tbuckley/cabot-search huggingface dataset:
Phase I trial of the addition of oral topotecan to standard 5-day temozolomide for malignant gliomas.
Authors: J. Kirkpatrick, J. J. Vredenburgh, D. A. Reardon, A. Desjardins, K. Peters, S. Gururangan, J. E. Herndon, J. Marcello, S. Woodring, H. S. Friedman
Journal: Journal of Clinical Oncology (2010)

2073 Background: Temozolomide is one of the most active agents to treat malignant gliomas. As an alkylating agent, the majority of tumors develop resistance. There are many mechanisms of resistance, including methyl guanine methyl transferase (MGMT), mismatched repair and single base excision repair. The addition of a topoisomerase 1 inhibitor may be synergistic with temozolomide and overcome resistance. Methods: We completed a phase I trial of oral topotecan and temozolomide, which was dosed at the standard 200 mg/m2/day for days 1-5. Topotecan was given days 2-6 of a 28 day cycle. The dose levels of topotecan are listed in the table. Dose limiting toxicity (DLT) was defined as ≥ grade 3 non-hematopoietic toxicity attributable to the treatment or ≥ grade 4 hematopoietic toxicity. The maximal tolerated dose (MTD) was the level in which ≤ 1 of 6 patients had DLT. There were 2 cohorts, one for patients on enzyme inducing anti-epileptic drugs (EIAED) and another cohort for patients not on EIAED (non-EIAED). Pharmacokinetic sampling was done for topotecan levels. Results: Sixty-two patients were enrolled, 33 on the EIAED cohort and 29 on the non-EIAED cohort. The major toxicities were hematologic, and every patient that had dose-limiting hematologic toxicity had both grade 4 thrombocytopenia and neutropenia. In the EIAED cohort, 2/6 patients at dose level 7 had dose-limiting hematologic toxicity, and 1/6 at dose level 6 had dose- limiting hematologic toxicity. In the non-EIAED cohort, 2/6 patients at dose level 5 had dose-limiting hematologic toxicity, and 1/6 at dose level 4 had dose- limiting hematologic toxicity. Interestingly, the pharmacokinetics of topotecan was similar in the two cohorts. The regimen was active, with many patients remaining stable over many cycles. Conclusions: The combination of standard 5-day temozolomide and oral topotecan was well tolerated and had clinical activity. The MTD of oral topotecan was 2.0 mg/M2/d in the EIAED cohort and 1.5 mg/M2/d in the non-EIAED cohort. A phase II trial for newly diagnosed GBM patients in combination with bevacizumab is planned. Dose level Dose topotecan mg/m2/d 1 0.75 2 1.0 3 1.25 4 1.5 5 1.75 6 2.0 7 2.3 Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Schering-Plough
Abstract P019: Association Between Hypertension and Kidney Function Trajectory: The Atherosclerosis Risk in Communities Study
Authors: Casey M Rebholz, Yuan Chen, Kunihiro Matsushita, Josef Coresh, Morgan E Grams
Journal: Circulation (2015)

Introduction: Cardiovascular disease, including hypertension, increases the risk of kidney disease progression. The relationship between hypertension and change in kidney function has not been fully elucidated. We hypothesized that hypertension is associated with faster kidney function decline. Methods: Hypertension status was assessed among Atherosclerosis Risk in Communities (ARIC) Study participants at baseline (1987-89) and defined as systolic blood pressure ≥140, diastolic blood pressure ≥90, or anti-hypertensive medication use in the last two weeks. Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) estimated glomerular filtration rate (eGFR) was calculated using creatinine measured at baseline and follow-up study visits (1990-92; 1996-98; 2011-13) and an eGFR value of 15 mL/min/1.73 m 2 was imputed for incident end-stage renal disease cases. Results: After excluding those with missing baseline measurements of blood pressure, missing serum creatinine, and prevalent end-stage renal disease, there were 15,622 study participants. Baseline mean age was 55 years, 55% were female, 26% were black, and 35% had hypertension. Mean annual eGFR decline was 1.98 mL/min/1.73 m 2 per year among those with hypertension and 1.54 mL/min/1.73 m 2 per year among those without hypertension, after adjusting for demographic characteristics and co-morbidities (Figure, p&lt;0.001). Participants with hypertension at baseline were more likely to develop chronic kidney disease than those without hypertension. Over 25 years, for those with hypertension and those without hypertension, respectively, the probability of developing chronic kidney disease stage 3A (eGFR &lt;60 mL/min/1.73 m 2 ) was 55.3% and 44.5%, stage 3B (eGFR &lt;45 mL/min/1.73 m 2 ) was 24.3% and 19.1%, stage 4 (eGFR &lt;30 mL/min/1.73 m 2 ) was 9.2% and 7.7%, and stage 5 (eGFR &lt;15 mL/min/1.73 m 2 ) was 3.9% and 3.5%. Conclusion: Hypertension status was associated with faster kidney function decline. Absolute risk increase was greater for earlier kidney disease stages.
Doctors test injecting drug victims for anthrax
Authors: Bryan Christie
Journal: BMJ (2000)

Doctors trying to trace the source of an infection that in recent weeks has killed 11injecting drug users in Scotland have tested tissue samples for the presence of anthrax after reports of a similar case in Norway.

Although two samples tested at the Centre for Applied Microbiology and Research at Porton Down in England have shown a weak positive reaction, anthrax has …
Notch promotes recurrence of dormant tumor cells following HER2/neu-targeted therapy
Authors: Daniel L. Abravanel, George K. Belka, Tien-chi Pan, Dhruv K. Pant, Meredith A. Collins, Christopher J. Sterner, Lewis A. Chodosh
Journal: Journal of Clinical Investigation (2015)

Breast cancer mortality is principally due to recurrent tumors that arise from a reservoir of residual tumor cells that survive therapy. Remarkably, breast cancers can recur after extended periods of clinical remission, implying that at least some residual tumor cells pass through a dormant phase prior to relapse. Nevertheless, the mechanisms that contribute to breast cancer recurrence are poorly understood. Using a mouse model of recurrent mammary tumorigenesis in combination with bioinformatics analyses of breast cancer patients, we have identified a role for Notch signaling in mammary tumor dormancy and recurrence. Specifically, we found that Notch signaling is acutely upregulated in tumor cells following HER2/neu pathway inhibition, that Notch signaling remains activated in a subset of dormant residual tumor cells that persist following HER2/neu downregulation, that activation of Notch signaling accelerates tumor recurrence, and that inhibition of Notch signaling by either genetic or pharmacological approaches impairs recurrence in mice. Consistent with these findings, meta-analysis of microarray data from over 4,000 breast cancer patients revealed that elevated Notch pathway activity is independently associated with an increased rate of recurrence. Together, these results implicate Notch signaling in tumor recurrence from dormant residual tumor cells and provide evidence that dormancy is a targetable stage of breast cancer progression.
PET imaging of cortical S2 serotonin receptors after stroke: lateralized changes and relationship to depression
Authors: H S Mayberg, R G Robinson, D F Wong, R Parikh, P Bolduc, S E Starkstein, T Price, R F Dannals, J M Links, A A Wilson
Journal: American Journal of Psychiatry (1988)

Patients with right-hemisphere strokes (N = 9) more than 1 year after injury had greater cortical binding of (3-N-[11C]methyl)spiperone than a similar group of patients with left-hemisphere strokes (N = 8) or normal control subjects (N = 17). The higher S2 serotonin receptor binding occurred in uninjured regions of the right parietal and temporal cortex. The ratio of binding in the ipsilateral to contralateral cortex showed a significant negative correlation with severity of depression scores in the left temporal cortex. These findings suggest that the biochemical response of the brain may be different depending on which hemisphere is injured and that some depressions may be a consequence of the failure to upregulate serotonin receptors after stroke.
Abstract P397: Cardiovascular Health Among US Adults In Metropolitan And Micropolitan Statistical Areas
Authors: Fleetwood Loustalot, Jing Fang, Latetia Moore, Nilay S Shah, Linda Schieb
Journal: Circulation (2014)

Background: Cardiovascular disease (CVD) is the leading cause of death in the US and primary risk factors for CVD are well known. Promoting the ideal state of cardiovascular (CV) health factors and behaviors has been previously defined as CV health. The objective of this study is to assess CV health among US adults in urban areas. Methods: Data from the Behavior Risk Factor Surveillance System (BRFSS) 2011 were used for analysis and included 307,101 participants from 198 metropolitan and micropolitan statistical areas (MMSA) with an adequate sample size for estimates (range: 493 to 9,241 participants). Seven indicators were used to define ideal levels of CV health using self-reported data: no hypertension, no diabetes, no high cholesterol, no current smoking, no obesity, and meeting physical activity guidelines and fruit and vegetable consumption targets. Each metric was given a score (0=no, 1=yes) and summed. The percentage achieving ideal CV health (all 7 metrics at ideal level), good CV health (6-7 metrics at ideal levels), poor CV health (0-2 metrics at ideal levels), and the mean CV health score were calculated for each MMSA. Estimates and 95% confidence intervals were age-standardized. Results: Overall, 16.7% (16.4-17.1) and 11.5% (11.2-11.8) of participants among the 198 MMSAs had good and poor CV health, respectively. Few respondents in MMSAs met all ideal CV health standards (&lt;1%), likely driven by the limited number of participants meeting fruit and vegetable consumption targets (5.7%) in this sample. The overall mean CV health score was 3.91 (3.90-3.92). The percentage of participants with good CV health varied from 3.0% (1.5-5.8) (Mobile, AL) to 23.8% (17.0-32.3) (Kalispell, MT). The percentage of participants with poor CV health varied from 6.1% (4.2-8.6) (Boulder, CO) to 26.5% (18.2-36.8) (Kingsport-Bristol-Bristol, TN-VA). The mean CV health score ranged from 3.44 (3.2-3.7) (Kingsport-Bristol-Bristol, TN-VA) to 4.7 (4.5-4.9) (Boulder, CO). Conclusions: Across select US MMSAs, few adults met ideal CV health standards, and only 16% had good CV health. CV health varied significantly across MMSAs. Reducing the burden and mitigating the deleterious effects of CVD can be achieved through the promotion of CV health. Local clinical and public health agencies have the unique opportunity to tailor evidenced-based interventions to promote CV health in their populations. The methodology and findings used in this study can be utilized by local jurisdictions to target lagging health indicators with focused interventions.
Eexpression and prognostic significance of Matrix Metalloproteinases 12 and Osteopontin in non-small cell lung cancer
Authors: Chong-Jen Yu, Yun-Chie Lee, Pan-Chyr Yang
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

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The matrix metalloproteinaes (MMP) are a family of matrix degrading enzymes that are important in tumor invasion, angiogenesis and metastasis. Osteopontin is a matrix protein identified to be important in tumor progression, and is commonly overexpressed in many types of cancer, includes non-small cell lung cancer. MMP-12 and OPN are recently reported to play important role in the prognosis of NSCLC. ( Hofmann et al. Clin Cancer Res 2005;11:1086 ; Donati et al. Clin Cancer Res 2005;11:6459 ). Using multiplex RT-PCR, the expression of MMP-1,-2,-9,-12 were evaluated in 70 NSCLC. Tumor tissues commonly expressed higher MMPs mRNA than their nontumrous counterparts, and MMP-12 is the most commonly overexpressed (overexpression of MMP-1, 53%; MMP-2, 30%; MMP-9, 59%; MMP-12, 83.3%). Overexpression of MMP-12 correlated with advanced T and N stage. Survival analysis disfavored patients with expression of higher amount of MMP-12 (P=0.025). To confirm the previous findings, we then used quantitative RT-PCR and immunohistochemical stain to evaluate the expression of MMP-12 in an irrelevant group of 96 NSCLC patients, in them the expression of osteopontin (OPN) was also evaluated. MMP-12 overexpressed in 93 of 96 (96.9%) tumors, with a median folds of expression of 53.45 in tumor tissues than in non-tumor counterparts. Overexpression of OPN is also common in 91 of 96 (94.8%) tumors (median folds of expression: 67.65). High level (>=53.45) of MMP-12 expression linked to poor overall survival (p=0.011), though not with disease-free survival (p=0.380). There was a tendency to worse prognosis in patients with high level of OPN expression, but not reached statistical significance. Interestingly, a correlation could be established between the expression amounts of MMP-12 and OPN (Pearson correlation coefficient =0.247, P=0.015). We concluded that the overexpression of MMP-12 and OPN is very common in NSCLC, and high expression of MMP-12 is associated with poor prognosis in NSCLC.
Abstract 2757: Inflammation and Descending Thoracic Aortic Calcification as Detected by Computed Tomography: the Multi-Ethnic Study of Atherosclerosis
Authors: Junichiro Takasu, Ronit Katz, David M Shavelle, Kevin O'Brien, SongShou Mao, J j carr, Mary Cushman, Matthew J Budoff
Journal: Circulation (2007)
Constitutive expression of GATA-1, EPOR, alpha-globin, and gamma-globin genes in myeloid clonogenic cells from juvenile chronic myelocytic leukemia
Authors: E Privitera, R Schiro, D Longoni, A Ronchi, A Rambaldi, S Bernasconi, S Ottolenghi, G Masera, A Biondi
Journal: Blood (1995)
Abstract 3: Hypothermic Total Liquid Ventilation Improves Survival and Neurological Recovery Following Experimental Cardiac Arrest and Resumption of Spontaneous Circulation in Rabbits
Authors: Renaud Tissier, Mourad Chenoune, Bijan Ghaleh, Fanny Lidouren, Lys Darbera, Jean-Luc Dubois-Rande, Patrick Bruneval, Jean-Damien Ricard, Alain Berdeaux
Journal: Circulation (2010)

Introduction: Ultra-fast cooling using hypothermic total liquid ventilation (TLV) has been experimentally investigated for a cardioprotective purpose or for the induction of intra-arrest hypothermia. Hypothesis: Our goal was to determine whether TLV also improves survival and neurological recovery when instituted after resumption of spontaneous circulation (ROSC) following cardiac arrest in rabbits. Methods: Ventricular fibrillation was induced in anesthetized rabbits. After 5 or 10-min of fibrillation (5′ and 10′ groups, respectively), cardiopulmonary resuscitation was attempted. After ROSC, rabbits randomly underwent a normothermic Control life support (conventional ventilation until weaning; Control-5′ and Control-10′ groups) or with rapid cooling (TLV-5′ and TLV-10′ groups). In those last groups, a 32°C hypothermia was induced by 20-min of TLV. Hypothermia was further maintained under conventional ventilation during 3h until rewarming and weaning. In all groups, hemodynamic and biochemical parameters ...
Regulation of epithelial cell proliferation by bronchial fibroblasts obtained from mild asthmatic subjects
Authors: A. Semlali, E. Jacques, M. Rouabhia, J. Milot, M. Laviolette, J. Chakir
Journal: Allergy (2010)

To cite this article: Semlali A, Jacques E, Rouabhia M, Milot J, Laviolette M, Chakir J. Regulation of epithelial cell proliferation by bronchial fibroblasts obtained from mild asthmatic subjects. Allergy 2010; 65 : 1438–1445. Abstract Background: Bronchial epithelium is considered a key player in coordinating airway wall remodelling. The function of epithelial cells can be modulated by the underlying fibroblasts through autocrine and paracrine mechanisms. Objective: To investigate the effect of phenotypic changes in bronchial fibroblasts from asthmatic subjects on epithelial cell proliferation. Methods: Epithelial cells and fibroblasts derived from bronchial biopsies of asthmatic and healthy controls were cultured in an engineered model. Proliferation was evaluated by 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyl‐tetrazolium‐bromid (MTT). Epidermal growth factor receptor (EGFR), cyclin‐dependent kinase inhibitors p21 and p27 were measured by western blots. Total and active forms of transforming growth factor (TGF)‐β 1 were measured using ELISA and bioassay. TGF‐β was inhibited using a recombinant TGF‐β soluble receptor II protein. Results: Proliferation of epithelial cells from asthmatics (AE) is increased when cells were cultured with fibroblasts from normal controls (NF). Fibroblasts from asthmatics (AF) significantly decreased the proliferation of epithelial cells from healthy subjects (NE). Activation of p21, p27, EGFR and TGF‐β 1 reflects the proliferation data by decreasing in AE cultured with NF and increasing in NE cultured with AF. Neutralization of TGF‐β increased proliferation of epithelial cells cultured in the asthmatic model. Conclusion: Fibroblasts from asthmatic subjects regulate epithelial cell prolifearation, and TGF‐β signalling may represent one of the pathway involved in these interactions.
Abstract P2-04-08: Accuracy of estrogen receptor, progesterone receptor, HER2 Status and Ki67 labeling index between core needle and surgical excisional tumour in 910 patients with breast cancer
Authors: Rikiya Nakamura, Naohito Yamamoto, Yoshiyuki Itookubo, Ayako Nakagawa, Makiko Itami
Journal: Cancer Research (2015)

Abstract Purpose Accurate determination of ER, PgR, HER2 status and Ki67 labeling index was very important in making decision for adjuvant and neoadjuvant treatment for patients with breast cancer. However discordance of ER, PgR, HER2 status and Ki67 labeling index (Ki67-LI) between core needle biopsy (CNB) and surgical specimens (SSp) varied among reported studies. The aim of the present study was to compare the accuracy of CNB with that of SSp for ER, PgR,HER-2 status, Ki67-LI detection in breast cancer. Patients and methods All patients diagnosed with an early breast cancer in our Cancer Center Hospital between January 2005 and May 2014 was included but exclusion criteria of patients with large tumour requiring neoadjuvant chemotherapy. All CNB were performed under ultrasound guidance, with at least four 14-gauce core biopsies being obtained for pathological examination. ER, PgR, HER-2 status and Ki67-LI were assessed in CNB and in SSp. ER and PgR were determined by Immunohistochemistry (IHC). The cut points for ER and PgR positive was10%. The cut point for Ki67-LI high expression was 20%. HER2 was determined by IHC and scored from 0 to 3+. FISH analysis was carried out in HER2 2+ cases and in discordant cases. Results A total of 910 patients were assessed. CNB can be used with confidence for ER and HER2 determination. Rates for sensitivity, specificity, negative predictive value and positive predictive value for CNB compared with SSp are 99.3%,95.6%,97.2%,98.5% for ER, 94.5%,81.8%,88.2%,90.7% for PgR ,93.0%,99.1%,99.6%,93.9% for HER2, and 87.7%,69.8%,81.1%,79.4% for Ki67-LI, respectively. Specially, the most impact factor of discordance for Ki67-LI and HER2 is Tumour size and that for ER and PgR is lobular carcinoma. Conclusion CNB can be used with confidence for ER and HER2 determination. For PgR and Ki67-LI due to substantial discordance results from CNB should be used with caution. Citation Format: Rikiya Nakamura, Naohito Yamamoto, Yoshiyuki Itookubo, Ayako Nakagawa, Makiko Itami. Accuracy of estrogen receptor, progesterone receptor, HER2 Status and Ki67 labeling index between core needle and surgical excisional tumour in 910 patients with breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P2-04-08.
Abstract 17123: Warning Symptoms Prior to Sudden Cardiac Arrest: Spotlight on Sub-Acute Prevention
Authors: Eloi Marijon, Audrey Uy-Evanado, Kyndaron Reinier, Carmen Teodorescu, Kumar Narayanan, Karen Gunson, Jonathan Jui, Sumeet S Chugh
Journal: Circulation (2014)

Introduction: Survival after sudden cardiac arrest (SCA) remains low despite significant developments in the field of resuscitation. While long-term strategies for primary prevention continue to evolve, the spotlight must shift to short-term primary prevention strategies. Sentinel events preceding SCA may be of special interest in this regard, especially in light of recent advances in communication and remote transmission technologies.

Hypothesis: We hypothesized that “warning events” in the hours, days and weeks prior to SCA may identify a subgroup of SCA cases that will benefit from a timely 911 call for resuscitation.

Methods and Results: From an ongoing prospective study of out-of-hospital SCA in an urban population of one million in the Northwestern US (2002-2012), we evaluated symptoms in the four weeks preceding SCA among middle-aged residents (35-65 years), using multiple sources. If symptoms were present and emergent health care sought, association with survival from SCA was assessed. Of 839 SCA cases with comprehensive assessment of symptoms (51±12 years, 75% males), 430 (51%) had symptoms, mainly chest pain and dyspnea. Symptoms recurred during the 24 hours preceding SCA in the majority (93%). Only 81 subjects (19%) called EMS (911) to report symptoms prior to SCA; these were more likely to be subjects with a history of heart disease (P=0.0001) and/or continuous chest pain (P<0.0001). Survival when 911 was called prior to SCA was 32.1% (95% confidence interval 21.7-42.4), compared to 6.0% (95% confidence interval 3.5-8.5) in those who did not call (P<0.0001).

Conclusions: Warning symptoms are frequent prior to SCA but the vast majority of these are not acted upon. Survival from SCA was significantly higher (five-fold) when symptoms prompted a 911 call, indicating the significant potential to enhance SCA survival by closely coupling warning symptoms to emergent care.