tbuckley/cabot-search huggingface dataset:
P102 Development of a Novel Assay for the Detection of Active Neutrophil Elastase in Patients with Chronic Obstructive Pulmonary Disease
Authors: KL Moffitt, SL Martin, J Chalmers, B Walker
Journal: Thorax (2015)

<h3></h3> Neutrophil elastase (NE), a biomarker of infection and inflammation, correlates with the severity of several respiratory diseases including chronic obstructive pulmonary disease (COPD). However, it’s detection and quantification in biological samples is confounded by a lack of reliable and robust methodologies. Standard assays using chromogenic or fluorogenic substrates are not specific when added to complex clinical samples containing multiple proteolytic and hydrolytic enzymes which have the ability to hydrolyse the substrate, thereby resulting in an over-estimation of the target protease. Furthermore, ELISA systems measure total protease levels which can be a mixture of latent, active and protease-inhibitor complexes. Therefore, we have developed a novel immunoassay (ProteaseTag™ Active NE Immunoassay) which is selective and specific for the capture of <b>active</b> NE in sputum and Bronchoalveolar Lavage (BAL) in patients with COPD. The objective of this study was to clinically validate ProteaseTag™ Active NE Ultra Immunoassay for the detection of NE in sputum from COPD patients. 20 matched sputum sol samples were collected from 10 COPD patients (M = 6, F = 4; 73 ± 6 years) during stable and exacerbation phases. Samples were assayed for NE activity utilising both ProteaseTag™ Active NE Ultra Immunoassay and a fluorogenic substrate-based kinetic activity assay. Both assays detected elevated levels of NE in the majority of patients (n = 7) during an exacerbation (mean = 217.2 µg/ml ±296.6) compared to their stable phase (mean = 92.37 µg/ml ±259.8). However, statistical analysis did not show this difference to be significant (p = 0.07, ProteaseTag™ Active NE Ultra Immunoassay; p = 0.06 kinetic assay), which is highly likely to be due to the low study number. A highly significant correlation was found between the 2 assay types (p ≤ 0.0001, r = 0.996). NE as a primary efficacy endpoint in clinical trials or as a marker of inflammation within the clinic has been hampered by the lack of a robust and simple to use assay. ProteaseTag™ Active NE Immunoassay specifically measures only <b>active</b> NE in clinical samples, is quick and easy to use (&lt;3 h) and has no dependency on a kinetic readout. ProteaseTag™ technology is currently being transferred to a lateral flow device for use at Point of Care.
Case 31-2002
Authors: Martin A. Samuels, Mary Etta King, Ulysses Balis
Journal: New England Journal of Medicine (2002)

Presentation of CaseA 61-year-old man was admitted to the hospital because of right hemiplegia, aphasia, and obtundation.According to the patient's family, he had been well at his home in Haiti until about one month earlier, when pain developed in his right leg. Two days later, an ultrasonographic examination of the leg revealed no abnormalities, and a physician advised him to take aspirin. The pain resolved, but three weeks before admission, headache, nausea, and vomiting developed and shortly thereafter disappeared; two days later, the patient had a problem with balance. An ultrasonographic study of the liver raised the possibility . . .
Case 11-2005
Authors: Lewis B. Holmes, Antonio R. Gargiulo, Allan S. Nadel, Catherine Racowsky
Journal: New England Journal of Medicine (2005)

A 32-year-old pregnant woman sought genetic counseling after her fetus had been found to have an abnormal karyotype. Ultrasonography for the evaluation of an ovarian cyst at 14 weeks of gestation showed increased fetal nuchal translucency; amniocentesis showed extra material on the short arm of fetal chromosome 18. The mother recalled a family history of birth defects. Diagnostic testing was performed, and the role of preimplantation genetic testing for future pregnancies was discussed.
Benign Prostatic Hyperplasia — Medical and Minimally Invasive Treatment Options
Authors: Joseph E. Oesterling
Journal: New England Journal of Medicine (1995)

Benign prostatic hyperplasia is a nonmalignant enlargement of the prostate that is due to excessive cellular growth of both the glandular and the stromal elements of the gland. The condition is very common in men over 40 years of age of all races and cultures.18 For the past 50 years, transurethral resection of the prostate has been the mainstay of treatment. Approximately 400,000 such resections are performed annually in the United States, making this operation the second most common after cataract extraction in men older than 65.9 The associated expense is considerable; the total cost is approximately $5 billion . . .
Chromosome Abnormalities in Constitutional Aplastic Anemia
Authors: Gerald E Bloom, Susan Warner, Park S. Gerald, Louis K. Diamond
Journal: New England Journal of Medicine (1966)

IN 1927 the condition now known as Fanconi's aplastic anemia was first described in 3 brothers with pancytopenia and multiple congenital anomalies.1 Since that time numerous reports have analyzed the clinical and hematologic aspects of this syndrome.2 3 4 It is now apparent that Fanconi's aplastic anemia is quite variable in its manifestations. Therefore, the designation "constitutional aplastic anemia" has been applied to all patients with aplastic anemia with or without congenital anomalies in whom a constitutional defect is suggested by the familial occurrence or congenital onset of the disease. Under this classification system Fanconi's aplastic anemia is considered as one variety . . .
Transient Schizophrenic Reaction as a Major Symptom of Cushing's Syndrome
Authors: Jack W. Hickman, Rosser P. Atkinson, Lloyd D. Flint, Lewis M. Hurxthal
Journal: New England Journal of Medicine (1961)

MENTAL symptoms, including nervousness, irritability, mild depression and paranoid tendencies, have long been known to be associated with Cushing's syndrome. The incidence varied from 20 to 67 per cent in four series described in reports dealing with this aspect of the disorder.1 2 3 The incidence of full-blown schizophrenia is much lower. Among 35 cases of Cushing's syndrome seen at the Lahey Clinic after the original description of the condition in 1932 up to 1958, 2 patients have had mental symptoms consistent with a diagnosis of schizophrenic reaction. The following is a report of the most recent case.Case ReportA 35-year-old . . .
The Prevention and Treatment of Osteoporosis
Authors: Alastair J.J. Wood, B. Lawrence Riggs, L. Joseph Melton
Journal: New England Journal of Medicine (1992)

OSTEOPOROSIS is one of the most important disorders associated with aging.1 , 2 More than 1.5 million Americans have fractures related to osteoporosis each year, with attendant pain, deformity, and loss of independence. The annual cost to the U.S. health care system is at least $10 billion.1 , 2 Because of the aging of the population and increases over time in the incidence of fractures, these already huge costs will more than double over the next 30 years3 unless a comprehensive program of prevention and treatment is initiated soon. The most important preventable cause of fractures is low bone mass. During the course of . . .
Abstract 200: Novel Interaction of Spinophilin with Alpha1a-Adrenergic Receptor and its Genetic Variant in Cardiovascular Cells
Authors: Ekaterina Babaeva, Irina Gradinaru, Debra A Schwinn, Anush Oganesian
Journal: Circulation Research (2014)

Activation of α 1 -Adrenergic Receptors (α 1 ARs), members of the G protein-coupled receptor (GPCR) superfamily, in response to stimulation of the sympathetic nervous system by catecholamines plays a major role in regulating cardiovascular (CV) function. Among three α 1 AR subtypes (α 1a ,α 1b ,α 1d ), α 1a ARs predominate in human resistant vessels and in heart. Recently, we discovered that naturally occurring human α 1a AR-G247R (247R) genetic variant, identified in the 3 rd intracellular loop (3iL) of the receptor in highly hypertensive patient, triggers constitutive hyperproliferation in CV cells (cardiomyoblasts, smooth muscle cells (SMC) and fibroblasts), which may lead to myocardial fibrosis and remodeling. In fibroblasts and cardiomyoblasts 247R triggered hyperproliferation is due to constitutive active coupling to Gq-independent βarrestin1/MMP/EGFR/ERK dependent pathway, while in SMC it is Gq- and MMP/EGFR/ERK-dependent. Here we report that α 1a AR-WT (WT) and 247R differentially interact with ubiquitous multi-domain scaffold protein spinophilin (SPL) that binds to 3iL of several GPCRs competing with arrestin thereby prolonging their signaling. The role of SPL in CV regulation is poorly studied. We hypothesized that SPL mediates constitutive signaling of 247R and examined whether SPL directly interacts with α 1a AR-WT or 247R. Our preliminary results reveal a direct interaction of SPL with WT and 247R: the SPL-WT interaction appears to be stronger as determined by co-immunoprecipitation. Different domains of SPL differentially interact with WT or 247R. SPL 1-480aa fragment interacts stronger with WT indicating interaction with 3iL, while SPL 480-817 fragment interacts stronger with 247R. Our preliminary results also demonstrate that 247R expression in all three cell types elevates endogenous SPL protein levels. Importantly, inhibition of SPL expression with specific siRNA reduces 247R-triggered hyperproliferation in SMC and cardiomyoblasts to near normal levels, while SPL knockdown has no effect in WT cells. Thus, we identified SPL as a novel protein involved in interacting and signaling of α 1a AR and its genetic variant in CV cells and that SPL could be considered as a potentially novel target in α 1a AR-mediated cardiovascular disorders.
Continuous Positive-Pressure Ventilation in Acute Respiratory Failure
Authors: Anil Kumar, Konrad J. Falke, Bennie Geffin, Carolyn F. Aldredge, Myron B. Laver, Edward Lowenstein, Henning Pontoppidan
Journal: New England Journal of Medicine (1970)

Abstract Continuous positive-pressure ventilation was used in eight patients with severe acute respiratory failure. Cardiac output and lung function were studied during continuous positive-pressure ventilation (mean end-expiratory pressure, 13 cm of water) and a 30-minute interval of intermittent positive-pressure ventilation. Although the mean cardiac index rose from 3.6 to 4.5 liters per minute per square meter of body-surface area, the mean intrapulmonary shunt increased by 9 per cent with changeover to intermittent positive-pressure ventilation. Satisfactory oxygenation was maintained in all patients during continuous positive-pressure ventilation with 50 per cent inspired oxygen or less. With intermittent positive-pressure ventilation arterial oxygen tension promptly fell by 161 mm of mercury, 79 per cent occurring within one minute. Prevention of air-space collapse during expiration and an increase in functional residual capacity probably explain improved oxygenation with continuous positive-pressur...
A phase I dose escalation study of sunitinib in combination with gemcitabine + cisplatin for advanced non-small cell lung cancer (NSCLC)
Authors: M. Reck, N. Frickhofen, U. Gatzemeier, H. Fuhr, S. Lanzalone, M. J. Lechuga, E. Wang, R. Chao, E. Felip
Journal: Journal of Clinical Oncology (2007)

18057 Background: Sunitinib malate (SU) is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET, and FLT3, approved internationally for the treatment of advanced RCC and imatinib-resistant or -intolerant GIST. SU has also shown single- agent activity in NSCLC. In this study we assess the safety, tolerability, and pharmacokinetics (PK) of SU in combination with gemcitabine (G) and cisplatin (C). Methods: This is a phase I, dose-finding study in pts with untreated, stage IIIB/IV NSCLC not amenable to curative treatment. Planned dose levels include: oral SU (37.5 or 50 mg/day for 2 wks followed by 1 wk off treatment [2/1 schedule]) plus G (1000 or 1250 mg/m 2 iv on days 1 and 8 of a 21-day cycle) and C (80 mg/m 2 iv on day 1 of each cycle). SU doses are escalated in serial pt cohorts to determine the maximum tolerated dose (MTD) for both schedules. SU continuous dosing (CD) schedule will also be tested. PK and antitumor efficacy are also assessed. Results: As of Oct 2006, 13 pts were treated on the 2/1 schedule: 6 pts with SU 37.5 mg + G 1000 mg/m 2 + C 80 mg/m 2 , and 7 pts with SU 50 mg + G 1000 mg/m 2 + C 80 mg/m 2 . No dose-limiting toxicities (DLTs) were observed with SU 37.5 mg, while 2 pts experienced neutropenia and infection as DLTs with SU 50 mg. Grade 3/4 hematological AEs included neutropenia (n=3 at dose level 1 and n=5 at dose level 2), thrombocytopenia (n=1 and 5) and anemia (n=2 and 0). 3 pts achieved a partial tumor response at the SU 50 mg/day dose level. There were no apparent drug-drug interactions between SU in combination with G and C based on their systemic exposures in this study. Conclusions: The combination of SU (37.5 mg) on schedule 2/1 with G (1000 mg/m 2 ) and C (80 mg/m 2 ) in advanced NSCLC appears safe and tolerable in this pt population. Testing with G escalated to 1250 mg/m 2 or with SU administered on a CD schedule is ongoing. No significant financial relationships to disclose.
Assisted Reproductive Technology and Birth Defects Among Liveborn Infants in Florida, Massachusetts, and Michigan, 2000-2010
Authors: Sheree L. Boulet, Russell S. Kirby, Jennita Reefhuis, Yujia Zhang, Saswati Sunderam, Bruce Cohen, Dana Bernson, Glenn Copeland, Marie A. Bailey, Denise J. Jamieson, Dmitry M. Kissin
Journal: JAMA Pediatrics (2016)

Use of assisted reproductive technology (ART) has been associated with increased risks for birth defects. Variations in birth defect risks according to type of ART procedure have been noted, but findings are inconsistent.To examine the prevalence of birth defects among liveborn infants conceived with and without ART and to evaluate risks associated with certain ART procedures among ART-conceived infants.Used linked ART surveillance, birth certificates, and birth defects registry data for 3 states (Florida, Massachusetts, and Michigan). Methods for ascertaining birth defect cases varied by state. Resident live births during 2000 to 2010 were included, and the analysis was conducted between Feburary 2015 and August 2015.Use of ART among all live births and use of certain ART procedures among ART births.Prevalence of selected chromosomal and nonchromosomal birth defects that are usually diagnosed at or immediately after birth.Of the 4 618 076 liveborn infants between 2000 and 2010, 64 861 (1.4%) were conceived using ART. Overall, the prevalence of 1 or more of the selected nonchromosomal defects was 58.59 per 10 000 for ART infants (n = 389) vs 47.50 per 10 000 for non-ART infants (n = 22 036). The association remained significant after adjusting for maternal characteristics and year of birth (adjusted risk ratio [aRR], 1.28; 95% CI, 1.15-1.42). Similar differences were observed for singleton ART births vs their non-ART counterparts (63.69 per 10 000 [n = 218] vs 47.17 per 10 000 [n = 21 251]; aRR, 1.38; 95% CI, 1.21-1.59). Among multiple births, the prevalence of rectal and large intestinal atresia/stenosis was higher for ART births compared with non-ART births (aRR, 2.39; 95% CI, 1.38-4.12). Among ART births conceived after fresh embryo transfer, infants born to mothers with ovulation disorders had a higher prevalence of nonchromosomal birth defects (aRR, 1.53; 95% CI, 1.13-2.06) than those born to mothers without the diagnosis, and use of assisted hatching was associated with birth defects among singleton births (aRR, 1.55; 95% CI, 1.10-2.19). Multiplicity-adjusted P values for these associations were greater than .05.Infants conceived after ART had a higher prevalence of certain birth defects. Assisted hatching and diagnosis of ovulation disorder were marginally associated with increased risks for nonchromosomal birth defects; however, these associations may be caused by other underlying factors.
Relation between Maternal Diet and Subsequent Primitive Neuroectodermal Brain Tumors in Young Children
Authors: Greta R. Bunin, Rene R. Kuijten, Jonathan D. Buckley, Lucy B. Rorke, Anna T. Meadows
Journal: New England Journal of Medicine (1993)

It has been hypothesized that a high dietary intake of nitrosamines and their precursors, nitrites and nitrates, is a risk factor for brain tumors. Vitamins C and E inhibit the formation of nitrosamines and thus may be protective.
Cost-effectiveness of docetaxel compared to paclitaxel in metastatic breast cancer: A UK health economic analysis
Authors: S. E. Jones, A. Benedict, D. Cameron, S. Jourdan
Journal: Journal of Clinical Oncology (2007)

1081 Background: Docetaxel was shown to be superior to paclitaxel in OS and TTP (median OS: 1.28 vs 1.06 yr, HR=1.41; median TTP: 0.47 vs 0.30 yr, HR= 1.64) for the treatment of patients with metastatic breast cancer progressing after an anthracycline-based regimen (Jones et al. J Clin Oncol. 2005;23:5542). A cost-effectiveness analysis based on this head-to-head comparison was performed considering clinical effectiveness, quality-adjusted life-years, and direct medical costs in the UK. Methods: A probabilistic Markov model was developed to examine results over a 10-yr long time-horizon. Patient level data were available on PFS and OS, treatment cycles and doses, number of cycles affected by adverse events, G-CSF use and post-failure treatment. Generalized gamma regression, fitting patient-level data best were used to model baseline PFS and OS in the paclitaxel arm. HRs adjusting for all covariates were applied to the baseline hazards to generate the docetaxel arm. Resource use and utility values for health states were obtained from published literature and practicing UK oncologists. Unit costs came from 2005 NHS reference costs; drug costs from the British National Formulary 2006 without hospital discount. Costs and benefits were discounted at 3.5%. A Monte-Carlo simulation and extensive 1-way sensitivity analyses were conducted. Results: Docetaxel is more costly (£13,500 vs £10,600), but yields higher health benefits than paclitaxel (2.01 vs 1.48 LYs and 1.18 vs 0.85 QALYs for docetaxel and paclitaxel, respectively) over a 10-yr time horizon. The discounted Incremental Cost-Effectivness Ratio (ICER) of docetaxel vs paclitaxel 3-weekly was estimated to be £5,532/LY gained (95% CI 2,250–12,700) and £8,741/QALY gained (95% CI 3,400–17,300). The ICER was most sensitive to the HR for PFS, OS and the cost of docetaxel and paclitaxel. However, ICERs remained below £20,000/QALY at extreme values of the parameters. Conclusions: Compared with paclitaxel 3-weekly, over a 10-yr time horizon docetaxel provides survival and quality-adjusted survival benefit to metastatic breast cancer patients failing anthracycline regimens at an acceptable cost in a UK setting. Docetaxel is cost-effective compared to paclitaxel. No significant financial relationships to disclose.
LUX-Lung 6: A randomized, open-label, phase III study of afatinib (A) versus gemcitabine/cisplatin (GC) as first-line treatment for Asian patients (pts) with EGFR mutation-positive (EGFR M+) advanced adenocarcinoma of the lung.
Authors: Yi Long Wu, Caicun Zhou, Cheng-Ping Hu, Ji Feng Feng, Shun Lu, Yunchao Huang, Wei Li, Mei Hou, Jian Hua Shi, Kye Young Lee, Dan Massey, Yang Shi, Jiongjie Chen, Victoria Zazulina, Sarayut Lucien Geater
Journal: Journal of Clinical Oncology (2013)

8016 Background: A is an oral, irreversible, ErbB Family Blocker, blocking signaling from EGFR (ErbB1), HER2 (ErbB2) and ErbB4. A was superior to first-line pemetrexed/cisplatin in a global phase III trial (LUX-Lung 3) in EGFR M+ NSCLC. This study compared the safety and efficacy of first-line A with GC in EGFR M+ Asian pts. Methods: The trial was conducted in Asian countries. Following central testing for EGFR mutations (TheraScreen EGFR RGQ PCR kit), 364 pts (stage IIIB/IV, PS 0–1, chemo-naïve) were randomized 2:1 (A: 242; GC: 122) to daily A 40 mg or IV GC (1,000 mg/m 2 D1, 8 + 75 mg/m 2 q21 days up to 6 cycles). Primary endpoint was PFS by central independent review. Results: Baseline characteristics were balanced in both arms: Female (64.0 vs 68.0%), non-smoker (74.8 vs 81.1%), exon 19 deletion (51.2 vs 50.8%), L858R (38.0 vs 37.7%) in A and GC arms, respectively. PFS was significantly prolonged with A compared with GC by independent review (median PFS 11.0 vs 5.6 months, HR=0.28, p&lt;0.0001); this finding was consistent across all subgroups. Results from the investigator review were similar: HR=0.26, p&lt;0.0001, median 13.7 (A) vs 5.6 months (GC). Objective response (66.9% vs 23.0%, p&lt;0.0001) and disease control (92.6% vs 76.2%, p&lt;0.0001) rates (ORR/DCR) were significantly higher with A. OS, based on 43% of events shows HR=0.95, p=0.7593. Drug-related AEs of ≥G3 were reported in 36.0% (A) and 60.2% (GC) of pts, the most common of which were rash/acne (14.6%), diarrhea (5.4%) and stomatitis/mucositis (5.4%) with A and neutropenia (17.7%), vomiting (15.9%) and leukopenia (13.3%) with GC. Related AEs led to discontinuation in 5.9% (A) and 39.8% (GC) of pts. Patient reported-outcomes (PROs) showed significantly better control of cancer-related dyspnea, cough and pain with A. Conclusions: In EGFR M+ Asian pts, A significantly prolonged PFS with significant improvements in ORR, DCR, PROs. AEs in both arms were as expected, with a more favorable safety profile with A. LUX-Lung 6 is the largest prospective trial in EGFR M+ lung cancer, providing further evidence of superiority of A over standard chemotherapy in this setting. Clinical trial information: NCT01121393.
Impaired Cellular Resistance to Herpes-Simplex Virus in Wiskott-Aldrich Syndrome
Authors: Joseph W. St. Geme, James T. Prince, Barbara A. Burke, Robert A. Good, William Krivit
Journal: New England Journal of Medicine (1965)

THIS familial syndrome of eczema, thrombocytopenia and recurrent infection was described by Wiskott1 in 1937, but it was not until 1954 that Aldrich, Steinberg and Campbell2 defined it as a sex-linked recessive disease. The majority of children afflicted with this baffling disorder have died as a result of overwhelming bacterial infection. Recently, however, visceral invasion by measles virus and cytomegalovirus has been described as an additional microbial complication.3 In our own hospital, within a period of two and a half years, we observed an alarming progression of primary herpetic gingivostomatitis in 3 boys with this syndrome. Two of these patients . . .
Femoral vs. Caval Interruption for Venous Thromboembolism
Authors: Chilton Crane
Journal: New England Journal of Medicine (1964)

AS hospitalized patients in increasing numbers survive a multiplicity of other medical and surgical crises, pulmonary embolism continues as a chief immediate cause of death. Although anticoagulant suppression of intravascular clotting has provided effective protection from embolism in innumerable cases, in many clinical settings, venous ligation above the thrombus, as proposed by Homans1 in 1939, is the treatment of choice.Situations Favoring Venous InterruptionIn addition to patients manifesting coagulation defects or established bleeding lesions, the embolic failures of adequate anticoagulant therapy and those having repeated thromboembolic episodes are prime candidates for venous interruption. On surgical services recent operation on . . .