tbuckley/cabot-search huggingface dataset:
MEDU-15. CCL2/CCR2/IL-6 LOOP: A POTENTIAL THERAPEUTIC TARGET FOR PEDIATRIC MEDULLOBLASTOMAS
Authors: Amy-Lee Bredlau, Ramin Eskandari, Jennifer Oletsky, Daniel McDonald, Samuel L Cooper, Stephen Lowe, Kenneth Vanek, Joseph M Jenrette, Samuel Cheshier, Arabinda Das
Journal: Neuro-Oncology (2017)

Medulloblastoma cells in situ are surrounded by microglia, suggesting medulloblastoma–microglia interactions to produce various outcomes. As chemokines are important mediators of cell–cell communication, we sought to identify common chemokines in mouse and human medulloblastoma lines. We found CCL2 (chemokine (C-C motif) ligand 2) messenger RNA was expressed by Group 3 and 4 medulloblastoma lines. However, these lines did not express the CCL2 receptor, CCR2, which was found on microglia. The MP-1 medulloblastoma cell line expresses low basal levels of CCL2. Hence, we overexpressed CCL2 plasmid with GFP tagging in MP-1 medulloblastoma cells to investigate the hypothesis that medulloblastoma-secreted CCL2 interacts with microglia to affect medulloblastoma growth and invasion. In medulloblastoma–microglia co-culture models, we observed increased proliferation of CCL2-overexpressing clones. ELISA protein analyses revealed that interleukin-6 (IL-6) was consistently increased in the co-culture. Recombinant IL-6 enhanced the invasion of medulloblastoma cells when these were cultured alone, whereas a neutralizing antibody to IL-6 attenuated the microglia-stimulated medulloblastoma invasion. This study reveals a mechanism by which medulloblastoma cells exploit microglia (M2-phenotype) for increased invasion. Specifically, medulloblastoma-derived CCL2 acts upon CCR2-bearing tumor associated microglias (TAMs), which produce IL-6 to stimulate medulloblastoma cells, in a CCL2/CCR2/IL-6 loop. We targeted this loop by combining radiation therapy with a 4-1BB (CD-137) monoclonal antibody (mAb), as CD-137 is involved in regulation of immune cell proliferation and survival. We re-educated microglia cells toward a cytotoxic M1-like phenotype and amplified effective anti-tumor immune responses in co-culture models. ELISA spot shows treatment with 50 ng of 4-1BB + 1Gy X-ray radiation converted the microglia from M2 to M1 phenotype via a decrease in CCR2. This treatment induces the M1 phenotype microglia to induce MP-1 cell death. Based on our results, the use of 4-1BB mAb plus radiation may prove to be beneficial for the treatment of medulloblastoma by targeting CCL2/CCR2/IL-6 loop.
Abstract 11: Acquisition of Mitochondrial DNA Mutations Impairs Mitochondrial Function in Cardiac Progenitor Cells
Authors: Amabel M Orogo, Eileen R Gonzalez, Dieter A Kubli, Anne N Murphy, Åsa B Gustafsson
Journal: Circulation Research (2015)

Activation of cardiac progenitor cells (CPCs) are critical for effective repair in response to pathologic injury. Stem cell activation and commitment involve increased energy demand and mitochondrial biogenesis. We have previously shown that incubation of c-kit+ CPCs in differentiation medium led to expansion of the mitochondrial network and lineage commitment. CPC function is reduced with age but the underlying mechanism is still unclear. Mitochondria contain their own DNA (mtDNA) which accumulates mutations over time that can impair mitochondrial function. In this study, we investigated the effects of acquiring mtDNA mutations on CPC proliferation, survival, and differentiation. We utilized a mouse model in which a mutation in the mtDNA polymerase gamma (POLGm/m) leads to accumulation of mtDNA mutations, mitochondrial dysfunction, and accelerated aging. Isolated CPCs from hearts of 2-month old POLGm/m mice had reduced proliferation and were more susceptible to oxidative stress and chemotherapeutic agents compared to WT CPCs. Incubation in differentiation medium resulted in fewer lineage committed POLGm/m CPCs compared to WT. In addition, the POLGm/m CPCs failed to activate mitochondrial biogenesis and did not increase levels of proteins involved in mitochondrial oxidative phosphorylation. We measured mitochondrial respiration with the Seahorse XF Analyzer and found that POLGm/m CPCs had undetectable oxygen consumption but still generated similar amounts of ATP as WT CPCs. Interestingly, POLGm/m CPCs produced increased amounts of l-lactate and were more sensitive to 2-deoxyglucose treatment, suggesting that these cells rely on glycolysis for energy production. Both WT and POLGm/m CPCs downregulated expression of glycolytic enzymes during differentiation. However, POLGm/m CPCs failed to undergo the metabolic transition from glycolysis to OXPHOS, which led to activation of cell death during differentiation. These data demonstrate that mitochondria play a critical role in CPC function, and accumulation of mtDNA mutations impairs CPC function and reduces their repair potential.
Is rituximab-based chemotherapy a standard practice in the treatment of B-NHLs in the developing world.
Authors: Rajesh Kota, Vijay Gandhi Linga, Muralidhar Gullipalli, Krishnamani Kalpathi, Vamshi Krishna Reddy Goteke, Rahul Narayan Maddi, Ranga Raman Ganta, Ravi Sankar Arigela, Srividya Nasaka, Sadashivudu Gundeti, Raghunadharao Digumarti
Journal: Journal of Clinical Oncology (2013)

e19533 Background: B Non Hodgkin Lymphoma (B-NHL) constitutes 90% of all NHLs. Surface CD20 is expressed in most of them. Standard of care worldwide for B NHLs currently is rituximab-based chemotherapy. In the present era, still rituximab-based chemotherapy is seldom used in India. We tried to analyze the proportion of eligible patients who received rituximab during their first line treatment and their outcome. Methods: We retrospectively analyzed all the cases of NHL patients registered at our center from 2001 to 2010. We defined “Refusal to treatment” as rejection of any therapeutic intervention, “abandonment” if treatment was initiated but not completed, “lost to follow up” as patients who have completed treatment, but missed the subsequent appointments. Results: A total of 1,351 cases of NHLs were registered during 2001-2010. B-NHLs constituted 90.6%. DLBCL accounted for 78.2% of all B-NHLs followed by follicular lymphoma (14.6%). Out of the 1,216 B-NHL patients registered, less than a third (377/1216 i.e 31%) were started on treatment, rest (69%) refused treatment. Four-fifths (79.3%) of the patients could complete at least 4 cycles of the intended chemotherapy, whereas 20.7% of them abandoned treatment in between. Rituximab-based chemotherapy could be initiated in only a quarter (94/377, 24.9%) of the eligible patients, out of which 68% (65/94) completed at least 4 cycles. Chemotherapy without rituximab was initiated in the remaining 75.1% of the patients, of which 78%(221/283) could complete at least 4 cycles. Among the 65 patients who completed at least 4 cycles of rituximab-based chemotherapy, 52% (34/65) were still alive without any evidence of disease as compared to 19% (42/221) of the patients who received chemotherapy without Rituximab at a median follow up of 17 months (range 1-125 months) p&lt;0.05. The proportion of patients who were lost to follow up with evidence of disease at their last visit in the clinic was 4%(3/65) vs. 39%(86/221), in the rituximab vs. non-rituximab-containing chemotherapy groups respectively. Conclusions: Only 7.7% (94/1216) of the eligible B-NHL patients were able to receive rituximab-based chemotherapy. A distinct survival advantage is noted in patients who received rituximab.
BIOL-04. INTEGRATED COPY-NUMBER AND CANCER DEPENDENCY ANALYSIS REVEALS ALTERED SPLICEOSOME STOICHIOMETRY AS A NOVEL VULNERABILITY IN GENOMICALLY DISRUPTED CANCERS
Authors: Brenton Paolella, William Gibson, Laura Urbanski, John Alberta, Travis Zack, Pratiti Bandopadhayay, Caitlin Nichols, Meredith Brown, Rebecca Lamothe, Yong Yu, Peter Choi, Esther Obeng, Guo Wei, Belinda Wong, Aviad Tsherniak, Francisca Vazquez, Barbara Weir, David Root, Glenn Cowley, Charles Stiles, Benjamin Ebert, William Hahn, Robin Reed, Rameen Beroukhim
Journal: Neuro-Oncology (2017)

Many pediatric cancers exhibit widespread somatic copy number alterations. We integrated a genome-scale shRNA viability screen and copy number profiles from 179 cancer cell lines to perform an unbiased analysis of copy-number associated gene-dependency interactions. We found most copy-number associated gene dependencies result from losses of genetic material rather than gains. Strikingly, the most enriched class of these dependencies was CYCLOPS (Copy-number alterations Yielding Cancer Liabilities Owing to Partial losS) genes. Hemizygous loss of CYCLOPS genes sensitizes cancer cells to their further suppression. One of the “top hits” from the analysis was the pre-mRNA splicing factor SF3B1, which is also frequently mutated in cancer. We then sought to evaluate SF3B1 as a CYCLOPS gene. Cancer cells with hemizygous SF3B1 copy-loss were uniquely sensitive to partial SF3B1 suppression by RNAi compared to cells with normal SF3B1 gene dosage. Mechanistically, cancer cells harboring partial SF3B1 copy-loss lack a reservoir of excess SF3b complex, a precursor complex of the U2 snRNP, which protects cells with normal SF3B1 copy number from cell death upon SF3B1 suppression. Our data highlight the prevalence of CYCLOPS dependencies in cancer and establish the spliceosome as a frequent CYCLOPS target. Further, these data indicate targeting wild-type SF3B1 as a novel cancer dependency in cells with hemizygous SF3B1 copy-loss.
Characterizing non-linear effects of hospitalisation duration on antimicrobial resistance in respiratory isolates: an analysis of a prospective nationwide surveillance system
Authors: R. Sommerstein, A. Atkinson, E.F. Lo Priore, A. Kronenberg, J. Marschall, A. Burnens, A. Cherkaoui, O. Dubuis, A. Egli, V. Gaia, D. Koch, A. Kronenberg, S.L. Leib, S. Luyet, P. Nordmann, V. Perreten, J.-C. Piffaretti, G. Prod’hom, J. Schrenzel, A.F. Widmer, G. Zanetti, R. Zbinden
Journal: Clinical Microbiology and Infection (2017)
Current and future methodologies for quantitative analysis of information transfer in sign language and gesture data
Authors: Evie Malaia
Journal: Behavioral and Brain Sciences (2017)

Abstract State-of-the-art methods of analysis of video data now include motion capture and optical flow from video recordings. These techniques allow for biological differentiation between visual communication and noncommunicative motion, enabling further inquiry into neural bases of communication. The requirements for additional noninvasive methods of data collection and automatic analysis of natural gesture and sign language are discussed.
Dual Cross‐Linked Biofunctional and Self‐Healing Networks to Generate User‐Defined Modular Gradient Hydrogel Constructs
Authors: Zhao Wei, Daniel M. Lewis, Yu Xu, Sharon Gerecht
Journal: Advanced Healthcare Materials (2017)

Gradient hydrogels have been developed to mimic the spatiotemporal differences of multiple gradient cues in tissues. Current approaches used to generate such hydrogels are restricted to a single gradient shape and distribution. Here, a hydrogel is designed that includes two chemical cross‐linking networks, biofunctional, and self‐healing networks, enabling the customizable formation of modular gradient hydrogel construct with various gradient distributions and flexible shapes. The biofunctional networks are formed via Michael addition between the acrylates of oxidized acrylated hyaluronic acid (OAHA) and the dithiol of matrix metalloproteinase (MMP)‐sensitive cross‐linker and RGD peptides. The self‐healing networks are formed via dynamic Schiff base reaction between N ‐carboxyethyl chitosan (CEC) and OAHA, which drives the modular gradient units to self‐heal into an integral modular gradient hydrogel. The CEC‐OAHA‐MMP hydrogel exhibits excellent flowability at 37 °C under shear stress, enabling its injection to generate gradient distributions and shapes. Furthermore, encapsulated sarcoma cells respond to the gradient cues of RGD peptides and MMP‐sensitive cross‐linkers in the hydrogel. With these superior properties, the dual cross‐linked CEC‐OAHA‐MMP hydrogel holds significant potential for generating customizable gradient hydrogel constructs, to study and guide cellular responses to their microenvironment such as in tumor mimicking, tissue engineering, and stem cell differentiation and morphogenesis.
The molecular mechanisms of obesity paradox
Authors: Alexios S. Antonopoulos, Dimitris Tousoulis
Journal: Cardiovascular Research (2017)

Clinical observations suggest a complex relationship between human obesity and cardiovascular disease. Whilst abdominal (visceral) adiposity leads to deleterious metabolic disturbances, subcutaneous fat accumulation has a benign effect on cardiometabolic risk. Notably, an accumulating body of evidence paradoxically links increased body mass index with a better prognosis in patients with established cardiovascular disease, a finding that has been termed the 'obesity paradox'. Whilst this is now acknowledged to be an epidemiological finding, a metabolically healthy obese group associated with low cardiovascular risk has also been identified. The current concept of adipose tissue (AT) biology suggests that AT expansion is feasible without accompanying adipocyte dysfunction. A metabolically healthy obese phenotype can be promoted by exercise, but is also linked with intrinsic AT molecular characteristics such as efficient fat storage and lipid droplet formation, high adipogenesis capacity, low extracellular matrix fibrosis, angiogenesis potential, adipocyte browning and low macrophages infiltration/activation. Such features are associated with a secretomic profile of human AT which is protective for the cardiovascular system. In the present review, we summarize the existing knowledge on the molecular mechanisms underlying the 'obesity paradox' and whether fatness can be healthy too.
Neoadjuvant bevacizumab: Surgical complications of mastectomy with and without reconstruction.
Authors: Kari Joanne Kansal, Laura Stewart Dominici, Sara M. Tolaney, Steven J. Isakoff, Ian E. Krop, Barbara L. Smith, Wei Jiang, Hannah Potler, Jane E. Brock, Eric P. Winer, Mehra Golshan
Journal: Journal of Clinical Oncology (2013)

1100 Background: Neoadjuvant therapy is commonly used in operable breast cancer. We prospectively evaluated the surgical complications in a cohort of patients who underwent mastectomy following neoadjuvant doxorubucin hydrochloride/cyclophosphamide/paclitaxel (AC/T) plus bevacizumab and compared the rate of complications to a matched cohort of neoadjuvant AC/T without bevacizumab. Methods: One hundred patients with HER2-negative breast cancer enrolled in a single-arm trial of neoadjuvant AC/T plus bevacizumab (cohort 1), 60 of these patients underwent mastectomy and were matched with 59 patients who received standard neoadjuvant AC/T (cohort 2) over a similar time period in the same healthcare system. All patients underwent mastectomy with or without reconstruction. Fisher’s exact tests were used to compare complication rates, with a p&lt;0.05 was considered significant. Results: Patients were matched well in terms of demographics. The overall complication rate was 33% in cohort 1 and 31% in cohort 2 (P-value=0.84; Table). In cohort 1, 7 of 23 (30%) patients who underwent immediate expander/implant reconstruction had complications, including 2 patients who had explantation of their reconstructions. In cohort 2, 0 of 8 (0%) had complications (p value=0.15). Conclusions: Nearly a third of patients undergoing neoadjuvant therapy with AC/T with or without bevacizumab developed a postoperative complication after mastectomy. The use of bevacizumab was not associated with a significant increase in surgical complications, although this is a non-randomized data with a small sample size. As larger data sets become available with the use of neoadjuvant bevacizumab with mastectomy, further refinement may be necessary. [Table: see text]
Aryl hydrocarbon receptor inhibition promotes hematolymphoid development from human pluripotent stem cells
Authors: Mathew G. Angelos, Paige N. Ruh, Beau R. Webber, Robert H. Blum, Caitlin D. Ryan, Laura Bendzick, Seonhui Shim, Ashley M. Yingst, Dejene M. Tufa, Michael R. Verneris, Dan S. Kaufman
Journal: Blood (2017)
Requirement of epidermal growth factor receptor tyrosine 845, Src, and Stat5b in the neurotensin-induced proliferation of human prostate cancer cells.
Authors: George P. Amorino, Sarah J. Parsons
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

5332 

Neuroendocrine (NE) cells have been shown to contribute to the progression of prostate cancer, and we have previously demonstrated that NE-like cells derived from LNCaP prostate cancer cells secrete greater amounts of neurotensin than undifferentiated LNCaP’s. Since PC3 androgen-independent prostate cancer cells express the neurotensin receptor (a G-protein-coupled receptor), we have examined the molecular mechanisms of growth stimulation by neurotensin in PC3 cells. Following a 48 h treatment of serum-starved PC3 cells with 100 nM neurotensin, up to a 2-fold increase in cell number was observed; corresponding increases in DNA synthesis (BrdU incorporation) were measured. Neurotensin-induced proliferation was also observed in androgen-dependent LNCaP prostate cancer cells, but not in RWPE-1 normal prostate epithelial cells. Similar data were obtained by treatment of PC3 cells with conditioned medium from NE-like cells, and this effect was partially inhibited by pre-incubation of PC3 cells with an EGFR inhibitor. Neurotensin induced a time-dependent increase in both general EGFR tyrosine and Tyr845 phosphorylation, and these effects were blocked by specific inhibition of Src (which mediates Tyr845 phosphorylation) or EGFR. Phosphorylation of Src and Stat5b (a downstream effector of Tyr845) was also induced by neurotensin, and these increases were abrogated by specific inhibition of EGFR or Src. Expression of EGFR (Tyr845) or Stat5b (Tyr699) mutants in PC3 cells resulted in the loss of neurotensin-induced stimulation of DNA synthesis, relative to wild-type controls. Moreover, neurotensin-induced increases in proliferation and DNA synthesis were abolished by selective inhibition of EGFR, Src, and matrix metalloproteinases (MMP’s). These data indicate that neurotensin can stimulate mitogenic activation of PC3 cells through a mechanism involving MMP’s, EGFR transactivation, EGFR Tyr845, Src, and Stat5b.
MEDU-30. GENES PRESERVING STEM CELL STATE IN GROUP 3 MB BTICS CONTRIBUTE TO THERAPY EVASION AND RELAPSE
Authors: David Bakhshinyan, Thusyanth Vijayakumar, Chitra Venugopal, Mohini Singh, Maleeha Qazi, Sujeivan Mahendram, Branavan Manoranjan, Nicole McFarlane, Ashley Adile, Sheila Singh
Journal: Neuro-Oncology (2017)

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Out of all the subgroups, Group 3 patients face the highest incidence of leptomeningeal spread and overall patient survival of less than 50%. Current clinical trials for recurrent MB patients based on genomic profiles of primary, treatment-naïve tumors, provide limited clinical benefit since recurrent metastatic MBs are highly genetically divergent from their primary tumors. By adapting the existing COG (Children’s Oncology Group) Protocol for children with newly diagnosed high-risk MB for treatment of immuno-deficient mice intracranially engrafted with human MB brain tumor initiating cells (BTICs), we have characterized the rare treatment-refractory cell population in Group 3 MBs. MB cell populations recovered separately from brains and spines during the course of tumor development and therapy were comprehensively profiled for gene expression analysis, stem cell and molecular features to generate a global, comparative profile of MB cells through therapy to relapse. One of the most intriguing observations from our gene expression data was consistent over-expression of proteins belonging to Inhibitor of DNA-binding/differentiation (ID) family, transcription factors with a basic helix-loop-helix motif that act as suppressors cellular differentiation and a longevity associated protein bactericidal/permeability-increasing fold-containing-family-B-member-4 (BPIFB4) in our refractory population. The persistent upregulation of genes preserving undifferentiated state and cellular longevity further strengthens the hypothesis of stem-cell like cells driving tumor relapse in MB. The upregulation of the top 90 genes in our relapse cohort was predictive of worse overall survival in patients diagnosed with Group 3 MB. Furthermore, through application of cellular barcoding technology, we next aim to determine how MB BTICs evolve in response to therapy. Our differential genomic and gene expression profiles of the “treatment-responsive” tumors against those that fail therapy will thus contribute to discovery of novel therapeutic targets for the most aggressive subgroup of MB.
Racial and Ethnic Disparities in Interval Colorectal Cancer Incidence
Authors: Stacey A. Fedewa, W. Dana Flanders, Kevin C. Ward, Chun Chieh Lin, Ahmedin Jemal, Ann Goding Sauer, Chyke A. Doubeni, Michael Goodman
Journal: Annals of Internal Medicine (2017)

Interval colorectal cancer (CRC) accounts for 3% to 8% of all cases of CRC in the United States. Data on interval CRC by race/ethnicity are scant.To examine whether risk for interval CRC among Medicare patients differs by race/ethnicity and whether this potential variation is accounted for by differences in the quality of colonoscopy, as measured by physicians' polyp detection rate (PDR).Population-based cohort study.Medicare program.Patients aged 66 to 75 years who received colonoscopy between 2002 and 2011 and were followed through 2013.Kaplan-Meier curves and adjusted Cox models were used to estimate cumulative probabilities and hazard ratios (HRs) of interval CRC, defined as a CRC diagnosis 6 to 59 months after colonoscopy.There were 2735 cases of interval CRC identified over 235 146 person-years of follow-up. A higher proportion of black persons (52.8%) than white persons (46.2%) received colonoscopy from physicians with a lower PDR. This rate was significantly associated with interval CRC risk. The probability of interval CRC by the end of follow-up was 7.1% in black persons and 5.8% in white persons. Compared with white persons, black persons had significantly higher risk for interval CRC (HR, 1.31 [95% CI, 1.13 to 1.51]); the disparity was more pronounced for cancer of the rectum (HR, 1.70 [CI, 1.25 to 2.31]) and distal colon (HR, 1.45 [CI, 1.00 to 2.11]) than for cancer of the proximal colon (HR, 1.17 [CI, 0.96 to 1.42]). Adjustment for PDR did not alter HRs by race/ethnicity, but differences between black persons and white persons were greater among physicians with higher PDRs.Colonoscopy and polypectomy were identified by using billing codes.Among elderly Medicare enrollees, the risk for interval CRC was higher in black persons than in white persons; the difference was more pronounced for cancer of the distal colon and rectum and for physicians with higher PDRs.American Cancer Society.