tbuckley/cabot-search huggingface dataset:
Cytokine signals through PI-3 kinase pathway modulate Th17 cytokine production by CCR6+ human memory T cells
Authors: Qi Wan, Lina Kozhaya, Aimee ElHed, Radha Ramesh, Thaddeus J. Carlson, Ivana M. Djuretic, Mark S. Sundrud, Derya Unutmaz
Journal: The Journal of Experimental Medicine (2011)

Human memory T cells (TM cells) that produce IL-17 or IL-22 are currently defined as Th17 or Th22 cells, respectively. These T cell lineages are almost exclusively CCR6+ and are important mediators of chronic inflammation and autoimmunity. However, little is known about the mechanisms controlling IL-17/IL-22 expression in memory Th17/Th22 subsets. We show that common γ chain (γc)–using cytokines, namely IL-2, IL-7, and IL-15, potently induce Th17-signature cytokine expression (Il17a, Il17f, Il22, and Il26) in CCR6+, but not CCR6−, TM cells, even in CCR6+ cells lacking IL-17 expression ex vivo. Inhibition of phosphoinositide 3-kinase (PI-3K) or Akt signaling selectively prevents Th17 cytokine induction by γc-cytokines, as does ectopic expression of the transcription factors FOXO1 or KLF2, which are repressed by PI-3K signaling. These results indicate that Th17 cytokines are tuned by PI-3K signaling in CCR6+ TM cells, which may contribute to chronic or autoimmune inflammation. Furthermore, these findings suggest that ex vivo analysis of IL-17 expression may greatly underestimate the frequency and pathogenic potential of the human Th17 compartment.
The Role of TLR4 in Chemotherapy-Driven Metastasis
Authors: Sophia Ran
Journal: Cancer Research (2015)

Tumor resistance to cytotoxic drugs is one of the main obstacles to successful cancer therapy. Emerging evidence suggests that chemoresistance is promoted by substances released from dead and damaged cells that activate the host repair program orchestrated by Toll-like receptor-4 (TLR4). TLR4 is often overexpressed in malignant and tumor-infiltrating immune cells. In addition to endogenous ligands released by therapy-induced tumor destruction, TLR4 is directly activated by paclitaxel, one of the most commonly used chemotherapeutic drugs against various human cancers. TLR4 activation promotes local and systemic inflammation, leading to induction of multiple circuits that create a regenerative environment favoring local recurrence and metastasis. Of particular importance is TLR4-mediated recruitment of endothelial progenitors derived from immature myeloid cells. These cells play a major role in rebuilding tumor-associated lymphatic and blood vessels, thereby promoting lymphatic and hematogenous metastasis. The latter is further enhanced by the premetastatic niche generated by mobilization of myeloid provascular cells to distant organs. This review summarizes the recent evidence demonstrating that paclitaxel and other clinically used anticancer drugs actively induce metastasis even while shrinking the primary tumor. Better understanding of the mechanisms underlying TLR4-dependent chemotherapy-driven metastasis might be the key to overcoming challenges of cancer eradication.
THE POSTMORTEM RIGOR OF THE MAMMALIAN HEART AND THE INFLUENCE OF AN ANTEMORTEM STIMULATION OF THE PNEUMOGASTRIC NERVES UPON ITS DEVELOPMENT
Authors: Don R. Joseph, S. J. Meltzer
Journal: The Journal of Experimental Medicine (1909)

In normal animals (dogs, cats and rabbits) which were killed by exsanguination, the beginning of rigor in practically all cases was separated from respiratory death by two well characterized periods: (1) a period of pulsation during which each ventricle still exhibited some spontaneous contractions, and (2) a period of relaxation during which the ventricles, while showing neither spontaneous contractions nor rigor, are more relaxed than in normal diastole, and during which the ventricles gradually lose their irritability. (The cardiac rigor or tonic contraction which was observed by recent investigators to set in immediately after death is an artificial phenomenon produced by filling the heart with saline and connecting it with a manometer.) In the right ventricle both periods are longer than in the left ventricle, i. e., rigor sets in later. Moreover the development of rigor from onset to maximum is also longer in the right ventricle than in the left, although here the difference is less striking. The stopping of spontaneous beating, the disappearance of irritability, and the development of rigor, manifest in both ventricles a topographical progress from the base toward the apex, i. e., the stoppage of beating, the disappearance of irritability and the setting in of rigor occur first at the uppermost part of the ventricle and last at the lowest point of the ventricle. It often occurred that rigor was already present in the basal part of a ventricle while the apex was still beating. It is probable also that the loss of vital activity and irritability and the development of rigor progress topographically from the endocardial to the epicardial surfaces. Prolonged etherization retards the onset, but hastens the development of rigor; atropinization hastens both onset and development. Repeated prolonged stoppages of the heart caused by antemortem (and postmortem) stimulations of the pneumogastric nerves hasten the onset as well as the development of rigor of the heart. All three periods are affected by the inhibitory influence of the stimulation, the period of relaxation, however, seems to be the one which is shortened most. The most probable interpretation of this phenomenon is the assumption that it is caused by an asphyxiation of the cardiac tissues. The stimulations of the pneumogastric nerves seem to hasten also the onset of the general rigor—probably this, too, is the result of some premature asphyxiation of the skeletal muscles.
Presentation of Telomerase Reverse Transcriptase, a Self-Tumor Antigen, is Down-regulated by Histone Deacetylase Inhibition
Authors: Ilenia Pellicciotta, Xochitl Cortez-Gonzalez, Roman Sasik, Yoram Reiter, Gary Hardiman, Pierre Langlade-Demoyen, Maurizio Zanetti
Journal: Cancer Research (2008)

Histone deacetylases (HDAC) modify the architecture of chromatin, leading to decreased gene expression, an effect that is reversed by HDAC inhibition. The balance between deacetylation and acetylation is central to many biological events including the regulation of cell proliferation and cancer but also the differentiation of immune T cells. The effects of HDAC inhibition on the interaction between antitumor effector T cells and tumor cells are not known. Here, we studied presentation of a universal self-tumor antigen, telomerase reverse transcriptase, in human tumor cells during HDAC inhibition. We found that HDAC inhibition with trichostatin A was associated with a decreased presentation and diminished killing of tumor cells by CTLs. Using gene array analysis, we found that HDAC inhibition resulted in a decrease of genes coding for proteasome catalytic proteins and for tapasin, an endoplasmic reticulum resident protein involved in the MHC class I pathway of endogenous antigen presentation. Our findings indicate that epigenetic changes in tumor cells decrease self-tumor antigen presentation and contribute to reduced recognition and killing of tumor cells by cytotoxic T lymphocytes. This mechanism could contribute to tumor escape from immune surveillance.
Arthropathy in Sickle-Cell Disease
Authors: H. RALPH SCHUMACHER
Journal: Annals of Internal Medicine (1973)

Individuals with sickle-cell disease may develop gout, septic arthritis, osteomyelitis, aseptic osteonecrosis, and possibly hemarthrosis. Other patients have only arthralgia or joint effusions. These effusions, studied here for the first time, are "noninflammatory," despite the frequent acute onset, warmth, and tenderness that might clinically suggest other types of arthritis. Joint effusions most often occurred with other evidences of painful crises. Synovial biopsies in five patients, aged 6 to 29 years, showed microvascular thrombosis that, along with vascular occlusion in adjacent tissues, may be the mechanism for the effusions. Sickled erythrocytes in effusions can suggest sickle-cell arthropathy. Adjacent bones may show evidence of previous infarctions.
Mechanism by which inhaled bronchodilators prevent exacerbations in chronic obstructive pulmonary disease
Authors: Worawan Sirichana, Chi-Hong Tseng, Igor Barjaktarevic, Eric C. Kleerup, Christopher B. Cooper
Journal: European Respiratory Journal (2013)

Introduction   Large-clinical trials show that various medications decrease exacerbation frequency (E) in chronic obstructive pulmonary disease (COPD). The mechanism is not understood but could relate to symptom relief (reducing exacerbation reporting), improved airway patency (promoting clearance of secretions and reduced bacterial colonization) or a true anti-inflammatory action of the bronchodilator therapy.   Aims and Objectives   We examined the hypothesis that improved airway patency is responsible for reducing E by studying the relationship between the risk reduction for exacerbations and changes in forced expiratory volume in one second (dFEV 1 ) during published clinical trials.   Methods   We included 10 COPD clinical trials and used meta-regression analysis to calculate the overall association between risk reduction for exacerbations and dFEV 1  (where dFEV 1  between parallel groups was calculated by adding differences at randomization plus those due to treatment).   Results   Altogether, 22,280 subjects were included in the analysis representing 52,031 years of patient observation. Mean E was 1.29 (0.73-2.41) /patient-year and mean FEV 1  was 44.1%. The data estimate an increase in FEV 1  of 100 ml is associated with a risk reduction for exacerbations of 0.31 /patient-year (SE 0.075, p=0.00004).   Conclusions   Using meta-regression analysis of 10 clinical trials in COPD, a significant correlation was found between changes in FEV 1  and decreased exacerbation rate. These findings support the hypothesis that improved airway patency through bronchodilatation is responsible for preventing exacerbations perhaps by improving pulmonary hygiene and reducing bacterial colonization.
Morphologic Evidence for Retrovirus Production by Epithelial Cells Derived From a Human Testicular Tumor Metastasis: Brief Communication 2
Authors: David L. Bronson, Donna M. Ritzi, Elwin E. Fraley, Albert J. Dalton
Journal: JNCI Journal of the National Cancer Institute (1978)

Ultrastructural examination of primary and subcultured epithelial cells established in vitro from an abdominal metastasis of a human testicular tumor revealed particles with the morphology of retroviruses. These structures, found only after extensive scanning of the cells, were observed budding from microvilli and from the outer cell membrane and as extracellular particles. Production of these virus particles was stimulated by the incubation of cells in culture medium containing 5-iodo-2′-deoxyuridine and dexamethasone.
General practice fundholding: Delivers what patients want
Authors: T Richardson, R Singer, E D M Tod, A Birchall, B A Sides, B Rumball, D G Black, A D Birchall, I M G Trimble, S O Fradd, J A G Paris, K Williams, M Waterland
Journal: BMJ (1994)

EDITOR, - Steve Iliffe and Ulrich Freudenstein decry the lack of scientific evaluationof fundholding yet offer none themselves.1 The costs of administering fundholding are less than the equivalent costs of managing a district health authority. During any period of transition some costs will be duplicated, but this will be rectified with the forthcoming changes in the configurations of both regional and districthealth authorities.

The political costs of “fast tracking” are a matter of opinion, perhaps coloured by ideology. My experience as a fundholder is that NHS providers, including consultants, are offering fast tracking to fundholders. We have not requested it specifically. It is surprising that so many specialists object to fast tracking (rather than it being the disadvantaged patients who object) but willingly fast track private patients.

Where is the evidence that fundholders cannot be ruthless as purchasers? Fundholders may be limited in choice, particularly in rural areas, but it is they who are making the most important changes to the way health care is provided for their patients. Increasinglythey are managing extended services, providing consultant clinics and physiotherapy on site and more counselling. Many are also now developing services such as radiology, ultrasonography, colposcopy, and minor and day case surgery on site.

Fundholders will act in concert with local health policies but only if those policies have been discussed and are thought to be in the interest of their patients. It is up to district health authorities to include fundholding as well as non-fundholding general practitioners in discussions.

The changes made by fundholders, with increasing provision of services in the community, facilitate rationalisation (deinstitutionalisation) of the often inefficient secondarycare system. In secondary care too many resources are tied up in underused and duplicatedfixed items such as estates, equipment, and sometimes specialist staff. Patients want quick, efficient, and cost …
Epiregulin as a Major Autocrine/Paracrine Factor Released From ERK- and p38MAPK-Activated Vascular Smooth Muscle Cells
Authors: Masanori Takahashi, Ken’ichiro Hayashi, Kenji Yoshida, Yasuyuki Ohkawa, Toshi Komurasaki, Akira Kitabatake, Akira Ogawa, Wataru Nishida, Masahiko Yano, Morito Monden, Kenji Sobue
Journal: Circulation (2003)

The coordinated activation of extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (p38MAPK) is critical for the induction of vascular and visceral smooth muscle cell (SMC) dedifferentiation. We previously reported that on the forced activation of both MAPKs, visceral SMCs secrete a non-heparin-binding protein factor(s) that is involved in the dedifferentiation of neighboring SMCs. In this study, we sought to identify the dedifferentiation factor(s) derived from vascular SMCs (VSMCs).We fractionated the VSMC dedifferentiation factor(s) in the conditioned medium obtained from differentiated VSMCs in which both ERK and p38MAPK were forcedly activated and identified epiregulin as a major autocrine/paracrine factor for VSMC dedifferentiation. The epiregulin-induced VSMC dedifferentiation was mediated through the coordinated activation of ERK and p38MAPK. Unsaturated lysophosphatidic acid and platelet-derived growth factor-BB, which are potent VSMC dedifferentiation factors, rapidly upregulated epiregulin mRNA expression in an ERK- and p38MAPK-dependent manner. Reverse transcriptase-polymerase chain reaction and/or immunohistological analyses revealed the restricted expression of epiregulin in human atherosclerotic and balloon-injured rat arteries, in which the phenotypic modulation of medial VSMCs occurred in vivo.Epiregulin is released from VSMCs primed by atherogenic factors and acts as a major autocrine/paracrine factor for VSMC dedifferentiation. It may be involved in the progression of vascular remodeling such as atherosclerosis.
The new definition of pulmonary hypertension
Authors: M. M. Hoeper
Journal: European Respiratory Journal (2009)

Despite the progress that has been made in the field of pulmonary hypertension (PH) 1–3, there is no unifying and globally accepted definition of the condition. The first official haemodynamic definition of PH was proposed at the First World Symposium on Pulmonary Hypertension which took place 1973 in Geneva, Switzerland as a World Health Organization (WHO)-sponsored meeting 4. This conference was triggered by the previous epidemic of PH associated with the appetite suppressant aminorex 5. As such, the focus of that meeting was primary pulmonary hypertension (PPH), as compared to the other forms of PH. After a long and sometimes heated debate the consensus was to define PPH by a mean pulmonary artery pressure ( P pa) >25 mmHg at rest or >30 mmHg during exercise in the presence of a pulmonary capillary wedge pressure ( P pcw) ≤15 mmHg.

This definition was later extended to other forms of pulmonary arterial hypertension (PAH) 6. It stood the test of time for >30 yrs, but was challenged during the Fourth World Symposium on Pulmonary Hypertension, which took place 2008 in Dana Point, CA, USA. There were several reasons for this: 1) the old definition did not take into account other forms of PH; 2) the threshold of P pa …
Wrist cysts and fistulae. An arthrographic study of the rheumatoid wrist.
Authors: J M Iveson, A G Hill, V Wright
Journal: Annals of the Rheumatic Diseases (1975)

An arthrographic study of the wrist joint, in which 65 rheumatoid wrist joints were satisfactorily shown, gave a high incidence of significant abnormalities even in the absence of clinical signs of wrist involvement. Several synovial protrusion cysts were shown and corresponded to localized clinical swellings on the volar aspect of the wrist joint. These cystic swellings may be apparent before the onset of polyarthritis and may be differentiated from ganglia arthrographically by their association with other features suggesting erosive synovitis. Cystic swelling over the lower end of the ulna is shown to be frequently due to synovial hypertrophy of the inferior radioulnar joint in either a dorsal or volar direction. In one case a fistulous tract was delineated connecting the midcarpal joint with the volar surface of the wrist by a flexor tendon sheath.
Inflammatory Actions, and their Treatment
Authors: C. H. Jones
Journal: BMJ (1857)

necessary by this observer.(See, moreover, a most interesting case, detailed in p. 33'9 of his work.)There yet remains a phenomenon in the case I have re- corded which requires comment; I allude to the partial reap- pearance of a weak respiratory murmur over a portion of the postero-middle region, towards the close of the case.If this were not a conducted murmur from the right lung (which was doubted by some observers), I can only explain it on the hypo- thesis that a portion of the tumour had yielded, and permitted part of the left lung to expand into its place.Finally, witlh reference to the differential diagnosis of intra- thoracic tumiiour: wheln we consider the possible sources of error inseparable from the velry nature of certain cases of chest affections and their associate signs, such as those very recently described by Drs.Moutard-Mlartin and Oulmont (Mied.-Chir.Review, Oct. 1856); aind when we find how, at times, the very ablest observers have been at fault in the diagnosis of ma- lignant disease of the chest, alike from the consideration of the symptoms and the physical signs (the latter, perhaps, are at their minimnum of value here), we cite, in special illustration, the well known cases of Boerhaave, Corvisart, Graves, and Stokes, etc., others of less ability may well be excused for hesitancy and doubt.Indeed, it vould appear, from a careful collation of the eases extant, that where the family history shows an absence of cancerous disease, where the expectorationi is simply catarrlhal, marked signs of centiic pressure absent, and no ex- ternal tuimour preseint, the physical signs and symptoms corre- spond so closely with those of pleuirisy, either general or Cir- cumscribed, that the diagnosis of ilntrathoracic cancer, at its early stages, is in most cases difficult, and in others, perhaps, occasionally impossible.At the samne time, it mnust be borne in rmind that relapsing pleurisy, witlh paini more or less constant, and radiating far and wide, combined with alteration of the chest-wall, and obstinately intractable to treatment, should at all times excite grave suspicion.
The Prevalence of Clinically Recognized Obsessive-Compulsive Disorder in a Large Health Maintenance Organization
Authors: Bruce Fireman, Lorrin M. Koran, Jeanne L. Leventhal, Alice Jacobson
Journal: American Journal of Psychiatry (2001)

OBJECTIVE: Little is known about the prevalence of obsessive-compulsive disorder (OCD) as recognized in clinical settings. The authors report data on the prevalence of clinically recognized OCD in a large, integrated, group practice health maintenance organization (HMO). METHOD: The authors examined the database of outpatient diagnoses for the 1.7 million people (age ≥6) in the San Francisco Bay Area and Sacramento who were continuously enrolled in Kaiser Permanente from May 1995 through April 1996. OCD diagnoses were confirmed by chart review. RESULTS: The 1-year prevalence of clinically recognized OCD was 84/100,000 (95% confidence interval: 80–89/100,000), or 0.084%. It varied among the 19 clinics within the HMO but was nowhere higher than 150/100,000. Prevalence was higher among women than among men but was higher among boys than among girls. Above age 65, OCD prevalence decreased markedly in both genders. Period prevalence rates increased by 60% as the length of the study period doubled from 1 to 2 years, more than would be expected for a chronic disease requiring regular care. About three-quarters of both children and adults with OCD had comorbid psychiatric diagnoses; major depression was common in both groups. CONCLUSIONS: Although previously reported prevalences of 1%–3% from community studies may have included many transient or misclassified cases of OCD not requiring treatment, the very low prevalence of clinically recognized OCD in this population suggests that many individuals suffering from OCD are not receiving the benefits of effective treatment.
p53-Binding Protein 1 Is Fused to the Platelet-Derived Growth Factor Receptor β in a Patient with a t(5;15)(q33;q22) and an Imatinib-Responsive Eosinophilic Myeloproliferative Disorder
Authors: Francis H. Grand, Sonja Burgstaller, Thomas Kühr, E. Joanna Baxter, Gerald Webersinke, Josef Thaler, Andrew J. Chase, Nicholas C. P. Cross
Journal: Cancer Research (2004)

Abstract We describe the fusion of TP53BP1 to PDGFRB in a patient with a chronic myeloid leukemia-like disorder associated with eosinophilia and a t(5;15)(q33;q22). TP53BP1 encodes 53BP1, a p53-binding protein that plays a role in cellular responses to DNA damage. The 53BP1-PDGFRβ fusion protein is predicted to retain the kinetochore-binding domain of 53BP1 fused to the transmembrane and intracellular tyrosine kinase domain of PDGFRβ. The presence of the fusion was confirmed by two-color fluorescence in situ hybridization, reverse transcription-PCR, and by characterizing the genomic breakpoints. The reciprocal fusion, which would contain the p53-binding 53BP1 BRCA1 COOH-terminal domains, was not detectable by fluorescence in situ hybridization or nested PCR. Imatinib, a known inhibitor of PDGFRβ, blocked the growth of patient colony-forming unit, granulocyte-macrophage in vitro and produced a clinically significant response before relapse and subsequent death with imatinib-resistant disease. We conclude that TP53BP1-PDGFRB is a novel imatinib target in atypical chronic myeloid leukemia.
Severe bleomycin lung toxicity: reversal with high dose corticosteroids.
Authors: J Maher, P A Daly
Journal: Thorax (1993)

A 42 year old man, treated for testicular carcinoma with combination chemotherapy that included bleomycin, developed life threatening interstitial pneumonitis. He recovered successfully after treatment with very high doses of corticosteroids and azathioprine. This report suggests that bleomycin lung toxicity may be reversible if treated aggressively.
New equipment optimized for emulsified vaccine prepation in the hospital
Authors: Stephane Ascarateil, Marie Eve Koziol
Journal: Journal for ImmunoTherapy of Cancer (2013)

Meeting abstracts Developing stable formulations is generally a common target to obtain efficacious emulsified vaccines. Process used to perform water in oil (W/O) emulsions are not all equivalent regarding vaccines physico-chemical parameters. Equipment generally used to realise emulsified