tbuckley/cabot-search huggingface dataset:
Abstract 5434: A high through-put bioluminescent assay to monitor the deamidation of asparagine and isomerization of aspartate residues in therapeutic proteins and antibodies
Authors: Said A. Goueli, Kevin Hsiao, Rushikesh Patel, Vishal Nashine
Journal: Cancer Research (2015)

Abstract Spontaneous degradation reactions such as oxidation, glycation, deamidation, Isomerization, and racemization are non-enzymatic modifications and produce functionally damaged species reflecting aging effect at the molecular level. L-asparagine (Asn) and L-aspartate (Asp) are among the most unstable residues in proteins- linked to deamidation, isomerization and racemization Rx. Under physiological conditions, succinimide-linked deamidation of Asn occurs with t1/2as short as 6 hrs while that for isoaspartate are generally 10-fold longer. A number of biological peptides and proteins possess labile Asn and Asp residues and the formation of IsoAsp at these sites adversely affect their function. The degradation of Asn and Asp sites via succinimide pathway has significant effect on protein function. Loss of function associated with isoAsp formation are found in many biologically critical proteins and is a major source of antibody instability and micro heterogeneity, Thus it is critical to accurately determine both the levels and the site of Asn deamidation in therapeutic antibodies and proteins. Although mass Spectroscopic platforms have been at the forefront of technologies to quantitate and identify sites of isoAsp formation, it fails in accurately determining Asn level and has problems with Asp isomerization due to the various steps required for sample preparation such as denaturation, reduction, alkylation, and enzyme digestion of the Ab before analysis resulting in problems with Asp isomerization and Asn determination artifacts. Although peptide mapping is the most powerful tool in isoAsp analyses, it is very time consuming and may itself actually cause sample degradation during preparation and analysis and is not always practical when large number of samples are needed for analysis. To improve on and complement existing technologies, we have developed a bioluminescent, homogenous, robust, sensitive and easy to use assay to accurately monitor the deamidation of Asn and isomerization of aspartate. The assay is based on the use of protein isoaspartate methyltransferase to catalyze the methylation of isoaspartate using S-adenosylmethionine (SAM) and resulting in the formation of S-adenosylhomocysteine and methylated isoaspartate. The assay is very sensitive, it can detect as little as 100 fmol of IsoAsp in as little as 5-10 pmol of proteins. Citation Format: Said A. Goueli, Kevin Hsiao, Rushikesh Patel, Vishal Nashine. A high through-put bioluminescent assay to monitor the deamidation of asparagine and isomerization of aspartate residues in therapeutic proteins and antibodies. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 5434. doi:10.1158/1538-7445.AM2015-5434
B16 Murine Melanoma and Aging: Slower Growth and Longer Survival in Old Mice23
Authors: William B. Ershler, James A. Stewart, Miles P. Hacker, Ann L. Moore, Barbara H. Tindle
Journal: JNCI Journal of the National Cancer Institute (1984)

The growth characteristics and colonization potential of a transplantable melanoma administered to young (3 mo) and old (24 mo) C57BL/6 mice were investigated. After sc injection of B16-F10 melanoma cells, tumor growth was slower, and final tumor volume was less in the older mice. Furthermore, after iv injection of B16-F1 melanoma cells, the number of pulmonary colonies was also less, and the survival was greater in the older mice. These findings indicate an age advantage in this experimental tumor model that may be attributed to either physical or immunologic factors.
Case 17-2008
Authors: M. Dror Michaelson, Othon Iliopoulos, David F. McDermott, Francis J. McGovern, Mukesh G. Harisinghani, Esther Oliva
Journal: New England Journal of Medicine (2008)

A 63-year-old man was admitted to this hospital because of a mass in the left kidney, associated with abdominal pain, weight loss of 3.2 kg, and cough. Physical examination disclosed scrotal varicoceles; imaging studies disclosed a mass in the left kidney, a mass in the left adrenal gland, and multiple pulmonary nodules. A diagnostic procedure was performed, and management decisions were made.
Fatal Massive Necrosis of the Liver as a Manifestation of Hypersensitivity to Probenecid
Authors: Edward S. Reynolds, Robert C. Schlant, Harvey C. Gonick, Gustave J. Dammin
Journal: New England Journal of Medicine (1957)

PROBENECID∥ was introduced in 1949 as an agent that would inhibit the renal tubular secretion of penicillin.1 Other uses were soon found, and probenecid is widely used for its uricosuric effect in chronic gout and gouty arthritis. In 1955 Boger and Strickland2 reviewed the side effects of probenecid as observed in over 2500 patients and reported no fatal reactions. The case described below is reported because it is interpreted as a fatal reaction to probenecid with the major lesion consisting of massive necrosis of the liver. The validity of this assumption will become apparent from a review of the time . . .
Factors Favoring Successful Transmetatarsal Amputation in Diabetes
Authors: Howard F. Root
Journal: New England Journal of Medicine (1948)

ALTHOUGH the emergency character of infectious or early gangrenous lesions of the toes and feet of diabetic patients has long been recognized by most physicians, a new aspect of this problem is presented by the demonstration that in many diabetic patients a useful and serviceable foot can be preserved through the proper use of the transmetatarsal amputation.1 , 2 Actually, in the last two years major amputations above the ankle have become less frequent at the New England Deaconess Hospital (Table 1). The danger inherent in minor lesions and the importance of teaching all older diabetic patients simple prophylactic measures appeared time . . .
Screening the Normal Population in Massachusetts for Phenylketonuria
Authors: Harvey L. Levy, Valerie Karolkewicz, Sally A. Houghton, Robert A. MacCready
Journal: New England Journal of Medicine (1970)

To ascertain the prevalence of phenylketonuria among the "normal" teen-age and adult population of Massachusetts, a total of 280,919 serum specimens submitted for routine syphilis testing were examined for elevated phenylalanine concentrations by a bacterial inhibition assay ("Guthrie test"). It was estimated that these represented about 250,000 separate persons. Only three adults with the biochemical findings of phenylketonuria were detected although, on the basis of findings from routine newborn screening, 17 cases might be anticipated in the general population. Each of the three adults was mentally subnormal. Mental normality is very rare among patients with phenylketonuria who have not received dietary therapy.
Cervical Venous Hum
Authors: Joseph E. Hardison
Journal: New England Journal of Medicine (1968)

Cervical venous hums are unusual in the adult unless a hyperdynamic circulatory state exists. Patients with intracranial arteriovenous malformations often have increased cerebral blood flow and increased venous return through the internal jugular veins, and cervical venous hums would therefore be expected to be more frequent. Two patients had large intracranial arteriovenous malformations, cranial bruits and very loud cervical venous hums. One patient hears and is annoyed by the hum. A cervical venous hum in a patient with a history of subarachnoid hemorrhage, migraine-like headache or epilepsy should alert the physician to the possibility of intracranial arteriovenous malformation.
Constitutive KIT Activity and IL-6 Production in Mast Cells Alters Levels of Reactive Oxygen Species (ROS) and the Scavenger Protein DJ-1 in Mastocytosis
Authors: Dokyun Kim, Michael A. Beaven, Joseph Kulinski, Avanti Desai, Glenn Cruse, Calman Prussin, Hirsh D. Komarow, Melody C. Carter, Dean D. Metcalfe, Ana Olivera
Journal: Journal of Allergy and Clinical Immunology (2016)
Acute Leukemia after Alkylating-Agent Therapy of Ovarian Cancer
Authors: Ronald R. Reimer, Robert Hoover, Joseph F. Fraumeni, Robert C. Young
Journal: New England Journal of Medicine (1977)

To estimatè the leukemogenic potential of alkylating agents, we surveyed 70 institutions using these drugs for the frequency of second cancers in patients with advanced ovarian cancer. Thirteen cases of acute nonlymphocytic leukemia occurred among 5455 patients, as compared to 0.62 cases expected (relative risk = 21.0). All 13 had received alkylating agents. Nine also received radiotherapy. The relative risk for patients given chemotherapy was 36.1 and rose to 171.4 for those surviving for two years (rate = 13.75 per 1000 patients per year). To evaluate the role of therapy versus underlying disease, a historical control of 13,309 patients with ovarian cancer in the National Cancer Institute's End Results Program was analyzed. No excess of leukemia was noted in this group, even among 6596 women receiving radiation. The excess of acute nonlymphocytic leukemia, therefore, appears attributable to alkylating agents, although the effect may be enhanced by exposure to radiation, as previously suggested for Hodgkin's disease. N Engl J Med 297:177–181, 1977)
P141 An evaluation of the acceptability of supervised ward-based exercise for patients admitted to hospital for acute exacerbation of COPD
Authors: L Hogg, S Madden-Scott, J Turnbull, L Osman
Journal: Thorax (2015)

<h3>Introduction</h3> Patients with COPD demonstrate peripheral muscle dysfunction and reduced physical activity. Both are compounded by admission for acute exacerbation (AECOPD). Supervised exercise during AECOPD has been shown to be safe and may ameliorate these deleterious physical effects. Debate remains as to the acceptability of exercise for patients admitted with AECOPD. <h3>Objective</h3> To evaluate the acceptability of supervised exercise for patients admitted with AECOPD. <h3>Methods</h3> Patients admitted with AECOPD between December 2013 and August 2014 were included if medically stable, had no other limiting factor to exercise and consented to participate. Physiotherapists prescribed a standardised progressive exercise programme comprising daily upper/lower limb strengthening exercises and walking, supervised by a physiotherapy assistant. Patients completed a self-reported Likert scale questionnaire on discharge. Data collection included MRC Dyspnoea score, COPD Assessment Test (CAT), Timed Up and Go (TUAG) and 4-metre gait speed (4MGS). <h3>Results</h3> 150 patients were screened, 78 (52%) participated. Mean (SD) age 70(10) years, 50% female, median (IQR) length of stay 7(5 -12) days, median number of exercise sessions 2(1–3). Median MRC 4(4–5) (n = 60); mean CAT at baseline 26 with a mean change of -3.7 (n = 50). 71 patients completed the questionnaire. 89% felt happy to participate in exercise when approached by a physiotherapist. 93% reported being able to undertake the exercises taught, 80% felt very or fairly confident to continue at home. 82% felt the exercise improved their ability to carry out functional tasks. 34% recalled previously completing Pulmonary Rehabilitation. Analysis of those who completed TUAG and 4MGS pre and post intervention (n = 15) showed mean baseline values of 23.7(10.7) secs and 0.44(0.21) mps respectively; mean changes of -6.8(9.45) secs and +0.08(0.16) mps respectively. <h3>Conclusions</h3> Supervised exercise is acceptable to patients admitted with AECOPD, even in those demonstrating significant frailty. However, the non-participation rate was high, reasons for which are unknown. It is unclear whether the improvement in health status and functional mobility during admission was due to exercise participation or natural recovery. Further work is required exploring the impact of initiating exercise during admission on physical activity behaviours post discharge as well as reasons for non-participation during admission.
Time Required for Complete Recovery from Chronic Propranolol Therapy
Authors: Scott L. Faulkner, Jack T. Hopkins, Robert C. Boerth, James L. Young, Leon B. Jellett, Alan S. Nies, Harvey W. Bender, David G. Shand
Journal: New England Journal of Medicine (1973)

Propranolol could not be detected in samples of plasma and left atrium obtained from eight patients during coronary bypass surgery 36 to 48 hours after withdrawal from chronic therapy. The norepinephrine sensitivity of strips of left atria obtained from four similar patients was not different from that in six control patients who had not previously received propranolol. In three ambulant patients, serial estimates of the chronotropic and inotropic responses to isoproterenol were made at daily intervals during withdrawal from propranolol. Isoproterenol sensitivity became stable or returned to control levels within 48 hours. These findings were confirmed by experiments in the rat. A withdrawal time of 48 hours thus appears sufficient for complete recovery from the cardiac effects of propranolol and any possibly active metabolites, and coronary bypass surgery should present no additional hazard. (N Engl J Med 289:607–609, 1973)
Increased Susceptibility to Infection Associated with Abnormalities of Complement-Mediated Functions and of the Third Component of Complement (C3)
Authors: Chester A. Alper, Neil Abramson, Richard B. Johnston, James H. Jandl, Fred S. Rosen
Journal: New England Journal of Medicine (1970)

In a patient with Klinefelter's syndrome and lifelong increased susceptibility to infection, no abnormalities were found in humoral antibody production, cellular immunity or leukocyte function. In contrast, the patient's serum complement-mediated functions were grossly deficient. The concentrations of serum complement components were normal except for that of C3 (β1C-globulin), which was less than one-third normal. The bulk of this was in the form of the inactive conversion product, C3b, at all times that the patient's serum or plasma was examined over a two-year period. Addition of small amounts of normal serum, but not purified C3, to the patient's serum improved all complement-mediated functions in vitro. This disorder, which may represent an inborn deficiency of a protein necessary for C3 stability in vivo and in vitro, is detected by the lowered serum C3 concentration and a positive non-gamma (C3) Coombs antiglobulin test.
Evidence for Defective Immunoregulation in the Syndrome of Familial Candidiasis Endocrinopathy
Authors: Karunyan Arulanantham, John M. Dwyer, Myron Genel
Journal: New England Journal of Medicine (1979)

We studied three children with candidiasis endocrinopathy syndrome, together with their parents and five siblings, to explore the possibility that defective immunoregulation allows autoimmune phenomena to be involved in the pathogenesis of this syndrome. Inheritance of the syndrome appeared to be autosomal recessive. Immunologic abnormalities in this family included hypergammaglobulinemia, selective IgA deficiency, anergy, autoimmune endocrinopathies and active chronic hepatitis. Defective suppressor T-cell function was noted in the two surviving children with clinically apparent disease and in a clinically normal sibling. Analysis of the immunologic abnormalities in the family suggests that defective immunoregulation rather than disordered effector mechanisms may explain the large number of immunologic defects noted. These defects, in turn, may result in the clinical manifestation of the syndrome.
Case 48-1988
Authors: Blake Cady, Carolyn C. Compton
Journal: New England Journal of Medicine (1988)

Presentation of CaseA 52-year-old man was admitted to the hospital with a diagnosis of Caroli's disease associated with recurrent obstructive jaundice, fever, and bacteremia.He was well until 28 years earlier, when jaundice developed. A liver biopsy, performed elsewhere, was complicated by perforation of the common bile duct, and an emergency cholecystectomy and choledochoduodenostomy were performed. The patient was well thereafter except for occasional brief bouts of jaundice, accompanied by the passage of dark urine and light stools that were usually associated with an upper respiratory tract infection, which was rarely accompanied by fever and never required admission to . . .
S16 Outcomes of multiple trigger wheeze and exclusive viral wheeze in early childhood: A comparison across two population cohorts
Authors: CN Cochrane, BD Spycher, R Granell, JAC Sterne, M Silverman, AM Pescatore, EA Gaillard, CE Kuehni, J Henderson
Journal: Thorax (2015)

<h3>Introduction</h3> Early childhood wheeze has been classified according to triggers; exclusive viral wheeze (EVW) and multiple trigger wheeze (MTW). It has been proposed that these phenotypes differ in their aetiology, severity and prognosis. <h3>Objectives</h3> To examine the prevalence and symptom severity of EVW and MTW in 2–6 year olds. To evaluate the stability of these phenotypes over time, and their association with later wheeze. <h3>Method</h3> In two longitudinal birth cohorts comprising 18,362 individuals, data on respiratory symptoms were collected at age 2, 4 and 6 years. Parent-reported triggers were used to classify wheeze as EVW or MTW for each 2-year period. Logistic regression analysis was used to estimate odds ratios for current wheeze and relative risk ratios for wheeze phenotypes versus no wheeze, at follow-up compared with baseline. <h3>Results</h3> At 2 years 17.6% and 22.6% (cohorts 1 and 2 respectively) had wheeze, of which 55.2% and 56.3% had MTW. At 6 years 69.7% and 75.7% of children with wheeze had MTW. Among children with wheeze at baseline, 58–76% with EVW and 46–67% with MTW were in remission 2 years later (cohort 1) and 14–20% and 4–11% (cohort 2). MTW had greater reported symptom-severity at all time-points compared with EVW. When adjusted for symptom-severity, children with EVW at baseline had relative risk ratios (RRR) of 2.9–7.4 and 4.1–15.5 (cohorts 1 and 2 respectively) for EVW and RRR 1.7–2.9 and 1.6–4.0 for MTW at follow-up. Children with MTW at baseline had RRR of 3.1–6.2 in cohort 1 and 3.6–15.6 in cohort 2 for MTW and 1.1–2.7 and 1.4–7.0 respectively for EVW at follow-up. <h3>Conclusions</h3> When adjusted for symptom severity, wheezing phenotypes based on reported triggers remained stable between 2–6 years of age. Symptom-severity may be a more important determinant than triggers of future wheeze classification in young children.
Correction of Retrograde Vertebral-Artery Flow and Acquired Coarctation of the Aorta
Authors: J. Edward McClenathan, M. William Voss, Robert B. Brown, David M. Long
Journal: New England Journal of Medicine (1963)

IN 1961 Reivich et al.1 called attention to the phenomenon of reversal of blood flow in the left vertebral artery after ligation or division of the left subclavian artery proximal to vertebral-artery takeoff. Perfusion of the ligated artery and its branches was accomplished through the vertebral artery rather than through other collateral pathways. Neurologic symptoms were attributed to the resulting decrease in perfusion pressure to the brain-stem and the cerebellar and cerebral structures supplied by the vertebral artery.We recently studied a patient with an unusual set of acquired vascular abnormalities consisting of stenosis of an aortic homograf t in . . .
Community mental health centers: returning to basics
Authors: S S Sharfstein
Journal: American Journal of Psychiatry (1979)

Community mental health centers (CMHCs) have made a significant contribution to making mental health services available to many Americans; in 1977 they served almost two million people. External fiscal constraints and internal service and accountability requirements now test the viability of CMHCs, but the most recent extension of the law allows increased flexibility on implementation, and the President's Commission on Mental Health has reinforced the original purpose of CMHCs by calling for an initiative to give special attention to the needs of children and youth, the elderly, minorities, the chronically mentally ill, and other underserved populations and areas.
Light-Chain Nephropathy
Authors: Neil Smithline, Jerome P. Kassirer, Jordan J. Cohen
Journal: New England Journal of Medicine (1976)

We observed idiopathic light-chain proteinuria in a patient with multiple abnormalities of proximal-tubule transport mechanisms (Fanconi syndrome), nephrogenic diabetes insipidus, and distal renal tubular acidosis. Seventeen of the 19 urinary amino acid levels measured were elevated. Uric acid and phosphate clearances were greater than 60 per cent and 50 per cent, respectively, of the simultaneous inulin clearance. When water deprivation was coupled with vasopressin administration, the maximum urinary concentration observed was 384 mOsm per kilogram of water. During ammonium-chloride loading, the level of hydrogen-ion concentration in the urine remained less than 100 times that in the blood. Kappa light-chain excretion was 149 mg per 24 hours. It appears that the concurrence of proximal tubular dysfunction, distal tubular dysfunction and light-chain proteinuria represents a distinct syndrome, which we call "combined light-chain nephropathy." Available evidence indicates that excessive light-chain production with subsequent filtration, reabsorption and catabolism, causes the complex tubular dysfunctions observed.
S34 Do bronchial washings improve the diagnostic sensitivity for lung cancer when endobronchial tumour is seen?
Authors: A Dewar, S Bartlett, R Breen
Journal: Thorax (2015)

<h3>Background/introduction</h3> Current BTS guidelines suggest that when endobronchial tumour is seen optimal diagnostic sensitivity is achieved when at least five mucosal biopsies are supplemented with bronchial washings and brushings. We review our bronchoscopy practice annually in line with current guidance, and strive to make continuous improvements. We have previously noted that bronchial brushings improve the diagnostic sensitivity for lung cancer when an endobronchial tumour is seen, but bronchial washing samples do not. <h3>Aims</h3> To confirm that bronchial washings do not increase diagnostic sensitivity for lung cancer where endobronchial tumour is seen at flexible bronchoscopy. <h3>Method</h3> We reviewed all flexible bronchoscopy procedures performed at our hospital during a two-year period (n = 365). We reviewed the Electronic Patient records for histology and cytology results in all cases where endobronchial tumour was visualised. <h3>Results</h3> Mucosal biopsies and either bronchial brushings or bronchial washings or brushings and washings were performed in all cases where an endobronchial lesion was seen (n = 65). Washings were performed in addition to mucosal biopsies in 95% of cases, bronchial brushings however were sent in 78% of cases. The diagnostic sensitivity for mucosal biopsies alone was 80% (n = 65), bronchial brushings in addition to mucosal biopsies improved diagnostic sensitivity to 86%. In the small number of cases (n = 4) mucosal biopsies were negative for malignancy but a malignant diagnosis made on bronchial brushings and washings, bronchial brushings were positive in all cases and whereas bronchial washings were positive in only 50%. <h3>Conclusion</h3> Bronchial washings did not add any additional value to the diagnosis of lung cancer when endobronchial tumour was seen. We suggest that mucosal biopsies and brushings combined provide optimal diagnostic sensitivity in these cases. Omitting bronchial washing would produce both cost saving (in our Trust processing bronchial washings costs £76.50 per sample), and time efficiencies; bronchoscopists could then focus on obtaining multiple good quality mucosal biopsies, which are of paramount importance in molecular subtyping of lung cancers.