tbuckley/cabot-search huggingface dataset:
Abstract 205: Recovery from Ischemia-Reperfusion Injury Is Metabolic Substrate-Dependent
Authors: Sergiy M Nadtochiy, Paul S Brookes
Journal: Circulation Research (2013)

Introduction: The adult heart utilizes mostly fat for energy production, with adaptation to different fuels (“metabolic plasticity”) being a hallmark of the healthy heart. However, metabolic maladaptation is known to occur in heart failure. As such, the ability of the heart to metabolize specific substrates could impact the outcome of pathological insults, such as ischemia-reperfusion (IR) injury. The aim of this study was to develop a system whereby adult mouse cardiomyocytes (AMC) subjected to IR injury could be supplied with different fuels, and metabolism measured in real-time. Methods: AMC were divided in 3 groups, supplied either with glucose (GLU, 5mM), palmitate/fat free BSA (FAT, 100µM) or GLU+FAT. A previously developed method for in-vitro IR injury using a Seahorse XF24 [1], was adopted for ACM. IR comprised 60 min. ischemia and 60 min. reperfusion, and additional metabolic parameters were measured separately using mitochondrial inhibitors and uncouplers [2]. Oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) were simultaneously measured during the IR protocol, followed by a cell death assay. Results: FAT cells showed higher baseline OCR and lower ECAR rates compare to GLU cells, although uncoupled OCR was lower in FAT group, suggesting a lower metabolic reserve capacity for cells respiring on fat. Upon IR, the drop in pH was significantly greater in GLU compare to FAT, indicating faster lactate production. During reperfusion, both OCR and ECAR recovered to pre-ischemic levels in GLU cells but failed to do so in FAT cells. Post-IR cell death was significantly higher in FAT vs. GLU. Surprisingly, GLU+FAT (modeling a “physiologic” substrate mix) replicated the same metabolic profile and cell death as GLU. Conclusions: (i) AMC had better recovery from IR injury using glucose as fuel. (ii) Lower cell viability in FAT (vs. GLU) correlated with smaller metabolic reserve capacity and with a smaller pH drop during ischemia. This is consistent with a known protective role for acidification during IR injury. (iii) Mixed substrates (GLU+FAT) gave a similar response to glucose alone, suggesting that fat may not be toxic, rather glucose is protective, in IR injury. [1] Circ Res. (2012), 110. 948-57. [2] J Vis Exp. (2010), 46. pii: 2511.
Significance of Karyopherin alfa 2 (KPNA2) expression in esophageal squamous cell carcinoma
Authors: Yutaka Shimada, Jiro Fujimoto, Fumiaki Sato, Kazuharu Shimizu, Tetsuo Ito, Stephen Meltzer, Atsushi Itami, Go Watanabe, Kazuhiro Tsukada
Journal: Cancer Research (2008)

AACR Annual Meeting-- Apr 12-16, 2008; San Diego, CA

170 

Background:    Recently, we identified Karyopherin alpha 2 (KPNA2) expression as a tumor specific gene in esophageal cancer (BBRC 2006). KPNA2, a nuclear transport protein, is known as Importin alpha 1 or RAG cohort 1. In breast cancer, KPNA2 is a prognostic factor and plays a role in the transportation of BRCA1. However, the role of KPNA2 in esophageal cancer has not yet been reported. To evaluate the clinical significance of KPNA2 in esophageal cancer, we examined KPNA2 expression in the esophageal cancer patients.    Methods:    KPNA2 expression was evaluated in 86 esophageal squamous cell carcinoma patients who received esophagectomies from 1995 to 2002 by immunohistochemistry, and the results were compared with the clinicopathological findings of the subjects.    Results:    The patients consisted of 13 in stage1, 17 in stage2a, 20 in stage 2b, 22 in stage 3, 4 in stage 4a, and 10 in stage 4b (UICC pTNM stage). Age was 62.5(+), consisting of 67 males and 19 females. Immunohistochemical staining was done mainly in nuclei but cytoplasm was also occasionally stained. Average staining count of 5 areas of each slide ranged from 6% to 78% (average 34.3%). In 95% of the cases, more than 10% of the tumor cells were stained. In the normal esophageal epithelial cells, KPNA2 was not stained in the layer cells of the basement membrane. Then, KPNA2 expression was classified as follows: The cases with KPNA2 positive expression with less than 30% of the tumor cells (weak expression n=35) and KPNA2 positive expression of more than 30% of the tumor cells (strong expression n=51). Finally, we classified strong KPNA2 expression as KPNA2 positive. KPNA2 positivity tended to be associated with pN factor (p=0.071), however, KPNA2 expression was not associated with other clinicopathological factors of the patients. As a result, the KPNA2 positive patients tended to have a worse prognosis than that of KPNA2 negative patients (Wilcoxon p=0.373), however, multivariate analysis revealed that KPNA2 positivity was not an independent prognostic factor of the patient .    Conclusion:    Our results suggested that nuclear transportation is activated in esophageal cancer patients. Although 95% of esophageal cancer patients expressed KPNA2 in more than 10% of the tumor cells, KPNA2 was not a prognostic factor of the esophageal cancer patients. However, KPNA2 was not expressed in the layer cells of the basement membrane in normal epithelial cells. Thus, KPNA2 may become a new therapeutic promoter target for esophageal cancer patients.
Effects of Teriparatide on Joint Erosions in Rheumatoid Arthritis: A Randomized Controlled Trial
Authors: D. H. Solomon, J. Kay, J. Duryea, B. Lu, M. B. Bolster, R. A. Yood, R. Han, S. Ball, C. Coleman, E. Lo, A. Wohlfahrt, M. Sury, M. Yin, Z. Yu, A. Zak, E. M. Gravallese
Journal: Arthritis & Rheumatology (2017)

Objective Articular erosions correlate with disability in rheumatoid arthritis (RA). Biologic agents reduce erosion progression in RA, but erosion healing occurs infrequently. This study was undertaken to assess the effects of the anabolic agent teriparatide on joint erosion volume in RA patients treated with a tumor necrosis factor inhibitor (TNFi). Methods We conducted a randomized controlled trial in 24 patients with erosive RA, osteopenia, and disease activity controlled by TNFi treatment for at least 3 months. Half were randomized to receive teriparatide for 1 year and the others constituted a wait‐list control group. Subjects and primary rheumatologists were not blinded with regard to treatment assignment, but all outcomes were assessed in a blinded manner. The primary outcome measure was change in erosion volume determined by computed tomography at 6 anatomic sites. Significance within each hand and anatomic site was based on a 2‐tailed test, with P values less than 0.05 considered significant. Results Baseline characteristics of the treatment groups were well balanced. After 52 weeks, the median change in erosion volume in the teriparatide group was −0.4 mm 3 (interquartile range [IQR] −34.5, 29.6) and did not differ significantly from that in controls (median change +9.1 mm 3 [IQR −29.6, 26.4]) ( P = 0.28). No significant difference in change in erosion volume was noted at the radius, ulna, or metacarpophalangeal joints. Bone mineral density improved at the femoral neck and lumbar spine in the teriparatide group. Conclusion Our findings indicate that teriparatide treatment for 1 year does not significantly reduce erosion volume in the hands or wrists of patients with established RA with disease activity controlled by TNFi treatment.
PAC: A novel curcumin analogue with potent anti-cancer properties
Authors: Abdelilah Aboussekhra, Ensaf Al-Hejaily, Khairya Youssef, Amal Al-hazaa
Journal: Clinical Cancer Research (2007)

C47  BACKGROUND: Curcumin (diferuloylmethane) is a flavoring, coloring and preservative agent that was used as therapeutic agent for various illnesses including, inflammation, smallpox, as well as chest pain. Importantly, curcumin has been shown to induce anti-carcinogenic effect both in vivo and in vitro. Indeed, oral administration of curcumin inhibited leukemia and various solid tumors including breast, prostate and skin. However, poor water solubility and unsatisfactory pharmacokinetics of curcumin limit its potential use as anticancer agent and necessitate design of analogous molecules with similar safety profile but higher anti-cancer activity.  METHODS: The cytotoxic effect of curcumin and its novel analogues was assessed using the WST1 assay, while the induced cell death pathway was determined with the annexinV/PI technique. In addition, flow cytometry has been utilized to study the effects of these agents on the cell cycle, and the Western blot technique allowed evaluating the expression of different oncoproteins. Finally, these products were administered intragastrically in rats and the animals were sacrificed and dissected to obtain different organs for histological examination of the in vivo effect of the agents.  RESULTS: In the present study we have investigated the effect of two cucumin analogues 1,7-Bis (4-hydroxy-3-ethoxyphenyl)-1,6-heptadien-3,5-dione (EAC) and 3,5-Bis (4-hydroxy-3-methoxybenzylidene)-N-methyl-4-piperidone (PAC) on normal and breast carcinoma cells. We have found that these analogues are more cytotoxic than curcumin, and PAC triggers apoptosis more effectively and more specifically than curcumin. Interestingly, PAC is the only agent that delayed the cell cycle of breast cancer cells. Furthermore, we have shown that PAC is more efficient than curcumin and EAC in up-regulating the tumor suppressor p53 and p21 proteins and in down-regulating the NF-kB, survivin and β-Catenin oncoproteins. Finally we present evidence that PAC is not toxic for the breast, liver and kidney of rats.
Abstract A66: Systemic effects of AC-T chemotherapy in breast cancer
Authors: Molly J. DeCristo, Sandra S. McAllister
Journal: Cancer Research (2016)

Abstract Cytotoxic chemotherapy is the only standard of care treatment currently available for patients with triple negative breast cancer (TNBC) because this breast cancer subtype lacks expression of therapeutic targets, namely, estrogen receptor, progesterone receptor, and amplification of Her2. Despite the efficacy of neoadjuvant chemotherapy for some TNBC patients, approximately 60-80% of TNBC patients will still present with local and distant disease after therapy, and these patients suffer poor prognosis. In addition to direct effects on tumor cells, systemic chemotherapy also has the potential to impact patient physiology. However, the implications of tumor-cell independent effects of chemotherapy for metastatic progression are not well understood. We are using mouse models of TNBC to study the effects of chemotherapy on host physiology and how these effects impact metastasis. Treatment of TNBC tumor-bearing mice with doxorubicin (A), cyclophosphamide (C), and paclitaxel (T) decreased overall bone marrow cell counts; although, the degree of decrease and subsequent recovery of individual bone marrow and circulating cell populations varied among populations. Notably, parallel experiments in tumor-free mice demonstrated that chemotherapy-dependent effects on the bone marrow and circulating cell populations dominate tumor-dependent effects. These findings highlight the potential implications of the physiological effects of chemotherapy on metastasis and response to therapy. Citation Format: Molly J. DeCristo, Sandra S. McAllister. Systemic effects of AC-T chemotherapy in breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Metastasis; 2015 Nov 30-Dec 3; Austin, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(7 Suppl):Abstract nr A66.
Impact of the distance from a radiation oncology treatment facilty on initiation of therapy and its influence on survival in patients with stage III and IV NSCLC.
Authors: Danielle M. File, Carlos Eduardo Arce-Lara, Jeffrey C. Whittle, Elizabeth Gore, Rafael Santana-Davila
Journal: Journal of Clinical Oncology (2013)

e17594 Background: Patients with stage III and IV lung cancer require multidisciplinary care. The Milwaukee VA is the only center within the Veterans Health Administration in the state that has a radiation oncology facility. Patients frequently travel from across the state to receive treatment here. We conducted a retrospective review of cases seen in our institution to determine if the distance from the patients’ home to our center influenced their outcome. Methods: Patients with NSCLC treated between 2000 and 2012 were identified from our internal registry. Type of treatment was identified from the registry and confirmed in a chart review.. SAS 9.2 was used for statistical analysis and to measure distance between the patients’ home address and our center. Results: We included 230 patients with stage III disease treated with radiation therapy and 139 patients with stage IV treated with chemotherapy. Of those with Stage III (53% with IIIA and 47% IIIB) 41.3% (n=95) received concurrent radiation therapy and chemotherapy, 14% received sequential therapy, 40% received radiation therapy alone and 5% were treated with chemotherapy followed by palliative radiation. In those with metastatic disease 61% received palliative radiation at some point during their treatment. Median distance between the patients’ home and the Milwaukee VA was 57miles (IQR 10-109) in patients with stage III disease and 22 (IQR 5-84) in those with metastatic disease. There was no correlation between the distance travelled and the time to first treatment in either stage (r=0.008 in stage III and r=0.05 in stage IV). In a univariate analysis living further than 50 miles did not appear to influence survival in stage III (median OS 14.6 vs. 16.4 months p=0.25) nor stage IV disease(9.7 vs 8 p=0.55). In a multivariate analysis when controlling for age, time to first treatment and distance as a continuous variable was not associated with survival in patients with stage III(HR 1.01, 95% CI 0.99-1.02 p=0.15) or stage IV disease (HR 1.01, 95%CI 0.98-1.04 p=0.35). Conclusions: Distance traveled to a radiation oncology treatment facility in this cohort did not influence survival in patients with stage III and IV NSCLC.
Survival impact of primary tumor resection in patients (pts) with unresectable metastatic colorectal cancer (mCRC): Findings from the South Australian Metastatic Colorectal Cancer Registry (SAMCRC).
Authors: Sina Vatandoust, Amitesh Chandra Roy, Timothy Jay Price, Shahid Ullah, Carol Beeke, Amanda Rose Townsend, Rob Padbury, David Roder, Guy Maddern, Christos Stelios Karapetis
Journal: Journal of Clinical Oncology (2015)

e14675 Background: The impact of primary tumor resection on survival in pts with mCRC and unresectable synchronous metastases is unclear. We aimed to examine the association of primary tumor resection with survival in pts with unresectable mCRC. Methods: We analysed data from the SAMCRC, a population based registry that collects data from all pts diagnosed with mCRC in the Australian state of South Australia from February 2006. Data for this study was collected in July 2014. Only pts diagnosed with synchronous metastastic cancer and not metachronous were included. Pts with resected metastatic cancer were excluded. We compared pts who underwent primary tumor resection and those with unresected primary tumor. A multivariate Cox proportional hazards model was fitted to compare the survival outcomes between the two groups. Results: Of 1930 pts with synchronous and unresectable metastatic disease, 52.3% (n = 1010) had the primary tumor resected and 47.7% (n = 920) had unresected primary tumor. Pts in the resected group were younger than the unresected group: median age 71.8y versus 75.0y (p < 0.001). In the adjusted multivariate Cox proportional hazards model resection of the primary tumor was associated with longer median survival: 16.9 mo (95%CI; 15.4-18.8) vs 6.9 mo, (95%CI; 5.9-12.6)) [HR = 0.59 95%CI 0.53-0.66 p < 0.001]. Of the 920 pts in the unresected group 37.2% (n = 346) did not receive any treatment (no surgery and no chemotherapy). When this sub-group was excluded the remaining 1584 patients: 63.7% (n = 1010) were in the primary resected group versus 36.3% (n = 574) in the unresected group. Pts in the resected group were older than the unresected group: (median age 71.8 y versus 69.4 y, p < 0.01). The multivariate analysis, again showed a significantly longer median survival in the resected group (16.9 mo 95%CI 15.4-18.8) compared with the unresected group (11.8 mo 95%CI 10.3-13) [HR = 0.71 95%CI 0.63-0.81 p < 0.001] Conclusions: Our data – within limits of a retrospective study – indicates that primary tumor resection is associated with significant survival benefit in pts with mCRC and unresectable metastases.
TRTH-30. PRELIMINARY EXPERIENCE WITH SERIAL WHOLE EXOME SEQUENCING OF PEDIATRIC CNS TUMORS AT DIAGNOSIS AND RECURRENCE.
Authors: Luca Szalontay, Danielle Pendrick, Neil Feldstein, Richard Anderson, Eileen Stark, Julia Glade Bender, Jennifer Oberg, Susan Hsiao, Andrew Turk, Anthony Sireci, Mahesh Mansukhani, James Garvin
Journal: Neuro-Oncology (2017)

INTRODUCTION: Whole exome sequencing (WES) of newly diagnosed pediatric central nervous system (CNS) tumors is quickly becoming part of routine care. Through the Precision in Pediatric Sequencing (PiPseq) program at Columbia University, we have found potentially actionable mutations in more than 40% of evaluable CNS cases at diagnosis. More recently, we have integrated this approach into the management of patients undergoing surgery for CNS tumor recurrence. METHOD: After obtaining informed consent, tumor-normal WES with transcriptome analysis was performed in a CLIA-certified laboratory on fresh frozen or paraffin embedded CNS tumor samples and peripheral blood. RESULTS: 7 cases (5 male, 2 female; median age 5 years) with adequate diagnostic and recurrent tumor tissue were tested. No case had a somatic mutation of established clinical utility (tier 1). Among 3 embryonal tumors, a splice site variant in TSC1 (tier 2 mutation of potential utility) was detected in a medulloblastoma, but only at recurrence and not at initial diagnosis. FOXR2 overexpression was detected at diagnosis and confirmed at early progression of a temporal lobe tumor, prompting revision of the initial diagnosis of high grade glioma to CNS neuroblastoma subtype of PNET, and treated accordingly. In a third patient initially diagnosed with medulloblastoma, overexpression of PDGFRA, MDM4, CDKN2A, EGFR, OLIG2, and GFAP supported a change in diagnosis to glioblastoma. Two gliomas had tier 2 mutations detected at initial diagnosis and progression: SETD2 p.R2040* (optic nerve lesion, called pseudotumor initially but glioma at progression), and H3F3A p.K28M (thalamic low grade glioma). In one patient with ependymoma, copy number gain of 1q25 (associated with poor prognosis) was seen only in the recurrence specimen. CONCLUSION: Our preliminary experience suggests that in pediatric CNS tumor patients referred for reoperation at recurrence, repeat WES may reveal a previously unrecognized treatment option, at least in embryonal tumors.
Unique clustering of uveal melanoma in young females.
Authors: Marlana M. Orloff, Carol L Shields, Jerry A Shields, Michael J. Mastrangelo, Takami Sato
Journal: Journal of Clinical Oncology (2015)

e20054 Background: Uveal melanoma is the most common primary intraocular tumor in adults, median age at diagnosis of 60 years. Despite a growing understanding of the molecular characteristics of uveal melanoma, the etiology remains unknown. We identified 2 clusters of uveal melanoma in young females with median ages 24 and 31 respectively. Information gained from this cluster evaluation would guide our investigation of potential risk factors for this rare disease. Methods: Descriptive data from medical records and patient questionnaires were obtained on 8 cases involving young females who previously resided in Huntersville, North Carolina (NC) and Auburn, Alabama (AL). Reports on standard incidence ratio (SIR) calculations were provided by the respective states’ departments of health. Results: In NC, 5 females who were identified as living in Huntersville, NC during the year of 2005, were diagnosed with uveal melanoma at ages 20, 22, 24, 30, and 31 in years 2013, 2009, 2008, 2014, and 2011, respectively. Three of these females attended the same high school. In AL, 3 females who were identified as living in the same dormitory while in college from 1989-1993, were diagnosed with uveal melanoma at ages 31, 31, and 42 in years 2000, 2001, and 2012 respectively. These patients were not blood-related relatives and none had a family history of melanoma. The SIR calculations considering the observed and expected incidence of uveal melanoma was 0.7 (95% CI 0.5-0.9), in Mecklenberg County, NC, and 1.15 (95% CI 0.989-1.328) in white females in AL, respectively, and did not show increased incidence of uveal melanoma patients in these regions. Conclusions: Considering the age distribution of uveal melanoma patients, the clustering of this disease in young females is unusual. No increased incidence of uveal melanoma in their communities might indicate existence of distinct causative agents in their shared living environments or lifestyle that might have contributed to the eventual development of uveal melanoma in this unique population. Further investigation into these cases considering infectious etiology, biomarkers for carcinogenesis, environmental exposures, and genetic predisposition to cancer is ongoing.
Cardiovascular and Metabolic Effects of <i>ANGPTL3</i> Antisense Oligonucleotides
Authors: Mark J. Graham, Richard G. Lee, Teresa A. Brandt, Li-Jung Tai, Wuxia Fu, Raechel Peralta, Rosie Yu, Eunju Hurh, Erika Paz, Bradley W. McEvoy, Brenda F. Baker, Nguyen C. Pham, Andres Digenio, Steven G. Hughes, Richard S. Geary, Joseph L. Witztum, Rosanne M. Crooke, Sotirios Tsimikas
Journal: New England Journal of Medicine (2017)

Epidemiologic and genomewide association studies have linked loss-of-function variants in ANGPTL3, encoding angiopoietin-like 3, with low levels of plasma lipoproteins.We evaluated antisense oligonucleotides (ASOs) targeting Angptl3 messenger RNA (mRNA) for effects on plasma lipid levels, triglyceride clearance, liver triglyceride content, insulin sensitivity, and atherosclerosis in mice. Subsequently, 44 human participants (with triglyceride levels of either 90 to 150 mg per deciliter [1.0 to 1.7 mmol per liter] or >150 mg per deciliter, depending on the dose group) were randomly assigned to receive subcutaneous injections of placebo or an antisense oligonucleotide targeting ANGPTL3 mRNA in a single dose (20, 40, or 80 mg) or multiple doses (10, 20, 40, or 60 mg per week for 6 weeks). The main end points were safety, side-effect profile, pharmacokinetic and pharmacodynamic measures, and changes in levels of lipids and lipoproteins.The treated mice had dose-dependent reductions in levels of hepatic Angptl3 mRNA, Angptl3 protein, triglycerides, and low-density lipoprotein (LDL) cholesterol, as well as reductions in liver triglyceride content and atherosclerosis progression and increases in insulin sensitivity. After 6 weeks of treatment, persons in the multiple-dose groups had reductions in levels of ANGPTL3 protein (reductions of 46.6 to 84.5% from baseline, P<0.01 for all doses vs. placebo) and in levels of triglycerides (reductions of 33.2 to 63.1%), LDL cholesterol (1.3 to 32.9%), very-low-density lipoprotein cholesterol (27.9 to 60.0%), non-high-density lipoprotein cholesterol (10.0 to 36.6%), apolipoprotein B (3.4 to 25.7%), and apolipoprotein C-III (18.9 to 58.8%). Three participants who received the antisense oligonucleotide and three who received placebo reported dizziness or headache. There were no serious adverse events.Oligonucleotides targeting mouse Angptl3 retarded the progression of atherosclerosis and reduced levels of atherogenic lipoproteins in mice. Use of the same strategy to target human ANGPTL3 reduced levels of atherogenic lipoproteins in humans. (Funded by Ionis Pharmaceuticals; ClinicalTrials.gov number, NCT02709850 .).