tbuckley/cabot-search huggingface dataset:
Association of germline mutations in EGFR and ABCG2 with gefitinib response in patients with non-small cell lung cancer (NSCLC)
Authors: V. Gregorc, G. Cusatis, A. Spreafico, M. G. Amoroso, A. Gianmarco, R. G. Ingersoll, A. Sparreboom, E. Villa, M. Hidalgo, S. D. Baker
Journal: Journal of Clinical Oncology (2005)

3022 Background: Gefitinib demonstrates substantial interindividual differences in response. Gefitinib interacts with its target EGFR and the efflux transporter ABCG2 (Ozvegy-Laczka, Mol Pharmacol 2004). Two SNPs in the EGFR promoter (-216G>T and -191C>A) are associated with increased gene expression (Liu, Proc AACR 2004). A 421C>A SNP in ABCG2 is associated with reduced protein expression. The aim of this study was to evaluate the effects of these variants on response to gefitinib treatment. Methods: Eighty-four patients with NSCLC received gefitinib orally at 250 mg/day and DNA from plasma was screened for SNPs in the EGFR and ABCG2 genes using direct nucleotide sequencing. Statistical significance of associations between variant genotypes and grade toxicity or activity was performed by χ2 tests. Results: Seventy-six patients (median age, 68 years; 24 F/54 M) were evaluable for genotyping studies, toxicity and activity. Six patients (8%) had a partial response, 24 (32%) had stable disease. Grade 1–2 skin rash and grade 1–2 diarrhea occurred in 29% and 32% of patients. The allele frequencies for EGFR -216G>T, EGFR -191C>A and ABCG2 421C>A were 0.50, 0.13 and 0.064, and all were in Hardy-Weinberg equilibrium. The two EGFR variants were in linkage disequilibrium (D’ = 0.83; P = 0.004). The most common haplotypes were T-C (frequency, 48.9%) and G-C (38.0%). Whereas 53% of patients with diplotype T-C/T-C were stable disease or partial responders, only 8.3% of patients with diplotype G-C/G-C were responders (χ2 = 6.37; P = 0.041). The frequency of EGFR -191C>A was significantly higher in patients with grade 2 skin rash (χ2 = 14.9; P = 0.0049). ABCG2 421C>A was associated with diarrhea (χ2 = 4.30; P = 0.038); 40% of patients heterozygote for ABCG2 421C>A developed grade 1 or 2 diarrhea versus 27% of patients carrying the wild-type sequence. Conclusions: In line with in vitro data, this study suggests an inherited genetic contribution to the variable response to gefitinib treatment. The association of diarrhea with a variant in ABCG2 suggests a role of this transporter in the oral absorption and/or elimination of gefitinib. Funded by the Commonwealth Foundation for Cancer Research. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZenica
Homozygous Familial Hypercholesterolemia
Authors: J Genest, M A Lavoie
Journal: New England Journal of Medicine (1999)

Figure 1. A 39-year-old man with homozygous familial hypercholesterolemia because of a G→C mutation at the acceptor-splice site of intron 7 of the low-density lipoprotein (LDL) receptor had undergone coronary-artery bypass grafting at the age of 29 years and carotid endarterectomy at the ages of 38 and 39 years. His plasma LDL cholesterol level ranged from 463 to 500 mg per deciliter (12 to 13 mmol per liter). Twice-monthly treatment with selective LDL filtration, with the use of apheresis and a macromolecular exclusion filter (pore size, approximately 2×106 daltons), was begun and was subsequently supplemented with atorvastatin at a dose . . .
Cytostatic Intravesical Instillation in Patients with Superficial Bladder Carcinoma for the Prevention of Recurrent Tumors
Authors: H Huland, G Klöppel, U Otto, I Feddersen, W Brachmann, H Hubmann, J Kaufmann, W Knipper, F Lantzius-Beninga
Journal: European Urology (1988)
Using Data to Guide Anticoagulation in Patients With Atrial Fibrillation
Authors: John H. Alexander, Laine E. Thomas
Journal: JAMA Cardiology (2016)

Fredrik Björck, MD; Henrik Renlund, PhD; Gregory Y. H. Lip, MD, PhD; Per Wester, MD, PhD; Peter J. Svensson, MD, PhD; Anders Själander, MD, PhD
Human Plasma and Amino Acids as Moderators of Uptake and Metabolic Consequences of Antifolates in WIL-2 and Human Leukemia Cells&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: M J Fyfe, W D Sedwick, O E Brown, J Laszlo
Journal: JNCI Journal of the National Cancer Institute (1981)

Plasma and medium composition significantly affect cellular association of the lipid-soluble antifolate 2,4-diamino-5-(3',4'-dichlorophenyl)-6-methylpyrimidine (DDMP). This was demonstrated by measuring association of labeled drug with cells and by assaying the antimetabolic effect of DDMP on incorporation of deoxyuridine into DNA. Uptake of both aqueous and lipid-soluble antifolates was substantially reduced in the human lymphoblastoid cell line WIL-2 when Eagle's minimum essential medium (EMEM) was substituted for a basal salts solution containing glucose [DDMP approximatley 50%, methotrexate (MTX) approximately 30%]. Uptake of DDMP, however, was inhibited by the amino acid fraction of EMEM or glutamine alone, whereas MTX uptake was unaffected by amino acids. Further studies with human leukemia cells showed that DDMP was only about 25% as effective an inhibitor of deoxyuridine incorporation in autologous human plasma when compared to its inhibitory effect in RPMI-1640 medium MTX inhibition of deoxyuridine incorporation in these cells was essentially unaffected by substitution of autologous human plasma for RPMI-1640 medium. Replacing EMEM with pooled human plasma resulted in a 60-70% decrease in DDMP uptake but had only a marginal effect upon MTX uptake. Thus the choice of medium is important in studies of lipid-soluble antifolates such as DDMP that have a high affinity for cellular and medium lipoprotein components.
Diagnostic and Physiologic Implications of the Angiotensin Infusion Test
Authors: James A. Nicotero, Spero E. Moutsos, Eliseo Perez-Stable, Henri E. Turrian, Alvin P. Shapiro
Journal: New England Journal of Medicine (1966)

MUCH effort is currently expended to separate patients with hypertension due to stenosis of the renal arteries from those with hypertension due to diseases that are not amenable to surgical therapy. The tests involved are difficult and have a significant morbidity.Kaplan and Silah1 described a relatively simple procedure that held out promise of differentiating patients with hypertension into those with and without renal-artery stenosis. They noted that patients with stenosis, when given infusions of angiotension II, required a larger dose than patients with essential hypertension to elevate the blood pressure. Eventually, the procedure was simplified to a screening test . . .
M28 Respiratory Clinicians’ Experiences of End-of-Life Care in Idiopathic Pulmonary Fibrosis
Authors: B Turnpenny, K Shepherd, Z Borrill
Journal: Thorax (2015)

<h3>Introduction</h3> Referral rates to Specialist Palliative Care are low in Idiopathic Pulmonary Fibrosis (IPF) despite mean survival of 3 years,<sup>1</sup> and a high symptom burden in the final year, in particular dyspnoea, chest pain, anxiety and depression, and fatigue.<sup>2</sup> This study aimed to explore chest clinicians' experiences in delivering care in advanced IPF. <h3>Methods</h3> Questionnaires were distributed at a regional Respiratory meeting, focussing on initiating End-of-Life discussions, predicting prognosis, training, and reasons for low palliative care referrals. <h3>Results</h3> 57 completed questionnaires - 17 chest consultants, 28 chest registrars, 11 physiotherapists, and 1 nurse clinician. 23 (40%) initiated End-of-Life discussions in severe IPF frequently or very frequently, and 47 (84%) felt it was a very important or important part of their role, but 42% felt predicting prognosis in advanced IPF was difficult or very difficult. More consultants felt End-of-Life discussions were an important part of their role than registrars. Several aspects of End-of-Life care were felt to be harder in severe IPF than advanced malignancy (Figure 1), although similar to advanced COPD. 22 (42%) referred patients with severe IPF to hospital palliative care services very frequently or frequently, and 19 (37%) to community palliative care very frequently or frequently. Less than 10% of all respondents felt they had significant training in initiating End-of-Life discussions, palliating symptoms, or services available. The three symptoms perceived to be experienced most in patients dying with IPF were breathlessness, anxiety and fatigue (cohort data supports this<sup>2</sup>). The three commonest reasons for low palliative care referrals were healthcare team perceptions that palliative care services focussed on cancer, patient's lack of awareness of prognosis, and difficulty clinicians have in predicting prognosis. <h3>Conclusion</h3> Chest clinicians find predicting prognosis in ILD difficult, and this contributes to low palliative care referrals. They have minimal training in End-of-Life issues in IPF and there is a lack of local services for such patients. Respiratory training, and commissioning groups, are challenged to develop better End-of-Life services for a condition carrying a high symptom burden and often distressing death. <h3>References</h3> 1 Hubbard R, Johnston I, Britton J. Survival in patients with cryptogenic fibrosing alveolitis: a population-based cohort study.<i> Chest</i>. 1998;<b>113</b>:396–400 2 Bajwah S, Higginson IJ, Ross JR. <i>et al.</i> Specialist palliative care is more than drugs: a retrospective study of ILD patients.<i> Lung</i>. 2012;<b>190</b>:215–20
Case 19-1996
Authors: Kenneth B. Miller, Fiona M. Graeme-Cook
Journal: New England Journal of Medicine (1996)

Presentation of CaseA 33-year-old man was admitted to the hospital for a bone marrow transplantation because of refractory acute myeloblastic leukemia, stage M1.He had had proteinuria 18 years earlier, followed 3 years later by severe hypertension and increasing proteinuria, with a subsequent rise in the creatinine level. A renal biopsy revealed focal glomerulosclerosis. Extracorporeal hemodialysis was begun. Ten years before the current admission, a right nephrectomy was performed, and a cadaveric kidney, matched for one of four HLA-A and HLA-B categories, was transplanted into the right iliac fossa. Five and a half years before admission, nephrolithiasis was discovered . . .
Diagnosis and Management of Hormone-Secreting Pituitary Adenomas
Authors: Jeffrey S. Flier, Lisa H. Underhill, Anne Klibanski, Nicholas T. Zervas
Journal: New England Journal of Medicine (1991)

DIAGNOSTIC, medical, and surgical advances over the past decade have greatly changed the management of secretory pituitary tumors. Improvements in magnetic resonance imaging have advanced the noninvasive visualization of smaller pituitary adenomas. Enhancement with gadolinium discloses the three-dimensional anatomy of most tumors and permits a precise assessment of their location, their volume, and the involvement of the carotid arteries, optic nerves, and chiasm. It is also possible to determine more confidently whether a tumor is fibrous or cystic and whether it has undergone necrosis or hemorrhage.The advent of bilateral sampling of the petrosal sinus for corticotropin coupled with advances . . .
Combined Effects of High-Dose Bisphenol A and Oxidizing Agent (KBrO <sub>3</sub> ) on Cellular Microenvironment, Gene Expression, and Chromatin Structure of Ku70-deficient Mouse Embryonic Fibroblasts
Authors: Natalie R. Gassman, Erdem Coskun, Pawel Jaruga, Miral Dizdaroglu, Samuel H. Wilson
Journal: Environmental Health Perspectives (2016)

Exposure to bisphenol A (BPA) has been reported to alter global gene expression, induce epigenetic modifications, and interfere with complex regulatory networks of cells. In addition to these reprogramming events, we have demonstrated that BPA exposure generates reactive oxygen species and promotes cellular survival when co-exposed with the oxidizing agent potassium bromate (KBrO3).We determined the cellular microenvironment changes induced by co-exposure of BPA and KBrO3 versus either agent alone.Ku70-deficient cells were exposed to 150 μM BPA, 20 mM KBrO3, or co-exposed to both agents. Four and 24 hr post-damage initiation by KBrO3, with BPA-only samples timed to coincide with these designated time points, we performed whole-genome microarray analysis and evaluated chromatin structure, DNA lesion load, glutathione content, and intracellular pH.We found that 4 hr post-damage initiation, BPA exposure and co-exposure transiently condensed chromatin compared with untreated and KBrO3-only treated cells; the transcription of DNA repair proteins was also reduced. At this time point, BPA exposure and co-exposure also reduced the change in intracellular pH observed after treatment with KBrO3 alone. Twenty-four hours post-damage initiation, BPA-exposed cells showed less condensed chromatin than cells treated with KBrO3 alone; the intracellular pH of the co-exposed cells was significantly reduced compared with untreated and KBrO3-treated cells; and significant up-regulation of DNA repair proteins was observed after co-exposure.These results support the induction of an adaptive response by BPA co-exposure that alters the microcellular environment and modulates DNA repair. Further work is required to determine whether BPA induces similar DNA lesions in vivo at environmentally relevant doses; however, in the Ku70-deficient mouse embryonic fibroblasts, exposure to a high dose of BPA was associated with changes in the cellular microenvironment that may promote survival.Gassman NR, Coskun E, Jaruga P, Dizdaroglu M, Wilson SH. 2016. Combined effects of high-dose bisphenol A and oxidizing agent (KBrO3) on cellular microenvironment, gene expression, and chromatin structure of Ku70-deficient mouse embryonic fibroblasts. Environ Health Perspect 124:1241-1252; http://dx.doi.org/10.1289/EHP237.
Autologous stem cell transplant for primary CNS lymphoma results in prolonged progression free and overall survival
Authors: P. B. Johnston, B. P. O’Neill, S. M. Ansell, D. J. Inwards, L. F. Porrata, I. N. Micallef
Journal: Journal of Clinical Oncology (2006)

7623 Background: Survival for patient with primary CNS lymphoma (PCNSL), in general, is poor with patients requiring frequent chemotherapy treatments or receiving whole-brain radiation therapy, which can potentially result in significant neurologic decline and dementia. Because of the improved survival of high risk patients with aggressive lymphoma undergoing autologous stem cell transplant (ASCT), we began ASCT for patients with PCNSL in first or later remission with chemotherapy sensitive disease. We now report on outcomes of patients who have had at least 1 year follow up post ASCT. Methods: Between June, 2000 and September, 2004, 11 patients underwent ASCT for PCNSL. The medical records of consenting patients were abstracted for the following information. Median age at transplant was 47 years old (range 30–67). Median number of prior treatments 1 (range 1–3). Median time from diagnosis to transplant was 7.5 months (range 2.9 to 75.8). Median International Extranodal Working Study Group Prognostic Score: 2 (range 0–3). Disease status at transplant: First CR 5 patients, later CR or PR 6 patients. Results: Eleven patients underwent ASCT for PCNSL and have a minimum of 1 year follow-up. All patients received BEAM conditioning. Median follow up was 28.3 months. Four patients have relapsed at a median of 200 days (range 40–523). Of the patients who relapsed, one has died of disease progression and the remaining three are alive after additional therapy. Median overall survival and progression free survival from transplant have not been reached. Two year overall and event free survival are 89% and 61%, respectively. Conclusions: Although limited by patient selection and retrospective biases, this review suggests that ASCT for PCNSL demonstrates improved overall survival when compared to historical controls with similar PCNSL Prognostic Scores (2 year survival for patients from diagnosis with PS 2–3 was 48% in a prior published study). ASCT in first remission in patients with PCNSL appears promising and may limit the need for additional therapy which can be myelosuppressive or result in neurologic decline. No significant financial relationships to disclose.
Journal Peer Review
Authors: John C. Bailar, Kay Patterson
Journal: New England Journal of Medicine (1985)

Journal peer review is a remote and mysterious business for many research investigators. Four paradigms seem to capture much current opinion about peer review of scientific works submitted for journal publication: the sieve (peer review screens worthy from unworthy submissions), the switch (a persistent author can eventually get anything published, but peer review determines where), the smithy (papers are pounded into new and better shapes between the hammer of peer review and the anvil of editorial standards), and the shot in the dark (peer review is essentially unpredictable and unreproducible and hence, in effect, random). How well do these paradigms, . . .
Case 39-1999
Authors: Allan H. Ropper, Didier P. Cros, Darryl E. Palmer-Toy
Journal: New England Journal of Medicine (1999)

Presentation of CaseA 74-year-old woman was admitted to the hospital because of diarrhea and fever followed by multiple cranial-nerve palsies.She had a one-week history of fever (temperature, 40°C), watery diarrhea, nausea, abdominal pain, weakness, and fatigue. Her physician prescribed diphenoxylate hydrochloride–atropine sulfate. At 9 p.m. on the day before admission, the patient was speaking normally. She later applied a benzocaine–eugenol preparation to her gingiva because of several hours of dental pain. At 3 a.m. on the next day, her speech became severely slurred.The patient was taken to another hospital. She was able to drink water and to . . .
The Development of Respiratory Syncytial Virus-Specific IgE and the Release of Histamine in Nasopharyngeal Secretions after Infection
Authors: Robert C. Welliver, David T. Wong, Martha Sun, Elliott Middleton, Russell S. Vaughan, Pearay L. Ogra
Journal: New England Journal of Medicine (1981)

We studied the development of respiratory syncytial virus (RSV)-specific IgE and the release of histamine in nasopharyngeal secretions from 79 infants with various forms of respiratory illness due to RSV. RSV-IgE was measured by an enzyme-linked immunosorbent assay; specificity was confirmed by appropriate blocking experiments. Histamine content in the secretions was determined by fluorimetric methods. RSV-IgE was detectable in only one of 19 patients with RSV infection without wheezing, but was detectable in the majority of 60 patients with wheezing (P less than 0.01). Titers of RSV-IgE were significantly higher in patients with wheezing (P less than 0.05). Histamine was detectable in secretions of some patients with all forms of illness but was detected significantly more often (P = 0.05) and in higher concentrations in patients with wheezing. Peak titers of RSV-IgE and concentrations of histamine correlated significantly with the degree of hypoxia (P less than 0.001). Formation of RSV-specific IgE and release of histamine may adversely affect the outcome of RSV infection.
Neglected for too long? — CD8+ Tregs release NOX2-loaded vesicles to inhibit CD4+ T cells
Authors: Christoph T. Berger, Christoph Hess
Journal: Journal of Clinical Investigation (2016)

Tregs are critical for control of self-reactive T cells that escape thymic selection and end up in the periphery. Treg subsets suppress effector T cell populations through the secretion of immunosuppressive molecules and inhibitory cytokines as well as cell contact-dependent mechanisms. In this issue of the JCI, Wen and colleagues describe another mechanism by which Tregs suppress effector T cell populations. Specifically, the authors reveal that CD8+ T cells in close contact with target T cells release NADPH oxidase 2-containing microvesicles that inhibit TCR activation by elevating ROS and thereby reducing phosphorylation of the TCR-associated kinase ZAP70. Together, the results of this study provide important insight into CD8+ Treg function and into the development of autoimmunity in older individuals.
Absence of Anatomic Arteriovenous Shunts in Paget's Disease of Bone
Authors: Buck A. Rhodes, N. David Greyson, Carlos R. Hamilton, Robert I. White, Frank A. Giargiana, Henry N. Wagner
Journal: New England Journal of Medicine (1972)

To determine whether anatomic shunting through arteriovenous (AV) anastomoses is responsible for the circulatory abnormalities associated with Paget's disease of bone, shunting of particles, 15 to 30 μ in diameter, was measured in nine patients. In addition, relative regional perfusion, radiographs and serum alkaline phosphatase were measured. Hemodynamic data were obtained in three of the patients. No AV shunting was found, despite the fact that blood flow to the involved bone was increased in every case and AV oxygen differences were decreased in some. We therefore conclude that hyperperfusion of diseased bone rather than AV shunting is responsible for the hyperkinetic circulation and decreased AV oxygen differences in patients with Paget's disease of bone.
Survival following surgical treatment of hepatic melanoma metastases
Authors: W. C. Conway, N. Wasif, S. Gagandeep, D. L. Morton
Journal: Journal of Clinical Oncology (2008)

9015 Background: The 4–6 month median overall survival (OS) traditionally associated with liver metastases from malignant melanoma treated with systemic medical therapy may not reflect the potential benefit of hepatic metastasectomy in patients whose selection and management are guided by modern imaging and surgical techniques. Methods: Since 1991, over 900 patients with hepatic melanoma metastases have been treated at our institution. Among these, 54 (5.9%) were treated with surgical therapy; 44 underwent metastasectomy (6 had simultaneous ablation) while 10 had lesion ablation alone. OS (from diagnosis of hepatic metastasis) and disease-free interval (DFI, from primary diagnosis to hepatic metastasis) were calculated; subgroup analysis evaluated the effects of primary tumor site and type of surgical therapy. Results: Median OS and 5-year rate of OS were 26 months and 33%, respectively, for 54 surgical patients, as compared with 7 months and 5%, respectively, for 867 nonsurgical patients (p<0.001). Median and 5-year OS tended to be better with resection (31 months and 36%, respectively) than with ablation (17 months and 15%, respectively, p=0.40). Median OS was 22 months for the 12 patients undergoing simultaneous hepatic and extrahepatic metastasectomy, as compared with 33 months for the 32 patients undergoing hepatic resection alone (p=0.59). Although not reaching significance, within the surgical group, ocular primaries (5) were associated with a longer median DFI (95 months) than those with cutaneous lesions (41, 53 months, p=0.36). There were 2 (3.7%) operative deaths. Conclusions: In this largest single- institution series, surgical therapy of metastatic melanoma to the liver was associated with a 5-year OS of 33%, comparable to rates reported for resection of melanoma metastatic to nonhepatic sites. Resection and/or ablation should be the initial therapy of choice for carefully selected patients since no other therapy is associated with such prolonged survival. No significant financial relationships to disclose.