tbuckley/cabot-search huggingface dataset:
Optimization of G-quadruplex binding and telomerase inhibition for telomere targeting agents
Authors: Cristina J. Alves Martins, Vaidehi Makwana, Mekala Gunaratnam, Michael Moore, Christoph Schultes, Anthony Reszka, John Stuart, Gary Parkinson, Lloyd Kelland, Stephen Neidle
Journal: Cancer Research (2005)

601  We have previously reported (Read et al, PNAS 2001, 98, 4844-4849) on the rational design of a new class of 3,6,9-trisubstituted acridine molecules that inhibit the ability of the telomerase enzyme from maintaining telomere length and viability in cancer cells, by stabilising the single-stranded telomeric overhang as G-quadruplex-ligand complexes. Furthermore, the identification of a 9-anilino derivative (BRACO-19) as a potent G-quadruplex binding agent and telomerase inhibitor has prompted us to undertake a systematic study of the various structural features in these molecules that maximise target affinity and biological activity, using a combined structural, medicinal chemistry and biophysical approach. Detailed molecular modelling studies have been used to provide the structural basis for these studies. We report now on a number of 9-anilino ring derivatives, where we have been able to differentiate which structural features enhance telomeric G-quadruplex selectivity from those exhibiting generalised nucleic acid binding and acute cytotoxicity. We shall also describe the effects of changes made at the 3- and 6- positions, which have enabled us to fine-tune the optimal length of side-chain and size of end groups in these structures. A detailed structure activity relationship will be presented and discussed based on a range of techniques including a fluorescence resonance energy transfer assay, the TRAP assay, and selectivity assays such as Taq polymerase and PCR stop assays. This overall strategy is facilitating the optimisation and selection of the first telomere targeting agent candidate for clinical development.
Abstract 1691: CD137 (4-1BB) costimulation of CD8 T cells is more potent when provided in cis than in trans with respect to CD3-TCR stimulation
Authors: Itziar Otano, Arantza Azpilikueta, Javier Glez-Vaz, Peter Ellmark, Sara Fritzell, Gabriela Fernandez-Hoyos, Michelle Hase Nelson, Maite Alvarez, María del Carmen Ochoa, Elixabet Bolaños, Doina Cuculescu, Patricia Jauregui, Sandra Sanchez, Iñaki Etxeberría, María E. Rodriguez-Ruiz, Miguel F. Sanmamed, Alvaro Teijeira, Pedro Berraondo, Igancio Melero
Journal: Cancer Research (2021)

Abstract CD137 (4-1BB, TNFSFR9) costimulation provides antigen-primed T cells with increased survival, proliferation and effector functions as well as metabolic advantages. These immunobiological mechanisms are being harnessed for cancer immunotherapy with agonist CD137-binding and crosslinking-inducing agents that elicit CD137 intracellular signaling. In this study, side-by-side comparisons show that provision of CD137 costimulation in-cis with regard to the TCR-CD3-ligating cells is far superior to that provided in-trans in terms of T-cell activation, proliferation, survival, cytokine secretion and mitochondrial fitness in mice and humans. Cis ligation of CD137 relative to the TCR-CD3 complex results in more intense canonical and non-canonical NF-κB signaling and provides a more robust induction of cell-cycle and DNA damage repair gene expression programs. Superiority of cis versus trans CD137-costimulation is readily observed in vivo and is relevant for understanding the immunotherapeutic effects of CAR T cells and CD137 agonistic therapies currently undergoing clinical trials, which provide costimulation either in cis or in trans. Citation Format: Itziar Otano, Arantza Azpilikueta, Javier Glez-Vaz, Peter Ellmark, Sara Fritzell, Gabriela Fernandez-Hoyos, Michelle Hase Nelson, Maite Alvarez, María del Carmen Ochoa, Elixabet Bolaños, Doina Cuculescu, Patricia Jauregui, Sandra Sanchez, Iñaki Etxeberría, María E. Rodriguez-Ruiz, Miguel F. Sanmamed, Alvaro Teijeira, Pedro Berraondo, Igancio Melero. CD137 (4-1BB) costimulation of CD8 T cells is more potent when provided in cis than in trans with respect to CD3-TCR stimulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1691.
Abstract LB192: Sulforaphane suppression of Prmt5 and Mep50 function suppresses the mesothelioma cancer stem cell phenotype
Authors: Geraldine C. Ezeka, Gautam Adhikary, Sivaveera Kandasamy, Joseph Friedberg, Richard Eckert
Journal: Cancer Research (2021)

Abstract Mesothelioma is an aggressive and fatal cancer of the mesothelial lining which is caused by asbestos exposure. The current treatment strategy is surgical resection followed by chemotherapy, but this is marginally successful and leads to drug resistant and recurrent disease. Mesothelioma cancer stem cells (MCS cells) comprise an important subpopulation of highly aggressive mesothelioma tumor cells that maintain tumor formation and mediate drug resistance. Our goal is to identify proteins that maintain the MCS cell and non-stem cancer cell survival as therapy targets. Protein arginine methyltransferase 5 (PRMT5) functions with the MEP50 cofactor to catalyze symmetric dimethylation of specific arginine resides in histones 3 and 4 to silence tumor suppressor gene expression and enhance cancer cell survival. Our studies show that loss of PRMT5 or MEP50 reduces H4R3me2s formation in MCS cells and that this is associated with a reduction in MCS cell spheroid formation, invasion and migration. Additionally, treatment with sulforaphane (SFN), a promising diet-derived cancer prevention and therapy agent, reduces PRMT5/MEP50 level and H4R3me2s formation, and suppresses the MCS cell phenotype. Moreover, forced expression of PRMT5/MEP50 antagonizes SFN suppression of the MCS cell phenotype, suggesting that loss of PRMT5/MEP50 is required for SFN action. SFN treatment also markedly reduces tumor formation and this is associated with reduced PRMT5/MEP50 expression and H4R3me2s formation. These findings suggest that SFN suppresses PRMT5/MEP50 function to attenuate the MCS cell phenotype and reduce tumor formation, and that SFN may be a useful mesothelioma prevention and therapy agent. Citation Format: Geraldine C. Ezeka, Gautam Adhikary, Sivaveera Kandasamy, Joseph Friedberg, Richard Eckert. Sulforaphane suppression of Prmt5 and Mep50 function suppresses the mesothelioma cancer stem cell phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB192.
Well controlled patients with diabetes mellitus has the potential to expand the kidney donor pool
Authors: K. Yoshinaga, M. Araki, K. Wada, T. Sekito, S. Watari, Y. Maruyama, T. Sadahira, S. Nishimura, T. Sako, K. Edamura, Y. Kobayashi, M. Watanabe, T. Watanabe, Y. Nasu
Journal: European Urology (2021)
Transthyretin variants as potential biomarkers for the detection of early stage ovarian cancer
Authors: Zhen Zhang, Lori J. Sokoll, Shanhua Lin, Xiao-Ying Meng, Scott R. Weinberger, Eric T. Fung, Daniel W. Chan
Journal: Cancer Research (2004)

5637  In a previously completed multi-center study, we obtained serum protein profiles of 503 samples from women with ovarian cancer or benign pelvic masses, and from healthy controls using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF/MS). Three biomarkers were discovered and independently validated to have discriminatory power in separating patients with early stage ovarian cancer from healthy controls. We have since identified the protein identities of these three biomarkers. One of them, corresponding to the peak at m/z 12.8kD, was purified and identified as a truncated form of transthyretin lacking the N-terminal ten amino acids. In a follow-up study, we observed using immunoassay that the serum level of full-length transthyretin was also down-regulated among patients with later stage ovarian cancer relative to that in healthy controls and patients with colorectal, breast, or prostate cancer. In this study, we further analyzed the roles of several individual variants of transthyretin in separating early stage ovarian cancer from healthy controls. Using SELDI mass spectrum data from 58 stage I/II invasive ovarian patients and 77 healthy controls, we identified two additional peaks, at m/z 6857D (doubly-charged) and 13.8kD, that are highly correlated with the originally identified peak at m/z 12.8kD (r = 0.83, 0.76, respectively) and between themselves (r = 0.83). Through immunoprecipitation and tandem mass spectrometry, these two peaks in turn were identified also to be variants of transthyretin. These two additional variants were both statistically significant in differentiating the early stage cancer cases and the healthy controls (p
Gastric per-oral endoscopic myotomy (G-POEM) for the treatment of gastric sleeve stenosis: a feasibility and safety study
Authors: Linda Y. Zhang, Marcia I. Canto, Michael A. Schweitzer, Mouen A. Khashab, Vivek Kumbhari
Journal: Endoscopy (2021)

Traditional endoscopic treatments have limited success in gastric sleeve stenosis (GSS). Gastric peroral endoscopic myotomy (G-POEM) could conceivably obliterate the twist/angulation that causes GSS through a tunneled stricturotomy. We report early outcomes of G-POEM for GSS treatment.We retrospectively reviewed all patients with GSS treated with G-POEM at our center. The primary end point was clinical success, defined as symptom improvement with resumption of adequate oral intake, without requiring further intervention.13 patients (mean age 43 ± 10.9 years; 12 female) underwent G-POEM for predominantly helical (11/13, 85 %) GSS. Three (23 %) had concurrent sleeve leak and 10 (77 %) had prior GSS treatment. Two intraoperative complications occurred, with no deviation to the procedure; no major complications occurred. At median follow-up of 175 (interquartile range [IQR] 119-260) days, clinical success was achieved in 10 patients (77 %). Median Gastroparesis Cardinal Symptom Index score in responders decreased from 2.06 (IQR 1.5-2.8) to 0.39 (IQR 0.2-0.5). Three patients (23 %) required surgical revision.G-POEM was feasible and safe, and may provide an alternative option for those averse to undergoing surgical revision for treatment of GSS.
Abstract 299: Self-assembling peptide hydrogel for delivery and conversion of temozolomide in glioblastoma treatment
Authors: Megan Pitz, Alexandra Nukovic, Margaret Elpers, Sarah Wilde, Angela Alexander-Bryant
Journal: Cancer Research (2021)

Abstract Traditional treatment methods for glioblastoma multiforme (GBM) including resection, radiation, and chemotherapy have been largely unsuccessful, with a current 5-year survival rate of 5.6%. In this project we examine the potential of nanosized self-assembling peptide hydrogels to locally deliver and convert temozolomide (TMZ), an FDA-approved pH-sensitive prodrug, for GBM treatment. The peptide hydrogel is designed to load TMZ into the hydrophobic regions of the hydrogels, and during hydrogel degradation in vivo, convert TMZ into its active form. Hydrogel characterization, drug loading and conversion, and cellular uptake and viability are examined to determine the in vitro efficacy of this delivery method. A combination of dynamic light scattering (DLS), scanning electron microscopy (SEM), and circular dichroism (CD) are used to characterize size and structure of the hydrogels. Loading and conversion of TMZ are quantified using UV-Vis spectroscopy. Fluorescent imaging and cell viability assays are used to determine uptake and anti-cancer effects of the drug-loaded hydrogels on glioblastoma cells. Our results show high uptake in drug-resistant T98G and non-resistant LN-18 glioblastoma cell lines using several of our tunable peptide formulations. CD has shown that all peptide formulations form mostly beta-sheet and random structures during self-assembly. SEM and DLS show that peptide hydrogels formed in a water solvent are more polydisperse than hydrogels in a PBS solvent. Using a pH-meter, we have shown that as the peptides in PBS degrade, there is an increase in local pH. Additionally, TMZ conversion is observed to occur more quickly in drug-loaded hydrogels than TMZ alone. Preliminary cell viability studies have shown that unassembled peptides are not cytotoxic; some of the assembled peptide hydrogels are cytotoxic while others maintain greater than 80% viability when compared to untreated cells. Future studies for the project will include cell viability assays with the most promising peptide formulations loaded with TMZ to determine efficacy of the delivery and conversion system. Finally, this project will culminate in an in vivo study to confirm the overall anti-cancer effect of the drug-loaded peptide hydrogels in a tumor model of GBM. Acknowledgements: This research was supported in part by the National Science Foundation EPSCoR Program under NSF Award # OIA-1655740, the National Institute of Health Award # P30GM131959, and National Science Foundation's Graduate Research Fellowship Program. Citation Format: Megan Pitz, Alexandra Nukovic, Margaret Elpers, Sarah Wilde, Angela Alexander-Bryant. Self-assembling peptide hydrogel for delivery and conversion of temozolomide in glioblastoma treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 299.
Repurposed floxacins targeting RSK4 prevent chemoresistance and metastasis in lung and bladder cancer
Authors: Stelios Chrysostomou, Rajat Roy, Filippo Prischi, Lucksamon Thamlikitkul, Kathryn L. Chapman, Uwais Mufti, Robert Peach, Laifeng Ding, David Hancock, Christopher Moore, Miriam Molina-Arcas, Francesco Mauri, David J. Pinato, Joel M. Abrahams, Silvia Ottaviani, Leandro Castellano, Georgios Giamas, Jennifer Pascoe, Devmini Moonamale, Sarah Pirrie, Claire Gaunt, Lucinda Billingham, Neil M. Steven, Michael Cullen, David Hrouda, Mathias Winkler, John Post, Philip Cohen, Seth J. Salpeter, Vered Bar, Adi Zundelevich, Shay Golan, Dan Leibovici, Romain Lara, David R. Klug, Sophia N. Yaliraki, Mauricio Barahona, Yulan Wang, Julian Downward, J. Mark Skehel, Maruf M.U. Ali, Michael J. Seckl, Olivier E. Pardo
Journal: Science Translational Medicine (2021)

RSK4 promotes invasiveness and drug resistance in lung and bladder cancer and inhibition of this kinase shows therapeutic potential.
A bird's eye view on the role of dendritic cells in SARS‐CoV‐2 infection: Perspectives for immune‐based vaccines
Authors: Domenico Galati, Serena Zanotta, Ludovica Capitelli, Marialuisa Bocchino
Journal: Allergy (2021)

Coronavirus disease-19 (COVID-19) is a complex disorder caused by the pandemic diffusion of a novel coronavirus named SARS-CoV-2. Clinical manifestations vary from silent infection to severe pneumonia, disseminated thrombosis, multi-organ failure, and death. COVID-19 pathogenesis is still not fully elucidated, while increasing evidence suggests that disease phenotypes are strongly related to the virus-induced immune system's dysregulation. Indeed, when the virus-host cross talk is out of control, the occurrence of an aberrant systemic inflammatory reaction, named "cytokine storm," leads to a detrimental impairment of the adaptive immune response. Dendritic cells (DCs) are the most potent antigen-presenting cells able to support innate immune and promote adaptive responses. Besides, DCs play a key role in the anti-viral defense. The aim of this review is to focus on DC involvement in SARS-CoV-2 infection to better understand pathogenesis and clinical behavior of COVID-19 and explore potential implications for immune-based therapy strategies.
Abstract 16373: Sarcoplasmic Reticulum Calcium ATPase Pump is a Major Regulator of Myocardial Glucose Transport and Whole Body Glucose Homeostasis in Healthy and Diabetic State
Authors: Amanda Waller, Anuradha Kalyanasundaram, Summer Hayes, Muthu Periasamy, Veronique A Lacombe
Journal: Circulation (2011)

Diabetes is characterized by sustained hyperglycemia resulting from decreased glucose uptake into insulin-sensitive tissues. Glucose uptake is tightly regulated by a family of glucose transporter p...
The effect of a neoadjuvant instillation of chemotherapy in the prevention of recurrences of non-muscle invasive bladder cancer. Preliminary results of the PRECAVE prospective, controlled, randomized clinical trial
Authors: D.M. Carrión Monsalve, J. Gomez Rivas, C.R. Trelles, C. Ballesteros Ruiz, M. Alvarez-Maestro, A. Aguilera Bazan, L. Martinez-Piñeiro
Journal: European Urology (2021)
Notice of Retraction. Walach H, et al. Experimental Assessment of Carbon Dioxide Content in Inhaled Air With or Without Face Masks in Healthy Children: A Randomized Clinical Trial. <i>JAMA Pediatr.</i> Published online June 30, 2021.
Authors: Dimitri Christakis, Phil B. Fontanarosa
Journal: JAMA Pediatrics (2021)

A Notice of Retraction about the article "Experimental Assessment of Carbon Dioxide Content in Inhaled Air With or Without Face Masks in Healthy Children: A Randomized Clinical Trial," by Walach H, et al, has been published.
Abstract 1935: Antitumor effect mechanism of statin in PCa cells focusing on autophagy
Authors: Yoshiyuki Miyazawa, Daisuke Oka, Hiroshi Nakayama, Yoshitaka Sekine, Seiji Arai, Kazuhiro Suzuki
Journal: Cancer Research (2021)

Abstract Antitumor effect mechanism of statin in prostate cancer cells focusing on autophagy Background:Statins have recently been studied for their proapoptotic and antimetastatic effects. However, the exact mechanisms of their anticancer actions remain unclear. We have studied the novel castration resistant prostate cancer (CRPC) treatment with statins. Using microarrays, we discovered up-regulation of ATG4B (Autophagy related 4 homolog B) in PC-3 cells after simvastatin treatment. In this study, we evaluated the effects of simvastatin focusing on androgen-independent prostate cancer cells. Methods:PC-3, LNCaP-LA, 22RV-1-LA (taht were derived from LNCaP and 22RV1 cells and cultured in 10% charcoal-stripped fetal bovine serum for 3 months), and DU145 human prostate cancer cell lines were used. Microarrays were performed using PC-3 untreated or administered with simvastatin (0 uM versus 5 uM). Proliferation, migration, and invasion were evaluated using MTS assay, Migration assay, and Invasion assay, respectively. The increases of autophagy were detected by western blot using microtubule associated protein 1 light chain 3 (LC-3) antibody and confirmed by a fluorescence microscope with staining autophagosomes by autophagy detection kit (abcam, Cambridge, UK). Results:Using microarrays, we discovered up-regulation of ATG4B in PC-3 cells after simvastatin treatment. Simvastatin inhibited the proliferation, migration, and invasion of PC-3, LNCaP-LA, 22RV1-LA and DU145 cells. The expression level of LC-3 was up-regulated by simvastatin in PC-3, LNCaP-LA, 22RV1-LA and DU145 cells. In PC-3 cells treated with statin, a significant increase in autophagosomes was confirmed by fluorescence microscopy. The expression of LC-3 and autophagosomes were increased in a concentration-dependent manner. Conclusions:It was found that statin administration enhances autophagy induction in a prostate cell line. We plan to study the combined effect with other drugs that induce autophagy. We would like to develop CRPC treatment by inducing autophagy cell death. Citation Format: Yoshiyuki Miyazawa, Daisuke Oka, Hiroshi Nakayama, Yoshitaka Sekine, Seiji Arai, Kazuhiro Suzuki. Antitumor effect mechanism of statin in PCa cells focusing on autophagy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1935.
A Text-Book of Legal Medicine and Toxicology.
Journal: JAMA (1904)

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Efficacy and effectiveness of COVID-19 vaccines against SARS-CoV-2 infection: interim results of a living systematic review, 1 January to 14 May 2021
Authors: Thomas Harder, Judith Koch, Sabine Vygen-Bonnet, Wiebe Külper-Schiek, Antonia Pilic, Sarah Reda, Stefan Scholz, Ole Wichmann
Journal: Eurosurveillance (2021)

Evidence on COVID-19 vaccine efficacy/effectiveness (VE) in preventing asymptomatic SARS-CoV-2 infections is needed to guide public health recommendations for vaccinated people. We report interim results of a living systematic review. We identified a total of 30 studies that investigated VE against symptomatic and/or asymptomatic infection. In fully vaccinated individuals, VE against symptomatic and asymptomatic infections was 80–90% in nearly all studies. Fully vaccinated persons are less likely to become infected and contribute to transmission.