tbuckley/cabot-search huggingface dataset:
Insulin-like growth factor binding protein-2 regulates β-catenin signaling pathway in glioma cells and together contributes to poor patient prognosis
Authors: Shilpa S. Patil, Priyanka Gokulnath, Mohsin Bashir, Shivayogi D. Shwetha, Janhvi Jaiswal, Arun H. Shastry, Arivazhagan Arimappamagan, Vani Santosh, Paturu Kondaiah
Journal: Neuro-Oncology (2016)

Upregulation of insulin-like growth factor binding protein 2 (IGFBP-2) is often associated with aggressiveness of glioblastoma (GBM) and contributes to poor prognosis for GBM patients. In view of the regulation of β-catenin by IGFBP-2 in breast cancer and the crucial role of β-catenin pathway in glioma invasion, proliferation and maintenance of glioma stem cells, the mechanism of regulation of β-catenin by IGFBP-2, and its role in GBM prognosis was studied.Regulation of the β-catenin pathway was studied by immunocytochemistry, Western blot analysis, luciferase assays, and real-time RT-PCR. The role of IGFBP-2 was studied by subcutaneous tumor xenografts in immunocompromised mice using glioma cells engineered to express IGFBP-2 and its domains. GBM patient tumor tissues (n = 112) were analyzed for expression of IGFBP-2 and β-catenin by immunohistochemistry. Survival analysis was performed employing Cox regression and Kaplan-Meier survival analyses.IGFBP-2 knockdown in U251, T98G, and U373 or overexpression in LN229 and U87 cells revealed a role for IGFBP-2 in stabilization of β-catenin and regulation of its nuclear functions involving integrin-mediated inactivation of GSK3β. Similar results were obtained upon overexpression of the C-terminal domain of IGFBP-2 but not the N-terminal domain. Subcutaneous xenograft tumors overexpressing either full-length or the C-terminal domain of IGFBP-2 showed larger volume as compared with controls. Coexpression of high levels of IGFBP-2 and β-catenin was associated with worse prognosis (P = .001) in GBM patients.IGFBP-2 potentiates GBM tumor growth by the activation of the β-catenin pathway through its C-terminal domain, and their coexpression possibly contributes to worse patient prognosis.
Transmission of Live, Attenuated Mumps Virus to the Human Placenta
Authors: Terry Yamauchi, Christopher Wilson, Joseph W. St. Geme
Journal: New England Journal of Medicine (1974)

Forty-five women between the ages of 16 and 35 years, scheduled for therapeutic abortions, were screened for susceptibility to primary mumps-virus infection. Susceptibility was established by a negative mumps-virus skin test and the absence of mumps-virus neutralizing antibody in the serum at the time of skin testing and seven to 10 days later. Five women, three susceptible and two immune, received live, attenuated mumps-virus vaccine seven to 10 days before termination of pregnancy by the intra-amniotic infusion of hypertonic saline. Mumps virus was recovered from the placentas of two of the three seronegative women, but virus was not isolated from the fetal tissues of any of those vaccinated. Live, attenuated mumps-virus vaccine should be used with caution in the post-pubertal female. (N Engl J Med 290:710–712, 1974)
Mechanism of Adrenal Atrophy in Cushing's Syndrome Due to Adrenal Tumor
Authors: Laurence H. Kyle, Richard J. Meyer, John J. Canary
Journal: New England Journal of Medicine (1957)

ATROPHY of the contralateral adrenal gland is a characteristic feature of Cushing's syndrome due to an adrenal tumor. Numerous studies, beginning with those of Ingle and Kendall,1 have shown this to be the result of pituitary suppression by the excessive corticoid hormones secreted by the tumor, with consequent inhibition of ACTH production or release. Before the development of effective replacement therapy this complication, for which Selye2 suggested the term compensatory atrophy, resulted in a formidable mortality after removal of the tumor. Available therapy now facilitates survival, thus providing the opportunity to study the mechanism of compensatory adrenal atrophy and to . . .
Effects of Dichloromethylene Diphosphonate on Skeletal Mobilization of Calcium in Multiple Myeloma
Authors: Ethel S. Siris, William H. Sherman, Delia C. Baquiran, John P. Schlatterer, Elliott F. Osserman, Robert E. Canfield
Journal: New England Journal of Medicine (1980)

Dichloromethylene diphosphonate (Cl2MDP), an inhibitor of osteoclast activity, was evaluated for its ability to decrease the excessive mobilization of skeletal calcium that complicates multiple myeloma. Ten patients with active myeloma, widespread bone disease, and hypercalciuria were studied in a double-blind, placebo-controlled, crossover-designed trial in which they took Cl2MDP for eight weeks and placebos for eight weeks. Two patients died during the placebo phase; of eight patients who received Cl2MDP, seven had rapid, sustained, and highly significant (P<0.001) decreases in urinary excretion of calcium. Six also had significant decreases in hydroxyproline excretion, and five reported lessening of skeletal pain. One patient did not respond. Although the patients received concurrent chemotherapy during the study, concentrations of myeloma proteins actually increased or decreased only slightly, indicating that declines in hypercalciuria resulted from Cl2MDP and not from improvement in the underlying disease. We conclude that Cl2MDP is a potentially useful inhibitor of osteoclast-mediated bone erosion in multiple myeloma. (N Engl J Med 302:310–315, 1980)
Low Sickle Cell Disease Mortality In Belgium and Benefit From Hydroxyurea Therapy
Authors: Phu-Quoc Lê, Laurence Dedeken, Beatrice Gulbis, Christiane Vermylen, Anna Vanderfaeillie, Catherine Heijmans, Christine Devalck, Sophie Huybrechts, Samantha Benghiat, André Efira, Marie-Francoise Dresse, Sophie Dupont, Alina Ferster
Journal: Blood (2013)
Lung Cancer in Chloromethyl Methyl Ether Workers
Authors: W. G. Figueroa, Robert Raszkowski, William Weiss
Journal: New England Journal of Medicine (1973)

An increased incidence of lung cancer (about eight times) occurred among men exposed to chloromethyl methyl ether at a chemical manufacturing plant. Of 14 men in whom lung cancer developed, histologic confirmation was obtained in 13, and 12 had oat-cell carcinomas. Three of the 14 men had never smoked. These observations suggest that the agent is an occupational hazard. (N Engl J Med 288:1096–1097, 1973)
Case 12-2000
Authors: Frances J. Hayes, John H. Eichhorn
Journal: New England Journal of Medicine (2000)

Presentation of CaseA 60-year-old man was referred to the hospital because of a pituitary macroadenoma.The patient had been well until three years earlier, when he became impotent and his libido decreased. Two months before his referral to this hospital, his nipples became sore. The prolactin level was 33.6 ng per milliliter (normal range, 0 to 15); the total testosterone level was 306 ng per deciliter (10.6 nmol per liter; normal range, 270 to 1070 ng per deciliter [9.36 to 37.1 nmol per liter]). Magnetic resonance imaging (MRI) revealed a mass, 11 mm in diameter, in the right pituitary . . .
Termination of Dietary Treatment of Phenylketonuria
Authors: Frederick A. Horner, Charles W. Streamer, Lourdes L. Alejandrino, Linda H. Reed, Frank Ibbott
Journal: New England Journal of Medicine (1962)

PREVIOUS reports have indicated that a phenylalanine-deficient diet initiated in the early months of life may be effective in preventing the severe mental retardation commonly seen in patients with phenylketonuria.1 2 3 4 5 When an infant with phenylketonuria has been so treated and has shown satisfactory mental development, the question how long the diet must be continued arises. Although our experience is in accord with that of Centerwall and his associates,6 who believe that the diet is readily manageable, it nevertheless is exacting, requires periodic blood sampling, means an added expense to the family and may have serious and possibly fatal complications.7 Centerwall . . .
Abstract 1510: Heterogeneity of Cell to Cell Communication in the Human Atrio-Ventricular Junction
Authors: Megan L McCain, William J Hucker, Igor R Efimov
Journal: Circulation (2006)

The atrio-ventricular (AV) junction serves as the only electrical connection between the atria and the ventricles, playing a critical role in slowing the rate of propagation of electrical signals from the sino-atrial (SA) node to the ventricles. The AV junction has a profoundly heterogeneous structure and pattern of protein expression. The expression patterns of connexins in the AV junction are unique and contribute to dual pathway electrophysiology in animal models. However, little is known about connexin distribution in the human AV junction and its relation to AV nodal reentrant tachycardia (AVNRT).   Methods:  We used Masson trichrome histology to reconstruct the 3D structure of the human AV junction (n=2), including the inferior nodal extension (INE), compact AV node (AVN), and the lower nodal and His bundles (HB). Immunohistochemistry was used to determine the density of Connexin 43 (Cx43), myocytes, and fibroblasts.   Results:  We found that connexins are distributed in a heterogeneous pattern in the human AV junction. The His bundle has a uniformly high density of Cx43. The AVN has an 8.3 ± 3.3 times higher Cx43 expression in the lower nodal bundle as compared to the compact AVN. The inferior nodal extension has two branches. The rightward branch expresses Cx43 at a level similar to the atrium. The leftward branch extends farther than the rightward branch and has a density of Cx43 4.9 ± 2.4 times less than the rightward branch.   Conclusions:  The heterogeneous expression of Cx43 in the AV junction may contribute to the dual pathway electrophysiology and AVNRT by providing a molecular and structural basis for the slow and fast pathways.
Catecholamine-Secreting Paraganglioma of Glomus-Jugulare Region Resembling Pheochromocytoma
Authors: Simon A. Levit, Sheldon G. Sheps, Raul E. Espinosa, William H. Remine, Edgar G. Harrison
Journal: New England Journal of Medicine (1969)

A paraganglioma of the glomus-jugulare region secreted norepinephrine and produced episodes of short-lived headache and palpitation similar to those seen in pheochromocytoma. The preoperative determination of excessive norepinephrine secretion permitted pharmacologic blockade by phenoxybenzamine and a smooth operative course. Until the true frequency of functioning tumors is known, all patients with craniocervical paragangliomas or chemodectomas should have routine preoperative determinations of urinary catecholamines and their metabolites to decrease surgical morbidity and mortality; two of the seven patients thus far reported have died.
Treatment of Cutaneous T-Cell Lymphoma by Extracorporeal Photochemotherapy
Authors: Richard Edelson, Carole Berger, Francis Gasparro, Brian Jegasothy, Peter Heald, Bruce Wintroub, Eric Vonderheid, Robert Knobler, Klaus Wolff, Gerhard Plewig, Glynis McKiernan, Inger Christiansen, Martin Oster, Hubert Honigsmann, Hubert Wilford, Eva Kokoschka, Thomas Rehle, Maritza Perez, George Stingl, Liliane Laroche
Journal: New England Journal of Medicine (1987)

Systemically disseminated cutaneous T-cell lymphoma is generally resistant to chemotherapy and radiotherapy. We tested a treatment involving the extracorporeal photoactivation of biologically inert methoxsalen (8-methoxypsoralen) by ultraviolet A energy to a form that covalently cross-links DNA. After oral administration of methoxsalen, a lymphocyte-enriched blood fraction was exposed to ultraviolet A (1 to 2 J per square centimeter) and then returned to the patient. The combination of ultraviolet A and methoxsalen caused an 88 +/- 5 percent loss of viability of target lymphocytes, whereas the drug alone was inactive. Twenty-seven of 37 patients with otherwise resistant cutaneous T-cell lymphoma responded to the treatment, with an average 64 percent decrease in cutaneous involvement after 22 +/- 10 weeks (mean +/- SD). The responding group included 8 of 10 patients with lymph-node involvement, 24 of 29 with exfoliative erythroderma, and 20 of 28 whose disease was resistant to standard chemotherapy. Side effects that often occur with standard chemotherapy, such as bone marrow suppression, gastrointestinal erosions, and hair loss, did not occur. Although the mechanism of the beneficial effect is uncertain, an immune reaction to the infused damaged cells may have restricted the activity of the abnormal T cells. This preliminary study suggests that extracorporeal photochemotherapy is a promising treatment for widespread cutaneous T-cell lymphoma.
Chromosome Analysis of Human Oocytes Recovered from Preovulatory Follicles in Stimulated Cycles
Authors: Håkan Wramsby, Karl Fredga, Percy Liedholm
Journal: New England Journal of Medicine (1987)

To investigate the incidence and types of abnormalities of chromosome number in oocytes, we recovered preovulatory oocytes from 17 women who were undergoing clomiphene stimulation and laparoscopy because of infertility. Twenty-three oocytes were recovered and studied after they had been fixed with a gradual-fixation method: 17 of the oocytes had numbers of chromosomes in the haploid range (19 to 25 second-metaphase chromosomes), 4 had only 1 to 5 chromosomes, 1 was not analyzable, and 1 had 23 chromosome bivalents in the first metaphase. Of the oocytes with chromosome numbers in the haploid range, nine had an apparently normal haploid set of 23 chromosomes. Two had 1 to 2 additional chromosomes, three lacked 2 to 4 chromosomes, and three had totals of chromosomes that were close to 23 but could not be determined with certainty. We conclude that infertile women undergoing clomiphene stimulation have a high proportion (nearly 50 percent) of oocytes with an abnormal karyotype. If this is also true of fertile women, including those not taking clomiphene, it may explain the high frequency of chromosome aberrations occurring in early spontaneous abortion and the low pregnancy rate after in vitro fertilization.
Epidemiologic Study of Abuse of Analgesics Containing Phenacetin
Authors: Ulrich C. Dubach, Bernard Rosner, Edith Pfister
Journal: New England Journal of Medicine (1983)

A study group of 623 working women 30 to 49 years old with objective evidence of intake of phenacetin-containing analgesics and a matched control group of 621 women without such intake in 1968 were assessed six times from 1969 to 1978 for laboratory evidence of urinary-tract disorders. The two groups did not differ in development of bacteriuria, hematuria, or proteinuria. However, a low specific gravity of urine (study group vs. control group, 23 vs. 7 per cent) and a raised level of serum creatinine (6.7 vs. 0.9 per cent) were significantly more frequent in the study group (P<0.001). Adjusted analyses of mortality over 11 years showed significant differences between the groups in overall mortality (study group vs. control group, 39 vs. 13 deaths; P<0.001), mortality due to urinary-tract disorders (P = 0.033), and cardiovascular diseases (P = 0.008). We conclude that heavy users of analgesic mixtures in the course of a decade have a higher incidence of both abnormal kidney function and kidney-related mortality than do casual users and nonusers, but the absolute incidences remain small even among heavy users. (N Engl J Med. 1983; 308:357–62.)
P146 Prescribing respiratory medicines without making a diagnosis of Asthma in UK Primary Care
Authors: S Clayton, V Carter, W Lenney, D Price, I Small, J Smith
Journal: Thorax (2015)

<h3>Introduction and objectives</h3> Despite asthma being one of the most prevalent worldwide chronic diseases, there remains a wide variation in prevalence.<sup>1</sup> The United Kingdom’s (UK) National Review of Asthma Deaths<sup>2</sup> suggests avoidable factors play a part in as many as three-quarters of cases of asthma death. There is need to highlight and address many aspects of asthma care including the variation in diagnosis across all ages to enable appropriate treatment and improve symptom control. Here we investigate the relationship between prescribing respiratory medications and making the diagnosis of asthma, in UK primary care. <h3>Methods</h3> GP recorded data were collected from 72 UK general practices participating in the pilot British Lung Foundation asthma management program in 3 health authority areas, (two Clinical Commissioning Groups in England and one Health Board in Scotland). A retrospective analysis was undertaken of the Optimum Patient Care Research Database. This included data on child and adult patients (aged between 0 and 89) in receipt of asthma medication without a diagnosis of a chronic respiratory disease, classified by the absence of a QoF recorded asthma diagnosis. Asthma medications prescribed in the previous 12 months were identified (beta2-agonists, inhaled corticosteroids, cromones or montelukast). <h3>Results</h3> 39,124 patients received at least one respiratory medication in the 12 months prior to data collection. Of these, 9,761 (25.0%) had no clinical diagnosis ever recorded for asthma or COPD. 3,655 patients were prescribed 2 or more respiratory prescriptions without a coded respiratory disease and 982 patients had a lower respiratory tract infection recorded within the same period. <h3>Conclusion</h3> These results raise concern about over and under-treatment of children and adults in whom no diagnosis of asthma or any other chronic respiratory disease has been made. It is important that future Primary Care studies highlight the importance of early accurate diagnosis before starting treatment. Also, we suggest the present UK national prevalence and morbidity data are likely to underestimate the total burden of asthma within the Primary Care setting. <h3>References</h3> 1 The NHS Atlas of Variation in Healthcare for Respiratory Disease, 2012 2 The National Review of Asthma Deaths London, NRAD, 2014
Multimodality treatment for distal esophageal (DE) and gastroesophageal junction (GEJ) adenocarcinoma (ACA) with celiac lymph node (CLN) involvement
Authors: G. Khan, D. J. Adelstein, T. W. Rice, L. A. Rybicki, G. M. Videtic, J. P. Saxton, S. C. Murthy, D. P. Mason, C. P. Rodriguez, D. I. Ives
Journal: Journal of Clinical Oncology (2009)

4574 Background: CLN involvement is a predictor of poor outcome in patients (pts) with DE or GEJ ACA. Pre-treatment identification of such patients depends on clinical staging including endoscopic ultrasound (EUS), computerized tomography (CT), and positron emission tomography (PET). This review of our CLN positive pts was undertaken to define the impact of clinical staging on prognosis after concurrent chemoradiotherapy (CCRT) and surgery. Methods: We retrospectively identified all pts with DE or GEJ ACA, CLN involvement by EUS, CT or PET, and no evidence of distant hematogenous metastases, who were treated with the same CCRT and surgery protocol at the Cleveland Clinic. Pts not staged with all three modalities were excluded. Induction CCRT consisted of radiation (30 Gy at 1.5 Gy bid), and chemotherapy with cisplatin (20 mg/m 2 /d) and fluorouracil (1000 mg/m 2 /d) both given as continuous intravenous infusions during the first 4 days of radiation. Surgery was performed in 4–6 weeks and identical CCRT was planned 6–10 weeks post-operatively. Outcomes examined included locoregional control (LRC), distant metastatic control (DMC), freedom from recurrence (FFR) and overall survival (OS). Results: Between 2/00 and 12/07, 54 pts with clinically staged CLN involvement were treated with this protocol. CLN involvement was found by EUS in 70%, CT in 69% and PET in 54% of pts. No single or combination of clinical staging tests proved predictive of outcome except for LRC which was worse in pts with all 3 tests positive (p = 0.008). With a median follow-up of 27 (range 8–71) months, the 2-year Kaplan-Meier projected LRC is 87%, DMC 18%, FFR 18%, and OS 28%. DE (vs. GEJ) primary site predicted for better DMC (p &lt; 0.001), FFR (p = 0.002), and OS (p = 0.025). Negative surgical margins predicted for better DMC and FFR (p=0.005 both outcomes). Only tumor location remained significant in multivariable analysis. Conclusions: CLN involvement portends a poor but not hopeless prognosis after multimodality therapy. Despite excellent LRC, distant failure predominates. DMC, FFR, and OS were worse in pts with GEJ primaries, but were independent of how the CLN involvement was clinically identified. No significant financial relationships to disclose.
P57 Immune mechanisms in Pigeon Fancier’s Lung
Authors: S Hasan, S Bourke, N Kakkar, A Heaps, C McSharry, S Todryk
Journal: Thorax (2015)

<h3>Background</h3> Pigeon fanciers have a 1 in 10 risk of developing Pigeon Fancier’s Lung (PFL), a form of hypersensitivity pneumonitis due to inhaled pigeon antigens. This manifests as acute episodes of breathlessness, cough and fever after antigen exposure, which may progress to chronic dyspnoea and lung fibrosis. The precise disease mechanisms are unclear but both antibody and T cell responses specific for pigeon antigens are implicated. We wish to better understand immune responses against pigeon antigens in PFL to give new insight into the disease mechanisms and provide disease markers. <h3>Methods</h3> We studied the antibody and cellular immune response in fanciers attending pigeon shows. 77 completed a questionnaire of symptoms, performed spirometry and gave a blood sample, 32 of whom had symptoms of acute PFL. Peripheral Blood Mononuclear Cells and serum were extracted from the blood, and T cell and antibody responses were measured against pigeon serum and mucin using in-house well-characterised assays (ELISA and ELIspot, respectively), as well as flow cytometry and multiplex cytokine assays. These provided quantitative outputs of specific antibody titre and reactive T cells per million PBMC, validated using positive controls. Correlations between immune responses and disease symptoms were analysed. <h3>Results</h3> All fanciers examined had significant antibody and T cell responses against pigeon serum and/or pigeon mucin antigen. A range of antibody avidities and isotypes were observed (Figure 1; n = 37; 2012 cohort), but only IgA appeared to correlate with symptoms score (p = 0.012). T cell responses to pigeon serum were measured in the form of proliferating cells positive for lung-homing receptors (alpha4beta1 integrin), and secreting gamma-interferon and large amounts of anti-inflammatory interleukin 10; but did not correlate with symptoms. <h3>Conclusions</h3> Pigeon fanciers have high levels of antigen exposure and demonstrate intense antibody and cellular immune responses, but these correlate minimally with clinical symptoms. The pathogenesis of PFL is complex and may involve an inflammatory cell-antibody axis.