tbuckley/cabot-search huggingface dataset:
Soundings: Looking on the bright side
Authors: Colin Douglas
Journal: BMJ (2003)

Here in Auchendreich we have had our troubles; all new hospitals, even private finance initiative (PFI) projects, must expect them. The important thing is to keep them in proportion: a task that occupied our public affairs subcommittee throughout a six hour meeting last Monday afternoon.

Ten days previously there had even been some quite favourable coverage (“Car-park angel saves a life”) following a successful out-of-hospital resuscitation by an off duty critical care nurse. But the unusual willingness of the patient to speak to the media later should perhaps have alerted us. The stories in the weekend papers were not so helpful.

The patient had driven himself to hospital in great pain because he had been told an ambulance might take up to two hours. After a day in our emergency department he was transferred, with a diagnosis of renal colic, to our 24 hour ward, where fortunately he passed his stone after only three days. But in a regrettable series of media interviews he made it clear that he'd had his heart attack only because he'd just discovered that getting out of our car park would cost him £154.80.

Lessons have been learnt, and a series of screening questions for apparently grateful patients is now being piloted. But even this initiative would not have helped with our next problem. The disappearance of frail elderly patients always gives rise to anxiety, and in normal circumstances the retrieval of the 95 year old man concerned would have been something to celebrate. But “Scotland's luckiest Granpa” was rescued by a sharp eyed young Albanian only seconds from the exit point of our advanced but problematical high speed clinical waste disposal pathway. And although it was recognised immediately that the young man's immigration status might be a sensitive issue, that was clearly not a matter for the trust, since his employer was our PFI partner, McEachern Services plc.

Would that it had been so simple. The “Albanian” turned out to be a Scottish tabloid journalist working under cover on an investigation of the alleged problems of our PFI. Another thorough mole hunt was indicated. The subcommittee was discussing this when, for reasons beyond our control, the meeting had to adjourn. Happily it was nothing serious: just another power cut.
Abstract 2667: FP-208, a novel mTOR inhibitor with potent antitumor activities
Authors: Zhenjian Du, Qi Ji, Bo Chen, Chunxiao Zhang, Ge Zhao, Xingmin Zhang
Journal: Cancer Research (2015)

Abstract The mammalian target of rapamycin (mTOR) is a master regulator of cell growth, proliferation and survival. The phosphatidylinositol 3-kinase (PI3K)/mTOR pathway is commonly dysregulated in cancer. FP-208, animidazolone derivatives, is a novel small molecule that primarily inhibits mTOR with potent antitumor activity. The compound is soluble with a good oral PK profile and excellent bioavailability in mice and rats. Here we report the in vitro and in vivo effects of FP-208 in multiple cancer cell lines and in xenograft tumor models. FP-208 inhibited mTOR enzymatic activity in vitro (IC50 = 0.3nM) in a kinase assay and cell proliferation in multiple cancer cell lines. Western blot analysis to examine the effect of FP-208 showed significant blockade of phosphorylation of S6 and AKTS473, suggesting inhibition of both mTORC1 and mTORC2 activities. The antitumor activity of FP-208 was evaluated in human cancer xenograft models as well. Oral administration of the compound in tumor bearing mice strongly inhibited tumor growth as a single agent. Further analysis demonstrated that treatment with FP-208 inhibited phosphorylation of mTORC1/2 pathway markers, S6 and AKTS473 in the tumors. Taken together, our data from both in vitro and in vivo studies suggest that FP-208 is a drug candidate for the treatment of human cancers. Citation Format: Zhenjian Du, Qi Ji, Bo Chen, Chunxiao Zhang, Ge Zhao, Xingmin Zhang. FP-208, a novel mTOR inhibitor with potent antitumor activities. [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 2667. doi:10.1158/1538-7445.AM2015-2667
Activated Cytotoxic T Cells as Prognostic Marker in Hodgkin's Disease
Authors: J.J. Oudejans, N.M. Jiwa, J.A. Kummer, G.J. Ossenkoppele, P. van Heerde, J.W. Baars, Ph.M. Kluin, J.C. Kluin-Nelemans, P.J. van Diest, J.M. Middeldorp, C.J.L.M. Meijer
Journal: Blood (1997)
Neoplastic and Non-Neoplastic Renal Disease in &lt;italic&gt;Praomys (Mastomys) Natalensis&lt;/italic&gt;
Authors: Katharine C. Snell, Harold L. Stewart
Journal: JNCI Journal of the National Cancer Institute (1967)

Five tumors of the kidney were observed in 188 of 195 untreated Mastomys necropsied: 2 clear-cell adenocarcinomas, 1 papillary cyst adenocarcinoma, 1 small cystic adenoma, and 1 hemangioma. All but 17 of the 188 animals from which histologic sections were available and suitable for diagnosis had some type of non-neoplastic renal disease. Approximately one Fourth of the Mastomys had hydronephrosis, suppurative pyelonephritis, or focal nephritic scars of the types observed in other rodents, but the predominant renal disease was glomerulonephritis. The lesions of glomerulonephritis were comparable to those of man except that, apart from the capillaries and efferent and afferent vessels of the glomerulus, the renal vascular system was unimpaired. Many renal changes in the Mastomys resembled those in the mice of the NZB/BI strain and its outcrosses.
Clonal Proliferation of Type 2 Helper T Cells in a Man with the Hypereosinophilic Syndrome
Authors: Elie Cogan, Liliane Schandene, Alain Crusiaux, Pascale Cochaux, Thierry Velu, Michel Goldman
Journal: New England Journal of Medicine (1994)

The hypereosinophilic syndrome is characterized by persistent eosinophilia of unknown origin often associated with the dysfunction of multiple organs as a result of tissue infiltration by eosinophils and the toxic effects of their products1. Previous studies have suggested that T lymphocytes may be involved in the induction of the syndrome through the secretion of an eosinophil differentiation factor2,3. Helper T lymphocytes (CD4+ T cells) play a central part in normal and pathologic immune responses through the secretion of cytokines. Interleukin-2, interferon gamma, and tumor necrosis factor are involved in cell-mediated immunity, whereas interleukin-4 stimulates the production of . . .
A Retrospective Analysis of Safety and Outcome of Radiotherapy Given Following Treatment with Ipilimumab for Metastatic Melanoma
Authors: E. Killick, B. Shepherd, A. King, L. Gorf, S. Ellis, D. Joseph-Pietras, C. Crowley, G. Sharpe, M. Wheater, C. Ottensmeier
Journal: Annals of Oncology (2014)
Effect of the epidermal growth factor receptor antibody panitumumab on triggering of ADCC
Authors: T. Valerius, M. Dechant, J. J. Lammerts van Bueren, T. Schneider-Merck, S. Berger, T. Beyer, M. Gramatzki, W. K. Bleeker, P. W. Parren, J. G. van de Winkel
Journal: Journal of Clinical Oncology (2009)

11055 Targeted therapy against the epidermal growth factor receptor (EGF-R) has been introduced into clinical practice for several solid tumors. Thus far, EGF-R- directed antibodies have received approval for the treatment of advanced colorectal and head and neck cancer. Recent studies demonstrated an association between Fcg receptor polymorphisms and clinical outcome. Here, we investigated effector mechanisms of the human IgG2 antibody pantitumumab and zalutumumab—a human IgG1 antibody against EGF-R, currently in phase III clinical evaluation. Both antibodies had similar binding characteristics, but differed in induction of antibody- dependent cellular cytotoxicity (ADCC). Zalutumumab induced potent MNC-mediated ADCC via FcgRIII (CD16), which was poorly triggered by panitumumab. Interestingly, not only zalutumumab but also panitumumab recruited neutrophils for ADCC. Neutrophil- mediated killing is triggered via FcgRIIa (CD32), and is potentially affected by its 131R/H polymorphism. Thus, panitumumab- mediated ADCC was more effective by neutrophils from FcgRIIa-131H homozygous individuals than from -131R individuals. ADCC induced by the IgG1 antibody zalutumumab was not affected by this polymorphism. In an experimental metastasis model in mice, both zalutumumab and panitumumab prevented establishment of metastases at low antibody concentrations which allowed the induction of ADCC but not the inhibition of signalling. Our results may implicate neutrophil- mediated ADCC in the in vivo mechanisms of action of EGF-R- directed antibodies, and suggest that heterogeneity in clinical responses due to the FcgRIIa-131R/H polymorphism can be expected for panitumumab. [Table: see text]
The Advanced Renal Cell Carcinoma Sorafenib (ARCCS) expanded access trial: Safety and efficacy in patients (pts) with non-clear cell (NCC) renal cell carcinoma (RCC)
Authors: W. M. Stadler, R. A. Figlin, M. S. Ernstoff, B. Curti, K. Pendergrass, S. Srinivas, V. Canfield, C. Weissman, M. Poulin- Costello, R. M. Bukowski
Journal: Journal of Clinical Oncology (2007)

5036 Background: A phase III trial showed that sorafenib (SOR) doubled progression-free survival (PFS) in previously treated pts with clear cell RCC. Activity of SOR in pts with NCC RCC has not been previously reported. Methods: Pts eligible for this open-label, nonrandomized trial in North America were not eligible for other SOR clinical trials, had recovered from prior treatment-related toxicity, and had advanced RCC; ECOG PS of 0–2; age =15 yrs; no treatment with other investigational drugs within 4 wks; life expectancy &gt;2 mos; no active coronary artery disease, ischemia or hypertension; and no severe renal impairment requiring dialysis. In the US, ARCCS enrollment ended with SOR approval in 12/05, and pts were transitioned to commercial drug with NCC pts being eligible for an additional 6-mo follow-up in an extension protocol (EP), which was designed to better assess PFS in NCC. Tumor assessments and radiological evaluations were conducted every 4 wks in the main protocol and every 8 wks in the EP. Results: Of 2,488 pts valid for safety in ARCCS, 212 (8.5%) had NCC RCC classified as papillary, chromophobe, collecting duct, or oncocytoma, of whom 24 enrolled in the EP. Baseline characteristics and efficacy are shown in the table . Grade 3 and 4 adverse events (AEs) with &gt; 2% incidence across all histologies included fatigue 7.1%, hand-foot skin reaction 6.6%, rash/ desquamation 6.2%, hypertension 4.7%, abdominal pain 3.8% dyspnea 3.8%, pleural effusion 3.3%, nausea 3.8%, vomiting 2.4%, and ascites 2.4%. Grade 3 and 4 serious AEs were reported in 20% of patients. Of those enrolled in the EP with NCC, median PFS was 34.5 wks (65.2% censored). Conclusions: SOR was well tolerated among pts with NCC RCC. Within the limitations of no central pathologic review, SOR toxicity in NCC RCC was similar to that in the broader ARCCS population and SOR may have antitumor activity in papillary and chromophobe subtypes. [Table: see text] [Table: see text]
Abstract 3672: Seasonal Variation in Ischemia Tolerance in a True Mammalian Hibernator
Authors: Athanasios P Peppas, Lin Yan, You-Tang Shen, Dorothy E Vatner, Stephen F Vatner, Raymond K Kudej
Journal: Circulation (2009)

True mammalian hibernation is a unique strategy for surviving extreme environmental stress during winter months. The molecular mechanisms of cardioprotection in hibernating models are not known, and furthermore, whether or not these mechanisms are innate to the myocardium or are switched on only in winter. We tested the hypothesis that a true mammalian hibernating species, the North American woodchuck ( Marmota monax ), might reveal mechanistic insight into ischemic preconditioning (IPC), during the winter when they are prepared to hibernate, but not in summer. Accordingly, woodchucks were studied in summer (n=5) and in winter (n=5). After surgical implantation of instrumentation to measure aortic, left atrial and left ventricular (LV) pressures, myocardial infarction was induced by 1 hr ligation of a proximal branch of the left anterior descending coronary artery (CA) followed by 2 hrs reperfusion. Body temperature, arterial blood gases, hemodynamics and tissue blood flows (radioactive microspheres) were similar between groups, at baseline and during CA occlusion (O). The ischemic area at risk (AAR), determined by alcian blue dye, was similar between groups (31±6 vs 30±3% of LV and septum). Myocardial infarction (measured using TTC and expressed as a fraction of the AAR) was 49±5.4% in summer woodchucks, and significantly less (p
A Comparison of Reteplase with Alteplase for Acute Myocardial Infarction
Authors: The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO III) Investigators
Journal: New England Journal of Medicine (1997)

Reteplase (recombinant plasminogen activator), a mutant of alteplase tissue plasminogen activator, has a longer half-life than its parent molecule and produced superior angiographic results in pilot studies of acute myocardial infarction. In this large clinical trial, we compared the efficacy and safety of these two thrombolytic agents.
A phase II study of palbociclib (PD-0332991) in adult patients with advanced hepatocellular carcinoma.
Authors: Susan Joy Littman, Christina Brus, Ashlie Burkart
Journal: Journal of Clinical Oncology (2015)

277 Background: The oral MKI sorafenib has been shown to significantly increase PFS, OS and DCR in treatment-naïve HCC in randomized Ph 3 trials. Despite these landmark studies OS benefit is modest, particularly for those with C-P cirrhosis grades B/C and toxicity is a major management problem. We report results of second-line treatment with palbociclib, PD-0332991, an orally available selective inhibitor of cyclin dependent kinases 4 and 6, which has potent anti-proliferative activity in pre-clinical studies. Methods: This is an open-label, nonrandomized single institution trial for pts with inoperable, advanced HCC, who have failed or are intolerant of first line therapy with sorafenib. Eligible subjects were treated with 125 mg PD-0332991 orally/day, 1-21 of a 28-day cycle, until disease progression, unacceptable toxicity, withdrawal from study or death. Tumor response by CT or MRI was assessed using mRECIST v1.1. Toxicity assessments were per NCI CTCAE v4.0. The primary endpoint is TTP. Secondary endpoints are safety/tolerability, OS &amp; RR. Results: 21 pts (18 M, 3 F) have been enrolled. Median age: 62 (32-78) yrs. 47% Cauc, 19% AA and 33% Asian. 17 C-P A, 4 C-P B. ETOH 19%, HCV 48%, HBV 24%, NASH 5%, unknown 10%. 71% had &gt;1 metastatic site. All had pathologically confirmed Retinoblastoma-positive HCC. Median duration of therapy was 17 (8-69) wks and (4.25 (2-17) cycles. Most common grade 3/4 AEs were neutropenia and thrombocytopenia. Non-serious AEs were anemia, pain, ascites and fatigue. 4 pts were non-evaluable, median OS = 10.5 (5.5-14) wks. In evaluable pts, there was 1 PR and 0 CRs. 6 pts died of ESLD without observable disease progression by RECIST, median OS = 19 (4 - 43) wks. Nine pts had disease control (PR or SD) followed by disease progression, median TTP was 24 (4-64) wks. Prolonged stability was seen in 3 pts. OS was 40 (24-96) wks, excluding 2 pts who are alive at 120 and 59 wks. 2 pts remain on trial. Conclusions: Palbociclib demonstrates activity in patients with advanced HCC after failure of first-line sorafenib. This trial will meet its primary endpoint. Consistent with a cytostatic MOA, some pts experienced HCC stabilization and OS was determined by ESLD. Palbociclib is well tolerated in cirrhotic patients with advanced HCC. Clinical trial information: NCT01356628.
Case 3-1996
Authors: A.H. De Cherney, J.H. Eichhorn
Journal: New England Journal of Medicine (1996)

Presentation of CaseA 31-year-old woman with a documented first pregnancy of four weeks' duration was admitted to the hospital because of severe pain in the left lower quadrant of the abdomen, nausea, and vomiting.The patient had been well until 9 p.m. on the evening before admission, when she suddenly had acute pain in the left lower quadrant and became pale. Nausea and vomiting occurred on four occasions. She came to the hospital at approximately 5 a.m.The patient had been exposed to diethylstilbestrol (DES) in utero. She had been infertile, with cervical stenosis after cervical biopsies and laser . . .
Immunologic Studies on a Protein Extracted from Human Secondary Amyloid
Authors: Edgar S. Cathcart, Francis R. Comerford, Alan S. Cohen
Journal: New England Journal of Medicine (1965)

LITTLE is known about the specific nature of amyloid except that it takes certain stains, contains protein and carbohydrate and is laid down in the tissues as discrete fibrils. More accurate determination of its physical and chemical properties has been lacking mainly because of the difficulties encountered in attempts to separate amyloid deposits from surrounding parenchymal and connective tissues.As it became clear from work proceeding in this laboratory that amyloid fibrils could, in fact, be isolated in relatively pure form by means of differential centrifugation of tissue homogenates1 and, of even greater import, that these fibrils could then be . . .
A New Class of Infectious Agents Detectable by the Production of Chorioallantoic Membrane Lesions by Human Lymphoblastoid Cell Lines and Their Culture Supernatants 2
Authors: B. M. Longenecker, J. Menezes, E. J. Sanders, F. Pazderka, R. F. Ruth
Journal: JNCI Journal of the National Cancer Institute (1977)

Intravenous injection of cells and their tissue culture supernatants (CS) from human lymphoblastoid cell lines (LCL) induced the formation of lesions on the chorioallantoic membrane (CAM) of the chicken embryo. Injection of cells and CS from non-LCL and normal human lymphocytes induced few or no lesions. Irradiated chick embryos were more sensitive to lesion formation than were nonirradiated embryos. The 10g10 CAM lesions induced in irradiated (500 rads) embryos were a linear function of the 10g10 cells (from LCL) in the inoculum; the slope was 1.0, within experimental error. The formation of CAM lesions did not depend on the presence of Epstein-Barr virus (EBV) since lesions were also induced by cells and extracts derived from EBV genome-free LCL. Lesion-inducing activity associated with CS was filterable through 0.22-µ filters, sedimented at 78,000×g, and sensitive to inactivation by heat (56° C for 30 min), UV irradiation, chloroform, sera from chickens immunized against CS, and certain human sera. Lesion-inducing activity associated with cells and extracts was resistant to 5,000 rads of γ-radiation. B2/B2 embryos (the B locus is the major histocompatibility locus of chickens) were more sensitive to lesion formation than were B15/B21 and outbred embryos; this suggested a genetic influence on lesion formation. Our data suggest that the irradiated chicken embryo may be a highly sensitive and useful means for the detection of an unidentified or unknown agent or agents that may play an important role in human oncogenic lymphocyte transformation or might interact with transforming viruses.
SAT0362 Incidence of Adverse Events in Patients with Rheumatoid Arthritis and Spondyloarthritis Exposed to Anti-Tnf Therapy. Data from the Brazilian Registry for Monitoring of Biologic Therapies in Rheumatic Diseases (Biobadabrasil)
Authors: R. Ranza, I. Laurindo, D. Titton, L. Barbosa, M. Bertolo, J. Bertaccini, C. Brenol, H. Carvalho, G. Castro, M. Cecconi, I. Costa, A. Duarte, V. Fernandes, M. Freire, P. Louzada, J. Macieira, J. Miranda, I. Pereira, G. Pinheiro, M. Pinheiro, M. Sauma, M. Silva, R. Toledo, V. Valin, W. Vieira, C. Baaklini, M. Descalzo
Journal: Annals of the Rheumatic Diseases (2015)

<h3>Background</h3> The safety profile of a-TNF drugs might have regional differences due to socio economic factors and epidemiology of infectious diseases. In 2009, the Brazilian Society of Rheumatology started BiobadaBrasil registry, part of a Latin America project (BiobadaAmerica) with methodological support of SER and Biobadaser <h3>Objectives</h3> To report the incidence of adverse events (AE) in patients exposed to a-TNF drugs in Brazil <h3>Methods</h3> Since 2009, 31 centers from 21/26 states included patients with active rheumatic diseases starting a biologic drug or a synthetic DMARD (control group). A constant monitoring of data quality has been done (online, by phone and ïn situ"). This study focuses on serious AE (SAE) and serious infectious AE (SIAE) in patients with RA and SpA (AS and PsA) exposed to a-TNF.Time of exposure was set from start of the drug to the date of last administration plus twice the half-life. Continuous variables were expressed as mean (SD).AE incidence rate as 1000 p/y with 95%CI.Data 31/12/13 <h3>Results</h3> 1483 subjects with RA (952) and SpA (531) exposed to a-TNF drugs were included in BiobadaBrasil, 3882 p/y, mean age 47 (12) yrs, mean dis dur 9 (8) yrs, 65% females. Controls were 529 (RA 491, SpA 38), 1607 p/y, mean age 50 (12) yrs, mean dis dur 6 (8) yrs, 82% females. The incidence rates of AE in the a-TNF vs control groups were: SAE 69 [61,78] vs 30 [23,40] (ratio 2.31 [1.7,3.14] p=0.000), SIAE 35 [30,41] vs 12 [8,19] (ratio 2.96 [1.83,4.79] p=0.000). First a-TNF was associated with lower incidence of SAE and SIAE when compared with the subsequent (SAE 66 vs 97, ratio 1.47 [1.05,2.06], p=0.024) (SIAE 34 vs 44, ratio 1.22 [0.78,2.10], p=0.3). SAE and SIAE were less frequent in SpA than in RA (SAE ratio 0.69 [0.52,0.93], p=0.014) (SIAE ratio 0.53 [0.33,0.83], p=0.006) <h3>Conclusions</h3> In BiobadaBrasil registry, patients exposed to a-TNF drugs have incidence rates of SAE and SIAE respectively 2 and 3-fold those of the control group, significantly lower in SpA than in RA. <h3>Acknowledgements</h3> BiobadaBrasil study group: P Cabral data quality control, BSR, A Kakehasi UFMG Belo Horizonte, A. Ximenes HGG, Goiania, F Sztajnbok UERJ Rio Janeiro, H. Pereira HUGV Manaus, I Silveira PUCRS Porto Alegre, A Ranzolin UFPE Recife, A Hayata CRO Osasco, M Abreu UFSC São Carlos, M Scheinberg HAS São Paulo, W Bianchi SCM Rio Janeiro, W Chahade HSPE São Paulo <h3>Disclosure of Interest</h3> None declared
Pancreatic and Biliary Endoscopy
Authors: William R. Brugge, Jacques Van Dam
Journal: New England Journal of Medicine (1999)

Dramatic improvements in the quality of instrumentation have established endoscopy as the primary method for diagnosing and treating many pancreatic and biliary diseases. Endoscopic retrograde cholangiopancreatography (ERCP) is the most commonly used procedure in pancreatic–biliary endoscopy. Through its use of detailed endoscopic and fluoroscopic images, ERCP has evolved into a predominantly therapeutic technique. A new endoscopic procedure, endoscopic ultrasonography, provides high-resolution ultrasound images of the pancreas and biliary ducts and complements the findings of ERCP. With continued improvements in instrumentation, small-diameter catheters will permit even better imaging of the ductal systems with high-resolution endoscopy and ultrasonography.InstrumentationThe duodenoscopes used . . .
Ectrodactyly, Ectodermal Dysplasia, and Cleft Lip/Palate Syndrome with Concomitant Lymphopenia: A Novel TP63 Mutation
Authors: Adeeb A. Bulkhi, Tara V. Saco, Richard F. Lockey, Mark C. Glaum
Journal: Journal of Allergy and Clinical Immunology (2016)