tbuckley/cabot-search huggingface dataset:
Interruption of base excision repair selectively enhances temozolamide and 1,3-bis(2-chloroethyl)-nitrosurea cytotoxicity in treatment of adult human malignant glioma cell lines
Authors: Meg Verrees, Lili Liu, Stanton L. Gerson
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

1548 

Introduction: Effective base excision repair (BER) confers resistance on tumor cells through reversal of damage inflicted alkylating chemotherapeutic agents. Temozolomide (TMZ) and 1,3-bis(2-chloroethyl)-nitrosurea (BCNU) produce their deleterious effects via attachment of bulky adducts to the DNA backbone or through formation of DNA interstrand crosslinks. The BER pathway intrinsically reverses damage by removal of altered bases, leaving exposed apurinic/apyrimidinic (AP) sites. Specific glycosylases instigate formation of the AP site, causing a kink in the backbone of DNA. AP endonuclease (APE) fits into the bend at the newly-formed AP site and cuts the DNA backbone, thus relieving the kink. DNA polymerase-beta then fills the gap with the proper base and DNA ligase fills the nick in the DNA backbone, respectively restoring genomic fidelity and structural integrity of DNA. Methoxyamine (MX) is a novel compound that inhibits BER by competing with APE for the AP site and preventing continuation of repair at this early juncture in the pathway. Methods: Glioblastoma cell lines SWB 33, SWB 39, SWB 40, SWB 61 and LN 18 were expanded on multi-well plates, exposed to TMZ or BCNU and incubated for 9 days with or without addition of MX. The plates were then analyzed via MTT assays. Five million cells of the SWB 40 and SWB 39 cell lines were injected into the bilateral flanks of athymic mice. Three weeks following inoculation, mice were treated with eitherTMZ, TMZ and MX or MX alone (control). Tumors were measured three times per week. Western blot analyses were used to elucidate the presence of BER proteins. Results: Significant increase in TMZ cytotoxicity was noted in SWB 40 in both MTT and nude mouse studies, with 2-fold increased sensitivity with MX at 10 uM TMZ in the in-vitro studies and tumor growth delay and tumor doubling time of > 21 days in-vivo. LN 18 demonstrated a > 2-fold increased sensitivity to TMZ and BCNU in presence of MX in in-vitro assays. SWB 33 exhibited a 2-fold increased sensitivity in presence of MX at 45 uM TMZ. SWB 39 and 61 demonstrated no potentiation by MX of TMZ toxicity in in-vitro studies. Similarly, SWB 39 exhibited no potentiation in nude mouse assays. All 5 cell lines demonstrated strong presence of BER proteins APE and DNA polymerase-beta, however only SWB 40 and LN 18—those cell lines most sensitized by MX—showed presence of presence of BER protein XRCC1. Conclusions: MX interrupts BER and sensitized 3 of 5 malignant glioma cell lines to TMZ and BCNU. Sensitization may be linked to expression of XRCC1. Select glioma cell lines may be targets for combined MX and TMZ or MX and BCNU therapy. Future directions: 1. To investigate other adult gliomas and pediatric brain tumors and include orthotopic xenograft analyses. 2. To characterize the role of XRCC1 in glioma sensitization. 3. To evaluate dose response.
Trends in utilization of neoadjuvant chemotherapy for gastric cancer: An analysis of the U.S. National Cancer Database.
Authors: Erin Greenleaf, Christopher S Hollenbeak, Yuxia Jia, Niraj Jaysukh Gusani, Joyce Wong
Journal: Journal of Clinical Oncology (2015)

e15008 Background: Current recommendations for advanced ( > T2) gastric cancer treatment include administration of neoadjuvant chemotherapy (NAC) following a landmark trial in 2006. This study evaluates the rate of use as captured by a large U.S. cancer database and whether use changed after 2006. Methods: The National Cancer Database from 2003-2012 was used to identify patients with a diagnosis of gastric cancer and restricted to those who underwent definitive gastrectomy (SURG), with complete data. The NAC cohort was defined as receipt of chemotherapy within six months prior to SURG. NAC patients were compared to those who underwent SURG only or SURG followed by adjuvant chemotherapy. Results: 16,128 patients were identified: 5,909 (36.7%) underwent NAC; 7,077 (43.9%) underwent SURG only and 3,142 (19.5%) underwent SURG followed by chemotherapy. The utilization of NAC increased annually, from 25.9% in 2003 to 46.3% in 2012, with an increased likelihood for receiving NAC after 2003, Odds Ratio 1.71, p < 0.0001. Interestingly, there was no further increase in odds of receiving NAC after 2006. Those receiving NAC were mostly Caucasian, male, had private or Medicare insurance, were 41-80 years old, and had 0 or 1 comorbidities. Patients treated in academic centers were more likely to undergo NAC than comprehensive community or community centers. Although significant geographic differences in utilization of NAC were observed, the geographic distribution did not change over time. Surgery as first treatment was more prevalent in stage 0, 1, 2 and 3 patients prior to 2006; after 2006, NAC was administered to over 50% of patients with stage 2 (51.4%) and 3 (58.8%) disease. There was an increase in NAC administration following 2006 in patients with clinical T1, T2, and T3 tumors as well as those with clinical nodal disease. Conclusions: In this contemporary review of a large U.S. cancer database, overall utilization of NAC in resected gastric cancer is relatively poor, with less than half of patients receiving NAC. Although patients with more advanced cancers now undergo NAC more frequently, increased awareness should be emphasized. More study is needed to determine the prognostic impact of NAC in gastric cancer care.
Diagnostic accuracy of post-mortem CT with targeted coronary angiography versus autopsy for coroner-requested post-mortem investigations: a prospective, masked, comparison study
Authors: Guy N Rutty, Bruno Morgan, Claire Robinson, Vimal Raj, Mini Pakkal, Jasmin Amoroso, Theresa Visser, Sarah Saunders, Mike Biggs, Frances Hollingbury, Angus McGregor, Kevin West, Cathy Richards, Laurence Brown, Rebecca Harrison, Roger Hew
Journal: The Lancet (2017)

BackgroundEngland and Wales have one of the highest frequencies of autopsy in the world. Implementation of post-mortem CT (PMCT), enhanced with targeted coronary angiography (PMCTA), in adults to avoid invasive autopsy would have cultural, religious, and potential economic benefits. We aimed to assess the diagnostic accuracy of PMCTA as a first-line technique in post-mortem investigations.MethodsIn this single-centre (Leicester, UK), prospective, controlled study, we selected cases of natural and non-suspicious unnatural death referred to Her Majesty's (HM) Coroners. We excluded cases younger than 18 years, known to have had a transmittable disease, or who weighed more than 125 kg. Each case was assessed by PMCTA, followed by autopsy. Pathologists were masked to the PMCTA findings, unless a potential risk was shown. The primary endpoint was the accuracy of the cause of death diagnosis from PMCTA against a gold standard of autopsy findings, modified by PMCTA findings only if additional substantially incontrovertible findings were identified.FindingsBetween Jan 20, 2010, and Sept 13, 2012, we selected 241 cases, for which PMCTA was successful in 204 (85%). Seven cases were excluded from the analysis because of procedural unmasking or no autopsy data, as were 24 cases with a clear diagnosis of traumatic death before investigation; 210 cases were included. In 40 (19%) cases, predictable toxicology or histology testing accessible by PMCT informed the result. PMCTA provided a cause of death in 193 (92%) cases. A major discrepancy with the gold standard was noted in 12 (6%) cases identified by PMCTA, and in nine (5%) cases identified by autopsy (because of specific findings on PMCTA). The frequency of autopsy and PMCTA discrepancies were not significantly different (p=0·65 for major discrepancies and p=0·21 for minor discrepancies). Cause of death given by PMCTA did not overlook clinically significant trauma, occupational lung disease, or reportable disease, and did not significantly affect the overall population data for cause of death (p≥0·31). PMCTA was better at identifying trauma and haemorrhage (p=0·008), whereas autopsy was better at identifying pulmonary thromboembolism (p=0·004).InterpretationFor most sudden natural adult deaths investigated by HM Coroners, PMCTA could be used to avoid invasive autopsy. The gold standard of post-mortem investigations should include both PMCT and invasive autopsy.FundingNational Institute for Health Research.
Reducing the Need for Amniocentesis in Women 35 Years of Age or Older with Serum Markers for Screening
Authors: James E. Haddow, Glenn E. Palomaki, George J. Knight, George C. Cunningham, Linda S. Lustig, Patricia A. Boyd
Journal: New England Journal of Medicine (1994)

As maternal age advances, the risk of fetal Down's syndrome increases. Pregnant women 35 years of age or older are routinely offered amniocentesis because of this risk. Recently, maternal serum markers have been reported to be useful in screening for Down's syndrome, primarily in younger women. We therefore investigated whether offering amniocentesis only to selected women 35 years of age or older who were identified by screening measurements in serum might prove a useful alternative to the current practice.
Mitochondrial Retroprocessing Promoted Functional Transfers of rpl5 to the Nucleus in Grasses
Authors: Zhiqiang Wu, Daniel B. Sloan, Colin W. Brown, Mónica Rosenblueth, Jeffrey D. Palmer, Han Chuan Ong
Journal: Molecular Biology and Evolution (2017)

Functional gene transfers from the mitochondrion to the nucleus are ongoing in angiosperms and have occurred repeatedly for all 15 ribosomal protein genes, but it is not clear why some of these genes are transferred more often than others nor what the balance is between DNA- and RNA-mediated transfers. Although direct insertion of mitochondrial DNA into the nucleus occurs frequently in angiosperms, case studies of functional mitochondrial gene transfer have implicated an RNA-mediated mechanism that eliminates introns and RNA editing sites, which would otherwise impede proper expression of mitochondrial genes in the nucleus. To elucidate the mechanisms that facilitate functional gene transfers and the evolutionary dynamics of the coexisting nuclear and mitochondrial gene copies that are established during these transfers, we have analyzed rpl5 genes from 90 grasses (Poaceae) and related monocots. Multiple lines of evidence indicate that rpl5 has been functionally transferred to the nucleus at least three separate times in the grass family and that at least seven species have intact and transcribed (but not necessarily functional) copies in both the mitochondrion and nucleus. In two grasses, likely functional nuclear copies of rpl5 have been subject to recent gene conversion events via secondarily transferred mitochondrial copies in what we believe are the first described cases of mitochondrial-to-nuclear gene conversion. We show that rpl5 underwent a retroprocessing event within the mitochondrial genome early in the evolution of the grass family, which we argue predisposed the gene towards successful, DNA-mediated functional transfer by generating a “pre-edited” sequence.
Abstract 124: Sam68 Impedes the Recovery of Arterial Injury by Augmenting Inflammatory Response
Authors: Shuling Han, Junlan Zhou, Baron T Arnone, Dauren Biyashev, Chan Boriboun, Raj Kishore, Douglas W Losordo, Gangjian Qin
Journal: Circulation Research (2015)

Background: The role of Src-associated in mitosis 68 kDa (Sam68) in cardiovascular biology has not been studied. A recent report suggests that Sam68 suppresses TNF-α-induced NF-κB activation. Since NF-κB plays a critical role in vascular inflammation and injury via generation of inflammatory cytokines and recruitment of inflammatory cells, we sought to dissect the mechanism by which Sam68 regulates NF-κB signaling and its functional significance during vascular injury. Methods &amp; Results: The endothelial denudation injury was induced in the carotid arteries of Sam68-/- and WT mice. Sam68-/- mice displayed an accelerated re-endothelialization and attenuated neointima hyperplasia, which was associated with a reduced number of macrophages and lowered expression of pro-inflammatory cytokines (i.e., TNF-α, IL-1β and IL-6) in the injured vessels. Importantly, the ameliorated vascular remodeling was recapitulated in WT mice after transplantation of bone marrow (BM) from Sam68-/- mice, suggesting beneficial role was attributed largely to BM-derived inflammatory cells. In cultured Raw264.7 macrophages, knockdown of Sam68 resulted in a significant reduction in the TNF-α-induced expression of TNF-α, IL-1β, and IL-6 and in the level of nuclear phospho-p65, indicating an attenuated NF-κB activation. These results were confirmed in peritoneal macrophages and macrophages differentiated from BM mononuclear cells of Sam68-/- and WT mice. To identify molecular mechanisms, Raw264.7 cells were treated with TNF-α and Vehicle, followed by Sam68 co-immunoprecipitation and mass-spec identification of Sam68-interacting proteins. Specifically, TNF-α treatment results in altered interactions of Sam68 with Filamin A (FLNA), a cytoskeleton protein known to be involved in NF-κB activation. Loss- and gain-of-function of Sam68 and FLNA suggest their mutual dependence in NF-κB activation and pro-inflammatory cytokine expression, and Sam68 is required for TRAF2-FLNA interaction. Conclusions: Our results for the first time suggest that Sam68 promotes pro-inflammatory response in injured arteries and impedes recovery, and this effect is attributed, in part, to the exaggerated NF-κB activity via Sam68-FLNA interaction and consequent TRAF2 stabilization.
‘Printability' of Candidate Biomaterials for Extrusion Based 3D Printing: State‐of‐the‐Art
Authors: Stuart Kyle, Zita M. Jessop, Ayesha Al‐Sabah, Iain S. Whitaker
Journal: Advanced Healthcare Materials (2017)

Regenerative medicine has been highlighted as one of the UK's 8 ‘Great Technologies' with the potential to revolutionize patient care in the 21st Century. Over the last decade, the concept of ‘3D bioprinting' has emerged, which allows the precise deposition of cell laden bioinks with the aim of engineering complex, functional tissues. For 3D printing to be used clinically, there is the need to produce advanced functional biomaterials, a new generation of bioinks with suitable cell culture and high shape/print fidelity, to match or exceed the physical, chemical and biological properties of human tissue. With the rapid increase in knowledge associated with biomaterials, cell‐scaffold interactions and the ability to biofunctionalize/decorate bioinks with cell recognition sequences, it is important to keep in mind the ‘printability' of these novel materials. In this illustrated review, we define and refine the concept of ‘printability' and review seminal and contemporary studies to highlight the current ‘state of play' in the field with a focus on bioink composition and concentration, manipulation of nozzle parameters and rheological properties.
Halting Zika’s resurgence with new rapid tests for the virus
Authors: Ranu S Dhillon, Devabhaktuni Srikrishna, David Beier
Journal: BMJ (2017)

Zika could re-emerge as many parts of the world enter warmer months. Problematically, we still have no effective control strategy: spraying mosquitoes has not worked in most places, and a vaccine will not be ready until at least 2018.12

When two of us (RSD and DS) with Jha proposed an interim solution to contain Zika,3 no …
MicroRNA-608 inhibits proliferation of bladder cancer via AKT/FOXO3a signaling pathway
Authors: Zhen Liang, Xiao Wang, Xin Xu, Bo Xie, Alin Ji, Shuai Meng, Shiqi Li, Yi Zhu, Jian Wu, Zhenghui Hu, Yiwei Lin, Xiangyi Zheng, Liping Xie, Ben Liu
Journal: Molecular Cancer (2017)

Current evidence indicates that miR-608 is widely down-regulated in various malignant tumors including liver cancer, colon cancer, lung cancer and glioma, and acts as a tumor suppressor by inhibiting cell proliferation, invasion and migration or by promoting apoptosis. The specific biological function of miR-608 in bladder cancer is still unknown. qRT-PCR and Chromogenic in Situ Hybridization (CISH) was conducted to assess the expression of miR-608 in paired BCa tissues and adjacent non-tumor bladder urothelial tissues. Bisulfite sequencing PCR was used for DNA methylation analysis. CCK-8, colony formation and flow cytometry assays were performed, and a xenograft model was studied. Immunohistochemistry staining was performed with peroxidase and DAB. The target of miR-608 was validated with a dual-luciferase reporter assay, quantitative RT-PCR, and Western blotting. miR-608 is frequently down-regulated in human BCa tissues. The methylation status of CpG islands is involved in the regulation of miR-608 expression. Overexpression of miR-608 inhibits the proliferation and tumorigenesis of BCa cells in vitro and in vivo. Additionally, up-regulation of miR-608 in BCa cells induces G1-phase arrest through AKT/FOXO3a signaling. In contrast, down-regulation of miR-608 promotes proliferation and cell cycle progression in BCa cells. Moreover, the expression of FLOT1 was directly inhibited by miR-608, the down-regulation of FLOT1 induced by siFLOT1 could be significantly reversed by miR-608 inhibitor. Similarly, the up-regulation of FLOT1 by FLOT1 overexpression plasmid (pFLOT1) could also reverse the suppressed cell proliferation caused by miR-608. miR-608 is a potential tumor suppressor in BCa, and the restoration of miR-608 might be a promising therapeutic option for BCa.
Abstract 254: Small Molecule Induced Caveolin Regulate GPCR Signaling In IPS cells Survival And Differentiation
Authors: ZEESHAN PASHA, MUHAMMAD ASHRAF
Journal: Circulation Research (2014)

Background: Previously we reported the use of a small molecule in upregulating cardiac genes by GPCR signaling. We further investigated the small molecule mediated effect involve caveolin and critical miRs that modulate the signaling pathway for increased survival reduced apoptosis and cardiac regeneration in ischemic myocardium. Methods and Results: IPs were treated with a small molecule (ZP-G;20uM) for three to five days. Increased cell survival and proliferative activity (p&lt;0.01 vs non treated IPS) with reduced cytochrome c release in cytosol was observed in small molecule treated IPS. Given the upregulation of cardiac genes, ultrastructure feature of small molecule treated IPS cells showed caveolin formation on transmission electron microscopy. miR Microarray analysis of treated IPS cells showed upregulation of miR 705,149, cardiac specific miR −133,762 and down regulation of miR-16, miR 34a, miR-290/292-5p modulating the downstream targets Chemokines, VEGFA, Vesicles associated membrane protein (Vamp), Cdk, E2f, Wnt3a and GPCR receptors. mRNA Microarray further validate 2 fold downregulation of Dnmt1,3b, Max gene associated protein, CDK2, NFkB repressing factor with concomitant 2-3 fold upregulation of caveolin, chemokines and integrins. Western blot analysis displayed significant upregulation of Gα protein, phospho Akt, and Bcl-2 levels as compared to nontreated IPS cells. Small molecule mediated effect was abolished by treatment of IPS cells with GPCR blocker. No tumor formation when treated IPS cells were injected in nude mouse. For Invivo study, female mice with myocardial infarction after permanent LAD ligation were transplanted with either DMEM (Gp1),or 2х105 non treated IPS (Gp 2), or treated IPS (Gp 3). At 4-week of engraftment of IPS cell derived cardiac progenitors (Gp 3) showed reduced apoptosis, extensive survival and myogenesis with attenuation of infarct size and improved heart function as compared to other groups. Conclusion: This study provides the first evidence that small molecule differentiate IPS to cardiac progenitors and regenerate the ischemic myocardium by targeting downstream targets that regulate the transcription of critical genes and proteins expression to facilitate receptor- tissue- cell signaling.
High-dose chemotherapy with autologous haematopoietic stem cell support for relapsed or refractory primary CNS lymphoma: a prospective multicentre trial by the German Cooperative PCNSL study group
Authors: B Kasenda, G Ihorst, R Schroers, A Korfel, I Schmidt-Wolf, G Egerer, L von Baumgarten, A Röth, J Bloehdorn, R Möhle, M Binder, U Keller, M Lamprecht, M Pfreundschuh, E Valk, H Fricker, E Schorb, K Fritsch, J Finke, G Illerhaus
Journal: Leukemia (2017)
Fibroblast-adapted human CMV vaccines elicit predominantly conventional CD8 T cell responses in humans
Authors: Susan E. Murray, Pavlo A. Nesterenko, Adam L. Vanarsdall, Michael W. Munks, Savannah M. Smart, Eren M. Veziroglu, Lavinia C. Sagario, Ronzo Lee, Frans H.J. Claas, Ilias I.N. Doxiadis, Michael A. McVoy, Stuart P. Adler, Ann B. Hill
Journal: The Journal of Experimental Medicine (2017)

Cytomegalovirus (CMV)-based vaccines have shown remarkable efficacy in the rhesus macaque model of acquired immune deficiency syndrome, enabling 50% of vaccinated monkeys to clear a subsequent virulent simian immunodeficiency virus challenge. The protective vaccine elicited unconventional CD8 T cell responses that were entirely restricted by MHC II or the nonclassical MHC I molecule, MHC-E. These unconventional responses were only elicited by a fibroblast-adapted rhesus CMV vector with limited tissue tropism; a repaired vector with normal tropism elicited conventional responses. Testing whether these unusual protective CD8 T responses could be elicited in humans requires vaccinating human subjects with a fibroblast-adapted mutant of human CMV (HCMV). In this study, we describe the CD8 T cell responses of human subjects vaccinated with two fibroblast-adapted HCMV vaccines. Most responses were identified as conventional classically MHC I restricted, and we found no evidence for MHC II or HLA-E restriction. These results indicate that fibroblast adaptation alone is unlikely to explain the unconventional responses observed in macaques.
Comparative Hazards of Chrysotile Asbestos and Its Substitutes: A European Perspective
Authors: Paul T. C. Harrison, Leonard S. Levy, Graham Patrick, Geoffrey H. Pigott, Lewis L. Smith
Journal: Environmental Health Perspectives (1999)

Although the use of amphibole asbestos (crocidolite and amosite) has been banned in most European countries because of its known effects on the lung and pleura, chrysotile asbestos remains in use in a number of widely used products, notably asbestos cement and friction linings in vehicle brakes and clutches. A ban on chrysotile throughout the European Union for these remaining applications is currently under consideration, but this requires confidence in the safety of substitute materials. The main substitutes for the residual uses of chrysotile are p-aramid, polyvinyl alcohol (PVA), and cellulose fibers, and it is these materials that are evaluated here. Because it critically affects both exposure concentrations and deposition in the lung, diameter is a key determinant of the intrinsic hazard of a fiber; the propensity of a material to release fibers into the air is also important. It is generally accepted that to be pathogenic to the lung or pleura, fibers must be long, thin, and durable; fiber chemistry may also be significant. These basic principles are used in a pragmatic way to form a judgement on the relative safety of the substitute materials, taking into account what is known about their hazardous properties and also the potential for uncontrolled exposures during a lifetime of use (including disposal). We conclude that chrysotile asbestos is intrinsically more hazardous than p-aramid, PVA, or cellulose fibers and that its continued use in asbestos-cement products and friction materials is not justifiable in the face of available technically adequate substitutes.