tbuckley/cabot-search huggingface dataset:
Coronary Arteriosclerosis Induced in Young Dogs by Prolonged Intra-aortic Infusions of Serotonin
Authors: Paolorossi, Maudestevenson, Parvizkhaksar, Samuelbellet
Journal: Circulation Research (1961)

The cardiac effects of serotonin were studied in 20 young mongrel dogs. Serotonin was slowly infused through a catheter inserted into the left carotid artery with the tip of the catheter located 1 or 2 cm. above the coronary orifices. The doses for different groups of dogs were 10, 5, 2, and 1 mg. in 500 cc. of normal saline, three to six times each week. The period of infusion lasted one to six weeks. A group of four dogs acted as controls. In dogs treated for more than two weeks with doses of 10 to 5 mg., and in those treated for more than four weeks with doses of 2 mg., the following pathological findings were observed: (a) fibrotic thickening of mitral, aortic, and tricuspid valves in this order of frequency; (b) myocardial hemorrhages partially organized ; (c) focal ischemic necrosis of myocardium with or without round cell infiltrations; (d) intimal thickening of small coronary arteries either in the form of cushions bulging into the lumen or extensive subendothelial thickening with asymmetrical red...
G20210A Prothrombin Gene Polymorphism and Prothrombin Activity in Subjects With or Without Angiographically Documented Coronary Artery Disease
Authors: CarlaRusso, DomenicoGirelli, OlivieroOlivieri, PatriziaGuarini, FrancoManzato, FrancescaPizzolo, BarbaraZaia, AlessandroMazzucco, RobertoCorrocher
Journal: Circulation (2001)

Background—G20210A prothrombin mutation has been associated with high prothrombin levels and an increased risk of venous thrombosis. The role of this common polymorphism, as well as that of prothrombin levels, in determining the risk of arterial disease is still somewhat controversial. Methods and Results—We determined the prevalence of the G20210A mutation and prothrombin activity in 660 individuals, of whom 436 had angiographically documented severe coronary artery disease (CAD patients) and 224 had normal coronary angiography (CAD-free control subjects). Heterozygosity for the 20210A allele was found in 5.3% of the CAD patients versus 3.1% of the CAD-free subjects (P=0.21). Similarly, no statistically significant difference was found between CAD patients with or without previous myocardial infarction (4.5% versus 5.3%, respectively; P=0.73). The genotype-phenotype correlation study showed a significant influence of the 20210A allele on prothrombin activity, with higher levels in carriers compared with ...
Abstract 860: Experimental alpha-radioimmunotherapy for liver metastasis of gastric cancer
Authors: Huizi Keiko Li, Sumitaka Hasegawa
Journal: Cancer Research (2018)

Abstract Gastric cancer (GC) is one of the leading causes of cancer-related death worldwide. Early stage of GC is curable by surgical therapy or endoscopic surgery. However, previous studies reported that 35% of patients is present with evidence of distant metastasis at the time of diagnosis of GC. Metastatic GC is fetal and the patients with metastatic GC has extremely poor prognosis because current therapeutic approaches to metastatic GC are still limited. Therefore, the development of new therapeutic options has been eagerly awaited. Liver metastasis of GC (LMGC) is often observed during GC progression. It has been shown that 4-14% of the patients has LMGC. It is believed that LMGC is occurred by blood-borne metastasis of GC cells via blood stream. A previous study reported that approximately 70% of LMGC was positive for human epidermal growth factor receptor 2 (HER2). Therefore, HER2 may be a reliable therapeutic target for LMGC. Alpha-particle radioimmunotherapy (alpha-RIT) is an emerging new therapy, in which radioisotopes emitting cytotoxic alpha-particle radiation are delivered to target cancer cells to kill the cells by target-specific antibody. Among alpha-particle emitters, astatine-211 (At-211) is a promising emitter because it emits highly cytotoxic alpha-particles during its decay process with a half-life of 7.2 hours. The aim of this study is to evaluate the therapeutic efficacy and toxicity of At-211-labled anti-HER2 antibody trastuzumab ([At-211]trastuzumab) in a preclinical mouse model of HER2-positive LMGC. We established a mouse model of LMGC by injection of luciferase-labelled HER2-positive human metastatic GC cells (NCI-N87) into splenic vein of severe combined immunodeficiency mouse. Biodistribution studies revealed that the maximum tumor uptake of [At-211]trastuzumab was about 12% of injected dose per tissue gram 24 hours after injection. In experimental therapies, a systemic injection of [At-211]trastuzumab (1 MBq) significantly reduced a tumor burden in the liver and prolonged the survival. Transient but recoverable leukocytopenia was observed in mice received 1 MBq of [At-211]trastuzumab at 5-7 days after injection. No body weight loss was found during the observation period. In this study, we provides a preclinical evidence that alpha-RIT using [At-211]trastuzumab may be a new therapeutic option against LMGC. Citation Format: Huizi Keiko Li, Sumitaka Hasegawa. Experimental alpha-radioimmunotherapy for liver metastasis of gastric 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 860.
Abstract 4715: Mifepristone extends both length and quality of life in a patient with advanced non-small cell lung cancer that progressed despite chemotherapy and check-point inhibitors
Authors: Jerome H. Check, Diane Check, Trina Poretta
Journal: Cancer Research (2018)

Abstract The US FDA approved an investigator initiated phase II 40 patient study to treat patients with stage IIIB or IV non-small cell lung cancer who have progressed despite a minimum of 2 rounds of chemo or immunotherapy with the progesterone receptor modulator mifepristone taken orally at 300mg/day (www.clinicaltrials.gov). The first patient in the study reported at the 2017 AACR meeting with stage IV lung cancer with brain metastasis has had non-progressive disease with excellent quality of life (ECOG-zero) after 24 months on mifepristone therapy. His lung cancer was PD-L1 negative, and thus he did not receive check-point inhibitors. We report, herein, the clinical outcome of the second patient with stage IV disease who not only progressed despite 3 chemotherapy regimens but also nivolumab (she was positive for the PD-L1 marker). The second patient in the study began 300mg/day oral mifepristone at age 68. Her stage IV lung cancer had progressed despite 4 cycles of carboplatin, permetrexed, and bevacizumab, 6 cycles of carboplatin and docetaxel, and 6 cycles of erlotinib. Finally she progressed and treatment was stopped after 11 cycles of nivolumab (PD-L1 marker present). After 1 year of oral mifepristone there have been no new metastatic lesions. She is ECOG 1 (related to chronic obstructive lung disease). Her cancer is stable with slight reduction in some metastatic lesions. More importantly she states she feels better than at any time since her initial diagnosis. The mechanism of action of mifepristone is hypothesized to be related to suppressing a key immunosuppressive protein that seems to be required for rapidly growing cells (e.g., possibly cancer stem cells), to proliferate known as the progesterone induced blocking factor (PIBF). This protein stablizes perforin granules in natural killer cells, thus obviating their mechanism for cytotoxicity. Mifepristone has been shown to suppress the intracytoplasmic immunosuppressive isoform in cancer cell line studies. Mifepristone can also diminish T-cell cytotoxicity. Progesterone receptor modulators may provide a new treatment option for advanced non-small cell lung cancer, even those positive for the PD-L1 marker that progresses despite treatment with chemotherapy and check-point inhibitors. Because intracytoplasmic PIBF is present in only mesenchymal, embryonic, trophoblast, or cancer cells suppressing this protein does not engender any health risks - oral mifepristone is well tolerated. Citation Format: Jerome H. Check, Diane Check, Trina Poretta. Mifepristone extends both length and quality of life in a patient with advanced non-small cell lung cancer that progressed despite chemotherapy and check-point inhibitors [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 4715.
Abstract 2292: Comparison of Q Path and Aperio Image Analysis System for quantification of ER and PR by IHC in breast carcinoma TMAs
Authors: Max Henry Jacobsen, Constance Temm, George Sandusky
Journal: Cancer Research (2018)

Abstract According to the Centers for Disease Control and Prevention, breast cancer is still one of the most common cancer in women, and top one or two in cancer mortality rates for all races of women. Novel drug treatments are needed to develop new treatments and clinical validation with IHC are common in research. Some common methods of validations are using Tissue MicroArrays (TMAs). In this study 5 TMAs containing approximately 100 cores each were stained with Estrogen Receptor (ER) and Progesterone Receptor (PR). Paraffin-embedded tissue blocks were obtained from the Indiana University Heath Pathology Laboratory under IRB approved protocols. Immunostainings with ER and PR antibodies (DAKO) were preformed using the DAKO-flex platform system at the IU Health Pathology Laboratory. The slides were digitally imaged using the Aperio Digital Imaging System. The SVS digital images were quantified using two different image analysis systems. One imaging system was the Aperio TMALab software, the other was Q Path image analysis software. Both systems were compared not only on the basis of performance, but among other parameters such as user friendliness and the ability to use a SVS image file type. When comparing the systems, the algorithm of Q Path was altered to closely match the algorithm of the standard Aperio positive pixel algorithm. Two measurements of antibody quantification were compared, one being positive pixel percentage, the other being an H Score. A regression line was used to show correlation between systems. Standard deviations were used to compare data against a standard pathology hand count of 0, 1, 2, and 3. The results show a strong correlation (R-squared value at or greater than 0.85) between the two imaging systems for both the positive pixel algorithm and H Score. The tightness may be due to consistent and rigorously explored in the past 20 years with both of these nuclear antibodies. Further studies should help distinguish any other possible errors using novel biomarkers and also delineate any discrepancies between a nuclear expressions against both a cytoplasmic and/or cell membranous expressions. In conclusion, Aperio Imaging analysis systems and Q path image analysis systems were in strong correlation, and therefore interchangeable in scientific research. Citation Format: Max Henry Jacobsen, Constance Temm, George Sandusky. Comparison of Q Path and Aperio Image Analysis System for quantification of ER and PR by IHC in breast carcinoma TMAs [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 2292.
Abstract 4895: Human ATP-binding cassette proteins ABCB1 and ABCG2 confer resistance to histone deacetylase 6 inhibitor ricolinostat (ACY-1215) in cancer cell lines
Authors: Sung-Han Hsiao, Shahrooz Vahedi, Suresh V. Ambudkar, Chung-Pu Wu
Journal: Cancer Research (2018)

Abstract Histone deacetylase 6 (HDAC6), localized primarily in the cytoplasm, is responsible for the deacetylation of non-histone substrates such as α-tubulin and heat shock protein 90 (Hsp90). HDAC6 has recently emerged as an important epigenetic therapeutic target for cancer, and much effort has been invested into developing novel inhibitors of HDAC6. Ricolinostat (ACY-1215) is the first safe and well tolerated inhibitor of HDAC6 that has progressed into human clinical trials, both as a single agent and in combination therapy. Ricolinostat is currently under evaluation in phase I and II clinical trials in patients with multiple myeloma, relapsed or refractory lymphoid malignancies, relapsed chronic lymphocytic leukemia, unresectable or metastatic breast cancer and for the treatment of gynecological cancer. The overexpression of ATP-binding cassette (ABC) drug transporters ABCB1 and ABCG2 in cancer cells is often associated with the development of multidrug resistance (MDR) phenotype and poor clinical outcome in patients with metastatic breast cancer, chronic lymphocytic leukemia or relapsed multiple myeloma. In this study, we report that ABCB1 and ABCG2 are capable of actively transporting and conferring resistance to ricolinostat. Moreover, we demonstrated that the efficacy of ricolinostat on the activity of HDAC6 and drug-induced apoptosis was significantly reduced in ABCB1- and ABCG2-overexpressing cancer cells, which can be fully restored by an competitive inhibitor of ABCB1 or ABCG2.Our finding is supported by biochemical data and a docking analysis of ricolinostat in the drug-binding pocket of ABCB1 and ABCG2. Taken together, our study indicate that the overexpression ABCB1 or ABCG2 in cancer cells may potentially play a significant role in the development of resistance to ricolinostat in cancer cells. Citation Format: Sung-Han Hsiao, Shahrooz Vahedi, Suresh V. Ambudkar, Chung-Pu Wu. Human ATP-binding cassette proteins ABCB1 and ABCG2 confer resistance to histone deacetylase 6 inhibitor ricolinostat (ACY-1215) in cancer cell lines [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 4895.
Success in Achieving the Targets of the 20-Year Infancy-Onset Dietary Intervention: Association With Insulin Sensitivity and Serum Lipids
Authors: Tomi T. Laitinen, Joel Nuotio, Markus Juonala, Harri Niinikoski, Suvi Rovio, Jorma S.A. Viikari, Tapani Rönnemaa, Costan G. Magnussen, Eero Jokinen, Hanna Lagström, Antti Jula, Olli Simell, Olli T. Raitakari, Katja Pahkala
Journal: Diabetes Care (2018)

OBJECTIVE We examined whether success in achieving the key targets of an infancy-onset 20-year dietary intervention associated with insulin sensitivity and serum lipids from early childhood to young adulthood. RESEARCH DESIGN AND METHODS The sample comprised 941 children participating in the prospective, randomized Special Turku Coronary Risk Factor Intervention Project (STRIP). Dietary counseling was given biannually based on the Nordic Nutrition Recommendations with the main aim to improve the quality of dietary fat in children’s diets and the secondary aim to promote intake of vegetables, fruits, and whole-grain products. Food records and serum lipid profile were studied annually from 1 to 20 years of age, and HOMA of insulin resistance (HOMA-IR) was assessed between 7 and 20 years of age. Meeting the intervention targets for quality of dietary fat was defined as the ratio of saturated fatty acids (SAFA) to monounsaturated and polyunsaturated fatty acids (MUFA + PUFA) &amp;lt;1:2 and intake of SAFA &amp;lt;10% of total energy intake (E%). Meeting the target for intake of whole-grain products, fruits, and vegetables was indicated by a fiber intake ≥3 g/MJ. RESULTS Participants in the intervention group had a higher probability of meeting the targets of SAFA/(PUFA + MUFA) &amp;lt;1:2 (risk ratio [RR] 3.91 [95% CI 3.33–4.61]), intake of SAFA &amp;lt;10 E% (RR 3.33 [95% CI 2.99–3.96]), and intake of fiber &amp;gt;3 g/MJ (RR 1.37 [95% CI 1.04–1.80]). Participants who achieved more targets had lower HOMA-IR, lower concentrations of fasting serum glucose, insulin, LDL cholesterol, and non-HDL cholesterol, and a lower ratio of apolipoprotein (Apo) B/ApoA1 (P values all ≤0.003). CONCLUSIONS Achieving the key targets of an infancy-onset 20-year dietary intervention was associated with better insulin sensitivity and serum lipid profile throughout the early life course.
Mechanism of Doxorubicin-Induced Inhibition of Sarcoplasmic Reticulum Ca2+-ATPase Gene Transcription
Authors: MasashiArai, AkemiYoguchi, TakakoTakizawa, TomoyukiYokoyama, TsugiyasuKanda, MasahikoKurabayashi, RyozoNagai
Journal: Circulation Research (2000)

Abstract—Doxorubicin (DOX)–induced cardiomyopathy has been found to be associated with impaired Ca2+ handling in the sarcoplasmic reticulum (SR), leading to reduced cardiac function. We have recently demonstrated that expression of mRNA encoding sarco(endo)plasmic reticulum Ca2+-ATPase 2 (SERCA2), a major Ca2+ transport protein in SR, is markedly decreased in DOX-treated hearts. To extend this observation, we have dissected the molecular mechanisms by which DOX downregulates SERCA2 gene transcription. Using cultured rat neonatal cardiac myocytes, we found that the antioxidant N-acetylcysteine blocked the DOX-induced decrease in SERCA2 mRNA levels, as well as the DOX-induced increase in H2O2 concentration; thus, H2O2 is an intracellular mediator of DOX activity. Using a luciferase reporter assay, we found that the sequence from −284 to −72 bp in the 5′ flanking region of the SERCA2 gene has a DOX-responsive element. Although several transcription factors have putative binding motifs in this region of the S...
Addition of Vincristine and Irinotecan to Vincristine, Dactinomycin, and Cyclophosphamide Does Not Improve Outcome for Intermediate-Risk Rhabdomyosarcoma: A Report From the Children’s Oncology Group
Authors: Douglas S. Hawkins, Yueh-Yun Chi, James R. Anderson, Jing Tian, Carola A.S. Arndt, Lisa Bomgaars, Sarah S. Donaldson, Andrea Hayes-Jordan, Leo Mascarenhas, Mary Beth McCarville, Jeannine S. McCune, Geoff McCowage, Lynn Million, Carol D. Morris, David M. Parham, David A. Rodeberg, Erin R. Rudzinski, Margarett Shnorhavorian, Sheri L. Spunt, Stephen X. Skapek, Lisa A. Teot, Suzanne Wolden, Torunn I. Yock, William H. Meyer
Journal: Journal of Clinical Oncology (2018)

Purpose Intermediate-risk rhabdomyosarcoma (RMS) includes patients with either nonmetastatic, unresected embryonal RMS (ERMS) with an unfavorable primary site or nonmetastatic alveolar RMS (ARMS). The primary aim of this study was to improve the outcome of patients with intermediate-risk RMS by substituting vincristine and irinotecan (VI) for half of vincristine, dactinomycin, and cyclophosphamide (VAC) courses. All patients received a lower dose of cyclophosphamide and earlier radiation therapy than in previous trials. Patients and Methods Patients were randomly assigned at study entry to either VAC (cumulative cyclophosphamide dose, 16.8 g/m2) or VAC/VI (cumulative cyclophosphamide dose, 8.4 g/m2) for 42 weeks of therapy. Radiation therapy started at week 4, with individualized local control plans permitted for patients younger than 24 months. The primary study end point was event-free survival (EFS). The study design had an 80% power (5% one-sided α-level) to detect an improved long-term EFS from 65% (with VAC) to 76% (with VAC/VI). Results A total of 448 eligible patients were enrolled in the study. At a median follow-up of 4.8 years, the 4-year EFS was 63% with VAC and 59% with VAC/VI ( P = .51), and 4-year overall survival was 73% for VAC and 72% for VAC/VI ( P = .80). Within the ARMS and ERMS subgroups, no difference in outcome by treatment arm was found. Severe hematologic toxicity was less common with VAC/VI therapy. Conclusion The addition of VI to VAC did not improve EFS or OS for patients with intermediate-risk RMS. VAC/VI had less hematologic toxicity and a lower cumulative cyclophosphamide dose, making VAC/VI an alternative standard therapy for intermediate-risk RMS.
Patient-reported pain and other symptoms as prognostic factors for overall survival (OS) in a phase III clinical trial of patients with advanced breast cancer.
Authors: Wei Shen, Ping Wang, Emily Nash Smyth, Lee Bowman, Patrick Peterson, William J. John, Allen S. Melemed
Journal: Journal of Clinical Oncology (2012)

1068 Background: The safety and efficacy of gemcitabine plus paclitaxel versus paclitaxel in advanced breast cancer after anthracycline-based adjuvant therapy has been reported previously (Albain et al. 2008). This post-hoc analysis evaluates the prognostic effect of baseline scores of the Brief Pain Inventory short form (BPI-SF) and the Rotterdam Symptom Checklist (RSCL) on OS. Methods: Patients completed theBPI-SF and the RSCL. BPI “worst pain” item and BPI interference subscale scores range from 0 (no pain or interference with daily living) to 10. Four RSCL subscales were transformed to 0-100, with 100 as best score. Univariate Cox models were used to determine the prognostic effect of each measure on OS. Multivariate Cox models were used to determine the prognostic effect of each measure in the presence of 11 demographic/clinical variables, including Karnofsky performance status, age, and estrogen and progesterone receptor status. Kaplan-Meier curves and log-rank tests were used to compare OS among patient groups categorized using clinically meaningful thresholds and the sample median of the BPI and RSCL scores. Results: Randomized patients were evaluable for this analysis (n=529). In the univariate analysis, significant prognostic effects on OS were observed for baseline scores of both BPI measures (worst pain and interference) (HRs, 1.07 for 1-point increase; all p≤0.0042) and three out of four RSCL subscales (activity level, physical distress, quality of life) (HRs, 0.86-0.91 for 10-point increase; all p≤0.0120). In the multivariate Cox models, BPI worst pain remained as a significant prognostic factor (p=0.0245), as did RSCL activity level (p=0.0004). The median OS for patients with BPI worst pain score 0 (no pain) was 23.8 months (mos) versus 17.9 mos and 14.8 mos for scores 1-4 (mild) and 5-10 (moderate/severe) (log-rank p=0.0066). The median OS was 23.8 mos for patients with RSCL activity scores greater than or equal to the sample median (≥95.2) versus 14.6 mos for patients with scores &lt;95.2 (log-rank p&lt;0.0001). Conclusions: This retrospective analysis resulted in strong evidence that BPI-SF and RSCL provide distinct prognostic information for OS.
Mitochondrial Control of Cellular Life, Stress, and Death
Authors: LorenzoGalluzzi, OliverKepp, ChristinaTrojel-Hansen, GuidoKroemer
Journal: Circulation Research (2012)

Since the discovery that mitochondrial membrane permeabilization represents a critical step in the regulation of intrinsic apoptosis, mitochondria have been viewed as pluripotent organelles, controlling cell death as well as several aspects of cell survival. Mitochondria constitute the most prominent source of ATP and are implicated in multiple anabolic and catabolic circuitries. In addition, mitochondria coordinate cell-wide stress responses, such as autophagy, and control nonapoptotic cell death routines, such as regulated necrosis. Thus, mitochondria seem to regulate a continuum of cellular functions, spanning from physiological metabolism to stress responses and death. The involvement of mitochondria in both vital and lethal processes is crucial for both embryonic and postembryonic development, as well as for the maintenance of adult tissue homeostasis. In line with this notion, primary mitochondrial defects or alterations in the signaling pathways that converge on or emanate from mitochondria underpi...