tbuckley/cabot-search huggingface dataset:
Mast cell ablation causes enhanced intestinal tumor formation in APCMin/+ mice.
Authors: Mark Sinnamon, Kathy Carter, Barbara Fingleton, Lynn Matrisian
Journal: Cancer Research (2007)

2452  The tumor microenvironment has been shown to both positively and negatively influence tumor progression. Matrix proteinases, often derived from stromal inflammatory cells, have been shown to affect all stages of tumorigenesis and tumor progression. Normally, matrix proteinases are important mediators of tissue remodeling and contribute to several normal physiological processes including wound healing and blood clotting as well as pathological processes such as inflammatory bowel disease, ulcerative colitis and cancer progression. An important consideration is that matrix proteinases often act in broad cascades, where one upstream proteolytic event has several downstream proteolytic consequences.  In the Min (Multiple intestinal neoplasia) mouse model, a single missense mutation in codon 850 of the APC tumor suppressor gene results in mice presenting with multiple focal tumors throughout the intestine, similar to human patients with familial adenomatous polyposis (FAP). Previously, our lab has shown that genetic ablation of MMP-7 results in a 58% reduction of tumor multiplicity in Min mice (Wilson et al., 1997). Furthermore, by in situ hybridization we have identified other MMPs that are more abundantly expressed in tumors compared with normal intestinal tissue. In order to examine broad proteolytic changes in tumors involving multiple classes of proteinases, in conjunction with the proteinase consortium and Affymetrix, we developed the Hu/Mu ProtIn array. This array contains probe sets for 1172 genes of human and murine origin including all known human and murine MMPs as well as other proteinases, substrates and inhibitors.  Using this array we assayed RNA derived from intestinal tumors of APCMin/+ mice and from age matched wild-type controls. In particular, we detected a striking increase in several proteases of mast cell origin present in tumor tissue absent from normal intestinal tissue. This apparent increase of mast cell protease expression was corroborated by histochemical detection of chymase, a mast cell marker, which demonstrated an increased density of mast cells in intestinal tumors. To assess whether mast cells functionally contributed to tumor formation in the Min model, we crossed c-kitW-sh/W-sh (Sash) mice, a mast cell deficient line, into the Min background. Sash mice lack mucosal mast cells, but otherwise have a normal complement of immune cells. Genetic ablation of mucosal mast cells was found to both increase tumor incidence by 50%, and increase tumor size in 17 week-old Min animals. Proliferation, as measured by BrdU incorporation, and apoptosis, as measured by TUNEL, were similar in both groups.  Although mast cells have been suggested to contribute to tumor formation through the production of histamine and proteases, our data suggest that they are protective at least in this spontaneous model of benign tumor development.
Abstract #1112: Analyzing \#945;v\#946;8 integrin functions in mouse and human glioma cells
Authors: Jeremy Tchaicha, Joseph McCarty
Journal: Cancer Research (2009)

Integrins are cell surface receptors for many extracellular matrix proteins and abnormal regulation of integrin function in the central nervous system can lead to the pathogenesis of glioma. Glioblastoma multiforme (GBM), the highest grade glioma, renders patients irresponsive to conventional therapeutic and surgical intervention grasping onto a dismal 12 month median survival rate. In this study we aim to determine the functional roles for \#945;v\#946;8 integrin in GBM-induced angiogenesis. These studies originate from our analyses of \#945;v\#946;8 integrin in developmental brain angiogenesis. \#945;v and \#946;8 knockout (KO) mice develop brain-specific vascular phenotypes that resemble vascular pathologies observed in GBM. These correlations have led us to hypothesize that altered \#945;v\#946;8 integrin expression and/or function in tumor cells leads to vascular pathologies like those in GBM. A mouse xenograft model of astrocytoma suggested a role for the integrin in glioma-induced angiogenesis. Wildtype and \#946;8 KO astrocytes were immortalized (HPV-E6/E7), transformed (H-Ras: V12) and intracranially injected into athymic mice. Tumors derived from transformed wild type cells, which express endogenous \#945;v\#946;8 integrin, displayed pathological features of grade III astrocytomas. In contrast, \#946;8 KO tumors were more similar to grade IV GBM. The KO tumors contained hyperproliferative endothelial cells as well as widespread edema and hemorrhage. In addition, tumors lacking \#945;v\#946;8 expression exhibited enhanced angiogenesis, as assessed by quantitation of CD34+ tumor blood vessels and measurement of intratumoral vessel diameters. Interestingly, astrocyte transformation resulted in a significant reduction in \#945;v\#946;8 integrin cell surface expression in wild type cells, as assessed by immunoprecipitation and FACS. Additionally, wildtype mouse transformed astrocytes lost \#945;v\#946;8 integrin expression after approximately eight passages in vitro. These data suggest that loss of \#945;v\#946;8 integrin expression correlates with tumorigenic potential of oncogene-transformed astrocytes. To compliment our studies of mouse xenograft models, several established human glioma cell lines were characterized for their expression of \#945;v\#946;8 integrin. Some of the cell lines displayed diminished expression of the integrin whereas others showed increased levels of \#945;v\#946;8 integrin, as compared to non-malignant human astrocytes. RNAi technology is currently being implemented to silence \#945;v\#946;8 integrin expression in human glioma cell lines, followed by intracranial injection into athymic mice and analysis of wild type and knockdown tumors. We are also evaluating \#945;v\#946;8 integrin cDNA from human glioma cell lines and resected tumors to determine if tumor cells express mutated forms of \#945;v\#946;8 integrin.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1112.
Haploidentical Allogeneic Hematopoietic Cell Transplantation for Mantle Cell Lymphoma Using Post-Transplantation Cyclophosphamide Graft-Versus-Host Disease Prophylaxis
Authors: Chiara De Philippis, Jacopo Mariotti, Reda Bouabdallah, Raynier Devillier, Stefania Bramanti, Samia Harbi, Sabine Furst, Faezeh Legrand, Barbara Sarina, Carmelo Carlo-Stella, Armando Santoro, Didier Blaise, Luca Castagna
Journal: Blood (2018)
Prediabetes is a risk factor for cardiovascular disease following renal transplantation
Authors: Esteban Porrini, Juan Manuel Díaz, Francesc Moreso, Ricardo Lauzurrica, Meritxel Ibernon, Irene Silva Torres, Rocío Benitez Ruiz, Ana Elena Rodríguez Rodríguez, Patricia Delgado Mallén, Beatriz Bayés-Genís, Francisco J. Gainza, José Manuel Osorio, Antonio Osuna, Rosa Domínguez, Juan Carlos Ruiz, Alejandro Jiménez Sosa, Ana González Rinne, Domingo Marrero Miranda, Manuel Macías, Armando Torres
Journal: Kidney International (2019)
Whole genome tiling-resolution array CGH identifies distinct DNA amplifications under vincristine selection of ovarian cancer cells
Authors: Timon P. H. Buys, Stephen Lam, Calum Macaulay, Victor Ling, Wan L. Lam
Journal: Cancer Research (2005)

4143  Not all patients respond to chemotherapy. Unresponsive cells within a heterogeneous tumor mass may clonally expand and result in tumor recurrence/progression. Gene amplification has previously been described as playing a role in conferring drug resistance. Identification of gene copy number alterations in drug-resistant cells will enhance our understanding of drug resistance mechanisms and will identify novel therapeutic targets. Objective: To generate comprehensive whole genome profiles for an ovarian carcinoma cell line (SKOV3) and its vincristine-resistant derivatives (SKVCRs) so as to identify novel genes impacting drug response. This will be accomplished through use of a Comparative Genomic Hybridization (CGH) array comprised of overlapping Bacterial Artificial Chromosomes (BACs) that span the entire human genome. Experimental Design: SKVCR cell lines were derived by growing SKOV3 cells in the presence of vincristine, with different levels of resistance obtained by serial passages of cells at increasing drug concentrations. Each SKVCR line was maintained and sub-cultured at the same drug concentration until doubling time was ≤48h. SKOV3 and SKVCRs were analyzed by tiling-set array CGH. Emerging drug resistance genomic alterations in the SKVCRs were identified by comparison against the SKOV3 genomic profile. Briefly, cell line was labelled and compared against a differentially labelled reference DNA sample by co-hybridization to the array. After imaging analysis, signal intensity ratios for each BAC clone were plotted against chromosomal location to reveal amplifications and deletions across the whole genome. DNA copy alterations were verified with fluorescence in situ hybridization. RNA was extracted from SKOV3 and all SKVCRs for gene expression analysis using reverse-transcriptase PCR and the U133 Plus 2.0 Array from Affymetrix. Gene expression data were correlated with tiling-set array CGH data to confirm their significance. Results: Alignment of whole genome array CGH profiles for SKOV3 and SKVCRs revealed distinct regional amplifications in response to drug selection and allowed the fine-mapping of DNA copy alterations at various loci. These include both previously characterized changes, such as amplification of the P-glycoprotein gene (MDR1 or ABCB1) and other ABC transporter genes, and novel DNA copy number gains and losses. Gene expression analysis demonstrated concurrent changes in expression for those genes identified by tiling-set array CGH. Conclusion: Increasing amplification and over-expression of MDR1 and other ABC transporters that drive drug resistance is observed across the SKVCRs. In addition, we identified novel genomic alterations that emerge with increasing drug selection. Functional analysis of those genes implicated by the tiling-set platform will follow.This work was supported by funds from Genome Canada/BC.
The putative tumor suppressor WWOX protein is normally expressed in surface ovarian epithelium and frequently lost in ovarian carcinomas
Authors: Maria I. Nunez, John H. Ludes-Meyers, Hyunsuk Kil, Daniel Rosen, Andres Klein-Szanto, Jinsung Liu, Andrew K. Godwin, Gordon Mills, C. Marcelo Aldaz
Journal: Cancer Research (2004)

4429  The WWOX gene spans the common chromosomal fragile site 16D (FRA16D) at chromosome 16q23.3-24.1. This region is a frequent target for loss of heterozygosity observed in ovarian, breast, hepatocellular and prostate tumors. The WWOX gene encodes a novel oxidoreductase that very likely participates in sex steroid metabolism. We have previously demonstrated that WWOX behaves as a putative tumor suppressor. To further address the role of WWOX in tumorigenesis we have developed a highly WWOX specific antibody that has been useful for determining WWOX expression by Western and immunohistochemical (IHC) analyses. Immunoblotting analysis from ten normal ovarian samples demonstrated a consistently strong WWOX specific signal. However, approximately 48% (14/29) ovarian adenocarcinomas had drastically reduced or lack WWOX protein expression. Additionally, we performed detailed IHC on normal human ovarian tissue sections confirming WWOX expression on specific cell types. Interestingly, strong positive staining was observed in the ovarian surface epithelium, in epithelial inclusion cysts within the cortex, and in Walthard nests within the ovarian hilus. Positive staining was also observed in granulosa cells surrounding various corpus albicans and in some stromal patches suggestive of hormone producing cells. Preliminary, multi-tissue microarray analyses (TMAs) allowed us to conclude that WWOX is preferentially expressed in glandular epithelium of multiple origins while consistently negative in keratinized squamous epithelia (e.g. skin). We are currently analyzing WWOX expression using ovarian specific TMAs representing over 700 ovarian carcinoma and benign tumors. This information and that of Western analyses is being correlated with multiple prognostic and diagnostic parameters including staging and patient outcome. (Supported in part by a Pharmacia award, R01 CA102444-01 and P50 CA083639-04)
Phase 1 Study Of TH-302, An Investigational Hypoxia-Targeted Drug, and Dexamethasone In Patients With Relapsed/Refractory Multiple Myeloma
Authors: Irene M. Ghobrial, Jacob P. Laubach, Noopur Raje, Philippe Armand, Robert L. Schlossman, Erica N Boswell, Courtney Hanlon, Stacey Chuma, Damian R Handisides, Stewart Kroll, Kenneth C. Anderson, Paul G. Richardson
Journal: Blood (2013)
Involvement of CHK1 pathway in protecting cells from taxotere-induced killing
Authors: Qing Ren, Adam P. Dicker, Ya Wang
Journal: Cancer Research (2004)

5326  Taxotere is an anticancer agent with demonstrated activity in a variety of solid tumors. Taxotere affects tubulin polymerization and interferes with mitotic transition. These changes activate the apoptosis process and elicit cytotoxicity. However, these changes can also slow down cell cycle progression by activating checkpoints that provide time for repair and thus reduce the cytotoxicity. Therefore, the cellular response to taxotere-cytotoxicity can impact the expected therapeutic efficacy. To date, the mechanism by which cell cycle checkpoints impact taxotere cytotoxicity remains unclear. Here our preliminary data show that a CHK1 over-expressing cell line, A1-5 cells (JBC, 276:17693, 2001) were more resistant to taxotere cytotoxicity than its counterpart cell line, B4 cells. Validation of the gene-specific effect was obtained when CHK1 protein expression was suppressed by siRNA and the taxotere resistance was eliminated in A1-5 cells. These data suggest that CHK1 pathway-regulated checkpoint can be important in protecting cells from the taxotere cytotoxicity. This work was supported by a grant from Aventis.
Imbalance of the renin–angiotensin system may contribute to inflammation and fibrosis in IBD: a novel therapeutic target?
Authors: Mayur Garg, Simon G Royce, Chris Tikellis, Claire Shallue, Duygu Batu, Elena Velkoska, Louise M Burrell, Sheila K Patel, Lauren Beswick, Anvesh Jackson, Kaushali Britto, Matthew Lukies, Pavel Sluka, Hady Wardan, Yumiko Hirokawa, Chin Wee Tan, Maree Faux, Antony W Burgess, Patrick Hosking, Shaun Monagle, Merlin Thomas, Peter R Gibson, John Lubel
Journal: Gut (2019)

Objective We evaluated the influence of the renin–angiotensin system (RAS) on intestinal inflammation and fibrosis. Design Cultured human colonic myofibroblast proliferation and collagen secretion were assessed following treatment with angiotensin (Ang) II and Ang (1–7), their receptor antagonists candesartan and A779, and the ACE inhibitor captopril. Circulating and intestinal RAS components were evaluated in patients with and without IBD. Disease outcomes in patients with IBD treated with ACE inhibitors and angiotensin receptor blockers (ARBs) were assessed in retrospective studies. Results Human colonic myofibroblast proliferation was reduced by Ang (1–7) in a dose-dependent manner (p&lt;0.05). Ang II marginally but not significantly increased proliferation, an effect reversed by candesartan (p&lt;0.001). Colonic myofibroblast collagen secretion was reduced by Ang (1–7) (p&lt;0.05) and captopril (p&lt;0.001), and was increased by Ang II (p&lt;0.001). Patients with IBD had higher circulating renin (mean 25.4 vs 18.6 mIU/L, p=0.026) and ACE2:ACE ratio (mean 0.92 vs 0.69, p=0.015) than controls without IBD. RAS gene transcripts and peptides were identified in healthy and diseased bowels. Colonic mucosal Masson’s trichrome staining correlated with Ang II (r=0.346, p=0.010) and inversely with ACE2 activity (r=−0.373, p=0.006). Patients with IBD who required surgery (1/37 vs 12/75, p=0.034) and hospitalisation (0/34 vs 8/68, p=0.049) over 2 years were less often treated with ACE inhibitors and ARBs than patients not requiring surgery or hospitalisation. Conclusions The RAS mediates fibrosis in human cell cultures, is expressed in the intestine and perturbed in intestinal inflammation, and agents targeting this system are associated with improved disease outcomes.
Bone Marrow Infiltrating T-Cell Signatures Following Allo-HCT for Adult Acute Lymphoblastic Leukaemia Differentiate between Patients in Continuous CR and Those with Persistent Minimal Residual Disease or Relapse
Authors: Dina Ahmed Said Aly Okasha, Amy A Kirkwood, Krisztina Zuborne Alapi, Rachel J Mitchell, Pedro Santos e Sousa, Daniel Leongamornlert, Elli Papaemmanuil, David Marks, Ronjon Chakraverty, Adele K Fielding
Journal: Blood (2017)
Optimizing the Power to Identify the Genetic Basis of Complex Traits with Evolve and Resequence Studies
Authors: Christos Vlachos, Robert Kofler
Journal: Molecular Biology and Evolution (2019)

Abstract Evolve and resequence (E&amp;R) studies are frequently used to dissect the genetic basis of quantitative traits. By subjecting a population to truncating selection for several generations and estimating the allele frequency differences between selected and nonselected populations using next-generation sequencing (NGS), the loci contributing to the selected trait may be identified. The role of different parameters, such as, the population size or the number of replicate populations has been examined in previous works. However, the influence of the selection regime, that is the strength of truncating selection during the experiment, remains little explored. Using whole genome, individual based forward simulations of E&amp;R studies, we found that the power to identify the causative alleles may be maximized by gradually increasing the strength of truncating selection during the experiment. Notably, such an optimal selection regime comes at no or little additional cost in terms of sequencing effort and experimental time. Interestingly, we also found that a selection regime which optimizes the power to identify the causative loci is not necessarily identical to a regime that maximizes the phenotypic response. Finally, our simulations suggest that an E&amp;R study with an optimized selection regime may have a higher power to identify the genetic basis of quantitative traits than a genome-wide association study, highlighting that E&amp;R is a powerful approach for finding the loci underlying complex traits.
Abstract 12144: Left Ventricular End-Diastolic Volume Predicts Exercise Capacity in Patients With a Normal Ejection Fraction
Authors: Lakshmi Nambiar, Anita Li, Alan Howard, Martin LeWinter, Markus Meyer
Journal: Circulation (2017)

Background: Exercise capacity is a powerful predictor of all-cause mortality. The duration of exercise with treadmill stress testing is an important prognostic marker in both healthy subjects and p...
Government pins hopes on £250m AI centre for faster diagnosis and treatment
Authors: Adrian O’Dowd
Journal: BMJ (2019)

Around £250m is to be invested in setting up a new centre for artificial intelligence for the NHS in England that promises to help doctors identify and treat disease more rapidly and effectively.

The health and social care secretary, Matt Hancock, announced on 8 August plans to invest in a “National Artificial Intelligence Lab,” housed within NHSX, the organisation that oversees the digitisation of the health service.

However, health experts have warned that such technology must be properly evaluated and standards agreed before being adopted widely, to ensure it is effective and doesn’t lead to potential harm, and that NHS staff are fully equipped with the necessary digital skills to make use of it.

The new centre …
Phase II trial comparing darbepoetin alfa every 3-week versus weekly epoetin alfa for the treatment of chemotherapy-induced anemia
Authors: M. A. Hassan, M. M. Sleem
Journal: Journal of Clinical Oncology (2009)

e20724 Background: Anemia is common in patients receiving chemotherapy and may adversely affect health-related quality of life. Erthyrpiotic factors darbepoetin alfa (DA) and epoetin alfa (EA) are currently approved for the treatment of anemia in patients with nonmyeloid malignancies who receive chemotherapy. Methods: Forty patients with a diagnosis of nonmyeloid malignancy with 8 weeks of planned chemotherapy, age 18 years, and anemia (hemoglobin 10 g/dL). 20 patients received DA 500 μg every three weeks (Q3W) and the others 20 patients received EA 40,000 units every week (QW) for up to 18 weeks. Treatment was hold at week 6 for nonresponse, which was defined as failure to achieve a hemoglobin increment of at least 2 g/dL above the baseline measurement. Efficacy was assessed by the incidence of RBC transfusion. Results: Forty patients with a diagnosis of nonmyeloid malignancy, the median age was 49 years and 52 years for DA and EA groups respectively, The majority of patients had solid tumors: Common cancer types for (DA - EA) groups were gastrointestinal (8 -5), breast (3–6), lung (3–3), soft tissue sarcoma (2–1), genitourinary (2–1), non-Hodgkin's lymphoma (1–1), multiple myeloma (1–1), Hodgkin's lymphoma (0–1), and metastatic with unknown primary in (1–0) respectively . 75% 0f the patients in both group achieved the target hemoglobin level. Transfusion incidence from week 6 to the end of the treatment phase (the primary end point) was required in 5 patients (25%) in both groups. The side effects reported in this study were thromboembolic in two patients in both groups 10%. Nausea, diarrhea and neutropnia were 25%, 15% and 10% for DA group respectively compare to 20%, 10%, and 15% in AE group respectively. Conclusions: This study demonstrates comparable efficacy and safety of DA 500 μg every three weeks (Q3W) and EA40, 000 units every week (QW). No significant financial relationships to disclose.
Association between vitamin D supplementation and mortality: systematic review and meta-analysis
Authors: Yu Zhang, Fang Fang, Jingjing Tang, Lu Jia, Yuning Feng, Ping Xu, Andrew Faramand
Journal: BMJ (2019)

Abstract Objective To investigate whether vitamin D supplementation is associated with lower mortality in adults. Design Systematic review and meta-analysis of randomised controlled trials. Data sources Medline, Embase, and the Cochrane Central Register from their inception to 26 December 2018. Eligibility criteria for selecting studies Randomised controlled trials comparing vitamin D supplementation with a placebo or no treatment for mortality were included. Independent data extraction was conducted and study quality assessed. A meta-analysis was carried out by using fixed effects and random effects models to calculate risk ratio of death in the group receiving vitamin D supplementation and the control group. Main outcome measures All cause mortality. Results 50 trials with a total of 74 655 participants were identified. Vitamin D supplementation was not associated with all cause mortality (risk ratio 0.98, 95% confidence interval 0.95 to 1.02, I 2 =0%), cardiovascular mortality (0.98, 0.88 to 1.08, 0%), or non-cancer, non-cardiovascular mortality (1.05, 0.93 to 1.18, 0%). Vitamin D supplementation statistically significantly reduced the risk of cancer death (0.85, 0.74 to 0.97, 0%). In subgroup analyses, all cause mortality was significantly lower in trials with vitamin D 3 supplementation than in trials with vitamin D 2 supplementation (P for interaction=0.04); neither vitamin D 3 nor vitamin D 2 was associated with a statistically significant reduction in all cause mortality. Conclusions Vitamin D supplementation alone was not associated with all cause mortality in adults compared with placebo or no treatment. Vitamin D supplementation reduced the risk of cancer death by 15%. Additional large clinical studies are needed to determine whether vitamin D 3 supplementation is associated with lower all cause mortality. Study registration PROSPERO registration number CRD42018117823.