tbuckley/cabot-search huggingface dataset:
Visual cortical dysfunction in Alzheimer's disease evaluated with a temporally graded "stress test" during PET
Authors: M J Mentis, B Horwitz, C L Grady, G E Alexander, J W VanMeter, J M Maisog, P Pietrini, M B Schapiro, S I Rapoport
Journal: American Journal of Psychiatry (1996)

Visual-processing abnormalities commonly contribute to typical Alzheimer's disease symptoms, but their detailed pathophysiology remains unknown. To investigate why patients with Alzheimer's disease have greater difficulty performing visuoconstructive (magnocellular-dominated) tasks than face- or color-perception (parvocellular-dominated) tasks, the authors measured brain activation in response to a temporally graded visual stimulus (neural stress test) during positron emission tomography.The stress test measured regional cerebral blood flow (CBF) in response to a patterned flash stimulus in the resting state (0 Hz in the dark) and at frequencies of 1, 2, 4, 7, and 14 Hz. Ten patients with Alzheimer's disease and 12 age- and sex-matched comparison subjects were studied.The striate response at 7 Hz and 14 Hz (the degree of regional CBF increase from that at 0 Hz) was significantly less in the patients than in the comparison subjects, whereas the change in regional CBF at the lower frequencies did not differ between groups. In bilateral middle temporal association areas activated by motion and dominated by magnocellular input, regional CBF at 1 Hz (the frequency with maximal apparent motion) was significantly greater than at 0 Hz in the comparison subjects but not in the patients.The magnocellular visual system normally responds to high-frequency input and motion; the failure of response in the striate cortex at high but not low frequencies in the Alzheimer's patients suggests greater magnocellular than parvocellular dysfunction at these levels. Activation failure in the middle temporal areas in the patients supports magnocellular dysfunction. The finding that the Alzheimer's disease group had abnormal visual cortical function emphasizes the importance of clinical visuospatial evaluation of patients with Alzheimer's disease to fully understand symptom production and to plan interventions.
Pressure-Independent Pulsatility Index (PIPI) Independently Predicts Cardiovascular Events in the Cafe Sub-Study of Ascot
Authors: JE Davies, T Tillin, A Malaweera, PS Lacy, K Cruickshank, A Stanton, D Collier, H Thurston, J Mayet, B Williams, KH Parker, SM Thom, AD Hughes
Journal: Circulation (2010)
A multi-center, open label trial to evaluate the efficacy and tolerability of aprepitant (A) and palonosetron (P) for the prevention of chemotherapy-induced nausea and vomiting in colorectal cancer (CRC) patients receiving FOLFOX chemotherapy
Authors: J. S. Bubalo, M. H. Takemoto, J. Herrington, C. F. Miller, L. Wong, A. Fisher, E. M. Roberson, P. Wilmann, C. Williams, M. S. Edwards, C. D. Blanke
Journal: Journal of Clinical Oncology (2008)

20684 Background: Colorectal cancer patients have seen significant recent advances in care with newly developed chemotherapeutic regimens. The risk of significant nausea/vomiting (N/V) with modern combination chemotherapy for CRC has not been well characterized, especially when evaluating newer classes of antiemetics have been used. The primary aim of this study is to test the ability of modern combination antiemetic therapy to control N/V and otherwise affect quality of life (QOL) both during and after FOLFOX. Methods: A, a neurokinin-1 antagonist, dexamethasone (D), and P were given prior to FOLFOX as follows: Patients received P 0.25 mg IV, D 12 mg PO and A 125 mg PO 1 hour prior to FOLFOX on Day 1 followed by A 80 mg daily days 2 and 3, and D 8 mg daily days 2–4. The primary aim of this study was to minimize N/V both during and after FOLFOX. Nausea, vomiting, rescue medication, and nutritional intake were evaluated Days 1–5. Responses were defined as complete (CR) = no emesis and no rescue medications, major (MR) = no emesis with nausea and/or rescue medication use, and Failure (F) = any emesis, all for the complete 5 day observation period. Results: First cycle responses for 32 patients are presented. Patient characteristics: Stage III/IV (28) vs. I/II (4), male/female 18/14, median 58 y/o (range 27–80). Clinically meaningful responses were seen in 29/32 (91%) of patients (CR 14/32 = 44% + MR 15/32 = 47%). Of the MR patients, 9/15 took rescue medication for their nausea. Three patients (9%) had an emetic event within 5 days of starting cycle 1 and were antiemetic failures. Adverse effects were mild with no grade 3 or 4 events in the first cycle. QOL endpoints evaluated showed improvements in patient appetite, nutritional intake, and decreased or stable nausea from baseline in the majority of patients. Conclusions: In this interim analysis, the ADP combination provided an emesis free chemotherapy experience in 91% of patients without undue toxicity, showing improvement over the 30–70% emesis rates seen historically with FOLFOX and standard antiemetic agents. Data on multiple cycles at the target accrual, plus additional QOL data will be available in June. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Merck Merck
High Efficiency Gene Transfer to Human Hematopoietic SCID-Repopulating Cells Under Serum-Free Conditions
Authors: Andrea J. Schilz, Gaby Brouns, Heike Knöβ, Oliver G. Ottmann, Dieter Hoelzer, Axel A. Fauser, Adrian J. Thrasher, Manuel Grez
Journal: Blood (1998)
Expression of phospho(p)-AMP-activated protein kinase (AMPK) in lung cancer
Authors: W. N. William, Q. Jin, E. S. Kim, L. Feng, L. Prudkin, J. J. Lee, C. Behrens, I. I. Wistuba, H. Lee
Journal: Journal of Clinical Oncology (2008)

11085 Background: Mammalian target of rapamycin (mTOR) plays a central role in carcinogenesis by coupling intracellular growth stimuli through tyrosine kinase receptors to cell-cycle progression. AMPK has been proposed to act as a cellular fuel sensor allosterically activated under conditions that decrease the ATP/AMP ratio. AMPK is also regulated by phosphorylation following activation of the upstream serine-threonine kinase LKB1. Besides contributing to energy metabolism control, AMPK has been shown to inhibit cell growth via mTOR suppression, thus suggesting a possible role in carcinogenesis. Methods: We determined the distribution of p-AMPK protein levels in tumor specimens from 277 patients (55% female) with non-small cell lung cancer (NSCLC) [94%] or SCLC [6%], using high throughput Western tissue microarrays, and evaluated its impact on survival. Biomarker expression levels in pre-specified subgroups were compared by Wilcoxon and Kruskal-Wallis tests. Survivals between the groups were compared using the log-rank test. Cox proportional hazards models were utilized for multivariate analysis. Results: There was no statistically significant differences in the distribution of p-AMPK in squamous carcinoma vs. adenocarcinoma vs. SCLC (p=0.12), Caucasians vs. non-Caucasians (p=0.83), T1 vs. T2 vs. T3 vs. T4 (p=0.89), N0 vs. N1 vs. N2 (p=0.72), and age (p=0.36). p-AMPK levels were significantly higher in smokers vs. former smokers vs. never smokers (p=0.0005) and trended higher in males vs. females (p=0.06). There was also a trend towards better survival in patients with a p-AMPK score < 25 (p=0.071, log-rank test; p=0.13, Cox model). This retrospective cohort of NSCLC patients was similar to historical controls as age < 67 (median), adenocarcinoma histology, early T and N stage were all associated with improved survival. Conclusions: This is the first study to demonstrate increased levels of p-AMPK in smokers with lung cancer and its possible impact on survival. Given the implications of differences in the biology of NSCLC in smokers vs. never smokers, the results presented herein are intriguing and should be further evaluated, in order to determine whether AMPK could become a valid therapeutic target in the future (Supported by grants NIH R01 CA109520, NIH R01CA100816, and ACS RSG-04–082). No significant financial relationships to disclose.
Garenoxacin (GRNX) for secondary prophylaxis against febrile neutropenia (FN) in chemotherapies for advanced lung cancer
Authors: Akito Hata, Nobuyuki Katakami, Shiro Fujita, Reiko Kaji, Jumpei Takeshita, Satoshi Morita, Daichi Fujimoto, Kazuma Nagata, Kojiro Otsuka, Keisuke Tomii
Journal: Annals of Oncology (2015)
Tennis injury data from The Championships, Wimbledon, from 2003 to 2012
Authors: I McCurdie, S Smith, P H Bell, M E Batt
Journal: British Journal of Sports Medicine (2016)

The primary aims of this retrospective study were to describe the burden of injury presenting to the medical team and the changes in injury profile over 10 years (2003-2012) at The Championships, Wimbledon. Secondary aims included description of gender difference in rates, distribution and pathology of injuries.Retrospective observational cohort of player injury presentations over 10 years (2003-2012) at The Championships, Wimbledon.The overall rate of presentation of injury for all players over the 10-year period was 20.7 per 1000 sets played. Injury rates were lower for male players (17.7 injuries per 1000 sets played) than female players (23.4 injuries per 1000 sets played). There was variability in the numbers of injuries reported by men and women players over the 10-year period.The rates of presentation of injury at this Grand Slam tennis tournament varied between male and female players, and between years. More robust systems of data collection are required in professional tennis to enable more sophisticated injury data analysis between sexes, years and different playing surfaces.
Postoperative concurrent radiochemotherapy versus radiotherapy in high-risk SCCA of the head and neck: Results of the German phase III trial ARO 96–3
Authors: R. Fietkau, C. Lautenschläger, R. Sauer, J. Dunst, A. Becker, M. Baumann, T. Wendt, K. Grüschow, C. Hess, V. Budach, H. Iro
Journal: Journal of Clinical Oncology (2006)

5507 Background: Despite resection and postoperative irradiation high-risk (3 or more involved lymph nodes, extra-capsular disease and/or microscopically involved mucosal margins of resection) squamous cell carcinomas (SCCAs) of the head and neck frequently recur in the tumor bed. Postoperatively radiochemotherapy (RCT) with cis-Platin (CDDP)/5-FU versus radiotherapy (RT) alone was compared in a randomized trial. Methods: Between 5/97 and 12/04, 440 patients who had high-risk SCCAs of the head and neck were enrolled in this prospectively randomized phase III trial. Following resection and neck dissection, 214 patients were randomly assigned to RT (66 Gy/33 Fx/6.6 weeks) and 226 patients to identical RT plus CDDP (20 mg/m 2 on day 1–5, 29–33) and 5-FU (600 mg/m 2 on day 1–5, 29–33). Results: The 5 year local-regional control rate is 72.2 ± 3.7% following RT and 88.6 ± 2.4% for the RCT group (p = 0.00259; 5-year progression free survival 50.1 ± 4.0% and 62.4 ± 4.4% (p = 0.024) and 5-year overall survival 48.6 ± 4.4% vs. 58.1 ± 4.6% (p = 0.11). There was no difference in the 5 year incidence of distant metastases (19.3 ± 3.6% vs 25.5 ± 4.6%; p = 0.45). The incidence of grade 3+ acute toxicity was higher during RCT: mucositis 12.6% vs. 20.8% (p = 0.04), leucopenia 0% vs. 4.4% (p = 0.007). Conclusions: Acute toxicity is increased to an acceptable level by RCT. Postoperative RCT compared to RT improves locoregional control and progression free survival; thus survival as a trend is improved by 10% after 5 years. Supported by Deutsche Krebshilfe 70–2140. No significant financial relationships to disclose.
Inference of imatinib (IM) effects on leukemic stem cell (SC) compartment via mathematical modeling of IRIS treatment response data
Authors: D. Bottino, Y. Chia, A. Stein, A. Georgieva, J. Yu, J. Kahn, G. Helmlinger, T. Kalebic
Journal: Journal of Clinical Oncology (2009)

7056 Background: Continuous treatment of chronic phase CML (CML-CP) patients with imatinib (IM) induces durable responses in majority of patients with a decreasing rate of relapse (Hochhaus et al, Blood. 2007;110). We present a mechanistic mathematical model which uses 6-year follow up data from the International Randomized Study of Interferon Versus STI571 (IRIS) trial (O'Brien et al, N Engl J Med. 2003;348:994) to explore IM effects on leukemic stem cells (SCs) across the patient population. Methods: The model approximates hemopoiesis as a 4-stage process in which only the first stage, corresponding to the SC compartment, is capable of self-renewal. Leukemic SCs, early and late progenitors were assumed to have higher self-renewal and expansion/differentiation rates than their normal counterparts. Model parameters describing the patient population distributions of leukemic/total SC ratio at diagnosis and sensitivity of leukemic cells to IM, were then fitted to individual cytogenetic and molecular response (CR/MR) data from 200 randomly selected newly-diagnosed CML-CP patients with 6-year follow-up. Results: Based on our analysis, successful characterization of the wide range of clinically observed treatment responses requires the inhibition of the leukemic SC compartment by IM. The median predicted inhibition of the leukemic SC proliferation rate was 79%. The model further predicted that after 6 years of IM treatment, 45% of patients would achieve a leukemic/total SC ratio below 0.1. Conclusions: We have developed a mathematical model of IM effects on CML-CP based on 6-year CR and MR data from the IRIS trial. In contrast to prior reports (Michor et al, Nature. 2005;435), our modeling predicts that IM reduces the leukemic SC compartment in most CML-CP patients, which could provide a mechanistic rationale for the decreasing rate of relapse observed in the study population. [Table: see text]
Testosterone may improve sexual function and mood in older men with low levels
Authors: Susan Mayor
Journal: BMJ (2016)

Treatment with testosterone improved sexual function and mood in men aged over 65 with low levels of the hormone but had no effect on physical functioning or vitality, a randomised trial has shown.1 But researchers warned that larger studies are needed to adequately assess any potential risks from this therapy.

Serum concentrations of testosterone fall with age, but the benefits of raising testosterone levels in older men have not previously been demonstrated as trials have given equivocal results.

Reviewing the issue in 2003, the Institute of Medicine found insufficient evidence that testosterone treatment was beneficial in older men and recommended that trials should assess the effect of raising …
Prostate-specific antigen (PSA) response as a surrogate endpoint for overall survival (OS): Analysis of the TAX 327 Study comparing docetaxel plus prednisone with mitoxantrone plus prednisone in advanced prostate cancer
Authors: M. Roessner, R. de Wit, I. F. Tannock, N. Yateman, S.-L. Yao, A. Yver, M. A. Eisenberger
Journal: Journal of Clinical Oncology (2005)

4554 Background: The TAX 327 Study showed that metastatic hormone-refractory prostate cancer (HRPC) patients randomized to q3wk docetaxel (D) plus prednisone (P) had superior survival and higher PSA and pain response rates compared with q3wk mitoxantrone (M) plus P. We evaluated the relationship between PSA response and OS in this study to explore whether PSA response may be a surrogate endpoint for OS. Methods: Patients with histologically proven metastatic HRPC, clinical and/or PSA progression, were randomized to P (5 mg bid) plus either q3wk D (75 mg/m2 q3wks x 10 cycles), weekly D (30 mg/m2/wk x 5 of 6 wks x 5 cycles), or q3wk M (12 mg/m2 q3wks x 10 cycles). Only patients with a baseline PSA of at least 20 ng/mL were evaluated for PSA response (PSA decrease of at least 50% from baseline and confirmed at least 3 wks later). Results: A total of 1006 patients were randomized and median baseline PSA levels were similar among treatment arms (114, 108, and 123 ng/mL). A total of 873 patients (87%) were evaluable for PSA response (q3wk D, n=291; weekly D, n=282; M, n=300). No reductions in PSA levels on treatment were observed in 19% of D and 34% of M patients. PSA response rates were significantly higher with q3wk D and weekly D compared with M (45% and 48% vs. 32%, respectively; P<0.001 for both). Overall survival was improved in patients evaluable for PSA response receiving q3wk D, with a 25% reduction in the risk of death compared with M (HR, 0.75; 95% CI, 0.61 to 0.94; log rank, P=0.01). Although the weekly D arm had the highest PSA response rate, it was not associated with increased OS compared with M. Patients with a PSA response had a 60% reduction in mortality risk compared with PSA non-responders (HR, 0.40; 95% CI, 0.31 to 0.51; time-dependent Cox model, P<0.001). Approximately half the treatment effect on OS was accounted for by the PSA response. Conclusions: The beneficial effect of treatment on OS in the TAX 327 study is only partially explained by the PSA response. Therefore, PSA response cannot replace OS as the primary endpoint in Phase III trials in metastatic HRPC to confirm overall clinical benefit. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration sanofi-aventis sanofi-aventis sanofi-aventis sanofi-aventis Innovex, sanofi-aventis
Effects of intravenous iron therapy in iron‐deficient patients with systolic heart failure: a meta‐analysis of randomized controlled trials
Authors: Ewa A. Jankowska, Michał Tkaczyszyn, Tomasz Suchocki, Marcin Drozd, Stephan von Haehling, Wolfram Doehner, Waldemar Banasiak, Gerasimos Filippatos, Stefan D. Anker, Piotr Ponikowski
Journal: European Journal of Heart Failure (2016)
Randomized, Double-Blind, Placebo-Controlled Phase III Trial of Apatinib in Patients With Chemotherapy-Refractory Advanced or Metastatic Adenocarcinoma of the Stomach or Gastroesophageal Junction
Authors: Jin Li, Shukui Qin, Jianming Xu, Jianping Xiong, Changping Wu, Yuxian Bai, Wei Liu, Jiandong Tong, Yunpeng Liu, Ruihua Xu, Zhehai Wang, Qiong Wang, Xuenong Ouyang, Yan Yang, Yi Ba, Jun Liang, Xiaoyan Lin, Deyun Luo, Rongsheng Zheng, Xin Wang, Guoping Sun, Liwei Wang, Leizhen Zheng, Hong Guo, Jingbo Wu, Nong Xu, Jianwei Yang, Honggang Zhang, Ying Cheng, Ningju Wang, Lei Chen, Zhining Fan, Piaoyang Sun, Hao Yu
Journal: Journal of Clinical Oncology (2016)

Purpose There is currently no standard treatment strategy for patients with advanced metastatic gastric cancer experiencing progression after two or more lines of chemotherapy. We assessed the efficacy and safety of apatinib, a novel vascular endothelial growth factor receptor 2 tyrosine kinase inhibitor, in patients with advanced gastric or gastroesophageal junction adenocarcinoma for whom at least two lines of prior chemotherapy had failed. Patients and Methods This was a randomized, double-blind, placebo-controlled phase III trial. Patients from 32 centers in China with advanced gastric or gastroesophageal junction adenocarcinoma, for whom two or more prior lines of chemotherapy had failed, were enrolled. Patients were randomly assigned to oral apatinib 850 mg or placebo once daily. The primary end points were overall (OS) and progression-free survival (PFS). Results Between January 2011 and November 2012, 267 patients were enrolled. Median OS was significantly improved in the apatinib group compared with the placebo group (6.5 months; 95% CI, 4.8 to 7.6 v 4.7 months; 95% CI, 3.6 to 5.4; P = .0149; hazard ratio, 0.709; 95% CI, 0.537 to 0.937; P = .0156). Similarly, apatinib significantly prolonged median PFS compared with placebo (2.6 months; 95% CI, 2.0 to 2.9 v 1.8 months; 95% CI, 1.4 to 1.9; P &lt; .001; hazard ratio, 0.444; 95% CI, 0.331 to 0.595; P &lt; .001). The most common grade 3 to 4 nonhematologic adverse events were hand-foot syndrome, proteinuria, and hypertension. Conclusion These data show that apatinib treatment significantly improved OS and PFS with an acceptable safety profile in patients with advanced gastric cancer refractory to two or more lines of prior chemotherapy.
An Atlas of the Human Kinome Reveals the Mutational Landscape Underlying Dysregulated Phosphorylation Cascades in Cancer
Authors: Aleksandra Olow, Zhongzhong Chen, R. Hannes Niedner, Denise M. Wolf, Christina Yau, Aleksandr Pankov, Evelyn Pei Rong Lee, Lamorna Brown-Swigart, Laura J. van ‘t Veer, Jean-Philippe Coppé
Journal: Cancer Research (2016)

Abstract Kinase inhibitors are used widely to treat various cancers, but adaptive reprogramming of kinase cascades and activation of feedback loop mechanisms often contribute to therapeutic resistance. Determining comprehensive, accurate maps of kinase circuits may therefore help elucidate mechanisms of response and resistance to kinase inhibitor therapies. In this study, we identified and validated phosphorylatable target sites across human cell and tissue types to generate PhosphoAtlas, a map of 1,733 functionally interconnected proteins comprising the human phospho-reactome. A systematic curation approach was used to distill protein phosphorylation data cross-referenced from 38 public resources. We demonstrated how a catalog of 2,617 stringently verified heptameric peptide regions at the catalytic interface of kinases and substrates could expose mutations that recurrently perturb specific phospho-hubs. In silico mapping of 2,896 nonsynonymous tumor variants identified from thousands of tumor tissues also revealed that normal and aberrant catalytic interactions co-occur frequently, showing how tumors systematically hijack, as well as spare, particular subnetworks. Overall, our work provides an important new resource for interrogating the human tumor kinome to strategically identify therapeutically actionable kinase networks that drive tumorigenesis. Cancer Res; 76(7); 1733–45. ©2016 AACR.
Glucagon Nasal Powder: A Promising Alternative to Intramuscular Glucagon in Youth With Type 1 Diabetes
Authors: Jennifer L. Sherr, Katrina J. Ruedy, Nicole C. Foster, Claude A. Piché, Hélène Dulude, Michael R. Rickels, William V. Tamborlane, Kathleen E. Bethin, Linda A. DiMeglio, Larry A. Fox, R. Paul Wadwa, Desmond A. Schatz, Brandon M. Nathan, Santica M. Marcovina, Emmanouil Rampakakis, Linyan Meng, Roy W. Beck
Journal: Diabetes Care (2016)

OBJECTIVE Treatment of severe hypoglycemia outside of the hospital setting is limited to intramuscular glucagon requiring reconstitution prior to injection. The current study examined the safety and dose-response relationships of a needle-free intranasal glucagon preparation in youth aged 4 to &amp;lt;17 years. RESEARCH DESIGN AND METHODS A total of 48 youth with type 1 diabetes completed the study at seven clinical centers. Participants in the two youngest cohorts (4 to &amp;lt;8 and 8 to &amp;lt;12 years old) were randomly assigned to receive either 2 or 3 mg intranasal glucagon in two separate sessions or to receive a single, weight-based dose of intramuscular glucagon. Participants aged 12 to &amp;lt;17 years received 1 mg intramuscular glucagon in one session and 3 mg intranasal glucagon in the other session. Glucagon was given after glucose was lowered to &amp;lt;80 mg/dL (mean nadir ranged between 67 and 75 mg/dL). RESULTS All 24 intramuscular and 58 of the 59 intranasal doses produced a ≥25 mg/dL rise in glucose from nadir within 20 min of dosing. Times to peak plasma glucose and glucagon levels were similar under both intramuscular and intranasal conditions. Transient nausea occurred in 67% of intramuscular sessions versus 42% of intranasal sessions (P = 0.05); the efficacy and safety of the 2- and 3-mg intranasal doses were similar in the youngest cohorts. CONCLUSIONS Results of this phase 1, pharmacokinetic, and pharmacodynamic study support the potential efficacy of a needle-free glucagon nasal powder delivery system for treatment of hypoglycemia in youth with type 1 diabetes. Given the similar frequency and transient nature of adverse effects of the 2- and 3-mg intranasal doses in the two youngest cohorts, a single 3-mg intranasal dose appears to be appropriate for use across the entire 4- to &amp;lt;17-year age range.