tbuckley/cabot-search huggingface dataset:
Abstract LB-219: Derivation of mathematical modeling for the diffusion and penetration of monoclonal antibody delivery into tumor
Authors: Hyeongi Kim, Yangjin Kim, Yong-Jin Lee, Jin-su Kim
Journal: Cancer Research (2019)

Abstract Background: Commonly malignant solid tumor have an abundant tumor-associated cellular matrix (ECM). Although radioimmunothrepy (RIT) have proven to be effective and precise treatment in cancer, yet RIT has a limited performance in solid tumor, due to highly distributed ECM inside solid tumor tissue. Previously, we designed the combination RIT to enhance the penetration of monoclonal antibody (mAb), where we investigated that, using Relaxin which contain oncolytic adenovirus (OA) as combination therapy decreases tumor associated ECM. In this study, we developed mathematical modeling to explain and describe the diffusion and penetration of mAb inside the tumor with ECM. To obtain the model parameters in our developed mathematical model, we performed related experiments such as immunofluorescence and qRT-PCR. Methods: We developed the reaction-diffusion partial differential equations (PDE) for describing the dependency of cancer cell, ECM density, diffusion and penetration of mAb and ECM modulated therapy that include our experimental data, also to overcome the classical limitation of PDE method. Model included the rapid decrease of ECM by OA, and density dependent diffusion coefficient. Initial condition for solving the PDE was derived using our experimental result. Diffusion coefficient for mAb and OA was modelled for simulating actual behavior of mAb and OA. Various condition of ECM density, and structure were modelled that derives the actual result of distribution of collagen. To confirm the mathematical prediction, we designed in vitro experiment with same condition as used as “in model”. Results: Using our developed model, we successfully described relationship between ECM and mAb transport by OA, and investigated the change of ECM. Diffusion and penetration of mAb and OA were well described from tumor vessel and tumor surface. Regardless of ECM structure, all ECM structure were degraded after spreading of OA. In addition, our model simulation results predicted that mAb uptake dramatically increased in combination approach and was more than mAb alone treatment. Our developed mathematical model predicted the optimal schedule of OA pretreatment and it shows great results more than mAb pretreatment. Pretreatment results with OA shows a great anti-tumor effect more than mAb pretreatment in experimental data. Our model could well predicted and matched the experimental results. Collectively, in our study, we suggested new theoretical mathematical model framework to explain various ECM condition with drug transport Citation Format: Hyeongi Kim, Yangjin Kim, Yong-Jin Lee, Jin-su Kim. Derivation of mathematical modeling for the diffusion and penetration of monoclonal antibody delivery into tumor [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-219.
Breast cancer and metastasis free survival are effected by PRMT2 and Rory; Expression: Understanding the Role of DNA Repair
Authors: Tae Gyu Oh, Peter Bailey, Eloise Dray, Joel Goode, Natalie Eriksson, John W Funder, Peter J Fuller, Evan R Simpson, Wayne D Tilley, Peter J Leedman, Christine L Clarke, Sean Grimmond, Dennis H Dowhan, George Eo Muscat
Journal: Endocrine Reviews (2014)
A phase 1 study of the selective cyclin dependent kinase inhibitor P276–00 in patients with advanced refractory neoplasms
Authors: H. W. Hirte, D. Raghunadharao, T. Baetz, S. Hotte, S. Rajappa, A. Iacobucci, S. Sharma, H. Parikh, S. Kulkarni, S. Patil, S. Gaston
Journal: Journal of Clinical Oncology (2007)

14117 Background: In human cancers, genetic and epigenetic events result in over-expression of cyclins or absence or diminished levels of Cdk inhibitors, providing tumor cells with selective growth advantage. This has prompted the development of pharmacological Cdk inhibitors that could potentially produce anti-tumor effect. P276–00 is a selective Cdk4-D1 and Cdk1-B inhibitor. This study was designed to determine the maximum tolerated dose (MTD), toxicity profile, pharmacokinetics, and antitumour activity of P276–00 given intravenously to patients with advanced refractory solid tumours. Methods: P276–00 was administered in escalating doses to cohorts of eligible patients (pts), starting with a dose of 9 mg/m 2 as a 30 minute iv infusion day 1 to 5, and day 8 to 12, q 3 weekly. To date 22 pts have been entered on the study (cohort 1 - 4 pts at 9 mg/m 2 , cohort 2 - 4 pts at 12.6 mg/m 2 , cohort 3 - 6 pts at 17.6 mg/m 2 , cohort 4 - 8 pts at 24.6 mg/m 2 ) with PS 0–2, and mean age of 56 years. Pharmacokinetic profiles were obtained on cycle 1 days 1 and 5. Skin biopsies were obtained immediately prior to starting study treatment and on day 21 of cycle 2 and will be analyzed for Ki67, cleaved caspase 3, phospho-Rb, cyclin D1 and cdk4, and microarray. Results: To date dose limiting toxicity has occurred in one pt. Grade 3 fatigue occurred in 1 pt at 17.6 mg/m 2 . The most common drug-related adverse events, which were all grade 1 or 2, were fatigue, nausea, hypotension, sweating, and dry mouth. No Grade 3 biochemical toxicities have been reported so far. There have been no responses noted to date. 4 pts have stable disease after 2 cycles. Pharmacokinetic results: The C max , t 1/2 , and AUC 0–8 on day 1 were as follows: 9 mg/m 2 - 315 ng/mL, 6.6 hr, 883 ng.h/mL; 12.6 mg/m 2 - 402 ng/mL, 5.5 hr, 848 ng.h/mL; 17.6 mg/m 2 - 589 ng/mL, 5.3 hr, 1289 ng.h/mL; 24.6 mg/m 2 - 621 ng/mL, 5.6 hr, 1286 ng.h/mL. Conclusions: P276–00 is well tolerated, but grade 3 fatigue has been noted in 1 pt at 17.6 mg/m 2 dose level. We have observed confirmed stable disease in one patient. PK results indicate that at 9 mg/m 2 ,12.6 mg/m 2 , 17.6 mg/m 2 and 24.6 mg/m 2 we are able to cross the cdk4 enzyme IC 50 approximately 10, 13, 19 and 20 times and cross the anti-proliferative IC 50 1.1, 1.4, 2.1 and 2.2 times respectively. Accrual continues at the 34.4 mg/m 2 dose level. No significant financial relationships to disclose.
Abstract 4655: Association of a new germline variant in the MUTYH DNA glycosylase gene with colorectal adenoma transformation into malignancy
Authors: Amjad A. Mahasneh, Fawaz Al-Shaheri, Mohamemd N. Banihani
Journal: Cancer Research (2019)

Abstract Background: Germline mutations in mutY homolog (E.coli) (MUTYH)DNA glycosylase gene have been associated with recessive inheritance of multiple s adenoma. Several studies revealed that germline mutations in this gene are ethnicity related. This study aimed to identify the germ-line mutations in MUTYH gene and determine their prevalence among Jordanian patients with colorectal adenoma. Methods: 150 colorectal adenoma patients and 150cancer free individuals with no previous history of polyps were recruited. Sanger DNA sequencing of the MUTYH genewas carried out using 3130xL Genetic Analyzer. Sequencing results were analyzed by ChromasPro and mutational effects were predicted by online bioinformatics tools(accession number for the transcript used as reference isNG_008189.1). Results: Two novel variants, g.87C&amp;gt;T and c.1264G&amp;gt;C, have been identified. G.87C&amp;gt;T was found in 60 (40%) patients and 10 (6.7%) controls.C.1264G&amp;gt;C was found in 90 (60%) patients and 7 (4.7%) controls. Thus, a significant association between g.87C&amp;gt;T and c.1264G&amp;gt;C variants and colorectal adenoma was found (p value for both variants was &amp;lt;0.0001). Moreover, the newly identified germline variant, c.1264G&amp;gt;C, was found to be significantly associated with colorectal adenoma transformation into malignancy (p&amp;lt; 0.0001). Conclusion: The data showed high prevalence of two germline mutations in MUTYH gene among Jordanians with colorectal adenoma, which may make them as potential early biomarkers for diagnosis of colorectal adenoma. Citation Format: Amjad A. Mahasneh, Fawaz Al-Shaheri, Mohamemd N. Banihani. Association of a new germline variant in the MUTYH DNA glycosylase gene with colorectal adenoma transformation into malignancy [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 4655.
Perihilar and distal extrahepatic cholangiocarcinomas show different genetic profiles but share MYC copy gain and TP53 mutation as independent poor prognostic markers
Authors: M. Simbolo, A. Mafficini, C. Vicentini, A. Ruzzenente, B. Rusev, M. Brunelli, S. Pedron, F. Bertuzzo, S. Barbi, M. Fassan, V. Corbo, F. Bagante, G. Turri, C. Luchini, R. Lawlor, A. Guglielmi, C. Bassi, A. Scarpa
Journal: Annals of Oncology (2019)
Inflammasome inhibitors: promising therapeutic approaches against cancer
Authors: Shengchao Xu, Xizhe Li, Yuanqi Liu, Yu Xia, Ruimin Chang, Chunfang Zhang
Journal: Journal of Hematology & Oncology (2019)

Inflammation has long been accepted as a key component of carcinogenesis. During inflammation, inflammasomes are potent contributors to the activation of inflammatory cytokines that lead to an inflammatory cascade. Considering the contributing role of inflammasomes in cancer progression, inflammasome inhibitors seem to have a promising future in cancer treatment and prevention. Here, we summarize the structures and signaling pathways of inflammasomes and detail some inflammasome inhibitors used to treat various forms of cancer, which we expect to be used in novel anticancer approaches. However, the practical application of inflammasome inhibitors is limited in regard to specific types of cancer, and the associated clinical trials have not yet been completed. Therefore, additional studies are required to explore more innovative and effective medicines for future clinical treatment of cancer.
Obeticholic acid may increase the risk of gallstone formation in susceptible patients
Authors: Samer Al-Dury, Annika Wahlström, Katrin Panzitt, Anders Thorell, Marcus Ståhlman, Michael Trauner, Peter Fickert, Fredrik Bäckhed, Lars Fändriks, Martin Wagner, Hanns-Ulrich Marschall
Journal: Journal of Hepatology (2019)
Abstract 14805: Right Ventricular-arterial Coupling Predicts Right Ventricular Ejection Fraction After Pulmonary Valve Implantation
Authors: Gianfranco Butera, Francesca Pluchinotta, Giorgia Galli, Luciane Piazza, Francesco Secchi, Antonio Saracino, Angelo Micheletti, Mario Carminati, Giuliano Giusti, Massimo Lombardi
Journal: Circulation (2017)

Introduction: Right ventricular-pulmonary arterial coupling (RV-AP-coup) plays a role in the occurrence of right ventricular failure. Ventricular-arterial coupling is defined as Emax (maximal systo...
Synaptic and memory dysfunction induced by tau oligomers is rescued by up-regulation of the nitric oxide cascade
Authors: Erica Acquarone, Elentina K. Argyrousi, Manon van den Berg, Walter Gulisano, Mauro Fà, Agnieszka Staniszewski, Elisa Calcagno, Elisa Zuccarello, Luciano D’Adamio, Shi-Xian Deng, Daniela Puzzo, Ottavio Arancio, Jole Fiorito
Journal: Molecular Neurodegeneration (2019)

Abstract Background Soluble aggregates of oligomeric forms of tau protein (oTau) have been associated with impairment of synaptic plasticity and memory in Alzheimer’s disease. However, the molecular mechanisms underlying the synaptic and memory dysfunction induced by elevation of oTau are still unknown. Methods This work used a combination of biochemical, electrophysiological and behavioral techniques. Biochemical methods included analysis of phosphorylation of the cAMP-responsive element binding (CREB) protein, a transcriptional factor involved in memory, histone acetylation, and expression immediate early genes c-Fos and Arc. Electrophysiological methods included assessment of long-term potentiation (LTP), a type of synaptic plasticity thought to underlie memory formation. Behavioral studies investigated both short-term spatial memory and associative memory. These phenomena were examined following oTau elevation. Results Levels of phospho-CREB, histone 3 acetylation at lysine 27, and immediate early genes c-Fos and Arc, were found to be reduced after oTau elevation during memory formation. These findings led us to explore whether up-regulation of various components of the nitric oxide (NO) signaling pathway impinging onto CREB is capable of rescuing oTau-induced impairment of plasticity, memory, and CREB phosphorylation. The increase of NO levels protected against oTau-induced impairment of LTP through activation of soluble guanylyl cyclase. Similarly, the elevation of cGMP levels and stimulation of the cGMP-dependent protein kinases (PKG) re-established normal LTP after exposure to oTau. Pharmacological inhibition of cGMP degradation through inhibition of phosphodiesterase 5 (PDE5), rescued oTau-induced LTP reduction. These findings could be extrapolated to memory because PKG activation and PDE5 inhibition rescued oTau-induced memory impairment. Finally, PDE5 inhibition re-established normal elevation of CREB phosphorylation and cGMP levels after memory induction in the presence of oTau. Conclusions Up-regulation of CREB activation through agents acting on the NO cascade might be beneficial against tau-induced synaptic and memory dysfunctions.
Abstract 17597: Quantitative T Wave Analysis Can Identify Patients With Symptomatic Long QT Syndrome
Authors: Alan Sugrue, J. Martijn Bos, Vaclav Kremen, Bo Qiang, Paul A Friedman, Michael J Ackerman, Peter A Noseworthy
Journal: Circulation (2015)

Introduction: Long QT syndrome (LQTS) is a genetic disorder associated with abnormal ventricular repolarization and a predisposition for torsade de pointes and sudden cardiac death. Identification of markers to elucidate high risk patients is of major practical importance. Our aim was to use a novel, automated quantitative T wave analysis program to distinguish symptomatic from asymptomatic LQTS patients. Methods: We analyzed a genotyped cohort of 420 patients (22 ± 15.7years, 43% male) with either LQT1 (61%) or LQT2 (39%). ECG analysis was conducted using novel software that we created to automatically detect subtle changes in T wave morphology. Symptomatic patients were defined as those with a history of syncope or resuscitated cardiac arrest that was suspected of being LQTS triggered. Classification was performed using the top three T wave features in a linear discriminant classifier by 10x10 cross-validation. Results: Symptomatic LQT1 patients have a greater QTc duration in lead aVF (437 msec vs 416 msec, p &lt;0.0001), a greater T wave center of gravity on the x axis (COGx) in lead V2 (0.304 vs 0.280, p &lt;0.0001) and longer Tpeak-Tend/QT in lead II (0.208 vs 0.188, p &lt; 0.0001) than asymptomatic patients with LQT1. Use of these 3 features enabled classification of symptomatic status in 72% of LQT1 cases, compared to 68% when QTc was used to classify alone. Symptomatic LQT2 patients had a longer QTc in Lead 1 (460 vs 418 msec, p &lt; 0.0001), COGx in 4th segment of T wave was greater in lead V5 (0.399 vs 0.350, p&lt;0.0001), and the Tpeak-Tend interval in V2 was longer (126 vs 99 msec, P =0.0004). Use of these 3 features enabled correct classification in 73% of LQT2 cases, compared to 67% when QTc was used alone. Conclusions: Application of an automated T wave analysis program was able to identify T wave features that distinguished the patients who presented as symptomatic LQTS, associated with syncope or resuscitated cardiac arrest. Use of these features could help assess arrhythmic risk and guide management strategies for patients with LQTS.
Abstract 287: A novel class III receptor tyrosine kinase inhibitor synergizes with olaparib by inhibition of DNA repair-related genes in non-small cell lung cancer cells
Authors: Hwani Ryu, Jie-young Song, Sang-Gu Hwang, Jiyeon Ahn
Journal: Cancer Research (2019)

Abstract The platelet-derived growth factor receptors (PDGFRs), which are classified with class III receptor tyrosine kinase (RTK) family, play critical roles in cell proliferation, differentiation, and malignancy in various types of human cancers. To develop novel class III RTK inhibitors, dozen novel oxazole amine derivatives were designed and synthesized. Among the synthesized compounds, KM201 showed inhibitory activities of pan-class III RTK by an in vitro kinase activity assay and potent anti-proliferative activities in variety of cancer cell lines including leukemia and solid cancer cells. Genome-wide RNAseq profiling revealed a significant decrease of DNA repair-related genes in non-small cell lung cancer A549 cells treated with KM201. Moreover, KM201-induced DNA damage was detected by H2AX phosphorylation, which led to cell cycle arrest in the G2/M phase. We hypothesized that KM201 in combination with a PARP inhibitor may exhibit synergistic effect on inhibition of proliferation since PARP inhibitors are primarily effective against cancers with loss-of-function mutations in BRCA1 and BRCA2. Combination of KM201 and olaparib (a PARP inhibitor) markedly more effective in anti-proliferation and apoptotic cell death in A549 and H1299 cells harboring wild type BRCA1/2, compared with either drug alone. Our results show that the novel class III RTK inhibitor KM201 inhibits proliferation of leukemia and solid tumor cells by potentiating DNA damage and exerts synergistic cytotoxicity in combination with olaparib. Further detailed studies could help to investigate the full potential of KM201 as a class III RTK inhibitor and a combination adjuvant of PARP inhibitors. Citation Format: Hwani Ryu, Jie-young Song, Sang-Gu Hwang, Jiyeon Ahn. A novel class III receptor tyrosine kinase inhibitor synergizes with olaparib by inhibition of DNA repair-related genes in non-small cell lung cancer cells [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 287.
Urbanisation and asthma in low-income and middle-income countries: a systematic review of the urban–rural differences in asthma prevalence
Authors: Alejandro Rodriguez, Elizabeth Brickley, Laura Rodrigues, Rebecca Alice Normansell, Mauricio Barreto, Philip J Cooper
Journal: Thorax (2019)

Background Urbanisation has been associated with temporal and geographical differences in asthma prevalence in low-income and middle-income countries (LMICs). However, little is known of the mechanisms by which urbanisation and asthma are associated, perhaps explained by the methodological approaches used to assess the urbanisation-asthma relationship. Objective This review evaluated how epidemiological studies have assessed the relationship between asthma and urbanisation in LMICs, and explored urban/rural differences in asthma prevalence. Methods Asthma studies comparing urban/rural areas, comparing cities and examining intraurban variation were assessed for eligibility. Included publications were evaluated for methodological quality and pooled OR were calculated to indicate the risk of asthma in urban over rural areas. Results Seventy articles were included in our analysis. Sixty-three compared asthma prevalence between urban and rural areas, five compared asthma prevalence between cities and two examined intraurban variation in asthma prevalence. Urban residence was associated with a higher prevalence of asthma, regardless of asthma definition: current-wheeze OR:1.46 (95% CI:1.22 to 1.74), doctor diagnosis OR:1.89 (95% CI:1.47 to 2.41), wheeze-ever OR:1.44 (95% CI:1.15 to 1.81), self-reported asthma OR:1.77 (95% CI:1.33 to 2.35), asthma questionnaire OR:1.52 (95% CI:1.06 to 2.16) and exercise challenge OR:1.96 (95% CI:1.32 to 2.91). Conclusions Most evidence for the relationship between urbanisation and asthma in LMICs comes from studies comparing urban and rural areas. These studies tend to show a greater prevalence of asthma in urban compared to rural populations. However, these studies have been unable to identify which specific characteristics of the urbanisation process may be responsible. An approach to understand how different dimensions of urbanisation, using contextual household and individual indicators, is needed for a better understanding of how urbanisation affects asthma. PROSPERO registration number CRD42017064470.
Abstract 16585: Comparison Between Steen and Somah as Primary Perfusate Components for ex vivo Heart Perfusion
Authors: Roberto V Ribeiro, Arash Ghashghai, Frank Yu, Liming Xin, Bryan Gellner, Giulia Maria Ruggeri, Juglans Alvarez, David Banner, Massimiliano Meineri, Vivek Rao, Mitesh V Badiwala
Journal: Circulation (2017)

Background: Ex Vivo Heart Perfusion (EVHP) has been proposed as an alternative preservation strategy to expand cardiac donations, enabling functional assessment of hearts donated after circulatory ...
Clinical onset of atopic eczema: Results from 2 nationally representative British birth cohorts followed through midlife
Authors: Katrina Abuabara, Morgan Ye, Charles E. McCulloch, Alice Sullivan, David J. Margolis, David P. Strachan, Lavinia Paternoster, Yik Weng Yew, Hywel C. Williams, Sinéad M. Langan
Journal: Journal of Allergy and Clinical Immunology (2019)

Atopic eczema onset is described primarily in early childhood, and the frequency and characteristics of adult-onset disease remain controversial.We sought to determine the proportion of subjects who report atopic eczema symptoms between birth and midadulthood and to examine demographic, immunologic, and genetic factors associated with period of symptom onset.We conducted a longitudinal study using data from 2 nationally representative community-based birth cohorts from the United Kingdom: the British Cohort Studies 1958 and 1970. Subjects were followed from birth through age 42 to 50 years. The primary outcome was the age period of self-reported atopic eczema symptom onset based on repeated measures of self-reported atopic eczema at each survey wave.The annual period prevalence of atopic eczema ranged from 5% to 15% in 2 cohorts of more than 17,000 participants each followed from birth through middle age. There was no clear trend in prevalence by age, and among adults reporting active atopic eczema during a given year, only 38% had symptom onset reported in childhood. When compared with subjects whose eczema started in childhood, those with adult-onset disease were more likely to be women, from Scotland or Northern England, of lower childhood socioeconomic group, smokers in adulthood, and less likely to have a history of asthma. In a subanalysis using data from the 1958 cohort only, genetic mutations previously associated with atopic eczema, including filaggrin-null mutations, and allergen-specific IgE were more common among those with childhood-onset disease.Rates of self-reported atopic eczema remain high after childhood, and adult-onset atopic eczema has different risk factor associations than childhood-onset eczema.