tbuckley/cabot-search huggingface dataset:
Emphasis on the deep or shallow parts of the tree provides a new characterization of phylogenetic distances
Authors: Julia Fukuyama
Journal: Genome biology (2019)

Phylogenetically informed distances are commonly used in the analysis of microbiome data, and analysts have many options to choose from. Although all phylogenetic distances share the goal of incorporating the phylogenetic relationships among the bacteria, they do so in different ways and give different pictures of the relationships between the bacterial communities.We investigate the properties of two classes of phylogenetically informed distances: the Unifrac family, including weighted, unweighted, and generalized Unifrac, and the DPCoA family, which we introduce here. Through several lines of evidence, including a combination of mathematical, data analytic, and computational methods, we show that a major and heretofore unrecognized cleavage in the phylogenetically informed distances is the relative weights placed on the deep and shallow parts of the phylogeny. Specifically, weighted Unifrac and DPCoA place more emphasis on the deep parts of the phylogeny, while unweighted Unifrac places more emphasis on the shallow parts of the phylogeny. Both the Unifrac and the DPCoA families have tunable parameters that can be shown to control how much emphasis the distances place on the deep or shallow parts of the phylogeny.Our results allow for a more informed choice of distance and give practitioners more insight into the potential differences resulting from different choices of distance.
Cell-Cycle–Dependent Phosphorylation of PRPS1 Fuels Nucleotide Synthesis and Promotes Tumorigenesis
Authors: Xiaoqian Jing, Xiong-jun Wang, Tao Zhang, Wencheng Zhu, Yi Fang, Haoxuan Wu, Xinyu Liu, Ding Ma, Xiaopin Ji, Yimei Jiang, Kun Liu, Xianze Chen, Yi Shi, Yaqi Zhang, Minmin Shi, Weihua Qiu, Ren Zhao
Journal: Cancer Research (2019)

Nucleotide supply is essential for DNA replication in proliferating cells, including cancer cells. Ribose-phosphate diphosphokinase 1 (PRPS1) is a key enzyme to produce the consensus precursor of nucleotide synthesis. PRPS1 participates in the pentose phosphate pathway (PPP) by catalyzing the phosphoribosylation of D-ribose 5-phosphate (R-5P) to 5-phosphoribosyl-1-pyrophosphate. Therefore, PRPS1 not only controls purine biosynthesis and supplies precursors for DNA and RNA biosynthesis but also regulates PPP through a feedback loop of the PRPS1 substrate R-5P. However, it is still elusive whether PRPS1 enhances nucleotide synthesis during cell-cycle progression. In this study, we explore the role and activation mechanism of PRPS1 in cell-cycle progression of colorectal cancer, and observed a peak in its enzymatic activity during S phase. CDK1 contributes to upregulation of PRPS1 activity by phosphorylating PRPS1 at S103; loss of phosphorylation at S103 delayed the cell cycle and decreased cell proliferation. PRPS1 activity in colorectal cancer samples is higher than in adjacent tissue, and the use of an antibody that specifically detects PRPS1 phosphorylation at S103 showed consistent results in 184 colorectal cancer tissues. In conclusion, compared with upregulation of PRPS1 expression levels, increased PRPS1 activity, which is marked by S103 phosphorylation, is more important in promoting tumorigenesis and is a promising diagnostic indicator for colorectal cancer. SIGNIFICANCE: These findings show that the enzymatic activity of PRPS1 is crucial for cell-cycle regulation and suggest PRPS1 phosphorylation at S103 as a direct therapeutic target and diagnostic biomarker for colorectal cancer.
PPARγ preservation via promoter demethylation alleviates osteoarthritis in mice
Authors: Xiaobo Zhu, Fang Chen, Ke Lu, Ai Wei, Qing Jiang, Wangsen Cao
Journal: Annals of the Rheumatic Diseases (2019)

Objectives Osteoarthritis (OA) is the most common degenerative joint disease in aged population and its development is significantly influenced by aberrant epigenetic modifications of numerous OA susceptible genes; however, the precise mechanisms that DNA methylation alterations affect OA pathogenesis remain undefined. This study investigates the critical role of epigenetic PPARγ (peroxisome proliferator–activated receptor-gamma) suppression in OA development. Methods Articular cartilage expressions of PPARγ and bioactive DNA methyltransferases (DNMTs) from OA patients and mice incurred by DMM (destabilisation of medial meniscus) were examined. DNA methylation status of both human and mouse PPARγ promoters were assessed by methylated specific PCR and/or bisulfite-sequencing PCR. OA protections by a pharmacological DNA demethylating agent 5Aza (5-Aza-2'-deoxycytidine) were compared between wild type and PPARγ knockout mice. Results Articular cartilages from both OA patients and DMM mice display substantial PPARγ suppressions likely due to aberrant elevations of DNMT1 and DNMT3a and consequential PPARγ promoter hypermethylation. 5Aza known to inhibit both DNMT1 and DNMT3a reversed the PPARγ promoter hypermethylation, recovered the PPARγ loss and effectively attenuated the cartilage damage in OA mice. 5Aza also inhibited the OA-associated excessive inflammatory cytokines and deficit anti-oxidant enzymes, which were blocked by a specific PPARγ inhibitor in cultured chondrocytes. Further, 5Aza-confered protections against the cartilage damage and the associated abnormalities of OA-susceptible factors were significantly abrogated in PPARγ knockout mice. Conclusion Epigenetic PPARγ suppression plays a key role in OA development and PPARγ preservation via promoter demethylation possesses promising therapeutic potentials in clinical treatment of OA and the related joint diseases.
Abstract 1985: Reassessment of exosome composition
Authors: Dennis K. Jeppesen, Jeffrey L. Franklin, James N. Higginbotham, Qin Zhang, Robert J. Coffey
Journal: Cancer Research (2019)

Abstract The heterogeneity of small extracellular vesicles and the presence of non-vesicular extracellular matter is a major obstacle to the study of exosomes. Here we employ two complementary methods, high-resolution density gradient fractionation and direct immunoaffinity capture, to demonstrate separation of small extracellular vesicles from non-vesicular material, and exosomes from other types of small extracellular vesicles. Cells secrete Argonaute 1-4 independently of exosomes. Extracellular RNA and RNA-binding proteins are differentially expressed between exosome and non-vesicle compartments. Exosomes do not possess a cytoskeleton and exclude glycolytic enzymes. Annexin A1 is a novel and specific membrane-associated protein marker of microvesicles shed directly from the cell plasma membrane, distinct from exosomes in vitro and in vivo. Small extracellular vesicles are not vehicles of active DNA release. Instead we propose a new model for active secretion of extracellular DNA through an autophagy- and multivesicular endosome-dependent but exosome-independent mechanism. A reassessment of exosome composition is necessary. Citation Format: Dennis K. Jeppesen, Jeffrey L. Franklin, James N. Higginbotham, Qin Zhang, Robert J. Coffey. Reassessment of exosome composition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1985.
The Maternal and Paternal Effects on Clinically and Surgically Defined Osteoarthritis
Authors: Eirik Weldingh, Marianne Bakke Johnsen, Kåre Birger Hagen, Nina Østerås, May Arna Risberg, Bård Natvig, Barbara Slatkowsky‐Christensen, Anne Marie Fenstad, Ove Furnes, Lars Nordsletten, Karin Magnusson
Journal: Arthritis & Rheumatology (2019)

It is currently unknown whether osteoarthritis (OA) is inherited mainly from the mother, father, or both. This study was undertaken to explore the effect of maternal and paternal factors on hip, knee, and hand OA in offspring.Participants from the Musculoskeletal Pain in Ullensaker Study (MUST) (69% female; mean ± SD age 64 ± 9 years) and a Norwegian OA twin study (Nor-Twin) (56% female; 49 ± 11 years) reported whether their mother and/or father had OA. Using a recurrence risk estimation approach, we calculated whether maternal and paternal OA increased the risk of 1) surgically defined hip and knee OA (i.e., total joint replacement) and 2) clinically defined hip, knee, and hand OA (i.e., the American College of Rheumatology criteria) using logistic regression. Relative risks (RRs) with 95% confidence intervals (95% CIs) were calculated.Maternal OA consistently increased the risk of offspring OA across different OA locations and severities. Having a mother with OA increased the risk of any OA in daughters (RR 1.13 [95% CI 1.02-1.25] in the MUST cohort; RR 1.44 [95% CI 1.05-1.97] in the Nor-Twin cohort) but not (or with less certainty) in sons (RR 1.16 [95% CI 0.95-1.43] in the MUST cohort; RR 1.31 [95% CI 0.71-2.41] in the Nor-Twin cohort). Having a father with OA was less likely to increase the risk of any OA in daughters (RR 1.00 [95% CI 0.85-1.16] in the MUST cohort; RR 1.52 [95% CI 0.94-2.46] in the Nor-Twin cohort) and sons (RR 1.08 [95% CI 0.83-1.41] in the MUST cohort; RR 0.93 [95% CI 0.35-2.48] in the Nor-Twin cohort).OA in the mother increased the risk of surgically and clinically defined hip, knee, and hand OA in offspring, particularly in daughters. Our findings imply that heredity of OA may be linked to maternal genes and/or maternal-specific factors such as the fetal environment.
Intraoperative versus external beam boost for breast cancer: A matched-pair analysis.
Authors: Elena Sperk, Daniela Astor, Grit Welzel, Axel Gerhardt, Marc Suetterlin, Frederik K. Wenz
Journal: Journal of Clinical Oncology (2013)

1120 Background: After breast conserving surgery, radiotherapy leads to a better overall survival. In addition to whole breast radiotherapy (WBRT) a boost to the tumor bed leads to a better local control. The tumor bed boost is usually added after WBRT or can be done intraoperative (IORT). Belletti et al. (Clin Cancer Res., 2008) described positive effects, an antitumoral effect and modulation of microenvironment after IORT with 50kV x-rays. A matched pair analysis was performed to investigate the impact of IORT boost on overall survival compared to standard external beam boost. Methods: Between 2002 – 2009, 370 patients were treated for breast cancer with WBRT + boost (external beam (EBRT) boost n = 146, IORT boost n =224). A matched pair analysis (1:1 propensity score matching for age, TNM, grading, hormonal treatment and chemotherapy) for overall survival and local recurrence free survival could be done for 53 pairs. All patients underwent breast conserving surgery and WBRT with 46-50Gy. 53 patients received an EBRT boost with 16Gy (2Gy/fraction, dedicated linear accelerator) and 53 patients received an IORT boost with 20Gy (INTRABEAM system, 50kV x-rays). Median follow-up was 6 months (range, 1-77 months) for the EBRT boost patients and 56 months (range, 2-97 months) for IORT boost patients. Kaplan Meier estimates were performed for overall survival and local recurrence free survival. Results: IORT boost patients had a longer follow-up than EBRT boost patients. Despite the difference in follow-up times, there was a strong trend towards better overall survival after IORT boost (90.2% vs. 62.3%, p = 0.375). One local recurrence was present in each group (EBRT boost after 15 months, local recurrence free survival 95%; IORT boost after 12 months, local recurrence free survival 98.1%). Conclusions: IORT given as a boost seems to have a positive impact on overall survival in breast cancer patients after breast conserving surgery. To identify such an effect a prospective randomized trial should be conducted.
Role of pre-operative serum magnesium (Mg) concentration on post-operative pain intensity and opioid usage in gynecologic surgery.
Authors: Laleh Azari, Sundae Stelts, Joseph T Santoso, Mehmet Kocak
Journal: Journal of Clinical Oncology (2013)

e20673 Background: Hypomagnesemia is a common problem, occurring in nearly 12% of hospitalized patients. Due to the link of hypomagnesemia with surgery and the potential antinociceptive effects of Mg multiple trials have been conducted. Unfortunately, the role of IV and epidural Mg supplementation in pain management perioperatively remains controversial. An unanswered question from the literature to date is whether low serum Mg concentrations correlate with pain intensity. This review of patients undergoing gynecological surgeries examines whether pre-operative serum Mg level can affect pain scores and opioid use postoperatively. Methods: This was a retrospective study of the electronic medical record at Methodist University Hospital from October 1 st , 2011 to July 31 st , 2012. Included for analysis are all cases that underwent a gynecologic surgery and were performed under one attending surgeon. Each patient included in the study had perioperative serum Mg levels, resting and moving pain intensity scores, and amount of opioids used. Patients were excluded for any of the following criteria: missing data, discharge in less than 24 hours, robotic surgery, and use of ketamine in anesthesia. Statistical analysis included descriptive statistics, Spearman’s rank correlation coefficient, and logistic regression. Results: The analysis included 121 patients; 54% were Caucasian, the mean age was 51.7 years and 89% of surgeries were for oncologic indications. Pre-operative serum Mg level was not significantly associated with resting or moving pain intensity scores on post operative day (POD) 1 (p=0.66; p=0.68) or POD 2 (p=0.58, p=0.83). Pre-operative Mg level was not significantly associated with opioid use on POD 1 or 2. Two variables had a possible correlation with opioid usage, on average older patients used a lower level of opioid on average and patients with higher BMI used a higher level of opioids. Conclusions: Preoperative magnesium level has no correlation with pain scores or opioid use. While repletion maybe warranted and magnesium supplementation has minimal toxicity and cost, effect on post-operative pain is uncertain. Larger randomized trials may be warranted.
Abstract 2752: Recognition of the hybrid-1 human telomeric G-quadruplex by a platinum(II)-based compound
Authors: Wenting Liu, Clement Lin, Zong-wan Mao, Danzhou Yang
Journal: Cancer Research (2019)

Abstract The human telomeric DNA, which consists of tandem repeat sequences of d(TTAGGG)n, plays an important role in cancers and cell aging. Previous studies in human cancer cells have demonstrated DNA G-quadruplex (G4) structure formation in telomeres. G-quadruplexes are four-stranded structures formed in guanine-rich sequences that are held together by guanine-guanine Hoogsteen hydrogen bonding, and G-quadruplex stabilization by small molecules induces tumor cell senescence and apoptosis by repressing telomerase activity and the DNA damage response pathway. Additionally, telomeric-overhang DNA can form biologically relevant higher-order DNA structures containing consecutive G-quadruplexes which provides additional binding sites for small molecules. Thus, telomeric DNA G-quadruplexes have attracted increasing interest as potential drug targets for cancer therapy. Here, we found that a novel platinum (II)-based tripod (Pt-tripod) specifically recognizes the hybrid-1 human telomeric G4, which is formed in the physiologically relevant K+ solution. Pt-tripod strongly represses telomerase activity and exhibits DNA-targeted photodynamic therapy anticancer activity. Using NMR, we show that Pt-tripod binds the hybrid-1 human telomeric G4 over other G-quadruplex structures and dsDNA. We determined solution structures of the 1:1 and the dimeric 4:2 Pt-tripod-hybrid-1 telomeric G4 complexes by NMR. Our 1:1 complex structure shows preferential binding of the Pt-tripod to the 5′-end of hybrid-1 telomeric G4. At higher ligand ratio, Pt-tripod binds to the 3′-end of the hybid-1 G4 and induces an unprecedented dimeric 4:2 structure interlocked by a non-canonical A:A pair at the 3′-end. The specific binding of the Pt-tripod with the hybrid-1 G4 is achieved by unique interaction modes including the π-π stacking, hydrogen bonding, and electrostatic interactions with the loop and flanking segments. The non-planar tertiary amine conformation and three properly sized cationic platinum arms are critical for the specific and strong binding. Our structures provide significant insights into understanding the dynamic binding of small molecules with G-quadruplexes, and a structural basis for future rational anticancer drug design of non-planar small molecules targeting the human telomeric G4. Our studies also provide a potential handle to study the specific protein interactions and biological functions of hybrid-1 human telomeric G4. Citation Format: Wenting Liu, Clement Lin, Zong-wan Mao, Danzhou Yang. Recognition of the hybrid-1 human telomeric G-quadruplex by a platinum(II)-based compound [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2752.
Abstract LB-311: Exosomal gain-of-function p53 protein promotes cancer-associated phenotype
Authors: Shaolin Ma, Michael H. McGuire, Elaine Stur, Emine Bayraktar, Alejandro Villar-Prados, Sherry Y. Wu, Akira Yokoi, Santosh K. Dasari, Cristian Rodriguez-Aguayo, Jinsong Liu, Gabriel Lopez-Berestein, Anil K. Sood
Journal: Cancer Research (2019)

Abstract TP53 is the most commonly mutated gene in cancer. Certain mutations can produce gain-of-function (GOF) phenotypes, resulting in pathogenic effects beyond the loss of p53 function. Recent study suggested that tumor cells could affect the p53 status of stromal cells while the mechanisms remains unclear. Exosomes have emerged as an important mode of extracellular communication and a major player in cancer pathogenesis, by promoting pro-tumor microenvironment. We hypothesized that packaging of mutated p53 protein into exosomes and dissemination via exosomes could impact a variety of stromal cell processes, producing a pro-tumorigenic microenvironment. In this study, we carried out a series of in vitro (immunoblot analysis, Q-PCR, Gene array, Co-Immunoprecipitation and lentiviral transfection) and in vivo (subcutaneous mouse models) experiments to determine the presence of mutant p53 in exosomes and its biological significance in tumor microenvironment. We demonstrated that gain-of-function (GOF) p53 protein is packaged into p53 mutant cancer cell-derived exosomes and transferred to fibroblasts. Further studies showed that this process is facilitated by the enhanced stability and consequent intracellular concentration of GOF p53. The packaging of GOF p53 into exosomes is selectively bound by HSP90 chaperone proteins. Inhibition of HSP90 blocks the packaging of GOF p53, but not wild-type into exosomes. Uptake of GOF p53-containing exosomes by fibroblasts results in conversion to a cancer-associated phenotype. In vivo study have shown that GOF p53 exosomes-induced cancer-associated fibroblasts promote tumor growth in a colon cancer cells (HT29 cells) xenograft mouse model. These findings reveal a crucial role of exosomes in modifying tumor microenvironment and hold great consequence in broadening our understanding of tumor biology. Citation Format: Shaolin Ma, Michael H. McGuire, Elaine Stur, Emine Bayraktar, Alejandro Villar-Prados, Sherry Y. Wu, Akira Yokoi, Santosh K. Dasari, Cristian Rodriguez-Aguayo, Jinsong Liu, Gabriel Lopez-Berestein, Anil K. Sood. Exosomal gain-of-function p53 protein promotes cancer-associated phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-311.
Abstract 2162: ActivSignal technology for multiplex analysis of signaling protein activation profiles
Authors: Ilya Alexandrov, Malcolm Mackenzie, Irina Brandina
Journal: Cancer Research (2019)

Abstract The IPAD assay technology from ActivSignal monitors activity of 26 major signaling pathways in multiplex by examining phosphorylation status or expression of 70 protein targets from canonical signaling pathways. The technology uses antibody pairs for each protein target to ensure high specificity, and these pairs are carefully selected and tested. Only if both antibodies in a pair bind to their specific target molecule will the detection take place during the analysis phase - avoiding false hits. The ActivSignal IPAD platform can be used to profile cell culture samples, tissues and different blood fractions. Human and mouse samples can be analyzed. The IPAD assay requires only a very small amount of your precious sample. Applications include: - Direct analysis of protein activity of the signaling cascades and not subsequent downstream events. - Testing physiological effects of compounds of interest. – Influence on specific protein targets, as well as the signaling pathways as a whole. – Secondary and/or off-target effects. - Similarly, analysis of signaling pathways activation status in response to different stimuli, such as: CRISPR, shRNA, hormones, stresses and other treatments. - Medium-throughput analysis (96-well format). - Tissue sample profiling from patients and animals (murine). - Profiling of tumor biopsies. Our collaborators analyzed the mechanism of action of JG-98, an Hsp70 inhibitor that exhibits anti-cancer activities that affect both cancer cells and tumor associated macrophages. Using gene expression and ActivSignal protein profiling assay, the signaling pathways influenced by JG-98 were identified, which predicted potential drug combinations that can be used with JG-98 for further preclinical development. ActivSignal is a breakthrough, low-cost tool for the analysis of signaling pathway activation profiles. It enables researchers to rapidly and efficiently gain insight into function of their favorite drug molecules, genes etc. Citation Format: Ilya Alexandrov, Malcolm Mackenzie, Irina Brandina. ActivSignal technology for multiplex analysis of signaling protein activation profiles [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2162.
Abstract 12703: First Experience of Transcatheter Leak Occlusion With Detachable Coils Following Left Atrial Appendage Closure: Safety and Acute Results
Authors: Domenico G Della Rocca, Rodney Horton, Alessio Gasperetti, Sanghamitra Mohanty, Chintan Trivedi, Veronica N Natale, Carola Gianni, Amin Al-Ahmad, John D Burkhardt, Fahim A Choudhury, Mustafa Abdul-Moheeth, Joseph G Gallinghouse, Patrick Hranitzky, Javier E Sanchez, Luigi Di Biase, Andrea Natale
Journal: Circulation (2018)

Introduction: Incomplete left atrial appendage (LAA) closure resulting in residual, significant leak is common after LAA exclusion procedures, potentially hindering an effective thromboembolic (TE)...