tbuckley/cabot-search huggingface dataset:
Remitting seronegative symmetrical synovitis with pitting oedema (RS3PE) syndrome: a prospective follow up and magnetic resonance imaging study
Authors: F. Cantini, C. Salvarani, I. Olivieri, L. Barozzi, L. Macchioni, L. Niccoli, A. Padula, P. Pavlica, L. Boiardi
Journal: Annals of the Rheumatic Diseases (1999)

<h3>OBJECTIVE</h3> To determine the clinical characteristics of patients with "pure" remitting seronegative symmetrical synovitis with pitting oedema (RS3PE) syndrome, and to investigate its relation with polymyalgia rheumatica (PMR). Magnetic resonance imaging (MRI) was used to describe the anatomical structures affected by inflammation in pure RS3PE syndrome. <h3>METHODS</h3> A prospective follow up study of 23 consecutive patients with pure RS3PE syndrome and 177 consecutive patients with PMR diagnosed over a five year period in two Italian secondary referral centres of rheumatology. Hands or feet MRI, or both, was performed at diagnosis in 7 of 23 patients. <h3>RESULTS</h3> At inspection evidence of hand and/or foot tenosynovitis was present in all the 23 patients with pure RS3PE syndrome. Twenty one (12%) patients with PMR associated distal extremity swelling with pitting oedema. No significant differences in the sex, age at onset of disease, acute phase reactant values at diagnosis, frequency of peripheral synovitis and carpal tunnel syndrome and frequency of HLA-B7 antigen were present between patients with pure RS3PE and PMR. In both conditions no patient under 50 was observed, the disease frequency increased significantly with age and the highest frequency was present in the age group 70–79 years. Clinical symptoms for both conditions responded promptly to corticosteroids and no patient developed rheumatoid arthritis during the follow up. However, the patients with pure RS3PE syndrome were characterised by shorter duration of treatment, lower cumulative corticosteroid dose and lower frequency of systemic signs/symptoms and relapse/recurrence. Hands and feet MRI showed evidence of tenosynovitis in five patients and joint synovitis in three patients. <h3>CONCLUSION</h3> The similarities of demographic, clinical, and MRI findings between RS3PE syndrome and PMR and the concurrence of the two syndromes suggest that these conditions may be part of the same disease and that the diagnostic labels of PMR and RS3PE syndrome may not indicate a real difference. The presence of distal oedema seems to indicate a better prognosis.
Intermittent positive pressure ventilation in the treatment of severe crushing injuries of the chest.
Authors: M Ambiavagar, J S Robinson, I M Morrison, E S Jones
Journal: Thorax (1966)

Details of patients treated without fixation in an intensive care unit by a team of nurses, physicians, anaesthetists, and surgeons are presented with particular emphasis on the principles underlying day-to-day management.Mechanical ventilation via a tracheostomy permits efficient removal of secretions, eliminates the work of breathing, corrects the pathological changes consequent upon abnormal mechanics of breathing, and is the most efficient means available of ensuring adequate gas exchange.Six case histories have been described in detail to illustrate problems in the treatment of major chest injuries, and some of these difficulties are discussed.The literature on the treatment of closed chest injuries has been reviewed, and the merits and demerits of traditional fixation methods are dis- cussed in comparison with treatment by mechani- cal ventilation.
Thymic dendritic cell precursors: relationship to the T lymphocyte lineage and phenotype of the dendritic cell progeny.
Authors: L Wu, C L Li, K Shortman
Journal: The Journal of Experimental Medicine (1996)

Successive T-precursors isolated from adult mouse thymus were examined for their developmental potential, by transfer to irradiated Ly 5-disparate recipients. The earliest, "low CD4" precursors formed T, B, and dendritic cells (DC), but not myeloid cells, in accordance with earlier studies. Surprisingly, the next downstream CD4-8-3 44+25+ precursor population still formed DC as well as T cells although it no longer formed B or myeloid cells. Further down-stream, the CD4-8 3-44-25+ population formed only T cells. The thymic and splenic DC progeny of the early thymic precursors all expressed high levels of CD8 alpha, in contrast with normal splenic DC and the splenic DC progeny of bone marrow stem cells, which consisted of both CD8 and CD8+ DC. A common precursor of T cells and of a subclass of DC is proposed, with CD8 alpha as a marker of the lymphoid-related DC lineage.
In vitro monocyte maturation as a prediction of survival in squamous cell carcinoma of the lung.
Authors: R G Dent, P Cole
Journal: Thorax (1981)

In vitro monocyte maturation was studied in patients with squamous cell carcinoma of the lung--limited to the ipsilateral hemithorax in 30 and more extensive in 40. The patients were studied prospectively and initial monocyte maturation was correlated with survival. Monocyte maturation in patients with limited disease before treatment ranged from 3.1 to 57.6% with a median value of 21.4%. The survival of those patients in whom monocyte maturation was less than the normal range (less than 30.4%) was significantly shorter than the survival in those with normal maturation ( p less than 0.05). Four of the five patients whose initial maturation was less than 10% proved to be inoperable at surgery. Patients with extensive disease had monocyte maturation ranging from 2.4 to 52.9% with a median value of 13.2%, significantly lower than in those with limited disease (p less than 0.025). Patients with extensive disease and low monocyte maturation survived a significantly shorter time than those with normal maturation ( p less than 0.005). The depression of monocyte development may explain the finding of negative delayed hypersensitivity skin reactions in many patients with lung carcinoma and may prove useful as an index of prognosis.
Hematopoiesis and RAS-driven myeloid leukemia differentially require PI3K isoform p110α
Authors: Kira Gritsman, Haluk Yuzugullu, Thanh Von, Howard Yan, Linda Clayton, Christine Fritsch, Sauveur-Michel Maira, Gregory Hollingworth, Christine Choi, Tulasi Khandan, Mahnaz Paktinat, Rachel O. Okabe, Thomas M. Roberts, Jean J. Zhao
Journal: Journal of Clinical Investigation (2014)

The genes encoding RAS family members are frequently mutated in juvenile myelomonocytic leukemia (JMML) and acute myeloid leukemia (AML). RAS proteins are difficult to target pharmacologically; therefore, targeting the downstream PI3K and RAF/MEK/ERK pathways represents a promising approach to treat RAS-addicted tumors. The p110α isoform of PI3K (encoded by Pik3ca) is an essential effector of oncogenic KRAS in murine lung tumors, but it is unknown whether p110α contributes to leukemia. To specifically examine the role of p110α in murine hematopoiesis and in leukemia, we conditionally deleted p110α in HSCs using the Cre-loxP system. Postnatal deletion of p110α resulted in mild anemia without affecting HSC self-renewal; however, deletion of p110α in mice with KRASG12D-associated JMML markedly delayed their death. Furthermore, the p110α-selective inhibitor BYL719 inhibited growth factor-independent KRASG12D BM colony formation and sensitized cells to a low dose of the MEK inhibitor MEK162. Furthermore, combined inhibition of p110α and MEK effectively reduced proliferation of RAS-mutated AML cell lines and disease in an AML murine xenograft model. Together, our data indicate that RAS-mutated myeloid leukemias are dependent on the PI3K isoform p110α, and combined pharmacologic inhibition of p110α and MEK could be an effective therapeutic strategy for JMML and AML.
New strategies and designs in pancreatic cancer research: consensus guidelines report from a European expert panel
Authors: J.-L. Van Laethem, C. Verslype, J.L. Iovanna, P. Michl, T. Conroy, C. Louvet, P. Hammel, E. Mitry, M. Ducreux, T. Maraculla, W. Uhl, G. Van Tienhoven, J.B. Bachet, R. Maréchal, A. Hendlisz, M. Bali, P. Demetter, F. Ulrich, D. Aust, J. Luttges, M. Peeters, M. Mauer, A. Roth, J.P. Neoptolemos, M. Lutz
Journal: Annals of Oncology (2011)
Inhalation rate of sodium cromoglycate determines plasma pharmacokinetics and protection against AMP-induced bronchoconstriction in asthma
Authors: R Richards, SF Simpson, AG Renwick, ST Holgate
Journal: European Respiratory Journal (1988)

We have investigated whether the inspiratory flow at which sodium cromoglycate (SCG) is inhaled influences the efficacy of SCG. Seven atopic asthmatic subjects (age 25 +/- 2 yrs) inhaled dry powder SCG from a Spinhaler on separate occasions at three flow rates, maximum (V1), 100 l.min-1 (V2), and 50 l.min-1 (V3), or placebo, according to a double-blind structured study. Thirty minutes after administration a bronchial provocation test was performed with adenosine 5'-monophosphate (AMP). Blood samples for measurement of plasma SCG concentration were taken and the area under the plasma concentration-time curve (AUC) calculated for each flow rate. Both inspiratory flow rate and AUC correlated significantly with the degree of protection afforded against AMP-induced bronchoconstriction (r = 0.73, p less than 0.001; r = 0.66, p less than 0.001). These findings indicate that the flow rate used to inhale powdered SCG is a major factor in determining the protective efficacy of this drug against bronchial challenge and therefore has important clinical implications.
LINGO-1 is a component of the Nogo-66 receptor/p75 signaling complex
Authors: Sha Mi, Xinhua Lee, Zhaohui Shao, Greg Thill, Benxiu Ji, Jane Relton, Melissa Levesque, Norm Allaire, Steve Perrin, Bryan Sands, Thomas Crowell, Richard L Cate, John M McCoy, R Blake Pepinsky
Journal: Nature Neuroscience (2004)
A Novel Breast Cancer–Associated <i>BRIP1</i> (<i>FANCJ/BACH1</i>) Germ-line Mutation Impairs Protein Stability and Function
Authors: Arcangela De Nicolo, Mariella Tancredi, Grazia Lombardi, Cristina Chantal Flemma, Serena Barbuti, Claudio Di Cristofano, Bijan Sobhian, Generoso Bevilacqua, Ronny Drapkin, Maria Adelaide Caligo
Journal: Clinical Cancer Research (2008)

Abstract Purpose: BRCA1-interacting protein 1 (BRIP1; FANCJ/BACH1), which encodes a DNA helicase that interacts with BRCA1, has been suggested to be a low-penetrance breast cancer predisposing gene. We aimed to assess whether BRIP1 mutations contribute to breast cancer susceptibility in our population and, if so, to investigate the effect of such mutation(s) on BRIP1 function. Experimental Design: A series of 49 breast/ovarian cancer families, devoid of a BRCA1/BRCA2 mutation, were screened for BRIP1 mutations. Functional analyses, including coimmunoprecipitation and stability assays, were employed to further characterize a previously unreported variant. Results: Five sequence alterations were identified, of which four had been already described. Herein, we report a novel BRIP1 germ-line mutation identified in a woman with early-onset breast cancer. The mutation consists of a 4-nucleotide deletion (c.2992-2995delAAGA) in BRIP1 exon 20 that causes a shift in the reading frame, disrupts the BRCA1-binding domain of BRIP1, and creates a premature stop codon. Functional analysis of the recombinant mutant protein in transfected cells showed that the truncation interferes with the stability of the protein and with its ability to interact with BRCA1. Loss of the wild-type BRIP1 allele with retention of the mutated one was observed in the patient's breast tumor tissue. Conclusions: These results, by showing that the newly identified BRIP1 c.2992-2995delAAGA mutation is associated with instability and functional impairment of the encoded protein, provide further evidence of a breast cancer–related role for BRIP1.
Lifetime risk of developing impaired glucose metabolism and eventual progression from prediabetes to type 2 diabetes: a prospective cohort study
Authors: Symen Ligthart, Thijs T W van Herpt, Maarten J G Leening, Maryam Kavousi, Albert Hofman, Bruno H C Stricker, Mandy van Hoek, Eric J G Sijbrands, Oscar H Franco, Abbas Dehghan
Journal: The Lancet Diabetes & Endocrinology (2015)
GLP-1: target for a new class of antidiabetic agents?
Authors: C M. B Edwards
Journal: Journal of the Royal Society of Medicine (2004)

In 1998 a large highly powered trial, the UK Prospective Diabetes Study (UKPDS), demonstrated that in type 2 diabetes several clinical endpoints were improved by better diabetic control. A 0.9% decrease in glycosylated haemoglobin (HbA1c) over ten years was associated with a 25% reduction in microvascular complications (P=0.0099) and a less impressive 16% reduction in myocardial infarction (P=0.052).1 With this evidence base, the pressure is on for physicians to improve the HbA1c of people with diabetes.
Gene expression alterations in ulcerative colitis patients after restorative proctocolectomy extend to the small bowel proximal to the pouch
Authors: Henit Yanai, Shay Ben-Shachar, Liran Baram, Hofit Elad, Gilad Gitstein, Eli Brazowski, Hagit Tulchinsky, Metsada Pasmanik-Chor, Iris Dotan
Journal: Gut (2014)

To evaluate molecular profiles in the small bowel (SB) mucosa proximal to the pouch in ulcerative colitis (UC) patients after pouch surgery.Patients were prospectively recruited and stratified according to disease behaviour: normal pouch (NP), chronic pouchitis (CP), and Crohn's-like disease of the pouch (CLDP). Biopsies obtained from the pouch and the normal-appearing proximal SB (40 cm proximal to the anal verge) were compared to ileal biopsies from normal controls (NC). A histopathological score based on the degree of polymorphonuclear and mononuclear infiltrates was used to assess inflammation in the pouch and the proximal SB. Gene expression analysis was performed using microarrays, and validated by real-time PCR. Gene ontology and clustering were evaluated by bioinformatics.Thirty-six subjects were recruited (age 18-71 years, 16 males). Histopathology scores demonstrated minimal differences in the normal-appearing proximal SB of all groups. Nonetheless, significant (fold change ≥2, corrected p [FDR] ≤ 0.05) molecular alterations in the proximal SB were detected in all groups (NP n=9; CP n=80; and CLDP n=230) compared with NC. The magnitude of DUOX2 alteration in the proximal SB was highest. An increase of 6.0, 9.8 and 21.7 folds in DUOX2 expression in NP, CP, CLDP, respectively was observed. This was followed by alterations in MMP1, SLC6A14 and PGC. Gene alterations in the proximal SB overlapped with alterations within the pouch (76% and 97% overlap in CP and CLDP, respectively). Gene ontology analysis in the proximal SB and pouch were comparable.Significant gene expression alterations exist in an apparently unaffected proximal SB. Alterations in the pouch and the proximal SB were comparable, suggesting that inflammation may not be limited to the pouch, but that it extends to the proximal SB.
The interleukin-1 beta-converting enzyme (ICE) is localized on the external cell surface membranes and in the cytoplasmic ground substance of human monocytes by immuno-electron microscopy.
Authors: I I Singer, S Scott, J Chin, E K Bayne, G Limjuco, J Weidner, D K Miller, K Chapman, M J Kostura
Journal: The Journal of Experimental Medicine (1995)

Interleukin-1 beta (IL-1 beta)-converting enzyme (ICE) is a novel cysteine protease that cleaves the 31-kD inactive cytoplasmic IL-1 beta precursor into active extracellular 17-kD IL-1 beta. The ICE gene product is a 45-kD proenzyme that requires proteolytic processing to activate ICE. Active ICE is a heterodimer consisting of equal amounts of p20 and p10 subunits. Generation of active ICE is affected by the removal of an 11-kD NH2-terminal precursor domain (p11) and an internal 19-amino acid sequence that separates the 20- and 10-kD subunits. Immuno-electron microscopy was performed on human monocytes with immunoglobulins recognizing the active (p20) or precursor (p11) domains of ICE. Elutriated monocytes were stimulated with 50 pM lipopolysaccharide followed by heat-killed Staphylococcus aureus under conditions that induce maximal rates of IL-1 beta secretion. Ultrathin cryosections were cut from fixed frozen pellets of these monocytes and were immunogold labeled with either antibody. Active and precursor domain ICE epitopes were localized in the cytoplasmic ground substance, but they were not detected within the endoplasmic reticulum, the Golgi apparatus, and secretory granules of activated or inactive monocytes. Importantly, numerous ICE p20 epitopes were also observed on the extracellular surfaces of the cell membrane, and were concentrated on the microvilli. Very similar patterns of ICE localization were obtained with unstimulated blood monocytes. In contrast, ICE p11 epitopes were not detected on the surfaces of these monocytes. Likewise, labeling of fixed ultrathin cryosections of monocytes with a biotinylated irreversible ICE inhibitor [Ac-Tyr-Val-Lys(biotin)-Asp-(acyloxy)-methyl-ketone] showed that the compound localized on the outer cell surface as well, and to a lesser extent, within the cytoplasmic ground substance. Furthermore, antipeptide antibodies specific for either the mature or precursor domains of IL-1 beta were both localized upon the cell membrane after stimulation of IL-1 beta secretion. Lipopolysaccaride-primed monocytes that synthesized, but did not secrete IL-1 beta, exhibited only cytoplasmic staining. The data suggests that mature IL-1 beta is generated via cleavage of the 31-kD inactive cytoplasmic IL-1 beta precursor by ICE after association with the plasma membrane during secretion.
Adjuvant Tamoxifen Therapy for Early Stage Breast Cancer and Second Primary Malignancies
Authors: L. E. Rutqvist, H. Johansson, T. Signomklao, U. Johansson, T. Fornander, N. Wilking
Journal: JNCI Journal of the National Cancer Institute (1995)

Tamoxifen is being increasingly used for the treatment of breast cancer and is undergoing study for the primary prevention of breast cancer. However, concerns have been raised that the drug may increase the incidence of new primary malignancies, such as endometrial, liver, and colorectal cancers. Purpose: Our goal was to assess the carcinogenic risks associated with long-term use of tamoxifen in women with early stage breast cancer. Methods: The incidence of new primary cancers among 2729 women participants of the Stockholm Trial was determined at a median follow-up of 9 years. In this trial, after primary surgery, postmenopausal patients aged less than 71 years with unilateral invasive breast cancer were randomly allocated to receive either 2 years of adjuvant tamoxifen (40 mg daily) or no adjuvant endocrine therapy. Information on second cancers was obtained by retrospective linkage to the Swedish Cancer Registry. To increase statistical power, a joint analysis of the incidence of endometrial and gastrointestinal cancers was performed in the following three major studies in Scandinavia evaluating adjuvant tamoxifen therapy: the Stockholm Trial, the Danish Breast Cancer Group Trial, and the South-Swedish Trial. These studies included a total of 4914 patients with a median follow-up of 8–9 years. All P values were calculated from two-tailed tests of statistical significance. Results: In the Stockholm Trial, there was a statistically significant (P =.008) reduction in the incidence of second primary cancers in the contralateral breast among the tamoxifen-treated patients. However, there was a nearly sixfold increase in endometrial cancers (P<.001) and a threefold increase in gastrointestinal cancers in the tamoxifen-treated patients. The results of the joint studies showed a statistically significant increase in endometrial cancers among the tamoxifen-treated patients (relative risk [RR] = 4.1; 95% confidence interval [CI] = 1.9–8.9). There was also an excess of gastrointestinal cancers associated with tamoxifen. Most of this excess involved colorectal cancers (RR = 1.9; 95% CI = 1.1–3.3) and stomach cancer (RR = 3.2; 95% CI = 0.9–11.7). There was no substantial increase in any other type of gastrointestinal cancer (e.g., liver cancer) among the tamoxifen-treated patients. Conclusion: The endometrium and gastrointestinal organs may be target sites for tamoxifen-induced carcinogenesis in humans. Implications: The increased incidence of colorectal and stomach cancers reported here should be regarded as tentative until supported by long-term data from a larger number of tamoxifen trials. Also, appropriate surveillance of cancer incidence is warranted for the protection of participants enrolled in current tamoxifen chemoprevention trials. [J Natl Cancer Inst 87: 645–651, 1995]
Mechanisms of <i>CHD5</i> Inactivation in Neuroblastomas
Authors: Hiroshi Koyama, Tiangang Zhuang, Jennifer E. Light, Venkatadri Kolla, Mayumi Higashi, Patrick W. McGrady, Wendy B. London, Garrett M. Brodeur
Journal: Clinical Cancer Research (2012)

Neuroblastomas (NBs) have genomic, biological, and clinical heterogeneity. High-risk NBs are characterized by several genomic changes, including MYCN amplification and 1p36 deletion. We identified the chromatin-remodeling gene CHD5 as a tumor suppressor gene that maps to 1p36.31. Low or absent CHD5 expression is associated with a 1p36 deletion and an unfavorable outcome, but the mechanisms of CHD5 inactivation in NBs are unknown.We examined (i) the CHD5 sequence in 188 high-risk NBs investigated through the TARGET initiative, (ii) the methylation status of the CHD5 promoter in 108 NBs with or without 1p36 deletion and/or MYCN amplification, and (iii) mRNA expression of CHD5 and MYCN in 814 representative NBs using TaqMan low-density array microfluidic cards.We found no examples of somatically acquired CHD5 mutations, even in cases with 1p36 deletion, indicating that homozygous genomic inactivation is rare. Methylation of the CHD5 promoter was common in the high-risk tumors, and it was generally associated with both 1p deletion and MYCN amplification. High CHD5 expression was a powerful predictor of favorable outcome, and it showed prognostic value even in multivariable analysis after adjusting for MYCN amplification, 1p36 deletion, and/or 11q deletion.We conclude that (i) somatically acquired CHD5 mutations are rare in primary NBs, so inactivation probably occurs by deletion and epigenetic silencing; (ii) CHD5 expression and promoter methylation are associated with MYCN amplification, suggesting a possible interaction between these 2 genes; and (iii) high CHD5 expression is strongly correlated with favorable clinical/biological features and outcome.