tbuckley/cabot-search huggingface dataset:
KDM5B Is Essential for the Hyperactivation of PI3K/AKT Signaling in Prostate Tumorigenesis
Authors: Guoliang Li, Thanigaivelan Kanagasabai, Wenfu Lu, Mike R. Zou, Shang-Min Zhang, Sherly I. Celada, Michael G. Izban, Qi Liu, Tao Lu, Billy R. Ballard, Xinchun Zhou, Samuel E. Adunyah, Robert J. Matusik, Qin Yan, Zhenbang Chen
Journal: Cancer Research (2020)

Abstract KDM5B (lysine[K]-specific demethylase 5B) is frequently upregulated in various human cancers including prostate cancer. KDM5B controls H3K4me3/2 levels and regulates gene transcription and cell differentiation, yet the contributions of KDM5B to prostate cancer tumorigenesis remain unknown. In this study, we investigated the functional role of KDM5B in epigenetic dysregulation and prostate cancer progression in cultured cells and in mouse models of prostate epithelium–specific mutant Pten/Kdm5b. Kdm5b deficiency resulted in a significant delay in the onset of prostate cancer in Pten-null mice, whereas Kdm5b loss alone caused no morphologic abnormalities in mouse prostates. At 6 months of age, the prostate weight of Pten/Kdm5b mice was reduced by up to 70% compared with that of Pten mice. Pathologic analysis revealed Pten/Kdm5b mice displayed mild morphologic changes with hyperplasia in prostates, whereas age-matched Pten littermates developed high-grade prostatic intraepithelial neoplasia and prostate cancer. Mechanistically, KDM5B governed PI3K/AKT signaling in prostate cancer in vitro and in vivo. KDM5B directly bound the PIK3CA promoter, and KDM5B knockout resulted in a significant reduction of P110α and PIP3 levels and subsequent decrease in proliferation of human prostate cancer cells. Conversely, KDM5B overexpression resulted in increased PI3K/AKT signaling. Loss of Kdm5b abrogated the hyperactivation of AKT signaling by decreasing P110α/P85 levels in Pten/Kdm5b mice. Taken together, our findings reveal that KDM5B acts as a key regulator of PI3K/AKT signaling; they also support the concept that targeting KDM5B is a novel and effective therapeutic strategy against prostate cancer. Significance: This study demonstrates that levels of histone modification enzyme KDM5B determine hyperactivation of PI3K/AKT signaling in prostate cancer and that targeting KDM5B could be a novel strategy against prostate cancer.
Abstract 3661: Association of mammographic density with blood DNA methylation
Authors: Rachel McFarland Lucia, Wei-Lin Huang, Andrea Alvarez, Irene Masunaka, Argyrios Ziogas, Deborah Goodman, Andrew O. Odegaard, Trina M. Norden-Krichmar, Hannah Lui Park
Journal: Cancer Research (2020)

Abstract Background: Mammographic density is a strong risk factor for breast cancer. While numerous genetic variations have been shown to be associated with mammographic density, an epigenetic signature of mammographic density has not yet been identified. The objective of this study was to identify a DNA methylation signature associated with mammographic density. Methods: Blood samples were collected from 197 postmenopausal women 45-65 years old with no personal history of breast cancer. For each participant, mammographic density according to the BI-RADs density classification was obtained from the most recent mammogram report. White blood cell DNA methylation at more than 850,000 CpG sites was measured using the Illumina HumanMethylationEPIC BeadChip. Differential methylation was assessed using genome-wide, probe-level, and regional approaches after filtering and normalization using the recommended steps for DNA methylation microarray data. All analyses were adjusted for appropriate confounding variables. Results: On average, genome-wide DNA methylation was higher in women with elevated mammographic density. Additionally, DNA methylation at 343 individual sites and in 34 regions was significantly associated with mammographic density after false discovery rate correction. Most density-associated sites were hypermethylated. The top differentially methylated sites were located near cell cycle regulatory genes (ICMT, DESI2, TCF21/TARID, ROBO3), as well as those encoding cytoskeletal or plasma membrane proteins (PALLD, ANO7, ATP8B3, MTUS2). We observed hypermethylation near the promoters of genes including RUFY1 and SLFN12 and within the bodies of genes including LCN6, SNED1, and LRFN1. Functional analysis of the differentially methylated sites revealed enrichment of gene ontology categories including angiogenesis and regulation of cell adhesion, as well as apoptotic signaling in response to DNA damage. Conclusions: White blood cell DNA methylation differed according to mammographic density in a sample of postmenopausal women. Probe-based and regional analysis identified differentially methylated regions located near genes implicated in cancer. These differentially methylated regions may serve as a signature of mammographic density, and future studies of the genes implicated may provide a deeper understanding of the connection between mammographic density and breast cancer risk. Citation Format: Rachel McFarland Lucia, Wei-Lin Huang, Andrea Alvarez, Irene Masunaka, Argyrios Ziogas, Deborah Goodman, Andrew O. Odegaard, Trina M. Norden-Krichmar, Hannah Lui Park. Association of mammographic density with blood DNA methylation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3661.
Leaders in Cardiovascular Research: Filippo Crea
Authors: Tomasz J Guzik, Filippo Crea
Journal: Cardiovascular Research (2020)

What is the secret of success in science-is it ambition, or talent?I think it is talent, determination and good luck.All of them are important.Q: What drives you on?What makes you come to work with so much enthusiasm every day?Curiosity.Let's learn from children.When they get a toy, they can spend hours exploring the toy because they're curious.We have to learn from children.Q: On that note, can you remember your earliest ambition in life?When I was still a child, I was inspired to become a good doctor able to reduce human suffering.That was the drive.Q: You have achieved a huge amount in your clinical and scientific career.What would you say is your greatest achievement?The demonstration that ischaemic heart disease is more than coronary stenosis.This is true for both chronic coronary syndromes, and acute.
Coagulation factors induce human skin mast cell and basophil degranulation via activation of complement 5 and the C5a receptor
Authors: Yuhki Yanase, Yoshimi Matsuo, Shunsuke Takahagi, Tomoko Kawaguchi, Kazue Uchida, Kaori Ishii, Akio Tanaka, Daiki Matsubara, Koichiro Ozawa, Michihiro Hide
Journal: Journal of Allergy and Clinical Immunology (2020)
FRI0222 Validation of two noninvasive diagnostic methods for xerostomia in sjogren’s syndrome
Authors: NN Cusumano, F Pelusa, B Meletti Madile, S Marquez
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Sjogren's Syndrome (SS) is a systemic autoimmune disease the mainly affects exocrine glands and usually presents a persistent dry mouth (xerostomia) and/or dry eyes (xeroftalmia). Xerostomia is an unsatisfactory diagnostic criteria because is subjective and can be caused by other conditions like: side effects drugs, stress, depression, dehydration, radiation therapy, and other systemic diseases like sarcoidosis, amyloidosis, lymphoma, VIH infection, etc. Altho minor salivary gland biopsy (MSGB) is an easy and safety objective diagnostic methods is rather invasive and unpleasant for the patients. <h3>Objectives</h3> Validate two simple, easy, noninvasive and nonexpensive diagnostic methods for xerostomia in Sjogren's Syndrome (SS). <h3>Methods</h3> Thirty-six (36) SS Patients with mean age 57 (range 31–74),32 female and 4 male, diagnosed according to revised European Community criteria were included in the study. 13 Patients with pSS (primary SS) 12 Patients with sSS (secondary SS) and 11 with probable pSS (3 criteria). We performed in all patients the Saliva Ferning Test (SFT), a qualitative test considered positive when fern leaf pattern was abnormal (Andonopoulos AP 1992; Cusumano NC 2000) and a semiquantitative unestimulated whole saliva flow rate test (UWSFR) considered positive for xerostomia when range for wet filter paper was 0–2 cm in 5 min (Lopez Jornet 1993). We evaluated the association between SFT and UWSFR with MSGB focus score III and IV according to Chisholm-Mason gradin system) Chi Squared test and Exact Fisher test was used to compared qualitative variables. P values &lt; 0.05 were considered significant. <h3>Results</h3> 21 Patients (58%) had abnormal SFT associated with MSGB focus score III-IV E. Fisher significant (p &lt; 0.05) 14 Patients (38%) had UWSFR range 0–2 cm in 5 min with MSGB focus score III-IV, Chi-Squared significant (p &lt; 0.05). 12 Patients (33%) both positive SFT and UWSFR had significantly association with MSGB focus score III-IV E. Fisher (p &lt; 0.05). We did not find significance, E. Fisher (p = 6) when compared SFT with UWSFR. <h3>Conclusion</h3> This study sugest that both, easy, safety noninvasive and nonexpensive saliva tests could be performed by the physician like a screening, in those patients with xerostomia and SS suspicion.
Abstract 3546: Prevalence of Lynch Syndrome among Middle Eastern endometrial cancer using targeted next generation sequencing
Authors: Sandeep K. Parvathareddy, Abdul K. Siraj, Rong Bu, Tariq Masoodi, Saud Azam, Wael Haqawi, Khadija Alobaisi, Maha Alrasheed, Valorie Balde, Nabil Siraj, Mark R. Diaz, Laila Ghazwani, Felisa DeVera, Hassan AlDossari, Khawla S. Al-Kuraya
Journal: Cancer Research (2020)

Abstract Endometrial carcinoma (EC) is the second most common gynecologic cancer worldwide. Although most ECs are sporadic, 2%-5% tend to be familial, with Lynch syndrome (LS) being the most commonly associated. The purpose of this study was to identify the incidence of LS in a large cohort of Middle eastern ECs and determine the feasibility of microsatellite instability (MSI) screening by immunohistochemistry (IHC) followed by molecular screening in deficient cases. We performed screening of 436 unselected EC for MSI status using IHC, followed by Target Capture sequencing of MSI deficient cases. MLH1 methylation analysis was performed by Real-time PCR, for cases showing deficient MLH1 by IHC. Complete loss of tumor nuclear protein expression in at least one of the four MMR genes was noted in 12.2% (53/436) of EC cases with 32 cases being MLH1 deficient, 10 MSH2 deficient, five MSH6 deficient and six PMS2 deficient. Of the 53 EC cases showing loss of expression in MMR genes, germline MMR mutations were found in four cases (0.9%). Promoter methylation analysis of 32 MLH1 deficient cases showed four cases to be unmethylated (12.5%). Our current study highlights the incidence of LS among patients with EC in Saudi Arabia. Screening of all EC patients using immunohistochemistry and reflex MLH1 promoter methylation testing followed by gene sequencing is feasible and desirable. Citation Format: Sandeep K. Parvathareddy, Abdul K. Siraj, Rong Bu, Tariq Masoodi, Saud Azam, Wael Haqawi, Khadija Alobaisi, Maha Alrasheed, Valorie Balde, Nabil Siraj, Mark R. Diaz, Laila Ghazwani, Felisa DeVera, Hassan AlDossari, Khawla S. Al-Kuraya. Prevalence of Lynch Syndrome among Middle Eastern endometrial cancer using targeted next generation sequencing [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3546.
Exposure to household air pollution over 10 years is related to asthma and lung function decline
Authors: Xin Dai, Dinh S. Bui, Jennifer L. Perret, Adrian J. Lowe, Peter A. Frith, Gayan Bowatte, Paul S. Thomas, Graham G. Giles, Garun S. Hamilton, Helen Tsimiklis, Jennie Hui, John Burgess, Aung K. Win, Michael J. Abramson, E. Haydn Walters, Shyamali C. Dharmage, Caroline J. Lodge
Journal: European Respiratory Journal (2020)

Introduction We investigated if long-term household air pollution (HAP) is associated with asthma and lung function decline in middle-aged adults, and whether these associations were modified by glutathione S -transferase (GST) gene variants, ventilation and atopy. Materials and methods Prospective data on HAP (heating, cooking, mould and smoking) and asthma were collected in the Tasmanian Longitudinal Health Study (TAHS) at mean ages 43 and 53 years (n=3314). Subsamples had data on lung function (n=897) and GST gene polymorphisms (n=928). Latent class analysis was used to characterise longitudinal patterns of exposure. Regression models assessed associations and interactions. Results We identified seven longitudinal HAP profiles. Of these, three were associated with persistent asthma, greater lung function decline and % reversibility by age 53 years compared with the “Least exposed” reference profile for those who used reverse-cycle air conditioning, electric cooking and no smoking. The “All gas” (OR 2.64, 95% CI 1.22–5.70), “Wood heating/smoking” (OR 2.71, 95% CI 1.21–6.05) and “Wood heating/gas cooking” (OR 2.60, 95% CI 1.11–6.11) profiles were associated with persistent asthma, as well as greater lung function decline and % reversibility. Participants with the GSTP1 Ile/Ile genotype were at a higher risk of asthma or greater lung function decline when exposed compared with other genotypes. Exhaust fan use and opening windows frequently may reduce the adverse effects of HAP produced by combustion heating and cooking on current asthma, presumably through increasing ventilation. Conclusions Exposures to wood heating, gas cooking and heating, and tobacco smoke over 10 years increased the risks of persistent asthma, lung function decline and % reversibility, with evidence of interaction by GST genes and ventilation.
Abstract IA20: Personalized whole-tumor antigen vaccines in ovarian cancer: Using tumors for therapy
Authors: Lana E. Kandalaft
Journal: Clinical Cancer Research (2020)

Abstract Disappointing results have been observed with the first-generation therapeutic cancer vaccines. However, the renaissance of immunotherapy with the checkpoint inhibitors and the demonstration, in preclinical models, that personalized vaccines can induce efficient antitumor T-cell responses have led to a renewed interest in cancer vaccination. Personalized whole-tumor lysate vaccines can encompass all putative antigens in a patient’s tumor and can potentially induce a broader, more efficient immune response. We report here a clinical study utilizing a personalized vaccine generated by autologous dendritic cells (DC) pulsed with autologous whole-tumor cell lysate (OCDC), in platinum-treated, immunotherapy-naïve, recurrent ovarian cancer patients in combination with bevacizumab or bevacizumab plus low-dose intravenous cyclophosphamide until disease progression or vaccine exhaustion. A total of 392 vaccine doses were administered without serious adverse events. Vaccine was shown to induce T-cell responses to autologous tumor antigen, which were associated with significantly prolonged survival (PFS). Vaccine was also shown to amplify T-cell responses against mutated neoepitopes derived from nonsynonymous somatic tumor mutations, and this included priming of T cells against previously unrecognized neoepitopes as well as novel T-cell clones of markedly higher avidity against previously recognized neoepitopes. Importantly, we demonstrate that the median PFS was 11.1 months in the population receiving the combination of vaccine plus bevacizumab and low-dose cyclophosphamide as compared to only 4.1 months in a historic population of patients from the same institution who received standard bevacizumab and low-dose cyclophosphamide without vaccine. We also demonstrate that survival at 2 years was 100% in the vaccine plus bevacizumab/cyclophosphamide group while it was only 40% in control patients receiving bevacizumab and cyclophosphamide alone. This proof-of-concept clinical study gives us a new horizon for the application of whole-tumor lysate personalized vaccines. Citation Format: Lana E. Kandalaft. Personalized whole-tumor antigen vaccines in ovarian cancer: Using tumors for therapy [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr IA20.
Loss of ZBTB24 impairs nonhomologous end-joining and class-switch recombination in patients with ICF syndrome
Authors: Angela Helfricht, Peter E. Thijssen, Magdalena B. Rother, Rashmi G. Shah, Likun Du, Sanami Takada, Mélanie Rogier, Jacques Moritz, Hanna IJspeert, Chantal Stoepker, Monique M. van Ostaijen-ten Dam, Vincent Heyer, Martijn S. Luijsterburg, Anton de Groot, Rianca Jak, Gwendolynn Grootaers, Jun Wang, Pooja Rao, Alfred C.O. Vertegaal, Maarten J.D. van Tol, Qiang Pan-Hammarström, Bernardo Reina-San-Martin, Girish M. Shah, Mirjam van der Burg, Silvère M. van der Maarel, Haico van Attikum
Journal: The Journal of Experimental Medicine (2020)

The autosomal recessive immunodeficiency, centromeric instability, and facial anomalies (ICF) syndrome is a genetically heterogeneous disorder. Despite the identification of the underlying gene defects, it is unclear how mutations in any of the four known ICF genes cause a primary immunodeficiency. Here we demonstrate that loss of ZBTB24 in B cells from mice and ICF2 patients affects nonhomologous end-joining (NHEJ) during immunoglobulin class-switch recombination and consequently impairs immunoglobulin production and isotype balance. Mechanistically, we found that ZBTB24 associates with poly(ADP-ribose) polymerase 1 (PARP1) and stimulates its auto-poly(ADP-ribosyl)ation. The zinc-finger in ZBTB24 binds PARP1-associated poly(ADP-ribose) chains and mediates the PARP1-dependent recruitment of ZBTB24 to DNA breaks. Moreover, through its association with poly(ADP-ribose) chains, ZBTB24 protects them from degradation by poly(ADP-ribose) glycohydrolase (PARG). This facilitates the poly(ADP-ribose)-dependent assembly of the LIG4/XRCC4 complex at DNA breaks, thereby promoting error-free NHEJ. Thus, we uncover ZBTB24 as a regulator of PARP1-dependent NHEJ and class-switch recombination, providing a molecular basis for the immunodeficiency in ICF2 syndrome.
Glucose as the Fifth Vital Sign: A Randomized Controlled Trial of Continuous Glucose Monitoring in a Non-ICU Hospital Setting
Authors: Addie L. Fortmann, Samantha R. Spierling Bagsic, Laura Talavera, Isabel Maria Garcia, Haley Sandoval, Amiry Hottinger, Athena Philis-Tsimikas
Journal: Diabetes Care (2020)

The current standard for hospital glucose management is point-of-care (POC) testing. We conducted a randomized controlled trial of real-time continuous glucose monitoring (RT-CGM) compared with POC in a non-intensive care unit (ICU) hospital setting.
Abstract 2784: Intratracheally delivered perflurocarbon nanoparticles to enhance radiotherapy against lung cancer
Authors: Lina Wu, Jin Xie
Journal: Cancer Research (2020)

Abstract Radiotherapy (RT) is a major treatment modality for lung cancer. Despite of technological advances, the five-year survival rate remains low. There is an urgent need of new and effective approaches that can selectively sensitize lung cancer cells to radiation. In this proof-of-concept study, we tested whether intratracheally(IT) delivered perfluorocarbon nanoparticles (PFC NPs) can enhance radiotherapy against lung cancer. We hypothesize that the approach can capitalize on the oxygen-loading capacity of PFC NPs and solve the unfavorable delivery problem associated with systemically injected PFC NPs. Therapy studies were performed in mice bearing subcutaneously inoculated H460 tumors and in orthotopicVX2 tumor models established on New Zealand white rabbits. PET/CT, 19F-MRI, and DCE-MRI were employed to assess PFC NPs delivery and treatment outcomes. 1H-MRS was performed on tumors from different treatment groups and the results were compared with in vivo imaging. For both tumor models, animals were divided into four groups (n=3 for rabbits and 5 for mice): (1) control; (2) PFC NPs only; (3) radiotherapy only; and (4) RT+PFC NPs group. Tumor tissues were subjected to pathology analysis and the results were compared with imaging data. Urine samples were collected and analyzed by UPLC-Q-TOF-MS/MS to assess metastasis. Our results showed that combining IT delivered PFC NPs and radiotherapy led to significantly enhanced tumor growth inhibition. Specifically, 19F-MRI confirmed that PFC NPs can deliver O2 to tumors and increase the mean pO2. DCE-MRI showed distinct tumor blood perfusion behaviors in the RT+PFC NPs group (P&amp;lt;0.05).We also compared the 18F-FDG accumulation in lesions in the early dynamic perfusion phase with the standard static metabolic phase by analyzing the peak value of the SUV mean, time to peak value, and the rate of the SUVmean increase. We found significant difference between the two phases in the RT+PFCNPs group. 1H-MRS found a decreased Cho/Cr ratio in animals treated by RT+PFC, suggesting that the combination treatment improved tumor suppression. Meanwhile, urine glutamine content is elevated in the RT+PFCNPs group, indicating a tendency to return to normal after treatment. Overall, our studies suggest the potential of IT delivered PFCNPs to enhance lung cancer radiotherapy. The delivery of the particles can be image-guided for efficient and site-specific radiosensitization. The approach holds great promise in clinical translation. Citation Format: Lina Wu, Jin Xie. Intratracheally delivered perflurocarbon nanoparticles to enhance radiotherapy against lung cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2784.
Abstract 5160: A GPCR candidate in pancreatic ductal adenocarcinoma: A potential repurposing opportunity
Authors: Cristina Salmerón, Krishna Sriram, Alyssa Baird, Paul A. Insel
Journal: Cancer Research (2020)

Abstract The 5-year survival of patients with pancreatic ductal adenocarcinoma (PDAC), the most common type of pancreatic cancer (90%), is very low (~9% all stages). PDAC thus requires new, effective and safe therapies. By comparing transcriptomic data for PDAC (in The Cancer Genome Atlas) with that of normal pancreas (in the GTEx database), we discovered that many G protein-coupled receptors (GPCRs) are increased in expression in PDAC. One such GPCR is the histamine receptor H1 (HRH1). GPCRs regulate metabolism, growth/death and functional activities of normal and cancer cells, including features of the malignant phenotype. GPCRs are the largest family of targets of approved drugs but have been largely ignored in cancer therapy. We found that HRH1 is prominently (~32-fold) overexpressed in PDAC tumors compared to normal pancreatic tissue and that high HRH1 expression is an unfavorable prognostic marker for PDAC patients. HRH1 mRNA is also highly expressed in multiple human PDAC cell lines. Studies with such cell lines revealed that histamine, acting via HRH1, increases intracellular Ca2+, cell proliferation and migration, effects blocked by multiple FDA-approved HRH1 antihistamines. PDAC tumors and cancer cells isolated from KPC mice also have high HRH1 expression compared to normal mouse pancreas. Similar to human PDAC cells, the KPC cells showed histamine/HRH1-promoted increase in intracellular Ca2+. Altogether, our findings identify HRH1 as a prominently overexpressed, functional GPCR in human and mouse PDAC tumors and cells. HRH1 may thus be a novel therapeutic target; its blockade by FDA-approved antihistamines represents a novel potential repurposing approach for the treatment of PDAC. Citation Format: Cristina Salmerón, Krishna Sriram, Alyssa Baird, Paul A. Insel. A GPCR candidate in pancreatic ductal adenocarcinoma: A potential repurposing opportunity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5160.