tbuckley/cabot-search huggingface dataset:
A dyad of lymphoblastic lysosomal cysteine proteases degrades the antileukemic drug l-asparaginase
Authors: Naina Patel, Shekhar Krishnan, Marc N. Offman, Marcin Krol, Catherine X. Moss, Carly Leighton, Frederik W. van Delft, Mark Holland, JiZhong Liu, Seema Alexander, Clare Dempsey, Hany Ariffin, Monika Essink, Tim O.B. Eden, Colin Watts, Paul A. Bates, Vaskar Saha
Journal: Journal of Clinical Investigation (2009)

l-Asparaginase is a key therapeutic agent for treatment of childhood acute lymphoblastic leukemia (ALL). There is wide individual variation in pharmacokinetics, and little is known about its metabolism. The mechanisms of therapeutic failure with l-asparaginase remain speculative. Here, we now report that 2 lysosomal cysteine proteases present in lymphoblasts are able to degrade l-asparaginase. Cathepsin B (CTSB), which is produced constitutively by normal and leukemic cells, degraded asparaginase produced by Escherichia coli (ASNase) and Erwinia chrysanthemi. Asparaginyl endopeptidase (AEP), which is overexpressed predominantly in high-risk subsets of ALL, specifically degraded ASNase. AEP thereby destroys ASNase activity and may also potentiate antigen processing, leading to allergic reactions. Using AEP-mediated cleavage sequences, we modeled the effects of the protease on ASNase and created a number of recombinant ASNase products. The N24 residue on the flexible active loop was identified as the primary AEP cleavage site. Sole modification at this site rendered ASNase resistant to AEP cleavage and suggested a key role for the flexible active loop in determining ASNase activity. We therefore propose what we believe to be a novel mechanism of drug resistance to ASNase. Our results may help to identify alternative therapeutic strategies with the potential of further improving outcome in childhood ALL.
Forming norms: informing diagnosis and management in sports medicine
Authors: J N Baldwin, M J McKay, C E Hiller, E J Nightingale, N Moloney, N Vanicek, P Ferreira, M Simic, K Refshauge, J Burns
Journal: British Journal of Sports Medicine (2015)

Clinicians aim to identify abnormalities, and distinguish harmful from harmless abnormalities.In sports medicine, measures of physical function such as strength, balance and joint flexibility are used as diagnostic tools to identify causes of pain and disability and monitor progression in response to an intervention.Comparing results from clinical measures against 'normal' values guides decision-making regarding health outcomes.Understanding 'normal' is therefore central to appropriate management of disease and disability.However, 'normal' is difficult to clarify and definitions are dependent on context.'Normal' in the clinical setting is best understood as an appropriate state of physical function.Particularly as disease, pain and sickness are expected occurrences of being human, understanding 'normal' at each stage of the lifespan is essential to avoid the medicalisation of usual life processes.Clinicians use physical measures to assess physical function and identify disability.Accurate diagnosis hinges on access to 'normal' reference values for such measures.However our knowledge of 'normal' for many clinical measures in sports medicine is limited.Improved knowledge of normal physical function across the lifespan will assist greatly in the diagnosis and management of pain, disease and disability.
Error in Tables 3, 5, and 6 and Text in Article by Jacobe et al (Arthritis Rheumatol, November 2014)
Authors: Heidi Jacobe, Chul Ahn, Frank C. Arnett, John D. Reveille
Journal: Arthritis & Rheumatology (2015)

In the article by Jacobe et al published in the November 2014 issue of Arthritis & Rheumatology (pages 3170−3177), a row listing the (nonexistent) allele DQA1*03:00 was inadvertently included in Tables 3, 5, and 6, as the result of a typographical error. The number of patients with morphea (overall, generalized, or linear) who had the allele as shown in Tables 3, 5, and 6 was referring to the allele DQA1*03. DQA1*03 is quite common in the population overall, and the percentage of subjects who had this allele did not differ significantly between morphea patients and controls. Therefore, this line should not have been included in these tables at all, as the tables were meant to list only alleles positively or negatively associated with morphea. Additionally, required corrections to article text are as follows: On page 3173, the sentence “HLA–DQA1*03:00 was present exclusively in patients with morphea” should not have been included. On page 3173, the sentence “The risk association of HLA−DQB1*02:01 and DQA1*03:00was maintained in the Caucasian patient subset, with the ORs and the proportion of cases with each allele being similar to those in the overall group analysis, implying that the association of these risk alleles was with the group of morphea cases overall” should have read “The risk association of HLA−DQB1*02:01was maintained in the Caucasian patient subset, with the OR and the proportion of cases with this allele being similar to that in the overall group analysis, implying that the association of this risk allele was with the group of morphea cases overall.” On page 3174, the sentence “In comparing patients with generalized morphea and controls (Table 5), the same HLA class I and class II alleles were present as when overall cases were compared with controls, including DQA1*03:00, DQB1*02:01, C*08, and C*15” should have read “In comparing patients with generalized morphea and controls (Table 5), the same HLA class I and class II alleles were present as when overall cases were compared with controls, including DQB1*02:01, C*08, and C*15.” We regret the errors.
DEPIGMENTATION FROM ADHESIVE TAPE
Authors: Cooper H. Stacey
Journal: JAMA (1952)

<h3>To the Editor:</h3> —Blank and Miller, in their excellent article on rubber adhesives in shoes as the cause of dermatitis of the feet (<i>J. A. M. A.</i><b>149</b>:1371 [Aug. 9] 1952) state that they did not observe depigmentation action of the monobenzyl ether of hydroquinone but only the sensitizing property. The photographs below are representative of several patients seen here in the last two years with what we call "adhesive tape vitiligo," i. e., depigmentation presumably due to the monobenzyl ether of hydroquinone used as an antioxidant in the rubber of ordinary surgical tape. All the patients of this type we have seen have been Negroes. Although their main depigmentation has been due to adhesive tape, both patients in these photographs show depigmentation of the feet in a pattern conforming to that of the rubber-containing shoes they wore. The patients we have observed have described no or very little
Abstract 2564: High-throughput siRNA library screen for discovery and identification of new melanoma therapeutic targets in combination with antioxidant pretreatment
Authors: Wuguo Deng, Nancy J. Poindexter, Suhendan Ekmekcioglu, John Kwon, Sandra A. Kinney, Elizabeth A. Grimm
Journal: Cancer Research (2010)

Abstract Melanoma is one of the most prevalent cancers in the United States, having the fifth highest cancer incidence in males and sixth highest incidence in females. Primary cutaneous melanoma can often be cured by surgery, but for those patients in whom metastasis has occurred, mortality is high in part due to numerous chemoresistance mechanisms. Thus, there is an urgent need to discover and identify novel therapeutic targets for the efficient treatment of this lethal disease. Gene silencing by RNA interference (RNAi) is a powerful tool to identify novel genes involved in specific biological processes. In our study, we used high-throughput druggable siRNA library (Dharmacon) targeting 6028 human genes to screen metastatic melanoma cell lines and found that knockdown of gene expression by siRNA pools targeting 885 genes significantly inhibited melanoma growth (p&amp;lt;0.005). Among them, 67 siRNA pools resulted in &amp;gt;50% inhibition of cell viability in the melanoma A375 cells which we employed for the screening analysis. We validated the top-six cancer-related genes (RRM2, BCAR3, PSMA2, UBB, RRM1, TCP1) as potential melanoma therapeutic target candidates, as knockdown of these 6 genes significantly inhibited cell growth and induced apoptosis in multiple melanoma cell lines. We have hypothesized that antioxidant treatment relieves resistance mechanisms, and showed that among the screened &amp;gt;6000 siRNA pools, treatment with 20 pools significantly increased the growth inhibition in the presence of nontoxic levels of bardoxolone methyl (p&amp;lt;0.005), a novel semi-synthetic triterpenoid (previously known as CDDO-Me) with potent antioxidant activity generously provided by Reata Pharmaceuticals. We also selected 5 additional cancer-related genes (GNPAT, SUMO1, SPINT2, FLI1 and SSX1) for further analysis and validated them as additional candidates for therapeutic targeting in the presence of antioxidant. Our results thus demonstrate the feasibility of the high-throughput siRNA library screen system in discovering new melanoma therapeutic targets and shows that these new candidate genes are promising for the development of novel therapeutic targets for melanoma treatment, many of which are revealed by antioxidant pretreatment. Results from our study provide the basis for significant advances in identifying targets for the treatment of melanoma patients. (This study was partially supported by the grant from the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation and the NIH Melanoma SPORE grant P50, CA093459). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2564.
Differentiation of Phagocytic Monocytes into Lymph Node Dendritic Cells In Vivo
Authors: Gwendalyn J Randolph, Kayo Inaba, Davide F Robbiani, Ralph M Steinman, William A Muller
Journal: Immunity (1999)

We investigated the differentiation and trafficking of inflammatory monocytes that phagocytosed subcutaneously injected fluorescent microspheres. As expected, most of the monocytes became microsphere+ macrophages, which remained in subcutaneous tissue. However, about 25% of latex+ cells migrated to the T cell area of draining lymph nodes, where they expressed dendritic cell (DC)-restricted markers and high levels of costimulatory molecules. Microsphere-transporting cells were distinct from resident skin DCs, and this transport was reduced by more than 85% in monocyte-deficient osteopetrotic mice. Thus, a substantial minority of inflammatory monocytes carry phagocytosed particles to lymph nodes and differentiate into DCs.
Serum p53 antibodies in patients with chronic inflammatory bowel disease
Authors: H FRICKE, S URBAN, N NOEHL, C FOLWACZNY
Journal: Gut (1998)

Editor,—We read the paper by Hammel et al ( Gut 1997; 40 :356–61) with interest. The authors studied antibodies to the p53 tumour suppressor gene product in serum of patients with colorectal cancer and reported a p53 positive patient (CC49) who developed colorectal cancer after a history of >10 years of ulcerous pancolitis. Hammel et al stated that p53 tumour suppressor gene mutations are frequent abnormalities in colorectal cancer. p53 mutations can lead to the accumulation of the p53 gene product in the cell and thus may trigger an antigen driven humoral response against …
Night Heart Rate Variability and Particulate Exposures among Boilermaker Construction Workers
Authors: Jennifer M. Cavallari, Ellen A. Eisen, Jiu-Chiuan Chen, Shona C. Fang, Christine B. Dobson, Joel Schwartz, David C. Christiani
Journal: Environmental Health Perspectives (2007)

BackgroundAlthough studies have documented the association between heart rate variability (HRV) and ambient particulate exposures, the association between HRV, especially at night, and metal-rich, occupational particulate exposures remains unclear.ObjectiveOur goal in this study was to investigate the association between long-duration HRV, including nighttime HRV, and occupational PM2.5 exposures.MethodsWe used 24-hr ambulatory electrocardiograms (ECGs) to monitor 36 male boilermaker welders (mean age of 41 years) over a workday and nonworkday. ECGs were analyzed for HRV in the time domain; rMSSD (square root of the mean squared differences of successive intervals), SDNN (SD of normal-to-normal intervals over entire recording), and SDNNi (SDNN for all 5-min segments) were summarized over 24-hr, day (0730–2130 hours), and night (0000–0700 hours) periods. PM2.5 (particulate matter with an aerodynamic diameter ≤ 2.5 μm) exposures were monitored over the workday, and 8-hr time-weighted average concentrations were calculated. We used linear regression to assess the associations between HRV and workday particulate exposures. Matched measurements from a nonworkday were used to control for individual cardiac risk factors.ResultsMean (± SD) PM2.5 exposure was 0.73 ± 0.50 mg/m3 and ranged from 0.04 to 2.70 mg/m3. We observed a consistent inverse exposure–response relationship, with a decrease in all HRV measures with increased PM2.5 exposure. However, the decrease was most pronounced at night, where a 1-mg/m3 increase in PM2.5 was associated with a change of −8.32 [95% confidence interval (CI), −16.29 to −0.35] msec nighttime rMSSD, −14.77 (95% CI, −31.52 to 1.97) msec nighttime SDNN, and −8.37 (95% CI, −17.93 to 1.20) msec nighttime SDNNi, after adjusting for nonworking nighttime HRV, age, and smoking.ConclusionMetal-rich particulate exposures were associated with decreased long-duration HRV, especially at night. Further research is needed to elucidate which particulate metal constituent is responsible for decreased HRV.
Adverse Event Reporting in Clinical Trials of Finasteride for Androgenic Alopecia
Authors: Steven M. Belknap, Imran Aslam, Tina Kiguradze, William H. Temps, Paul R. Yarnold, John Cashy, Robert E. Brannigan, Giuseppe Micali, Beatrice Nardone, Dennis P. West
Journal: JAMA Dermatology (2015)

Two meta-analyses conclude that finasteride treatment of androgenic alopecia (AGA) is safe but do not assess quality of safety reporting.To assess safety reporting for clinical trial reports of finasteride for AGA.MEDLINE, ClinicalTrials.gov, and a clinical data repository for an academic medical center.Published clinical trial reports for finasteride treatment of AGA.For each trial, we assessed quality of adverse event reporting, extracted the number and type of adverse events in treatment and placebo groups, and assessed duration of safety evaluation and adequacy of blinding. Two observers independently extracted the data; differences were resolved by consensus. We assessed generalizability in a large cohort of men prescribed finasteride, 1.25 mg/d or less, by assessing for eligibility in the finasteride-AGA pivotal trials.Quality was assessed as adequate, partially adequate, inadequate, or no events reported. We used funnel plots of the hazard ratio to assess bias.Of 34 clinical trials, none had adequate safety reporting, 19 were partially adequate, 12 were inadequate, and 3 reported no adverse events. Funnel plots were asymmetric with a bias toward lower odds ratio for sexual adverse effects, suggesting systematic underdetection. No reports assessed adequacy of blinding, 18 (53%) disclosed conflicts of interest, and 19 (56%) received funding from the manufacturer. Duration of drug safety evaluation was 1 year or less for 26 of 34 trials (76%). Of 5704 men in the clinical data repository who were treated for AGA with finasteride, 1.25 mg/d or less, for AGA, only 31% met inclusion criteria for the pivotal trials referenced in the manufacturer's full prescribing information and 33% took finasteride for more than 1 year.Available toxicity information from clinical trials of finasteride in men with AGA is very limited, is of poor quality, and seems to be systematically biased. In a cohort of men prescribed finasteride for routine treatment of AGA, most would have been excluded from the pivotal studies that supported US Food and Drug Administration approval for AGA. Published reports of clinical trials provide insufficient information to establish the safety profile for finasteride in the treatment of AGA.
Bone marrow aplasia associated with proliferation of large granular lymphocytes and subsequent transformation to acute lymphoblastic leukemia
Authors: Gary J. Schiller, Faramarz Naeim, Richard E. Champlin
Journal: American Journal of Hematology (1989)

Abstract Proliferation of large granular lymphocytes may be associated with neutropenia and, less frequently, thrombocytopenia. In this report, we describe a patient with severe aplastic anemia in the setting of a proliferation of cells with natural killer (NK) phenotype. We demonstrated evolution to acute lymphoblastic leukemia by cells of identical phenotype.
Comparative Effectiveness of Minimally Invasive and Open Distal Pancreatectomy for Ductal Adenocarcinoma
Authors: Deepa Magge, William Gooding, Haroon Choudry, Jennifer Steve, Jennifer Steel, Amer Zureikat, Alyssa Krasinskas, Mustapha Daouadi, Kenneth K. W. Lee, Steven J. Hughes, Herbert J. Zeh, A. James Moser
Journal: JAMA Surgery (2013)

<h3>Importance</h3>Multicenter studies indicate that outcomes of open (ODP) and minimally invasive distal pancreatectomy (MIDP) are equivalent for benign lesions. However, data for pancreatic carcinoma are limited.<h3>Objective</h3>To compare outcomes of ODP and MIDP for early-stage pancreatic ductal carcinoma to determine relative safety and oncologic efficacy.<h3>Design</h3>Retrospective analysis of 62 consecutive patients undergoing ODP or MIDP for pancreatic ductal carcinoma by intention to treat with propensity scoring to correct for selection bias.<h3>Setting</h3>A high-volume university center for pancreatic surgery.<h3>Participants</h3>Sixty-two patients at a single institution.<h3>Interventions</h3>Patients underwent ODP or MIDP.<h3>Main Outcome Measures</h3>Perioperative mortality, morbidity, readmission, postoperative complications, disease progression, and overall survival.<h3>Results</h3>Thirty-four patients underwent ODP, and 28 underwent MIDP with 5 conversions to ODP. No significant differences in age, body mass index, performance status, tumor size, or radiographic stage were identified. High rates of margin-negative resection (ODP, 88%; MIDP, 86%) and median lymph node clearance (ODP, 12; MIDP, 11) were achieved in both groups with equal rates and severity of postoperative complications (ODP, 50%; MIDP, 39%) and pancreatic fistula (ODP, 29%; MIDP, 21%). Despite conversions, intended MIDP was associated with reduced blood loss (P = .006) and length of stay (P = .04). Conversion was associated with a poor histologic grade and positive nodes. Median overall survival for the entire cohort was 19 (95% CI, 14-47) months. Minimally invasive distal pancreatectomy was performed increasingly in later study years and for patients with a higher Charlson–Age Comorbidity Index. Overall survival after ODP or intended MIDP was equivalent after adjusting for comorbidity and year of surgery (relative hazard, 1.11 [95% CI, 0.47-2.62]).<h3>Conclusions and Relevance</h3>We detected no evidence that MIDP was inferior to ODP based on postoperative outcomes or overall survival. This conclusion was verified by propensity score analysis with adjustment for factors affecting selection of operative technique.
Modulation of the atopy patch test reaction by topical corticosteroids and tar
Authors: Elisabeth G. Langeveld-Wildschut, Hannes Riedl, Theo Thepen, Ilse C. Biharia, Piet L.B. Bruijnzeel, Carla A.F.M. Bruijnzeel-Koomen
Journal: Journal of Allergy and Clinical Immunology (2000)
Results of a questionnaire concerning the staffing and administration of endoscopy in England and Wales.
Authors: A T Axon, P M Bottrill, D Campbell
Journal: Gut (1987)

The enidoscopy scctioni comillittee of the British Society of Giastroenitcrology convened a working party to advise on the staffing and administration ot endoscopy in Engliand and Wales.At its initial mecting it was aigreed to circulate a questionnaire to ai randomly selected group of hospitals in England aind Wales in order to obtain a background on which the workiiig party could makc recommendiations.TIhis paper describcs the reSults of the questionnalirc which wias circulated and analysed during 1986. MethodsFifty ol the 202 health districts in England aind Wales, straitilied for region.were randomly selected.A tclephone call wais maide to ealch of the hospitals selected to enquire which clinician provided the cndoscopy service and two questionnaires were despatched.one for the clinician and the other for the nurse in charge of endoscopic services.Questions were designed to obtain information concerning quantity aind variety of endoscopic work, the number of endoscopists and assistants providing the service, and the different areas within the district where services were provided.Further questions related to administration.RE.SUITIS 0OF CI INI(CIA\NS QU ST1IONNAIRI.Forty two replies were retLirned (84%) representino 21 (0o of the totall number of districts in England and Wales.Not all questiolis had been answered, and percentages quoted take 42 as 100% except where otherwise indicated.Thirty three