tbuckley/cabot-search huggingface dataset:
The impact of metformin on progression-free survival of patients with advanced pancreatic well-differentiated neuroendocrine tumor receiving everolimus plus somatostatin analog treatment.
Authors: Sara Pusceddu, Roberto Buzzoni, Luca Giacomelli, Vincenzo Mazzaferro, Laura Concas, Massimo Milione, Barbara Formisano, Elisa D'Autilia, Fabrizio Festinese, Filippo G. De Braud
Journal: Journal of Clinical Oncology (2014)

e15172 Background: Metformin has recently shown some anti-cancer activity, both in vitro and in vivo studies. This analysis evaluates the effect of concomitant metformin (M) administeredduring everolimus (EVE) plus somatostatin analog (SSA) therapy in patients (pts) with pancreatic well-differentiated neuroendocrine tumor (pWDNETs) and diabetes. Methods: We retrospectively evaluated the difference in terms ofprogression-free survival (PFS) between consecutive diabetic pts on M and those or insulin (I) as concomitant drugs during EVE plus SSA therapy. Normoglycemic patients served as controls. Results: Between 2009 and 2012, 31 pts (age 55.5 years; 22 males) were treated with EVE plus SSA. Six pts received M, 6 received I and 19 pts were normolgycemic. In the overall population, median PFS was 12 months (mo) (95%CI 6.3-17.7); mPFS was 24 mo (95% CI 8.6-59.9) in diabetic patients and 12 mo (95% CI 8.7- 15.3) in normoglycemic pts (HR 3.17, 95% CI 1.18-8.49; p=0.016). Median PFS in patients on M was “not achieved” versus 12.2 mo in patients treated with I (95% CI 0-28). At the time of analysis, 4 pts (67%) on M are still receiving EVE plus SSA, with a median duration of treatment of 19.5 mo (range 10-27+ mo). Conclusions: Although the limited number of pts hampers the analysis, these retrospective results may suggest that the addition of M to EVE plus SSA can provide clinical benefits to pWDNETs pts. A prospective evaluation is required to either confirm or discard these preliminary findings.
Abstract 4538: Heterochromatin protein 1 alpha modulates the invasive potential of malignant cells
Authors: Xiaoyan Cui, Lance Stimpson, Tracy Hale, Alejandro Contreras
Journal: Cancer Research (2016)

Abstract Altered chromatin patterning is observed in neoplastic cells, with loss of heterochromatin associated with aggressive malignancies. Heterochromatin is the tightly packed form of chromatin characterized by limited transcription and is identified by the localization of Heterochromatin Protein 1 alpha (HP1 alpha) and Heterochromatin Protein 1 beta (HP1 beta). HP1 alpha and HP1 beta help to maintain chromatin organization during the cell cycle and regulate gene expression. We have previously shown that HP1 alpha and HP1 beta are both downregulated in papillary thyroid carcinomas and that both proteins are lost to a greater degree in 3 out of 4 metastatic lesions of papillary thyroid carcinomas. In addition, others have shown a loss of HP1 alpha is associated with increased invasive potential and metastatic lesions in a range of human tumors. By modulating the level of HP1 alpha in breast cancer cell lines we demonstrate a causal role for HP1 alpha in regulating invasive potential. To identify the molecular pathways through which HP1 alpha regulates this phenotype, RNA-seq was used to measure changes in both miRNA and mRNA expression after knock-down of HP1 alpha in the poorly invasive breast cancer cell line, MCF7. Reduction of HP1 alpha levels increased their invasive potential by 44% and this corresponded with differential expression of genes that promote an epithelial to mesenchymal transition (EMT). In addition, a tissue microarray containing 56 invasive breast carcinomas was immunohistochemically stained for HP1 alpha and HP1 beta. A majority of the breast carcinomas showed decreased expression of HP1 alpha when compared to HP1 beta (32/56 tumors). Taken together, these data suggest that loss of HP1 alpha results in a phenotype that is an intermediate of the EMT, and is supported by their altered cytoskeleton, cell-cell and cell-matrix interactions. HP1 alpha loss may confer a more aggressive, invasive potential in breast carcinomas. By exploring these HP1 alpha −δϵπϵνδϵντ pathways, we seek to further elucidate the regulatory signals that allow a malignant epithelial cell to undergo EMT and begin to invade surrounding tissue. Citation Format: Xiaoyan Cui, Lance Stimpson, Tracy Hale, Alejandro Contreras. Heterochromatin protein 1 alpha modulates the invasive potential of malignant 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 4538.
Abstract 3519: Paroxetine induces apoptosis in human breast cancer MCF-7 cells through mitochondrial dysfunction and modulation of K+ channels
Authors: Kee R. Kang, Young-Woo Cho, Ji Hyun Ryu, Eun-Jin Kim, Jaehee Han, Dawon Kang
Journal: Cancer Research (2016)

Abstract Purpose: Selective serotonin reuptake inhibitors (SSRIs) are widely used for the treatment of patients with depression. Approximately 60% of women with breast cancer suffer from depression. This study was performed to investigate the effect of SSRIs on cell viability of human breast cancer MCF-7 cells. Methods: Cell viability, ROS generation, and Ca2+ increase were quantified using MTT, H2DCFDA, and Fluo-3 AM. Apoptotic signaling pathways were analyzed by immuno-blotting and -staining. Plasma and mitochondrial membrane potentials were determined by DiO PMP and JC-1 dyes, respectively. K+ channel activity was analyzed by whole-cell and single-channel recordings. Results: Of the antidepressants tested in this study, paroxetine most reduced the viability of MCF-7 cells. Paroxetine (10 and 30 μM) treatment resulted in a significant increase in the number of apoptotic cells, an increase in Bax/Bcl-2 ratio, an activation of caspase-8, 9, and PARP, and a release of cytochrome c from mitochondria. In addition, paroxetine markedly increased ROS generation and intracellular Ca2+ levels. Moreover, paroxetine blocked K+ channels, such as large conductance Ca2+-activated K+ channel and TASK-3 channel, which are present in plasma membrane and mitochondria. The paroxetine-induced apoptosis was reduced by antioxidants, in particular NAC. Combination with SB202190 (a p38 MAPK inhibitor) prevented cells from undergoing apoptosis. Conclusion: Our findings show that apoptotic effect of paroxetine is mediated by mitochondrial dysfunction and modulation of K+ channels in MCF-7 cells. We suggest that paroxetine could be an agent for anti-tumor therapy in breast cancer. Citation Format: Kee R. Kang, Young-Woo Cho, Ji Hyun Ryu, Eun-Jin Kim, Jaehee Han, Dawon Kang. Paroxetine induces apoptosis in human breast cancer MCF-7 cells through mitochondrial dysfunction and modulation of K+ channels. [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 3519.
Hidradenitis suppurativa (HS) is associated with low socioeconomic status (SES): A cross-sectional reference study
Authors: Inge E. Deckers, Ineke C. Janse, Hessel H. van der Zee, Tamar Nijsten, Jurr Boer, Barbara Horváth, Errol P. Prens
Journal: Journal of the American Academy of Dermatology (2016)
Abstract 1732: The analysis of stem cell property and mesenchymal feature of anaplastic pancreatic cancer
Authors: Kenjiro Kimura, Kotaro Miura, Ryosuke Amano, Sadaaki Yamazoe, Naoki Kametani, Kohei Nishio, Masaichi Ohira, Kosei Hirakawa
Journal: Cancer Research (2016)

Abstract Background: Anaplastic pancreatic cancer (APC) is the subtype of pancreatic ductal adenocarcinoma (PDAC). APC is poorer prognosis than ordinary PDAC. However, it is unclear what feature of APC is different from that of ordinary PDAC. Our previous studies suggested that the angiogenesis and the tolerance of hypoxia might related to the higher in vivo proliferation of APC than ordinary PDAC. Purpose: We tried to estimate the difference between APC and PDAC using SP cells which reflected cancer stem-like cell and drug resistance and western blotting of E-cadherin and vimentin which reflected epithelial-mesenchymal transition. Materials and Methods: For SP cell analysis, OCUP-A1 and OCUP-A2 were used as APC cell lines and Panc-1 and MIAPaCa2 were used as ordinary PDAC cell lines. These cells were incubated in the medium including Hoechst 33342 with or without verapamil. Then, propidium iodide was added. And the analysis was performed using FACS Aria II. For western blotting, OCUP-A1 and OCUP-A2 were used as APC cell lines. And breast cancer cell line MCF-7 was used as control. Results: The proportion of SP cells in all cells was as follows; OCUP-A1/ OCUP-A2/ Panc-1/ MIAPaCa2 = 1.8±0.28%/ 1.7±0.12%/ 1.1±0.20%/ 0.6±0.058%. The proportion of SP cells of OCUP-A1 and OCUP-A2 were similar to that of Panc-1. However the proportion of SP cells of OCUP-A1 and OCUP-A2 significantly larger than that of MIAPaCa2. In western blotting, the expression of vimentin was observed and the expression of E-cadherin was lost in OCUP-A1 and OCUP-A2. Inversely, the expression of E-cadherin was observed and the expression of E-cadherin was lost in MCF-7. Discussion: It was reported that SP cells might contribute to tumorigenesis and drug resistance the same as cancer stem-like cell. Our current study suggested that larger proportion of SP cells in APC might induce higher malignancy of APC. Also, it was reported that mesenchymal feature might related to cancer stem cell properties. In this study, it was suggested that APC cell lines might have mesenchymal feature. However, it has been unclear whether mesenchymal feature of APC would affect the proportion of SP cells of APC from this study. So, we need to confirm the correlation with cancer stem sell property and mesenchymal feature of APC. Conclusion: The large proportion of SP cells and the mesenchymal feature might contribute to higher malignant property of APC. Citation Format: Kenjiro Kimura, Kotaro Miura, Ryosuke Amano, Sadaaki Yamazoe, Naoki Kametani, Kohei Nishio, Masaichi Ohira, Kosei Hirakawa. The analysis of stem cell property and mesenchymal feature of anaplastic pancreatic cancer. [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 1732.
Characterizing human lung tissue microbiota and its relationship to epidemiological and clinical features
Authors: Guoqin Yu, Mitchell H. Gail, Dario Consonni, Michele Carugno, Michael Humphrys, Angela C. Pesatori, Neil E. Caporaso, James J. Goedert, Jacques Ravel, Maria Teresa Landi
Journal: Genome biology (2016)

The human lung tissue microbiota remains largely uncharacterized, although a number of studies based on airway samples suggest the existence of a viable human lung microbiota. Here we characterized the taxonomic and derived functional profiles of lung microbiota in 165 non-malignant lung tissue samples from cancer patients. We show that the lung microbiota is distinct from the microbial communities in oral, nasal, stool, skin, and vagina, with Proteobacteria as the dominant phylum (60 %). Microbiota taxonomic alpha diversity increases with environmental exposures, such as air particulates, residence in low to high population density areas, and pack-years of tobacco smoking and decreases in subjects with history of chronic bronchitis. Genus Thermus is more abundant in tissue from advanced stage (IIIB, IV) patients, while Legionella is higher in patients who develop metastases. Moreover, the non-malignant lung tissues have higher microbiota alpha diversity than the paired tumors. Our results provide insights into the human lung microbiota composition and function and their link to human lifestyle and clinical outcomes. Studies among subjects without lung cancer are needed to confirm our findings.
Final Results for the 1703 Phase 1b/2 Study of Elotuzumab in Combination with Lenalidomide and Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma
Authors: Paul G. Richardson, Sundar Jagannath, Philippe Moreau, Andrzej Jakubowiak, Marc S Raab, Thierry Facon, Ravi Vij, Darrell White, Donna E. Reece, Lotfi Benboubker, Jeffrey Zonder, L. Claire Tsao, Kenneth C. Anderson, Eric Bleickardt, Anil K Singhal, Sagar Lonial
Journal: Blood (2014)
Wnt7b Signaling from the Ureteric Bud Epithelium Regulates Medullary Capillary Development
Authors: LaToya Ann Roker, Katrina Nemri, Jing Yu
Journal: Journal of the American Society of Nephrology (2016)

The renal vasculature is integral to the physiologic function of the kidneys in regulating hemodynamics of the body and maintaining organ health. The close inter-relationship of capillaries and the renal epithelium is key to renal physiology, but how renal tubules regulate capillary development remains unclear. Our previous work showed that Wnt7b is expressed in the ureteric trunk epithelium and activates canonical Wnt signaling in the surrounding medullary interstitium, where the capillaries reside. In this study, we showed by immunofluorescence that the target interstitial cells of Wnt7b/canonical Wnt signaling are mural cells of periureteric bud capillaries in the nascent renal medulla of embryonic mice. Genetic ablation of Wnt7b enhanced the proliferation of Wnt7b target mural cells, an effect that associated with decreased expression of PDGFRβ and p57kip2, a cyclin-dependent kinase inhibitor, in these cells. Furthermore, Wnt7b regulated lumen formation of the capillary endothelium in the renal medulla. In the absence of Wnt7b signaling, the periureteric bud medullary capillaries displayed narrower lumens lined with less flattened endothelial cells and a significantly increased presence of luminal endothelial cell-cell junctions, a transient configuration in the forming blood vessels in the controls. Moreover, the absence of Wnt7b led to greatly diminished levels of vascular endothelial (VE)-cadherin at the cell surface in these blood vessels. VE-cadherin is essential for blood vessel lumen formation; thus, Wnt7b may regulate lumen formation through modulation of VE-cadherin localization. Overall, these results indicate a novel role of Wnt7b signaling and the ureteric bud epithelium in renal medullary capillary development.
Phase I trial of a sequence-specific combination of the HDAC inhibitor, vorinostat (SAHA) followed by doxorubicin in advanced solid tumor malignancies
Authors: A. Daud, M. Schmitt, D. Marchion, E. Bicaku, S. Minton, M. Egorin, J. Zwiebel, A. Chiappori, D. Sullivan, P. Munster
Journal: Journal of Clinical Oncology (2007)

3502 Background: Preclinical cell culture and xenograft studies suggest that pre-exposure of cancer cells to a histone deacetylase inhibitor (HDACi) may potentiate topoisomerase (topo) inhibitors. The HDACi-induced histone acetylation and chromatin modulation facilitates DNA access and target recruitment for topo II inhibitors. Methods: This Phase I trial explores the safety, tolerability and maximum tolerated dose (MTD) of a weekly schedule of escalating vorinostat doses (twice daily days 1–3) followed by doxorubicin (20 mg/m 2 ) on day 3 (3 out of 4 weeks). Histone acetylation and topo II expression are evaluated in pre-and post-vorinostat peripheral blood mononuclear cells and in tumor cells of the 30 patients treated at the MTD. Results: To date, 15 patients [median age 54 (38–73)] have been treated in 4 vorinostat cohorts: 200, 300, 400, 500 mg bid. Tumor types included: breast (3), melanoma (3), pancreatic (2) and one each of SCLC, sarcoma, endometrial, colon, prostate, renal cell and bladder cancer. Dose-limiting toxicities included a grade 3 thrombocytopenia (1/6) at the 400 mg bid dose. Non-dose limiting Grade 3 and 4 toxicities include neutropenia, thrombocytopenia, fatigue, pulmonary embolus, and anemia (1 pt each). Currently, vorinostat doses of 500 mg bid are being evaluated. One confirmed partial response in a breast cancer patient, as well as minor responses in a melanoma and a prostate cancer patient were seen in 10 evaluable patients. Patients received a median number of 2 (1–9+) treatment cycles. Doxorubicin is stopped after 6 cycles and patients continue on vorinostat alone. H3 and H4 histone acetylation and topo II expression will be correlated with vorinostat dose, plasma concentration and response. Conclusion: A sequence-specific combination of vorinostat and doxorubicin is active without exacerbation of doxorubicin toxicity. The tolerated vorinostat dose exceeds the proposed single agent dose for vorinostat derived from patients with hematological malignancies. Histone hyperacetylation occurs in peripheral blood mononuclear cells at all levels. The anti-tumor activity in breast cancer and melanoma will be further explored. No significant financial relationships to disclose.
Abstract 1040: Differential levels of glycogen in breast cancer cell lines: A potential new target
Authors: Joel A. Yates, Megan Altemus, Zhifen Wu, Michelle L. Wynn, Sofia D. Merajver
Journal: Cancer Research (2016)

Abstract Cancer cells have been known to alter their metabolic processes in order to survive and proliferate. Normally in muscle and liver, excess glucose is stored within the cells as glycogen. Elevated levels of glycogen have also been found in various cancers, including breast cancers. Recent studies have implicated glycogen metabolism as important in promoting survival of cancer cells, suggesting targeting of glycogen metabolism as a possible treatment to inhibit cancer cell growth. In general, modulation of cancer metabolism is believed to be an attractive adjunct strategy to conventional or targeted therapies. Here we set out to investigate glycogen levels as well as levels of proteins involved in glycogen synthesis and degradation vary across different breast cancer cell lines. A glucose metabolism qPCR array found differential levels of the alpha subunit of phosphorylase kinase 1, a key enzyme involved in glycogen degradation among three different breast cancer cell lines. Expression levels of glycogen synthesis and degradation enzymes were assessed using qPCR and immunoblot in various breast cancer cell lines. Glycogen levels in these breast cancer cell lines were quantified using an amyloglucosidase reaction coupled with other enzymatic reactions to produce a fluorescent product. It was found that MDA-MB-231, SUM149, and MCF7 cell lines had increased levels of glycogen, between 6.5 and 23.5 μg glycogen per mg protein, whereas SUM190 and normal-like breast epithelial cell line MCF10A had undetectable levels of glycogen. These findings demonstrate that glycogen metabolism can vary widely amongst cancer types, indicating that therapies targeted to disrupt glycogen degradation may produce differential results and that further study of the role of glycogen metabolism in cancer is warranted. Citation Format: Joel A. Yates, Megan Altemus, Zhifen Wu, Michelle L. Wynn, Sofia D. Merajver. Differential levels of glycogen in breast cancer cell lines: A potential new target. [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 1040.
Bone Mineral Density Testing Disparities Among Patients With Breast Cancer Prescribed Aromatase Inhibitors
Authors: John Charlson, Elizabeth C Smith, Alicia J Smallwood, Purushottam W Laud, Joan M Neuner
Journal: Journal of the National Comprehensive Cancer Network (2016)

Objectives: Aromatase inhibitors (AIs) are standard adjuvant therapy for postmenopausal women with early-stage, estrogen receptor–positive breast cancer. We designed our study to determine whether women initiating adjuvant therapy with an AI underwent baseline bone mineral density testing, as well as what factors predicted adherence with testing guidelines. Methods: Medicare Parts A, B, and D claims were used to identify a cohort of women aged 67 years and older with incident breast cancer in 2006 and 2007 who started AI therapy. Medicare claims provided information about bone density testing, as well as demographic and other treatment data through 2012. We also ascertained which patients were treated with bisphosphonates and studied the relationship of bisphosphonate therapy with bone density testing. Results: Approximately two-thirds of patients had baseline bone density testing. Older age, comorbidity, low income, and black race were associated with lower rates of baseline bone density testing. Testing rates decreased substantially with increasing age from 73% for women aged 67 to 70 years to 51% for those 85 years of age and older (adjusted odds ratio for not being tested, 2.48 [Cl, 2.17–2.82]). The proportion of women who had neither bone density testing nor bisphosphonate therapy increased with age as well. Conclusions: Despite the importance of age as a risk factor for fractures, older women starting treatment with AIs for treatment of breast cancer are less likely to undergo recommended bone density assessment.
Dose-finding study of vinblastine in combination with nilotinib in children, adolescents and young adults with refractory or recurrent low-grade glioma: Results of the ITCC/SIOPE-Brain VINILO phase I trial (NCT01887522).
Authors: Jacques / Grill, Marie-Cecile Le Deley, Gwenael / Le Teuff, Samuel / Abbou, Birgit Geoerger, Francisco Bautista, Katty Malekzadeh, Angelo Paci, Emilie De Carli, Anne-Isabelle Bertozzi, Anne Pagnier, Pierre Leblond, Frederic / Millot, Isabelle Aerts, Christelle Dufour, Claire Berger, Fanny Fouyssac, Karsten Nysom, Gilles Vassal
Journal: Journal of Clinical Oncology (2016)

10555 Background: Chemotherapy (CT) is frequently used as first adjuvant treatment for low-grade gliomas (LGG) when surgery cannot be completed. Relapses are frequent and new rescue regimens are needed. Vinblastine (VBL) is a known effective drug in LGG. Nilotinib (NIL) is a multitargeted agent with potential synergistic effects with VBL against angiogenesis or tumor cell growth as well as immunostimulatory effects. The trial aimed at determining the recommended doses of VBL and NIL in combination for phase II trials (RP2D) in refractory/recurrent LGG. Methods: Histologically-confirmed LGG or NF1-associated tumors previously treated with at least 1 previous line of CT or radiotherapy. NIL was given orally (planned BID doses: 115, 230 & 350 mg/m2) in combination with VBL weekly injections (planned doses: 3, 4, 5 & 6 mg/m2), for a maximum of 12 28-day cycles. The dose-escalation scheme followed the dual agent model-based method (Wang & Ivanova, Biometrics 2005). Results: 35 pts were enrolled across 4 dose levels: VBL=3 + NIL=115, 3+230, 4+230, and 3+350. Median age, 7 yrs (range, 1-19), 10/35 NF1 (29%). Patients were heavily pretreated with a median of 3 prior lines of treatment (1-10). Among the 30 evaluable pts, dose limiting toxicity (DLT) consisted in hematological toxicity in 3 pts, skin toxicity in 2 pts, and hypertension complicated with seizure associated with febrile neutropenia in 1 pt. Identified RP2D: 3 mg/m2 weekly for VBL + 230 mg/m2 BID for NIL (estimated probability of DLT =18%). Overall, 13 pts completed the 12 cycles and 1 is still on treatment; 3 stopped therapy due to toxicity (none at the RP2D), and 18 due to disease progression. 7 pts (2 with NF1) had a minor or partial radiological response. The estimated 12-month PFS was 45% (95%CI, 30-61%). Pharmacokinetic analyses showed that effective levels of NIL were achievable at steady state. Conclusions: VINILO dosing was limited mostly by myelosuppression. Efficacy of the VINILO combination at the RP2D will be evaluated in a randomized Phase II comparing this regimen to VBL alone. (Study sponsored by INCa-PHRC, I4M charity and Novartis). Clinical trial information: NCT01887522.