tbuckley/cabot-search huggingface dataset:
Abstract 98: Embryonic Extracellular Matrix and Cell Fate Determination
Authors: Stefan M Kren, Christopher S Chapman, Andrew Loza, Daniel J Garry, Mary G Garry
Journal: Circulation Research (2015)

Background - The determination of cell fate during development is governed by intrinsic factors, but also by interaction with the milieu in which they reside. The extracellular matrix (ECM) from rapidly developing tissue should form a rich signaling environment for cellular proliferation and differentiation. Hypothesis - Murine embryonic ECM can be prepared by detergent decellularization that is morphologically preserved, biocompatible for cell culture, and at E13.5 substantial enough to permit vascular catheterization and recellularization by perfusion. Methods and Results - To test the contribution of embryonic extracellular matrix (ECM) to the determination of cell fate, we undertook isolation of ECM from developing murine embryos. Triton X-100 and SDS detergent decellularization were used to isolate ECM from E10.5 and E13.5 embryos. Acellularity was confirmed by pico-green DNA assay (98.7 % ± 0.95 of DNA removed compared to control), as well as the lack of visible nuclei by H &amp; E and DAPI histology. The matrix scaffolds were washed thoroughly with PBS and culture media to return them to a biocompatible state. Murine embryonic stem cells (mESC) modified to express EGFP were cultured on the exterior or the interior of the ECM scaffolds. mESCs seeded on the exterior of the E10.5 scaffolds or perfused through the E13.5 umbilical vasculature were highly adherent and proliferative during the 17 day culture period as evidenced by fluorescent microscopy. Perfused mESCs exhibited engrafted in the heart, liver, and vascular conduit E13.5 matrix 2 days post-infusion. Histology confirmed the attachment and morphologic alteration of the cultured cells on the exterior of the E10.5 ECM and presence of the perfused cells in the E13.5 embryo matrix interior. Conclusion - Biocompatible, acellular morphologically preserved embryonic ECM can be extracted from E10.5 and E13.5 murine embryos. By E13.5 the structural integrity of the acellular matrix can sustain vascular perfusion for delivery of mESCs to internal organoid structures. These ECM preparations support the proliferation and maintenance of mESCs externally and internally.
The activity of HDAC and mTOR inhibitors in three dimensional in-vitro model of BRCA-2 mutated breast cancer cell line.
Authors: Peter C. Kurniali, Omar Abed Alkharabsheh, Burra V Madhukar, Cheryl Leece, Nikolay V. Dimitrov, Bashar S Aldeen, Deimante Tamkus
Journal: Journal of Clinical Oncology (2015)

e22221 Background: Targeted therapies for breast cancer patients carrying BRCA-1/2 mutations are emerging. Histone deacytelase inhibitors (HDACi) represent a promising class of drugs for the treatment of breast cancer. Previous studies had shown that HDACi down regulate multiple components of DNA damage response and repair. There is also an evidence that PI3K/mTOR inhibition potentiates HDAC inhibition activity in some tumors. Therefore, we explored the efficacy of HDACi and mammalian target of rapamycin inhibitor (mTORi) and their combination in BRCA-2 mutated breast cancer cell line. Methods: The activity of HDACi (scriptaid) and mTORi (everolimus) as single agent or in combination was evaluated in 3 breast cancer cell lines (MCF-7, ER+; MDA-MB-231, ER-; BCSV, cell line derived from BRCA-2 mutated metastatic breast cancer which was ER positive and Her-2 negative at diagnosis but lost ER expression during tumor progression). The effects of the treatment were determined by a colorimetric MTT assay, Ki67 expression by immunohistochemistry (IHC), and in vitro chemosensitivity testing of three-dimentional tumor spheroids. Treatment responses after drug exposure were assessed on day 5, 10, 15 and 20. Results: When compared with control, HDACi 10 µM decreased tumor spheroids growth by 66% and 28% in BCSV and MCF-7 cells, respectively (p < 0.001). Furthermore, additive inhibitory effect was achieved when HDACi 5 µM was combined with mTORi 5 µM (reduction by 72% and 44% in BCSV and MCF7 cells, respectively, when compared to control (p < 0.001)). Tumor spheroid proliferation rate (as assessed by Ki67 protein expression) was markedly decreased with HDACi and with HDACi+mTORi treatment in BCSV cell line. Cell viability was significantly reduced in BCSV and MDA-MB-231 cells treated with HDACi. Conclusions: Treatment with HDACi and combination of HDACi and mTORi significantly reduced cell viability, proliferation, and tumor spheroid growth in BRCA-2 mutated breast cancer cell line. Our results indicate anticancer activity of dual HDACi and mTORi therapy in breast cancer cell lines, especially in those with BRCA mutation, and warrants further investigation.
Exome Sequencing of African-American Prostate Cancer Reveals Loss-of-Function <i>ERF</i> Mutations
Authors: Franklin W. Huang, Juan Miguel Mosquera, Andrea Garofalo, Coyin Oh, Maria Baco, Ali Amin-Mansour, Bokang Rabasha, Samira Bahl, Stephanie A. Mullane, Brian D. Robinson, Saud Aldubayan, Francesca Khani, Beerinder Karir, Eejung Kim, Jeremy Chimene-Weiss, Matan Hofree, Alessandro Romanel, Joseph R. Osborne, Jong Wook Kim, Gissou Azabdaftari, Anna Woloszynska-Read, Karen Sfanos, Angelo M. De Marzo, Francesca Demichelis, Stacey Gabriel, Eliezer M. Van Allen, Jill Mesirov, Pablo Tamayo, Mark A. Rubin, Isaac J. Powell, Levi A. Garraway
Journal: Cancer Discovery (2017)

African-American men have the highest incidence of and mortality from prostate cancer. Whether a biological basis exists for this disparity remains unclear. Exome sequencing (
Low Serum Galectin-1 Levels Predict Future Lymphoma Development in HIV-Positive Patients
Authors: Maja Ludvigsen, Maja Ølholm Vase, Rikke Hjortebjerg, Irma Petruskevicius, Court Pedersen, Gitte Pedersen, Betina Sørensen, Mette Bjerre, Niels Obel, Bent Honoré, Carsten Schade Larsen, Francesco d'Amore
Journal: Blood (2016)
Soluble TACI and soluble BCMA as biomarkers in primary central nervous system lymphoma
Authors: Franziska S Thaler, Sarah A Laurent, Marion Huber, Matthias Mulazzani, Martin Dreyling, Uwe Ködel, Tania Kümpfel, Andreas Straube, Edgar Meinl, Louisa von Baumgarten
Journal: Neuro-Oncology (2017)

B-cell survival is regulated through interactions of B-cell-activating factor and a proliferation-inducing ligand with their receptors transmembrane activator and CAML interactor (TACI) and B-cell maturation antigen (BCMA). We evaluated the diagnostic potential of soluble TACI (sTACI) and soluble BCMA (sBCMA) in CSF and serum as biomarkers in primary CNS lymphoma (PCNSL).CSF (n = 176) and serum samples (n = 105) from patients with clinically or radiologically suspected PCNSL as well as from control patients were collected prospectively. Levels of sTACI and sBCMA were analyzed by enzyme-linked immunosorbent assay. Additionally, in patients with PCNSL, CSF was analyzed during disease course (time of diagnosis, n = 26; relapse, n = 10; remission, n = 14), and in 2 patients long-term longitudinal analysis was performed.Soluble TACI and sBCMA are significantly increased in patients with PCNSL (sTACI, median: 445 pg/mL; sBCMA, median: 760 pg/mL) compared with control patients (sTACI, median: 0 pg/mL; sBCMA, median: 290 pg/mL). At a cutoff value of 68.4 pg/mL, sTACI shows high sensitivity (87.9%) and specificity (88.3%) for the diagnosis of active PCNSL. Soluble BCMA is less sensitive (72.7%) and specific (71.8%) (cutoff: 460 pg/mL). When both markers are combined, specificity increases, however, at the cost of a lower sensitivity. In serum, both sTACI and sBCMA are not increased in PCNSL patients. Both soluble receptors correlate with clinical course and therapy response.Our results suggest that sTACI and sBCMA in the CSF are promising new biomarkers for diagnosis and therapy monitoring in PCNSL. However, our findings need to be validated in an independent cohort.
AACR Cancer Progress Report 2013
Authors: Charles L. Sawyers, Cory Abate-Shen, Kenneth C. Anderson, Anna Barker, Jose Baselga, Nathan A. Berger, Margaret Foti, Ahmedin Jemal, Theodore S. Lawrence, Christopher I. Li, Elaine R. Mardis, Peter J. Neumann, Drew M. Pardoll, George C. Prendergast, John C. Reed, George J. Weiner
Journal: Clinical Cancer Research (2013)

### AACR Staff

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On April 8, 2013, in an unprecedented effort to highlight the critical importance of biomedical research, the American Association for Cancer Research (AACR) joined with more than 200 organizations representing a broad spectrum of research interests and diseases
Reply to Van Lange et al.: Proximate and ultimate distinctions must be made to the CLASH model
Authors: Tomás Cabeza de Baca, Steve C Hertler, Curtis S Dunkel
Journal: Behavioral and Brain Sciences (2017)

Abstract Transcending reviewed proximate theories, Van Lange et al.'s CLASH model attempts to ultimately explain the poleward declension of aggression and violence. Seasonal cold is causal, but, we contend, principally as an ecologically relevant evolutionary pressure. We further argue that futurity and restraint are life history variables, and that Life History Theory evolutionarily explains the biogeography of aggression and violence as strategic adaptation.
Panex: A pooled analysis of EXPERT and EXPERT-C, two trials of neoadjuvant chemotherapy (NACT) and chemoradiotherapy (CRT) in high-risk locally advanced rectal cancer (LARC).
Authors: Francesco Sclafani, Clare Peckitt, David Cunningham, Jessica Evans, Gina Brown, Josep Tabernero, Bengt Glimelius, Andres Cervantes, Diana M. Tait, Andrew Wotherspoon, Janet Thomas, Jacqueline Rose Oates, Ian Chau
Journal: Journal of Clinical Oncology (2014)

3575 Background: After the use of preoperative radiotherapy and TME, survival of LARC has reached a plateau. More effective therapies, predictive/prognostic factors for treatment selection and valid endpoints for clinical trials are needed. We report the results of PANEX, a pooled analysis of EXPERT and EXPERT-C, the two largest trials of neoadjuvant CAPOX followed by CRT, TME and adjuvant CAPOX ± cetuximab in MRI-defined, high-risk, LARC. Methods: Individual patient data were collected from the central database of each trial. Survival endpoints were analysed using Kaplan-Meier methods and multivariate Cox-regression. Results: 269 patients (EXPERT=105, EXPERT-C=164) were included. Baseline features: T3c/T3d (60%), T4 (22%), CRM+ (63%), distal tumour (61%), N+ (72%), EMVI (71%). Radiologic response was 62% after NACT and 80% after CRT. Surgery was performed in 91% (R0 in 87%) and T/N downstaging was achieved in 56%/55% of cases. Pathologic complete response rate was 19%. After a median follow-up of 69 mo, 5-year local progression-free survival (PFS), distant PFS, PFS and overall survival (OS) were 94%, 79%, 70% and 73%, respectively. Baseline and treatment-related factors with statistically significant independent prognostic value in multivariate analyses are shown in the Table. Conclusions: Short- and long-term outcomes of NACT followed by CRT in high-risk LARC compare favourably with those reported with standard CRT in risk-unselected patients. Age, T4 and EMVI may be used as baseline factors for patient stratification and treatment selection. Tumour downstaging may be a surrogate endpoint to use in future phase II trials of NACT. Variable Local PFS Distant PFS PFS OS Baseline1 - EMVI HR 2.07 p=0.03 Age HR 1.52 p=0.04 Age HR 1.68 p=0.02 T4 HR 1.75 p=0.02 Treatment-related2,3 - T downstaging HR 0.51 p=0.03 N downstaging HR 0.49 p=0.02 T downstaging HR 0.47 p=0.002 T downstaging HR 0.36 p<0.001 1Include: trial, treatment with cetuximab, age, sex, WHO PS, T3c/d, T4, EMVI, CRM+, distal tumour. 2Include: T/N downstaging, R0 resection, pCR. Also, adjusted for significant baseline variables. 3R0 vs R1/R2 resection significant for all outcome measures.
Expression profiling reveals a set of seven genes that may be required for lymph node metastasis in lung and breast cancer
Authors: Michael Mitas, Andras Khoors, Amanda Graham, Yian Chen, Kaidi Mikhitarian, David Lewin, David Cole, Carolyn Reed, Michael B. Wallace
Journal: Cancer Research (2006)

4296  Studies suggest that although cancer cells can potentially invade the blood vessels to gain access to the general circulation, the lymphatics are typically used for the initial spread of solid tumors. To identify membrane-bound or secreted proteins required for metastasis in lymphatic tissue, we first performed two separate microarray analyses using Affymetrix U133A chips whereby expression values of a pool of normal lymph node tissue (n=4) were compared to either 1) four non-small cell lung cancer (NSCLC) cell lines, or 2), three metastatic lymph nodes derived from breast cancer patients. Separate lists of the 35 most highly overexpressed genes were generated for each cancer type. Each list contained 20 tissue-specific genes and 15 potential cancer-specific genes. Seven genes were common to both lists (p
Efficacy of Neonatal Ocular Prophylaxis for the Prevention of Chlamydial and Gonococcal Conjunctivitis
Authors: Margaret R. Hammerschlag, Cynthia Cummings, Patricia M. Roblin, Theresa H. Williams, Issac Delke
Journal: New England Journal of Medicine (1989)

Opinions differ concerning the efficacy of prophylaxis against neonatal chlamydial and gonococcal conjunctivitis. From January 1986 through June 1988, we gave all infants born at Kings County Hospital Medical Center one of three prophylactic agents — silver nitrate drops, erythromycin ophthalmic ointment, or tetracycline ophthalmic ointment. The treatments were rotated monthly. Gonococcal ophthalmia occurred in 8 of the 12,431 infants born during the study (0.06 percent), 1 in the silver nitrate group, 4 in the erythromycin group, and 3 in the tetracycline group (P not significant). Seven of these infants were born to women who had received no prenatal care. From September 1985 through December 1987, we screened 4357 pregnant women for cervical chlamydial infection, of whom 341 (8 percent) had positive cultures. Of their offspring, 230 were evaluated for neonatal chlamydial conjunctivitis; the incidence was 20 percent in the silver nitrate group, 14 percent in the erythromycin group, and 11 percent in the tetracycline group (P not significant). We conclude that neonatal ocular prophylaxis with either erythromycin or tetracycline ophthalmic ointment does not significantly reduce the incidence of chlamydial conjunctivitis in the offspring of mothers with chlamydial infection as compared with silver nitrate, and that better management of maternal chlamydial infection is therefore required. We also conclude that there is a small but appreciable incidence of neonatal gonococcal ophthalmia that could be prevented by better prenatal screening and treatment of maternal gonococcal infection. (N Engl J Med 1989;320:769–72.)
Annual rhythm in filgrastim use in southeast Florida.
Authors: Dinah Huff, William J. Hrushesky, Sharon Davis, Laura Rose Bobolts, Akhil Kumar, William S. Shimp, James Edward Krook, Jurgen Wilhelm Kogler, Val Fishman, Carol Anthony, Robert Walton, Marc L. Fishman
Journal: Journal of Clinical Oncology (2013)

e20697 Background: Circadian, seasonal and annual temporal organization characterizes earth-evolved life forms. Cellular proliferation in human bone marrow shares this temporal organization. Careful clinical trials have documented that bone marrow damage from a range of cytotoxic anti-cancer drugs is predictably greater and lesser when these drugs are given at specific times of day and seasons of the year to human beings with cancer. Filgrastim is a human growth factor, which is given to stimulate the production of neutrophils that have been depressed to low levels by cancer chemotherapy, in order to prevent infectious complications. We hypothesized that administration of filgrastim, stimulated by dangerously low neutrophil counts, would be initiated non-randomly with reproducible seasonality and annual rhythmicity. Methods: All claims from contracted healthplans submitted by oncologists in southeast Florida were tabulated by month of service date, during the calendar years of 2010, 2011, and 2012 (n=2,506). These numbers were de-trended, tested by linear regression, ANOVA and multi-component least squares cosine curve fitting for annual rhythmicity. Results: Similar stable annual time structures characterize filgrastim use in this population for each of these three years. An overall increasing trend (p 0.004) was present in its use during this three year span. Time of year effects were present (ANOVA p&lt;0.058), demonstrating a prominent annual rhythm (p 0.006). The annual use pattern peaks during late winter and early spring and is lower in summer and fall. Conclusions: A large literature documents expected annual rhythmicity of cytotoxic drug bone marrow damage as reflected in circulating neutrophil count. Substantial annual rhythms characterize the clinical use of filgrastim in southeast Florida for this indication. The relative contributions of “snowbird” migration and the temporal organization of hematopoiesis remain to be fully elucidated. [Table: see text]
Evesor: The first phase I trial combining multiple dose/dosing schedules—Pharmacodynamic assessments and mathematical modeling to optimize the benefit/toxicity ratio of everolimus and sorafenib association.
Authors: Benoit You, Gilles Freyer, Michel Tod, Claire Rodriguez, Philippe Alexandre Cassier, Juliette Hommel-Fontaine, Pierre-Jean Valette, Jerome Guitton, Emilie Henin
Journal: Journal of Clinical Oncology (2013)

TPS2625 Background: In 2004, FDA declared the abandon rate of new oncology drugs was too high and new trial designs should be developed. The combination of everolimus (EVE) and sorafenib (SOR) is rational, and has been studied in 11 phase I studies, where approved monotherapy regimens have been used (EVE qd and SOR bid). Although promising efficacy outcomes were found, the combination may be abandoned due to metabolical and skin toxicity. The best doses and dosing schedules of EVE and SOR associated with the optimal benefit/toxicity ratio may be identified using mathematical modeling of data from an adequately designed multiparameter trial. Methods: This academic study is composed of 4 arms with different dosing schedules of EVE and SOR (qd; 1 week/2; 3 days-on …), and dose escalations. Patients with different tumor types potentially sensitive to the combination are enrolled. Multiparameter assessments include: pharmacokinetics (PK); pharmacodynamics (PD) with control of signaling pathway inhibition (ERK, AKT, S6K) in 2 tumor biopsies &amp; repetitive PBMC assays; kinetics of circulating tumor DNA kinetics &amp; angiogenesis markers; tumor angiogenesis changes using repeated DCE-ultrasounds; and radiological/clinical effects. These data enrich a translational multiscale model meant to quantify the relationships between drug dosing modalities, PK, PD, radiological and clinical effects, developed in parallel. The doses and dosing schedules of EVE and SOR which enable maximization of benefit/toxicity ratio (utility function) will be searched using simulations, and then tested. The protocol was approved by ethic committee in 2012. Two patients a month have been enrolled in 2 centers since January 2013. Expected results: Mathematical modeling of the relationships between dosing modalities; PK; PD; radiological and clinical effects based on the data from an adequately designed trial may help determine the optimal doses and dosing schedules of EVE and SOR (with the best benefit/toxicity ratio), and avoid the combination abandon. EVESOR study may embody the proof of concept of this new model-based trial design. Clinical trial information: 2012-002818-39.
A CK1δ/CK1ε-to-Wnt/β-Catenin Circuit Is a Therapeutic Vulnerability in Primary and Drug Resistant Multiple Myeloma
Authors: Karen L. Burger, Mark B Meads, Ariosto Silva, Allison Distler, Maria Coelho Siqueira Silva, Timothy Jacobson, Jamie K Teer, William R. Roush, Kenneth H. Shain, John L. Cleveland
Journal: Blood (2016)
Bullying when it's hot? The CLASH model and climatic influences on bullying
Authors: Anthony A Volk
Journal: Behavioral and Brain Sciences (2017)

Abstract A novel predictor of bullying may be underlying regional weather conditions (i.e., climate). Bullying data support the CLASH model of aggression by suggesting that climate may moderate the forms and severity of bullying, as well as predict its prevalence across countries. Furthermore, bullying data also suggest that the CLASH model may apply to forms of aggression beyond reactive aggression.
Idarucizumab, a Specific Reversal Agent for Dabigatran: Immediate, Complete and Sustained Reversal of Dabigatran-Induced Anticoagulation in Japanese Healthy Male Volunteers
Authors: Joanne van Ryn, Masahiro Yasaka, Ippei Ikushima, Akiko Harada, Atsushi Taniguchi, Susumu Imazu, Stephen Norris, Dietmar Gansser, Joachim Stangier
Journal: Blood (2016)
Inhibition of Carcinogenesis by Tea
Authors: Chung S. Yang, Pius Maliakal, Xiaofeng Meng
Journal: The Annual Review of Pharmacology and Toxicology (2002)

Tea has received a great deal of attention because tea polyphenols are strong antioxidants, and tea preparations have inhibitory activity against tumorigenesis. The bioavailability and biotransformation of tea polyphenols, however, are key factors limiting these activities in vivo. The inhibition of tumorigenesis by green or black tea preparations has been demonstrated in animal models on different organ sites such as skin, lung, oral cavity, esophagus, forestomach, stomach, small intestine, colon, pancreas, and mammary gland. Epidemiological studies, however, have not yielded clear conclusions concerning the protective effects of tea consumption against cancer formation in humans. The discrepancy between the results from humans and animal models could be due to 1) the much higher doses of tea used in animals in comparison to human consumption, 2) the differences in causative factors between the cancers in humans and animals, and 3) confounding factors limiting the power of epidemiological studies to detect an effect. It is possible that tea may be only effective against specific types of cancer caused by certain etiological factors. Many mechanisms have been proposed for the inhibition of carcinogenesis by tea, including the modulation of signal transduction pathways that leads to the inhibition of cell proliferation and transformation, induction of apoptosis of preneoplastic and neoplastic cells, as well as inhibition of tumor invasion and angiogenesis. These mechanisms need to be evaluated and verified in animal models or humans in order to gain more understanding on the effect of tea consumption on human cancer.