tbuckley/cabot-search huggingface dataset:
Effect of Acetanilide and p-Hydroxyacetanilide on the Carcinogenicity of N-2-Fluorenylacetamide and N-Hydroxy-N-2-fluorenylacetamide in Mice, Hamsters, and Female Rats2
Authors: John H. Weisburger, Elizabeth K. Weisburger, Russell M. Madison, Martin L. Wenk, David S. Klein
Journal: JNCI Journal of the National Cancer Institute (1973)

Simultaneous dietary administration of acetanilide (AA) or p-hydroxyacetanilide (p-OHAA) with the carcinogen N-2-fluorenylacetamide (FAA) inhibited mammary tumor formation in female Sprague-Dawley-derived rats. p-OHAA had no effect on the mammary tumor incidence from N-hydroxy-2-fluorenylacetamide (N-OHFAA). In male mice on similar regimens, AA was more effective than p-OHAA in reducing the liver cancer incidence from FAA. Neither AA nor p-OHAA altered the yield of bladder tumors induced by FAA in mice. p-OHAA decreased the bladder but not the liver tumor incidence caused by N-OHFAA in male mice. Either AA or p-OHAA reduced the number of liver tumors in female mice fed FAA, and p-OHAA had a similar action with N-OHFAA. Either AA or p-OHAA inhibited liver tumors in male or female hamsters fed FAA, and p-OHAA did likewise with N-OHFAA. The incidence of gastric papillomas and carcinomas From N-OHFAA was not markedly decreased by p-OHAA.
Government will pause introduction of junior doctor contract for five days
Authors: Abi Rimmer
Journal: BMJ (2016)

The UK government has said that it will pause the introduction of a new contract for junior doctors for five days if the BMA agrees to discuss unsocial hours and Saturday pay.

Speaking in the House of Lords on Thursday 5 May, the peer David Prior, minister for NHS productivity, said that the health secretary for England, Jeremy Hunt, would write to the Academy of Medical Royal Colleges “explaining that …
Lead Exposure during Early Human Development and DNA Methylation of Imprinted Gene Regulatory Elements in Adulthood
Authors: Yue Li, Changchun Xie, Susan K. Murphy, David Skaar, Monica Nye, Adriana C. Vidal, Kim M. Cecil, Kim N. Dietrich, Alvaro Puga, Randy L. Jirtle, Cathrine Hoyo
Journal: Environmental Health Perspectives (2015)

Lead exposure during early development causes neurodevelopmental disorders by unknown mechanisms. Epidemiologic studies have focused recently on determining associations between lead exposure and global DNA methylation; however, such approaches preclude the identification of loci that may alter human disease risk.The objective of this study was to determine whether maternal, postnatal, and early childhood lead exposure can alter the differentially methylated regions (DMRs) that control the monoallelic expression of imprinted genes involved in metabolism, growth, and development.Questionnaire data and serial blood lead levels were obtained from 105 participants (64 females, 41 males) of the Cincinnati Lead Study from birth to 78 months. When participants were adults, we used Sequenom EpiTYPER assays to test peripheral blood DNA to quantify CpG methylation in peripheral blood leukocytes at DMRs of 22 human imprinted genes. Statistical analyses were conducted using linear regression.Mean blood lead concentration from birth to 78 months was associated with a significant decrease in PEG3 DMR methylation (β = -0.0014; 95% CI: -0.0023, -0.0005, p = 0.002), stronger in males (β = -0.0024; 95% CI: -0.0038, -0.0009, p = 0.003) than in females (β = -0.0009; 95% CI: -0.0020, 0.0003, p = 0.1). Elevated mean childhood blood lead concentration was also associated with a significant decrease in IGF2/H19 (β = -0.0013; 95% CI: -0.0023, -0.0003, p = 0.01) DMR methylation, but primarily in females, (β = -0.0017; 95% CI: -0.0029, -0.0006, p = 0.005) rather than in males, (β = -0.0004; 95% CI: -0.0023, 0.0015, p = 0.7). Elevated blood lead concentration during the neonatal period was associated with higher PLAGL1/HYMAI DMR methylation regardless of sex (β = 0.0075; 95% CI: 0.0018, 0.0132, p = 0.01). The magnitude of associations between cumulative lead exposure and CpG methylation remained unaltered from 30 to 78 months.Our findings provide evidence that early childhood lead exposure results in sex-dependent and gene-specific DNA methylation differences in the DMRs of PEG3, IGF2/H19, and PLAGL1/HYMAI in adulthood.Li Y, Xie C, Murphy SK, Skaar D, Nye M, Vidal AC, Cecil KM, Dietrich KN, Puga A, Jirtle RL, Hoyo C. 2016. Lead exposure during early human development and DNA methylation of imprinted gene regulatory elements in adulthood. Environ Health Perspect 124:666-673; http://dx.doi.org/10.1289/ehp.1408577.
Improvement in Clinical Outcomes With Biventricular Versus Right Ventricular Pacing
Authors: Anne B. Curtis, Seth J. Worley, Eugene S. Chung, Pei Li, Shelly A. Christman, Martin St. John Sutton
Journal: Journal of the American College of Cardiology (2016)

Sustained right ventricular (RV) apical pacing may lead to deterioration in ventricular function and an increased risk of heart failure, especially in patients with pre-existing systolic dysfunction. The BLOCK HF (Biventricular Versus Right Ventricular Pacing in Heart Failure Patients With Atrioventricular Block) trial demonstrated that biventricular-paced patients had a reduced incidence of a composite endpoint of death, heart failure–related urgent care, and adverse left ventricular remodeling. In a pre-specified analysis, this study examined clinical outcomes, including clinical composite score, quality of life (QOL), and change in New York Heart Association (NYHA) functional classification. The BLOCK HF trial randomized patients with atrioventricular block, NYHA symptom class I to III heart failure, and left ventricular ejection fraction ≤50% to biventricular or RV pacing. NYHA functional classification, QOL, and clinical composite score were assessed at 6, 12, 18, and 24 months. Bayesian statistical methods were used, with the pre-specified metric of benefit being a posterior probability ≥0.95. Patients with biventricular pacing showed greater improvement in NYHA functional class at 12 months, with 19% improved, 61% unchanged, and 17% worsened, compared with 12%/62%/23% in the RV arm. QOL was improved through 12 months. At 6 months, clinical composite score was improved/unchanged/worsened in 53%/24%/24% in the biventricular arm compared with 39%/33%/28% in the RV arm. This improvement in clinical composite score was sustained through 24 months. For patients with atrioventricular block and systolic dysfunction, biventricular pacing not only reduces the risk of mortality/morbidity, but also leads to better clinical outcomes, including improved QOL and heart failure status, compared with RV pacing. (Biventricular Versus Right Ventricular Pacing in Heart Failure Patients With Atrioventricular Block [BLOCK HF]; NCT00267098)
Risk factors for neutropenic fever in lymphoma patients receiving chemotherapy
Authors: S. R. Teegala, X. Zhou, A. Huen, Y. Ji, L. E. Fayad, J. E. Romaguera, S. Vadhan-Raj
Journal: Journal of Clinical Oncology (2007)

19616 Background: Neutropenic fever (NF) can be a serious complication of chemotherapy (CT) in lymphoma patients (pts), however the exact incidence with the current regimens and risk factors for NF are not well known. Methods: A retrospective cohort study was conducted to determine the incidence of NF, and logistic regression analysis were performed to identify the clinical and laboratory features correlated with NF in lymphoma. Medical records of all newly referred lymphoma pts (n=1046) in 2003 were reviewed. Results: 425 pts who received ≥ 1 cycle of treatment at MDACC were included in the analysis. Median age was 57 (range 17–87) with 262 (62%) newly diagnosed. Most common first regimens were (± rituxan) CHOP (29%), Hyper-CVAD ± Ara-c-MTX (23%), and ABVD (8%), with the total number of cycles were 1638 (median 3, range, 1–10). NF was observed in 23 % (97/425) of pts and 8 % (123/1638) of cycles, with the highest number in cycle 1 (49/123). The NF incidence among most common regimens were (± rituxan) Hyper-CVAD/ Ara-c/MTX 53% (31/58), Hyper-CVAD 24% (9/37), CHOP 22% (27/125), and ABVD 6% (2/34), and most common subtypes were MCL (33%), LCL (23%), HD (16%), and FL (13%). In the univariate regression analysis, CT, Hb, Ca, LDH, lymphocyte (ALC) and neutrophil (ANC) counts, were significantly associated with the NF. Using multivariate logistic regression, baseline ALC count (=1000 vs. &gt;1000/μL: OR=2.251, 95% CI, 1.194 to 4.244, p=0.0121), Hb (&lt;12 g/dL vs. ≥ 12g/dL: OR=2.117, 95% CI, 1.122 to 3.996, p=0.0207), age (&gt;60 vs. ≤60: OR=2.035, 95% CI, 1.066 to 3.884, p=0.0312), CT (high vs. low risk: OR=2.913, 95% CI, 1.520 to 5.583, p=0.0013) were the most important baseline risk factors for NF in cycle-1. Conclusions: The incidence of NF in this population is high in cycle 1. Baseline pt characteristics including old age, high risk CT, low ALC and Hb were found to be significant risk factors predictive for NF in cycle-1. These findings could be useful to identify high risk pts for consideration of treatment approaches for prevention of NF. No significant financial relationships to disclose.
Targeted Radioimmunotherapy Using Anti-CD45 Antibody-Mediated Delivery Of An In Vivo Nanoparticle-Based Alpha Generator In a Xenograft Model Of Human Leukemia
Authors: Aimee L. Kenoyer, Alexandra H. Hernandez, Mazyar Shadman, Mark McLaughlin, David Robertson, Chen Fang, Oliver W. Press, John M. Pagel
Journal: Blood (2013)
Hypercalcemia of malignancy in the era of zolendronic acid and effective chemotherapy
Authors: Z. He, S. G. Naik, C. Rathnasabapathy, H. Chenthil, A. Agheli, A. Sangal, M. Kalavar, W. Steier
Journal: Journal of Clinical Oncology (2008)

20675 Background: Intravenous bisphosphonates are the current standard of care for the treatment of hypercalcemia of malignancy. We evaluated patients with diagnosis of malignancy for severity of hypercalcemia and response to treatment. Methods: We reviewed data for 273 patients (mean age:63.7years, 52.7%F) with diagnosis of malignancy admitted to our hospital between July 2005 and December 2007. All had received cancer-related therapy simultaneously with hydration. Results: Hypercalcemia >10g/dl was seen in 41 (15%) patients with following diagnoses: adenocarcinoma: 16 (39%), squamous carcinoma: 8 (19.5%), multiple myeloma: 8 (19.5%), bladder carcinoma: 3 (7.3%), lymphoma: 3 (7.3%), papillary thyroid carcinoma: 1 (2.4%), CLL: 1 (2.4%), trophoblastic tumor: 1 (2.4%). Hypercalcemia was mild (10–12mg/dl) in 23 pts (56%), moderate (12–14mg/dl) in 11 pts (26.8%) and severe >14mg/dl in 7 (17.1%) pts. Bone involvement was seen in 17 pts (41.4%) with hypercacemia. Mild Hypercalcemia was managed in 23 (56%) pts with hydration alone. Moderate hypercalcemia was effectively controlled with zolendronic acid and hydration in 8/11 (72.7%) and combination of zolendronic acid, hydration and chemotherapy in 3/11 (27.3%) pts. Severe hypercalcemia >14 g/dl warranted institution of chemotherapy as well as calcitonin in all 7 pts. 4 (9.7%) of total 41 pts also received steroids for control of hypercalcemia. Two pts (4.8%) developed recurrent refractory episodes of hypercalcemia. Renal sufficiency was seen in 9 (21.9%) pts who needed adjustment of zolendronic acid dose. Conclusions: Severe hypercalcemia >14 g/dl warrants institution of chemotherapy as well as concurrent use of calcitonin till zolendronic acid had its full effect. Recurrent cases of hypercalcemia are refractory to all modalities of treatment including chemotherapy. Thus controlling the tumor burden may be of utmost importance in the management of hypercalcemia of malignancy. Table 1: Underlying malignancies in patients with hypercalcemia Total 41 patients Adenocarcinoma 16 (39%) (13 lung, breast: 3, colon: 2, gastric: 1) Squamous carcinoma 8 (19.5%) (lung: 5, head & neck: 2, anal: 1) Multiple myeloma 8 (19.5%) Bladder carcinoma 3 (7.3%) Lymphoma 3 (7.3%) Papillary thyroid carcinoma 1 (2.4%) CLL 1 (2.4%) Trophoblastic tumor 1 (2.4%) No significant financial relationships to disclose.
The Junior Doctor Contract – How have medical students been affected and what does this mean for the NHS?
Authors: Benjamin Langridge, Bamidele Famokunwa, Rahul Ghelani, Jonathan Webb, Maria Gregori, Viva Levee
Journal: Journal of the Royal Society of Medicine (2016)

Meghji et al. wrote in their article on the JuniorDoctor Contract that increased staffing requirements of a ‘7day NHS’ coupled with locum cost caps would cause ‘recruitment issues and potentially dangerous staffing levels’.We are concerned that issues of staff recruitment may be more intractable than even they surmise. The effect of the proposed Junior Doctor Contract on current doctors has been well publicised; yet, current medical students stand to be hit even harder and for a greater number of years. Our concern is that this contract will force medical students away from the NHS in such a way that even current staffing requirements may fail to be met. The Junior Doctor Contract disputes are having a negative effect on prospective medical students; a survey of 1550 school students reported that 37% of individuals who had once hoped to study medicine now no longer wish to. Current medical students have marched in protest and over 7000 have signed a British Medical Association pledge of solidarity, but other than this, little is known about the intentions of these future doctors. We recently surveyed 130 clinical medical students in a London medical school to gauge the effects of the Junior Doctor Contract; 89% reported feeling demoralised about their future careers in the NHS and 91% felt that the NHS would struggle to retain staff. If the contract is imposed, 35% stated that they would not work in the NHS at all, either moving to work abroad or leaving the medical profession altogether. Protracted training periods and caps on locum costs may be important challenges to the staffing of a proposed ‘7-day service’, but if the contract debates and threat of imposition have had as large an effect on future doctors as the evidence suggests, we may be unable to sustain even current staffing levels.
Impact Of Baseline (BL) Mutations, Including Low-Level and Compound Mutations, On Ponatinib Response and End Of Treatment (EOT) Mutation Analysis In Patients (Pts) With Chronic Phase Chronic Myeloid Leukemia (CP-CML)
Authors: Michael W. Deininger, Neil P. Shah, Jorge E. Cortes, Dong-Wook Kim, Franck E. Nicolini, Moshe Talpaz, Michele Baccarani, Martin C Muller, Jin Li, Stephanie Lustgarten, Tim Clackson, Christopher D Turner, Frank G Haluska, Graeme Hodgson, Victor M. Rivera, Francois Guilhot, John M Goldman, Hagop M. Kantarjian, Simona Soverini, Andreas Hochhaus, Timothy P. Hughes, Susan Branford
Journal: Blood (2013)
Optimizing Treatment for Locally Advanced Pancreas Cancer
Authors: Deborah Schrag
Journal: JAMA (2016)

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Management of Chronic Insomnia Disorder in Adults: A Clinical Practice Guideline From the American College of Physicians
Authors: Amir Qaseem, Devan Kansagara, Mary Ann Forciea, Molly Cooke, Thomas D. Denberg
Journal: Annals of Internal Medicine (2016)

Description: The American College of Physicians (ACP) developed this guideline to present the evidence and provide clinical recommendations on the management of chronic insomnia disorder in adults. Methods: This guideline is based on a systematic review of randomized, controlled trials published in English from 2004 through September 2015. Evaluated outcomes included global outcomes assessed by questionnaires, patient-reported sleep outcomes, and harms. The target audience for this guideline includes all clinicians, and the target patient population includes adults with chronic insomnia disorder. This guideline grades the evidence and recommendations by using the ACP grading system, which is based on the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. Recommendation 1: ACP recommends that all adult patients receive cognitive behavioral therapy for insomnia (CBT-I) as the initial treatment for chronic insomnia disorder. (Grade: strong recommendation, moderate-quality evidence) Recommendation 2: ACP recommends that clinicians use a shared decision-making approach, including a discussion of the benefits, harms, and costs of short-term use of medications, to decide whether to add pharmacological therapy in adults with chronic insomnia disorder in whom cognitive behavioral therapy for insomnia (CBT-I) alone was unsuccessful. (Grade: weak recommendation, low-quality evidence)
A Public Health Paradox: The Women Most Vulnerable to Malaria Are the Least Protected
Authors: Raquel González, Esperança Sevene, George Jagoe, Laurence Slutsker, Clara Menéndez
Journal: PLoS Medicine (2016)

Raquel Gonzalez and colleagues highlight an urgent need to evaluate antimalarials that can be safely administered to HIV-infected pregnant women on antiretroviral treatment and cotrimoxazole prophylaxis.
ZoptEC: Phase III study of zoptarelin doxorubicin (AEZS-108) in platinum-taxane pretreated endometrial cancer (Study AEZS-108-050).
Authors: David S. Miller, Hani Gabra, Guenter Emons, D. Scott McMeekin, Amit M. Oza, Sarah Madhu Temkin, Ignace Vergote
Journal: Journal of Clinical Oncology (2014)

TPS5630^ Background: A platinum-taxane combination is commonly used both as adjuvant and first line therapy for advanced, recurrent, and metastatic endometrial cancer (EC). Zoptarelin doxorubicin (AEZS-108) is a hybrid anticancer agent in which doxorubicin is chemically linked to zoptarelin, a D-Lys6-analogue of luteinizing hormone releasing hormone (LHRH). Zoptarelin doxorubicin was initially evaluated in tumor types reported to express receptors for LHRH. Depending on the method used to determine LHRH receptor expression, LHRH receptors have been found in 40% to 90% of ECs. A Phase II study of zoptarelin doxorubicin in EC patients showed activity, including those previously treated with platinum-taxane [Emons et al. 2014]. Methods: This open-label, randomized-controlled study compares the efficacy and safety of AEZS-108 and doxorubicin (ClinicalTrials.gov Identifier: NCT01767155; EudraCT No: 2012-005546-38; ZoptEC: Zoptarelin doxorubicin in endometrial cancer). The study is expected to include 500 EC patients progressing after prior therapy with platinum-taxane-based chemotherapy. There are about 120 expected study sites in North America, Western and Central/Eastern Europe, and Israel. Patients are centrally randomized in a 1:1 ratio and receive either AEZS-108 (267 mg/m2) or doxorubicin (60 mg/m2) intravenously, every 3 weeks and for up to 9 cycles. Response will be evaluated every 3 cycles during treatment, thereafter every 12 weeks until progression. All patients will be followed for survival as the primary efficacy endpoint (EP). The final analysis is planned after about 384 deaths have occurred, interim analyses after about 128 (futility only) and 192 deaths. Secondary EPs include progression-free survival (PFS), objective response rate (ORR), and clinical benefit rate (CBR). Quality of life will be compared based on EORTC QLQ-30 and EN-24 questionnaires. A substudy in about 40 patients compares the pharmacokinetics of AEZS-108 and doxorubicin and doxorubicinol. Clinical trial information: NCT01767155.
Cytokine production during in vitro hemodialysis with new and formaldehyde- or renalin-reprocessed cellulose dialyzers.
Authors: B J Pereira, B Snodgrass, G Barber, C Perella, S Chopra, A J King
Journal: Journal of the American Society of Nephrology (1995)

Critics of reuse have suggested that patients treated with reprocessed dialyzers are exposed to pyrogen trapped from the water or solutions used during the reprocessing cycle, thereby triggering the synthesis and release of proinflammatory cytokines, resulting in cachexia. To test this hypothesis, the production of interleukin (IL)-1 alpha by peripheral blood mononuclear cells (PBMC) during in vitro dialysis with new or reprocessed cellulose dialyzers was compared. An in vitro closed-loop dialysis circuit was created with standard hemodialysis blood lines and either new cellulose dialyzers or dialyzers reprocessed 10 times with either formaldehyde/bleach (formaldehyde) or peracetic acid/hydrogen peroxide mixture (Renalin). The circuit was rinsed with 2 L or more of pyrogen-free normal saline before the start of in vitro dialysis until the blood compartment tested negative for residual formaldehyde/Renalin. Heparinized whole blood from healthy volunteers was circulated for 3 h in the blood compartment at 100 mL/min at 37 degrees C. The dialysate compartment was sealed. Peripheral blood mononuclear cells (PBMC) were harvested from the blood compartment before and at the end of 3 h of in vitro dialysis. Total IL-1 alpha synthesis (cell associated plus secreted) by unstimulated and endotoxin-stimulated PBMC was measured by a specific, non-cross-reactive radioimmunoassay. After 3 h of in vitro dialysis, IL-1 alpha production (in picograms per 2.5 million PBMC) by unstimulated PBMC increased from 354 +/- 63 at baseline to 454 +/- 57 with new dialyzers (P = 0.25), from 453 +/- 101 to 450 +/- 67 with formaldehyde-reprocessed dialyzers (P = 0.98), and from 360 +/- 61 to 538 +/- 144 with Renalin-reprocessed dialyzers (P = 0.23). IL-1 alpha production by endotoxin-stimulated PBMC increased from 5,214 +/- 996 to 9,237 +/- 929 with new dialyzers (P < = 0.001), from 6,395 +/- 955 to 9,636 +/- 1,058 with formaldehyde-reprocessed dialyzers (P = 0.006), and from 7,561 +/- 1,000 to 10,092 +/- 2,470 with Renalin-reprocessed dialyzers (P = 0.32). However, there were no significant differences among groups with respect to IL-1 alpha production by unstimulated or endotoxin-stimulated PBMC either before or after 3 h of in vitro dialysis. These data argue against the suggestion that exposure to reprocessed dialyzers results in enhanced synthesis of proinflammatory cytokines. In fact, reprocessed dialyzers probably induce less cytokine production than do new cellulose dialyzers.