tbuckley/cabot-search huggingface dataset:
Abstract 3380: BRIP1/FANCJ is vital for efficient response to and repair of replication-associated DNA damage
Authors: David W. Clark, Chinnadurai Mani, Komariah Palle
Journal: Cancer Research (2018)

Abstract BRCA1-Interacting Protein 1 (BRIP1), a DNA helicase and tumor suppressor also known as FANCJ, is implicated in breast and ovarian cancers as well as the genetic instability syndrome Fanconi anemia (FA) which predisposes patients to multiple neoplasms. This study investigates the role of FANCJ in repair of replication-associated DNA damage which can lead to DNA strand breaks, chromosomal instability, and tumorigenesis. FANCJ has long been known to function in repair of DNA crosslinks; however, its role in protecting cells from replication-associated DNA damage is less well known. We have shown that loss of FANCJ sensitizes cells to damage caused by compounds that block DNA replication, such as hydroxyurea (HU) and the topoisomerase I poison camptothecin (CPT). Loss of FANCJ disrupts the cell's response to replication-associated DNA damage by impairing Chk1 and Chk2 phosphorylation and stability and activation of multiple DNA repair proteins. FANCJ-deficient cells exposed to low levels of CPT failed to progress through S-phase indicating that FANCJ is important for intra-S phase DNA damage checkpoint and recovery from replication fork blocks. FANCJ depletion leads to a 90% decrease in homologous recombination repair in assays designed to measure repair of DNA double strand breaks as well as a loss of expression of repair-associated proteins and DNA repair foci in response to damage from HU and CPT. Loss of FANCJ impairs DNA replication and leads to accumulation of gross chromosomal aberrations. Importantly, some of the DNA damage response functions of FANCJ are independent of its helicase activity, as a helicase-deficient mutant is able to compensate for loss of FANCJ in activation and stability of FANCD2 and other HR proteins. Collectively our findings indicate a novel role for FANCJ as a key regulator of the DNA damage response to errors in DNA replication potentially leading to mutagenesis and tumorigenesis. Citation Format: David W. Clark, Chinnadurai Mani, Komariah Palle. BRIP1/FANCJ is vital for efficient response to and repair of replication-associated DNA damage [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3380.
Abstract 483: BRCA1 protein expression is downregulated by miR-185, miR-93 and miR-107 in breast cancer tumors
Authors: Valentina A. Zavala, Patricia Gajardo, Paola Faundez, Carolina Alvarez, Pilar Carvallo
Journal: Cancer Research (2018)

Abstract BRCA1 is a tumor-suppressor gene whose mutations confer a high risk to breast cancer. Fifty percent of hereditary breast cancer tumors without germline mutation have impaired BRCA1 expression, as well as 30% of sporadic cases. Somatic events that silence BRCA1 expression have been described in breast cancer tumors, such as promoter hypermethylation and BRCA1 gene deletion; however, these mechanisms do not completely explain the loss of BRCA1 expression in breast tumors. Our aim is to identify miRNAs differentially expressed in tumors with negative or moderate BRCA1 protein, which could regulate BRCA1 expression. Total RNA from 50 fresh-frozen breast cancer tumors was isolated and miRNA profiling was performed using miRNA microarrays. Sixteen miRNAs were found exclusively upregulated in BRCA1-negative, and ten in BRCA1-moderate tumors. Among them, in silico analyses predicted eleven miRNAs that could regulate BRCA1 expression. The effect of five of these microRNAs was assessed using a luciferase reporter assay in HEK293T cells, where the complete BRCA1 3'UTR, or a segment of its coding region, was cloned within the 3' end of the Luciferase gene. Cells were co-transfected with each of the selected microRNAs. MiR-185, miR-93 and miR-107 significantly downregulated luciferase activity by binding to the 3'UTR. Also, we transfected these microRNAs into a nontumorigenic breast cell line (MCF10A), where miR-93 diminished endogenous BRCA1 expression in 48%, miR-185 in 39% and miR-107 in 38%, in relation to non-transfected cells. These results strongly support that these microRNAs are potential regulators of BRCA1 expression in breast cancer tumors. FONDECYT1120200, CONICYT21120269. Citation Format: Valentina A. Zavala, Patricia Gajardo, Paola Faundez, Carolina Alvarez, Pilar Carvallo. BRCA1 protein expression is downregulated by miR-185, miR-93 and miR-107 in breast cancer tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 483.
Interleukin 12 and interleukin 23 play key pathogenic roles in inflammatory and proliferative pathways in giant cell arteritis
Authors: Richard Conway, Lorraine O’Neill, Geraldine M McCarthy, Conor C Murphy, Aurelie Fabre, Susan Kennedy, Douglas J Veale, Sarah M Wade, Ursula Fearon, Eamonn S Molloy
Journal: Annals of the Rheumatic Diseases (2018)

The pathogenesis of giant cell arteritis (GCA) remains unclear. TH1 and TH17 pathways are implicated, but the proximal initiators and effector cytokines are unknown. Our aim was to assess the role of interleukin 12 (IL-12) and interleukin 23 (IL-23) in GCA pathogenesis.IL-12 and IL-23 expression were quantified by immunohistochemistry in temporal artery biopsies (TABs). Temporal artery (TA) explant, peripheral blood mononuclear cell (PBMC) and myofibroblast outgrowth culture models were established. PBMCs and TA explants were cultured for 24 hours in the presence or absence of IL-12 (50 ng/mL) or IL-23 (10 ng/mL). Gene expression in TA was quantified by real-time PCR and cytokine secretion by ELISA. Myofibroblast outgrowths were quantified following 28-day culture.Immunohistochemistry demonstrated increased expression of interleukin 12p35 (IL-12p35) and interleukin 23p19 (IL-23p19) in biopsy-positive TAs, localised to inflammatory cells. IL-12p35 TA expression was significantly increased in those with cranial ischaemic complications (p=0.026) and large vessel vasculitis (p=0.006). IL-23p19 TA expression was increased in those with two or more relapses (p=0.007). In PBMC cultures, exogenous IL-12 significantly increased interleukin 6 (IL-6) (p=0.009), interleukin 22 (IL-22) (p=0.003) and interferon γ (IFN-γ) (p=0.0001) and decreased interleukin 8 (IL-8) (p=0.0006) secretion, while exogenous IL-23 significantly increased IL-6 (p=0.029), IL-22 (p=0.001), interleukin 17A (IL-17A) (p=0.0003) and interleukin 17F (IL-17F) (p=0.012) secretion. In ex vivo TA explants, IL-23 significantly increased gene expression of IL-8 (p=0.0001) and CCL-20 (p=0.027) and protein expression of IL-6 (p=0.002) and IL-8 (p=0.004). IL-12 (p=0.0005) and IL-23 (p<0.0001) stimulation increased the quantity of myofibroblast outgrowths from TABs.IL-12 and IL-23 play central and distinct roles in stimulating inflammatory and proliferative pathways relevant to GCA pathogenesis.
Near-infrared fluorescence imaging in the largely unexplored window of 900-1,000 nm
Authors: Guanjun Deng, Sanpeng Li, Zhihong Sun, Wenjun Li, Lihua Zhou, Jiali Zhang, Ping Gong, Lintao Cai
Journal: Theranostics (2018)

Near-infrared (NIR) fluorescence imaging has relied on fluorophores that emit in the 700-900 nm NIR-Ia or 1,000-1,700 nm NIR-II window for generating deep-tissue images. Up until now, there have been few fluorophores developed for the 900-1,000 nm NIR-Ib window. This is largely because NIR-Ib light is thought to be strongly absorbed by water. Methods: Here we found that six heptamethine dyes had distinct emission peaks in both the NIR-Ia and NIR-Ib window. We tested the performance of these contrast agents by introducing them into the leaves of the common house plant Epipremnum aureum with early stage anthracnose leaf infections from Khaya senegalensis, as well as injecting them into the hind feet of nude mice and tails of tumour-bearing mice in vivo. Results: Heptamethine dyes yielded superior images of leaf venation, anthracnose infection locations, sentinel lymph nodes, brain tumours and subcutaneous tumours in the NIR-Ib window. We found that NIR-Ib images had markedly enhanced signal-to-background ratio because autofluorescence, scattering and light absorption by biological tissues and water were weaker at longer wavelengths. Conclusion: NIR-Ib fluorescence imaging was a powerful method for studying sentinel lymph nodes, tumours, leaf veins and early anthracnose infection locations in plant leaves. The findings challenge our current view of NIR fluorescence imaging and may have important implications for biomedical research and image-guided cancer surgery.
Response to Letter Regarding Article, “Does Sodium Nitroprusside Decrease the Incidence of Atrial Fibrillation After Myocardial Revascularization? A Pilot Study”
Authors: RaifCavolli, KaanKaya, SebnemErturk, OguzMehmet, AlpAslan, OzanEmiroglu, OzgeKorkmaz, RefikTasoz, UmitOzyurda
Journal: Circulation (2009)
Abstract 643: An ultra-sensitive multiplex allele-specific real-time PCR (Udx-PCR) assay for detection of <i>KRAS</i>/<i>BRAF</i>/<i>NRAS</i> mutations in colorectal cancer
Authors: Jianxin Zhai, Youmin Wu, Xuan Luo, Xinsheng Li, De-Hua Yu
Journal: Cancer Research (2018)

Abstract RAS and BRAF gene mutation assessment is essential for therapy decision in metastatic colorectal cancer patients with anti-EGFR monoclonal antibody treatment. However the currently approved assays in clinic is mainly focusing on tissue samples with detecting sensitivity lower than 1% in 10ng genomic DNA background. The emerging analysis of ctDNA offers advantages in clinical diagnosis as a feasible method, which requires much more sensitive methodology due to low abundance in plasma samples. Herein, we developed a multiplex allele-specific real-time (ARMS) PCR assay for detection fourteen mutations of KRAS/BRAF/NRAS in an 8-tube PCR strip. The reagent and format of mutation detection were particularly optimized to reach high specificity and sensitivity. Performance evaluation showed that the assay is remarkably sensitive with lower detection limit of 0.1% in a background of 10ng wild-type genomic DNA. A total of 136 CRC FFPE samples were screened by using the assay. Sixty-two samples were positive for KRAS/BRAF/NRAS mutations, and fifty-eight were confirmed by the Sanger sequencing. The four discrepant samples were tested further by ddPCR and the results revealed that the allelic frequencies in these samples were as low as 0.1% to 5%. The evaluation of ctDNA detection is being carried in metastatic colorectal cancer patients. The multiplex allele-specific real-time PCR assay provides a rapid, reliable and low-cost diagnostic tool for accurate detection of KRAS/BRAF/NRAS mutations for clinical application. Citation Format: Jianxin Zhai, Youmin Wu, Xuan Luo, Xinsheng Li, De-Hua Yu. An ultra-sensitive multiplex allele-specific real-time PCR (Udx-PCR) assay for detection of KRAS/BRAF/NRAS mutations in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 643.
Abstract 12872: External Stenting for Tracheobronchomalacia Associated With Congenital Heart Disease
Authors: YukiNakamoto, MakotoAndo, HisayaHasegawa
Journal: Circulation (2014)

Introduction: Tracheobronchomalacia (TBM) is a disease of symptomatic obstruction of tracheal or bronchial portions either related to congenital instability or secondary to vascular compression. Patients with TBM associated with congenital heart disease (CHD) often remain difficult to manage after cardiac surgery, requiring prolonged artificial respiratory support. Under these circumstances, several treatments such as aortopexy, internal stenting, or high positive end-expiratory pressure ventilation, have been attempted, although satisfactory results have not been obtained. In 2008, we started the external stenting technique using a ringed expanded polytetrafluoroethylene graft, and we have treated 39 patients with this technique. We review the results of our experience with external stenting for TBM in children. Methods: Clinical records of 42 procedures in 39 patients with TBM, who underwent external stenting in our institute from February 2008 to March 2014, were reviewed. The diagnosis of TBM was made...
Abstract SY24-02: Improving radio-sensitivity in cervical cancer by targeting tumor metabolism
Authors: Julie K. Schwarz
Journal: Cancer Research (2018)

Abstract Our group has previously shown that cervical cancers that take up large quantities of glucose, as defined by pretreatment 18F-fluoro-deoxy-glucose positron emission tomography (FDG-PET) imaging, are resistant to standard-of-care treatment (cisplatin plus concurrent pelvic irradiation). In this session, we will review the clinical evidence that supports this finding, and translational studies that support a connection between aberrant PI3K/AKT signaling and increased glucose uptake in tumors. We will then detail recent preclinical evidence that supports simultaneous inhibition of glycolysis and redox metabolism as an effective and safe alternative treatment strategy for highly glycolytic, radiation-resistant cervical cancers. Ongoing efforts to identify, characterize, and validate biomarkers to guide this strategy will be discussed. Citation Format: Julie K. Schwarz. Improving radio-sensitivity in cervical cancer by targeting tumor metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr SY24-02.
Regulation of Very-Low-Density Lipoprotein Receptor in Hypertrophic Rat Heart
Authors: HiroakiMasuzaki, HisatoJingami, NaokiMatsuoka, OsamuNakagawa, YoshihiroOgawa, MegumiMizuno, YasunaoYoshimasa, TokuoYamamoto, KazuwaNakao
Journal: Circulation Research (1996)

Abstract To elucidate the regulation of very-low-density lipoprotein (VLDL) receptor, we have studied its gene expression in the heart of spontaneously hypertensive rats–stroke prone (SHR-SP, an animal model for hypertension-induced cardiac hypertrophy) compared with Wistar-Kyoto rats. RNase protection assay showed that ventricular VLDL receptor mRNA falls to 41% of normal levels at 4 weeks, when hypertension is not yet fully developed, and drops further to 14% at 13 weeks, when cardiac hypertrophy is established. Lipoprotein lipase mRNA decreases in parallel with VLDL receptor mRNA. In cultured neonatal rat ventricular cardiomyocytes, VLDL receptor mRNA decreases in parallel with the process of cardiocyte hypertrophy during the 24 hours after treatment with 10−8 mol/L endothelin-1, falling to 40% of the initial value. These results demonstrate that there is downregulation of VLDL receptor gene expression in cardiac hypertrophy both in vivo and in vitro and suggest that the regulation of the VLDL receptor...
Mass azithromycin distribution for hyperendemic trachoma following a cluster-randomized trial: A continuation study of randomly reassigned subclusters (TANA II)
Authors: Jeremy D. Keenan, Zerihun Tadesse, Sintayehu Gebresillasie, Ayalew Shiferaw, Mulat Zerihun, Paul M. Emerson, Kelly Callahan, Sun Y. Cotter, Nicole E. Stoller, Travis C. Porco, Catherine E. Oldenburg, Thomas M. Lietman
Journal: PLoS Medicine (2018)

Background The World Health Organization recommends annual mass azithromycin administration in communities with at least 10% prevalence of trachomatous inflammation–follicular (TF) in children, with further treatment depending on reassessment after 3–5 years. However, the effect of stopping mass azithromycin distribution after multiple rounds of treatment is not well understood. Here, we report the results of a cluster-randomized trial where communities that had received 4 years of treatments were then randomized to continuation or discontinuation of treatment. Methods and findings In all, 48 communities with 3,938 children aged 0–9 years at baseline in northern Ethiopia had received 4 years of annual or twice yearly mass azithromycin distribution as part of the TANA I trial. We randomized these communities to either continuation or discontinuation of treatment. Individuals in the communities in the continuation arm were offered either annual or twice yearly distribution of a single directly observed dose of oral azithromycin. The primary outcome was community prevalence of ocular chlamydial infection in a random sample of children aged 0–9 years, 36 months after baseline. We also assessed the change from baseline to 36 months in ocular chlamydia prevalence within each arm. We compared 36-month ocular chlamydia prevalence in communities randomized to continuation versus discontinuation in a model adjusting for baseline ocular chlamydia prevalence. A secondary prespecified analysis assessed the rate of change over time in ocular chlamydia prevalence between arms. In the continuation arm, mean antibiotic coverage was greater than 90% at all time points. In the discontinuation arm, the mean prevalence of infection in children aged 0–9 years increased from 8.3% (95% CI 4.2% to 12.4%) at 0 months to 14.7% (95% CI 8.7% to 20.8%, P = 0.04) at 36 months. Ocular chlamydia prevalence in communities where mass azithromycin distribution was continued was 7.2% (95% CI 3.3% to 11.0%) at baseline and 6.6% (95% CI 1.1% to 12.0%, P = 0.64) at 36 months. The 36-month prevalence of ocular chlamydia was significantly lower in communities continuing treatment compared with those discontinuing treatment (P = 0.03). Limitations of the study include uncertain generalizability outside of trachoma hyperendemic regions. Conclusions In this study, ocular chlamydia infection rebounded after 4 years of periodic mass azithromycin distribution. Continued distributions did not completely eliminate infection in all communities or meet WHO control goals, although they did prevent resurgence. Trial registration This study was prospectively registered at clinicaltrials.gov (clinicaltrials.gov NCT01202331).
Abstract 2825: PIN1-SCFFBW7 proteolytic signaling regulates the Fanconi anemia pathway
Authors: Jingming Wang, Bryan Chan, Michael Tong, Markus Seeliger, Hyungjin Kim
Journal: Cancer Research (2018)

Abstract Genome instability caused by defective DNA repair mechanisms is a hallmark of cancer and drives tumorigenesis. The Fanconi anemia (FA) DNA repair pathway contributes to the integrity of the genome by resolving DNA interstrand cross-links (ICLs) encountered during DNA replication. Deregulation of the FA pathway is associated with cancer predisposition and affects therapeutic outcomes against DNA-damaging cytotoxic chemotherapy. FANCD2 monoubiquitination by a multi-subunit ubiquitin E3 ligase, the FA core complex, is an essential gateway that connects the DNA damage response to enzymatic steps of DNA ICL repair. We have previously identified FAAP20 as a critical component of the FA pathway; and demonstrated that the phosphorylation of the Cdc4 phospho-degron (CPD) motif in FAAP20 by GSK3β is required for its proteasomal degradation mediated by the E3 ligase, SCFFBW7 complex. However, the upstream signaling that governs the FAAP20 phosphorylation status and its detailed mode of action for FAAP20 degradation remain elusive. Here, we show that PIN1, a phosphorylation-specific prolyl isomerase, is a key regulator of the integrity of the FA core complex and, therefore, FA pathway activity as a whole. By catalyzing a proline cis-trans isomerization of the phosphorylated backbone and thereby converting the substrate into a conformation that is favorable or refractory to downstream proteolytic signaling, PIN1 modulates the rate of protein turnover. We demonstrate that PIN1 interacts and catalyzes a phosphorylated Ser48-Pro49 motif of FAAP20 and by inducing a conformational change of FAAP20, PIN1 enhances the affinity of FAAP20 with PP2A (Protein phosphatase 2), the phosphatase of the CPD motif in FAAP20 and thereby prevents its degradation from the GSK3β-FBW7 mediated proteolytic signaling. Collectively, our studies uncover PIN1-dependent isomerization as a new regulatory mechanism for DNA ICL repair. Given that PIN1 overexpression is prevalent in diverse human cancers, identifying a way to regulate PIN1 activity in the FA pathway may help develop a PIN1 inhibitor as a chemosensitizer for cytotoxic chemotherapy to increase its therapeutic efficacy. Citation Format: Jingming Wang, Bryan Chan, Michael Tong, Markus Seeliger, Hyungjin Kim. PIN1-SCFFBW7 proteolytic signaling regulates the Fanconi anemia pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2825.
Effect of Medroxyprogesterone Acetate on Endothelium-Dependent Vasodilation in Postmenopausal Women Receiving Estrogen
Authors: AkihikoWakatsuki, YujiOkatani, NobuoIkenoue, TakaoFukaya
Journal: Circulation (2001)

Background Estrogen increases endothelium-dependent vasodilation in postmenopausal women. However, use of progestins in combination with estrogen may counter beneficial effects of estrogen on endothelium. We investigated the effect of medroxyprogesterone acetate (MPA) on estrogen-induced increase in endothelium-dependent vasodilation in postmenopausal women. Methods and Results Postmenopausal women were treated daily with conjugated equine estrogen (CEE) 0.625 mg (n=14), CEE 0.625 mg and MPA 2.5 mg (n=15) or CEE 0.625 mg and MPA 5.0 mg (n=16) for 3 months. Plasma lipids and hormones were measured before and after treatment. Vasodilatory responses of the brachial artery were evaluated by measuring flow-mediated vasodilation (FMD) and nitroglycerin-induced vasodilation by use of high-resolution ultrasonography. Susceptibility of LDL to oxidation was analyzed by incubation with CuSO4 while kinetics of conjugated diene formation was monitored. Plasma total and LDL cholesterol concentrations were decreased sig...