tbuckley/cabot-search huggingface dataset:
Abstract 20347: Does Electrophysiological Toxicity Limit the Therapeutic Window of Serca2a Gene Therapy?
Authors: Chaoqin Xie, Jun Hu, Dongtak Jeong, Erik Kohlbrenner, Roger J Hajjar, Fadi G Akar
Journal: Circulation (2014)

Rescue of SERCA2a expression by gene transfer to the endstage failing heart improves its mechanical and electrophysiological (EP) function. However the safety profile of SERCA2a gene therapy as a preventive measure in patients at early stages of remodeling prior to SERCA2a downregulation is unknown. Examination of the EP consequences of SERCA2a gene therapy in non-failing hearts is imperative in determining its potential EP toxicity. Hypothesis: SERCA2a upregulation using high titer adeno associated virus type 9 (AAV9) mediated gene transfer to normal rats may promote arrhythmogenic triggers, thereby limiting the therapeutic window for this approach. Methods: Using high resolution optical action potential (AP) imaging, we investigated the EP substrate 6 weeks post gene transfer of 5E11 AAV9.SERCA2a (N=13) or AAV9.GFP (N=6) to normal rats. Arrhythmia susceptibility was determined under conditions that promoted Ca overload by burst pacing &amp; ischemia reperfusion (IR) injury. Results: AAV9.SERCA2a hearts exhibited a 50% increase in SERCA2a expression at the mRNA and protein levels compared to AAV9.GFP. No differences in heart weight to body weight were found between groups (3.85 vs 3.74 mg/g). During baseline perfusion, AAV9.GFP hearts exhibited significantly prolonged (by 30%, p&lt;0.05) AP durations (APD) and a strong trend (p=0.07) towards greater APD heterogeneity. Challenge with rapid pacing resulted in the onset of sustained VF in 4/6 AAV9.GFP and 0/13 AAV9.SERCA2a hearts (p=0.004). Despite significant SERCA2a upregulation, APD and conduction velocity were identical in AAV9.SERCA2a compared to normal hearts indicating lack of EP toxicity. During prolonged low flow ischemia, AAV9.SERCA2a hearts exhibited a trend towards higher incidence of arrhythmias compared to normal hearts, but differences were not statistically significant (p=0.08). Finally, all AAV9.SERCA2a hearts exhibited rapid recovery of APD and excitability upon reperfusion following 10 min of no flow ischemia. Conclusions: High titer gene transfer of AAV9.GFP but not AAV9.SERCA2a elicits adverse EP remodeling in normal rat myocardium. The lack of an EP phenotype of AAV9.SERCA2a despite 50% upregulation in SERCA2a levels is consistent with a wide safety margin for this therapy.
Phase II study of AC (doxorubicin and cyclophosphamide) followed by weekly paclitaxel as neoadjuvant chemotherapy in operable patients with primary breast cancer
Authors: S. Iwase, D. Yamamoto, K. Kitamura, H. Odagiri, S. Teramoto, S. Ohtani, T. Doi, K. Kinebuchi, Y. Kuroda, Y. Nagumo
Journal: Journal of Clinical Oncology (2009)

e11587 Background: The objective of this multi center Phase II clinical study prove the benefit of neoadjuvant combination therapy using anthracycline based AC therapy (doxorubicin and cyclophosphamide), which is useful as a standard therapy, followed by weekly PTX(paclitaxel) in patients with early stage breast cancer. Methods: Forty-seven patients with operable breast cancer were enrolled to the study. Patients received four cycles of AC followed by weekly PTX. The primary endpoint was disease free survival (DFS) stratified by the absence of presence of Quasi-pCR (QpCR: absence of invasive tumor or only focal residual tumor cells). Secondary endpoints were predictors for QpCR, clinical response, breast conservation rate, and safety. The planned sample size was 25. Results: Of 43 assessable patients, 25.6% achieved QpCR. With 28.6 months median follow-up, DFS was estimated at 72% for all patients. 3 year DFS for patients with QpCR was 80% vs. 72% without QpCR. HER2 status and response to AC were independent predictors of QpCR. The overall clinical response was 79%; 58% of patients achieved breast conservation. Nausea was the most common adverse event, observed in 62.8% and 33.3% of patients during AC and PTX respectively. The second common adverse event was peripheral neuritis, observed in 9.3% and 57.1% of patients during AC and PTX respectively. Conclusions: Despite the small sample size, these data shows that AC followed PTX is a highly active neoadjuvant therapy for women with early stage breast cancer. No significant financial relationships to disclose.
Targeted immunotherapy for Epstein-Barr virus: Positive central nervous system lymphoma in immunosuppressed patients.
Authors: P. Z. New, C. M. Bollard
Journal: Journal of Clinical Oncology (2010)

e12529 Background: The occurrence of central nervous system (CNS) lymphoma in patients who have been treated with immunosuppressive therapy after organ transplantation or for chronic autoimmune disease, is rare. Most of these tumors are positive for Epstein-Barr virus (EBV). There is no standard therapy for this rare disease. Two patients are presented who developed isolated CNS lymphoma 12 years after renal transplant (Case #1) and 10 years after initiating imunosuppressive treatment for Sjorgren's syndrome (Case #2). They participated in a study specificly for post-transplant lymphocytic disorder (PTLD). Methods: Case #1 is a 56 year old female who underwent kidney transplant in 1990, serology was EBV positive. The kidney failed in 2001 and another transplant was performed. In Aug., 2004, a cervical cord B-cell lymphoma was diagnosed. The lesion was CD-20 positive, LMP1and EBNA 2 positive. Case #2 is a 63 year old female who developed confusion and aphasia in Feb., 2008. She was diagnosed with lt. parietal lymphomatoid granulomatosis. Malignant lymphocytes were CD20/CD30 and CD 68 positive. Prior to treatment, both patients had 40 cc of blood withdrawn. 5–10 x 10-6 peripheral blood monocytes (PBMC) were used for the development of EBV-transformed lymphoblastoid cell lines. EBV specific cytotoxic T lymphocyte (CTL) cultures were then developed. Both patients were treated with high dose methotrexate (8 gms/m-2) with adjustments for creatinine clearance. They also received 4 courses of rituximab. Magnetic Resonance Imaging studies revealed resolution of disease. Two months after completion of chemotherapy the patients received infusions of their CTLs. Results: Both patients remain free of disease at 65 months (Case #1), and 23 months (Case #2). There were no side effects associated with infusion of CTLs. Conclusions: EBV CTLs can be delivered safely to patients with EBV positive lymphomas and offer a form of therapy which can correct an EBV specific immunodeficiency state. This has been shown in a much larger cohort of patients with systemic PTLD. An additional nontoxic form of therapy for post-transplant and immunosuppressed patients with brain lymphoma is important, especially in the elderly. No significant financial relationships to disclose.
Mir-148a and Mir-25 Target TULA-2 and Regulate Human Platelet FcγRIIA Signaling
Authors: Yuhang Zhou, Shaji Abraham, Pierrette Andre, Leonard C. Edelstein, Chad Shaw, Alexander Tsygankov, Satya P. Kunapuli, Paul F Bray, Steven E. McKenzie
Journal: Blood (2014)
Enhanced atheroprotection and lesion remodelling by targeting the foam cell and increasing plasma cholesterol acceptors
Authors: Se-Hee Son, Young-Hwa Goo, Mihyun Choi, Pradip K. Saha, Kazuhiro Oka, Lawrence C. B. Chan, Antoni Paul
Journal: Cardiovascular Research (2015)

Atherosclerosis development can be ameliorated by promoting reverse cholesterol transport (RCT) from arteries. The process involves cholesterol efflux from foam cells to extracellular acceptors such as apolipoprotein A-I (apoA-I) and high-density lipoprotein (HDL) that mediate transport to the liver. Perilipin-2 (PLIN2) is a lipid droplet (LD)-associated protein that in macrophages facilitates cholesterol storage and prevents efflux. We hypothesized that atheroprotection would be enhanced by concurrently targeting PLIN2 to increase the efflux capacity of foam cells and increasing plasma apoA-I and HDL. PLIN2-knockout and wild-type mice lacking apolipoprotein E (PLIN2–/–/apoE–/– and PLIN2+/+/apoE–/–) were treated with a helper-dependent adenoviral vector encoding human apoA-I (HDAd-AI) or with control empty vector. Treatment with HDAd-AI increased hepatic apoA-I production, plasma apoA-I and HDL-cholesterol (HDL-C), and apoA-I deposition in lesions to a similar extent in PLIN2–/–/apoE–/– and PLIN2+/+/apoE–/– mice. However, atherosclerosis development at the aortic sinus was considerably lower in HDAd-AI-treated PLIN2–/–/apoE–/– mice. A more stable lesion phenotype, with increased collagen content, was primarily associated to treatment with HDAd-AI, but was enhanced under PLIN2 deficiency. PLIN2 deficiency and apoA-I cumulatively reduced LDs and cholesterol ester content in cultured macrophages. Neutral lipid in atheroma was significantly reduced in HDAd-AI-treated PLIN2–/–/apoE–/– mice, and RCT from macrophages to feces was enhanced in PLIN2–/– macrophages. These studies demonstrate a mutually beneficial relationship between PLIN2 deficiency and elevated apoA-I/HDL-C in preventing atherosclerosis development. The data support that targeting foam cell components to mobilize cholesterol may be a promising strategy to enhance the atheroprotection of plasma cholesterol acceptors.
Clinical significance of molecular detection of carcinoma cells in lymph nodes and peripheral blood by reverse transcription-polymerase chain reaction in patients with gastrointestinal or breast carcinomas.
Authors: M Mori, K Mimori, H Ueo, K Tsuji, T Shiraishi, G F Barnard, K Sugimachi, T Akiyoshi
Journal: Journal of Clinical Oncology (1998)

PURPOSE This study evaluates the clinical significance of detection of carcinoembryonic antigen (CEA) mRNA in the dissected lymph nodes and peripheral blood samples of patients with gastrointestinal or breast carcinomas. PATIENTS AND METHODS A total of 406 lymph nodes obtained from 65 patients were analyzed by both histologic and molecular examination of CEA-specific reverse transcriptase-polymerase chain reaction (RT-PCR). Peripheral blood samples from another 102 patients were also analyzed by CEA-specific RT-PCR. Patients were followed up prospectively for 24 +/- 12 months. RESULTS Of 406 lymph nodes, the positive detection rate increased from 20% by histologic examination to 60% by RT-PCR examination. The recurrence rate was 40% in 15 cases showing positive results in both examinations, 14% in 29 cases showing histologically negative but RT-PCR positive results, and none in 21 cases showing negative results in both examinations. The positive detection rate for CEA mRNA in peripheral blood samples increased with advancing stage of disease. With respect to 62 curatively operated cases, CEA mRNA was detected in 12 cases. Four of these 12 cases developed metastatic disease after surgery whereas none of 50 cases negative by RT-PCR developed metastasis. CONCLUSION It has been shown that RT-PCR is a powerful tool to detect CEA mRNA in the lymph nodes or the peripheral blood. This is potentially very useful to determine high-risk patients for metastasis. Serial analysis is warranted to assess the long-term significance of this method and its therapeutic and prognostic implications.
Comparison of chlorambucil and prednisone versus cyclophosphamide, vincristine, and prednisone as initial treatment for chronic lymphocytic leukemia: long-term follow-up of an Eastern Cooperative Oncology Group randomized clinical trial.
Authors: B Raphael, J W Andersen, R Silber, M Oken, D Moore, J Bennett, H Bonner, R Hahn, W H Knospe, J Mazza
Journal: Journal of Clinical Oncology (1991)

The Eastern Cooperative Oncology Group (ECOG) conducted a study in which patients with advanced chronic lymphocytic leukemia (CLL) were randomized between a regimen consisting of chlorambucil (30 mg/m2 orally day 1) and prednisone (80 mg orally days 1 to 5) (C + P) administered every 2 weeks and a more intensive regimen of cyclosphosphamide (300 mg/m2 orally days 1 to 5), vincristine (1.4 mg/m2 intravenously [IV] day 1), and prednisone (100 mg/m2 orally days 1 to 5) (CVP) given every 3 weeks. Treatment was continued for up to 18 months to maximal response. Of the 122 eligible patients, 60 received C + P, while 62 received CVP. With a median follow-up of 7 years, there were no significant differences in survival (4.8 v 3.9 years, P = .12), complete remission (CR) rate (25% v 23%; P = .83), or duration of response (2.0 v 1.9 years; P = .78) between C + P and CVP. Toxicity was modest despite the prolonged treatment. The long median survival of 4.1 years for stage III and IV patients is superior to that usually reported. This could stem from continuing treatment to maximal response rather than an increase in intensity of therapy. These results are comparable to those reported with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy by other investigators. The data suggest that intermittent C + P administered to maximal response continues to be the standard treatment approach for advanced CLL.
Abstract 16069: Low-Density Lipoprotein of Systemic Lupus Erythematosus Patients Contains Lysophosphatidylcholine-Rich Lipid That Induces Overexpression of CX3CL1 in Endothelial Cells
Authors: Hua-Chen Chan, Liang-Yin Ke, Hsiu-Chuan Chan, Hung Su, An-Sheng Lee, Jonathan Lu, Wen-Chan Tsai, Tsan-Teng Ou, Cheng-Chin Wu, Chih-Sheng Chu, Jentaie Shiea, Jeng-Hsien Yen, Chu-Huang Chen
Journal: Circulation (2014)

Background: Patients with systemic lupus erythematosus (SLE) are twice more likely to develop cardiovascular disease than the general population, even though their plasma LDL cholesterol (LDL-C) levels are usually not elevated. To delineate the mechanisms, we examined the chemical properties of their LDL. Methods and Results: LDL isolated from SLE patients (LDL-C, 105±33 mg/dL; n=24) exhibited greater mobility in agarose gel electrophoresis than LDL of healthy control subjects (LDL-C, 121±25 mg/dL; n=24), secondary to an increased distribution of L5 (2.30±1.3% vs. 0.7±0.3%; P &lt;0.0001), the most electronegative subfraction of LDL identified by anion-exchange chromatography, in total LDL. CX3CL1 is a membrane-bound chemokine expressed in injured endothelial cells (ECs). CD16 + monocytes are CX3CR1-expressing cells that recognize CX3CL1. Compared with control, SLE patients had a twofold ( P &lt;0.001) increase in CX3CL1 and a threefold ( P &lt;0.0001) increase in CD16 + monocytes in the plasma. Moreover, there was a positive correlation between the CX3CL1 and L5 levels (R=0.45; P &lt;0.018). MALDI/TOF mass spectrometry of the lipid extracted from SLE-LDL revealed a shift from phosphatidylcholines (PCs) to lyso-PCs (LPCs), including m/ z 496.33, 524.36, 537.01, 550.94, when compared with the lipid of control LDL (Figure). The shift was especially prominent in L5. Exposing human aortic ECs to L5 but not normal LDL resulted in a fivefold ( P &lt;0.0001) increase in CX3CL1 expression with concomitant apoptosis. These effects of L5 were significantly attenuated by blocking the platelet-activating receptor, confirming the role of phospholipids in L5’s bioactivity. Conclusions: The increased distribution of LPC-rich electronegative LDL, which induces CX3CL1-CX3CR1 interactions between vascular cells, may contribute to the increased cardiovascular disease prevalence in SLE in the absence of LDL-C elevation.
Prospective Evaluation of Cancer Clinical Trial Accrual Patterns: Identifying Potential Barriers to Enrollment
Authors: Primo N. Lara, Roger Higdon, Nelson Lim, Karen Kwan, Michael Tanaka, Derick H.M. Lau, Ted Wun, Jeanna Welborn, Frederick J. Meyers, Scott Christensen, Robert O’Donnell, Carol Richman, Sidney A. Scudder, Joseph Tuscano, David R. Gandara, Kit S. Lam
Journal: Journal of Clinical Oncology (2001)

PURPOSE: Well-conducted cancer clinical trials are essential for improving patient outcomes. Unfortunately, only 3% of new cancer patients participate in clinical trials. Barriers to patient accrual in cancer clinical trials must be identified and overcome to increase patient participation. MATERIALS AND METHODS: We prospectively tracked factors that potentially affected patient accrual into cancer clinical trials at the University of California Davis Cancer Center. Oncologists seeing new outpatients were asked to complete questionnaires regarding patient characteristics and the physician’s decision-making on patient eligibility, protocol availability, and patient opinions on participation. Statistical analysis was performed to correlate these parameters with subsequent protocol accrual. RESULTS: There were 276 assessable patients. At the initial visits, physicians did not consider clinical trials in 38% (105/276) of patients principally because of a perception of protocol unavailability and poor performance status. Physicians considered 62% (171/276) of patients for participation in clinical trials. Of these, only 53% (91/171) had an appropriate protocol available for site and stage of disease. Seventy-six of 90 patients (84%) with available protocols met eligibility criteria for a particular study. Only 39 of 76 patients (51%) agreed to participate in cancer clinical trials, for an overall accrual rate of 14% (39/276). The remainder (37/76, 49%) declined trial participation despite meeting eligibility criteria. The most common reasons were a desire for other treatment (34%), distance from the cancer center (13%), patient refusal to disclose reason (11%), and insurance denial (8%). Patients with private insurance were less likely to enroll in clinical trials compared to those with government-funded insurance (OR, 0.34; P = .03; 95% CI, 0.13 to 0.9). CONCLUSION: Barriers to cancer clinical trial accrual can be prospectively identified and addressed in the development and conduct of future studies, which may potentially lead to more robust clinical trials enrollment. Investigation of patient perceptions regarding the clinical trials process and the role of third party–payers is warranted.
Coronary CT Angiography for Suspected ACS in the Era of High-Sensitivity Troponins
Authors: Admir Dedic, Marisa M. Lubbers, Jeroen Schaap, Jeronymus Lammers, Evert J. Lamfers, Benno J. Rensing, Richard L. Braam, Hendrik M. Nathoe, Johannes C. Post, Tim Nielen, Driek Beelen, Marie-Claire le Cocq d’Armandville, Pleunie P.M. Rood, Carl J. Schultz, Adriaan Moelker, Mohamed Ouhlous, Eric Boersma, Koen Nieman
Journal: Journal of the American College of Cardiology (2016)
Phase 3, randomized, placebo-controlled trial of orteronel (TAK-700) plus prednisone in patients (pts) with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) (ELM-PC 4 trial)
Authors: Ronald De Wit, Karim Fizazi, Viorel Jinga, Eleni Efstathiou, Peter C.C. Fong, Manfred Wirth, Kazuhiro Suzuki, Susan Moran, Ling Wang, Hideyuki Akaza, Joel Nelson, Howard I. Scher, Robert Dreicer, Niels Geert Borgstein, Fred Saad
Journal: Journal of Clinical Oncology (2014)

5008 Background: Orteronel, an investigational, non-steroidal, selective 17,20-lyase inhibitor, demonstrated improved radiographic PFS (rPFS) but not OS in men with mCRPC post-docetaxel (Dreicer et al, ASCO GU 2014, Abstract 7). The double-blind ELM-PC 4 trial (NCT01193244) evaluated orteronel in pts with chemotherapy-naïve mCRPC. Methods: Men with progressive mCRPC (rising PSA and/or radiographic evidence) and testosterone < 50 ng/dL (post-orchiectomy or with maintained GnRH suppression) were randomized 1:1 to orteronel 400 mg twice daily (BID) + prednisone 5 mg BID (O+P) or placebo + prednisone (P), stratified by region and radiographic progressive disease at baseline. Co-primary endpoints were OS and rPFS. Based on 90% power to test OS (> 90% for rPFS), an initial HR of 1.25 in favor of orteronel was anticipated with 1454 pts and 900 deaths (pre-assigned alpha: OS 0.045, rPFS 0.005). The final analysis for rPFS was conducted at an interim analysis (IA) for OS; the final analysis for OS was conducted at 600 deaths, with 78% power. Results: 1560 pts were randomized. The study met the co-primary endpoint of rPFS; at the IA (final for rPFS), median rPFS with O+P v P was 11 v 8.3 months (HR 0.7; 95% CI: 0.5–0.8; P < .001). At the final analysis for OS the updated median rPFS benefit with O+P v P had increased to 5.1 months (median 13.8 v 8.7 mo; HR 0.7; 95% CI: 0.6–0.8; P < .00001). The co-primary endpoint of OS was not met. Median OS with O+P v P was 31.4 v 29.5 months (HR 0.9; 95% CI: 0.8–1.1; P = .314), with no notable differences across regions. More pts had a ≥ 50% PSA decrease (43% v 25%, P < .00001) and a favorable circulating tumor cell count (15% v 9%, P = .00016) at 12 weeks with O+P v P. Common all-grade adverse events with O+P v P included nausea (36% v 15%), fatigue (34% v 20%), constipation (33% v 15%), and diarrhea (28% v 14%); 30% v 18% of pts discontinued due to AEs. In O+P v P groups, 45% v 51% of pts received subsequent therapy, including docetaxel/abiraterone/enzalutamide in 31%/14%/6% v33%/20%/6%. Conclusion: O+P demonstrated a significant improvement in rPFS but no statistically significant improvement in OS v P in chemotherapy-naive mCRPC. Clinical trial information: NCT01193244.
Abstract 12280: Endothelial Cell Inflammation and Antioxidant Capacity are Associated With Exercise Performance and Microcirculation in Patients With Peripheral Artery Disease
Authors: Andrew W Gardner, Donald E Parker, Polly S Montgomery, Danuta Sosnowska, Ana I Casanegra, Zoltan Ungvari, Anna Csiszar, William E Sonntag
Journal: Circulation (2014)

Background: We determined whether exercise performance and lower extremity microcirculation were associated with endothelial cell inflammation, oxidative stress, and apoptosis, and with circulating biomarkers of inflammation and antioxidant capacity. Methods: One hundred sixty symptomatic patients with PAD were characterized on the endothelial effects of circulating factors present in the sera using a cell culture-based bioassay on primary human arterial endothelial cells. Patients were further evaluated on circulating inflammatory and vascular biomarkers, physical examination, medical history, exercise performance measured during treadmill evaluation by peak walking time (PWT), and claudication onset time (COT), and lower extremity microcirculation measured by calf muscle hemoglobin oxygen saturation (StO 2 ) during treadmill exercise. Results: In the multivariate regression model for PWT, the significant independent variables included ankle-brachial index (p&lt;0.001), age (p=0.017), hydroxyl radical antioxidant capacity (HORAC) (p=0.008), and endothelial cell NF-κB activity (p=0.015). In the multivariate regression model for COT, the significant independent variable was endothelial cell NF-κB activity (p=0.013). In the multivariate analyses for the average rate of decline in calf muscle StO 2 during exercise, the significant independent variables included body mass index (p&lt;0.001) and HORAC (p=0.024). Conclusions: Endothelial cell inflammation and circulating biomarkers of inflammation and antioxidant capacity are significant factors for exercise performance and microcirculation of the ischemic calf musculature during exercise. The clinical implication is that interventions designed to alleviate endothelial cell inflammation and circulating inflammatory biomarkers, such as antioxidant therapy, may improve exercise performance of symptomatic patients with PAD.