tbuckley/cabot-search huggingface dataset:
Could baseline health-related quality of life (QoL) improve prognostication of overall survival in metastatic colorectal cancer? Results from GERCOR OPTIMOX 1 study.
Authors: M. Diouf, F. Bonnetain, B. Chibaudel, C. Tournigand, L. Teixeira, H. Marijon, N. Perez-Staub, A. De Gramont
Journal: Journal of Clinical Oncology (2011)

3632 Background: Health related quality of life (QoL) had a prognostic value in numerous metastatic cancers. A recent study underlined that existing prognostic scores could be improved in metastatic colorectal cancer (mCRC; Chibaudel et al, ASCO 2010,#3577). The present study evaluated the prognostic value of QoL for overall survival duration in patients with mCRC. Methods: QoL was assessed at baseline before randomization using the Euro QoL (EQ-5D) in OPTIMOX1 phase III trial, in which FOLFOX chemotherapy was given either continuously or using an oxaliplatin stop-and-go strategy in patients with previously untreated mCRC. Two multivariate Cox proportional hazard models were built with a backward selection. First model was established with baseline biological variables only. The second one added baseline QoL dimensions to the first model. In order to quantify the improvement of discriminate capability for OS prediction, we used Harrell’s C index. Bootstrapping was done for internal validation. Results: At baseline 252 patients had HR-QOL data (41% of 620). Baseline characteristics did not differ between patients with or without available HR-QoL. Independent prognostic factors for survival in the first model were LDH (HR=1.60 95%CI [1.20-2.12]), APL (HR=1.32 CI [1.07-1.63]), CEA (HR=1.30 CI [1.04-1.63]), number of metastatic sites (HR=1.51 CI [1.26-1.82]), and PS (HR=1.50; CI [1.24-1.80), and C-index was 0.64 (CI [0.61-0.67]). Based on univariate Cox, Mobility (HR=1.76 CI [1.25-2.48], 2-3 vs. 1), pain (HR=1.44 CI [1.09-1.90], 2-3 vs. 1) and Anxiety (HR=1.41 CI [1.07-1.86], 2-3 vs. 1) QoL dimensions were found to be significantly associated with OS. In the second multivariate model, mobility (HR=1.50 CI [1.05-2.14]) was retained as the only independent QoL dimension improving prognostic information as compared to the previous clinical model: C-index was improved from 0.64 to 0.68 (CI [0.64-0.71]). Conclusions: Adding mobility QoL dimension of EQ-5D to usual clinical parameters improve the prediction of OS in mCRC. Next steps will be to externally validate these results and then to investigate QoL as stratification factor for randomization.
Sequential Cytarabine and Alpha-Particle Immunotherapy with Bismuth-213 (213Bi)-Labeled-HuM195 (Lintuzumab) for Acute Myeloid Leukemia (AML)
Authors: Todd Rosenblat, Michael R. McDevitt, Deborah A. Mulford, Neeta Pandit-Taskar, Mark A. Weiss, Mark L. Heaney, Suzanne Chanel, Alfred Morgenstern, Steven M. Larson, David A. Scheinberg, Joseph G. Jurcic
Journal: Blood (2008)
Abstract 4989: Cannabinoid receptor 2 and C-X-C chemokine receptor 4 interact to abrogate CXCL12-mediated cellular response
Authors: Christopher Coke, Ahriea Johnson, Kia Jones, Cimona Hinton
Journal: Cancer Research (2015)

Abstract The expression of C-X-C Chemokine Receptor 4 (CXCR4) has been correlated with increased metastatic potential of cancer cells. CXCR4 increases tumor malignancy by encouraging tumors cells to migrate to distal organs expressing its cognate ligand, CXCL12, facilitating metastasis. Thus, targeting the CXCR4/CXCL12 signaling axis provides a good strategy to inhibit the metastatic spread of tumor cells and slow cancer progression. Recent studies suggest that cannabis may have anti-proliferative as well as anti-metastatic properties, though a biochemical mechanism describing how this occurs has yet to be discovered. Our lab has confirmed that an interaction between agonist-bound CXCR4 and agonist-bound Cannabinoid Receptor 2 (CB2) can decrease cancer cell migration. Simultaneous treatment of the breast cancer cell line, MDA-MB-231 with CXCL12 and AM1241, a synthetic ligand for CB2, desensitized the intrinsic cellular response to migrate toward areas of high CXCL12 concentration. Furthermore, through co-immunoprecipitation, we determined that there was increased interaction between the two receptors with co-stimulation. When CXCR4 and CB2 were activated simultaneously with various agonists, decreases in migration were observed, confirming that the regulatory activity was receptor-based, not agonist-based. Moreover, when cells were treated with the CB2 antagonist (AM630) and CXCL12 simultaneously, the decrease in migration was no longer seen, as CXCL12 was able to induce cell movement. In order to determine whether receptors were activated in response to simultaneous stimulation, calcium mobilization assays were performed and results showed that transiently activated calcium levels were significantly lower in response to simultaneous treated cells when compared to cells treat with their individual ligands. Therefore, we propose that the interaction of CB2 with CXCR4 may play a role in inhibiting the cells response to CXCL12, leading to a loss in metastatic potential and presenting a new mechanism for regulating oncogenic signaling. Citation Format: Christopher Coke, Ahriea Johnson, Kia Jones, Cimona Hinton. Cannabinoid receptor 2 and C-X-C chemokine receptor 4 interact to abrogate CXCL12-mediated cellular response. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4989. doi:10.1158/1538-7445.AM2015-4989
Abstract 3942: Identification Of Endothelin Type-A Receptor-expressing Cells Involved In Embryonic Brain Angiogenesis
Authors: Toshiyuki Ko, Koichi Nishiyama, Hiroaki Koseki, Sho Hasegawa, Takahiro Sato, Rieko Asai, Yumiko Kawamura, Yukiko Kurihara, Hiroki Kurihara
Journal: Circulation (2008)

Interaction between endothelial cells (ECs) and mural cells (pericytes/smooth muscle cells) is crucial for vascular stabilization and maturation during the late phase of angiogenesis. However, underlying mechanisms and its role in the early sprouting angiogenesis remain largely unveiled. Recently, we have established mice in which EGFP is knocked-in into the endothelin type-A receptor (EdnrA) locus by Cre recombinase-mediated cassette exchange method (RMCE), resulting in the visualization of EdnrA-expressing cells including neural crest (NC)-derived ectomesenchymal cells. We found sporadic distribution of EGFP+cells also in the neural tube (NT) after E9.5, when sprouting angiogenesis into the brain starts. We then examined possible involvement of these cells in angiogenesis. EGFP+cells were first observed between E9.5 to E10.0 in the NT close to its outer surface. Thereafter, the cells tended to distribute toward the ventricular zone. Interestingly, most EGFP+cells in the NT were associated with forming vessels marked by CD31. At E9.5, when migrating CD31+cells were penetrating into the NT, many sprouts were accompanied by EGFP+cells. EGFP+cells expressed PDGFRβ, a marker for mesenchyme-derived mural cells, whereas the cells were negative for CD31, PDGFRα, GFAP, nestin and Iso-B4-lectin binding. At the late gestation stage (E18.5), EGFP+cells formed a layer underlying ECs and became partly positive for α-smooth muscle actin. These results are consistent with the previous finding that mural cells of the forebrain blood vessels originate from the NC, and indicate that CD31+EC/angioblasts and EGFP+immature cells may coordinately give rise to vascular networks in the brain from the early angiogenic stage. It is also noteworthy that EGFP+cells were closely associated with angiogenic ECs in aortic ring assay and in vivo ischemic lesion in the mouse hindlimb. Although these EGFP+cells are not apparently of NC origin, the identification of EdnrA-expressing cells may clarify mechanisms for mural cell differentiation and cell-to-cell interaction involved in angiogenesis. Furthermore, the RMCE knock-in system enables us to unveil the secrets of mural cells in angiogenesis by various genetic modifications.
In vitro degradation and surface bioactivity of iron-matrix composites containing silicate-based bioceramic
Authors: Sanguo Wang, Yachen Xu, Jie Zhou, Haiyan Li, Jiang Chang, Zhiguang Huan
Journal: Bioactive Materials (2016)

Iron-matrix composites with calcium silicate (CS) bioceramic as the reinforcing phase were fabricated through powder metallurgy processes. The microstructures, mechanical properties, apatite deposition and biodegradation behavior of the Fe-CS composites, as well as cell attachment and proliferation on their surfaces, were characterized. In the range of CS weight percentages selected in this study, the composites possessed compact structures and showed differently decreased bending strengths as compared with pure iron. Immersion tests in simulated body fluid (SBF) revealed substantially enhanced deposition of CaP on the surfaces of the composites as well as enhanced degradation rates as compared with pure iron. In addition, the composite containing 20% CS showed a superior ability to stimulate hBMSCs proliferation when compared to pure iron. Our results suggest that incorporating calcium silicate particles into iron could be an effective approach to developing iron-based biodegradable bone implants with improved biomedical performance.
A phase II study of neoadjuvant docetaxel (D) plus bevacizumab (B) in patients (pts) with high-risk localized prostate cancer.
Authors: W. K. Oh, M. D. Galsky, M. Barry, F. Fennessey, J. P. Richie, J. H. Hayes, R. S. Bhatt, M. Taplin, P. G. Febbo, R. W. Ross
Journal: Journal of Clinical Oncology (2011)

4642 Background: Treatment options for high-risk localized prostate cancer remain inadequate, with most pts relapsing despite local therapy. We conducted a phase II multicenter trial of neoadjuvant D +B prior to radical prostatectomy in pts with high-risk localized prostate cancer. Methods: Eligibility included any of the following: PSA >20 ng/mL or PSA velocity >2 ng/mL/yr, cT3 disease, any biopsy Gleason 8–10, Gleason 7 with T3 disease by endorectal (er) MRI. In addition, pts with ≥50% biopsy cores involved and either Gleason 7 or PSA >10 or cT2 disease were eligible. Pts were treated with D 70 mg/m2 q3 weeks x 6 cycles and B 15 mg/m2 q3 weeks x 5 cycles. The primary end point was erMRI partial response (PR, defined as ≥50% decrease in tumor volume) in a single target lesion after chemotherapy. Results: 42 pts were enrolled, and 41 were treated. Median age was 55 yrs (range, 40–66 yrs). Baseline characteristics included: median PSA 10.1 ng/mL (range, 2.1–72.4 ng/mL), cT2 49%, cT3 32%, and Gleason 8–10 73%. Thirty-eight of 41 (93%) pts completed all 6 cycles. Grade ≥ 3 adverse events included hyperglycemia (1/41), allergic reaction (1/41), cough, lymphopenia (3/41), and febrile neutropenia (3/41). Thirty-seven of the 41 pts underwent radical prostatectomy. Reasons for not proceeding with surgery included: a bladder neck injury, positive lymph nodes, and withdrawal of consent in 2 pts. Response data are shown in the Table. No pts achieved a complete pathologic response. Conclusions: Neoadjuvant D+B demonstrates clinical activity in men with high-risk localized prostate cancer. The role of neoadjuvant chemotherapy in prostate cancer, and perioperative antiangiogenic therapy in solid tumors in general, requires further elucidation through ongoing and planned randomized trials. Response assessments. Outcome measure Number (%) erMRI partial response 12/41 (29%) Any PSA decline 31/41 (76%) > 50% PSA decline 9/41 (22%) Pathologic downstaging 14/41 (34%) Pathologic node positive 8/41 (20%) Positive margins 14/41 (34%) Extracapsular extension 23/41 (56%) Seminal vesicle involvement 12/41 (29%)
290. Baboon Envelope Pseudo Typed Lentiviral Vectors Mediate High-Level Gene Transfer in Human B Cells Allowing Secretion of FIX at Therapeutic Levels in NSG Mouse
Authors: Camille Lévy, Fouzia Amirache, Caroline Costa, Floriane Fusil, Anais Girard-Gaignepain, Didier Nègre, Ornellie Bernadin, Guillermo Garaulet, Antonio Rodriguez, Thierry Vandendriessche, Marinee Chua, François-Loïc Cosset, Els Verhoeyen
Journal: Molecular Therapy (2015)

B lymphocytes are attractive targets for gene therapy of genetic diseases associated with B-cell dysfunction. In addition, long-lasting transgene expression in B cells is of particular interest for immunotherapy by its potential to induce specific immune activation or tolerance. Moreover, B cells are potent specialized protein secreting cells. One obstacle though is that primary B cells are poorly transduced by VSVG pseudotyped lentiviral vectors (LVs) even when stimulated through the BCR to induce proliferation. We demonstrated that this is due to the poor expression of the low density lipid (LDL) receptor, identified as the VSV receptor (Amirache et al, 2014). Since we recently showed that baboon retroviral envelope pseudotyped LVs (BaEV) outperform VSV-G-LVs for gene transfer into cytokine-stimulated and resting hematopoietic stem cells, we evaluated them here for gene transfer into primary human B cells. Upon B cell receptor stimulation, BaEV-LVs transduced up to 70% of the B cells. As expected, VSV-G-LVs were unable to transduce activated nor unstimulated resting human B cells efficiently, even at high vector doses (MOI= 100, VSV-G-LV < 5% transduction). Remarkably, BaEV-LVs permitted highly efficient transduction of 30% of resting B cells. Moreover, they transduced as well memory as naive B cells without inducing phenotypic changes. In addition, BaEV-LVs permitted up to 80% transduction of human plasmocytes. Adaptive transfer of mature BaEV-LV transduced human B cells into NSG mice allowed differentiation into plasmablasts and plasma B cells, both characterized by a high level gene marking in the lymphnodes, spleen and bone marrow. These results encouraged us to evaluate BaEV-LV mediated gene transfer of Factor IX into human B cells for treatment of heamophelia, a severe blood disorder. We produced high-titer BaEV-LVs carrying a codon optimized FIX with a hyperactivating FIX-R338L mutation. These BaEV-FIX-LVs efficiently transduced plasmocytic B cell lines leading to high-level FIX secretion (20-70% of normal levels in human serum). Transduction of primary human B cells followed by adaptive transfer into NSG mice resulted in therapeutic levels of FIX in the serum (7-25% of normal FIX levels) at 3 to 4 weeks of engraftment. Moreover, a faster coagulation of the blood proved that FIX was functional. Concluding, the BaEV-LVs might represent in the future valuable tools for therapeutic protein secretion from autologous B cells for treatment of heamophelia and other disorders in vivo.
768. The CRISPR/Cas9 System as an Anti-Viral Treatment to Prevent Primary Infection by HCMV Positive Hematopoietic Stem Cells
Authors: Janina Gergen, Flora Coulon, Alison Creneguy, Jean-Marie Heslan, Ignacio Anegon, Tuan Huy Nguyen, Franck Halary, Fabienne Haspot
Journal: Molecular Therapy (2016)

HCMV is a beta-herpes virus, which induces a life long latency in hematopoietic stem cells after an asymptomatic primary infection. In hematopoietic stem cell transplantation, donor hematopoietic stem cells will engraft and differentiate in the recipient. This differentiation induces the reactivation of HCMV in the myeloid compartment and the release of new virions from the donor cells. The HCMV spread leads a primary infection of the immunocompromised HCMV negative recipient and can cause severe end organ diseases. The common treatments of HCMV in immunosuppressed patients are viral DNA replication inhibitors, which cause strong side effects, such as inhibition of hematopoiesis, kidney toxicity, and are likely to promote resistant strain emergence. As a consequence, none of the available drugs can target the HCMV in latent state. To circumvent this, we aim to directly alter the HCMV genome by using the CRIPSR/Cas9 system to knock-out the immediate early gene (IE) encoding essential viral proteins for lytic replication as well as the end of latency. We transduced the low HCMV-permissive U373-MG cells with a lentiviral vector encoding the Cas9 and tree different single gRNA targeting the IE gene. We FACS sorted those cell lines based on their Cas-9-GFP expression and then infected them with a HCMV laboratory strain. We detected mutations at the target site in up to 70% of the viral genomes. We observed a concomitant reduction of 50% less infected cell by FACS staining of the IE protein. Moreover, we set up an assay to analyze the virion release of infected U373-MG cells, which will allow us to address the decrease or inability to release new virions form U373-MG-gRNA-Cas9 HCMV infected cells. We are currently investigating a multiplex strategy with 3 gRNA targeting different parts of the IE gene which are delivered within the same lentiviral vector. The multiplex strategy is auspicious to show higher efficiency than a single gRNA. This strategy will be also tested on HCMV latently infected CD34+ hematopoietic stem cells to prevent viral reactivation. The CRISPR/Cas9 system anti-HCMV is a promising tool to block viral replication. With this anti-HCMV tool we will be able to treat HCMV positive donor cells in order to prevent the primary infection of the immunosuppressed recipient.
Similar Efficacies of Endoscopic Ultrasound Gallbladder Drainage With a Lumen-Apposing Metal Stent Versus Percutaneous Transhepatic Gallbladder Drainage for Acute Cholecystitis
Authors: Shayan Irani, Saowanee Ngamruengphong, Anthony Teoh, Uwe Will, Jose Nieto, Barham K. Abu Dayyeh, S. Ian Gan, Michael Larsen, Hon Chi Yip, Mark D. Topazian, Michael J. Levy, Christopher C. Thompson, Andrew C. Storm, Gulara Hajiyeva, Amr Ismail, Yen-I Chen, Majidah Bukhari, Yamile Haito Chavez, Vivek Kumbhari, Mouen A. Khashab
Journal: Clinical Gastroenterology and Hepatology (2016)
Mice Lacking PIP5Kβ or PIP5Kγ Have Unique Cytoskeletal Changes within Their Megakaryocytes &amp; Platelets.
Authors: Xinsheng Chen, Yanfeng Wang, Tami L. Bach, Lurong Lian, Rustem I. Litvinov, John W. Weisel, Charles S. Abrams
Journal: Blood (2005)
Neoadjuvant chemotherapy followed by concurrent chemoradiation versus concurrent chemoradiation alone in locally advanced carcinoma of oropharynx, hypopharynx, and larynx.
Authors: B. Satapathy, S. N. Senapati, D. R. Samanta
Journal: Journal of Clinical Oncology (2011)

e16016 Background: The study is designed, to evaluate the response rate, tolerance and disease free survival inpatients of Locally advanced carcinoma of oropharynx, hypopharynx and larynx, receiving neoadjuvant chemotherapy followed by concurrent chemo radiation vs. concurrent chemo radiation alone. Methods: From Sep 2007 to Nov 2009, Fifty eligible patients of carcinoma of oropharynx, hypopharynx and larynx, satisfied the eligible criteria, were accrued and treated at the AHRCC, Cuttack, India. They were randomized in two arms, among those in Arm A, 25 patients received cisplatin 80 mg/m2 (D1-D3) and 5 FU 500mg per m2 (D1D3) administered as neoadjuvant chemotherapy for three cycles in 21 days intervals followed by concurrent chemoradiation i.e. weekly Cisplatin 40mg /m2 and radiotherapy in a dose of 66Gy and in Arm B, 25 patients received concurrent chemoradiation with weekly cisplatin alone. The median age was 55 years and male’s out numbered females in both the arms. In Arm A, 60% patients were in stage III and 88 % in Arm B. Most common histologic type was GrII (60%). Majority patients presents with symptoms like dysphagia, cervicaladenopathy and hoarseness. Results: With a median follow up of 9 months in Arm A, the complete response were 60%, partial response32% and 4 % progressive disease. In Arm B, complete response 28%, partial response 68% and 4% progressive disease and 4% patients showed no response in both the arms. The adverse reactions like leucopenia, vomiting, mucositis, dermatitis, dysphagia were comparable and found more in Arm B. Conclusions: The CRT is still considered as a standard treatment in locally advanced head and neck cancer. The completeresponse was much better in neoadjuvant chemotherapy followed by concurrent chemo radiation than CRT alone. Further investigations in prospective studies with large sample size longer duration of follow up are required to evaluate this regimen.
CD133+ Acute Myeloid Leukemia (AML) Cells Exhibit Higher Clonogenic Capacity and Higher Levels of pAKT and Bcl-2 Proteins Than Their Negative Counterpart
Authors: Francoise Solly, Lauren Rigollet, Pascale Flandrin-Gresta, Karine Augeul-Meunier, Emmanuelle Tavernier-Tardy, Nathalie Nadal, Denis Guyotat, Lydia Campos
Journal: Blood (2010)
Rapid improvement in evidence-based, quality care of cancer patients with initiation of ASCO’s Quality Oncology Practice Initiative (QOPI).
Authors: M. A. Amin, M. H. Hashmi, S. A. Taylor
Journal: Journal of Clinical Oncology (2011)

6134 Background: ASCO’s Quality Oncology Practice Initiative (QOPI) is an oncologist-led, practice-based quality improvement program to promote excellence in cancer care. QOPI uses evidence based, quality measures from clinical guidelines or published standards from ASCO/NCCN quality measures. Whether initiation of QOPI leads to improvements in these measures is unknown. Methods: QOPI was implemented by oncology fellows at a single, academic center for 2 years (2009 and 2010). Data from 48 outpatient clinic charts were abstracted. Information about the QOPI core measures, disease specific modules, domain specific modules and symptom toxicity management were compared for the 2 years. Results: We observed low rates of several evidence-based measures at the start of the QOPI initiative. Initiation of QOPI led to substantial improvements in both the QOPI Core measures as well as the disease specific modules (Table). Furthermore we observed substantial reduction in the variation for all of these measures (implying more uniformity of quality care) in the second year (Table). Conclusions: The initiation of QOPI by oncology fellows for only 2 years demonstrated a rapid improvement in several evidence based guideline measures, to achieve a higher quality and evidence-based care for cancer patients. Such initiatives may lead to greater uniformity and less variation in guideline based care, which in turn, may improve outcomes for patients. It may also improve fellow education and train them to practice more evidence-based medicine when taking care of cancer patients. QOPI measure Site rate (%) 2009 Site rate (%) 2010 Core 6: Pain addressed appropriately 87.5 100 Core 9: Documented plan for CTX 60 94.12 Core 10: CTX intent (curative vs. palliative) 80 100 Symptom 27: Steroids/serotonin antagonist for emesis 64.86 100 Symptom 33: Infertility discussed before CTX 9.09 100 Breast 56: Trastuzumab for stage I to III Her-2/neu breast Ca 66.67 100 Colon/Rectal 64: CEA < 4 months of curative resection 50 100 Colon/Rectal 66: Adjuvant CTX < 4 months for stage III colon Ca 0 100 Colon/Rectal 71: Colonoscopy < 6 mo of curative resection 50 100 QOPI certification overall quality score 83.65 94.5