tbuckley/cabot-search huggingface dataset:
Broccoli-Derived Nanoparticle Inhibits Mouse Colitis by Activating Dendritic Cell AMP-Activated Protein Kinase
Authors: Zhongbin Deng, Yuan Rong, Yun Teng, Jingyao Mu, Xiaoying Zhuang, Michael Tseng, Abhilash Samykutty, Lifeng Zhang, Jun Yan, Donald Miller, Jill Suttles, Huang-Ge Zhang
Journal: Molecular Therapy (2017)

The intestinal immune system is continuously exposed to massive amounts of nanoparticles derived from food. Whether nanoparticles from plants we eat daily have a role in maintaining intestinal immune homeostasis is poorly defined. Here, we present evidence supporting our hypothesis that edible nanoparticles regulate intestinal immune homeostasis by targeting dendritic cells (DCs). Using three mouse colitis models, our data show that orally given nanoparticles isolated from broccoli extracts protect mice against colitis. Broccoli-derived nanoparticle (BDN)-mediated activation of adenosine monophosphate-activated protein kinase (AMPK) in DCs plays a role in not only prevention of DC activation but also induction of tolerant DCs. Adoptively transferring DCs pre-pulsed with total BDN lipids, but not sulforaphane (SFN)-depleted BDN lipids, prevented DSS-induced colitis in C57BL/6 (B6) mice, supporting the role of BDN SFN in the induction of DC tolerance. Adoptively transferring AMPK+/+, but not AMPK−/−, DCs pre-pulsed with SFN prevented DSS-induced colitis in B6 mice, further supporting the DC AMPK role in SFN-mediated prevention of DSS-induced colitis. This finding could open new preventive or therapeutic avenues to address intestinal-related inflammatory diseases via activating AMPK.
Abstract A16: Establishment and characterization of CCGL007, a novel human chronic lymphocytic leukemia cell line
Authors: Ching-Chuan Kuo, Chih-Cheng Chen, Chih-Hsiang Huang, Lin Li-Mei
Journal: Clinical Cancer Research (2016)

Abstract Chronic lymphocytic leukemia (CLL) is a monoclonal disorder characterized by a progressive accumulation of functionally incompetent lymphocytes. However, lack of immortalized cell line representative of the CLL disease has hampered a full understanding of disease pathogenesis and development of novel therapeutic agents for treatment. There were very few representative CLL cell lines are available now. To this end, we have tested different culture condition with addition of growth factor supplements to generate CLL cell lines from highly purified peripheral blood B cells of CLL patients. Recently, we have successfully established a new CLL cell line, named CCGL007. CCGL007 cells grow as suspension in liquid culture. Surface marker analysis with a panel of monoclonal antibodies revealed that CCGL007 cell line expresses B cell markers. The chromosomal, immunophenotypic, molecular biologic characteristics, and in vivo tumorigenesis potential of CCGL007 is under investigation. We have used this cell model to test the efficacy of selected standard chemotherapy drugs and new therapeutic agents, such as ibrutinib and several novel in-house BTK inhibitors, against CLL cell growth, and CCGL007 represents as a suitable preclinical model for testing pharmacological agents. Citation Format: Ching-Chuan Kuo, Chih-Cheng Chen, Chih-Hsiang Huang, Lin Li-Mei. Establishment and characterization of CCGL007, a novel human chronic lymphocytic leukemia cell line. [abstract]. In: Proceedings of the AACR Special Conference: Patient-Derived Cancer Models: Present and Future Applications from Basic Science to the Clinic; Feb 11-14, 2016; New Orleans, LA. Philadelphia (PA): AACR; Clin Cancer Res 2016;22(16_Suppl):Abstract nr A16.
Nrf2 Activation and Fetal Hemoglobin Induction in Sickle Cell Disease
Authors: Sriram Krishnamoorthy, Dipti Gupta, William E. Hobbs, Christine Loh, David R. Light, Robert Peters, Sarah Sturtevant, Betty Pace, Yukio Nakamura, Brian Lucas, Benjamin F. Vieira
Journal: Blood (2016)
Colorectal Cancer Incidence Patterns in the United States, 1974–2013
Authors: Rebecca L. Siegel, Stacey A. Fedewa, William F. Anderson, Kimberly D. Miller, Jiemin Ma, Philip S. Rosenberg, Ahmedin Jemal
Journal: JNCI Journal of the National Cancer Institute (2016)

Colorectal cancer (CRC) incidence in the United States is declining rapidly overall but, curiously, is increasing among young adults. Age-specific and birth cohort patterns can provide etiologic clues, but have not been recently examined.CRC incidence trends in Surveillance, Epidemiology, and End Results areas from 1974 to 2013 (n = 490 305) were analyzed by five-year age group and birth cohort using incidence rate ratios (IRRs) and age-period-cohort modeling.After decreasing in the previous decade, colon cancer incidence rates increased by 1.0% to 2.4% annually since the mid-1980s in adults age 20 to 39 years and by 0.5% to 1.3% since the mid-1990s in adults age 40 to 54 years; rectal cancer incidence rates have been increasing longer and faster (eg, 3.2% annually from 1974-2013 in adults age 20-29 years). In adults age 55 years and older, incidence rates generally declined since the mid-1980s for colon cancer and since 1974 for rectal cancer. From 1989-1990 to 2012-2013, rectal cancer incidence rates in adults age 50 to 54 years went from half those in adults age 55 to 59 to equivalent (24.7 vs 24.5 per 100 000 persons: IRR = 1.01, 95% confidence interval [CI] = 0.92 to 1.10), and the proportion of rectal cancer diagnosed in adults younger than age 55 years doubled from 14.6% (95% CI = 14.0% to 15.2%) to 29.2% (95% CI = 28.5% to 29.9%). Age-specific relative risk by birth cohort declined from circa 1890 until 1950, but continuously increased through 1990. Consequently, compared with adults born circa 1950, those born circa 1990 have double the risk of colon cancer (IRR = 2.40, 95% CI = 1.11 to 5.19) and quadruple the risk of rectal cancer (IRR = 4.32, 95% CI = 2.19 to 8.51).Age-specific CRC risk has escalated back to the level of those born circa 1890 for contemporary birth cohorts, underscoring the need for increased awareness among clinicians and the general public, as well as etiologic research to elucidate causes for the trend. Further, as nearly one-third of rectal cancer patients are younger than age 55 years, screening initiation before age 50 years should be considered.
Analysis of the genetic reprogramming that defines cell maturation along the intestinal crypt-villus axis
Authors: John Mariadason, Courtney Nicholas, Kaitlin L’italien, Georgia Corner, Sharon Simpson, Wancai Yang, Andrew Wilson, Lidija Klampfer, Barbara Heerdt, Diego Arango, Leonard Augenlicht
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

1653 

To define the genetic reprogramming events that drive epithelial cell maturation along the intestinal crypt-villus, enterocytes were sequentially isolated along the villus-crypt axis in mouse small intestine using the Weiser fractionation method. The fractionation process was validated by measurement of alkaline phosphatase and maltase activities, and PCNA expression in the various cellular fractions. Changes in gene expression were assessed using 27K cDNA microarrays. Of the 27,000 sequences analyzed, approximately 15% were altered in expression along the crypt-villus axis. Among those upregulated in expression in cells in the villus tip were the well-established differentiation markers villin, dipeptidylpeptidase IV, trefoil factor 3 and p21WAF1/Cip1 . Consistent with the confinement of cell proliferation to the crypts, several cyclins ( A, B1, B2, C and D2 ), cell division cycle proteins ( cdc3, cdc20 and cdc28 ) and checkpoint control genes ( bub1, mad2 ) were maximally expressed in cells isolated from the crypts. Categorization of genes on the arrays according to biological function demonstrated that the 15% of sequences altered in expression during the maturation program were significantly enriched for genes with a role in cell cycle regulation, apoptosis, differentiation, cytoskeletal organization, xenobiotic detoxification, lipid metabolism uptake and transport, membrane channel formation, metabolism, and membrane trafficking. Further dissection of genes involved in metabolism indicated a coordinate upregulation of genes encoding proteins in the glycolysis / gluconeogenesis pathways in the differentiated cells of the villus tip. Consistent with this, multiple genes encoding components of the mitochondrial electron transport chain were similarly upregulated in expression. Several transcription factors both up and down regulated in expression were also identified. Among those upregulated in the villus tip were KLF4, MAD4, aryl hydrocarbon receptor and ID-2 , while c-myc and HDAC2 were downregulated in expression. This database should serve as an important resource for the study of intestinal cell maturation, and to further our understanding of how perturbations in the maturation process may lead to the onset of gastrointestinal tumorigenesis.
Abstract P3-04-24: Identification of preclinical mechanisms driving acquired resistance to selective ERa degraders (SERDs), CDK4/6 inhibitors, or to combinations of both agents
Authors: T O'Brien, Y Xiao, C Ong, A Daemen, L Friedman
Journal: Cancer Research (2017)

Abstract Estrogen positive (ER+) breast cancer accounts for the majority of all breast cancers and standard practice is treatment with endocrine therapy. Recently a series of CDK4/6 inhibitors have emerged that can be effectively combined with estrogen modulators to treat ER+ breast cancer patients. The most advanced of these compounds, palbociclib, is now approved in the US in combination with letrozole or fulvestrant. Even though these combinations are effective, invariably patients will relapse. Our understanding of the mechanisms of acquired resistance to CDK4/6 inhibitors is still relatively nascent, and it is not known whether acquired resistance to combination treatments (e.g. palbociclib with fulvestrant) will be the same as mechanisms for the individual single agents. Additionally, it is not known if tumors that no longer respond to one combination regimen will remain sensitive to other standard of care treatments. To pre-clinically address these questions we generated cell lines that have acquired resistance to three Selective Estrogen Receptor Degraders (SERDs) and to two CDK4/6 inhibitors, palbociclib and abemaciclib. Additionally, we also generated cells with acquired resistance to the combination of fulvestrant and palbociclib. Characterization of cells resistant to each of these treatments will be presented. Initial data indicate that MCF7 cells with acquired resistance to SERDs have increased PI3K signaling and MEK/ERK signaling and have increased sensitivity to inhibitors of these pathways when treated with single agents. These cells are also more sensitive to palbociclib relative to parental cells. All 11 clones with acquired resistance to abemaciclib lose Retinoblastoma (Rb) expression and 20/24 palbociclib-resistant clones lose Rb expression, indicating the importance of Rb to CDK4/6 inhibitor activity. Interestingly, palbociclib resistant clones have decreased sensitivity to fulvestrant and to PI3K inhibitors, and investigation is under way to determine if that relates to slower doubling times for the clones. Detailed characterization of resistant clones reveals a surprisingly complex interaction between ERa and CDK4/6 signaling, and further results, including acquired resistance to drug combinations, will be presented. These preclinical studies may inform biomarkers of sensitivity and resistance to endocrine agents and CDK4/6 inhibitors. Citation Format: O'Brien T, Xiao Y, Ong C, Daemen A, Friedman L. Identification of preclinical mechanisms driving acquired resistance to selective ERa degraders (SERDs), CDK4/6 inhibitors, or to combinations of both agents [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-04-24.
PP78. PRIMARY CNS LYMPHOMA OUTCOMES IN A SINGLE CENTRE: A 7 YEAR STUDY
Authors: Mr Ravindran Visagan, Ms Beverly Cheserem, Mr Simon Stapleton, Dr Leslie Bridges, Mr George Eralil
Journal: Neuro-Oncology (2017)

INTRODUCTION: Primary CNS Lymphoma (PCNSL) in the immunocompetent population is reported as comprising 3–5% of all primary CNS neoplasms. They are considered aggressive tumours and their management remains controversial. We report a single centre experience of PCNSL over 7 years. METHODS: This is a retrospective cohort study of all biopsy confirmed PCNSLs between 2009 and 2016 in a busy London neurosurgical unit. Data was sourced from the lymphoma database, pathology reports, patient notes and radiology. We then reviewed their oncology treatment and outcomes. Primary endpoints were mortality, relapse and treatment complication rates. RESULTS: We had 58 patients (35 males and 23 females). 13 (22.4%) had a previous history of cancer and 10(17.2%) were immunocompromised. The rate of mortality during the seven years was 58.6% (34/58). The mean survival was 1.9 years (11 days to 7.16 years) Biopsies for tissue diagnosis had a low complication rate in our cohort (1 patient with biopsy related intracranial haematoma; 1 patient with wound breakdown). We were able to review treatment plans of 30 patients of whom 19 underwent chemotherapy and 10 had palliative radiotherapy only. 3 patients were not fit for either chemotherapy or radiotherapy. Neutropenic sepsis occurred in 26.1% (6/30) of the treated group with a similar proportion having neurological problems such as short term memory loss, seizures and hydrocephalus. 21.7% (5/30) had relapse despite treatment. CONCLUSIONS: 40% of our cohort had a history of cancer or being immunocompromised which can be attributed to the presence of activated oncogenes and failure of cell cycle repair mechanisms. A significant proportion (21.7% in our cohort) had relapse despite treatment which supports previous studies of PCNSL as an aggressive disease. It remains a disease with a high mortality and significant complications during treatment.
Molecular Mechanisms of Pro-Survival and Differentiating Function of Bone Marrow-Derived Adipocytes On Acute Monoblastic Leukemia Cells.
Authors: Linhua Jin, Marina Konopleva, Masato Shikami, Takako Ikegami, Kensuke Kojima, Michael Andreeff, Takashi Miida, Yoko Tabe
Journal: Blood (2012)
Preirradiation chemotherapy with methotrexate, rituximab, and temozolomide and post-irradiation temozolomide for primary central nervous system lymphoma: RTOG 0227 phase II study results.
Authors: Jon Glass, Minhee Won, Christopher J. Schultz, Daniel Brat, Nancy Bartlett, John H. Suh, Barbara Jean Fisher, Marcia K. Liepman, Minesh P. Mehta
Journal: Journal of Clinical Oncology (2013)

2033 Background: This prospective phase II study tested a methotrexate (MTX), temozolomide (TMZ) and rituximab (RTX) pre-irradiation regimen with hyperfractionated whole brain radiation therapy (hWBRT) followed by post-irradiation TMZ for patients with primary CNS lymphoma (PCNSL). The primary phase II endpoint was the 2-year overall survival (OS) rate compared with the 2-year OS from RTOG 93-10 (MTX, procarbazine, vincristine, whole brain radiation therapy, cytarabine). Secondary endpoints were pre-irradiation chemotherapy tumor response rates (compared to RTOG 93-10), progression free survival (PFS), acute and late neurologic toxicities, and quality of life. Methods: 53 patients (28 women, 25 men), median age 57.5 years, median Zubrod 1 were treated with RTX 375 mg/m 2 3 days prior to first cycle of MTX; 5 cycles of intravenous MTX 3.5 g/m 2 with leucovorin rescue on weeks 1, 3, 5, 7, 9; TMZ 100 mg/m 2 daily for 5 days weeks 4 and 8; hWBRT 1.2 Gy twice daily fractions 5 days/week on weeks 11, 12, 13 for a total of 36 Gy and TMZ 200 mg/m 2 daily for 5 days on weeks 14, 18, 22, 26, 30, 34, 38, 42, 46, 50. Results: Dosing of pre-irradiation temozolomide at 100 mg/m 2 was determined in the phase I portion of the study. With a median follow-up of 3.6 years, 2-year OS and PFS rates were 80.8% and 63.6%, respectively. Compared with historical controls from RTOG 93-10, 2-year OS and PFS were significantly improved (p = 0.006 and 0.03). The overall response rate to the pre-irradiation chemotherapy was 37.7% (complete response 11.3%, partial response 26.4%). 38% experienced grade 3 and 25% experienced grade 4 toxicities before the start of hWBRT. 33% experienced grade 3 and 21% experienced grade 4 toxicities attributable to post-hWBRT chemotherapy. Conclusions: The combination of MTX, TMZ, RTX followed by hWBRT and TMZ for PCNSL is safe with demonstrated improved 2 year OS and PFS compared with RTOG 93-10. Further investigations regarding the role of hWBRT and post-hWBRT TMZ are indicated. This project was supported by RTOG grant U10 CA21661 and CCOP grant U10 CA37422 from the National Cancer Institute (NCI) and Schering-Plough. Clinical trial information: NCT00068250.
Abstract P3-13-23: Predicting residual disease in breast conservative surgery after neoadjuvant treatments in breast cancer patients using the margin index tool
Authors: IT Rubio, I Loinaz, AJ Esgueva-Colmenarejo
Journal: Cancer Research (2017)

Abstract Background. The appropriate surgical margin after neoadjuvant treatment (NAT) is controversial. Margin index, a relationship of the margin obtained to the size of the tumor, is a reliable method for the prediction of residual disease after breast conservative surgery (BCS) in the adjuvant setting. Our aim was to apply the margin index to patients with BCS after NAT to predict residual disease. Material and Methods. From a prospectively maintained database, patients with stage I - III with NAT who underwent BCS between July 2008 and December 2012 were included. Margin index was calculated as for the adjuvant setting: margin index = closest margin (mm)/tumor size (mm) × 100 considering the tumor size of the lumpectomy specimen. A receiver operating curve was created using the derived margin index and the presence or absence of residual disease in the re-excision specimen. Patients with pathologic complete response (pCR) (no invasive tumor) were excluded. Results. Of the 206 patients, 63 (30.5%) had a pCR and were excluded. Of the 143 patients, 76 (53%) had an intraoperative re-excision depending on the surgeon or the intraoperative pathology report. Of the 76 patients, 23 (32%) had residual tumor in the intraoperative re-excision specimen. There were no statistically significant differences in residual disease regardless of who indicates intraoperative re-excision. (p= 0.56) Twenty-three patients (16%) underwent a second surgery for positive or close margins ( &amp;lt; 2mm). Residual disease, whether infiltrating or in situ or both, was found in 10 (43%) patients. The overall c index for the receiver operating curve was 0.76. A margin index &amp;gt; 5 had a sensitivity of 80% and a specificity of 63%. Conclusion. Rates of re-excision after NAT in BCS patients are similar to the adjuvant setting. Margin index may be a valuable tool for determine residual disease after NAT in patients undergoing BCS. Further validation of this index is warranted in a larger cohort of patients after NAT to confirm these results. Citation Format: Rubio IT, Loinaz I, Esgueva-Colmenarejo AJ. Predicting residual disease in breast conservative surgery after neoadjuvant treatments in breast cancer patients using the margin index tool [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-13-23.
Abstract P2-06-04: Breast cancer after Hodgkin lymphoma: Influence of endogenous and exogenous gonadal hormones on the radiation dose-response relationship
Authors: IM Krul, AWJ Opstal - van Winden, BMP Aleman, CPM Janus, AM van Eggermond, ML de Bruin, M Hauptmann, ADG Krol, M Schaapveld, A Broeks, KR Kooijman, S Fase, ML Lybeert, JM Zijlstra, RWM van der Maazen, A Kesminiene, I Diallo, F de Vathaire, NS Russell, FE van Leeuwen
Journal: Cancer Research (2017)

Abstract Background After chest radiotherapy (RT) for Hodgkin lymphoma (HL), women experience a dose-dependent increased breast cancer (BC) risk. It is unknown whether endogenous and exogenous gonadal hormones affect the radiation dose-response relationship. Methods We conducted a nested case-control study among female 5-year HL survivors treated before 41 years between 1965-2000. Data were collected through medical records and questionnaires for 174 BC cases and 466 matched controls. RT charts, simulation films and mammography reports were used to estimate the radiation dose to the location of the breast tumor. Results The median interval between HL and BC diagnosis was 21.9 years. 98% of BC cases had received chest RT, compared to 92% of controls. We observed a linear radiation dose-response curve with an adjusted excess odd ratio (EOR) of 5.4%/Gray (95%CI:1.8%-13.37%). Women with menopause &amp;lt;30 years (caused by high-dose procarbazine or pelvic RT) had a lower BC risk (OR:0.13, 95%CI:0.03-0.54) than women with menopause ≥50 years. BC risk increased with 7.4% for each additional year of intact ovarian function after RT (P&amp;lt;0.001). Among women with an early menopause (&amp;lt;45 years), the use of hormone replacement therapy (HRT) for ≥2 years did not increase BC risk (OR:0.81, 95%CI:0.30-2.21). Endogenous and exogenous hormones did not statistically significantly modify the slope of the radiation dose-response relationship. Conclusion HRT use did not appear to increase BC risk in female HL survivors with a therapy-induced early menopause. Moreover, there was no evidence for interaction between RT dose and years with intact ovarian function or HRT use. Citation Format: Krul IM, Opstal - van Winden AWJ, Aleman BMP, Janus CPM, van Eggermond AM, de Bruin ML, Hauptmann M, Krol ADG, Schaapveld M, Broeks A, Kooijman KR, Fase S, Lybeert ML, Zijlstra JM, van der Maazen RWM, Kesminiene A, Diallo I, de Vathaire F, Russell NS, van Leeuwen FE. Breast cancer after Hodgkin lymphoma: Influence of endogenous and exogenous gonadal hormones on the radiation dose-response relationship [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-06-04.
THE PROTECTIVE ACTION OF TYPE I ANTIPNEUMOCOCCUS SERUM IN MICE
Authors: Kenneth Goodner, Frank L. Horsfall
Journal: The Journal of Experimental Medicine (1936)

1. The addition of small amounts of cholesterol and of cephalin reduces markedly the protective action of antipneumococcus horse serum. 2. These lipids do not affect the protective action of antipneumococcus rabbit serum. 3. These findings may be explained (a)by the selective adsorption of lipid on the antigen-antibody complex, and (b) by certain lipid antagonisms. 4. The failure of large amounts of immune horse serum to protect mice against pneumococcus infection is explicable on the basis of selective participation of lipids dependent upon the species from which the antibody is derived. 5. The lipids modify the results of protection tests only through participation in the process of specific sensitization.
Erratum: Corrigendum: Long-term glycemic control using polymer-encapsulated human stem cell–derived beta cells in immune-competent mice
Authors: Arturo J Vegas, Omid Veiseh, Madsörtler G, Jeffrey R Millman, Felicia W Pagliuca, Andrew R Bader, Joshua C Doloff, Jie Li, Michael Chen, Karsten Olejnik, Hok Hei Tam, Siddharth Jhunjhunwala, Erin Langan, Stephanie Aresta-Dasilva, Srujan Gandham, James J McGarrigle, Matthew A Bochenek, Jennifer Hollister-Lock, Jose Oberholzer, Dale L Greiner, Gordon C Weir, Douglas A Melton, Robert Langer, Daniel G Anderson
Journal: Nature Medicine (2016)