tbuckley/cabot-search huggingface dataset:
Abstract P025: Associations of Fetuin-A with Incident Heart Failure in Participants with and without Diabetes and Insulin Resistance: The Cardiovascular Health Study
Authors: Nketi I Forbang, Traci M Bartz, Kenneth J Mukamal, Luc Djousse, Jorge R Kizer, Sue J Zieman, David S Siscovick, Majken K Jensen, Michael Shlipak, Joachim H Ix
Journal: Circulation (2014)

Background: In animal models, the hepatic secretory protein fetuin-A simultaneously inhibits arterial calcification and causes insulin resistance. Increased calcification and insulin resistance lead to arterial stiffness, an important risk factor for heart failure (HF). The relationship between serum fetuin-A concentrations and HF, and whether it is modified by diabetes or insulin resistance has not been extensively studied. Research Design, Methods, and Objectives: In a prospective study of 4182 community-dwelling participants aged ≥ 65 years, Cox proportional hazards models were used to determine the association of fetuin-A (measured in 1992) with incident HF (followed up through June 2008). Multiplicative interaction terms determined whether diabetes or insulin resistance status modified the association. Results: Mean age was 75 ∓ 5 years, fetuin-A levels were 0.47 ∓ 0.10 g/L, and 1,186 incident HF events occurred during follow-up. In multivariable models adjusting for demographics and CVD risk factors, fetuin-A was not significantly associated with incident HF [HR per SD fetuin-A: 0.97, 95% CI (0.91, 1.04), p-value=0.40] and was not modified by prevalent diabetes status (p-interaction=0.54). However, when prevalent insulin resistant status was defined as previously by the presence of diabetes, or HOMA IR &gt; median (2.22), or obesity (body mass index, kg/m 2 &gt; 30), a significant interaction was observed (p-interaction=0.03). In 1,679 participants with no evidence of insulin resistance by the definition, each SD greater fetuin-A level was associated with a 12% lower risk of HF (95% CI: 2-22%) in a fully adjusted model (Table 1). Conclusions: Future studies should consider the presence of insulin resistance when evaluating the relationship between serum fetuin-A with adverse health outcomes.
Desmoplakin Variants Are Associated with Idiopathic Pulmonary Fibrosis
Authors: Susan K. Mathai, Brent S. Pedersen, Keith Smith, Pamela Russell, Marvin I. Schwarz, Kevin K. Brown, Mark P. Steele, James E. Loyd, James D. Crapo, Edwin K. Silverman, Deborah Nickerson, Tasha E. Fingerlin, Ivana V. Yang, David A. Schwartz
Journal: American Journal of Respiratory and Critical Care Medicine (2015)

Sequence variation, methylation differences, and transcriptional changes in desmoplakin (DSP) have been observed in patients with idiopathic pulmonary fibrosis (IPF).
Caspase-mediated cleavage of p21 is associated with apoptosis in prostate and bladder cancer cells treated with TRAIL plus bortezomib in vitro
Authors: Keyi Zhu, Laura M. Lashinger, David J. McConkey
Journal: Cancer Research (2005)

Proc Amer Assoc Cancer Res, Volume 46, 2005

5316 

Bortezomib (PS-341, Velcade™) is a dipeptidyl boronic acid derivative that is a selective and potent inhibitor of the proteasome. Recently, Bortezomib was FDA-approved for the treatment of multiple myeloma, and it is currently under investigation for the treatment of solid tumors. We show that combined treatment with bortezomib plus TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis in human LNCaP-Pro5 prostate and 253J B-V bladder cancer cells in vitro, two cell lines that are completely resistant to TRAIL alone. Analysis of the biochemical mechanisms involved revealed that bortezomib synergized with TRAIL to promote proteolytic processing and activation of caspases 8 and 3. The effects of bortezomib were associated with increased expression of p21, and a siRNA construct specific for p21 partially prevented bortezomib’s enhancement of TRAIL-induced apoptosis. Interestingly, immunoblotting studies revealed that cells exposed to bortezomib plus TRAIL displayed a 15 kD p21 cleavage product, the formation of which was blocked by z-VAD-fmk, a pan peptide-based caspase inhibitor. Results of mutagenesis studies to identify the site(s) of p21 cleavage and their functional significance will be discussed. Together, our data demonstrate that bortezomib-induced accumulation and possibly caspase-mediated cleavage of p21 is required for TRAIL sensitization in human genitourinary cancer cells. The Bortezomib and TRAIL combination appears promising in terms of its ability to overcome apoptosis resistance, and it therefore warrants further investigation for the treatment of solid tumors.
Effect of toremifene in lowering total cholesterol, LDL, and triglycerides and raising HDL in prostate cancer patients on androgen deprivation therapy
Authors: M. Smith, F. Chu, J. Forrest, S. B. Malkowicz, D. Price, P. Sieber, K. G. Barnette, D. Rodriguez, M. S. Steiner
Journal: Journal of Clinical Oncology (2007)

5124 Introduction: Androgen deprivation therapy (ADT) is the standard treatment for men with advanced prostate cancer. ADT has been shown to detrimentally affect lipids (average 9% increase in total cholesterol and 26% increase in triglycerides) and is associated with increased risk of coronary heart disease and myocardial infarction. Toremifene, a selective estrogen receptor modulator (SERM), improves bone mineral density and lipid profiles in women. An ongoing phase III trial will assess the safety and efficacy of toremifene in treating multiple side effects of ADT including osteoporosis, hot flashes, gynecomastia and lipid profiles. Given the emerging recognition of increased cardiovascular risk during ADT, an interim analysis was conducted to assess the effects of toremifene on lipid profiles in the ongoing phase III study. Methods: 1,392 men = 50 years old with histologically documented prostate cancer and receiving ADT were randomized to toremifene (80 mg/day) or placebo. An interim analysis evaluated changes in lipids from baseline to month 12 in the first 197 subjects to complete one-year follow up. The outcomes measured in this interim analysis were total cholesterol, LDL cholesterol, triglycerides, total cholesterol/HDL ratio, and HDL cholesterol. Results: Compared to treatment with placebo, toremifene decreased total cholesterol (7.1%; p=0.001 for between group comparison), LDL cholesterol (9.0%; p=0.003), and triglycerides (20.1%; p=0.009) levels, and the total cholesterol/HDL ratio (11.7%; p&lt;0.001). Toremifene also significantly increased HDL levels (5.4%; p=0.018) compared to placebo. The effects of toremifene were observed in both statin users and nonusers. Conclusions: Toremifene decreases total cholesterol, LDL cholesterol, and triglycerides and increases HDL cholesterol in men receiving ADT for advanced prostate cancer compared to placebo. Conclusions regarding the clinical significance of these observations will be based on the full cohort of patients at the conclusion of the trial. No significant financial relationships to disclose.
The benefit of whole-body low-dose unenhanced multidetector computer tomography (WBLD-MDCT) for follow up and therapy response monitoring in patients with multiple myeloma: Correlation with hematologic parameters
Authors: M. S. Horger, C. Driessen, C. Brodoefel, C. Faul, P. Pereira, W. Vogel, C. D. Claussen, L. Kanz
Journal: Journal of Clinical Oncology (2006)

7607 Background: To assessthe value of whole-body low-dose multidetector computer tomography (WBLD-MDCT) as diagnostic and survey modality in multiple myeloma (MM), and as a one-stop alternative (Horger et al. EJR 2005;54:289–297) to established imaging techniques (e.g. x-ray and MRI). Methods: Between 7/2001 and 2/2005, WBLD-MDCT scans were obtained in 90 consecutive patients with histologically proven stage II-III MM, all patients having 2 or more scans (mean = 3,8; range = 2–6). CT-scans were performed using a standardized low-dose protocol and the number, size and density of focal or diffuse medullary (in the appendicular skeleton and pelvis) and extra-medullary lesions as well as osteolysis were analysed for each examination and at follow up. Results were correlated with current standard MM laboratory data and at follow up in order to assess correct temporal recognition of significant myeloma changes by both methods. Results: Detection and follow up of medullary and extra-medullary MM lesions and osteolysis by WBLD-MDCT resulted in a sensitivity of 92%, a specificity of 93%, a NPV of 95%, a PPV of 85% and a likelihood ratio for patients with CT-abnormalities to present changes in the course of their disease of 12. Results of radiologic and hematologic analysis showed high agreement at follow up (median, 3 mo). However, agreement of both techniques at the time of investigation was only moderate (κ = 0.629), with CT being correct in 60% of mismatching cases. Thus, CT enabled earlier detection of MM changes. WBLD-MDCT assessed correctly the course of disease in all 4 patients with nonsecretory MM. Evaluation of stability was optimal in all patients. Conclusions: WBLD-MD represents a reliable, widespread, quick (75s acquisition time), and cost-effective imaging technique in MM, allowing detection of bone marrow involvement, extra-medullary tumors and lytic bone lesions in different clinical settings (staging, follow up, therapy monitoring, evaluation of stability). WBLD-MDCT repeatedly allowed detection of changes in the course of the disease prior to laboratory data, especially in extramedullary MM relapse and nonsecretory MM. No significant financial relationships to disclose.
Excellent outcome of stage II neuroblastoma is independent of residual disease and radiation therapy.
Authors: K K Matthay, H N Sather, R C Seeger, G M Haase, G D Hammond
Journal: Journal of Clinical Oncology (1989)

The optimal management for patients with stage II neuroblastoma has not yet been established. In order to determine the impact of adding chemotherapy and/or radiation therapy to surgery, we reviewed by questionnaire 156 patients with stage II neuroblastoma treated by 28 Childrens Cancer Study Group (CCSG) institutions from 1978 to 1985. Survival and progression-free survival (PFS) were analyzed by life-table methods with respect to age at diagnosis, site and size of primary tumor, spinal cord involvement, extent of initial resection, and treatment in addition to surgery. The overall 5-year survival was 96%; the PFS was 90%, similar to previous CCSG studies. Age at diagnosis had a small impact on PFS, with 92% PFS for patients less than 2 years of age at diagnosis, and 84% for those greater than 2 (P = .10). The only site with an adverse outcome was the head and neck (n = 11), with a PFS of 68% compared with 93% for the remaining sites (P = .02). Size of primary and intraspinal extension of primary did not affect PFS. The extent of resection and subsequent treatment with radiation therapy and/or chemotherapy did not affect the PFS. The outcome for 75 patients treated with surgery alone (6-year PFS, 89%) was not significantly different from that of 66 patients receiving radiation therapy (6-year PFS, 94%). There was no significant difference between 40 patients with gross or microscopic residual disease treated with surgery alone (PFS, 92%) and 59 patients with residual disease who also received radiation (PFS, 90%). Five of seven patients who progressed after surgery alone have been salvaged with further therapy and are now free of disease. One survives with disease, so that the 6-year survival is 98% for those treated initially with surgery alone, compared with 95% for those receiving radiation therapy and/or chemotherapy. These data suggest that surgery alone, even if complete resection is not achieved, is sufficient initial therapy for stage II neuroblastoma. The data also identify another stage of neuroblastoma, in addition to stage IV-S, for which almost all patients have a favorable prognosis because their tumor may be biologically limited in growth.
Abstract P125: A Novel Role for Survivin in Insulin-induced Inhibition of Myocardial Apoptosis in Ischemic/reperfused Heart
Authors: Rui Si, Qiujun Yu, Ning Zhou, Ling Tao, Wenyi Guo, Haichang Wang, Feng Gao
Journal: Circulation (2008)

Objectives: Insulin reduces post-ischemic myocardial apoptotic death, but the mechanism remains unclear. Survivin, an anti-apoptotic protein has recently found participating in vascular repair. This study aimed to test the hypothesis that the up-regulation of survivin by insulin may play a role in the antiapoptotic and cardioprotective effects in the ischemic/reperfused (I/R) heart, and further investigate the signaling mechanism involved. Methods : Isolated adult Sprague-Dawley rat hearts were subjected to 30 min regional ischemia and 3 h of reperfusion. The hearts were randomized to receive insulin, insulin plus LY294002 (specific inhibitor of PI3K), or insulin plus rapamycin (specific inhibitor of mTOR) at the start of reperfusion. To further confirm the correlation between survivin and myocardial survival in vitro, cardiomyocytes were infected with adenovirus encoding survivin or transfected with siRNA targeting survivin. Phosphorylation of Akt, mTOR, p70S6K and the expression of protein survivin were determined and infarct size was assessed using TTC staining, cardiomyocytes apoptosis were evaluated after reperfusion by TUNEL staining and DNA laddering. Results: I/R increased myocardial survivin expression. Insulin reperfusion (10 −7 mol/L) resulted in a 4.2-fold increase in survivin expression (P&lt;0.01 vs. I/R alone), which was almost completely blocked by LY294002. Both of the mTOR phosphorylation and survivin expression were inhibited in the group of insulin reperfusion plus LY294002. Rapamycin reperfusion did not change Akt phosphorylation but partially inhibited survivin expression (16.7±1.2 vs. 9.8±1.6, P&lt;0.01 vs. I/R+Ins), which indicated a cardioprotective effect of survivin and a possible PI3K/Akt/mTOR/SVV signaling pathway during I/R. Moreover, over-expressed survivin provides protection against stimulated ischemia reperfusion induced cardiomyocyte apoptosis, while targeting survivin blunted the anti-apoptotic effect of insulin. Conclusion: This study demonstrates that insulin up-regulates myocardial survivin expression, partly at least, via PI3-kinase-mTOR mechanism, which contributes to the anti-apoptotic effect of insulin in the I/R heart.
Encouraging responses with bevacizumab in recurrent low-grade serous ovarian cancer.
Authors: K. M. Schmeler, X. Tao, C. C. Sun, A. Malpica, M. Deavers, A. Sood, R. L. Coleman, D. C. Bodurka, J. J. Kavanagh, D. M. Gershenson
Journal: Journal of Clinical Oncology (2010)

e15503 Background: Low-grade serous ovarian carcinomas (LGSOC) represent approximately 10% of serous ovarian cancers, but are notoriously resistant to conventional chemotherapeutic agents. The objective of this study was to examine the clinical efficacy of bevacizumab with concurrent chemotherapy in patients with recurrent LGSOC. Methods: A retrospective review of patients with recurrent LGSOC treated with bevacizumab between 2005 and 2008 was performed. All cases were reviewed by a gynecologic pathologist to confirm low-grade serous histology. Demographic and clinical variables were abstracted from the medical record. Response was determined using the modified RECIST. Results: We identified 17 patients with LGSOC treated with bevacizumab. All patients had recurrent disease and were previously treated with cytotoxic chemotherapy and/or hormonal agents with a median of 4 regimens (range 1-11). Bevacizumab was given in combination with other agents including taxane and platinum (n = 4), taxane alone (n = 3), cyclophosphomide (n = 3), topotecan (n = 2), gemcitabine (n = 2), capecitabine (n = 1), fluorouracil and oxaliplatin (n = 1), and leuprolide (n = 1). Of the 13 patients evaluable for response, 5 (39%) had a partial response and 3 (23%) had stable disease for a clinical benefit rate of 62%. One patient (6%) developed a bowel perforation and one patient (6%) developed an enterocutaneous fistula while on treatment with bevacizumab. Both patients were managed conservatively. No other serious adverse events were noted. Conclusions: Our results suggest that bevacizumab may have activity in LGSOC. Further study is warranted to develop anti-VEGF therapy in this group of patients. No significant financial relationships to disclose.
The nurses perspective of the effectiveness and value of the respiratory distress observation scale.
Authors: Kerstin Scheper
Journal: Journal of Clinical Oncology (2014)

139 Background: The nurses on the oncology unit at Overlook Medical Center have been using the Respiratory Distress Observation Scale (RDOS) since September 2013 to assess and manage respiratory distress and dyspnea at end of life for our cognitively impaired patients. The gold standard for managing dyspnea has been the ability of the patient to self-report. Cognitive impairment may interfere with the assessment of respiratory distress and dyspnea leading to under recognition and under or over medication of symptoms. Methods: A nurse focus group was formed and elicited discussion, information, and opinion of the implementation and effectiveness of the RDOS on the medical oncology unit. The nurses were tasked with identifying if the RDOS improved their ability to assess and manage respiratory symptoms for this patient population. The group consisted of eight nurses from the oncology unit who shared a passion for end of life care, but varied in levels of expertise and years of experience. The participants answered nine open-ended questions relating to the implementation and effectiveness of the RDOS, its use in communicating with patient’s family, and their experiences with end of life care both on their unit and throughout the hospital. Approximately fifty six patients were evaluated with the RDOS by these nurses prior to the focus group meeting. Results: All participants stated the RDOS was easy, took two minutes to perform and has improved their ability to assess and manage dyspnea while enhancing their ability to effectively communicate with physicians. All were passionate in their belief that the RDOS is a tool that validates their decision to medicate and facilitates educating families that may be resistant to pharmacological intervention. Conclusions: Our focus group results were similar to research findings identifying the RDOS as effective in managing dyspnea. The group advocated its use and support implementation of the RDOS house wide. The group produced useful information and elicited candid discussion on its ability to favorably impact care.
Mechanisms for the Specific Properties of γ‐Hydroxybutyrate in Brain
Authors: Michel Maitre, Christian Klein, Ayikoe G. Mensah‐Nyagan
Journal: Medicinal Research Reviews (2016)

Abstract γ‐Hydroxybutyrate (GHB) is both a natural brain compound with neuromodulatory properties at central GABAergic synapses (micromolar concentration range) and also a drug (Xyrem R ) clinically used for the treatment of various neurological symptoms (millimolar dose range). However, this drug has abuse potential and can be addictive for some patients. Here, we review the basic mechanistic role of endogenous GHB in brain as well as the properties and mechanisms of action for therapeutic clinical doses of exogenous GHB. Several hypotheses are discussed with a preference for a molecular mechanism that conciliates most of the findings available. This conciliatory model may help for the design of GHB‐like drugs active at lower doses and devoid of major side effects.
The causal crux of selection
Authors: Robert Alan Skipper
Journal: Behavioral and Brain Sciences (2001)

Hull et al. make a direct connection between selection and replication. My view is that selection, at its causal crux, is not inherently connected to replication. I make plain the causal crux of selection, distinguishing it from replication. I discuss implications of my results for Hull et al.'s critique of Darden and Cain (1989).
Neoadjuvant paclitaxel for operable breast cancer: Multicenter phase II trial with clinical outcomes, analysis of mutation of the class I β-tubulin gene
Authors: N. Sato, M. Sano, M. Hino, M. Kimura, M. Fujimori, K.-I. Ito, K. Maeno, H. Nakagomi, K. Negishi
Journal: Journal of Clinical Oncology (2004)

609 Background: It has been reported that paclitaxel given on a weekly schedule was more effective than the same drug given every 3 weeks. We conducted a multi-center phase II study to investigate the efficacy and tolerability of paclitaxel as neoadjuvant chemotherapy in Japanese women with stage II-III primary breast cancer. We also evaluated the effect of class I β tubulin gene mutation on the sensitivity to paclitaxel which is one of the possible mechanisms of resistance to paclitaxel. Methods: Patients (pts) (n=50) were treated with 3 cycles of paclitaxel at 80 mg m(-2) every 7 days, followed by surgery. The tumor had to be larger than 3 cm in diameter (clinical T2–4, N0–1, M0). Median age (range) was 53 (24–72) years old. Eleven pts showed overexpression of human epidermal growth factor receptor 2 (HER2) by 3+-positive by IHC. We analyzed the frequency of mutations occurring in the class I β-tubulin gene. Results: Out of 50 pts, 42 pts completed the course of 3 cycles of paclitaxel. After 3 cycles of paclitaxel, the overall clinical response rate was 68.1%, including 14.9% complete response (CR). A pathological CR rate was confirmed in 3 patients (6.4%). Breast conservation was achieved in 46% of the pts. Two pts developed grade 3 neutropenia. There was no case of serious adverse events. HER2-overepressing tumor had higher clinical response (complete or partial) rate than did non HER2-overepxressing tumors (91% vs. 50%, respectively). It is interesting to note that there was a statistically non-significant trend that HER2-overexpressing tumors are more sensitive to weekly paclitaxel in this setting. No mutations showing amino acid substitution of the β-tubulin gene were detected in the pts regardless of clinical response.Conclusion: Neoadjuvant weekly paclitaxel induces a high clinical response rate with a high safety profile. However, pathological CR rate and breast-conservation rate are not satisfactory. Further studies need to determine whether an increase in the cycles of paclitaxel and/or adding anthracyclines may lead to higher pathological CR and breast-conservation rates in the neoadjuvant setting. No significant financial relationships to disclose.