tbuckley/cabot-search huggingface dataset:
Calmodulin kinase II inhibition limits the pro-arrhythmic Ca<sup>2+</sup>waves induced by cAMP-phosphodiesterase inhibitors
Authors: Pierre Bobin, Audrey Varin, Florence Lefebvre, Rodolphe Fischmeister, Grégoire Vandecasteele, Jérôme Leroy
Journal: Cardiovascular Research (2016)

A major concern of using phosphodiesterase (PDE) inhibitors in heart failure is their potential to increase mortality by inducing arrhythmias. By diminishing cyclic adenosine monophosphate (cAMP) hydrolysis, they promote protein kinase A (PKA) activity under β-adrenergic receptor (β-AR) stimulation, hence enhancing Ca2+ cycling and contraction. Yet, cAMP also activates CaMKII via PKA or the exchange protein Epac, but it remains unknown whether these pathways are involved in the pro-arrhythmic effect of PDE inhibitors. Excitation–contraction coupling was investigated in isolated adult rat ventricular myocytes loaded with Fura-2 and paced at 1 Hz allowing coincident measurement of intracellular Ca2+ and sarcomere shortening. The PDE4 inhibitor Ro 20-1724 (Ro) promoted the inotropic effects of the non-selective β-AR agonist isoprenaline (Iso) and also spontaneous diastolic Ca2+ waves (SCWs). PDE4 inhibition potentiated RyR2 and PLB phosphorylation at specific PKA and CaMKII sites increasing sarcoplasmic reticulum (SR) Ca2+ load and SR Ca2+ leak measured in a 0Na+/0Ca2+ solution ± tetracaine. PKA inhibition suppressed all the effects of Iso ± Ro, whereas CaMKII inhibition prevented SR Ca2+ leak and diminished SCW incidence without affecting the inotropic effects of Ro. Inhibition of Epac2 but not Epac1 diminished the occurrence of SCWs. PDE3 inhibition with cilostamide induced an SR Ca2+ leak, which was also blocked by CaMKII inhibition. Our results show that PDE inhibitors exert inotropic effects via PKA but lead to SCWs via both PKA and CaMKII activation partly via Epac2, suggesting the potential use of CaMKII inhibitors as adjuncts to PDE inhibition to limit their pro-arrhythmic effects.
Adherence to anemia treatment guidelines in U.S. community oncology practices
Authors: L. Friedman, A. Naeim, D. J. Pasta, E. P. Elkin, H. Viswanathan, J. Kallich, J. Glaspy
Journal: Journal of Clinical Oncology (2007)

19525 Background: Adherence to anemia guidelines may improve patient outcomes including health-related quality of life. This analysis presents baseline guideline adherence among community-based oncology practices prior to an educational intervention targeted to health care providers to improve adherence to anemia guidelines. Methods: Medical records of a sequential sample of adult cancer patients receiving chemotherapy from 47 participating sites during the year prior to site randomization to an educational intervention were abstracted. Each chart was analyzed to determine (1) whether or not the patient met the criteria for anemia treatment with an erythropoiesis- stimulating agent (ESA) or a blood transfusion, and (2) whether the patient received anemia treatment. A complex algorithm was developed to evaluate whether treatment adhered to guideline recommendations. Results: This baseline analysis included 2463 patient charts. Most patients were female (66%); with a mean duration of cancer of 14.5 months and a mean age of 61.8 years. According to guidelines, 523 patients (21%) met the criteria for anemia treatment and of these, 286 (55%) received an ESA or transfusion. In 1103 patients (45%), guidelines suggested that anemia treatment may be inappropriate. However, 216 (20%) of the 1103 patients for whom guidelines recommend against treatment received an ESA or transfusion. For 837 patients (34%), the guidelines did not provide a definitive recommendation and 242 (29%) of such patients received an ESA or transfusion. Conclusions: Baseline assessment found that many patients did not receive treatment consistent with anemia guidelines. This study will evaluate whether a year long educational intervention can improve clinician adherence to guideline recommendations, thereby improving patient outcomes. No significant financial relationships to disclose.
Phylostratigraphic Profiles in Zebrafish Uncover Chordate Origins of the Vertebrate Brain
Authors: Martin Sebastijan Šestak, Tomislav Domazet-Lošo
Journal: Molecular Biology and Evolution (2014)

An elaborated tripartite brain is considered one of the important innovations of vertebrates. Other extant chordate groups have a more basic brain organization. For instance, cephalochordates possess a relatively simple brain possibly homologous to the vertebrate forebrain and hindbrain, whereas tunicates display the tripartite organization, but without the specialized brain centers. The difference in anatomical complexity is even more pronounced if one compares chordates with other deuterostomes that have only a diffuse nerve net or alternatively a rather simple central nervous system. To gain a new perspective on the evolutionary roots of the complex vertebrate brain, we made here a phylostratigraphic analysis of gene expression patterns in the developing zebrafish (Danio rerio). The recovered adaptive landscape revealed three important periods in the evolutionary history of the zebrafish brain. The oldest period corresponds to preadaptive events in the first metazoans and the emergence of the nervous system at the metazoan–eumetazoan transition. The origin of chordates marks the next phase, where we found the overall strongest adaptive imprint in almost all analyzed brain regions. This finding supports the idea that the vertebrate brain evolved independently of the brains within the protostome lineage. Finally, at the origin of vertebrates we detected a pronounced signal coming from the dorsal telencephalon, in agreement with classical theories that consider this part of the cerebrum a genuine vertebrate innovation. Taken together, these results reveal a stepwise adaptive history of the vertebrate brain where most of its extant organization was already present in the chordate ancestor.
Doxorubicin induced cardiotoxicity in adult Indian patients on chemotherapy
Authors: N. Khattry, S. Varma, P. Malhotra, A. Grover, S. Sharma
Journal: Journal of Clinical Oncology (2005)

2123 Objective: To study the incidence of anthracycline induced cardiotoxicity by serial resting echocardiography in patients on chemotherapy. Material and Methods: Thirty patients aged more than 15 years who were started on doxorubicin based chemotherapy for hematological or solid malignancies and completed at least 300mg/m2 cumulative dose were taken in the study. All patients were evaluated with a detailed medical history, physical examination, hemogram, renal and liver function tests at baseline and at follow up. Electrocardiography (ECG), chests X-ray and echocardiography to measure left ventricular ejection fraction (LVEF) were done at baseline, at 300 mg/m2 and at 450mg/m2 cumulative doses of doxorubicin. Subclinical cardiac dysfunction was defined as LVEF fall greater than 10% during follow-up echocardiography. Results: Cardiac dysfunction was seen in 9 patients (30%) on follow-up. One patient (3%) developed congestive cardiac failure while 8 patients (27%) developed subclinical cardiac dysfunction. By using multiple logistic regression analysis cardiac dysfunction was related with concomitant use of chemotherapy with cyclophosphamide (r=3.22, p=.048), while low BMI and associated cardiac disease showed a trend towards increased incidence of cardiac dysfunction but did not reach statistically significant levels (p=.07 for both). Conclusion: The incidence of subclinical cardiac dysfunction was high with doxorubicin in the cumulative dose range of 300–450 mg/m2, though the incidence of congestive heart failure is low. Combination chemotherapy with cyclophosphamide was associated with higher incidence of cardiotoxicity. No significant financial relationships to disclose.
Partnership between healthcare staff and carers on wards
Authors: Caroline Nicholson, Jill Maben, Emma Ream
Journal: BMJ (2015)

Jennings and Oliver’s correspondence illuminates tensions inherent in carer involvement in secondary care.1 2 The knowledge and experience of carers provides essential continuity of care, yet for some carers, admission provides a welcome and much needed break.

The active involvement of carers requires both them and hospital staff—with differentiated expertise and expectations—to understand, appreciate, and work together for the best interests of patients. Sounds simple, but …
Phase II trial of sagopilone (ZK-EPO), a novel synthetic epothilone, with significant activity in metastatic melanoma
Authors: A. Daud, J. Weber, P. Urbas, S. Andrews, N. Maker, V. K. Sondak, R. C. DeConti
Journal: Journal of Clinical Oncology (2009)

9031 Background: Sagopilone (ZK-Epothilone) is a novel, fully synthetic epothilone with promising preclinical activity in several cancer models. This phase II study aims to define the efficacy and safety of sagopilone in patients with metastatic melanoma, as well as perform pharmacokinetic evaluation of this dose and schedule. Methods: Patients with unresectable stage III or IV malignant melanoma, with up to 2 prior chemotherapy and any prior immunotherapy regimens with measurable disease were eligible. Sagopilone was administered at 16 mg/m2 as a 3-hour IV infusion every 21 days. The primary end point of the trial was response rate, and secondary endpoints included time to progression, overall survival, and tolerability. Pharmacokinetic analysis was done on the first 10 patients. A total of 37 patients were to be accrued to have 33 evaluable patients. The trial had a 0.90 power and assumed α of 0.03. Results: Thirty four patients have been enrolled to date. Sagopilone appears to be well tolerated: The most common side effects seen have been sensory neuropathy, (55%, 19/34, 5 Grade 2, 14Grade 1) motor neuropathy (23%, 8/34, All Grade 1); anemia (26 %, 9/34) neutropenia (14%, 5/34 1 Grade 2, 4 Grade 1) thrombocytopenia (14%, 5/34) and fatigue (38%, 13/34). Two patients have shown grade 3 events (syncope and mental status changes, respectively, possibly related to therapy), both of which resolved and an additional patient had a pulmonary embolism which was considered unlikely to be related to therapy. Responses have been seen in 4 patients (3 RECIST confirmed PR, 1 unconfirmed PR). Stable disease was seen for at least 12 weeks in an additional 10 patients for a clinical benefit rate (CR+PR+SD) of 44%. No grade 4 events have been reported. Conclusions: Unlike the epothilone analogs patupilone or ixabepilone, sagopilone appears to be an active drug in advanced melanoma. The side effect profile seen to date at 16 mg/m2 given over 3 hours repeated every 3 weeks appears to be notably free of myelosuppression indicating that it could be combined with other drugs active in melanoma. Pharmacokinetic studies show a prolonged terminal half life, probably due to release from deep tissue compartments. [Table: see text]
Phase 1 study of combination rituximab with apolizumab in relapsed/refractory B-cell lymphoma and chronic lymphocytic leukemia
Authors: K. Dunleavy, T. White, N. Grant, M. Shovlin, M. Stetler-Stevenson, S. Pittaluga, E. S. Jaffe, G. Marti, J. Janik, W. H. Wilson
Journal: Journal of Clinical Oncology (2005)

6607 Background: Apolizumab (Apo), a humanized IgG1 mAb, targets ID10, and rituximab (R), a chimeric IgG1 mAb, targets CD20, both of which are expressed on normal and malignant B-cells. These mAb's may induce apoptosis through direct signaling, ADCC and/or CDC, and in vitro studies suggest additive effects in B-cell lymphomas. Methods: We undertook a phase 1 study of R at 375 mg/m2 followed by Apo at 4 dose levels (0.5; 1.5; 3 and 5 mg/kg) on days 1–2 for 4 weekly doses. Due to DLT, the administration sequence of Apo and R was reversed during the study and re-escalation of Apo commenced. Cycles were repeated q3 months for up to 3 cycles in stable or responding pts. 3–10 pts were enrolled at each dose level and MTD was defined as 0–1 DLT in 6 pts. Results: Of 64 pts screened for ID10 expression, 49 (77%) were positive; FL 17/23 (74%); CLL/SLL 17/20 (85%); MCL 8/10 (80%); DLBCL 4/5 (80%) and other B-cell lymphomas 3/5 (60%). Characteristics of 29 enrolled pts include median (range) age 62 (28–76) and male sex 22 (76%). The median (range) prior chemotherapy regimens was 2 (1–9), and 22 (76%) pts had received R. Histologies include CLL/SLL in 10 (34%), FL in 9 (31%), MCL in 4 (14%), DLBCL in 4 (14%) and other B-cell lymphomas in 2 (7%) pts. There were 3, 10, 9 and 8 pts treated at dose levels 1, 2, 3 and 4, respectively. Pts received a median (range) of 4 (range 1–12) doses. DLT included hemolytic uremic syndrome (HUS) at dose levels 3 and 4 and grade 3 arterial thrombosis at dose level 2. ID10 was found on endothelial cells in some pts and may be implicated in HUS. Because Apo alone had not been reported to cause HUS, the last 7 pts were treated with Apo on day 1 and R on day 2. No further HUS has occurred. Of 24 evaluable pts, RR is 42% with 5 (21%) CR/CR(u)s and 5 (21%) PRs. In the 5 CRs, 4 pts had FL, 1 pt had CLL/SLL, and 3 pts (60%) had received prior R. Conclusions: Apo and R may induce endothelial injury through up-regulation of HLA-DR4. The RR and CR rates suggest this combination may be more effective than R alone. Accrual continues. No significant financial relationships to disclose.
A multicenter phase II study of pemetrexed and cisplatin in patients with advanced gastric cancer (AGC)
Authors: Y. Bang, Y. Kim, H. C. Chung, W. Kang, S. Park, S. Yang, H. Park, C. Kim, B. Park, J. C. Otero
Journal: Journal of Clinical Oncology (2006)

14008 Background: Pemetrexed is a novel folate antimetabolite, and it inhibits a number of folate-dependent enzymes. This agent has demonstrated activity in a variety of tumor types including AGC. This study was performed to evaluate the combination of pemetrexed and cisplatin in the treatment of AGC. The primary endpoint was response rate, and secondary endpoints were duration of response, time to progressive disease, time to treatment failure, overall survival, and toxicity. Methods: Patients with stage IV AGC not to be amendable to curative surgery and measurable disease were eligible. Pemetrexed 500 mg/m 2 and cisplatin 75 mg/m 2 were given on day 1, every 21 days. Treatment was supplemented with folic acid, vitamin B 12 , and dexamethasone. Response was assessed by RECIST, and toxicity was assessed by NCI-CTC v 2.0. Results: From October 2003 to September 2004, 51 patients were enrolled, but 1 did not meet the eligibility criteria. There were 37 men and 13 women with a median age of 56 years (range, 24–69) and an ECOG PS 0/1 for 14/36 patients; all had metastatic disease. Of 50 evaluable patients, there were no complete responses, and 13 had confirmed partial responses (26%; 95% CI, 14.6%-40.3%). Fifteen patients (30%) had stable disease, and 21 (42%) progressed, and 1 (2%) was unknown. Among 13 responders, the median durarion of response was 3.60 months (95% CI, 2.80–9.40). Median time to progressive disease was 2.8 months (95% CI, 2.20–4.40), and median overall survival was 6.6 months (95% CI, 4.80–10.40). The median time to treatment failure was 2.10 months (95% CI, 1.00–2.80). Survival estimates were 32.0% at 3 months and 7.0% at 6 months. A total of 212 cycles were administered to 51 patients (median 4 [range, 1–13]). Based on 51 patients, most common grade 3/4 hematologic toxicities were neutropenia (49.0%), leukopenia (19.7%), and anemia (13.7%); the most common grade 3/4 nonhematologic toxicities were hyponatremia (15.7%), anorexia (9.8%), nausea (7.8%), and vomiting (7.8%). Conclusions: : The combination of pemetrexed and cisplatin in the current dose and schedule has a modest activity and a mild toxicity profile in patients with AGC. Further study is warranted using a different dose and treatment schedule. [Table: see text]
Effect of Notch inhibition on radiation in an explant model of glioblastoma multiforme
Authors: K. E. Hovinga, R. Wang, F. Shimizu, H. Moayedparadazi, J. Menon, A. Correia, T. Major, V. Tabar
Journal: Journal of Clinical Oncology (2009)

e22080 Background: Glioblastoma Multiforme (GBM) is highly radioresistant, possibly due to a subpopulation of Brain Tumor “Stem-like‘ Cells (BTSC) capable of repopulating the tumor. The Notch signaling pathway is essential for maintaining normal neural stem cells. We asked whether Notch inhibition can overcome radioresistance by allowing BTSCs to exit their stem cell state. Methods: To maintain the BTSCs in their original niche we used an organotypic culture method (explants). GBM explants are cultured on a semiporous membrane in an air-medium interface. They are treated with the Notch inhibitor DAPT, radiation or a combination thereof. Proliferation and neurosphere forming capacity are assessed. Results: The explant model faithfully maintained the cytoarchitecture of the tumor (preservation of blood vessels and pericytes) and its high proliferation rate (%ki67+ cells: 14.3% -17.1%). The effect of DAPT or radiation treatment alone differed among tumors (from no change to a two-fold and nine-fold decrease post DAPT or radiation respectively). However, in all tumors tested the combination of DAPT and radiation dramatically decreased the proliferation rate compared to either treatment alone (%ki67 + cells: 0.19%-2.24%). Interestingly the rate of neurosphere formation was highest following radiation alone (threefold increase). Neurosphere formation after DAPT treatment differed amongst the tumors from a decrease (fourfold) to an increase (twofold). The combination treatment resulted in a modest increase over control (twofold). Conclusions: Our data demonstrates that inhibition of proliferation does not correlate with the status of neurosphere forming ability, arguably a surrogate for cancer stem cell function. Combining radiation with notch inhibition has a profound effect on GBM proliferation, most likely due to selectively inhibiting the BTSC repopulating ability. Ongoing studies will determine the impact of this approach on tumor growth and progression in in vivo tumor models. No significant financial relationships to disclose.
Dose-response relationship of epirubicin-based first-line chemotherapy for advanced breast cancer: a prospective randomized trial.
Authors: C Focan, J M Andrien, M T Closon, M Dicato, P Driesschaert, D Focan-Henrard, M Lemaire, J P Lobelle, L Longree, F Ries
Journal: Journal of Clinical Oncology (1993)

PURPOSE We compared prospectively the antitumor efficacy of two combination chemotherapy regimens with two different dose levels of epirubicin as first-line treatment for advanced breast cancer. PATIENTS AND METHODS One hundred forty-one fully assessable patients were randomized to receive either our intensified schedule (group A, n = 71) of epirubicin 50 mg/m2 on days 1 and 8 (every 3 weeks), or a non-intensified program (group B, n = 70) in which epirubicin was only administered on day 1. Both groups also received fluorouracil (5 FU) and cyclophosphamide 500 mg/m2 on day 1 of each course. RESULTS A statistically significant difference in response rate was observed (69% in group A v 41% in group B, P &lt; .001) for both locally advanced (LA) and recurrent metastatic (RM) disease. Response duration (22 v 14 months, P &lt; .01) and time to progression (TTP; 19 v 8 months, P &lt; .02) were also significantly improved. Overall survival was similar in both groups. However, univariate and/or multivariate analyses showed a meaningful relationship between type of treatment allocated, dose-intensity (DI) of epirubicin, and response rate, as well as between TTP and survival. Ultimately, TTP and survival were also influenced by further treatment modalities, namely, hormonotherapy and chemotherapy. CONCLUSION This study validates prospectively the concept of a dose-response relationship for an anthracycline-based chemotherapy in previously untreated advanced breast cancer.
Abstract 19753: Hdl Cholesterol Efflux Capacity is Inversely Associated With Incident Chd Events Independent of Hdl-c and Apoa-i Concentrations
Authors: Danish Saleheen, Robert Scott, Sunda Javad, Wei Zhao, Amrith Rodrigues, Antonino Picataggi, Daniya Lukmanova, Megan Mucksavage, Robert Luben, Kay-Tee Khaw, Jeffery Billheimer, Nick Wareham, Daniel J Rader
Journal: Circulation (2014)

Background: Although plasma HDL-C levels are strongly associated with risk of coronary heart disease (CHD), interventions that raise HDL-C have not been shown to reduce CHD risk. A prototypical measure of HDL function, namely HDL cholesterol efflux capacity, has been shown to be associated with prevalent CHD even after adjusting for HDL-C, but its association with incident CHD events remains uncertain. Methods: We measured HDL cholesterol efflux capacity and assessed its relationship to incident CHD events in a nested case control sample within a prospective study (EPIC-Norfolk) of 25,639 individuals aged 40-79 years examined in 1993-1997 and followed up to 2009. We quantified efflux capacity in 1895 incident CHD cases and 2474 control participants free of any cardiovascular disorders, by using a validated ex-vivo radiotracer assay that involved incubation of J774 macrophages with apoB-depleted serum from the study participants. Results: HDL cholesterol efflux capacity was positively correlated with HDL-C levels (r2=0.27; P-value&lt;5x10-5) and apoA-I (r2=0.24;P-value&lt; 5x10-5). In analyses comparing top versus bottom third, cholesterol efflux capacity was significantly inversely associated with incident CHD, independent of age, sex, diabetes, hypertension, smoking and alcohol use, waist-to-hip ratio, BMI, LDL-C levels and even after controlling for HDL-C or apoA-I (OR: 0.75 [0.53, 0.97];P-value:9.1x10-3) (Figure). Conclusions: HDL cholesterol efflux capacity is significantly and inversely associated with incident CHD events, independent of established vascular risk factors and after adjusting for HDL-C and apoA-I levels.
A phase I, open-label study of lapatinib (GW572016) plus trastuzumab; a clinically active regimen
Authors: A. M. Storniolo, H. Burris, M. Pegram, B. Overmoyer, K. Miller, S. Jones, P. Silverman, E. Paul, J. Loftiss, L. Pandite
Journal: Journal of Clinical Oncology (2005)

559 Background: Lapatinib is a selective and highly potent dual, competitive inhibitor of ErbB1 and ErbB2 tyrosine kinases leading to cell growth arrest and/or apoptosis in ErbB1 and ErbB2 dependent tumor cell lines and xenografts. Combining two ErbB2-targeted therapies, e.g., anti-ErbB2 antibody with small molecule tyrosine kinase inhibitor, that act at different sites of the receptor with distinct mechanisms of action, may enhance the efficacy of both drugs. Methods: Patients (pts) with metastatic breast cancer that overexpress the ErbB2 protein 2+ or 3+ were enrolled at escalating dose levels of lapatinib (750 - 1500 mg/d) in combination with weekly, standard dosing of trastuzumab (4 mg/kg loading dose followed by weekly 2 mg/kg infusions). Three pts were treated at each dose level, with expansion to 6 in the event of dose-limiting toxicity (DLT). Gr 1 - 3 diarrhea, anorexia, fatigue and rash were the common toxicities. Assessments of clinical response per RECIST criteria were performed every 8 weeks. Cardiac assessments included left ventricular ejection fraction, and 12-lead electrocardiogram at week 4, 8 and then every 8 weeks. Results: 48 pts were treated (750 mg -3; 1000 mg - 32 expanded cohort of 10 + 22 PK pts; 1250 mg - 10 expanded cohort, 1500 mg - 3). Median age was 54 years (28 - 81). Total of 152 treatment periods (4 weeks = 1 treatment period) were completed: median 2. Twenty-seven pts were evaluable for response: (1 CR, duration 8 mo.; 5 PR, duration 2 - 7 months; 10 SD, duration 1 - 5 mo. and 11 PD). Conclusions: 1000 mg lapatinib + standard dose trastuzumab was chosen as the optimally tolerated regimen due to a favorable tolerability profile with chronic dosing and evidence of clinical activity. The combination demonstrated encouraging clinical activity in this heavily pretreated population. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline GlaxoSmithKline