tbuckley/cabot-search huggingface dataset:
Time to chemotherapy following treatment with sipuleucel-T: Data from PROCEED.
Authors: Christopher Michael Pieczonka, Raoul S. Concepcion, Ronald F. Tutrone, David F. Penson, James L. Bailen, Carl A. Olsson, John B. Forrest, Vahan Kassabian, Bryan A. Mehlhaff, Neal D. Shore, Raymond S. Lance, Robert Claude Tyler, Andrew Sandler, Candice McCoy, James Boyd Whitmore, Matthew R. Cooperberg
Journal: Journal of Clinical Oncology (2014)

5040 Background: Sipuleucel-T (sip-T) is an autologous cellular immunotherapy that targets prostatic acid phosphatase and is approved by the US FDA and EMA for the treatment of certain patients (pts) with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer. PROCEED is an ongoing multicenter Phase 4 registry in the US that enrolled pts treated with commercial sip-T. PROCEED is collecting information on chemotherapy treatments (C) after sip-T treatment; these data will allow us to assess C predictability and determine characteristics associated with time to C after sip-T treatment. Methods: PROCEED enrolled >1,900 mCRPC pts who were treated with sip-T within the prior 6 months. Demographics, disease characteristics, and prior and ongoing prostate cancer treatments were recorded at baseline. We further characterized data from patients who received C after sip-T and used statistical modeling to identify predictors of time to first C. Results: As of May 2013, 1,254 enrolled pts had completed sip-T treatment. Time to first C ranged from 0.4 – 19.2 months. Median time to first C was shorter at oncology vs. urology practices (11.6 vs. 18.0 months, Kaplan-Meier method; HR= 2.154; p<0.001). A stepwise Cox model for time to C was developed from preliminary analysis of several baseline factors. Conclusions: The final stepwise Cox model indicates that pts who are younger, have lower baseline hemoglobin, have higher baseline PSA, or who received prior C, receive subsequent C sooner. Clinical trial information: NCT01306890.Predictors of time to C1. Kaplan-Meier estimate of median time (95% CI2) to first C, months3 13.1 (12.2, 15.4) Final Stepwise Cox model for time to first C Baseline covariate4 Hazard ratio (95% CI4) P value Age, yrs (median = 72.0) 0.604 (0.480, 0.758) <0.001 Baseline hemoglobin, g/dL (median = 12.7) 0.703 (0.561, 0.881) 0.002 Prior C (15.4%) 1.341 (1.005, 1.788) 0.046 Baseline PSA5, ng/mL (median = 16.1) 1.704 (1.360, 2.135) <0.001 1Chemotherapy. 2Confidence interval. 3Changes in the enrolled population over time may result in the time to C differing in subsequent analyses. 4Continuous variables dichotomized at median value. 5Prostate-specific antigen.
Abstract 1153: Hand-1 overexpression inhibits medulloblastoma cell invasion and metastatic ability via Oct-3/4 / β-catenin interaction
Authors: Swapna Asuthkar, Maheedhara R. Guda, Andrew J. Tsung, Reuben Antony, Dzung H. Dinh, Kiran K. Velpula
Journal: Cancer Research (2016)

Abstract Medulloblastoma (MB) is the most common malignant brain tumor in children. Treatment of medulloblastoma includes surgery, radiation and chemotherapy. Despite long-term survival for the majority of children, 50% of medulloblastomas recur. Recently, medulloblastomas are classified into four distinct molecular subgroups, viz., WNT, SHH, group 3, and group 4 based on constitutive activation of WNT/β-catenin, SHH, and NOTCH signaling pathways that regulate cancer stem cell pluripotency, tumor growth, progression and metastasis. Previously, we investigated the molecular machinery underlying uPAR and WNT/β-catenin interdependent signaling pathways in medulloblastoma stem cells. Further, we showed that ionizing radiation-induced uPAR overexpression is associated with increased accumulation of β-catenin in the nucleus. Complementing to this we demonstrated that uPAR protein act as cytoplasmic sequestration factor for a novel basic helix-loop-helix transcription factor, Hand-1. Here, we show that Hand-1 expression is observed to be downregulated in all the molecular subgroups of medulloblastoma. We also showed that the pluripotency marker, Oct-3/4 (encoded by the Pou5f1 gene) interacts with β-catenin and Hand-1 that ultimately regulated the uPAR expression. Our preliminary study demonstrated that Oct-3/4 preferentially cooperated with β-catenin in medulloblastoma to maintain tumor progression. Immunohistostaining of clinical specimens also confirmed our aforementioned results. Taken together, our studies show that overexpression of Hand-1 in medulloblastoma cells may effectively inhibit uPAR-induced invasion and metastatic ability, thereby regulating Oct-3/4/β-catenin balance. Citation Format: Swapna Asuthkar, Maheedhara R. Guda, Andrew J. Tsung, Reuben Antony, Dzung H. Dinh, Kiran K. Velpula. Hand-1 overexpression inhibits medulloblastoma cell invasion and metastatic ability via Oct-3/4 / β-catenin interaction. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1153.
Abstract 4774: Hypoxic bio-reduction of novel NBQ48 in treated tumor cells and the activity of cytochrome P450 reductase
Authors: Beatriz Zayas, Vivian Lebron, Juan P. Rivera, Christian Velez, Osvaldo Cox
Journal: Cancer Research (2016)

Abstract The main goal of this research was to evaluate the reduction activity of a novel Nitrobenzazolo[3,2-a]quinolinium (NBQ48) compound under hypoxic environment thru the formation of a fluorescent metabolite and further to evaluate the activity of the cytochrome P450 (CYP450) reducatase in the reduction of these compounds. To evaluate the reduction of NBQ48 and the formation of its fluorescent metabolite two (2) tumor cell lines in culture Toledo (lymphoma) and A431 (endothelial) where treated under nitrogen or argon saturated environments to create a hypoxic (low oxygen) environment. In a 15 ml conical tube 4×106 cells in RPMI 1640 media were treated with NBQ 48 (3mM) for a final volume of 5mL and incubated with argon or nitrogen saturated environment at 37ºC, 5%. Cells were exposed at different time periods (0 to 48 hours) to evaluate the effect of exposure time in the reduction of the NBQ48 by detecting the reduced fluorescent product, the amino-substituted ABQ48. In addition NBQ48 treated tumor cells were located inside a hypoxic chamber to evaluate the formation of the fluorescent metabolites indicative of a metabolically active cell. To determine if the CYP450 reductase enzyme is activated in the reduction of the NBQ towards the formation of the ABQ metabolite, an experiment containing the NBQs and the CYP reductases was designed. Four (4) samples were prepared: blank media hypoxic, NBQ experimental hypoxic, positive ABQ spiked and negative aerobic control NBQ. Samples with NBQ48 (0.4mM) were incubated for 24 hours. After the incubation period, fluorescence emissions indicating the reductive fluorescent product were measured using a Modulus fluorometer (blue filter). The results on tumor cells treated with NBQ48 under hypoxic conditions demonstrated reduction and the formation of a fluorescent product, amino-substituted ABQ48. The time dependent increase in fluorescence in comparison with non treated cells indicated that the reduction of the NBQ increased with time. Results on the determination of the activity of CYP450 in the reduction of the NBQ48 indicated that only samples containing the CYP450 showed the formation of a fluorescent species presumably, ABQ48. This study provides evidence of the reduction of NBQ48 and the formation of a fluorescent metabolite thru the activations of the CYP450 reductases. The implemented experimental design could also be used to determine activity of hypoxic tissues with clinical applications. Citation Format: Beatriz Zayas, Vivian Lebron, Juan P. Rivera, Christian Velez, Osvaldo Cox. Hypoxic bio-reduction of novel NBQ48 in treated tumor cells and the activity of cytochrome P450 reductase. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4774.
Fresh versus Frozen Embryos for Infertility in the Polycystic Ovary Syndrome
Authors: Zi-Jiang Chen, Yuhua Shi, Yun Sun, Bo Zhang, Xiaoyan Liang, Yunxia Cao, Jing Yang, Jiayin Liu, Daimin Wei, Ning Weng, Lifeng Tian, Cuifang Hao, Dongzi Yang, Feng Zhou, Juanzi Shi, Yongle Xu, Jing Li, Junhao Yan, Yingying Qin, Han Zhao, Heping Zhang, Richard S. Legro
Journal: New England Journal of Medicine (2016)

The transfer of fresh embryos is generally preferred over the transfer of frozen embryos for in vitro fertilization (IVF), but some evidence suggests that frozen-embryo transfer may improve the live-birth rate and lower the rates of the ovarian hyperstimulation syndrome and pregnancy complications in women with the polycystic ovary syndrome.In this multicenter trial, we randomly assigned 1508 infertile women with the polycystic ovary syndrome who were undergoing their first IVF cycle to undergo either fresh-embryo transfer or embryo cryopreservation followed by frozen-embryo transfer. After 3 days of embryo development, women underwent the transfer of up to two fresh or frozen embryos. The primary outcome was a live birth after the first embryo transfer.Frozen-embryo transfer resulted in a higher frequency of live birth after the first transfer than did fresh-embryo transfer (49.3% vs. 42.0%), for a rate ratio of 1.17 (95% confidence interval [CI], 1.05 to 1.31; P=0.004). Women who underwent frozen-embryo transfer also had a lower frequency of pregnancy loss (22.0% vs. 32.7%), for a rate ratio of 0.67 (95% CI, 0.54 to 0.83; P<0.001), and of the ovarian hyperstimulation syndrome (1.3% vs. 7.1%), for a rate ratio of 0.19 (95% CI, 0.10 to 0.37; P<0.001), but a higher frequency of preeclampsia (4.4% vs. 1.4%), for a rate ratio of 3.12 (95% CI, 1.26 to 7.73; P=0.009). There were no significant between-group differences in rates of other pregnancy and neonatal complications. There were five neonatal deaths in the frozen-embryo group and none in the fresh-embryo group (P=0.06).Among infertile women with the polycystic ovary syndrome, frozen-embryo transfer was associated with a higher rate of live birth, a lower risk of the ovarian hyperstimulation syndrome, and a higher risk of preeclampsia after the first transfer than was fresh-embryo transfer. (Funded by the National Basic Research Program of China and others; ClinicalTrials.gov number, NCT01841528.).
Abstract 2787: Expression of Olfactomedin 4 is regulated by methylation in the benign prostate epithelial cell-RWPE1 and PC-3 prostate cancer cells
Authors: Hongzhen Li
Journal: Cancer Research (2016)

Abstract Expression of Olfactomedin 4 gene (OLFM4) plays a critical tumor suppressor role in human and murine prostate cancer. We have previously reported that loss or reduced OLFM4 expression is associated with the progression of human prostate cancer. We and others have further determined that deletions within the OLFM4 gene are present in about 10 to 25% of human prostate cancer samples. However, we have observed that loss of expression of OLFM4 were found in more than 58% of the samples obtained from advanced prostate cancer patients. Therefore, we sought to study the role of epigenetic factors in the regulation of OLFM4 gene expression in normal and prostate cancer cell lines. Methylation of CpG sites in the promoter region of key genes is an important epigenetic mechanism in cancer development. We examined the methylation status of CpG sites in the OLFM4 promoter region in the benign immortalized prostate epithelial cell line (RWPE1), androgen-responsive cancer cells (LNCaP, VCaP), and androgen-independent cancer cells (PC-3 and DU145). There are eight CpG sites (-681, -666, -562, -486, -91, +4, +34) in the promoter regions of OLFM4 gene. The pattern of methylation status was detected and compared between RWPE1 cell and cancer cell lines LNCaP, VCaP, PC-3 and Du145. To test whether hypermethylation of CpG sites of OLFM4 gene can block the expression of OLFM4 gene, RWPE1 cells were treated with 5-azadeoxycytidine (5-Aza.) (5 μM) from 24h to 96h and PC-3 cells were treated with 5-azadeoxycytidine (5-Aza.) (5 μM) for 3 days and 7 days. The methylation status of CpG sites was compared in the presence or absence of 5-Aza. at different time points. The addition of 5-Aza. consistently reduced the percent methylation of the CpG sites. Correspondingly, the expression of the OLFM4 gene was induced after treatment with 5-Aza. in both RWPE1 and PC-3 cells. These results suggest that expression of OLFM4 is regulated by the methylation status of OLFM4 gene in the RWPE1 and PC-3 prostatic cell lines. Citation Format: Hongzhen Li. Expression of Olfactomedin 4 is regulated by methylation in the benign prostate epithelial cell-RWPE1 and PC-3 prostate cancer cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2787.
Evaluating the role of phase I expansion cohorts in drug development.
Authors: Mohadese Behtaj, Pingfu Fu, Neelesh Sharma, Afshin Dowlati
Journal: Journal of Clinical Oncology (2015)

e13585 Background: There is a perception that the use of expansion cohorts (EC) in phase I trials is increasing. Yet the role of expansion cohorts in aiding drug development is unclear. Theoretical advantages include better description of toxicities, refinement of recommended phase II dose (RP2D), and observation of responses in selected malignancies. We sought to determine factors associated with conducting expansion cohorts, and their impact on RP2D, impact on subsequent phase II studies of the agents and finally FDA approval of the studied agent. Methods: We reviewed all phase I trials between June 2004 to May 2014 published in Journal of Clinical Oncology. Mechanism of action of the study agent, MTD/RP2D, number of participants in EC, tumor type and source of funding were identified from all phase I trials. FDA approval of the study drug and subsequent conduct of phase II study for same drug were assessed. The dose and number of patients in phase II studies were compared to similar data for the same drug in phase I studies with EC. Results: From 253 phase I studies identified, 102 studies (40.3%) used expansion cohort at MTD/RP2D. Only in 8.8%, MTD/RP2D changed after adding EC and 96% did not provide statistical sample size for EC. Comparison between studies with/without EC showed, trials for monoclonal antibody and chemotherapy drugs were less likely to use EC (p = 0.038), Phase I studies funded by pharmaceutical company were more likely to have expansion cohort (p = 0.013). Trials with EC did not have a higher rate of subsequent FDA approval. Furthermore the use of EC did not circumvent the need for phase II trials of the same agent. Conclusions: The importance of using EC before phase II is subject to ongoing debate. It is used in less than half of phase I trials and frequently implemented by pharmaceutical sponsors. It rarely results in changing the recommended RP2D and does not result in higher chances of FDA approval. Statistical justification for EC is uniformly missing.
Abstract 1457: Regulatory T cells and its impact on prostate cancer development and clearance
Authors: Sanjay Kumar, James Stokes, Karyn Scissum Gunn, Udai Singh, Selvarangan Ponnazhagan, Manoj K. Mishra
Journal: Cancer Research (2016)

Abstract Prostate Cancer (PCa) is the most common non-skin malignancy and the most commonly diagnosed cancer in men in United States. The immunotherapeutic role of immune cells in regulation of PCa have been studied but still the specific roles of regulatory T cells needs further investigation. In this study, the role of immune cells, particularly the role of regulatory T cells, in tumor development and progression was analyzed using TRAMP (transgenic adenocarcinoma of mouse prostate) model system. TRAMP cells (TRAMP C1, C2 and C3) were used to induce tumor in C57/B6 mouse. Interestingly, the TRAMP-C3 is non-tumorigenic whileTRAMP-C1 and TRAMP-C2 are tumorigenic. Briefly, tumor induction studies were performed on different groups of mice. Mice were inoculated with these three cell lines, tumors were analyzed at different time points, and the percentage and absolute number of different immune cells (CD4, CD8, NK, NKT, Macrophages, regulatory T cells, and Dendritic cells) were analyzed. Our data demonstrated that the capacity of TRAMP-C1 and TRAMP-C2 cells to form tumors and the inability of TRAMP-C3 cells to induce tumors is mediated by number of regulatory T cells in the tumor microenvironment. Therefore, the data suggest an understanding of function and effect of regulatory T cells during tumor progression and clearance is needed to successfully develop a targeted therapy to modulate the number of immune cells in the tumor microenvironment. Citation Format: Sanjay Kumar, James Stokes III, Karyn Scissum Gunn, Udai Singh, Selvarangan Ponnazhagan, Manoj K. Mishra. Regulatory T cells and its impact on prostate cancer development and clearance. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1457.
A Long-Term (5-Year) Sustained Efficacy of Tocilizumab for Multicentric Castleman’s Disease and the Effect on Pulmonary Complications.
Authors: Norihiro Nishimoto, Osamu Honda, Hiromitsu Sumikawa, Takeshi Johkoh, Katsuyuki Aozasa, Yuzuru Kanakura
Journal: Blood (2007)
Abstract 1741: The association between menopause symptoms and risk of postmenopausal breast cancer among non-users of hormone therapy
Authors: Tricia Li, Jiali Han, Chunyan He
Journal: Cancer Research (2016)

Abstract Background: Hot flashes are a common symptom among women during their menopause transition, likely due to the changes of endogenous hormone levels. Previous research suggested that hot flashes symptoms were associated with a reduced risk of cardiovascular diseases. Few studies have investigated the association of hot flashes symptoms with the risk of breast cancer. Furthermore, the confounding effect by hormone use has not been sufficiently addressed in previous studies. Methods: We investigated the association between hot flashes symptoms and risk of postmenopausal breast cancer in the Nurses’ Health Study (NHS). In order to eliminate the confounding by hormone use, we investigated the association only among women who never used hormone therapy. We calculated relative risk of breast cancer using a multivariate Cox model, adjusting for potential confounders, including age, race, family history of breast cancer, age at menarche, age at menopause, parity, age at first birth, body mass index, smoking, alcohol use, and education. We further investigated the severity of hot flashes symptoms in association with risk of postmenopausal breast cancer. Results: We documented 1079 incidence of breast cancer during 396,166 person-years of follow-up. Hot flashes symptoms were not associated with risk of postmenopausal breast cancer after adjustment for potential confounders (RR = 1.02, 95% CI, 0.90-1.15) among non-users of hormone therapy. Relative risk of breast cancer across symptom severity categories (mild, moderate, severe) were 1.01 (95% CI, 0.87-1.17), 1.04 (95% CI, 0.88-1.22), and 1.05 (95% CI, 0.75-1.46), respectively. Conclusion: These data suggested that menopausal symptoms were not associated with risk of postmenopausal breast cancer. Citation Format: Tricia Li, Jiali Han, Chunyan He. The association between menopause symptoms and risk of postmenopausal breast cancer among non-users of hormone therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1741.
The TMSB4 Pseudogene LncRNA Functions as a Competing Endogenous RNA to Promote Cartilage Degradation in Human Osteoarthritis
Authors: Qiang Liu, Xiaoqing Hu, Xin Zhang, Linghui Dai, Xiaoning Duan, Chunyan Zhou, Yingfang Ao
Journal: Molecular Therapy (2016)

Mechanical stress plays a key role in the development of cartilage degradation in osteoarthritis (OA). Nevertheless, the role of long noncoding RNAs in mechanical stress-induced regulation of chondrocytes remains unclear. The aim of this study was to explore the function of mechanical stress-related long noncoding RNAs in cartilage. Tissue samples were collected from 50 patients and chondrocytes were exposed to cyclic tensile strain (CTS). A total of 107 lncRNAs were differentially expressed in damaged cartilage versus intact cartilage. Of these lncRNAs, 51 were upregulated and 56 were downregulated in the damaged tissue. The TMSB4 pseudogene, lncRNA-MSR, was upregulated in the damaged cartilage and was activated in chondrocytes in response to mechanical stress. Furthermore, lncRNA-MSR regulated the expression of TMSB4 by competing with miRNA-152 in chondrocytes. Our results demonstrated that upregulation of lncRNA-MSR initiates pathological changes that lead to cartilage degradation, and the inhibition of lncRNA-MSR could represent a potential therapeutic target for OA.
Abstract 1911: ΔNp63α promotes TGFβ-induced metastasis by silencing a microRNA network restraining wound healing
Authors: Lidia Rodriguez Calleja, camille Jacques, Francois Lamoureux, Marc Baud’huin, Thibault Quillard, Franck Verrecchia, Dominique Heymann, Leif Ellisen, Benjamin Ory
Journal: Cancer Research (2016)

Abstract Primary cancer cell dissemination is the key event in metastasis, yet context-specific determinants remain largely undefined. Multiple reports have suggested an anti-metastatic role for the p53 family member p63 linked to its minor epithelial isoform, TAp63. However, the role and contribution of the major p63 isoform, ΔNp63α, remain largely undefined. Here we report a distinct and TAp63-independent mechanism in which ΔNp63α-expressing cells, in a TGFβ-rich microenvironment, are positively selected for metastatic dissemination. We define the molecular mechanism of this effect, through ΔNp63α-mediated repression of miR-527 and miR-665 and the subsequent upregulation of two TGFβ pathway major effectors, SMAD4 and TβRII. Furthermore, we provide evidence that this mechanism reflects a fundamental role for ΔNp63α in the normal wound healing response. We show that ΔNp63α and miR-527/665 control the TGFβ-dependent signaling that switches off anti-migratory miR-198 by downregulating the regulatory factor KSRP. Collectively, these findings reveal a novel microRNA network orchestrated selectively by ΔNp63α that is involved in the physiological regulation of wound healing but is hijacked by tumors to promote metastatic dissemination. Citation Format: Lidia Rodriguez Calleja, camille Jacques, Francois Lamoureux, Marc Baud’huin, Thibault Quillard, Franck Verrecchia, Dominique Heymann, Leif Ellisen, Benjamin Ory. ΔNp63α promotes TGFβ-induced metastasis by silencing a microRNA network restraining wound healing. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1911.