tbuckley/cabot-search huggingface dataset:
PTEN Level in Tumor Suppression: How Much Is Too Little?
Authors: Arkaitz Carracedo, Andrea Alimonti, Pier Paolo Pandolfi
Journal: Cancer Research (2011)

The importance of PTEN (phosphatase and tensin homolog located on chromosome 10) in cancer has surpassed all predictions and expectations from the time it was discovered and has qualified this gene as one of the most commonly mutated and deleted tumor suppressors in human cancer. PTEN levels are frequently found downregulated in cancer, even in the absence of genetic loss or mutation. PTEN is heavily regulated by transcription factors, microRNAs, competitive endogenous RNAs (such as the PTEN pseudogene), and methylation, whereas the tumor suppressive activity of the PTEN protein can be altered at multiple levels through aberrant phosphorylation, ubiquitination, and acetylation. These regulatory cues are presumed to play a key role in tumorigenesis through the alteration of the appropriate levels, localization, and activity of PTEN. The identification of all these levels of PTEN regulation raises, in turn, a key corollary question: How low should PTEN level(s) or activity drop in order to confer cancer susceptibility at the organismal level? Our laboratory and others have approached this question through the genetic manipulation of Pten in the mouse. This work has highlighted the exquisite and tissue-specific sensitivity to subtle reductions in Pten levels toward tumor initiation and progression with important implications for cancer prevention and therapy.
Pharmacodynamic Studies of Gefitinib in Tumor Biopsy Specimens From Patients With Advanced Gastric Carcinoma
Authors: Federico Rojo, Josep Tabernero, Joan Albanell, Eric Van Cutsem, Atsushi Ohtsu, Toshihiko Doi, Wasaburo Koizumi, Kuniaki Shirao, Hiroya Takiuchi, S. Ramon Cajal, José Baselga
Journal: Journal of Clinical Oncology (2006)

Epidermal growth factor receptor (EGFR) is highly expressed in some gastric cancers and is implicated in cancer cell growth and proliferation. The objective of this study was to assess the in situ biologic activity of the EGFR tyrosine kinase inhibitor gefitinib in gastric tumor samples in a phase II study.Patients with previously treated stage IV adenocarcinoma of the stomach or gastroesophageal junction were randomly assigned to receive gefitinib (250 or 500 mg/d). Tumor biopsies, obtained at screening and on day 28 of treatment, were assessed for biomarker expression using immunohistochemistry and analysis of apoptosis.One hundred sixteen tumor samples from 70 patients were available, 70 were baseline and 46 were on-therapy biopsies. At baseline, levels of EGFR expression significantly correlated with levels of phosphorylated EGFR (pEGFR; P < .001) and Ki67 expression (P = .011), but not with phosphorylated mitogen-activated protein kinase (pMAPK). After gefitinib treatment, levels of pEGFR in tumor cells were significantly reduced (P = .001); this was not the case for pMAPK and phosphorylated Akt (pAkt). However, in some cases gefitinib inhibited pAkt and these tumors had enhanced apoptosis. Likewise, there was a significant correlation between increased exposure to geftinib and enhanced apoptosis.Gefitinib reached the tumors at concentrations sufficient to inhibit EGFR activation in advanced gastric carcinoma patients, although this did not translate into clinical benefit. Overall, intratumoral phosphorylation of MAPK and Akt was not significantly inhibited by gefitinib. However, the finding that decreases in pAkt correlated with enhanced apoptosis deserves further exploration.
Induction of Labour in Contracted Pelvis by Digital Separation of Membranes
Authors: D. C. Wiseman
Journal: BMJ (1944)

MEDICAL MEMORANDAMEDATLt OURNAL 221 varying in diameter from 1/4 to 1 in., firm in consistency, and tender.The colour faded on pressure but did not completely dis- appear.There were enlarged soft lymph nodes in the left posterior triangle and right axilla.There was an area of impaired resonance with diminished air entry and rales in the left axilla.TIhe Ilverl Was enlarged to 1/2 in.below the costal margin, and the tip of the spleen was just palpable.A blood count gave: erythrocytes, 3,910,000; haemoglobin, 62%o; colour index, 0.8%; leucocytes, 13,400 (poly- morphonuclears 10,251, lymphocyLes 2,680, eosinophils nil, basophils njil, large mononuclears 469).The Paul-Bunnell test was negative,as was blood culture.The urine was normal.The patient ran an irregular pyrexia up to 103 °.Fresh skin lesions appeared during the next two days and then gradually faded and disappeared.None were visible at the time of her death.
The c-Jun NH2-Terminal Kinase 2 Plays a Dominant Role in Human Epidermal Neoplasia
Authors: Hengning Ke, Rebecca Harris, Jonathan L. Coloff, Jane Y. Jin, Benjamin Leshin, Paula Miliani de Marval, Shiying Tao, Jeffrey C. Rathmell, Russell P. Hall, Jennifer Y. Zhang
Journal: Cancer Research (2010)

The c-Jun NH(2)-terminal kinase (JNK) signaling cascade has been implicated in a wide range of diseases, including cancer. It is unclear how different JNK proteins contribute to human cancer. Here, we report that JNK2 is activated in more than 70% of human squamous cell carcinoma (SCC) samples and that inhibition of JNK2 pharmacologically or genetically impairs tumorigenesis of human SCC cells. Most importantly, JNK2, but not JNK1, is sufficient to couple with oncogenic Ras to transform primary human epidermal cells into malignancy with features of SCC. JNK2 prevents Ras-induced cell senescence and growth arrest by reducing the expression levels of the cell cycle inhibitor p16 and the activation of NF-kappaB. On the other hand, JNK, along with phosphoinositide 3-kinase, is essential for Ras-induced glycolysis, an energy-producing process known to benefit cancer growth. These data indicate that JNK2 collaborates with other oncogenes, such as Ras, at multiple molecular levels to promote tumorigenesis and hence represents a promising therapeutic target for cancer.
HIV-1 Nef Interacts with Inositol Trisphosphate Receptor to Activate Calcium Signaling in T Cells
Authors: Aki Manninen, Kalle Saksela
Journal: The Journal of Experimental Medicine (2002)

HIV-1 pathogenicity factor Nef has been shown to modulate calcium signaling in host cells, but the underlying molecular mechanisms have remained unclear. Here we show that calcium/calcineurin-dependent activation of nuclear factor of activated T cells (NFAT) by Nef in Jurkat T cells requires the endoplasmic reticulum-resident inositol trisphosphate receptor (IP3R), but yet does not involve increase in phospholipase-Cγ1 (PLCγ1)-catalyzed production of IP3 or depletion of IP3-regulated intracellular calcium stores. Nef could be coprecipitated with endogenous IP3R type-1 (IP3R1) from Nef-transfected Jurkat T cells as well as from HIV-infected primary human peripheral mononuclear cells. Thus, the Nef/IP3R1-interaction defines a novel T cell receptor–independent mechanism by which Nef can promote T cell activation, and appears to involve atypical IP3R-triggered activation of plasma membrane calcium influx channels in a manner that is uncoupled from depletion of intracellular calcium stores.
Characteristics of Cavotricuspid Isthmus–Dependent Atrial Flutter After Left Atrial Ablation of Atrial Fibrillation
Authors: Aman Chugh, Rakesh Latchamsetty, Hakan Oral, Darryl Elmouchi, David Tschopp, Scott Reich, Petar Igic, Tammy Lemerand, Eric Good, Frank Bogun, Frank Pelosi, Fred Morady
Journal: Circulation (2006)

Patients who have previously undergone ablation of atrial fibrillation may experience cavotricuspid isthmus (CTI)-dependent atrial flutter during follow-up. The effects of left atrial (LA) ablation on the characteristics of CTI-dependent flutter have not been described.Fifteen patients underwent ablation of CTI-dependent flutter late after LA ablation of AF. The ECG, biatrial activation patterns, and LA voltage maps during flutter were analyzed. Thirty age- and gender-matched patients who underwent ablation of CTI-dependent flutter without prior LA ablation served as control subjects. Among the patients with prior LA ablation, mapping revealed counterclockwise activation around the tricuspid annulus in 12 of 15 patients (80%) and clockwise activation in 3 of 15 patients (20%). The flutter waves in the inferior leads were upright in 9 of the 15 patients (60%) with prior LA ablation and in none of the control subjects (P<0.001). The upright flutter waves in the inferior leads in patients with counterclockwise flutter corresponded to craniocaudal activation of the right atrial free wall. LA activation contributed little to the genesis of the flutter waves in these patients because of a significant reduction in bipolar LA voltage (0.44+/-0.20 versus 1.54+/-0.19 mV in patients with biphasic/negative flutter waves; P<0.001).CTI-dependent flutter that occurs after LA ablation of atrial fibrillation often has atypical ECG characteristics because of altered LA activation. In patients presenting with atrial flutter after LA ablation, entrainment mapping should be performed at the CTI even if the ECG is uncharacteristic of CTI-dependent flutter.
Challenges with cost-utility analyses of behavioural interventions among older adults at risk for dementia
Authors: Jennifer C Davis, Stirling Bryan, Carlo A Marra, Ging-Yuek R Hsiung, Teresa Liu-Ambrose
Journal: British Journal of Sports Medicine (2013)

Background Cognitive decline is one of the most prominent healthcare issues of the 21st century. Within the context of combating cognitive decline through behavioural interventions, physical activity is a promising approach. There is a dearth of health economic data in the area of behavioural interventions for dementia prevention. Yet, economic evaluations are essential for providing information to policy makers for resource allocation. It is essential we first address population and intervention-specific methodological challenges prior to building a larger evidence base. We use a cost-utility analysis conducted alongside the exercise for cognition and everyday living (EXCEL) study to illustrate methodological challenges specific to assessing the cost-effectiveness of behavioural interventions aimed at older adults at risk of cognitive decline. Methods A cost-utility analysis conducted concurrently with a 6-month, three-arm randomised controlled trial (ie, the EXCEL study) was used as an example to identify and discuss methodological challenges. Results Both the aerobic training and resistance training interventions were less costly than twice weekly balance and tone classes. In critically evaluating the economic evaluation of the EXCEL study we identified four category-specific challenges: (1) analysing costs; (2) assessing quality-adjusted life-years; (3) Incomplete data; and (4) ‘Intervention’ activities of the control group. Conclusions Resistance training and aerobic training resulted in healthcare cost saving and were equally effective to balance and tone classes after only 6 months of intervention. To ensure this population is treated fairly in terms of claims on resources, we first need to identify areas for methodological improvement.
Impact of COPD in North America and Europe in 2000: subjects' perspective of Confronting COPD International Survey
Authors: S. Rennard, M. Decramer, P.M.A. Calverley, N.B. Pride, J.B. Soriano, P.A. Vermeire, J. Vestbo
Journal: European Respiratory Journal (2002)

To date, no international surveys estimating the burden of chronic obstructive pulmonary disease (COPD) in the general population have been published. The Confronting COPD International Survey aimed to quantify morbidity and burden in COPD subjects in 2000. From a total of 201,921 households screened by random-digit dialling in the USA, Canada, France, Italy, Germany, the Netherlands, Spain and the UK, 3,265 subjects with a diagnosis of COPD, chronic bronchitis or emphysema, or with symptoms of chronic bronchitis, were identified. The mean age of the subjects was 63.3 yrs and 44.2% were female. Subjects with COPD in North America and Europe appear to underestimate their morbidity, as shown by the high proportion of subjects with limitations to their basic daily life activities, frequent work loss (45.3% of COPD subjects of &lt;65 yrs reported work loss in the past year) and frequent use of health services (13.8% of subjects required emergency care in the last year), and may be undertreated. There was a significant disparity between subjects' perception of disease severity and the degree of severity indicated by an objective breathlessness scale. Of those with the most severe breathlessness (too breathless to leave the house), 35.8% described their condition as mild or moderate, as did 60.3% of those with the next most severe degree of breathlessness (breathless after walking a few minutes on level ground). This international survey confirmed the great burden to society and high individual morbidity associated with chronic obstructive pulmonary disease in subjects in North America and Europe.
Different Tumor Microenvironments Contain Functionally Distinct Subsets of Macrophages Derived from Ly6C(high) Monocytes
Authors: Kiavash Movahedi, Damya Laoui, Conny Gysemans, Martijn Baeten, Geert Stangé, Jan Van den Bossche, Matthias Mack, Daniel Pipeleers, Peter In't Veld, Patrick De Baetselier, Jo A. Van Ginderachter
Journal: Cancer Research (2010)

Abstract Tumor-associated macrophages (TAM) form a major component of the tumor stroma. However, important concepts such as TAM heterogeneity and the nature of the monocytic TAM precursors remain speculative. Here, we show for the first time that mouse mammary tumors contained functionally distinct subsets of TAMs and provide markers for their identification. Furthermore, in search of the TAM progenitors, we show that the tumor-monocyte pool almost exclusively consisted of Ly6ChiCX3CR1low monocytes, which continuously seeded tumors and renewed all nonproliferating TAM subsets. Interestingly, gene and protein profiling indicated that distinct TAM populations differed at the molecular level and could be classified based on the classic (M1) versus alternative (M2) macrophage activation paradigm. Importantly, the more M2-like TAMs were enriched in hypoxic tumor areas, had a superior proangiogenic activity in vivo, and increased in numbers as tumors progressed. Finally, it was shown that the TAM subsets were poor antigen presenters, but could suppress T-cell activation, albeit by using different suppressive mechanisms. Together, our data help to unravel the complexities of the tumor-infiltrating myeloid cell compartment and provide a rationale for targeting specialized TAM subsets, thereby optimally “re-educating” the TAM compartment. Cancer Res; 70(14); 5728–39. ©2010 AACR.
Relations between innate endowments, cognitive development, domain specificity, and a taxonomy-creator
Authors: Adee Matan, Sidney Strauss
Journal: Behavioral and Brain Sciences (1998)

Atran proposes that humans have a unique, innate, domain-specific tendency to create taxonomies of biological kinds. We show that: (1) in ontogenesis, children develop a notion Atran claims to be innate; (2) what Atran claims is unique to biological kinds may be found in artifact kinds; and (3) although Atran proposes a domain-specific mental construct for biological rank, it can be explained in domain- general terms.
Thymic tumours: Diagnostic and therapeutic approach
Authors: Sotirios Moraitis, Konstantinos Kanakakis, Panagiotis Hountis, Ioannis Gkiozos, Andriani Charpidou, Konstantinos Syrigos
Journal: European Respiratory Journal (2012)

Introduction : Thymic tumours represent 0.2—1.5% of all malignancies, with an incidence of 0.15 cases per 100,000 populations.We present our experience in the management of patients (pts) with thymic tumours.   Materials and Methods : We evaluated retrospectively the records of 16 consecutive pts who underwent thymectomy in our department. All but one pts underwent radical thymectomy, through a median sternotomy. The upper and lower thymic poles were traced and all fatty tissue between the phrenic nerves was resected. Diagnostic procedures included contrast enhanced CT of thorax and/or MRI and in the case of 2 pts, F-18 FDG PET-CT was performed. Myasthenia gravis was present in 2 pts (12.5%).   Results : There were 8 male and 8 female pts (mean age: 42.8 years). The histopathology revealed 11 thymomas, 1 endocrine carcinoma and 4 hyperplasias. Type A thymomas were found in 2 pts (12.5%), AB in 3 pts (18.75%), B1 in 1pt (6.25%) and B3 in 1pt (6.25%), while 4 thymomas (25%) were unclassified. The mean diameter of the resected masses was 8.31 cm. Two pts were classified as Masaoka IIA stage (12.5%) and one as Masaoka IIB (6.25%), who received adjuvant radiotherapy. All the others were classified as Masoka I. All tumours were totally resected. The 5 year survival was 100%. There was recurrence of the endocrine carcinoma within 5 years.   Conclusions : Tumours of the thymus are a heterogeneous group of tumours, ranging from relatively benign thymomas to highly aggressive carcinomas. Surgery continues to be the mainstay of treatment and complete resection of the tumour remains the most important prognostic factor. A recurrence should be completely resected whenever possible, because this approach is associated with good long-term survival.
Serum secretory IgA and secretory component in patients with non-cirrhotic alcoholic liver diseases
Authors: Estelle Seillès, Mireille Rossel, Dominique A. Vuitton, Mariette Mercier, Oudou Njoya, Jean-Pierre Capron, Bertrand Nalpas, Roger Gibey, Revillard Jean Pierre
Journal: Journal of Hepatology (1995)
Genomic Screening for Genes Silenced by DNA Methylation Revealed an Association between RASD1 Inactivation and Dexamethasone Resistance in Multiple Myeloma
Authors: Masanori Nojima, Reo Maruyama, Hiroshi Yasui, Hiromu Suzuki, Yumiko Maruyama, Isao Tarasawa, Yasushi Sasaki, Hideki Asaoku, Hajime Sakai, Toshiaki Hayashi, Mitsuru Mori, Kohzoh Imai, Takashi Tokino, Tadao Ishida, Minoru Toyota, Yasuhisa Shinomura
Journal: Clinical Cancer Research (2009)

Epigenetic changes such as DNA methylation play a key role in the development and progression of multiple myeloma. Our aim in the present study was to use genomic screening to identify genes targeted for epigenetic inactivation in multiple myeloma and assess their role in the development of resistance to dexamethasone.Gene expression was examined using microarray screening, reverse transcription-PCR, and real-time quantitative PCR. DNA methylation was examined using bisulfite PCR, bisulfite sequencing, and bisulfite pyrosequencing in 14 multiple myeloma cell lines, 87 multiple myeloma specimens, and 12 control bone marrow samples. WST-8 assays were used to assess cell viability after treatment with 5-aza-2'-deoxycytidine and/or dexamethasone.Microarray analysis was done to screen for genes up-regulated by 5-aza-2'-deoxycytidine. In RPMI8226 cells, 128 genes were up-regulated, whereas 83 genes were up-regulated in KMS12PE cells. Methylation of 22 genes with CpG islands in their 5' regions, including RASD1, was confirmed. Methylation of RASD1 was associated with its inactivation, which correlated with resistance to dexamethasone. Treating multiple myeloma cells with 5-aza-2'-deoxycytidine restored sensitivity to dexamethasone. Methylation of RASD1 was also detected in a subset of primary multiple myeloma specimens, and the levels of methylation were increased after repeated antitumor treatments. Gene signature analysis revealed various genes to be synergistically induced by treatment with a combination of 5-aza-2'-deoxycytidine plus dexamethasone.Our findings indicate that epigenetic inactivation of genes, including RASD1, plays a key role in the development of dexamethasone resistance in multiple myeloma. Moreover, they show the utility of demethylation therapy in cases of advanced multiple myeloma.
Functional genetic polymorphisms in ILT3 are associated with decreased surface expression on dendritic cells and increased serum cytokines in lupus patients
Authors: Mark A Jensen, Karen C Patterson, Akaash A Kumar, Marissa Kumabe, Beverly S Franek, Timothy B Niewold
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Objective</h3> Hyperactivity of the type I interferon (IFN) pathway is involved in the pathogenesis of systemic lupus erythematosus (SLE). Immunoglobulin like transcript (ILT3) is an immunohibitory transmembrane molecule which is induced by type I IFNs. ILT3 is expressed by plasmacytoid dendritic cells (PDCs), monocytoid dendritic cells (MDCs), and monocytes/macrophages. Given the pathogenic role of IFN in SLE, we hypothesised that the IFN-induced immunosuppressive ILT3 receptor may be dysfunctional in human SLE. <h3>Methods</h3> 132 European-derived and 79 Hispanic-American SLE patients were genotyped for two coding-change single nucleotide polymorphisms (SNPs) predicted to interfere with protein folding in ILT3 (rs11540761 and rs1048801). 116 control DNA samples and sera from healthy controls were also studied. We detected associations between ILT3 genotype and serum cytokine profiles. ILT3 expression levels on PDCs and MDCs from 18 patients and 10 controls were studied by flow cytometry. <h3>Results</h3> The rs11540761 SNP in the extracellular region was associated with decreased cell surface expression of ILT3 on circulating MDCs and to a lesser extent PDCs in SLE patients. The cytoplasmically located rs1048801 SNP was not associated with a change in dendritic cells expression of ILT3. Both SNPs were significantly and independently associated with increased levels of serum type I IFN activity in SLE patients. The rs1048801 SNP was also associated with increased serum levels of TNF-α. <h3>Conclusions</h3> Loss-of-function polymorphisms in ILT3 are associated with increased inflammatory cytokine levels in SLE, supporting a biological role for ILT3 in SLE.
Sequential Circulatory Changes following Acute Myocardial Infarction in Man
Authors: W. GLENN FRIESEN
Journal: Circulation (1973)

After informed consent, 12 men with documented acute myocardial infarction had hemodynamic studies performed within 18 hours after onset of symptoms. These were repeated on the second day, at 3-5 weeks, and at 3-5 months in the 10 who survived. One half of the patients were "uncomplicated" and significant differences with the "complicated" patients were seen in pulmonary artery pressure, mean arterial pressure on the first day, acute phase stroke volume and cardiac index, and the total blood volume within 48 hours. The optimal heart rate at each stage was determined by atrial pacing and was found to be 110 ± 10 beats/min. Abnormalities in p H, blood gases, and circulation time were related to the cardiac index. Control groups with and without coronary artery disease were studied prior to angiography to obtain information regarding preinfarction circulatory status, and significant impairment of the ejection fraction was noted even in angina patients without prior infarction. The sequential circulatory changes and possible compensatory mechanisms available were discussed.
Gain of Function Mutants: Ion Channels and G Protein-Coupled Receptors
Authors: Henry A. Lester, Andreas Karschin
Journal: Annual Review of Neuroscience (2000)

Many ion channels and receptors display striking phenotypes for gainof-function mutations but milder phenotypes for null mutations. Gain of molecular function can have several mechanistic bases: selectivity changes, gating changes including constitutive activation and slowed inactivation, elimination of a subunit that enhances inactivation, decreased drug sensitivity, changes in regulation or trafficking of the channel, or induction of apoptosis. Decreased firing frequency can occur via increased function of K + or Cl − channels. Channel mutants also cause gain-of-function syndromes at the cellular and circuit level; of these syndromes, the cardiac long-QT syndromes are explained in a more straightforward way than are the epilepsies. G protein– coupled receptors are also affected by activating mutations.