tbuckley/cabot-search huggingface dataset:
Abstract 4433: Novel and highly selective CDK9 inhibitors suppress proliferation of triple negative breast cancer (TNBC) cells <i>in vitro</i>
Authors: Jean M. Winter, Ebtihal H. Mustafa, Shudong Wang, Luke A. Selth, Theresa E. Hickey, Wayne D. Tilley
Journal: Cancer Research (2019)

Abstract This study evaluates the efficacy of two newly developed selective CDK9 inhibitors (CDK9i) across a panel of TNBC cell lines. MDA-MB-453, MFM-223, MDA-MB-468 and MDA-MB-231 TNBC cells were treated with increasing concentrations of two novel and highly selective CDK9 inhibitors and the effect on proliferation, apoptosis and expression of CDK9 targets determined. MDA-MB-453 and -468 cells showed significant growth inhibition with as little as 150nM of CDK9i, evident 3 days after commencement of treatment. Both MDA-MB-231 and MFM-223 cells were less sensitive to the CDK9 inhibitors, with MDA-231 cells requiring at least 300nM to suppress growth. MFM-223 cells did not demonstrate any growth inhibition after 7 days of culture with CDK9i concentrations up to 1.2uM. Protein expression of CDK9 targets, including RNA Polymerase II (RNAPII), phosphorylated-RNAPII, the proto-oncogene C-MYC, and apoptotic marker cleaved caspase-3, were examined by Western blot after optimal CDK9i exposure across each cell line. CDK9i suppressed phosphorylated-RNAPII, but not total RNAPII, indicative of targeted CDK9 inhibition. The master transcription factor C-MYC, which is highly expressed in TNBC, was downregulated, and cleaved-caspase-3 was upregulated with CDK9i treatment. These data demonstrate cell specific efficacy of novel CDK9 inhibitors in cell line models of TNBC via transcriptional suppression of proto-oncogenes and upregulation of apoptotic pathways. Future studies will identify molecular markers of response to CDK9 inhibition and evaluate these novel inhibitors in TNBC patient derived xenografts. Citation Format: Jean M. Winter, Ebtihal H. Mustafa, Shudong Wang, Luke A. Selth, Theresa E. Hickey, Wayne D. Tilley. Novel and highly selective CDK9 inhibitors suppress proliferation of triple negative breast cancer (TNBC) cells in vitro [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 4433.
Pembrolizumab with or without chemotherapy versus chemotherapy for first-line treatment of advanced gastric or gastroesophageal junction (G/GEJ) adenocarcinoma: The Phase 3 KEYNOTE-062 Study
Authors: J. Tabernero, E. Van Cutsem, Y. Bang, C. Fuchs, L. Wyrwicz, K. Lee, I. Kudaba, M. Garrido, H. Chung, H. Castro Salguero, W. Mansoor, M. Braghiroli, E. Goekkurt, J. Chao, Z. Wainberg, U. Kher, S. Shah, S. Kang, K. Shitara
Journal: Annals of Oncology (2019)
Abstract 3398: Interaction of STAT proteins with genistein: A computational analysis
Authors: Sneha Govardhanagiri, Shipra Reddy Bethi, Madhu Sudhana Saddala, Bassel F. El-Rayes, Ganji Purnachandra Nagaraju
Journal: Cancer Research (2019)

Abstract Background: Signal transducer and activator of transcription (STAT) proteins are a seven-member family of cytoplasmic proteins. A conserved SH2 domain facilitates STAT initiation by allowing binding to phosphotyrosine motifs for STAT-receptor interactions and STAT dimerization. STAT proteins (STAT1, STAT2 and STAT3) are promising targets for anti-cancer drugs, because irregular facilitation of STAT initiation may result in cancer, inflammation and auto-immunity. Methods: The crystal structure of the phosphotyrosine STAT1 and STAT3 dimers bound to DNA was obtained from a protein data bank (PDB), while STAT2 was modelled through Swiss-Model workspace by using 1YVL as a template. The stereochemical quality and integrity of STAT2 was tested by RAMPAGE server, ERRAT, ProSA, and Verify3D programs. The active sites were predicted using CASTp 3.0 with a new algorithm, which identifies and measures surface accessible pockets and interior inaccessible cavities on STAT1, STAT2, and STAT3. MD (molecular dynamics) simulation was conducted with STAT2 protein. Molecular Docking was used to predict the binding modes and approximate binding free energies of genistein to STAT1, STAT2 and STAT3 SH2 dimerization sites. Genistein was docked into the active site with AutoDock Vina in PyRx Virtual Screening tool. Results: Genistein showed best binding energies. The most successful binding energies were -5.6 (STAT1), -6.7 (STAT2), -6.3 (STAT3) kcal/mol respectively. The binding interactions of this compound with the active site of STAT proteins suggested that amino acid residues (Tyr631, Leu639, Tyr640, Glu643, His647, Met648, Gln649, Ile659, Met660 and LYS16) play a crucial role in anti-cancer activity. Conclusion: These observations increase the understanding of the functional role of STAT proteins in cancer and allow better development for additional druggable STAT inhibitors with high potency, specificity and outstanding bioavailability. Citation Format: Sneha Govardhanagiri, Shipra Reddy Bethi, Madhu Sudhana Saddala, Bassel F. El-Rayes, Ganji Purnachandra Nagaraju. Interaction of STAT proteins with genistein: A computational analysis [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 3398.
Abstract 2095: AsiDNATM, a targeted therapy with no acquired resistance
Authors: Wael Jdey, Maria Kozlac, Sergey Alekseev, Danielle Johnson, françoise Bono, Srividya bhaskara, frederic thomas, Marie Dutreix
Journal: Cancer Research (2019)

Abstract The Achilles heel of conventional and targeted anticancer treatments is intrinsic or acquired resistance following Darwinian selection, i.e. treatment toxicity place the surviving cells under intense evolutionary selective pressure to develop resistance. Here, we demonstrate that AsiDNA, the first antitumor drug with an agonist activity, can instead drive the evolution of malignant cells toward a different trajectory. Specifically, long term exposure of cancer cells to the strong alarm signal, generated by the AsiDNATM DNA repair inhibitors, did not promote resistance emergence. It induces a stable new state characterized by the down regulation of the targeted pathways that persists for months after treatments. This property is due to the original mechanism of action of AsiDNATM, which acts by over-activating a “false” signaling of DNA damage through DNA-PK and PARP enzymes, and is not observed with other DNA repair inhibitors such as the PARP inhibitors olaparib and talazoparib. Transcriptomic analysis of AsiDNATM treated independent populations derived from lung and breast cancers revealed the common evolution of independent AsiDNA-treated samples, resulting in a general down-regulation of enzymes involved in DNA repair and oncogenesis, and a specific down regulation of DNA-PK targets. Similar down regulation of DNA-PK targets was observed in xenografted tumor in animal models after three cycles of AsiDNA treatment. Chromatin analysis revealed a major change in AsiDNATM treated populations with an increased nucleosome stability that could be responsible for the epigenetic modification observed. Long term treatment with AsiDNATM induces a new “alarm down” state in the tumor cells that increase its efficacy. These results suggest that agonist drugs such as AsiDNATM could promote a state-dependent tumor cell evolution by lowering their ability to respond to damage signal as predicted by the ecological and evolutionary “smoke detector principle”. Citation Format: Wael Jdey, Maria Kozlac, Sergey Alekseev, Danielle Johnson, françoise Bono, Srividya bhaskara, frederic thomas, Marie Dutreix. AsiDNATM, a targeted therapy with no acquired resistance [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 2095.
Objective measurement of breast density, a marker of breast cancer risk, using fully automated radiation- and compression-free MRI.
Authors: Georg Wengert, Thomas Helbich, Stephan Polanec, Peter Christian Dubsky, Zsuzsanna Bago-Horvath, Rupert Bartsch, Wolf-Dieter Vogl, Michael Curda, Katja Pinker-Domenig
Journal: Journal of Clinical Oncology (2013)

11088 Background: Women may have contraindications to mammography (MG) or simply refuse the test due to subjective reservations usually concerning compression and/or radiation. Other than the detection of suspicious findings these women do not have standardized information concerning their breast density (BD), one of the strongest independent predictors of breast cancer (BC) risk. We developed a fully-automated quantitative magnetic resonance imaging (MRI) based BD measurement system, provided correlation to MG BD estimation and compared BD in BC patients and age-matched healthy controls. Methods: In this IRB-approved prospective study 35 healthy women and 19 BC patients age-matched to one of the healthy controls were included. BD for healthy women and BC patients was assessed using a) subjective qualitative radiologist´s review allocating 1 of 4 ACR BIRADS BD categories, b) Cumulus, a MG based semi-automatic method and c) a radiation- and compression-free MRI measurements system, which automatically calculates volume of breast (cm 3 ), % of fatty tissue and % of glandular tissue. Descriptive statistics were used to define the typical range of quantitative MRI BD readings corresponding to the qualitative four ACR BIRADS BD categories. Áppropriate statistical tests were used to compare mean values of method b) and c) and BD readings of cancers and controls. Results: % MRI BD correlated well with % MG BD (r = 0.83; P &lt; 0.0001). MRI BD measurements ranged from 1.7% to 61.9% (mean 29.05%). MG BD measurements ranged from 5.42% to 74.33% (mean 40.23%). Equivalent values were found with MRI BD readings of 0-7.2%, 7.3-26%, 26.1-39.6% and &gt;39.7% respectively for each of the four ACR BIRADS BD categories. Mean BD (%) was higher in BC patients than in healthy controls: 24% (SD 16.9%) vs. 18.4% (16.6). Conclusions: MRI BD measurement strongly correlates with MG based BD readings. The data suggest that objective, radiation- and compression-free MRI BD measurement is a convenient alternative to MG for assessment of BD. MRI BD measurement confirms higher breast density in BC patients compared to healthy women. The data is entirely consistent with the fact that BD is a strong independent risk factor for BC.
Impact of body mass index (BMI) on the prognosis of women with high-risk early breast cancer (BC) receiving adjuvant chemotherapy (CT).
Authors: Alessandra Gennari, Oriana Nanni, Emanuela Scarpi, Lorenzo Cecconetto, Samanta Sarti, Dino Amadori
Journal: Journal of Clinical Oncology (2013)

552 Background: Obesity has been shown to impact the prognosis of early BC; this effect was not consistently observed across the different biological subtypes, and is less clear when aggressive tumor phenotypes are considered. The aim of this study was to evaluate the influence of BMI (kg/m2) on the prognosis of women with high risk early BC enrolled into a phase III clinical trial of adjuvant CT. Methods: The relationship between BMI and Disease Free (DFS) or Overall Survival (OS) was assessed in 1066 early BC patients with rapidly proliferating tumors (Thymidine Labeling Index &gt; 3% or G3 or Ki67 &gt; 20%), randomized to receive adjuvant CT with or without anthracyclines (Epirubicin → CMF vs CMF → Epirubicin vs CMF). BMI was defined as follows: normal &lt; 25 kg/m2, overweight 25-30 kg/m2, obese &gt;30 kg/m2. DFS and OS were calculated by Kaplan-Meier estimation; multivariate Cox analysis was performed according to menopausal status, type of CT, hormonal, HER-2 and nodal status. Results: Information on BMI at baseline, was available on 959 women. Of these, 430/959 (44.8%) were normal, 331 (34.5%) were overweight and 198 (20.7%) were obese. Median age was 52 years (range 26 to 70); 48% was node positive, 62% was ER positive and 33% was HER-2 positive. At a median follow-up of 69 mos (range 1-119), 5-year DFS was 80% (95% CI 78-83) and 5-year OS was 94% (95% CI 90–94). 5-year DFS was 81% (95% CI 77-85), 82% (95% CI 77-86) and 76% (95% CI 70-83), in normal, overweight and obese women, respectively (p 0.6). 5-year OS was 92% (95% CI 89-95), 94% (95% CI 91-96) and 89% (95% CI 84-93), respectively (p 0.4). By multivariate analysis only ER, HER-2 and nodal status were significantly associated with differences in DFS and/or OS. Conclusions: BMI at baseline was not associated with the prognosis of early BC patients with rapidly proliferating tumors, receiving adjuvant CT. These results confirm those achieved in triple negative BC and suggest that neither dietary restriction or medical interventions aimed at reducing BMI and/or underlying insulin resistance nor specific anticancer strategies seem to be appropriate in this subgroup.
Peptide-guided nanoparticles for glioblastoma targeting
Authors: Pille Säälik, Prakash Lingasamy, Kadri Toome, Ignacio Mastandrea, Liat Rousso-Noori, Allan Tobi, Lorena Simón-Gracia, Hedi Hunt, Päärn Paiste, Venkata Ramana Kotamraju, Gabriele Bergers, Toomas Asser, Tõnu Rätsep, Erkki Ruoslahti, Rolf Bjerkvig, Dinorah Friedmann-Morvinski, Tambet Teesalu
Journal: Journal of Controlled Release (2019)
Pharmacokinetics, Safety, and Efficacy of Glecaprevir/Pibrentasvir in Adolescents With Chronic Hepatitis C Virus: Part 1 of the DORA Study
Authors: Maureen M. Jonas, Robert H. Squires, Susan M. Rhee, Chih‐Wei Lin, Kazuhiko Bessho, Cornelia Feiterna‐Sperling, Loreto Hierro, Deirdre Kelly, Simon C. Ling, Tatiana Strokova, Antonio del Valle‐Segarra, Sandra Lovell, Wei Liu, Teresa I. Ng, Ariel Porcalla, Yuri Sanchez Gonzalez, Margaret Burroughs, Etienne Sokal
Journal: Hepatology (2019)

The pangenotypic regimen of glecaprevir and pibrentasvir (G/P) is approved to treat adults with chronic hepatitis C virus (HCV) infection and has yielded high cure rates in adults in clinical trials. Approved treatment options for pediatrics may include ribavirin. A pangenotypic regimen for pediatric patients remains an unmet need. DORA is an ongoing phase 2/3, nonrandomized, open-label study evaluating the pharmacokinetics (PK), safety, and efficacy of G/P in pediatric patients with chronic HCV. This analysis includes Part 1 of the study, conducted in adolescent patients 12-17 years of age given the adult regimen of G/P (300 mg/120 mg) once daily for 8-16 weeks according to the indication durations used in adults. Patients were either treatment naïve or experienced with interferon-based regimens. The primary PK endpoint was steady-state exposures for glecaprevir and pibrentasvir; the primary efficacy endpoint was sustained virologic response 12 weeks after treatment (SVR12). The secondary efficacy endpoints were on-treatment virologic failure, relapse, and reinfection. Safety and tolerability were monitored. Part 1 enrolled 48 adolescent patients infected with genotypes 1, 2, 3, or 4, of whom 47 were administered G/P. All 47 patients (100%) achieved SVR12. No on-treatment virologic failures or relapses occurred. PK exposures of glecaprevir and pibrentasvir were comparable to exposures in adults. No adverse events (AEs) led to treatment discontinuation, and no serious AEs occurred. Conclusion: Adolescent patients with chronic HCV infection treated with G/P achieved a comparable exposure to adults, 100% SVR12 rate, and safety profile consistent with that in adults. This pangenotypic regimen demonstrated 100% efficacy within the adolescent population in as little as 8 weeks of treatment.
Abstract 4113: Quantitative cell-based bioassays to advance immunotherapy programs targeting immune checkpoint receptors
Authors: Jamison Grailer, Julia Gilden, Pete Stecha, Denise Garvin, Jun Wang, Michael Beck, Jim Hartnett, Gopal Krishnan, Frank Fan, Mei Cong, Zhi-jie Jey Cheng
Journal: Cancer Research (2019)

Abstract The human immune system is comprised of a complex network of immune checkpoint receptors that are promising new immunotherapy targets for the treatment of a variety of cancers and autoimmune disorders. The Nobel prize for Medicine in 2018 was awarded for seminal studies on the role of immune checkpoint targets in T cell activation and furthermore, combining different strategies to release the brakes on the immune system with the aim of eliminating tumor cells even more efficiently. Immunotherapies designed to block co-inhibitory receptors (e.g. PD-1, CTLA-4, TIGIT) are showing unprecedented efficacy in the treatment of cancer. However, not all patients and tumor types respond to this approach. This has resulted in broadening of immunotherapy research programs to target additional co-inhibitory (e.g. LAG-3, TIM-3) and co-stimulatory (e.g. 4-1BB, GITR, OX40, ICOS) receptors individually and in combination. A major challenge in the development of antibody-based biologics is access to quantitative and reproducible functional bioassays. Existing methods rely on primary cells and measurement of complex functional endpoints. These assays are cumbersome, highly variable and fail to yield data required for drug development in a quality-controlled environment. To address this need, we have developed a suite of cell-based functional bioassays to interrogate modulation of immune checkpoint receptors individually (e.g. PD-1, LAG-3, TIM-3, GITR, 4-1BB) and in combination (e.g. PD-1+CTLA-4, PD-1+LAG-3). These assays consist of stable cell lines that express luciferase reporters driven by response elements under the precise control of mechanistically relevant intracellular signals. Thus, the bioassays reflect mechanisms of action for the drug candidates designed for each immune checkpoint receptor and demonstrate high specificity, sensitivity and reproducibility. Here we describe the application of MoA-based immune checkpoint receptor bioassays as tools for biologics drug discovery, development, potency and stability studies. Citation Format: Jamison Grailer, Julia Gilden, Pete Stecha, Denise Garvin, Jun Wang, Michael Beck, Jim Hartnett, Gopal Krishnan, Frank Fan, Mei Cong, Zhi-jie Jey Cheng. Quantitative cell-based bioassays to advance immunotherapy programs targeting immune checkpoint receptors [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 4113.
Translation of nanomedicines from lab to industrial scale synthesis: The case of squalene-adenosine nanoparticles
Authors: Flavio Dormont, Marie Rouquette, Clement Mahatsekake, Frédéric Gobeaux, Arnaud Peramo, Romain Brusini, Serge Calet, Fabienne Testard, Sinda Lepetre-Mouelhi, Didier Desmaële, Mariana Varna, Patrick Couvreur
Journal: Journal of Controlled Release (2019)

A large variety of nanoparticle-based delivery systems have become increasingly important for diagnostic and/or therapeutic applications. Yet, the numerous physical and chemical parameters that influence both the biological and colloidal properties of nanoparticles remain poorly understood. This complicates the ability to reliably produce and deliver well-defined nanocarriers which often leads to inconsistencies, conflicts in the published literature and, ultimately, poor translation to the clinics. A critical issue lies in the challenge of scaling-up nanomaterial synthesis and formulation from the lab to industrial scale while maintaining control over their diverse properties. Studying these phenomena early on in the development of a therapeutic agent often requires partnerships between the public and private sectors which are hard to establish. In this study, through the particular case of squalene-adenosine nanoparticles, we reported on the challenges encountered in the process of scaling-up nanomedicines synthesis. Here, squalene (the carrier) was functionalized and conjugated to adenosine (the active drug moiety) at an industrial scale in order to obtain large quantities of biocompatible and biodegradable nanoparticles. After assessing nanoparticle batch-to-batch consistency, we demonstrated that the presence of squalene analogs resulting from industrial scale-up may influence several features such as size, surface charge, protein adsorption, cytotoxicity and crystal structure. These analogs were isolated, characterized by multiple stage mass spectrometry, and their influence on nanoparticle properties further evaluated. We showed that slight variations in the chemical profile of the nanocarrier's constitutive material can have a tremendous impact on the reproducibility of nanoparticle properties. In a context where several generics of approved nanoformulated drugs are set to enter the market in the coming years, characterizing and solving these issues is an important step in the pharmaceutical development of nanomedicines.
HPV vaccine: high coverage could eradicate cervical cancer within decades, say researchers
Authors: Ingrid Torjesen
Journal: BMJ (2019)

HPV vaccination programmes for adolescent girls have led to a dramatic reduction in the number of HPV infections, precancerous cervical lesions (CIN2+), and anogenital warts in countries that offer them, a meta-analysis published in the Lancet shows.1

Benefits of vaccination have also not been limited to girls, as rates of HPV infection have fallen in older women and men as a consequence of herd immunity. The benefits of herd immunity were greatest in countries with high rates of vaccination coverage and those such as the UK that ran catch-up campaigns for older girls when vaccination was first introduced, the study found.

Marc Brisson of Laval University in Quebec City, a study coauthor, told a press conference in London on 26 June that the World …
Social media: suicide promotion and anti-vaccine content must be banned, says BMA
Authors: Abi Rimmer
Journal: BMJ (2019)

The UK government must implement standards to prevent social media from sharing content that promotes self harm or suicide as a way of dealing with mental health problems, doctors have said.

Delegates at the BMA’s annual meeting in Belfast on 26 June voted for a motion saying that these standards should be binding on social media networks.

Doctors at the conference also voted in favour of a motion calling for government standards to compel social media companies to “actively prevent the dispersal of false or misleading information on the effects of …