmol/L showed little effect on expression levels of other IAP- or Bcl-2-related proteins. In a s.c. xenografted PC-3 tumor model in mice, 3-day continuous infusions of YM155 at 3 to 10 mg/kg induced massive tumor regression accompanied by suppression of intratumoral survivin. YM155 also completely inhibited the growth of orthotopically xenografted PC-3 tumors. No significant decreases in body weight were observed in mice treated with YM155 during the experimental period. Pharmacokinetic analyses indicated that YM155 is highly distributed to tumors and at concentrations approximately 20-fold higher than those in plasma. Our findings represent the first attempt to show tumor regression and suppression of survivin in p53-deficient human HRPC cells by a single small molecular compound treatment. Further extensive investigation of YM155 in many types of cancer, including HRPC, seems to be worthwhile to develop this novel therapeutic approach.
Development of the Neuromuscular Junction: Inductive Interactions Between Cells
Authors: M J Dennis
Journal: Annual Review of Neuroscience (1981)

The brain's default mode network consists of discrete, bilateral and symmetrical cortical areas, in the medial and lateral parietal, medial prefrontal, and medial and lateral temporal cortices of the human, nonhuman primate, cat, and rodent brains. Its ...Read More
Interleukin-17-producing T-helper cells and related cytokines in human airways exposed to endotoxin
Authors: P. Glader, M.E. Smith, C. Malmhäll, B. Balder, M. Sjöstrand, I. Qvarfordt, A. Lindén
Journal: European Respiratory Journal (2010)

Previous studies on mouse models have indicated that interleukin (IL)-17 and IL-17-producing T-helper (Th) cells are important for pulmonary host defence against Gram-negative bacteria. Human correlates to these findings have not yet been demonstrated. The aim of the present study was to determine whether or not IL-17-producing Th cells are present and whether IL-17 and other Th17-associated cytokines are involved in the immunological response to endotoxin in human airways. Segmental exposure to endotoxin and contralateral exposure to vehicle were performed in the lungs of healthy volunteers, with subsequent bronchoalveolar lavage 12 or 24 h after exposure to study local changes in cytokines and inflammatory cells. Endotoxin exposure increased concentrations of IL-17, IL-22 and their downstream effector molecules, human β-defensin-2 and IL-8/CXC chemokine ligand 8, in bronchoalveolar lavage fluid. Th cells with the capacity to produce IL-17 were found among the bronchoalveolar lavage cells, and expression of IL-17 mRNA correlated with expression of the transcription factor, retinoic-acid-receptor-related orphan receptor C variant 2. Moreover, endotoxin increased the numbers of neutrophils, macrophages and IL-17-producing T-cells, as well as the concentration of the Th17-regulating cytokines, IL-21 and IL-23. In conclusion, IL-17-producing Th cells are present, and IL-17, as well as other Th17-associated cytokines, is involved in the immunological response to endotoxin in human airways.
A randomized phase II study of alternating and sequential regimens of docetaxel and doxorubicin as first-line chemotherapy for metastatic breast cancer
Authors: R. Paridaens, F. Van Aelst, V. Georgoulias, H. Samonnig, V. Cocquyt, C. Zielinski, H. Hausmaninger, P. Willemse, Y. Boudraa, J. Wildiers, C. Ramazeilles, N. Azli
Journal: Annals of Oncology (2003)

This phase II study evaluated the feasibility and efficacy of alternating and sequential regimens of docetaxel and doxorubicin as first-line chemotherapy for metastatic breast cancer (MBC).Women with MBC requiring first-line chemotherapy for progressive disease (n = 106) were randomized and received 3-weekly monotherapy with docetaxel (T, 100 mg/m2, 1-h i.v. infusion) and doxorubicin (A, 75 mg/m2, 20-30-min i.v. infusion) either on a cycle-by-cycle alternating basis (ATATATAT, n = 51) or sequentially each for four cycles (TTTTAAAA, n = 55).For both regimens, the median number of cycles administered was the maximum of eight. The alternating and sequential groups achieved similar objective tumor response rates (60% and 67%, respectively) and similar median duration of response (47 and 44 weeks, respectively). With a median follow-up of 31 months, median survival times were estimated at 20 and 26 months in the alternating and sequential groups, respectively. No unexpected toxicities were reported. Compared with alternating therapy, patients receiving sequential therapy were more likely to complete the planned eight chemotherapy cycles (69% versus 63%), and had a lower incidence of febrile neutropenia (2% versus 14%).Alternating and sequential docetaxel-doxorubicin regimens are viable alternatives to simultaneous combination therapy in MBC, with sequential therapy achieving slightly higher response rates and improved tolerability compared with alternating therapy.
The inhibitory effect of pyrroloquinoline quinone on the amyloid formation and cytotoxicity of truncated alpha-synuclein
Authors: Jihoon Kim, Ryuichi Harada, Masaki Kobayashi, Natsuki Kobayashi, Koji Sode
Journal: Molecular Neurodegeneration (2010)

Abstract Background Parkinson's disease (PD) involves the selective damage of dopaminergic neuron cells resulting from the accumulation and fibril formation of alpha-synuclein. Recently, it has been shown that not only full-length alpha-synuclein, but also C-terminal truncated forms exist in the normal brain, as well as Lewy bodies, which are cytoplasmic inclusions in PD. It is known that truncated alpha-synuclein has a much higher ability to aggregate and fibrillate than full-length alpha-synuclein. Since the fibrils and precursor oligomers of alpha-synuclein are cytotoxic to the neuron, inhibitors that prevent the formation of oligomers and/or fibrils might open the way to a novel therapeutic approach to PD. However, no inhibitor for truncated alpha-synuclein has been reported yet. Results In this study, we first characterized the aggregation and cytotoxicity of C-truncated alpha-synuclein119 and alpha-synuclein133 which have been found in both the normal and the pathogenic brain. Alpha-synuclein119 aggregated more rapidly and enhanced significantly the fibril formation of alpha-synuclein. Although both of alpha-synuclein119 and alpha-synuclein133 showed a high cytotoxicity, alpha-synuclein133 showed a similar aggregation with full-length alpha-synuclein and no acceleration effect. We showed that PQQ dramatically inhibits the fibril formation of C-terminal truncated alpha-synuclein110119, and 133 as well as the mixtures of full-length alpha-synuclein with these truncated variants. Moreover, PQQ decreases the cytotoxicity of truncated alpha-synuclein. Conclusions Our results demonstrate that PQQ inhibits the amyloid fibril formation and cytotoxicity of the C-truncated alpha-synuclein variants. We believe that PQQ is a strong candidate for a reagent compound in the treatment of PD.
Inflammatory Breast Cancer as a Model Disease to Study Tumor Angiogenesis: Results of a Phase IB Trial of Combination SU5416 and Doxorubicin
Authors: Beth Overmoyer, Pingfu Fu, Charles Hoppel, Tomas Radivoyevitch, Robert Shenk, Marjie Persons, Paula Silverman, Kelly Robertson, Nicholas P. Ziats, Jay K. Wasman, Fadi W. Abdul-Karim, John A. Jesberger, Jeffrey Duerk, Paul Hartman, Shelli Hanks, Jonathan Lewin, Afshin Dowlati, Keith McCrae, Percy Ivy, Scot C. Remick
Journal: Clinical Cancer Research (2007)

We used inflammatory breast cancer (IBC) as a model disease to investigate biological changes associated with an antiangiogenesis agent, SU5416, combined with doxorubicin.Patients with stage IIIB or IV IBC were treated neoadjuvantly with the combination of SU5416 and doxorubicin for induction therapy. The dose of SU5416 (administered on days 1 and 4, every 3 weeks) and doxorubicin (administered on day 1 every 3 weeks) were escalated in cohorts of three patients starting at 110 and 60 mg/m2, respectively, for a total of five cycles leading up to mastectomy. Patients underwent serial assessment (pharmacokinetic sampling, biopsy of breast, tumor blood flow dynamic contrast-enhanced magnetic resonance imaging, plasma angiogenesis, and endothelial cell damage markers) prior to treatment, at the end of cycles no. 2 and no. 5, and after mastectomy.Eighteen patients were enrolled; neutropenia was dose-limiting, and overall median survival was not reached (50 months of study follow-up). Four patients (22%) experienced congestive heart failure, which resolved and were likely attributable to a smaller volume of distribution and higher Cmax of doxorubicin in combination with SU5416. We did observe a significant decline in tumor blood flow using Kep calculated by Brix (pretreatment versus post-cycle no. 5; P = 0.033), trend for a decline in tumor microvessel density after treatment, and low baseline levels of soluble intracellular adhesion molecule were associated with improved event-free survival.This study showed evidence of an unfavorable cardiac interaction between SU5416 and doxorubicin, which prohibits further investigation of this combination. However, this study supports the importance of using IBC as a model for investigating angiogenesis inhibitors.
Donor Myocardial Infarction Impairs the Therapeutic Potential of Bone Marrow Cells by an Interleukin-1–Mediated Inflammatory Response
Authors: Xiaoyin Wang, Junya Takagawa, Viola C. Lam, Daniel J. Haddad, Diana L. Tobler, Pamela Y. Mok, Yan Zhang, Brian T. Clifford, Kranthi Pinnamaneni, Shereen A. Saini, Robert Su, Maya J. Bartel, Richard E. Sievers, Larry Carbone, Scott Kogan, Yerem Yeghiazarians, Michelle L. Hermiston, Matthew L. Springer
Journal: Science Translational Medicine (2011)

Inflammation after myocardial infarction may explain failure of bone marrow cells to improve cardiac function in infarcted recipient hearts.
Tracer norepinephrine kinetics in coronary circulation of patients with heart failure secondary to chronic pressure and volume overload.
Authors: C P Rose, J H Burgess, D Cousineau
Journal: Journal of Clinical Investigation (1985)

Controversy exists over the nature of the abnormality in cardiac sympathetic nerves in heart failure. In the cardiomyopathy of the Syrian hamster, reduction in tissue stores and increased turnover of norepinephrine is clearly associated with excessive sympathetic stimulation but in animal models and humans with heart failure secondary to mechanical overload there is evidence for depression of neuronal uptake. Because norepinephrine is both released and taken up by sympathetic fibers it is impossible to assess norepinephrine kinetics in an intact heart without separating these two functions. A technique for doing so has recently been developed in normal dogs and we therefore acquired similar data in humans with heart failure secondary to chronic pressure and volume overload. The technique involves the combination of transient norepinephrine tracer coronary sinus outflow in relation to intravascular and interstitial references after simultaneous injection into the left coronary artery and the measurement of endogenous norepinephrine concentrations in artery and coronary sinus. We found a marked reduction in cardiac norepinephrine release and uptake in a group of patients with clinical left ventricular failure secondary to mechanical overload, relative to a group of patients with no failure. Norepinephrine balance and overflow across the heart were not significantly different. We conclude that there is hypofunction of the cardiac sympathetic nerves in heart failure secondary to mechanical overload and that traditional methods are inadequate in assessing cardiac norepinephrine kinetics when there are simultaneous changes in neuronal uptake and release.
The C-type Lectin Receptors Dectin-1, MR, and SIGNR3 Contribute Both Positively and Negatively to the Macrophage Response to Leishmania infantum
Authors: Lise Lefèvre, Geanncarlo Lugo-Villarino, Etienne Meunier, Alexis Valentin, David Olagnier, Hélène Authier, Carine Duval, Christophe Dardenne, José Bernad, Jean loup Lemesre, Johan Auwerx, Olivier Neyrolles, Bernard Pipy, Agnès Coste
Journal: Immunity (2013)
Appearance of sinusoidal inclusion-containing endothelia cells in liver disease
Authors: Shinichi Iwamura, Hideaki Enzan, Toshiji Saibara, Saburo Onishi, Yasutake Yamamoto
Journal: Hepatology (1994)

Sinusoidal "inclusion-containing endothelial cells" were studied histopathologically and immunohistochemically in various liver diseases, and their clinical importance was investigated. A total of 498 needle liver biopsies were examined. Endothelial inclusions inside the cells were recognized as eosinophilic granules in hematoxylin-eosin-stained sections. Electron microscopy showed that these inclusions corresponded to round cytoplasmic dense bodies with a single limiting membrane. The contents of these bodies were generally homogeneous, but sometimes heterogeneous. The inclusions appeared to contain protein, but were resistant to trypsin digestion, and immunohistochemistry failed to identify any immunoglobulins or hepatocyte-derived proteins. These endothelial cells also contained an increased number of micropinocytotic vesicles when compared with ordinary cells. The inclusion-containing endothelial cells appeared frequently in chronic hepatitis, but were relatively rare in other liver diseases. The incidence was higher in chronic aggressive hepatitis than in chronic persistent hepatitis or inactive cirrhosis. Although the density of these cells varied considerably even among patients with the same histological diagnosis and the phenotypical changes of these endothelial cells, assessed by monoclonal antibodies, were not apparent, the serum gamma globulin level tended to increase in relation to the density of inclusion-containing endothelial cells and the correlation was significant in hepatitis C.
THE PULMONARY ABNORMALITIES IN MYXEDEMA*†
Authors: William R. Wilson, George N. Bedell
Journal: Journal of Clinical Investigation (1960)

The purpose of this paper is to report a study of lung function in patients with myxedema.Re- cently we studied 28 obese persons and found 10 who had alveolar hypoventilation manifested by increased arterial Pco2 (2).They had either lung disease or myxedema in association with their obesity.The nature of pulmonary involvement in patients with myxedema has not been studied.Why did patients with obesity and myxedema de- velop alveolar hypoventilation?We postulated that patients with myxedema might have one or all of the following: a depression of the respiratory center in the brain, interference with neural con- duction or with neuromuscular transmission to the respiratory muscles, disease of the respiratory muscles, or a change in the character of the alveolar capillary membrane.The existence of central nervous system abnor- malities in myxedema is known.In 1904, Gull (3) included myxedema under "Diseases of the Nervous System" in a collection of his writings.Scheinberg, Stead, Brannon and Warren (4) measured cerebral blood flow in eight patients with myxedema by the nitrous oxide technique and found that the average cerebral blood flow was 38 per cent below normal, oxygen and glucose consumption 27 per cent below normal, and cere- bral vascular resistance 91 per cent above normal.Browning, Atkins and Weiner (5) found en- cephalographic changes in seven psychotic adults with myxedema.The electroencephalogram re- turned toward normal as the patient's myxedema improved.These are a few of the many studies
Phase I/II Trial of Bevacizumab and Radiotherapy for Locally Advanced Inoperable Colorectal Cancer: Vasculature-Independent Radiosensitizing Effect of Bevacizumab
Authors: Michael I. Koukourakis, Alexandra Giatromanolaki, Helen Sheldon, Francesca M. Buffa, George Kouklakis, Ioannis Ragoussis, Efthimios Sivridis, Adrian L. Harris
Journal: Clinical Cancer Research (2009)

Anti-vascular endothelial growth factor therapy enhances the activity of radiotherapy in experimental models, and bevacizumab has therapeutic activity in patients with metastatic colorectal cancer.Twenty-two patients with locally advanced inoperable colorectal carcinomas (LA/I-CRC) were treated with conformal hypofractionated (3.4 Gy/fraction x 15) split-course accelerated radiotherapy (biological equivalent dose, 67.2 Gy) supported with amifostine, capecitabine (600 mg/m2 daily, 5 days/week), and bevacizumab (5 mg/kg every 2 weeks, five cycles). Biopsies from nine patients, performed before and 1 week after bevacizumab administration, were analyzed for changes in mRNA expression with Illumina gene arrays.No serious grade 3 chemotherapy-related side effects were recorded. There was low acute toxicity, with moist perineal desquamation noted in 2 of 22 patients, diarrhea grade 2 to 3 in 5 of 22 patients, and severe proctalgia in 2 of 22 patients. One patient died from Fournier's gangrene before treatment completion. Within a median follow-up of 18 months, two patients with preradiotheraphy direct involvement of adjacent organs expressed recto-vaginal/perineal fistula. Out of 19 evaluable cases, 13 (68.5%) showed complete response and 4 showed (21.1%) partial response. Fourteen patients are alive with no evidence of loco-regional relapse. In the gene array analysis, 30 known genes associated with transcription factors, DNA repair, and proliferation were downregulated by bevacizumab. DUSP1 gene was the most consistently downregulated transcript.The combination of radiotherapy with bevacizumab is feasible and results in a high rate of durable complete responses in patients with LA/I-CRC. Radiosensitization may occur through a direct effect on tumor cells followed by a wide scale suppression of transcription factors and genes involved in DNA repair and proliferation.
The Use of Superlatives in Cancer Research
Authors: Matthew V. Abola, Vinay Prasad
Journal: JAMA Oncology (2015)

from work, child care, and transportation could also improve access to clinical trials for lower-income patients.Future research should investigate how to overcome financial barriers to clinical trial participation.The identification of patient income level as an independent predictor of trial participation is important for multiple reasons.If income is associated with health status, then improving representativeness of lower-income patients in trials would improve the generalizability of study outcomes.Also, greater participation of lower-income patients would allow trials to be conducted more quickly, speeding the development of new treatments.Crucially, since clinical trial treatments represent the newest available treatments, access to this vital resource should be available to individuals of all income levels.