tbuckley/cabot-search huggingface dataset:
Mimotope vaccination for epitope-specific induction of “Herceptin-like” anti-HER-2 antibodies
Authors: A. B. Riemer, M. Klinger, G. Kraml, O. Scheiner, E. Jensen-Jarolim, C. C. Zielinski
Journal: Journal of Clinical Oncology (2005)

2521 Background: Immunizations with the oncogenic protein HER-2 (also known as Her-2/neu or ErbB2) elicit antibodies exerting diverse biological effects: depending upon epitope specificity, tumor growth may be inhibited or enhanced. Trastuzumab (Herceptin) is a growth-inhibitory humanized monoclonal anti-HER-2 antibody, currently used for passive immunotherapy in the treatment of breast cancer. However, antibody therapies are expensive and have to be repeatedly administered for long periods of time. In contrast, active immunizations produce ongoing immune responses. Therefore, the aim of the present study was to generate peptide mimics of the epitope recognized by trastuzumab for vaccine formulation, ensuring the subsequent induction of tumor growth inhibitory antibodies. Methods: We employed the phage display technique to generate epitope mimics - mimotopes - complementing the screening antibody trastuzumab. A computational surface screen of the HER-2 antigen indeed resulted in matching the obtained mimotopes exactly to the trastuzumab binding site. Subsequently, immunogenicity of a selected mimotope was examined in BALB/c mice and rabbits. Results: Immunizations with the synthetic mimotope conjugated to an immunogenic carrier resulted in antibodies recognizing HER-2 in a blotted cell lysate as well as on the cell surface of SK-BR-3 breast cancer cells. Analogous to trastuzumab, the induced antibodies caused internalization of the receptor from the cell surface to endosomal vesicles. Further functional assays included examination of proliferation inhibition, cell cycle arrest and MAP-kinase activity. Antibody-mediated cytotoxicity (ADCC, antibody-dependent cell-mediated cytotoxicity and CDC, complement-dependent cytotoxicity) potential was analyzed as well. Conclusions: Our results indicate that trastuzumab mimotopes are suitable tools for formulation of a functional breast cancer vaccine, as the resulting antibodies show similar biological features as trastuzumab. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration BioLife Science BioLife Science
Use of plasma level of 5-fluorouracil to predict the efficacy in patients with advanced gastric cancer receiving first-line capecitabine plus cisplatin.
Authors: Weifeng Song, Xun Cai, Xiaoyu Li, Liwei Wang
Journal: Journal of Clinical Oncology (2012)

e14508 Background: Capecitabine is an oral 5-Fluorouracil prodrug that provided prolonged high levels of 5-FU within tumor cells and has improved efficacy and tolerability compared with protracted infusion 5-FU. The aim was to assess the value of plasma level of 5-Fluorouracil predicting the efficacy and safety in patients with advanced gastric cancer receiving first-line capecitabine plus cisplatin. Methods: The clinical data from 113 advanced gastric cancer patients receiving capecitabine plus cisplatin in Shanghai first people hospital from September 2006 to December 2009 were retrospectively collected. Fluorouracil plasma concentrations were examined at each cycle. The relationships between Fluorouracil plasma concentration and overall survival, progress free survival, response rate were determined by statistical analysis. Results: The mean plasma concentration was 24.8ug/L. We divided the patients with high mean 5-FU plasma concentration (&gt; 25ug/L) into group A (n=59) and patients with low mean 5-FU plasma concentration (&lt; 25ug/L) into group B (n=54). Median OS was 14.4 months in the group A and 9.6 months in the group B (HR= 0.36, p=0.000). Median PFS was 8 months in the group A and 4.9 months in the group B (HR= 0.37, p=0.000). The objective response rate was 55.9% for group A and 33.3% for group B (p=0.023). COX multivariate analysis showed that high 5-FU plasma concentration was an independent prognostic factors for improved OS (p=0.000) and PFS (p=0.000). All toxicities occurred more frequently in group A than group B. The grade 3/4 mocositis and hand-foot syndrome were significantly increased in group A compared with group B (19% vs 9%, p=0.08; 22% vs 8%, p=0.036). Conclusions: In advanced gastric cancer, high 5-FU plasma concentration might predict efficacy and toxicities for capecitabine plus cisplatin chemotherapy.
Survey of oncology fellows’ end-of-life training
Authors: M. K. Buss, D. S. Lessen, A. M. Sullivan, J. H. von Roenn, R. M. Arnold, S. D. Block
Journal: Journal of Clinical Oncology (2005)

8032 Background: Caring for the dying is a core competency for oncology practice, yet no rigorous assessment of oncology fellowship training in end-of-life (EOL) has been undertaken. We aimed to assess the education, knowledge, and preparation of oncology fellows in EOL care and to compare EOL training with other aspects of fellowship training. Methods: A convenience sample of 120 ASCO 2004 pre-conference attendees responded to a 112-item questionnaire, which assessed fellows’ attitudes, training, experience, knowledge and preparation in key EOL care topics. Results: Respondents were: 51% male; 58% White, 26% Asian; 20% first year, 38% second year and 28% third year fellows. Overall, 20% had completed a hospice or palliative care rotation. Education - EOL v. Overall: Fellows rated EOL education less highly than their general fellowship training (Mean: 2.6 [+/- 1.2] v. 2.4 [+/- 1.0]; p < .001). Fellows viewed attendings as more expert in non-EOL than EOL care, such as, managing spinal cord compression versus managing pain (78% v 54%; p < .001). Of those who had performed them, fellows were more likely to receive feedback on a bone marrow biopsy than on an EOL discussion (73% v 56%; p = .0006). Depression: 96% of fellows felt depression was treatable in the terminally ill; however, only 45% assessed depression in their patient who had most recently died, and 26% reported explicit teaching on depression at the EOL. Pain Management: 94% of fellows felt prepared to manage pain in the dying; 75% assessed pain in their patient who died most recently; 41% were explicitly taught when to rotate opioids; only 30% performed an opioid conversion correctly. Conclusions: Current oncology fellows describe less effective and rigorous training on EOL issues than general oncology issues. Our results suggest that fellows may benefit from improved educational experiences related to EOL care and enhanced attention to the achievement of core competencies. No significant financial relationships to disclose.
Tandem HD-chemotherapy and myeloablative radioimmunotherapy with 131I-anti-CD20 rituximab in relapsed and refractory B-cell lymphoma: Results of a phase II study of the German RAIT Study Group
Authors: K. Hohloch, G. Wulf, W. Jung, E. Stitz, J. Meller, B. Glass, L. Truemper, F. Griesinger
Journal: Journal of Clinical Oncology (2006)

13007 Background: Radioimmunotherapy has been shown to be effective in CD20 + B-cell lymphomas. Both non-myeloablative as well as myeloablative regimens have been employed for low grade and high grade lymphomas with impressive response rates and remission durations. Recently, the Press group and our group published data on myeloablative 131-I-anti-CD20 RAIT with high response rates and favourable long term survival especially in follicular lymphomas and transformed FL. Therefore, a phase II study is currently being done within the German Radioimmunotherapy Group, interim analysis data are presented. Methods: Patients were to receive R-Dexa-BEAM, followed by BEAM and HD-RAIT 2–6 months after BEAM. 131-I-Rituximab was administered with a maximum kidney and lung dose of 25 Gy. Sample size was calculated to be 16 to evaluate toxicity and feasibility of the tandem approach as primary endpoint. Results: 16 pts with relapsed (14) or primary refractory (2) B-cell lymphomas (FLI,II: 4pts; DLBCL: 4pts (all early relapses); transformed FL: 6 pts; MCL:1 pt, marginal zone lymphoma: 1 pt) were treated with 1 (15 pts) or 2 cycles (1 pt) of R-Dexa-BEAM. 13/16 pts achieving PR (5) or CRu (8) were treated with BEAM, 2 pts with PD and 1 with subdural hematoma were drop outs. After BEAM, 9/13 pts were in CR, 3/13 PR, 1/13 PD. Of 12 responding pts, 6 received HD-RAIT (1 pancytopenia, 1 hepatic, 2 pulmonary toxicity, 3 too early). After HD RAIT, 5/6 pts were in CR, 1 in PR. 4/6 pts (3 CR, 1 PR) are alive for 22–31 months, 2 pts died in CR, 1 of interstitial lung disease 2 months after HD-RAIT, 1 pt of pneumonia 8 months after HD-RAIT. Conclusions: Myeloablative RAIT is a feasible and effective treatment modality for relapsed poor prognosis CD20+ B-NHL not having severe toxicity due to the salvage regimen and HD-chemotherapy. HD RAIT offers the potential for long term relapse free survival. Final analysis of toxicity and outcome of this phase II study will be presented at the meeting. No significant financial relationships to disclose.
Guided bone regeneration is promoted by the molecular events in the membrane compartment
Authors: Alberto Turri, Ibrahim Elgali, Forugh Vazirisani, Anna Johansson, Lena Emanuelsson, Christer Dahlin, Peter Thomsen, Omar Omar
Journal: Biomaterials (2016)

The working hypothesis of guided bone regeneration (GBR) is that the membrane physically excludes non-osteogenic tissues from interfering with bone healing. However, the underlying mechanisms are insufficiently explained. This study aimed to investigate the molecular and structural pattern of bone healing in trabecular bone defects, with and without naturally derived resorbable membrane. Defects were created in rat femurs and treated with the membrane or left empty (sham). After 3d, 6d and 28d, the defect sites and membranes were harvested and analyzed with histology, histomorphometry, quantitative-polymerase chain reaction (qPCR), Western blot (WB) and immunohistochemistry (IHC). Histomorphometry demonstrated that the presence of the membrane promoted bone formation in early and late periods. This was in parallel with upregulation of cell recruitment and coupled bone remodeling genes in the defect. Cells recruited into the membrane expressed signals for bone regeneration (BMP-2, FGF-2, TGF-β1 and VEGF). Whereas the native membrane contained FGF-2 but not BMP-2, an accumulation of FGF-2 and BMP-2 proteins and immunoreactive cells were demonstrated by WB and IHC in the in vivo implanted membrane. The results provide cellular and molecular evidence suggesting a novel role for the membrane during GBR, by acting as a bioactive compartment rather than a passive barrier.
Clinical relevance of the use of FDG PET/CT in locally advanced breast cancer.
Authors: Marie-Jeanne TFD Vrancken Peeters, Bas Koolen, Emiel J. Rutgers, Sjoerd Rodenhuis, Renato O. Valdés Olmos
Journal: Journal of Clinical Oncology (2012)

195 Background: As opposed to patients with early-stage breast cancer who are in general treated with primary surgery, patients with locally advanced tumors are usually treated with neoadjuvant chemotherapy (NAC). Optimal locoregional treatment after NAC starts with optimal staging before the start of NAC. Methods: Patients with stage II-III breast cancer underwent an FDG PET/CT of the thorax in prone position with hanging breasts. A panel of experienced reviewers blindly interpreted PET/CT images. Results: In 154 patients the FDG PET/CT was compared with conventional staging procedures (bone scintigraphy, ultrasound of the liver and chest radiography). We have shown that PET/CT has a higher sensitivity for the detection of distant metastases as no metastases were missed with the PET/CT and in 16 (80%) of 20 patients with proven metastases, one or more lesions were exclusively found with PET/CT. This resulted in a change of treatment in 13 (8%) of 154 patients. Furthermore we have shown that the FDG PET/CT offers a non-invasive procedure for the assessment of number of tumor-positive axillary nodes prior to NAC, enabling guidance for postoperative radiotherapy planning. In 311 patients a PET/Ct scan was performed prior to the start of NAC for this purpose. A substantial proportion of patients (16%) has been upstaged because of the detection of occult lymph node metastases in the internal mammary chain and periclavicular region, changing treatment in the majority of them. Conclusions: Based on these results we recommend performing an FDG PET/CT as a standard diagnostic procedure in stage II and III breast cancer patients prior to NAC. Current research regarding the use of PET/CT in breast cancer focuses on monitoring the response of the primary tumor and axillary node metastases to NAC in order to optimize locoregional treatment after NAC according to the tumor response.
Screening for Breast Cancer: U.S. Preventive Services Task Force Recommendation Statement
Authors: Albert L. Siu
Journal: Annals of Internal Medicine (2016)

Description: Update of the 2009 U.S. Preventive Services Task Force (USPSTF) recommendation on screening for breast cancer. Methods: The USPSTF reviewed the evidence on the following: effectiveness of breast cancer screening in reducing breast cancer–specific and all-cause mortality, as well as the incidence of advanced breast cancer and treatment-related morbidity; harms of breast cancer screening; test performance characteristics of digital breast tomosynthesis as a primary screening strategy; and adjunctive screening in women with increased breast density. In addition, the USPSTF reviewed comparative decision models on optimal starting and stopping ages and intervals for screening mammography; how breast density, breast cancer risk, and comorbidity level affect the balance of benefit and harms of screening mammography; and the number of radiation-induced breast cancer cases and deaths associated with different screening mammography strategies over the course of a woman's lifetime. Population: This recommendation applies to asymptomatic women aged 40 years or older who do not have preexisting breast cancer or a previously diagnosed high-risk breast lesion and who are not at high risk for breast cancer because of a known underlying genetic mutation (such as a BRCA1 or BRCA2 gene mutation or other familial breast cancer syndrome) or a history of chest radiation at a young age. Recommendations: The USPSTF recommends biennial screening mammography for women aged 50 to 74 years. (B recommendation) The decision to start screening mammography in women prior to age 50 years should be an individual one. Women who place a higher value on the potential benefit than the potential harms may choose to begin biennial screening between the ages of 40 and 49 years. (C recommendation) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening mammography in women aged 75 years or older. (I statement) The USPSTF concludes that the current evidence is insufficient to assess the benefits and harms of digital breast tomosynthesis (DBT) as a primary screening method for breast cancer. (I statement) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of adjunctive screening for breast cancer using breast ultrasonography, magnetic resonance imaging (MRI), DBT, or other methods in women identified to have dense breasts on an otherwise negative screening mammogram. (I statement)
Abstract P273: Influence of Fatigue and Depressive Symptoms on Physical Functioning 30-Days after Treatment for Stable Coronary Artery Disease
Authors: Michelle M Fennessy, Holli DeVon, Catherine Ryan, Julie J Zerwic
Journal: Circulation (2012)

Fatigue and depressive symptoms are pervasive in patients with coronary heart disease. It is unknown how these symptoms impact physical functioning and secondary prevention efforts in patients with stable coronary artery disease (SCAD) who are treated with either percutaneous coronary intervention (PCI) and optimal medical therapy (OMT) or OMT alone. The purpose of this study was to evaluate the influence of fatigue and depressive symptoms on physical functioning in patients with SCAD 30-days after treatment with PCI/OMT or OMT. In this prospective design, a convenience sample of SCAD patients ( n =180, age M=65.1, SD=8.3) were recruited after treatment with PCI/OMT ( n =90) or OMT ( n =90). Data collection occurred at baseline (post-procedure) and 30-days after discharge. Mailed surveys were used at 30-days with a 52.8% (94/180) response rate (OMT n =46, PCI/OMT n =48). Measurements included the Profile of Mood States (POMS) for fatigue, Patient Health Questionnaire-9 (PHQ-9) for depressive symptoms, and Short Form-36 (SF-36) for physical functioning. Two linear regression models (see table ) were conducted to evaluate physical functioning predictors at 30-days for patients treated with PCI/OMT and OMT. Fatigue was a significant contributor for physical functioning after treatment with PCI/OMT and OMT. For PCI/OMT, fatigue ( b =-.434, p &lt;.001) and age ( b =-.245, p =.03, bivariate: r=-.414, p=.003) were significant predictors for physical functioning at 30-days. For OMT, fatigue ( b =-.630, p =.03) and gender ( b =.499, p &lt;.01) were found to influence physical functioning after treatment, with men demonstrating lower functioning at 30-days (m=37.6, sd=9) compared to women (m=49.6, sd=9.1). Depressive symptoms did not influence physical functioning in treatment groups (PMI/OMT: b =-.239, p =.05; OMT: b =.019, p =.89). Persistent fatigue may deter patients from engaging in physical activity to promote secondary prevention. Further research is needed to investigate the impact of fatigue on physical functioning. Predictors of Physical Functioning 30-Days After Treatment for Stable Coronary Artery Disease PCI/OMT Predictors Standardized Beta t value p value 95% CI (Lower Bound) 95% CI (Upper Bound) Age −.245 −.21 .03 −.495 −.017 Gender .082 .82 .41 −.273 6.505 Ejection Fraction .097 .85 .40 −.078 .191 POMS-Fatigue −.434 −.38 &lt;.01 −1.419 −.441 PHQ-9 Depressive Symptoms −.239 −.20 .05 −1.673 −.002 OMT Predictors Standardized Beta t value p value 95% CI (Lower Bound) 95% CI (Upper Bound) Age .268 1.96 .05 −.008 .606 Gender .499 .42 &lt;.01 6.470 18.401 Ejection Fraction −.195 −1.31 .19 −.427 .090 POMS-Fatigue −.630 −4.37 &lt;.01 −2.319 −.852 PHQ-9 Depressive Symptoms .019 .13 .890 −1.474 1.691 Abbreviations: CI, Confidence Interval. Model Information: PCI/OMT n=48, f=11.23, df=6, r2=.622,p&lt;.01. OMT: n=46, f=6.91, df=6, r2=.516, p&lt;.01
The Deubiquitinase USP9X Maintains DNA Replication Fork Stability and DNA Damage Checkpoint Responses by Regulating CLASPIN during S-Phase
Authors: Edel McGarry, David Gaboriau, Michael D. Rainey, Umberto Restuccia, Angela Bachi, Corrado Santocanale
Journal: Cancer Research (2016)

Coordination of the multiple processes underlying DNA replication is key for maintaining genome stability and preventing tumorigenesis. CLASPIN, a critical player in replication fork stabilization and checkpoint responses, must be tightly regulated during the cell cycle to prevent the accumulation of DNA damage. In this study, we used a quantitative proteomics approach and identified USP9X as a novel CLASPIN-interacting protein. USP9X is a deubiquitinase involved in multiple signaling and survival pathways whose tumor suppressor or oncogenic activity is highly context dependent. We found that USP9X regulated the expression and stability of CLASPIN in an S-phase-specific manner. USP9X depletion profoundly impairs the progression of DNA replication forks, causing unscheduled termination events with a frequency similar to CLASPIN depletion, resulting in excessive endogenous DNA damage. Importantly, restoration of CLASPIN expression in USP9X-depleted cells partially suppressed the accumulation of DNA damage. Furthermore, USP9X depletion compromised CHK1 activation in response to hydroxyurea and UV, thus promoting hypersensitivity to drug-induced replication stress. Taken together, our results reveal a novel role for USP9X in the maintenance of genomic stability during DNA replication and provide potential mechanistic insights into its tumor suppressor role in certain malignancies. Cancer Res; 76(8); 2384-93. ©2016 AACR.
Abstract 15383: Rapid in vivo Maturation of Biotube Vascular Grafts by Giant Drops Patching of Adipose-Derived Vascular Stromal Cells Spheroids
Authors: Ryosuke Iwai
Journal: Circulation (2013)

Introduction:  Adipose-derived stromal cells (ADSCs) is considered to be one of the most promising cell sources for use in cardiovascular tissue regeneration because of their angiogenic potential and easy isolation by liposuction. However, even though ADSCs in suspension were injected into conventional scaffold-based vascular grafts during transplantation, most of them were diffused into surrounding tissues and were hardly engrafted into any vascular grafts. In this study, giant drops of ADSC spheroids were prepared on our specially designed, charged culture dishes for the application to enhancement of in vivo maturation of in-body tissue engineered BIOTUBE autologous vascular grafts.   Methods and Results:  ADSCs from subcutaneous fat of GFP transgenic rats could self-aggregate only single spheroid in the charged dishes at 24 h after cell seeding with controlling its size from 0.1 mm to over 2 mm in diameter according to the dish size. The ADSC spheroids over 1 mm in diameter could be easily handling by tweezers. On the other hand, BIOTUBEs (diameter: 1.5 mm, length: 10 mm) prepared by placing silicone rods as a mold into dorsal subcutaneous pouches in wild rats for 4 weeks were auto-implanted to abdominal aortas by end-to-end anastomosis with outer surface patching of the three drops of ADSC spheroids having 3.0х105 cells. After 3 weeks of implantation, BIOTUBEs were patent without any aneurysm formation and the drops were not recognized macroscopically. Histological analysis revealed that the GFP expressing cells originated from the implanted ADSCs covered outer surface of BIOTUBEs homogeneously and infiltrated its wall. Surprisingly, the luminal surface of BIOTUBEs were completely covered with endothelial lining, whereas it took more than 3 month to achieve endothelialization in traditional BIOTUBE without patching.   Conclusion:  Rapid maturation with endothelialization of BIOTUBE grafts was achieved by patching of giant drops of ADSCs spheroids. The combination of these ADSCs-drops with other vascular grafts also may enable us to achieve their rapid vascularization for high patency rate even in long or small caliber grafts as use in coronary arterial bypass grafting.