tbuckley/cabot-search huggingface dataset:
Immune Escape Associated with Functional Defects in Antigen-Processing Machinery in Head and Neck Cancer
Authors: Robert L. Ferris, Theresa L. Whiteside, Soldano Ferrone
Journal: Clinical Cancer Research (2006)

Abstract Recent revival of interest in the role of immune surveillance in the pathogenesis and control of malignant diseases has focused attention on escape mechanisms used by tumor cells to evade immune recognition. Defects in the host's tumor antigen–specific immune responses and abnormalities in tumor cell expression of HLA class I molecules and tumor antigen are known to contribute to tumor progression. However, the mechanism(s) responsible for the lack of tumor cell recognition by functional HLA class I antigen–restricted, tumor antigen–specific CTLs despite expression of the restricting HLA class I allele and targeted tumor antigen by tumor cells remain(s) unexplained. In squamous cell carcinomas of the head and neck (SCCHN), this type of tumor escape is a rule rather than the exception. Here, we discuss evidence pointing to functional defects in the antigen-processing machinery as one mechanism underlying resistance of SCCHN cells to recognition and lysis by HLA class I antigen–restricted, tumor antigen–specific CTL. In addition, based on the restoration by IFN-γ of SCCHN cell sensitivity to recognition by these CTL, we suggest strategies that may improve the clinical course of the disease by enhancing susceptibility of malignant cells to immune recognition.
Antipsychotic Drugs: Importance of Dopamine Receptors for Mechanisms of Therapeutic Actions and Side Effects
Authors: P G Strange
Journal: Pharmacological Reviews (2001)

Interaction of the antipsychotic drugs with dopamine receptors of the D2, D3, or D4 subclasses is thought to be important for their mechanisms of action. Consideration of carefully defined affinities of the drugs for these three receptors suggests that occupancy of the D4 subclass is not mandatory for achieving antipsychotic effects, but actions at D2 or D3 receptors may be important. A major difference between typical and atypical antipsychotic drugs is in the production of extrapyramidal side effects by the typical drugs. Production of extrapyramidal side effects by typical drugs seems to be due to the use of the drugs at doses where striatal D2 receptor occupancy exceeds approximately 80%. Use of these drugs at doses that do not produce this level of receptor blockade enables them to be used therapeutically without producing these side effects. The antipsychotic drugs have been shown to act as inverse agonists at D2 and D3 dopamine receptors, and this property may be important for the antipsychotic effects of the drugs. It is suggested that the property of inverse agonism leads to a receptor up-regulation upon prolonged treatment, and this alters the properties of dopamine synapses. Several variants of the dopamine receptors exist with different DNA sequences and in some cases different amino acid sequences. These variants may have different properties that alter the effects of dopamine and the antipsychotic drugs. The determination of such variants in patients may help in the prediction of drug responsiveness.
Randomized Cross-Over Trial of Insulin Glargine Plus Lispro or NPH Insulin Plus Regular Human Insulin in Adolescents With Type 1 Diabetes on Intensive Insulin Regimens
Authors: Nuala P. Murphy, Suzanne M. Keane, Ken K. Ong, Martha Ford-Adams, Julie A. Edge, Carlo L. Acerini, David B. Dunger
Journal: Diabetes Care (2003)

OBJECTIVE—To compare blood glucose control and incidence of nocturnal hypoglycemia in adolescents with type 1 diabetes on multiple injection regimens managed with either an insulin analog combination or NPH insulin plus regular human insulin. RESEARCH DESIGN AND METHODS—In a randomized cross-over study, 28 adolescents with type 1 diabetes on multiple injection therapy received either insulin glargine prebedtime plus lispro preprandially (LIS/GLAR) or NPH insulin prebedtime plus regular human insulin preprandially (R/NPH). During each 16-week treatment arm, subjects completed home blood glucose profiles, and at the end of each treatment arm, they were admitted for an overnight metabolic profile. A total of 25 subjects completed the study. RESULTS—Compared with R/NPH therapy, LIS/GLAR was associated with lower mean blood glucose levels (LIS/GLAR versus R/NPH): fasting (8.0 vs. 9.2 mmol/l, P &amp;lt; 0.0001), 2 h postbreakfast (8.1 vs. 10.7 mmol/l, P &amp;lt; 0.0005), prelunch (8.9 vs. 10.1 mmol/l, P &amp;lt; 0.01), and 2 h postlunch (8.0 vs. 9.5 mmol/l, P &amp;lt; 0.002). However, there was no difference in mean blood glucose levels before or after the evening meal. Incidence of nocturnal hypoglycemia on overnight profiles was 43% lower on LIS/GLAR compared with R/NPH therapy; however, there was no difference in rates of self-reported symptomatic hypoglycemia. Total insulin dose required to achieve target blood glucose control was lower on LIS/GLAR (1.16 IU/kg) compared with R/NPH therapy (1.26 IU/kg, P &amp;lt; 0.005), but there was no significant difference in HbA1c levels (LIS/GLAR versus R/NPH: 8.7 vs. 9.1%, P = 0.13). CONCLUSIONS—Combination therapy with insulin glargine plus lispro reduced the incidence of nocturnal hypoglycemia and was at least as effective as R/NPH insulin therapy in maintaining glycemic control in adolescents on multiple injection regimens.
Particulate matter exposure and differences in pulmonary vascular structure: The MESA lung and air pollution studies
Authors: Carrie P. Aaron, Eric A. Hoffman, Karen Hinckley Stukovsky, John H.M. Austin, Karol E. Watson, Matthew Budoff, Steven M. Kawut, Joel D. Kaufman, R. Graham Barr
Journal: European Respiratory Journal (2014)

Rationale:  Exposure to particulate matter l2.5μ in diameter (PM 2.5 ) has been associated with increased mortality. After inhalation, PM 2.5  may have direct effects on the pulmonary circulation. We hypothesized that PM 2.5  exposure would be associated with pulmonary vascular changes on CT in a large population-based study.   Methods:  The Multi-Ethnic Study of Atherosclerosis (MESA) enrolled participants 45-84 years old without clinical cardiovascular disease. The MESA Lung Study measured total pulmonary vascular volume (TPVV) on non-contrast CT. TPVV is the sum of the volumes of arteries and veins (≥ approx. 1mm) per unit lung in the 2cm “peel” (Figure). Exposures to outdoor residential PM 2.5  in the year prior to CT were estimated by a spatiotemporal model. Linear regression adjusted for age, sex, race, education, height, weight, smoking and scanner terms.   Results:  Mean PM 2.5  exposure of the 2675 participants (69±9 years, 47% male, 46% never smokers) was 11.1±1.5 μg/m 3 . Mean TPVV was 2.29 cm 3  vessel/cm 3  lung. In the fully adjusted model a 5 μg/m 3  increase in PM 2.5  was associated with an increase in TPVV (0.06 cm 3  vessel/cm 3  lung; Pl0.001).   Conclusions:  Exposure to PM 2.5  was associated with increased TPVV, suggesting that PM 2.5  may contribute to pulmonary vascular changes including microvascular damage.
5-Hydroxymethylcytosine Is Strongly Depleted in Human Cancers but Its Levels Do Not Correlate with <i>IDH1</i> Mutations
Authors: Seung-Gi Jin, Yong Jiang, Runxiang Qiu, Tibor A. Rauch, Yinsheng Wang, Gabriele Schackert, Dietmar Krex, Qiang Lu, Gerd P. Pfeifer
Journal: Cancer Research (2011)

The base 5-hydroxymethylcytosine (5hmC) was recently identified as an oxidation product of 5-methylcytosine in mammalian DNA. Here, using sensitive and quantitative methods to assess levels of 5-hydroxymethyl-2'-deoxycytidine (5hmdC) and 5-methyl-2'-deoxycytidine (5mdC) in genomic DNA, we investigated whether levels of 5hmC can distinguish normal tissue from tumor tissue. In squamous cell lung cancers, levels of 5hmdC were depleted substantially with up to 5-fold reduction compared with normal lung tissue. In brain tumors, 5hmdC showed an even more drastic reduction with levels up to more than 30-fold lower than in normal brain, but 5hmdC levels were independent of mutations in isocitrate dehydrogenase-1. Furthermore, immunohistochemical analysis indicated that 5hmC is remarkably depleted in many types of human cancer. Importantly, an inverse relationship between 5hmC levels and cell proliferation was observed with lack of 5hmC in proliferating cells. The data therefore suggest that 5hmdC is strongly depleted in human malignant tumors, a finding that adds another layer of complexity to the aberrant epigenome found in cancer tissue. In addition, a lack of 5hmC may become a useful biomarker for cancer diagnosis.
Macrophage ADAM17 Deficiency Augments CD36-Dependent Apoptotic Cell Uptake and the Linked Anti-Inflammatory Phenotype
Authors: Will S. Driscoll, Tomas Vaisar, Jingjing Tang, Carole L. Wilson, Elaine W. Raines
Journal: Circulation Research (2013)

Rationale: Apoptotic cell phagocytosis (efferocytosis) is mediated by specific receptors and is essential for resolution of inflammation. In chronic inflammation, apoptotic cell clearance is dysfunctional and soluble levels of several apoptotic cell receptors are elevated. Reports have identified proteolytic cleavage as a mechanism capable of releasing soluble apoptotic cell receptors, but the functional implications of their proteolysis are unclear. Objective: To test the hypothesis that ADAM17-mediated cleavage of apoptotic cell receptors limits efferocytosis in vivo. Methods and Results: In vivo comparison of macrophage efferocytosis in wild-type and Adam17 -null hematopoietic chimeras demonstrates that ADAM17 deficiency leads to a 60% increase in efferocytosis and an enhanced anti-inflammatory phenotype in a model of peritonitis. In vitro uptake of phosphatidylserine liposomes identifies the dual-pass apoptotic cell receptor CD36 as a major contributor to enhanced efferocytosis, and CD36 surface levels are elevated on macrophages from Adam17 -null mice. Further, temporal elevation of CD36 expression with inflammation may also contribute to its impact. Soluble CD36 from macrophage-conditioned media comprises 2 species based on Western blotting, and mass spectrometry identifies 3 N-terminal peptides that represent probable cleavage sites. Levels of soluble CD36 are decreased in Adam17 -null conditioned media, providing evidence for involvement of ADAM17 in CD36 cleavage. Importantly, enhanced efferocytosis in vivo by macrophages lacking ADAM17 is CD36 dependent and accelerates macrophage clearance from the peritoneum, thus promoting resolution of inflammation and highlighting the impact of increased apoptotic cell uptake. Conclusions: Our studies demonstrate the importance of ADAM17-mediated proteolysis for in vivo efferocytosis regulation and suggest a possible mechanistic link between chronic inflammation and defective efferocytosis.
Surviving Metabolic Stress: Of Mice (Squirrels) and Men
Authors: William N. Hait, Matthias Versele, Jin-Ming Yang
Journal: Cancer Discovery (2014)

Abstract Summary: Understanding how cancer cells survive harsh environmental conditions may be fundamental to eradicating malignancies proven to be impervious to treatment. Nutrient and growth factor deprivation, hypoxia, and low pH create metabolic demands that require cellular adaptations to sustain energy levels. Protein synthesis is one of the most notable consumers of energy. Mounting evidence implicates exquisite control of protein synthesis as a survival mechanism for both normal and malignant cells. In this commentary, we discuss the role of protein synthesis in energy conservation in cancer and focus on elongation factor-2 kinase, a downstream component of the PI3K–AKT pathway that behaves as a critical checkpoint in energy consumption. Cancer Discov; 4(6); 646–9. ©2014 AACR.
Phosphoinositide-3-Kinase Signaling Controls S-Phase Kinase–Associated Protein 2 Transcription via E2F1 in Pancreatic Ductal Adenocarcinoma Cells
Authors: Maximilian Reichert, Dieter Saur, Rainer Hamacher, Roland M. Schmid, Günter Schneider
Journal: Cancer Research (2007)

Abstract The phosphoinositide-3-kinase (PI3K)/AKT signaling pathway controls fundamental processes of cancer cell biology like proliferation and cell survival. The PI3K/AKT pathway is activated in pancreatic ductal adenocarcinoma (PDAC) cells. The molecular mechanisms linking PI3K signaling to the cell cycle machinery in PDAC cells are not investigated in detail. Using the PI3K inhibitor Ly294002 as well as small interfering RNA targeting AKT1 expression, we show that PI3K controls the proliferation and G1 phase progression of PDAC cells. Gene profiling revealed several important regulators of G1-S phase progression controlled by PI3K signaling like p21Cip1, S-phase kinase–associated protein 2 (SKP2), CDC25a, cyclin A, cyclin D2, CDK2, and cyclin E. We show that the F-box protein SKP2, an oncogene up-regulated in PDAC, is transcriptionally regulated by the PI3K/AKT1 pathway in PDAC cells. At the molecular level, the control of the SKP2 gene by PI3K is due to the regulation of E2F1 binding to the proximal SKP2 gene promoter. The complex and profound connection of PI3K/AKT1 signaling to the cell cycle qualifies this pathway as a suitable target for therapeutic intervention in PDAC. [Cancer Res 2007;67(9):4149–56]
Oncostatin M causes eotaxin-1 release from airway smooth muscle: Synergy with IL-4 and IL-13
Authors: Débora S. Faffe, Lesley Flynt, Matthew Mellema, Paul E. Moore, Eric S. Silverman, Venkat Subramaniam, Matthew R. Jones, Joseph P. Mizgerd, Timothy Whitehead, Amy Imrich
Journal: Journal of Allergy and Clinical Immunology (2005)
Longitudinal Neuropsychological Follow-Up Study of Patients With First-Episode Schizophrenia
Authors: A L Hoff, M Sakuma, M Wieneke, R Horon, M Kushner, L E DeLisi
Journal: American Journal of Psychiatry (1999)

The primary purpose of this article was to determine if cognitive abilities decline, remain unchanged, or modestly improve throughout the course of schizophrenic illness.Forty-two patients with a first hospitalization for schizophrenia or schizophreniform disorder and 16 normal comparison subjects had a battery of neuropsychological tests and a magnetic resonance imaging (MRI) brain scan at approximate yearly intervals for the first 2 to 5 years of illness. Summary rating scales for language, executive, memory, processing speed, and sensory-perceptual functions were constructed.Patients with schizophrenia scored 1 to 2 standard deviations below normal comparison subjects on neuropsychological test measures during the course of the study. Patients exhibited less improvement than comparison subjects on measures of verbal memory. In general, improvement in positive symptoms over the time interval was associated with improvement in cognition. No changes in regional brain measurements were correlated with cognitive change in the patient group.Patients with schizophrenia have considerable cognitive dysfunction in the first 4 to 5 years of illness, which is stable at a level of 1 to 2 standard deviations below that of comparison subjects. There is little evidence for deterioration of cognitive abilities over the first few years of illness, with the exception of verbal memory, which shows significantly less improvement in patients over time relative to that of comparison subjects.
Endogenous Interleukin 4 Is Required for Development of Protective CD4+ T Helper Type 1 Cell Responses to <i>Candida albicans </i>
Authors: Antonella Mencacci, Giuseppe Del Sero, Elio Cenci, Cristiana Fè d'Ostiani, Angela Bacci, Claudia Montagnoli, Manfred Kopf, Luigina Romani
Journal: The Journal of Experimental Medicine (1998)

Interleukin (IL)-4–deficient mice were used to assess susceptibility to systemic or gastrointestinal Candida albicans infections, as well as parameters of innate and elicited T helper immunity. In the early stage of systemic infection with virulent C. albicans, an unopposed interferon (IFN)-γ response renders IL-4–deficient mice more resistant than wild-type mice to infection. Yet, IL-4–deficient mice failed to efficiently control infection in the late stage and succumbed to it. Defective IFN-γ and IL-12 production, but not IL-12 responsiveness, was observed in IL-4–deficient mice that failed to mount protective T helper type 1 cell (Th1)-mediated acquired immunity in response to a live vaccine strain of the yeast or upon mucosal immunization in vivo. In vitro, IL-4 primed neutrophils for cytokine release, including IL-12. However, late treatment with exogenous IL-4, while improving the outcome of infection, potentiated CD4+ Th1 responses even in the absence of neutrophils. These findings indicate that endogenous IL-4 is required for the induction of CD4+ Th1 protective antifungal responses, possibly through the combined activity on cells of the innate and adaptive immune systems.
Running Forward
Authors: Glenn C. Rowe, Adeel Safdar, Zolt Arany
Journal: Circulation (2014)

content in muscle fibers (Figure 2).How does this process occur?Research done during the last 10 years has begun to answer this question at the molecular level (Figure 3).Much of this work has relied on the study of genetically modified mice (eg, that depicted in Figure 4).Rodents are natural-born endurance exercisers.Provided with in-cage running wheels, most mice will voluntarily run 5 to 8 km per night.Although this level of exercise does not precisely model the human condition, the ability to model endurance exercise in an organism amenable to genetic manipulation has proven invaluable.Conceptually, the adaptation process can be divided into mechanisms that sense endurance activity and mechanisms that carry out the desired adaptations (Figure 3). How Does Muscle Sense Exercise Activity? Nerves and EnergyKey molecular sensors of exercise include the calcium oscillations and other signaling cascades activated by neural stimulation and the profoundly altered metabolic state of contracting myofibers.Stimulation of muscle by motor nerves generates cytosolic calcium transients that are detected by various intracellular pathways, including those regulated by the calcium/calmodulin-modulated phosphatase (calcineurin) and kinase (CaMK).Continuous low-amplitude transients, typical of endurance activity, activate calcineurin.Transgenic overexpression of calcineurin in skeletal muscle of mice promotes the formation of slow red fibers. 19Conversely, genetic deletion of calcineurin or treatment with calcineurin inhibitors has the opposing effect, blocking exercise-induced adaptations. 32CaMK is likely another decoder of calcium transients. 33CaMKII is the predominant isoform in skeletal muscle, but experiments with transgenic expression of a constitutively active CaMKIV isoform showed that CaMK can promote the formation of slow red fibers. 30Conversely, mice with decreased CAMKII activity have lower expression of slow genes. 34Sensing of calcium
T cell clones reactive with sperm whale myoglobin. Isolation of clones with specificity for individual determinants on myoglobin.
Authors: A J Infante, M Z Atassi, C G Fathman
Journal: The Journal of Experimental Medicine (1981)

We have been able to isolate clones of sperm whale muscle myoglobin (Mb)-reactive T cells from (C57BL/6 x A/J)F1 [(B6A)F1] mice. Four types of clones were isolated, distinguished by their patterns of recognition of Mb cyanogen bromide (CNBr) fragments and antigen presenting cell (APC) requirements. Individual T cell clones proliferated in response to one of three CNBr fragments of Mb. Dose-response curves of all clones were identical for native Mb and the appropriate fragment. T cell clones reactive to fragment 1-55 did not proliferate in response to peptide 15-22 (a peptide that binds to serum antibody directed against 1-55). These data support previous findings suggesting differences between antigen recognition by T and B cells, i.e., T cells may not recognize antigen in its native conformation and/or T and B cells may recognize distinct epitopes on the same antigen. Using T cell clones to analyze genetic control of responsiveness to Mb, we found that certain (B6A)F1 T cells recognize Mb presented by low responder strain APC. Thus, genetically determined low responsiveness in this case is probably not due to failure of APC function. We also found that responsiveness to certain Mb epitopes mapped to the I-A subregion whereas others mapped, via gene complementation, to the I-A and I-E subregions. We found no examples of responsiveness mapping to the I-C subregion and suggest an alternative explanation for previous reports mapping genetic control of responsiveness to certain Mb determinants to I-C.
The detection and generation of sequences as a key to cerebellar function: Experiments and theory
Authors: Valentino Braitenberg, Detlef Heck, Fahad Sultan
Journal: Behavioral and Brain Sciences (1997)

Starting from macroscopic and microscopic facts of cerebellar histology, we propose a new functional interpretation that may elucidate the role of the cerebellum in movement control. The idea is that the cerebellum is a large collection of individual lines (Eccles's "beams": Eccles et al. 1967a) that respond specifically to certain sequences of events in the input and in turn produce sequences of signals in the output. We believe that the sequence-in/sequence-out mode of operation is as typical for the cerebellar cortex as the transformation of sets into sets of active neurons is typical for the cerebral cortex, and that both the histological differences between the two and their reciprocal functional interactions become understandable in the light of this dichotomy. The response of Purkinje cells to sequences of stimuli in the mossy fiber system was shown experimentally by Heck on surviving slices of rat and guinea pig cerebellum. Sequential activation of a row of eleven stimulating electrodes in the granular layer, imitating a "movement" of the stimuli along the folium, produces a powerful volley in the parallel fibers that strongly excites Purkinje cells, as evidenced by intracellular recording. The volley, or "tidal wave," has maximal amplitude when the stimulus moves toward the recording site at the speed of conduction in parallel fibers, and much smaller amplitudes for lower or higher "velocities." The succession of stimuli has no effect when they "move" in the opposite direction. Synchronous activation of the stimulus electrodes also had hardly any effect. We believe that the sequences of mossy fiber activation that normally produce this effect in the intact cerebellum are a combination of motor planning relayed to the cerebellum by the cerebral cortex, and information about ongoing movement, reaching the cerebellum from the spinal cord. The output elicited by the specific sequence to which a "beam" is tuned may well be a succession of well timed inhibitory volleys "sculpting" the motor sequences so as to adapt them to the complicated requirements of the physics of a multijointed system.
The protection of clean athletes through the IOC research fund
Authors: Richard Budgett, Lars Engebretsen
Journal: British Journal of Sports Medicine (2014)

The IOC as the leader of the Olympic movement and the sport sector at large is committed to the protection of clean athletes for the sake of the future of sport and for the protection of athletes’ health.

To this end, the IOC has committed US$20 million to research the protection of athletes and fair play, half of which will be used for programmes to combat match fixing and illegal betting and half for research into anti-doping.

WADA, jointly funded by the IOC and governments, has …