tbuckley/cabot-search huggingface dataset:
The effect of motesanib treatment on the gallbladder: A randomized phase Ib study in patients (pts) with advanced solid tumors.
Authors: N. C. Tebbutt, L. R. Lipton, T. J. Price, N. D. Belman, R. V. Boccia, H. Hurwitz, J. Stephenson, L. J. Wirth, S. McCoy, R. Sikorski, Y. J. Hei, L. S. Rosen
Journal: Journal of Clinical Oncology (2011)

e13555 Background: Gallbladder toxicity, including cholecystitis, has been seen in studies of motesanib, an orally administered small-molecule antagonist of VEGFRs 1, 2 and 3; PDGFR; and Kit. We assessed effects of motesanib on gallbladder size and function in pts with advanced solid tumors. Methods: Pts (≥18 y) with advanced metastatic solid tumors ineligible for or having progressed on standard-of-care therapies, with ECOG ≤2, and with no history of cholecystitis or biliary disease were randomized 2:1:1 to receive 3-wk cycles of motesanib 125 mg once daily (Arm A); 75 mg twice daily (BID), 14 d on/7 d off (Arm B); or motesanib 75 mg BID, 5 d on/2 d off (Arm C). The primary endpoints were mean change from baseline in gallbladder size (volume by ultrasound per independent review) and function (ejection fraction [EF] by CCK-HIDA per investigator assessment). Ultrasound and CCK-HIDA were performed at screening, regular intervals during the study, and the safety follow-up. A linear regression model assessed the effects of covariates on gallbladder volume. Results: 49 pts received ≥1 dose of motesanib (Arms A/B/C, n=25/12/12). Across all pts, gallbladder volume increased by a mean 22.2 cc (from 38.6 cc at baseline) and EF decreased by a mean 19.1% (from 61.3% at baseline) during treatment. Changes were similar across arms and appeared reversible after treatment discontinuation. A linear regression model identified nonsteroidal anti-inflammatory drug use as a potential covariate for gallbladder volume (P=.01); there was no association with treatment schedule, age or sex. The incidence of sludge was 39%, 36%, and 27% in Arms A, B, and C. Two pts developed de novo gallstones during treatment. Three pts had cholecystitis (1 serious) that resolved after treatment discontinuation, 1 pt had serious grade 3 acute cholecystitis requiring cholecystectomy, and 2 pts had grade 1 gallbladder disorder; all were in Arm A. Eleven pts had right upper quadrant pain (Arms A/B/C, n=7/1/3). Conclusions: Motesanib treatment was associated with increased gallbladder volume and decreased EF. Further investigation of the etiology of this toxicity and the potential role of gallbladder sludge in its development is warranted.
The Rodent Liver Undergoes Weaning-Induced Involution and Supports Breast Cancer Metastasis
Authors: Erica T. Goddard, Ryan C. Hill, Travis Nemkov, Angelo D'Alessandro, Kirk C. Hansen, Ori Maller, Solange Mongoue-Tchokote, Motomi Mori, Ann H. Partridge, Virginia F. Borges, Pepper Schedin
Journal: Cancer Discovery (2016)

Abstract Patients with postpartum breast cancer are at increased risk for metastasis compared with age-matched nulliparous or pregnant patients. Here, we address whether circulating tumor cells have a metastatic advantage in the postpartum host and find the postlactation rodent liver preferentially supports metastasis. Upon weaning, we observed liver weight loss, hepatocyte apoptosis, extracellular matrix remodeling including deposition of collagen and tenascin-C, and myeloid cell influx, data consistent with weaning-induced liver involution and establishment of a prometastatic microenvironment. Using intracardiac and intraportal metastasis models, we observed increased liver metastasis in post-weaning BALB/c mice compared with nulliparous controls. Human relevance is suggested by a ∼3-fold increase in liver metastasis in patients with postpartum breast cancer (n = 564) and by liver-specific tropism (n = 117). In sum, our data reveal a previously unknown biology of the rodent liver, weaning-induced liver involution, which may provide insight into the increased liver metastasis and poor prognosis of women diagnosed with postpartum breast cancer. Significance: We find that patients with postpartum breast cancer are at elevated risk for liver metastasis. We identify a previously unrecognized biology, namely weaning-induced liver involution, that establishes a prometastatic microenvironment, and which may account in part for the poor prognosis of patients with postpartum breast cancer. Cancer Discov; 7(2); 177–87. ©2016 AACR. This article is highlighted in the In This Issue feature, p. 115
Abstract A2-46: Melanoma Profiler web tool for integrative genomic analysis of melanoma
Authors: Kashef Qaadri, Steven Stones-Havas, Brett Ammundsen, Alexander Trevarton, Cristin Print
Journal: Cancer Research (2015)

Abstract Despite ongoing research, metastatic melanoma five-year survival rates remain low and treatment options limited. Researchers can access a rapidly growing amount of molecular and clinical information about melanoma that may be critical to understanding this disease and making clinically relevant treatment decisions. However, this information is becoming difficult to collate and clinically interpret due to its dispersed nature. Presented here is Melanoma Profiler, a new cloud-based web application for clinically relevant metastatic melanoma genomic research. It performs a tumor/normal comparative variant analysis, comparing proband modified genes and pathways to those in a curated set of characterized melanoma tumor samples. To provide clinical decision support, modified genes and pathways are cross-referenced with clinical and molecular data. These data are incorporated from publicly available sources, including: associations between gene expression and patient survival, data concerning drug targets, biomarkers, and druggability as well as past clinical trials. The resultant MelanomaDB cross-reference database integrates data from cutting edge research on a continuous basis. The interface is presented in two tiers: a front-panel summary tier and an evidential detail tier. For the busy clinician, immediately presented in the summary view is a dynamic report clearly highlighting the relevant actionable information, potential drug targets, and a summary of affected genes and pathways. For researchers that wish to dig deeper, they may browse annotated pathway data, and view a comprehensive comparative summary of affected genes in waterfall and heatmap reports. Melanoma Profiler is a free research tool hosted by Biomatters, produced in collaboration with the University of Auckland, New Zealand. A recent Frontiers in Oncology methods article describing the research behind the application can be found at http://bit.ly/1bUilqS. The Melanoma Profiler web application can be found at https://apps.biomatters.com/melanoma-profiler/. Citation Format: Kashef Qaadri, Steven Stones-Havas, Brett Ammundsen, Alexander Trevarton, Cristin Print. Melanoma Profiler web tool for integrative genomic analysis of melanoma. [abstract]. In: Proceedings of the AACR Special Conference on Translation of the Cancer Genome; Feb 7-9, 2015; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(22 Suppl 1):Abstract nr A2-46.
Abstract 2057: Protocadherin 10-mediated suppression of tumorigenesis and metastasis in colorectal cancer
Authors: yu-lin hung
Journal: Cancer Research (2015)

Abstract Colorectal cancer (CRC) is one of the leading types of cancer death worldwide, and over one third of these patients will die of their disease mainly due to distant metastasis. Genomic deletion that occurs at tumor suppressor loci is a common genetic aberration in CRC. By using loss of heterozygosity analysis, we identified Protocadherin 10 (PCDH10) as a novel tumor suppressor gene in CRC. Ectopic expression of PCDH10 reduced cancer cell proliferation, anchorage-independent growth, migration and invasion, as well as increased serum starvation-induced apoptosis in vitro. Subcutaneous injection of PCDH10-expressing CRC cells in SCID mice showed the reduction of tumor growth compared with that observed in mock-inoculated mice. Furthermore, via intrasplenic implantation, the re-expression of PCDH10 in silenced cells restrained liver metastasis and improved survival in SCID mice. The molecular mechanisms of PCDH10-mediated tumor suppression are involved in the up-regulation of p53-p21 pathway and down-regulation of active β-catenin. Taken together, PCDH10 could restrain cell growth and epithelial-to-mesenchymal transition, and thus inhibit the development and progression of CRC. Keywords: PCDH10, tumor suppressor gene, colorectal cancer, molecular mechanism Category : MCB04 Oncogenes and Tumor Suppressor Genes Citation Format: yu-lin hung. Protocadherin 10-mediated suppression of tumorigenesis and metastasis in colorectal cancer. [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 2057. doi:10.1158/1538-7445.AM2015-2057
CCL2/CCR2, but not CCL5/CCR5, mediates monocyte recruitment, inflammation and cartilage destruction in osteoarthritis
Authors: Harini Raghu, Christin M Lepus, Qian Wang, Heidi H Wong, Nithya Lingampalli, Francesca Oliviero, Leonardo Punzi, Nicholas J Giori, Stuart B Goodman, Constance R Chu, Jeremy B Sokolove, William H Robinson
Journal: Annals of the Rheumatic Diseases (2016)

While various monocyte chemokine systems are increased in expression in osteoarthritis (OA), the hierarchy of chemokines and chemokine receptors in mediating monocyte/macrophage recruitment to the OA joint remains poorly defined. Here, we investigated the relative contributions of the CCL2/CCR2 versus CCL5/CCR5 chemokine axes in OA pathogenesis.Ccl2-, Ccr2-, Ccl5- and Ccr5-deficient and control mice were subjected to destabilisation of medial meniscus surgery to induce OA. The pharmacological utility of blocking CCL2/CCR2 signalling in mouse OA was investigated using bindarit, a CCL2 synthesis inhibitor, and RS-504393, a CCR2 antagonist. Levels of monocyte chemoattractants in synovial tissues and fluids from patients with joint injuries without OA and those with established OA were investigated using a combination of microarray analyses, multiplexed cytokine assays and immunostains.Mice lacking CCL2 or CCR2, but not CCL5 or CCR5, were protected against OA with a concomitant reduction in local monocyte/macrophage numbers in their joints. In synovial fluids from patients with OA, levels of CCR2 ligands (CCL2, CCL7 and CCL8) but not CCR5 ligands (CCL3, CCL4 and CCL5) were elevated. We found that CCR2+ cells are abundant in human OA synovium and that CCR2+ macrophages line, invade and are associated with the erosion of OA cartilage. Further, blockade of CCL2/CCR2 signalling markedly attenuated macrophage accumulation, synovitis and cartilage damage in mouse OA.Our findings demonstrate that monocytes recruited via CCL2/CCR2, rather than by CCL5/CCR5, propagate inflammation and tissue damage in OA. Selective targeting of the CCL2/CCR2 system represents a promising therapeutic approach for OA.
Sorafenib and locoregional treatment in patients with stage B and stage C HCC: Sardinian experience.
Authors: T. Zolfino, M. R. Piras, S. Zaru, M. C. Santona, F. Arcadu, G. Serra, L. Chessa, G. Vidili, F. Spada, P. Enne, F. Bandiera
Journal: Journal of Clinical Oncology (2011)

e14577 Background: Unresectable HCC is a hypervascular tumor with poor prognosis affecting patients with liver cirrhosis. TACE improves media survival from 16 to 22 months in patients with intermediate (stage B) HCC; media survival in advanced HCC (stage C) varies from 3 to 6 months. Sorafenib is the only systemic therapy with demonstrated benefit in term of progression disease and survival in stage C HCC. There is poor experience in stage B HCC already treated with chemoembolisation. We report our regional experience with sorafenib in Sardinian patients, particularly in patients with stage B HCC treated with loco-regional therapy and sorafenib. Methods: 71 cirrhotic patients (males/females 61/10), received sorafenib 800 or 400 mg daily from September 2007 to May 2010. Etiology: 31 HCV cirrhosis, 14 ALD, 12 HBV, 13 multiple etiology, 1 NASH. 4 patients were BCLC stage A (after technically failure of loco-regional therapies), 23 stage B and 44 stage C HCC. Median age at diagnosis was 65.4 years in overall groups. Before or during sorafenib treatment 12 patients underwent TACE, 9 Radiofrequency (RF), 28 received both TACE and RF; 22 patients received uniquely sorafenib. Results: No patients interrupted treatment because of adverse events; 62% of patients had diarrhea (5.6% G3), 73% complained fatigue (18% G3), 41% weight loss (3% G3), 41% HFS (7% G3), 41% dermatitis (4% G3), 37% pruritus (1% G3), 27% hypertension (none G3). Overall median survival was 28.5 months, 29 months and 21.4 months respectively in BCLC stage A, stage B and stage C. Looking in particular at patients who received previous or concomitant loco-regional treatment median survival was 29 months compared to 12.5 months in patients who received only systemic treatments with respectively 32 patients alive and 17 death in the first group and 11 patients alive and 11 death in the second. Conclusions: Sorafenib was well tolerated and when administered after or during loco-regional treatments improved survival to 29 months. Clinical Trials are necessary to demonstrate that combined treatment improves survival compared to loco-regional monotherapy.
National and subnational all-cause and cause-specific child mortality in China, 1996–2015: a systematic analysis with implications for the Sustainable Development Goals
Authors: Chunhua He, Li Liu, Yue Chu, Jamie Perin, Li Dai, Xiaohong Li, Lei Miao, Leni Kang, Qi Li, Robert Scherpbier, Sufang Guo, Igor Rudan, Peige Song, Kit Yee Chan, Yan Guo, Robert E Black, Yanping Wang, Jun Zhu
Journal: The Lancet Global Health (2016)

China has achieved Millennium Development Goal 4 to reduce under-5 mortality rate by two-thirds between 1990 and 2015. In this study, we estimated the national and subnational levels and causes of child mortality in China annually from 1996 to 2015 to draw implications for achievement of the SDGs for China and other low-income and middle-income countries.
713. Optimization and Scale-Up of a Manufacturing Process for Clinical-Grade Adenovirus-Based Vectors
Authors: Maria Fe C. Medina, Shabnam Shoaebargh, Natasha Kazhdan, Uma Sankar, David R. Latulippe, Brian Lichty
Journal: Molecular Therapy (2016)

We have developed a manufacturing protocol for clinical-grade Adenovirus-based vectors utilizing suspension 293 cells grown with chemically defined media in disposable spinner flasks. We have manufactured four batches of clinical-grade Adenovirus vectors utilizing this protocol, and some vectors have been administered in TB or cancer vaccine clinical trials in Canada. The maximum volume for a batch was from a 30-liter infected cell culture consisting of three lots with 10 liters. Each 10-liter lot was purified by cesium chloride density gradient ultracentrifugation and desalted by a Biogel column. The purified vectors were then pooled, filtered and filled into cryovials. In an effort to increase manufacturing capacity, we have investigated the use of a Pall XRS-20 Bioreactor with a maximum cell culture capacity of 20 liters. We assessed cell growth kinetics/infection kinetics and found that at the minimum, we can achieve triple the maximum cell density compared with the use of spinner flasks. We have observed virus yields similar to what can be achieved with spinner flasks, and are currently optimizing the infection protocol to assess if virus yields can still be improved. In order to address the scale-up concerns associated with the cesium chloride density gradient ultracentrifugation method, we are also developing a chromatography-based virus purification protocol. We are using a high-throughput test protocol to identify the critical process parameters (e.g. specific buffer species, pH, ionic strength) in resin binding experiments that achieve the required removal of impurities but also maintain immunogenic activity. A design-of-experiment strategy is being used to minimize the overall number of experiments.
A Phase I, Single and Fractionated, Ascending Dose Study Evaluating the Safety, Pharmacokinetics, Pharmacodynamics, and Immunogenicity of an Erythropoietic Mimetic Antibody Fusion Protein, CNTO528, in Healthy Male Subjects.
Authors: K. L. Franson, J. Burggraaf, E. A. Bouman-Trio, A. F. Cohen, B. E. Miller, H. Jang, S. J. Marciniak, E. P.S. van de Ketterij, B. Frederick, Q. Jiao, J. Getsy, E. H. Bald, H. Walker, A. Schantz, J. A. Ford, K. Mascioli, J. B. Kowalchick
Journal: Blood (2005)
CCI-779 in metastatic melanoma: A phase II trial of the California Cancer Consortium
Authors: K. A. Margolin, J. Longmate, T. Baratta, T. Synold, J. Weber, T. Gajewski, I. Quirt, S. Christensen, J. H. Doroshow
Journal: Journal of Clinical Oncology (2004)

7523 Background: CCI-779 mTOR kinase inhibitor is a targeted chemotherapeutic agent that inhibits malignant cell cycle progression by binding to FK506-binding protein-12 and forming a complex that interacts with the “mammalian target of rapamycin” (mTOR), resulting in inhibition of signal transduction pathways required for progression through the G1 phase of the cell cycle. CCI-779 has demonstrated activity against melanoma in preclinical models and shown clinical benefit in breast and renal cancer. CCI-779 is not immunosuppressive when administered on an intermittent schedule, and its toxicities are modest, consisting of nausea, diarrhea, hypertriglyceridemia, thrombocytopenia, asthenia and follicular dermatitis. Methods: This trial was designed to detect a median time to progression of >18 weeks in metastatic (mets) melanoma patients (pts) treated with CCI-779, 250 mg intravenously weekly after diphenhydramine premedication. Pts had measurable disease, ≤ one prior chemotherapy regimen for mets, normal organ function. Exclusions: CNS mets, cytochrome P450-inducing or -suppressing drugs, hypertriglyceridemia. Results: 33 pts (21 male), PS 0/1/≥2=17/10/6, 21 previously-treated with chemo- and/or biological agents. One pt had a partial response (4+ months) and remains on therapy. The median time to progression and overall survival were 10 weeks and 5 months, respectively. Toxicities were mild, consisting of mucositis (1 grade [gr] 3, 8 gr 2), diarrhea (2 gr 3), and rash (1 gr 3, 4 gr 2). Hyperlipidemia was cumulative and managed with lipid-lowering agents, rarely requiring treatment delay or dose adjustments. Conclusions: CCI-779 is not sufficiently active in melanoma to warrant further testing as a single agent. Support: Phase II NO1 CM17101 No significant financial relationships to disclose.
708. Treatment of Inherited Eye Defects By Systemic Hematopoietic Stem Cell Transplantation
Authors: Celine J. Rocca, Alexander Kreymerman, Sarah N. Ur, Katie E. Frizzi, Swati Naphade, Athena Lau, Tammy Tran, Nigel A. Calcutt, Jeffrey L. Goldberg, Stephanie Cherqui
Journal: Molecular Therapy (2015)

Corneal disease is a significant cause of blindness worldwide, largely due to the low availability of donor corneas and the risks associated with transplantation, such as immune rejection, cataract, and glaucoma. Stem cell transplantation represents an attractive alternative for corneal repair because of their capacity to differentiate into corneal cells. Limbal epithelial stem (LEST) cells, which reside within the corneo-limbus, have been used for more than a decade to repair corneal epithelium, and mesenchymal stem cells (MSCs) have been shown to migrate and promote corneal healing and even differentiate into epithelial/keratocyte-like cells. However, risks of immune rejection with LEST cells, and heterogeneity in repair mechanisms with MSCs have led to discrepancies in treatment outcomes. Alternatively, very little is known about the potential for hematopoietic stem cells (HSCs) in eye repair. HSCs have attractive features; they are multipotent cells capable of self-renewal and easily mobilized from bone marrow into the circulatory system. Here we report that engraftment of HSPCs can treat corneal defects in a mouse model of a degenerative hereditary metabolic disorder, cystinosis. Cystinosis is caused by a deficiency in the lysosomal cystine transporter, cystinosin, resulting in cystine crystal accumulation in tissues. In eyes, a primary affected organ, crystals accumulate within the cornea causing photophobia and eventually blindness, if untreated. Using the mouse model of cystinosis, Ctns-/- mice, which develops similar eye anomalies than patients, we showed that systemic HSC transplantation led to the long-term preservation of the eyes. Effective therapy, however, was dependent on achieving relatively high level of donor-derived blood cell engraftment (more than 50%). Abundant GFP-expressing bone marrow-derived cells were detected within the cornea but also in the sclera, ciliary body, retina, choroid, and lens. In addition, HSCs engraftment led to substantial decrease in corneal cystine crystals, restoration of normal corneal thickness and intraocular pressure, and improved vision after one-year post-transplantation. Finally, we showed that HSCs mainly differentiated into MHC class II+ macrophages, which transferred cystinosin-bearing lysosomes via tunneling nanotubes to disease cells. This work is the first demonstration that HSCs can rescue corneal defects, which brings forth a new potential therapeutic strategy for treating ocular pathologies.
427. In Vivo Inhibition of HIV-1 in NSG Mice After Transduction of Primary Human T Cells with CXCR4 Conjugated to an HR2 Peptide
Authors: George J. Leslie, Max Richardson, Jianbin Wang, Philip Gregory, James Riley, Michael Holmes, James Hoxie
Journal: Molecular Therapy (2016)

Introduction: We previously reported that a 34 a.a. peptide from the C-terminal heptad repeat-2 domain (HR2) of HIV-1 gp41 (C34) when fused to the N-terminus of CXCR4 (C34-X4) inhibits HIV-1 infection in transduced cells in vitro. This construct provided protection irrespective of HIV viral tropism (i.e., C34-X4 could inhibit R5, X4 or dual-tropic isolates). Methods: To assess the ability of C34-conjugated coreceptor to exert transdominant inhibition of R5- and X4-tropic HIV-1 in vivo, C34-X4 was transduced using a lentiviral vector into CD3/CD28-stimulated primary human CD4+ T cells with GFP-transduced T cells serving as a control. Cells were infused in NOD-scid-gamma (NSG) mice either undiluted or mixed (25% of total cells) with untransduced T cells. After 21 days, mice were challenged i.v. with R5 (US1, Clade B) and X4 (CMU02 Clade A/E) tropic HIV-1 and infection assessed by plasma viral RNA levels and by survival of C34-X4-expressing cells. Results: In NSG mice receiving C34-X4 transduced cells, at Day 18 there was significant expansion of the CD4+/CD45+/CXCR4+ T cell population, but not of GFP control cells (p=0.005). Viral loads were significantly lower in mice receiving C34-X4 transduced cells compared to those receiving GFP-transduced cells (p=0.047). At necropsy (Day 28) in splenocytes there was an approximate 2 log increase in the number of CD4 T cells in mice receiving C34-X4 transduced cells (p=0.001). Conclusion: These studies demonstrate that the C34 peptide conjugated CXCR4 confers resistance of CD4 T cells to HIV-1 infection irrespective of viral tropism, providing a proof of concept that targeting an HR2 inhibitory peptide to a coreceptor exerts potent transdominant inhibition of HIV-1 in vivo. This novel genetic approach to confer HIV resistance to CD4 T cells, coupled with high barriers for viral resistance to C34-coreceptors, may provide a novel approach for HIV control in humans.