tbuckley/cabot-search huggingface dataset:
Abstract 18544: The Association of Kidney Disease Measures With Left-Sided Cardiac Structure and Function: The Atherosclerosis Risk in Communities (ARIC) Study
Authors: Kunihiro Matsushita, Yingying Sang, Amil M Shah, Hicham Skali, Josef Coresh, Scott D Solomon
Journal: Circulation (2013)

Introduction: Small studies with selected population such as hypertensives or diabetics reported the association of kidney disease with cardiac structure and function. A more comprehensive examination for glomerular filtration rate (GFR) and albuminuria regarding their relationships to cardiac structure and function in a large sample from the general population is needed. Hypothesis: Both estimated GFR (eGFR) and albuminuria (urinary albuinu-cratinine ratio [ACR]) are associated with left-sided cardiac structure (left atrial volume index [LAVI], left ventricular end-diastolic diameter [LVEDD], and left ventricular mass index [LVMI]) and function (left ventricular ejection fraction [LVEF]). Methods: We studied 4041 participants (mean age 75±5 years) of the ARIC Study who did not have prior coronary heart disease or heart failure at visit 5 (2011-13) and underwent transthoracic echocardiography. The association between the kidney measures and cardiac echo parameters was assessed using regression models incorporating spline terms of kidney measures (knots at their clinical cutpoints) with the adjustment for potential confounders. Results: There were 1051 and 725 participants with reduced eGFR (&lt;60 ml/min/1.73m 2 ) and elevated ACR (≥30 mg/g), respectively. Reduced eGFR was associated with LAVI and LVMI only when it reached &lt;30 ml/min/1,73m 2 (Figure). In contrast, higher ACR was steadily associated with high LAVI, LVMI, and LVEDD and low LVEF (all P &lt;0.001). Conclusions: Elevated albuminuria was consistently associated with altered left-sided cardiac structure and function, whereas the alteration was restricted to some indices at moderate to severe stage for low eGFR. These findings suggest that kidney damage or its precedent conditions, e.g., endothelial dysfunction, are more involved in the pathophysiology of cardiac structural and functional alteration compared to kidney dysfunction.
The composition of diesel exhaust particles affects differently the cell signaling and cytoskeleton in bronchial epithelial cells
Authors: Mariangela Macchione, Robson Seriani, Mara S. Junqueira, Alessandra C. Toledo, Diana Martinez, Adriano M. Alencar, Milton A. Martins, Paulo H.N. Saldiva, Elnara M. Negri, Thais Mauad
Journal: European Respiratory Journal (2014)

Backgroung:  Diesel exhaust particles (DEP) have a major contribution of the ultrafine particles to the air pollution. Hydrocarbons and metals adsorbed on surface of DEP cause physiological and molecular disturbances in cells of the respiratory system.  Methods : We used four samples of DEP with different compositions after treatment: 1) Acid extraction (HNO 3 65%) to remove mainly metals (DEP/NA); 2) solvents: a) methanol to remove organic composed with high and medium polarity (DEP/MET), b) hexane to remove organic compound with low polarity (DEP/MET) and DEP crude to study MAPKs activation (ERK and JNK) and cell rheology (OMTC technical). The cells were exposed to 100µg/mL of DEPs fractions in air-liquid system during 15, 30 and 60 minutes. The MAPKs JNK and ERK are activated simultaneously in DEP crude and DEP/MET.  Results:  In DEP/NA and DEP/HEX only JNK was activated. The compositions of DEP/MET are mainly iron, cupper and cadmium and Benz[a]anthracene and pyrene. DEP/NA and DEP/HEX had a reduction of 50% of PHAs concentration, but the copper and cadmium appear to be the most available causing JNK activation, significant (p=0.03) reduction in fiber coherence and increased viscoelasticity at short time (15 minutes).  Conclusion:  The adverse findings detected after exposure to DEPs fractions represents the toxic potential of diesel compounds and could be consequence of using bad fuel with low-technology engines. In addition the activation of these MAPKs is a major indication that the chemical composition of the DEP around the world can influence the onset of or worsening of respiratory diseases via MAPKs activation.
Biological warfare and bioterrorism
Authors: Craig Smith
Journal: BMJ (2002)

home."In this category, incidents described in general terms such as "collapse" fell from 35% to 20%, whereas those attributed more specifically to cardiac problems rose from 22% to 31% and those attributed to respiratory problems from 12% to 21% (see table C on bmj.com).We thank members of Wiltshire Ambulance Services Trust who provided data, tea, and moral support during long days of searching for records.
Cetuximab (C225) plus irinotecan/cisplatin (CPT/Cis) for CPT/Cis-refractory esophageal cancer
Authors: G. Y. Ku, M. A. Shah, L. H. Tang, B. Miron, D. P. Kelsen, D. H. Ilson
Journal: Journal of Clinical Oncology (2008)

15580 Background: In esophageal cancer, weekly CPT/Cis is an active regimen, with a response rate (RR) of 57% and time-to- progression (TTP) of 4.2 months (JCO 17:3270;1999). Epidermal growth factor receptor (EGFR) is overexpressed in 30–90% of esophageal tumors and is associated with advanced stage, chemotherapy resistance and poor prognosis. In colon cancer (CA), adding C225, an anti-EGFR monoclonal antibody, to CPT for CPT-refractory patients (Pts) increases RR and TTP (NEJM 351: 337;2004). Methods: Pts with metastatic esophageal/gastroesophageal junction CA who progressed by RECIST criteria on prior CPT/Cis within 3 months of enrollment were eligible. Up to a total of 2 prior regimens were allowed, including interim therapy between progression on prior CPT/Cis and enrollment. CPT/Cis was continued at the prior dose to a maximum of CPT 65 mg/m2/Cis 30 mg/m2 weekly 2 of 3 weeks. C225 was added at 400 mg/m2 week 1, then 250 mg/m2 weekly. Tumor tissue was tested for EGFR overexpression by immunohistochemistry (IHC). Results: 8 Pts were enrolled. 6 male (75%), 2 (25%) female, median age 53, median Karnofsky performance status 80%, 7 adenocarcinoma (adenoCA), 1 squamous cell (SCC). 6 of 8 Pts were EGFR positive (2 1+/ 2 2+/2 3+ by IHC). Median TTP on prior CPT/Cis was 4.4 months (range, 1.8 to 14.4 months). 1 confirmed partial response (PR) was seen in a Pt with adenoCA (EGFR 3+). 2 Pts had stable disease (SD) and 5 had progressive disease (PD). 1 Pt with SD for 2.9 months had SCC (EGFR 2+) while the other with SD for 3.7 months had adenoCA (EGFR negative). Significant grade 3/4 toxicities included lymphopenia (4 Pts, all grade 3), neutropenia (1 Pt, grade 4), hypomagnesemia (1 Pt, grade 3). Rash was manageable, with 4 Pts with grade 1 and 3 Pts with grade 2 skin toxicity. 1 Pt died of non-neutropenic sepsis from PD after 3 weeks of therapy (this Pt was off treatment for 3–4 weeks prior to death). Conclusions: Adding C225 to CPT/Cis for CPT/Cis-refractory esophageal cancer is well-tolerated; 1 PR has been observed to date. Accrual is ongoing to 25 Pts. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bristol-Myers Squibb, Genentech, Pfizer, sanofi-aventis
High-density genotyping of immune-related loci identifies new SLE risk variants in individuals with Asian ancestry
Authors: Celi Sun, Julio E Molineros, Loren L Looger, Xu-jie Zhou, Kwangwoo Kim, Yukinori Okada, Jianyang Ma, Yuan-yuan Qi, Xana Kim-Howard, Prasenjeet Motghare, Krishna Bhattarai, Adam Adler, So-Young Bang, Hye-Soon Lee, Tae-Hwan Kim, Young Mo Kang, Chang-Hee Suh, Won Tae Chung, Yong-Beom Park, Jung-Yoon Choe, Seung Cheol Shim, Yuta Kochi, Akari Suzuki, Michiaki Kubo, Takayuki Sumida, Kazuhiko Yamamoto, Shin-Seok Lee, Young Jin Kim, Bok-Ghee Han, Mikhail Dozmorov, Kenneth M Kaufman, Jonathan D Wren, John B Harley, Nan Shen, Kek Heng Chua, Hong Zhang, Sang-Cheol Bae, Swapan K Nath
Journal: Nature Genetics (2016)
Association of hypertension with overall outcome in patients taking sorafenib in advanced hepatocellular carcinoma (HCC).
Authors: R. D. Kim, M. T. Byrne, J. Hammel, G. El-Gazzaz, F. Aucejo
Journal: Journal of Clinical Oncology (2010)

e14536 Background: Hypertension is a commonly reported side effect following administration of vascular endothelial growth factor receptor (VEGFR) inhibitors. There have been multiple studies in renal cell carcinoma which showed elevated blood pressure correlates with better outcome in patients these drugs. In this study we assessed the predictive effect of HTN in patients taking sorafenib for advanced HCC. Methods: We looked at 41 patients from 2007 to 2009 in patients who received sorafenib for advanced HCC. Blood pressure was monitored at baseline and every 4 weeks. Elevated BP was defined as 20% increase in systolic or diastolic pressure from baseline or > 140/90 if baseline BP was within normal limits. Logrank tests were used to compare Kaplan-Meier estimates of overall survival. Results: Out of 41 patients who received sorafenib, 38 patients had complete blood pressure assessment. 15 (38%) were on HTN meds at baseline. 27 (65.9%) patients were classified as Child-Pugh (CP) A, 11 (26.8%) CP B and 3 (7.3%) CP C. Median follow-up was 5.8 months including deaths, 17.4 months among living patients. 24 (58.5%) patients received some form of prioe local therapy before initiation of sorafenib. 19 (50%) patients had elevated BP as defined on method section on at least one follow-up. Overall survival was 40.4% at 1 year, and 18.0% at 2 years. Patients with elevated BP on follow-up had a greater 1-year survival rate (60.2% vs. 24.0%, p = 0.021) for all patients. Subgroup analysis of CP B and C also showed increased 1-year survival rate in patients with elevated BP (50.0% vs. 0%, p = 0.016). Conclusions: In this analysis elevated BP was a positive predictive marker for overall survival in patients taking sorafenib for advanced HCC. Further studies need to be done to confirm these findings. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Onyx
SGN-75 in the treatment of patients with CD70-positive malignancies including metastatic renal cell carcinoma.
Authors: John A. Thompson, Andres Forero, Elisabeth I. Heath, Sumanta Kumar Pal, Stephen Maxted Ansell, Jeffrey R. Infante, Sven De Vos, Paul A. Hamlin, Nancy Cherry Whiting, Baiteng Zhao, Nizar M. Tannir
Journal: Journal of Clinical Oncology (2013)

368 Background: SGN-75 is an antibody-drug conjugate composed of a humanized anti-CD70 mAb conjugated to the microtubule-disrupting agent MMAF via a plasma-stable linker. Upon binding to CD70, SGN-75 internalizes and releases cys‑mcMMAF which binds tubulin and induces G2/M arrest and apoptosis. Methods: A phase 1, dose-escalation, multicenter study was initiated to investigate the safety, tolerability, PK, and antitumor activity of SGN-75 monotherapy in pts with CD70-positive metastatic RCC or relapsed/refractory NHL (ClinicalTrials.gov #NCT01015911). SGN-75 was administered IV in cohort-specific doses using 2 schedules [every 3 weeks (q3wk) or weekly (days 1, 8, 15 q28 days)] at doses of 0.3-4.5 mg/kg. Pts were eligible to receive treatment until PD. Results: A total of 58 pts (39 RCC/19 NHL) with a median age of 60.5 yrs (range 30-82) were treated. The MTD was 3 mg/kg q3wk; 2 pts had DLTs at 4.5 mg/kg q3wk (NHL pt had neutropenia and RCC pt had proteinuria). Weekly dosing (N=11) was terminated at the 0.6 mg/kg dose level after 2 pts with NHL developed idiopathic thrombocytopenic purpura. At the MTD, adverse events (AEs) in ≥30% of RCC pts (N=21) were fatigue (52%), dry eye (48%), nausea (38%), constipation (33%), and corneal epithelium defect (33%). AEs ≥ Grade 3 in &gt;10% of RCC pts treated at the MTD were corneal epithelium defect (19%) and thrombocytopenia (14%). PK analysis suggested that SGN-75 exposure was approximately dose-proportional with a mean terminal half-life of 6-11 days. Among the 32 pts with RCC treated in the q3wk schedule, all had prior nephrectomy and a median of 3 prior therapies (range 1-6). All pts had clear cell RCC, with the exception of 2 pts who had papillary RCC. Most pts had high CD70 expression by central IHC analysis (2 or 3+, 80-100% of cells). The best clinical responses of RCC pts treated q3wk were 2 PR, 12 SD, 12 PD, and 6 were not evaluable. Durations of response for the 2 responding pts were 23 and 41 weeks. The median duration of disease control (PR and SD) was 46.4 weeks [95% CI (12, 46)]. Conclusions: SGN-75 monotherapy was generally well tolerated in pts with metastatic RCC. Evidence of antitumor activity was observed in heavily pretreated RCC pts and further studies of SGN-75 in RCC are warranted. Clinical trial information: NCT01015911.
Histologic and Autoradiographic Studies on the Forestomach of Hamsters Treated With 2-&lt;italic&gt;tert&lt;/italic&gt;-Butylated Hydroxyanisole, 3-&lt;italic&gt;tert&lt;/italic&gt;-Butylated Hydroxyanisole, Crude Butylated Hydroxyanisole, or Butylated Hydroxytoluene&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: M Hirose, A Masuda, Y Kurata, E Ikawa, Y Mera, N Ito
Journal: JNCI Journal of the National Cancer Institute (1986)

The inductions of hyperplasia and neoplastic lesions in the forestomach of Syrian golden hamsters by 2-tert-butylated hydroxyanisole [(2-tert-BHA) CAS: 121-00-6], 3-tert-butylated hydroxyanisole [(3-tert-BHA) CAS: 88-32-4], crude butylated hydroxyanisole [(BHA) CAS: 25013-16-5], and butylated hydroxytoluene [(BHT) CAS: 128-37-0] were compared histopathologically and autoradiographically. In hamsters fed the 2-tert-BHA diet, severe hyperplasia developed from week 4, reaching a maximum level in week 16 of 0.56 cm/10 cm basement membrane (bm), and papillomatous lesions appeared in week 16 (0.13 cm/10 cm bm). In hamsters fed 3-tert-BHA or crude BHA, severe hyperplasia developed from week 1, which reached a maximum level in week 4 of 3.63 cm/10 cm bm with 3-tert-BHA and 5.10 cm/10 with crude BHA; it then decreased. Papillomatous lesions were found in week 3 in hamsters fed 3-tert-BHA and in week 4 in hamsters fed crude BHA; they increased to maximum levels in week 16 of 0.50 cm/10 cm bm with 3-tert-BHA and 0.29 cm/10 cm bm with crude BHA. Mild hyperplasia occurred slightly more often in hamsters fed the BHT diet than in the control group. BHT induced no severe hyperplasia and papillomatous lesions. Changes in the labeling index of the forestomach epithelium paralleled the histologic changes, except in hamsters fed the BHT diet in which no significant increase in the labeling index was observed throughout the experiment. These data suggest that the tumorigenic action of crude BHA on hamster forestomach is largely due to 3-tert-BHA and that BHT does not induce forestomach tumors in hamsters.
Estimating the impact of the 2009 influenza A(H1N1) pandemic on mortality in the elderly in Navarre, Spain
Authors: J Castilla, J Etxeberria, E Ardanaz, Y Floristán, R López Escudero, M Guevara
Journal: Eurosurveillance (2010)

We analysed mortality among people aged 65 years or older in Navarre, Spain in 2009 and compared it with the mean for the same period of time in the previous three years. In the pandemic weeks 24 to 52 2009 we observed 4.9% more deaths than expected (p=0.0268). Excess mortality occurred during the circulation of seasonal influenza (8.0%, p=0.0367) and the first wave of pandemic influenza (9.9%, p=0.0079). In the second wave of pandemic influenza there was a non-significant excess of deaths (5.2%, p=0.1166). Surveillance of laboratory-confirmed severe influenza cases detected only one death in this age group.
Cognition enhancing drugs (‘nootropics’): time to include coaches and team executives in doping tests?
Authors: Ryan M Rodenberg, John T Holden
Journal: British Journal of Sports Medicine (2016)

The use of brain boosting drugs by athletes has been well documented and testing for such cognition enhancing drugs is now implemented. Largely absent from the purview of antidoping agencies, however, is the drug testing of coaches and team executives. This editorial introduces commonly used nootropics (drugs that influence cognition) and describes their on-label effects. We then examine the off-label uses of these drugs and consider whether sport organisations, if they are genuinely determined to eliminate performance enhancing drugs among all participants, should also incorporate the testing of coaches and team executives. Advances in sport analytics have changed coaching and executive roles, with decision-making acumen more important than ever.

Brain enhancing drugs including modafinil (Provigil), methylphenidate (Ritalin), and dextroamphetamine (Adderall) were developed to treat sleep problems, attention deficit disorders (ADD), memory …
Targeted down regulation of TGF-beta2 in pancreatic carcinoma: A phase I/II dose escalation study to evaluate the safety and tolerability of the antisense oligonucleotide AP 12009
Authors: K.-H. Schlingensiepen, A. Bischof, T. Egger, M. Hafner, H. Herrmuth, M. Kielmanowicz, S. Ludwig, S. Schmaus, G. Stauder
Journal: Journal of Clinical Oncology (2005)

4253 Background: Pancreatic carcinoma is one of the most aggressive human cancers with a 5-year-survival rate of less than 5%. Overexpression of TGF-beta2 in tumors such as pancreatic carcinoma and glioma closely correlates with advanced tumor stage. It plays a pivotal role in malignant progression by inducing key mechanisms including immunosuppression, metastasis, angiogenesis and tumor cell growth. Methods: AP 12009, a phosphorothioate antisense oligonucleotide specific for the human TGF-beta2 mRNA, has been developed as a targeted anti-tumor therapy. It was tested for its anti-tumor activity in a variety of preclinical studies in pancreatic carcinoma. In its lead indication, malignant glioma, phase I/II studies with AP 12009 have been completed. A phase IIb actively controlled study is ongoing with more than 120 patients enrolled. Results: TGF-beta2 levels of pancreatic carcinoma patients were more than 3fold elevated as compared to controls (control: median 378 pg/ml; patients: median 1198 pg/ml). AP 12009 inhibited the TGF-beta2 secretion in several human pancreatic carcinoma cell lines (Hup-T3, Hup-T4, PA-TU-8902). In functional assays AP 12009 reduced pancreatic tumor cell proliferation in a dose-dependent manner by up to 76%. Migration of tumor cells was completely blocked as compared to untreated controls in a spheroid migration model in contrast to a TGF-beta2 antibody which had no effect. After AP 12009 treatment cytotoxicity from IL-2 activated PBMC co-incubated with pancreatic carcinoma cells was increased by up to 401% of the untreated control (effector/target ratio 20:1) showing a reversal of TGF-beta2 induced immunosuppression. Systemic and local tolerability studies in rodents, rabbits and monkeys showed a very favorable toxicology profile. Conclusions: AP 12009 has already shown clinical anti-tumor activity in phase I/II studies as therapy for malignant glioma. Based on this successful clinical application and the preclinical efficacy in pancreatic carcinoma a multi-site dose escalation trial with AP 12009 in pancreatic carcinoma patients has been started to assess the maximum tolerated dose (MTD). Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Antisense Pharma GmbH
Biweekly irinotecan (CPT-11) plus 5-FU as first-line chemotherapy for elderly patients with metastatic colorectal cancer (MCRC). Final results of the Spanish Digestive Group (TTD) study
Authors: E. Marcuello, J. Sastre, B. Masutti, M. Navarro, S. Gil, A. Anton, A. Abad, E. Diaz-Rubio
Journal: Journal of Clinical Oncology (2004)

3597 Background: Elderly patients are frequently excluded from clinical studies due to comorbidity. However, clinical trials in this setting are needed to avoid extrapolating the results obtained in a younger population. We designed this study to evaluate the RR of a standard first-line therapy in elderly patients with MCRC. Secondary objectives were safety profile, TTP and OS Methods: Patients ≥ 72 years old with histologically confirmed MCRC, measurable disease, ECOG <2, adequate bone marrow, renal and hepatic function were included. Previous chemotherapy for advanced disease, CNS involvement or geriatric syndromes were not allowed. Treatment: CPT-11, 180 mg/m2 and 5-FU, 3 g/m2 as a 48h ci, were administered biweekly until progressive disease, unbearable toxicity or consent withdrawal Results: 91 patients were included and 85 were evaluable. Median age of 77 (72–85), male/female (51/34) and ECOG PS 0–1: 100%. Primary tumor sites were colon (67%), rectum (32%) or both (1%). Main comorbidities were hypertension (46%), diabetes (18%), cardiopathy (17%) and chronic pulmonary disease (8%). Median No. of metastatic locations was 1 (33% with ≥2 sites) mainly located in liver (77%) and lung (27%). 28% of patients received previous adjuvant chemotherapy. Up to date, 919 cycles (median 12, range 1–26) were administered, with a median RDI of 91% for both CPT-11 and 5-FU. 85 patients were evaluable for toxicity. Grade 3/4 toxicity per patient were neutropenia (21%), diarrhea (17%), asthenia (13%), leukopenia (8%), abdominal pain (7%) and vomiting (6%). Only 1 patient had febrile neutropenia in 1 cycle. There were 2 treatment related deaths (diarrhea n=1, and digestive hemorrhage n=1). Efficacy: On an ITT analysis of 85 patients, 3 achieved CR, 27 PR, 28 SD and 15 progressed, resulting in an ORR of 35 % (95% CI: 25–46) and tumour growth control (RR + SD) in 68% of patients. With a median follow-up of 10.9 months, TTP was 8.0 months (95% CI: 6.1–9.9) and OS was 15.1 months (95% CI: 13.3–16.9) Conclusions: CPT-11 plus 5-FU is an active and feasible treatment for patients older than 72 years old with MCRC. No significant financial relationships to disclose.