tbuckley/cabot-search huggingface dataset:
Exploiting the cancer niche: Tumor-associated macrophages and hypoxia as promising synergistic targets for nano-based therapy
Authors: Vera L. Silva, Wafa' T. Al-Jamal
Journal: Journal of Controlled Release (2017)

The tumor microenvironment has been widely exploited as an active participant in tumor progression. Extensive reports have defined the dual role of tumor-associated macrophages (TAMs) in tumor development. The protumoral effect exerted by the M2 phenotype has been correlated with a negative outcome in most solid tumors. The high infiltration of immune cells in the hypoxic cores of advanced solid tumors leads to a chain reaction of stimuli that enhances the expression of protumoral genes, thrives tumor malignancy, and leads to the emergence of drug resistance. Many studies have shown therapeutic targeting systems, solely to TAMs or tumor hypoxia, however, novel therapeutics that target both features are still warranted. In the present review, we discuss the role of hypoxia in tumor development and the clinical outcome of hypoxia-targeted therapeutics, such as hypoxia-inducible factor (HIF-1) inhibitors and hypoxia-activated prodrugs. Furthermore, we review the state-of-the-art of macrophage-based cancer therapy. We thoroughly discuss the development of novel therapeutics that simultaneously target TAMs and tumor hypoxia. Nano-based systems have been highlighted as interesting strategies for dual modality treatments, with somewhat improved tissue extravasation. Such approach could be seen as a promising strategy to overcome drug resistance and enhance the efficacy of chemotherapy in advanced solid and metastatic tumors, especially when exploiting cell-based nanotherapies. Finally, we provide an in-depth opinion on the importance of exploiting the tumor microenvironment in cancer therapy, and how this could be translated to clinical practice.
A phase I/II study of cabazitaxel (Cbz) combined with abiraterone acetate (AA) and prednisone (P) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) whose disease has progressed after docetaxel (D) chemotherapy: Preliminary results.
Authors: Christophe Massard, Carmel Pezaro, Dmitri Bobilev, Aurelius Gabriel Omlin, Diletta Bianchini, David Lorente Estelles, Laurence Albiges, Yohann Loriot, Andrea Varga, Thi Xuan Quyen Nguyen, Karim Fizazi, Johann Sebastian De Bono
Journal: Journal of Clinical Oncology (2013)

5049^ Background: Both Cbz and AA have demonstrated significantly improved survival in randomized Ph 3 studies in pts with mCRPC and progressive disease after D treatment. Cbz and AA have established non-overlapping adverse event (AE) profiles. A Ph 1/2 study was initiated to investigate the combination of Cbz + AA for the treatment of mCRPC (NCT01511536). Methods: Pts with progressive mCRPC after D were enrolled. The primary objectives were to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of Cbz + AA (Ph 1), and the PSA response rate (RR) with this combination (Ph 2). Secondary endpoints included AEs, pharmacokinetics (PK) and efficacy. All pts received oral AA 1000 mg QD and P 5 mg BID. In Ph 1, pts received 1 of 2 dose levels (DL) of Cbz (20 and 25 mg/m 2 IV Q3W) according to a 3+3 design. A 2-cycle DLT observation period was used. Here, we report results of Ph 1. Results: Ten pts were enrolled in Ph 1; 9 were evaluable: 3 at DL1 and 6 at DL2 completed 2 cycles without DLTs (total number of cycles = 46). In general, AEs were Grade (Gr) 1/2; the most frequent all-Gr AEs by pt cycle were asthenia (39%), diarrhea (37%; Gr 3 in 1 pt), back pain (26%), nausea (20%), constipation (20%), anemia (17%), decreased appetite (17%) and fatigue (15%; Gr 3 in 2 pts). In the safety population, 0/3 pts at DL1 and 2/7 pts at DL2 experienced Gr 3–4 neutropenia. The MTD was established at the full approved doses of both drugs (Cbz 25 mg/m 2 /AA 1000 mg). In 6 pts evaluable for PK (DL1 and DL2), median Cbz clearance (coefficient of variation %) was similar at cycle 1 (Cbz alone: 28.9 L/h/m 2 [11%]) and cycle 2 (Cbz + AA coadministration: 28.6 L/h/m 2 [42%]). In 9 evaluable pts, 55% PSA RR was observed. Conclusions: In this Ph 1 study, Cbz in combination with AA appeared to have a manageable safety profile. Gr 3–4 neutropenia was observed in 2 of 10 patients. Daily AA treatment did not affect Cbz clearance; Cbz exposure was comparable to previous studies of Cbz + P treatment. The Ph 2 portion is ongoing at the established MTD. Detailed safety, PK and preliminary efficacy data (Ph 1) will be presented. Clinical trial information: NCT01511536.
Abstract B25: Black-white differences in colorectal cancer screening and incidence over time by age and sex
Authors: Stacey A. Fedewa, Douglas Corley, Ahmedin Jemal, Rebecca Siegel, Michael Goodman, Chyke Doubeni
Journal: Cancer Research (2017)

Abstract Introduction: Blacks have the highest colorectal cancer (CRC) burden of any racial/ethnic group and the underlying reason for this disparity has not been fully elucidated. Continued examination of incidence in relation to screening, which is recommended for men and women beginning at age 50 years, may provide valuable insights into these disparities. The present study examined black-white differences in CRC incidence and screening patterns by age and sex over time. Methods: National Health Interview Surveys between 2000-2015 were used to estimate screening prevalence and prevalence ratios (PR) among adults 50 years and older by non-Hispanic white/black race and sex. Data from the SEER were used to estimate age-sex-specific incidence rates from 1992-2013. Results: From 2000 to 2015, CRC screening prevalence in age 50 years and older increased by 69% in whites (from 39.4% to 66.5%) and by 98% in blacks (from 31.1% to 61.4%) on a relative scale. Increases in CRC screening were evident in both men and women. During this time period, black-white differences also narrowed, such that CRC screening in blacks was 19% lower than in whites in 2000 (PR=0.81, 95%CI 0.71,0.92) but only 6% lower in 2015 (PR=0.94, 95%CI 0.88, 1.00). Absolute black-white differences in CRC incidence rates were slightly larger for men than for women (men: 3.0-6.0 versus women: 2.8-5.4 per 100,000) in people 35-49 years old, but decreased overtime in both groups. In 50-79-year-olds, absolute black-white incidence differences were larger for men prior to 2003 (men: 19.8-28.9 versus women: 28.3-33.1 per 100,000) and during 2004-2013 (men: 27.7-53.3 versus women: 20.6-38.7 per 100,000). In 35-49-year-olds, black-white incidence rate ratios (IRR) decreased overtime from 1992-2000 to 2009-2013 in both men (1.47 to 1.19) and women (1.49 to 1.17), but increased in both men (1.06 to 1.38) and women (1.15 to 1.49) for those 50 years and older. Conclusions: Black-white differences in CRC incidence in both absolute and relative terms are greatest in screening-eligible adults and have persisted in recent years whereas absolute differences in incidence in those younger than 50 are relatively small. These patterns may reflect racial gaps in screening uptake. However, disparities in CRC screening prevalence have narrowed in recent years and may portend convergence in CRC incidence rates. Note: This abstract was not presented at the conference. Citation Format: Stacey A. Fedewa, Douglas Corley, Ahmedin Jemal, Rebecca Siegel, Michael Goodman, Chyke Doubeni. Black-white differences in colorectal cancer screening and incidence over time by age and sex. [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer: From Initiation to Outcomes; 2016 Sep 17-20; Tampa, FL. Philadelphia (PA): AACR; Cancer Res 2017;77(3 Suppl):Abstract nr B25.
Abstract B44: When murine tumors are thought to be human: A drawback of patient derived xenografts.
Authors: Camino Menéndez, Beatriz Salvador, Manuel Muñoz, Natalia Baños, Francesca Sarno, Pedro P López-Casas, Manuel Hidalgo
Journal: Clinical Cancer Research (2016)

Abstract The use of preclinical models is essential in every aspect of translational cancer research, from the biologic understanding of the disease to the development of new treatments. Patient Derived Xenograft (PDX) models are increasingly used in translational cancer research due to their advantages over other preclinical models. However, although it has been widely demonstrate that these kind of models are predictive of clinical outcome, there are also some drawbacks when working with them. Analyzing our PDX model collection, we have observed that there is a small percentage of cases in which a murine tumor is developed instead of the original human one by a process that has been called horizontal oncogenesis. This process was already observed and described in the early 80´s, however, it is still not well understood and the molecular mechanisms by which it happens remain unknown. In order to determine the origin of the different murine tumors observed in our mice, we performed immunohistochemistry characterization of our altered models and found two different types of murine tumors: murine fibrosarcomas, which were observed in Colorectal and Pancreatic Ductal Adenocarcinoma PDX models; and murine lymphomas, that were observed mainly in Lung PDX models when they were implanted in Nod-scid mice. We also found a case in which a human lymphoproliferation grew in the animals instead of the sample from the small cell lung cancer obtained from the patient. As these murine tumors grow in the same place where the human donor tumor was implanted, it is important to have a quick and effective method to identify them before performing any study with these altered models. In this regard, we have implemented a simple technique based on PCR analysis with primers that recognize K-Ras. We have designed an estrategy in which we can obtain amplicons of different sizes depending on their human or murine origin. Although we still have to analize some of our PDX models, using this methodology we have confirmed that murine tumors appear in a very low percentage of cases (less than 5% to date). However, even with this low incidence we consider that is essential to identify those murine tumors as soon as possible in order to avoid wasting time, money and resources. Citation Format: Camino Menéndez, Beatriz Salvador, Manuel Muñoz, Natalia Baños, Francesca Sarno, Pedro P López-Casas, Manuel Hidalgo. When murine tumors are thought to be human: A drawback of patient derived xenografts.. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr B44.
The Use of Eicosanoids to Enhance Donor Cell Engraftment after in Utero Hematopoietic Cell Transplantation (IUHCT)
Authors: Matthew M Boelig, Jacqueline Tsai, Aimee G Kim, Michael A Conner, Stavros Loukogeorgakis, Haiying Li, Pulin Li, Leonard I. Zon, Alan W Flake, William H Peranteau
Journal: Blood (2015)
65 plus: A randomized phase III trial of pemetrexed and bevacizumab versus pemetrexed, bevacizumab, and carboplatin as first-line treatment for elderly patients with advanced nonsquamous, non-small cell lung cancer (NSCLC).
Authors: Wolfgang Schuette, Sylke Nagel, Claus-Peter Schneider, Walburga Engel-Riedel, Christian Schumann, Martin Kohlhaeufl, Monika Serke, Gert Hoeffken, Cornelius Kortsik, Martin Reck
Journal: Journal of Clinical Oncology (2013)

8013 Background: Pemetrexed (P) and bevacizumab (B) are efficacious drugs for treatment of non-squamous NSCLC. In this trial the benefit of combining PB with carboplatin (C) was investigated in elderly patients (pts) ≥ 65 years with NSCLC. Methods: In this German multicenter (27 centers), open-label phase III trial pts with stage IIIb/IV non-squamous NSCLC were recruited. Pts were randomized 1:1 to P (500 mg/m 2 ) + B (7.5 mg/kg) or P+B+C (AUC5) d1 q3 wks for 4 to 6 cycles followed by maintenance therapy with B or P+B. The primary endpoint was progression-free survival (PFS), while secondary endpoints included overall survival (OS), 1-year survival rate, overall response rate (ORR) as well as tolerability (AEs/SAEs). Results: 271 pts were enrolled from Sep 2009 to Jan 2012, the ITT population consists of 251 evaluable pts, less than 10 pts are still receiving maintenance therapy. Baseline characteristics were balanced between both treatment groups (PB 118 pts, PBC 133 pts). Median age was 71 years in PB and 72 in PBC. Median PFS time was 4.8 mo in PB and 6.8 mo in PBC. Treatment comparison for ECOG performance status (PS) 0-1 subgroup (PB 112 pts, PBC 126 pts): p=0.0426 (Wilcoxon test), hazard ratio (HR) = 1.31 (95% CI 0.99-1.73). ORR was 31.4% in PB vs. 44.4% in PBC (p=0.0343). Median OS time was 11.6 mo in PB vs. 15.2 mo in PBC. Treatment comparison ECOG PS 0-1: p=0.2050, HR = 1.20 (95% CI 0.85-1.70). 1-year survival rates were 48.2% and 58.8%, respectively. Compared to this the median OS time in the small group of pts with ECOG PS 2 was 11.5 mo in PB vs. 3.8 mo in PBC. AE grade 3/4 and SAE profiles were comparable in both treatment arms, 76 pts (64.4%) with AEs grade 3/4 in PB and 87 pts (65.4%) in PBC, 58 pts (49.2%) with SAEs in PB and 64 pts (48.1%) in PBC. 46 pts (39.0%) in PB vs. 69 pts (51.9%) in PBC received maintenance therapy. Conclusions: Combination of PBC demonstrates with a median OS of 15.2 mo a strong efficacy with acceptable toxicity profile for elderly patients. Addition of carboplatin is recommended for eligible patients. However, in patients with ECOG PS 2 the administration of carboplatin must be carefully reviewed. Clinical trial information: NCT00976456.
Effectiveness of interventions for diagnosis and treatment of tuberculosis in hard-to-reach populations in countries of low and medium tuberculosis incidence: a systematic review
Authors: Charlotte C Heuvelings, Sophia G de Vries, Patrick F Greve, Benjamin J Visser, Sabine Bélard, Saskia Janssen, Anne L Cremers, René Spijker, Beth Shaw, Ruaraidh A Hill, Alimuddin Zumla, Andreas Sandgren, Marieke J van der Werf, Martin P Grobusch
Journal: The Lancet Infectious Diseases (2017)
BCG-unresponsive non-muscle-invasive bladder cancer: recommendations from the IBCG
Authors: Ashish M. Kamat, Marc Colombel, Debasish Sundi, Donald Lamm, Andreas Boehle, Maurizio Brausi, Roger Buckley, Raj Persad, Joan Palou, Mark Soloway, J. Alfred Witjes
Journal: Nature Reviews Urology (2017)
Analysis of fibrinogen variants at gamma 387Ile shows that the side chain of gamma 387 and the tertiary structure of the gamma C-terminal tail are important not only for assembly and secretion of fibrinogen but also for lateral aggregation of protofibrils and XIIIa-catalyzed gamma-gamma dimer formation
Authors: S Kani, F Terasawa, K Yamauchi, M Tozuka, N Okumura
Journal: Blood (2006)
Regulation of the New CXCR7 Receptor in Plasma Cell Dyscrasias.
Authors: Anne-Sophie Moreau, Xavier Leleu, Xiaoying Jia, Judith Runnels, Costas Pitsillides, Alicia L. Carlson, Hai T. Ngo, Aldo M. Roccaro, Abdelkareem Azab, Feda Azab, Charles P. Lin, Irene M. Ghobrial
Journal: Blood (2007)
Hybrid AAV6/2-Mediated Human β-Globin Expression in β-Thalassemia Patient Hematopoietic Stem Cells Transplanted Into Irradiated BALB/c Nude Mouse
Authors: Mengqun Tan, Zhenqing Liu, Juan Zhang, Zhiyan Li, Liujiang Song, Xiaolin Yin, Xinhua Zhang
Journal: Blood (2011)
Influence of Myeloablative Conditioning Regimens on Outcomes after Single Unrelated Cord Blood Transplantation for Adults with Leukemia: An Analysis on Behalf of Eurocord-EBMT-Netcord
Authors: Samir Kanaan Nabhan, Vanderson Rocha, William Arcese, Anne Sirvent, Irina Ionescu, Renata Bizzetto, Karim Boudjedir, Wagnara Chaves, Andrée-Laure Herr, Eliane Gluckman, Guillermo Sanz
Journal: Blood (2008)
Histone Deacetylase Inhibitors and Filgrastim Do Not Synergize with ATRA in the Induction of Changes of Acute Promyelocytic Leukemia Cells Adhesive Properties.
Authors: Gil C. De Santis, Suzana E. Moreno, Hamilton L.G. Teixera, Ana Silvia G. Lima, Aglair B. Garcia, Roberto P. Falcao, Fernando Q. Cunha, Eduardo M. Rego
Journal: Blood (2004)
Derivation and external validation of the PLASMIC score for rapid assessment of adults with thrombotic microangiopathies: a cohort study
Authors: Pavan K Bendapudi, Shelley Hurwitz, Ashley Fry, Marisa B Marques, Stephen W Waldo, Ang Li, Lova Sun, Vivek Upadhyay, Ayad Hamdan, Andrew M Brunner, John M Gansner, Srinivas Viswanathan, Richard M Kaufman, Lynne Uhl, Christopher P Stowell, Walter H Dzik, Robert S Makar
Journal: The Lancet Haematology (2017)
Cap Analysis of Gene Expression (CAGE) Sequencing Reveals Alterations of the Transcriptional Signatures of FLT3-ITD with Secondary D835 TKD Mutations in Acute Myeloid Leukemia
Authors: Yoko Tabe, Kazumasa Sekihara, Kaori Saitoh, Norikazu Monma, Kazuho Ikeo, Bogumil Kaczkowski, Weiguo Zhang, Yasunari Yamanaka, Takashi Miida, Neil P. Shah, Hironori Harada, Yoshihide Hayashizaki, Marina Konopleva, Michael Andreeff
Journal: Blood (2016)
MDM4 actively restrains cytoplasmic mTORC1 by sensing nutrient availability
Authors: Francesca Mancini, Emanuela Teveroni, Giusy Di Conza, Valentina Monteleone, Ivan Arisi, Marsha Pellegrino, Marianna Buttarelli, Luisa Pieroni, Mara D’Onofrio, Andrea Urbani, Alfredo Pontecorvi, Massimiliano Mazzone, Fabiola Moretti
Journal: Molecular Cancer (2017)

Many tumor-related factors have shown the ability to affect metabolic pathways by paving the way for cancer-specific metabolic features. Here, we investigate the regulation of mTORC1 by MDM4, a p53-inhibitor with oncogenic or anti-survival activities depending on cell growth conditions. MDM4-mTOR relationship was analysed through experiments of overexpression or silencing of endogenous proteins in cell culture and using purified proteins in vitro. Data were further confirmed in vivo using a transgenic mouse model overexpressing MDM4. Additionally, the Cancer Genome Atlas (TCGA) database (N = 356) was adopted to analyze the correlation between MDM4 and mTOR levels and 3D cultures were used to analyse the p53-independent activity of MDM4. Following nutrient deprivation, MDM4 impairs mTORC1 activity by binding and inhibiting the kinase mTOR, and contributing to maintain the cytosolic inactive pool of mTORC1. This function is independent of p53. Inhibition of mTORC1 by MDM4 results in reduced phosphorylation of the mTOR downstream target p70S6K1 both in vitro and in vivo in a MDM4-transgenic mouse. Consistently, MDM4 reduces cell size and proliferation, two features controlled by p70S6K1, and, importantly, inhibits mTORC1-mediated mammosphere formation. Noteworthy, MDM4 transcript levels are significantly reduced in breast tumors characterized by high mTOR levels. Overall, these data identify MDM4 as a nutrient-sensor able to inhibit mTORC1 and highlight its metabolism-related tumor-suppressing function.
Yttrium 90 (90Y) Ibritumomab Tiuxetan (Zevalin®) Induces Long-Term Responses in Patients with Relapsed or Refractory Follicular Lymphoma (FL).
Authors: Russell J. Schilder, Thomas E. Witzig, Ian Flinn, Leo I. Gordon, Christos Emmanouilides, Hua Wang, Katie Vo, Arturo Molina
Journal: Blood (2004)
Expansion of peptide-specific T cells from human melanoma-draining lymph nodes.
Authors: Madeleine Strohl, Hallie Graor, Mei Zhang, Anthony Visioni, John Brian Ammori, Isabelle Rivers-McCue, Julian Kim
Journal: Journal of Clinical Oncology (2014)

3047 Background: Adoptive immunotherapy using T lymphocytes is a novel therapy under investigation in patients with advanced stage melanoma. We have evidence that melanoma-draining lymph nodes (MDLN) from patients with stage III disease can be cultured to result in the generation of melanoma specific T cells. These T cells have demonstrated the ability to stop and reverse the progression of disease in vitro and in mouse models. We hypothesized that a proportion of our cultured T cells from MDLNs will demonstrate specific, measurable responses to one or more of known melanoma antigens in vitro. Methods: Human lymph nodes derived from patients with melanoma (IRB CASE 3610) containing T cells, B cells, monocyte/macrophages and dendritic cells were cultured with anti-CD3/CD28 beads, IL-2 and VEGF-blocking antibody. On day 11, cells were cultured with overlapping peptides spanning the sequences of four known melanoma antigens. Cells were incubated for 72 hours prior to undergoing FACS analysis to characterize intracellular IFN-γ, TNF-α and IL-2 expression in CD4+ and CD8+ subpopulations. Stimulation indexes were calculated as stimulated sample /MDLN alone sample expression. Results: Coculture of CD4+ (helper T) cells with MAGEA1, NY-ESO1 and Prame/OIP4 resulted in a TNF-α stimulation index of 1.65,1.6 and 3, respectively. Coculture of CD4+ cells with Melan-A/MART-1 and NY-ESO1 resulted in an IL-2 stimulation indexes of 1.66 and 2.73. CD8+ (cytotoxic T) cells cocultured with MAGEA1 and Prame/OIP4 resulted in TNF-α stimulation indexes of 1.85 and 3.85, while coculturing with Melan-A/MART-1 and NY-ESO1 resulted in IL-2 stimulated indexes of 1.56 and 2.22. Conclusions: This data demonstrates that activated T cells which recognize defined melanoma peptide antigens can be generated from melanoma draining lymph nodes. Development of a novel assay to identify peptide-specific T cells will have significant applications to monitoring immune responses in patients with melanoma. Our goal will be to incorporate the use of this assay in immune monitoring of peripheral blood T cells in patients enrolled into a Phase I clinical trial of T cell therapy in patients with advanced melanoma.
Cotylenin Α, a Fusicoccane Diterpene Glycoside with a Complex Sugar Moiety, and Vincristine Synergistically Inhibit the Growth of Myeloma Cell in Vitro and in Vivo
Authors: Tsutomu Takahashi, Yoshio Honma, Koshi Kawakami, Junji Suzumiya
Journal: Blood (2014)