tbuckley/cabot-search huggingface dataset:
A randomized trial of vitamin D<sub>3</sub> in aromatase inhibitor-associated musculoskeletal symptoms.
Authors: Alice C. Shapiro, Susan A Adlis, Shuang Liang, Kim Robien, Mark N. Kirstein, Elsie Anderson, Rachel E. Lerner
Journal: Journal of Clinical Oncology (2015)

9608 Background: Vitamin D3 supplementation (D3) has been suggested as a treatment for aromatase inhibitor (AI)-associated musculoskeletal symptoms (AIMSS), but efficacy and safety are unclear. Methods: We randomly assigned 113 post-menopausal women ( ≥ 18 years; stage I-IIIA breast cancer; taking an AI and experiencing AIMSS), to either 600 IU D3 (control: n = 56) or 4,000 IU D3 (experimental: n = 57), daily for 6 months (6 mos). The primary study endpoint was change in musculoskeletal symptoms (MS) from baseline to 6 mos, measured by: The Breast Cancer Prevention Trial Symptom Scales-MS subscale (BCPT-MS), the Australian/Canadian Osteoarthritis Hand Index (AUSCAN), the Western Ontario and McMaster Osteoarthritis Index (WOMAC) and hand grip strength (Dynamometer). Plasma AI pharmacokinetics (AI-PK) were estimated using non-linear mixed-effects modeling. Effects of D3 on AI-PK were tested by likelihood ratio test. Serum 25(OH)D was quantified by chemiluminescent immunoassay (DiaSorin, Stillwater, MN). Sample size was calculated on a change of 0.62 in BCPT-MS score. Assuming a two-tailed test with α = 0.05 and power = 80%, adequate sample size was 116 (58 per group). Primary endpoint analyses were based on intent-to-treat and determined using a General Linear Model controlling for possible effect modifiers. Results: The groups did not differ on demographic or clinical characteristics nor on AIMSS measures. After 6 mos, serum 25(OH)D was 33±8 ng/mL vs. 46±11 (mean±sd; control vs experimental; p < 0.001). There were no statistically significant differences between groups (control vs exp) in mean change in AIMSS scales from baseline to 6 mos: BCPT-MS: -0.45 vs. -0.24; WOMAC function: -1.23 vs -3.96; WOMAC pain: -0.56 vs. -1.18; WOMAC stiffness: -0.47 vs -0.54; AUSCAN function: -0.75 vs -1.12; AUSCAN pain: -0.24 vs. -0.90; AUSCAN stiffness: -0.11 vs. -0.08; hand grip: 1.06 vs 1.78 (all p > 0.1). AI clearance did not differ significantly between groups (baseline vs 6 mos; p > 0.5). Conclusions: Women randomly assigned to higher dose D3 (4,000 IU) showed no improvement in AIMSS over usual dose D3 (600 IU). While D3 does not appear to adversely affect AI drug metabolism, it may have other health effects in this population. Clinical trial information: NCT01509079.
Emerging Roles of Vascular Endothelium in Metabolic Homeostasis
Authors: Xinchun Pi, Liang Xie, Cam Patterson
Journal: Circulation Research (2018)

Our understanding of the role of the vascular endothelium has evolved over the past 2 decades, with the recognition that it is a dynamically regulated organ and that it plays a nodal role in a variety of physiological and pathological processes. Endothelial cells (ECs) are not only a barrier between the circulation and peripheral tissues, but also actively regulate vascular tone, blood flow, and platelet function. Dysregulation of ECs contributes to pathological conditions such as vascular inflammation, atherosclerosis, hypertension, cardiomyopathy, retinopathy, neuropathy, and cancer. The close anatomic relationship between vascular endothelium and highly vascularized metabolic organs/tissues suggests that the crosstalk between ECs and these organs is vital for both vascular and metabolic homeostasis. Numerous reports support that hyperlipidemia, hyperglycemia, and other metabolic stresses result in endothelial dysfunction and vascular complications. However, how ECs may regulate metabolic homeostasis remains poorly understood. Emerging data suggest that the vascular endothelium plays an unexpected role in the regulation of metabolic homeostasis and that endothelial dysregulation directly contributes to the development of metabolic disorders. Here, we review recent studies about the pivotal role of ECs in glucose and lipid homeostasis. In particular, we introduce the concept that the endothelium adjusts its barrier function to control the transendothelial transport of fatty acids, lipoproteins, LPLs (lipoprotein lipases), glucose, and insulin. In addition, we summarize reports that ECs communicate with metabolic cells through EC-secreted factors and we discuss how endothelial dysregulation contributes directly to the development of obesity, insulin resistance, dyslipidemia, diabetes mellitus, cognitive defects, and fatty liver disease.
Effect of Rosiglitazone Treatment on Soluble CD40L in Patients With Type 2 Diabetes and Coronary Artery Disease
Authors: NikolausMarx, ArminImhof, JohannesFroehlich, LailaSiam, JochenIttner, GerhardWierse, ArnoldSchmidt, WinfriedMaerz, VinzenzHombach, WolfgangKoenig
Journal: Circulation (2003)

Background— Interaction of CD40L with its receptor CD40 is critically involved in inflammatory cell activation in atherogenesis. In addition, serum levels of soluble CD40L are elevated in acute coronary syndromes and have been associated with increased cardiovascular risk in healthy subjects, thus making sCD40L an intriguing target to modulate the inflammatory response in the vasculature. PPARγ-activating thiazolidinediones, novel insulin-sensitizing antidiabetic agents, have recently been shown to exhibit antiinflammatory effects in the vessel wall. To examine whether thiazolidinedione treatment might modulate serum levels of sCD40L in high-risk patients, we performed a randomized, placebo-controlled, single-blinded trial to assess the effect of rosiglitazone on sCD40L levels in patients with type 2 diabetes and coronary artery disease (CAD). Methods and Results— Thirty-nine patients with diabetes and angiographically proven CAD were randomized to receive rosiglitazone (4 mg BID) or placebo for 12 weeks....
Abstract 1831: PKCδ as a novel target for HER2-positive, trastuzumab resistant breast cancer
Authors: Debra L. Wyatt, Andrei Zlobin, Emily Ma, Mitchell F. Denning, Clodia Osipo
Journal: Cancer Research (2018)

Abstract Breast cancer is the most common cancer diagnosis and second leading cause of cancer related deaths among women in the United States. This poor prognosis is in part due to the high rates of resistance. In particular, resistance to anti-HER2-based therapy remains a clinical challenge for women with breast cancer suggesting that better treatment strategies are needed. Results demonstrate that resistance to trastuzumab correlates with lower PKC activity compared to trastuzumab sensitive breast cancer cells, suggesting that downregulation of PKC activity may contribute to trastuzumab resistance. The exact mechanism by which PKCs contribute to trastuzumab resistance is not well understood. Here, we hypothesized that activation of PKCs could prevent trastuzumab resistance and thus inhibit the survival and recurrence of HER2+ breast cancer. Our results show that in two distinct trastuzumab-resistant cell lines (HCC1954 and BT474), activation of PKC by the phorbol ester TPA inhibits both proliferation of bulk cells and survival of cancer stem cells (CSC) as assessed by mammosphere formation. Further, treatment using a pharmacological PKC inhibitor (GF109203X) almost completely rescued the anti-proliferative and anti-CSC survival effects of TPA in two distinct trastuzumab-resistant cell lines. Measurement of PKC isoforms at the transcript and protein levels showed that PKCδ was overexpressed in the resistant cell line compared to the sensitive cell line. PKCδ depletion using a siRNA prevented the anti-proliferative and anti-CSC survival effects of TPA, suggesting that PKCδ was the target of TPA activation in trastuzumab resistant cells. TPA-mediated activation of PKCδ was found to cause G2/M cell cycle arrest, almost complete inhibition of AKT phosphorylation at serine 473, and decreased expression of the CSC marker, ALDH1A1. These results suggest that phorbol ester-mediated activation of PKCδ could be a novel therapeutic strategy for HER2+ breast cancer that is resistant to trastuzumab-based therapy. Citation Format: Debra L. Wyatt, Andrei Zlobin, Emily Ma, Mitchell F. Denning, Clodia Osipo. PKCδ as a novel target for HER2-positive, trastuzumab resistant breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1831.
A Targeted Quantitative Proteomic Approach Assesses the Reprogramming of Small GTPases during Melanoma Metastasis
Authors: Ming Huang, Tianyu F. Qi, Lin Li, Gao Zhang, Yinsheng Wang
Journal: Cancer Research (2018)

Small GTPases of the Ras superfamily are master regulators of intracellular trafficking and constitute essential signaling components in all eukaryotes. Aberrant small GTPase signaling is associated with a wide spectrum of human diseases, including cancer. Here, we developed a high-throughput, multiple reaction monitoring-based workflow, coupled with stable isotope labeling by amino acids in cell culture, for targeted quantification of approximately 100 small GTPases in cultured human cells. Using this method, we investigated the differential expression of small GTPases in three pairs of primary and metastatic melanoma cell lines. Bioinformatic analyses of The Cancer Genome Atlas data and other publicly available data as well as cell-based assays revealed previously unrecognized roles of RAB38 in promoting melanoma metastasis. Diminished promoter methylation and the subsequent augmented binding of transcription factor MITF contributed to elevated expression of RAB38 gene in metastatic versus primary melanoma cells. Moreover, RAB38 promoted invasion of cultured melanoma cells by modulating the expression and activities of matrix metalloproteinases-2 and -9. Together, these data establish a novel targeted proteomic method for interrogating the small GTPase proteome in human cells and identify epigenetic reactivation of RAB38 as a contributing factor to metastatic transformation in melanoma.Significance: A novel quantitative proteomic method leads to the discovery of RAB38 as a new driver of metastasis in melanoma. Cancer Res; 78(18); 5431-45. ©2018 AACR.
Abstract 557: Aberrant methylation of tumor-suppressor genes in pediatric myelodysplastic syndrome/acute myeloid leukemia
Authors: Akira Shimada, Hirotaka Kanzaki, Hisashi Ishida, Takehiro Matsubara, Michinori Aoe
Journal: Cancer Research (2018)

Abstract Introduction: Not only somatic mutations, but also epigenetic modifications in acute myeloid leukemia (AML) are estimated to have a pivotal role in leukemogenesis and it could be a therapeutic target. Especially, aberrant methylation of the promotor region of tumor suppressor genes (TSGs) were the causative events in leukemogenesis, however, there was only limited information in pediatric myelodysplastic syndrome (MDS) and AML. Materials and Methods: We analyzed the aberrant methylation of promotor region of 25 TSGs in pediatric 7 low grade MDS, 4 advanced MDS and 22 AML patients by FAB classification by Methylation-Specific Multiplex Ligation-dependent Probe Amplification (MS-MLPA) method (10 Male, 12 female, 0-14 years old, median 6 years ols). Simultaneously, detection of SNVs, In/del, and copy number variants were also analyzed by target sequence of more than 150 leukemia related genes. Especially, specific chimeras were analyzed in each patient. Results: Total 12/22(54.5%) patients had more than one methylated TSGs (number of methylated TSGs was 0-5 in each patient, median 1). More than 20% of patients had methylated TSGs including CDKN2B, CADM1, CDH13 and ESR1. Especially, there was a specific methylation pattern of TSGs, for example, all (4/4) t(8;21) patients had CDH13 methylation, 3/4 (75%) patients with inv(16) had ESR1 mutation and normal karyotype did not. Normal control samples, complete remission samples, and low grade MDS samples were not completely methylated. All advanced MDS patients had 1 or 2 methylated TSGs. Simultaneously, several leukemogenic genes were mutated such as GATA1, IKZF1, KRAS, KIT, FLT3, SH2B3, PIK3CD, PU.1, SMARC1, ALK, etc. Several genes were deleted such as CTCF, RB1, SRP72, ATM, NF1, U2AF1 etc. Discussion: In adult MDS, the increased number of methylated TSGs correlated to the development of AML and the poor prognosis. In this study, a few TSGs were methylated as the adult study (Hess CJ., Leuk Lymphoma 2008), furthermore, many genes related to epigenetic modification such as ASXL1, TET2 and EZH2 were not mutated in this study. Recently, anti-methylation drug were used in adult MDS/AML, larger study will be needed for adjusted use of epigenetic modifier in pediatric MDS/AML. Citation Format: Akira Shimada, Hirotaka Kanzaki, Hisashi Ishida, Takehiro Matsubara, Michinori Aoe. Aberrant methylation of tumor-suppressor genes in pediatric myelodysplastic syndrome/acute myeloid leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 557.
Abstract 2529: GENT 2.0, a newly updated database: Gene expression across normal and tumor tissues
Authors: Seung-Jin Park
Journal: Cancer Research (2018)

Abstract We previously developed GENT1.0 (Gene Expression Database of Normal and Tumor tissues), a web-accessible database that provides gene expression patterns across diverse human cancer and normal tissues. GENT shows gene expression patterns in various tissues easily and has more than 40,000 samples for 25 normal-cancer paired tissues. Here, we made updated database called GENT2.0 based on 60,000 microarray data for 36 normal-cancer paired tissues with various functions. GENT2.0 1) has collected over 60,000 amounts of data for 36 normal cancer paired tissues; 2) can analyze histologic or molecular subtypes or tumor stages for 19 tissues; 3) provides all sorts of plots in svg (Scalable Vector Graphics) format with a high-resolution figure; 4) has twice the amount of data compared to GENT1.0, and the web page loading speed is almost the same as GENT1.0; and 5) data will be accessible on the web. We hope GENT2.0 will be a useful resource for cancer researchers in many stages from target discovery to target validation. Citation Format: Seung-Jin Park. GENT 2.0, a newly updated database: Gene expression across normal and tumor tissues [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2529.
Abstract 5452: Pimozide suppresses the growth of brain tumor by targeting oncogenic pathways
Authors: Itishree Kaushik, Alok Ranjan, Blake Schwettmann, Sanjay Srivastava
Journal: Cancer Research (2018)

Abstract Brain tumor is considered as one of the most aggressive and incurable form of cancer. Majority of the brain tumors have a median survival rate of only 12%. Even though advanced treatments such as surgical removal, chemotherapy and radiotherapy are available, brain tumor persists to be lethal. Obstacles associated with the current treatment options are: recurrence, development of resistance and inability to cross blood brain barrier (BBB). BBB restricts majority of drugs to reach the brain thus resulting in an ineffective treatment. Pimozide (PMZ) is an antipsychotic drug used for the treatment of schizophrenia and chronic psychosis. In this study, pimozide has shown significant reduction in the viability of U-87MG, U-251MG, DAOY and T98G cell lines with an IC50 ranging from 11µM to 20µM after 24 h of treatment. Pimozide induced apoptosis in these cell lines as evaluated by FITC/Annexin assay and further validated by the cleavage of caspase 3 as well as PARP by western blot analysis. Pimozide treatment resulted in the concentration dependent decrease in the expression of GLI1, OCT4, SOX2 and NANOG in U87MG, U251MG, DAOY and T98G brain cancer cell lines, depicting a reduction in the stem cell like property of these cell lines. In addition, pimozide treatment inhibited the expression of proto-oncogene c-Myc. Inhibition of Gli1 and c-Myc demonstrates that pimozide might also inhibit the growth of cancer cells by targeting SHH signaling. Our results further demonstrated that oral administration of pimozide (25mg/kg) inhibits the brain tumors in intracranial tumor model with no significant difference in average weight of critical organs. It is important to note that pimozide is an FDA approved drug with no considerable toxicity. Overall, this study depicts that pimizode is a potential candidate to target brain tumors. Citation Format: Itishree Kaushik, Alok Ranjan, Blake Schwettmann, Sanjay Srivastava. Pimozide suppresses the growth of brain tumor by targeting oncogenic pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5452.
Abstract P028: MY Program - Modified Yoga After Cardiac Surgery Reduces Stress, Pain and Anxiety
Authors: Sharon McGonigle, Rima Styra, Arianne St.Jacques, Barbara Bailey, Michelle Dimas
Journal: Circulation (2017)

Introduction: Despite the physical benefits associated with cardiac surgery procedures, between 30-60% of all patients experience moderate to high levels of anxiety and/or depression, which can remain elevated up to 6 months post surgery. Traditional postoperative education classes do not provide an avenue for patients and families to deal with their physical and mental stress. Studies indicate that a holistic class, allowing individuals to focus on their inner-self would prove to have positive outcomes. We hypothesized that a modified yoga program (MY Program), tailored to the physical needs of post cardiac surgery patients, would have a positive effect on participants perceived stress, pain and anxiety levels. Method: Postoperative cardiac surgery patients at our institution were eligible to participate in our innovative MY Program during their hospitalization. Sessions were held twice weekly in an education room on the surgical ward, and were led by a certified yoga instructor. Participants were seated, with all positions and postures (asanas) being modified for a seated position. The forty-five minute sessions started and finished with relaxation and meditation, including the incorporation of breathing exercises that are modified to account for post-operative difficulties such as splinting. The patients completed two questionnaires: anxiety questions of the HADS (Hamilton Anxiety and Depression Scale) and a survey regarding their overall experience post-yoga. Results: There were 112 participants, of which 61% ( 68 of 112) were male, age range of 20 to 89. Female patients reported experiencing lower levels of state anxiety compared to men, although not statistically significant ( p = .11). Overall feelings of anxiety were relatively low-moderate amongst the participants post-yoga anxiety scores. Post-yoga questionnaire data analysis indicated that 98.8% (110 of 112) of patients found the session helpful, 91.1% (102 of 112) thought the setting was comfortable, 93.7% (104 of 112) would attend the class again, 100% (112 of 112) of patients would recommend the class to others, 89.2% (99 of 112) found that the session helped with their pain after surgery, 97.4% (109 of 112) reported that the session helped with their stress, and 91.7% (102 of 112) of patients found that their breathing improved after the class. Overall, males and females agreed on their satisfaction with the yoga intervention. Conclusion: Cardiac surgery is physically and mentally challenging for patients and families. Educational sessions do not currently provide adequate stress and anxiety relief. The MY program demonstrated that a holistic yoga class, incorporating breathing exercises, meditation and relaxation techniques reduced levels of stress, pain and anxiety in participants.
Abstract LB-045: Iron depletion suppress the stemness markers and functions of cancer stem cells
Authors: Toshiaki Ohara, Yuki Katsura, Kazuhiro Noma, Toru Narusaka, Takuya Kato, Hiroaki Sato, Satoshi Komoto, Yasuko Tomono, Takayuki Ninomiya, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara
Journal: Cancer Research (2018)

Abstract Background: Cancer stem cells (CSCs) have been proposed to be responsible for tumor initiating, drug resistance, metastasis, and recurrence. Although CSCs are considered to be important targets therapeutically, clinically effective CSC targeting strategies have not yet been established. Iron plays an important role in critical cellular processes, such as energy production and DNA synthesis. Although adequate iron levels are essential for human health, iron overload is known to cause some types of cancer. CSCs are considered to be involved in the tumor regardless of early stage. Thus we have focused on the relationship between iron and CSCs. We previously reported that the expression of stemness markers was suppressed by iron chelator in miPS and miPS inducible CSC model cells (miPS-LLCcm). Here, we hypothesized that the expression of stemness markers and function were also suppressed by iron chelator in high malignant cancer cells with stemness potential. Method: We used 4 stemness markers expressing cancer cell lines (HSC-2: Oral squamous cancer, TE-4 and OE33: Esophageal cancer, and NT-2: Embryonal cell carcinoma). Deferasirox (DFX), an oral iron chelator, was used. The stemness markers expression including Nanog, Sox2, Oct3/4, Klf-4 and c-Myc was examined by western blot analysis. Self-renewal ability was examined by sphere formation assay. Anti-proliferative effect of DFX was assessed combined with CDDP using HSC-2 cells. Result: DFX suppressed the expression of stemness markers and sphere formation ability in 4 cancer cell lines. In contrast, CDDP could not suppressed them. In HSC-2 cells, combination therapy with CDDP and DFX synergistically suppressed the proliferation with suppression of stemness markers. Conclusion: Our results indicated that iron depletion generally suppressed the stemness markers and functions of high malignant cells same as miPS and miPS-LLCcm. Thus iron depletion can be a novel therapy for CSCs via suppression of CSCs function. Citation Format: Toshiaki Ohara, Yuki Katsura, Kazuhiro Noma, Toru Narusaka, Takuya Kato, Hiroaki Sato, Satoshi Komoto, Yasuko Tomono, Takayuki Ninomiya, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara. Iron depletion suppress the stemness markers and functions of cancer stem cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr LB-045.