tbuckley/cabot-search huggingface dataset:
Abstract 1181: Neratinib induces synthetic lethality with PARP inhibitors in triple negative breast cancer cells <i>in vitro</i> and <i>in vivo</i>
Authors: Chuan Xing, Zhuo Zhang, Deborah Della Manna, Irmina Diala, Lisa Eli, Alshad S. Lalani, Eddy Shih-Hsin Yang
Journal: Cancer Research (2021)

Abstract Background: We previously showed preclinical and clinical activity of combined inhibition of EGFR and PARP with lapatinib and veliparib in triple negative breast cancer (Nowsheen et al. PLoS One 2012;7(10):e46614; Reasor et al. J Clin Onc 2018; 36(15_suppl):1095), due to an induced homologous recombination repair defect with EGFR inhibition sensitizing cells to PARP inhibition. In this study, we tested the in vitro and in vivo activity of the irreversible pan-HER tyrosine kinase inhibitor, neratinib, with the PARP inhibitor olaparib or niraparib. Methods: Human triple negative breast cancer (TNBC) cells MDA-MB231 (BRCA wt), MDA-MB453 (BRCA wt), and MDA-MB436 (BRCA1 mutant) and Mouse TNBC 4T1 cells (BRCA wt) were used. Cell proliferation and colony formation assays were performed to assess the in vitro activity of various concentrations of neratinib and olaparib. Markers of DNA damage were measured via gamma-H2AX western blot analysis. In vivo effects of combination treatments on tumor metastasis were tested using intracardiac injection of tumor cells labelled with luciferase and mice were monitored for survival. Results: Combining neratinib with olaparib or niraparib significantly decreased proliferation compared to either agent alone in MDA-MB231, MDA-MB453, MDA-MB436 and 4T1 cells. Similar results were observed using colony formation assays. Cytotoxicity was associated with increased gamma-H2AX levels, indicating persistent DNA damage. Mice treated with 20mg/kg/day of neratinib and 100mg/kg/day of olaparib after MDA-MB231-Luc intracardiac injection exhibited reduced tumor metastases compared to either agent alone, resulting in better survival (p=0.0088). Conclusions: Combining neratinib with PARP inhibition induces synthetic lethality resulting in increased anti-tumor activity in TNBC in cell lines and in xenografts. Future clinical trials testing these combinations are warranted. Citation Format: Chuan Xing, Zhuo Zhang, Deborah Della Manna, Irmina Diala, Lisa Eli, Alshad S. Lalani, Eddy Shih-Hsin Yang. Neratinib induces synthetic lethality with PARP inhibitors in triple negative breast cancer cells in vitro and in vivo [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 1181.
Abstract 1310: Peptide delivery of siRNA in GBM
Authors: Jessica Boulos, Angela Alexander-Bryant
Journal: Cancer Research (2021)

Abstract Glioblastoma Multiforme (GBM), a grade VI glioma, is an aggressive malignant tumorwith a poor prognosis. With an incidence rate of 3.19 per 100,000, GBM has a median survivalrate of 12-15 months and a five-year survival rate of less than 5%. Typical treatments involvesurgical removal, chemotherapy, and radiation; however, these treatments still result in a lowsurvival rate and can lead to potential harm to healthy cells. Therefore, a new therapeutic isneeded for GBM treatment to improve patient outcomes. RNAi, a naturally found process,utilizes siRNA to target specific mRNA for degradation to inhibit protein translation and hasshown clinical potential for targeting and silencing oncogenes. However, barriers to siRNAdelivery, such as cellular uptake, non-specificity, and lack of endosomal escape hinder clinicaltranslation of RNAi therapeutics. Peptides are a promising carrier for siRNAs and havedemonstrated the potential to overcome barriers to delivery. The purpose of this study is todesign a novel tandem peptide for siRNA delivery, evaluate ability to mediate knockdown of atarget oncogene, and compare the efficacy of the tandem peptide to the individual peptidesalone. The tandem peptide is a novel combination of a fusogenic peptide and a targetingpeptide. STAT3, the target gene, is an oncogene that plays a role in cell proliferation,differentiation, apoptosis, and angiogenesis in GBM. Initial results have confirmed basal expression of EGFR and STAT3 in all three GBM cell lines, LN18, U118, and T98G.Characterization of the fusogenic, targeting, and tandem peptides indicated formation of monodispere nanoparticles with diameters less than 150 nm when complexed with siRNA. Furthermore, gel shift assays were conducted and confirmed that the tandem peptide protectedthe siRNA from degradation in 50% FBS. MTS assays conducted in all three cell lines for eachpeptide confirmed that there was no significant cytotoxicity due to the vehicles alone. Finally, flow cytometry confirmed uptake of the tandem peptide in T98G cell line. Therefore, it ishypothesized that the tandem peptide composed of both fusogenic targeting peptide willenhance cell-specific uptake of STAT3 siRNA into glioblastoma cells for mediating endosomalescape, resulting in more effective gene silencing and associated downstream effects comparedto the fusogenic and targeting peptides alone. Future studies include immunofluorescence for uptake and endosomal escape, knockdown studies (MTS, Western Blot, and qPCR assays), and assays to examine the downstream effect of silencing STAT3, such as migration and invasion assays. Citation Format: Jessica Boulos, Angela Alexander-Bryant. Peptide delivery of siRNA in GBM [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 1310.
Persistent consolidation: a MALT-easer
Authors: Garyfallia Perlepe, Ourania S Kotsiou, Eleni Karetsi, Dimitris Papadopoulos, Maria Ioannou, Konstantinos I Gourgoulianis
Journal: Thorax (2021)

A 78-year-old man with a 40 pack-year history of smoking presented to the emergency department with 3 days of hemoptysis in a volume less than 20 mL/day, cough, low-grade fever, and 1-month history of dyspnoea on exertion. Previously, cefuroxime axetil had been administered with no response. He denied chest pain, wheezing, decreased appetite or weight loss. He experienced fatigue over the last 4 years. No occupational or environmental exposures were noted. His medical history included coronary disease and hypertension. He was found to have IgM lambda monoclonal gammopathy on serum protein electrophoresis with a serum M-protein concentration of 2.300 g/dL (normal 0.64–1.30 g/dL) 3 years ago, received no firm diagnosis. No myeloid or lymphoid neoplasia was detected in the bone marrow biopsy. He had undergone six chest CT examinations over the prior 4 years, demonstrating an irregularly shaped mass-like consolidation in the left lower lobe (figure 1A,B). He underwent a bronchoscopy 4 years earlier with negative bronchial cytology and cultures of bronchial washings for bacteria, fungi, and mycobacteria species. The last chest CT was 6 months ago revealed worsening of left lower lobe consolidation with distended bronchi (figure 1C,D). Unfortunately, he stated that he did not want any further investigation.



Figure 1 
Serial chest CT imaging, haematological, bronchoscopic and histological findings of the patient. (A, B) Chest CT performed 4 years ago revealed an irregularly shaped mass-like consolidation in the left lower lobe. (C, D) Chest CT performed 6 months ago showed an enlarged left lower lobe consolidation with airways within the lesion. (E, F) The chest CT performed at admission showed a worsening of left lower lobe consolidation associated with bilateral ground-glass opacities and a left pleural effusion. (G) Serum protein electrophoresis showed elevated levels of gamma globulin. (H) Serum immunofixation electrophoresis showed a dense abnormal zone of restriction in the IgM lane and the lambda light chain lane. (I, J) The …
Abstract 2964: Immuno-reactive cancer organoid models to examine microbiome metabolite effects on immune checkpoint blockade efficacy
Authors: Ethan Shelkey, David Soto-Pantoja, Yong Lu, Shay Soker
Journal: Cancer Research (2021)

Abstract Introduction: As the number of available immunotherapies for solid tumors increase, their prevalence in the clinic continues to rise as well. While the results are promising, and immunotherapies have benefits over traditional chemotherapeutics, a sizable percentage of patients are non-responders to all types of immunotherapy. These differences in sensitivity can be either innate or acquired. Yet, there has been limited 3D in vitro models to assess tumor immune-reactivity. These systems are ideal for isolating specific molecular mechanisms that dictate cell behavior and interactions. Our goal was to create an organoid model containing cancer cells paired with cytotoxic T-cells to model immune checkpoint blockade (ICB) efficacy. This model could then be used to examine novel microbiome-ICB interactions shown by recent research to alter therapeutic response levels in patients. Methods: We created tumor organoids consisting of tumor and immune cells, embedded in extracellular matrix (ECM)-like hydrogels. Organoids were treated with therapeutic equivalent doses of anti-PD-1 and anti-CTLA-4 or single dose of anti-CD-47 and cell viability assays, flow cytometry, RT-qPCR, and immunohistochemistry staining were performed to determine the effects of ICB. Physiologic concentrations of metabolites derived from likely effector bacterial species were then evaluated for their effects on genetic expression and immunotherapy efficacy. Results and Discussion: We showed that ICB therapy stimulated internally localizing T-cells, inducing T-cell-mediated tumor cell killing. ICB treated samples resulted significant loss of viability with corroborating readings from the other methods of characterization. RT-qPCR resulted in some elucidation of potential cellular changes due to bacterial metabolites with further quantification ongoing. Conclusion: We have created an ex-vivo tumor immune-reactive organoid model for studying immunotherapy. We can now continue to change individual microenvironment factors, such as microbiome metabolites, and observe their impacts on immunotherapy efficacy to better understand what conditions are conducive or detrimental to successful ICB treatment. Citation Format: Ethan Shelkey, David Soto-Pantoja, Yong Lu, Shay Soker. Immuno-reactive cancer organoid models to examine microbiome metabolite effects on immune checkpoint blockade efficacy [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 2964.
Quantitative Photothermal Characterization with Bioprinted 3D Complex Tissue Constructs for Early‐Stage Breast Cancer Therapy Using Gold Nanorods
Authors: Ki‐Hwan Nam, Chan Bae Jeong, HyeMi Kim, Minjun Ahn, Sung‐Jun Ahn, Hwan Hur, Dong Uk Kim, Jinah Jang, Hui‐Jeong Gwon, Youn‐Mook Lim, Dong‐Woo Cho, Kye‐Sung Lee, Ji Yong Bae, Ki Soo Chang
Journal: Advanced Healthcare Materials (2021)

Plasmonic photothermal therapy (PPTT) using gold nanoparticles (AuNPs) has shown great potential for use in selective tumor treatment, because the AuNPs can generate destructive heat preferentially upon irradiation. However, PPTT using AuNPs has not been added to practice, owing to insufficient heating methods and tissue temperature measurement techniques, leading to unreliable and inaccurate treatments. Because the photothermal properties of AuNPs vary with laser power, particle optical density, and tissue depth, the accurate prediction of heat generation is indispensable for clinical treatment. In this report, bioprinted 3D complex tissue constructs comprising processed gel obtained from porcine skin and human decellularized adipose tissue are presented for characterization of the photothermal properties of gold nanorods (AuNRs) having an aspect ratio of 3.7 irradiated by a near-infrared laser. Moreover, an analytical function is suggested for achieving PPTT that can cause thermal damage selectively on early-stage human breast cancer by regulating the heat generation of the AuNRs in the tissue.
Drugs associated the most with retroperitoneal fibrosis: Assessment of the 2015-2020 Food and Drug Administration (FDA) pharmacovigilance database
Authors: N. Schifano, P. Capogrosso, L. Boeri, E.P. Pozzi, F. Belladelli, S. Chiappini, O.O. Cakir, M. Rewhorn, F. Castiglione, H.M. Alnajjar, A. Muneer, F. Deho’, F. Schifano, F. Montorsi, A. Salonia
Journal: European Urology (2021)
Effectiveness of mRNA-BNT162b2, mRNA-1273, and ChAdOx1 nCoV-19 vaccines against COVID-19 in healthcare workers: an observational study using surveillance data
Authors: Christophe Paris, Sophie Perrin, Stephanie Hamonic, Baptiste Bourget, Clémence Roué, Olivier Brassard, Emilie Tadié, Vincent Gicquel, François Bénézit, Vincent Thibault, Ronan Garlantézec, Pierre Tattevin
Journal: Clinical Microbiology and Infection (2021)
GJB5 association with BRAF mutation and survival in cutaneous malignant melanoma
Authors: M. Scatolini, A. Patel, E. Grosso, M. Mello-Grand, P. Ostano, R. Coppo, M. Vitiello, T. Venesio, A. Zaccagna, A. Pisacane, I. Sarotto, D. Taverna, L. Poliseno, D. Bergamaschi, G. Chiorino
Journal: British Journal of Dermatology (2021)

Summary Background Gap-junctional intercellular communication is crucial for epidermal cellular homeostasis. Inability to establish melanocyte–keratinocyte contact and loss of the intercellular junction’s integrity may contribute to melanoma development. Connexins, laminins and desmocollins have been implicated in the control of melanoma growth, where their reduced expression has been reported in metastatic lesions. Objectives The aim of this study was to investigate connexin 31·1 (GJB5) expression and identify any association with BRAF mutational status, prognosis of patients with melanoma and mitogen-activated protein kinase (MAPK) inhibitor (MAPKi) treatment. Methods GJB5 expression was measured at RNA and protein level in melanoma clinical samples and established cell lines treated (or not) with BRAF and MEK inhibitors (MEKi), as well as in cell lines which developed MAPKi resistance. Findings were further validated and confirmed by analysis of independent datasets. Results Our analysis reveals significant downregulation of GJB5 expression in metastatic melanoma lesions compared with primary ones and in BRAF-mutated vs. BRAF-wildtype (BRAFWT) melanomas. Likewise, GJB5 expression is significantly lower in BRAFV600E compared with BRAFWT cell lines and increases on MAPKi treatment. MAPKi-resistant melanoma cells display a similar expression pattern compared with BRAFWT cells, with increased GJB5 expression associated with morphological changes. Enhancement of BRAFV600E expression in BRAFWT melanoma cells significantly upregulates miR-335-5p expression with consequent downregulation of GJB5, one of its targets. Furthermore, overexpression of miR-335-5p in two BRAFWT cell lines confirms specific GJB5 protein downregulation. Reverse transcriptase quantitative polymerase chain reaction analysis also revealed upregulation of miR-335 in BRAFV600E melanoma cells, which is significantly downregulated in cells resistant to MEKi. Our data were further validated using the TCGA_SKCM dataset, where BRAF mutations associate with increased miR-335 expression and inversely correlate with GJB5 expression. In clinical samples, GJB5 underexpression is also associated with patient overall worse survival, especially at early stages. Conclusions
Validation and survival of biopsy Gleason Grade Group V patients treated with radical prostatectomy or external beam radiation therapy: 4+5 vs. 5+4 vs. 5+5
Authors: M. Wenzel, C. Würnschimmel, C. Collà Ruvulo, L. Nocera, S.F. Shariat, F. Saad, A. Briganti, D. Tilki, M. Graefen, P. Mandel, F. Roos, F.K.H. Chun, P.I. Karakiewicz
Journal: European Urology (2021)
Abstract 1232: Using mesoporous silica nanoparticles (MSNs) for delivering the mesoionic compound MIH 2.4Bl in treating breast cancer
Authors: Dipti Debnath, Sami Nazzal, Suchismita Acharya, Helivaldo Diógenes da Silva Souza, Petrônio Filgueiras de Athayde Filho, Rafal Fudala, J Michael Mathis
Journal: Cancer Research (2021)

Abstract Breast cancer is the most frequently diagnosed cancer and the leading cause of cancer death in women worldwide, accounting for approximately 24% of all new cancer cases and is the leading cause of cancer death in over 100 countries. Thus, breast cancer is one of the most critical public health problems in the world facing women. There is a growing interest in studying the biological activity of mesoionic compounds, which possesses a 5-membered heterocyclic aromatic ring associated with a sextet of electrons. Mesoionic compounds have shown promising potential as anti-cancer agents due to their unique structure and reaction properties. We reported the synthesis of a new 1,3-thiazolium-5-thiolate derivative of a mesoionic compound (MIH 2.4Bl) and the characterization of its selective cytotoxicity on a panel of breast cancer cells lines. The results of our studies suggest a possible induction of apoptotic death through mitochondrial dysfunction by the treatment with MIH 2.4Bl. Based on our previous findings, MIH 2.4Bl is a promising candidate for treating breast cancer. However, a major challenge facing cancer therapy is the selective destruction of malignant cells while sparing normal cells to preserve tissue integrity. The development and use of drug delivery systems is a recognized approach to improve the efficacy of chemotherapy agents. Nonetheless, drug delivery systems have been unexplored in the context of mesoionic compounds. Drug delivery based on nanotechnology has flourished as a platform applicable to cancer therapy. Among various types of nanoparticles, mesoporous silica nanoparticles (MSNs) are more attractive nanomaterials for a broad range of functionality including gene/drug delivery, cancer therapy and bioimaging due to their broad surface area, less toxicity, low density, excellent biocompatibility, higher drug loading capacity, and impressive mechanical and thermal stability. In this preliminary work, we present an improved delivery strategy of a newly developed formulation of MIH 2.4BI compound with MSNs as the delivery agent. Also, physico-chemical characterization of the nanoparticles and cytotoxicity analyses using a panel of breast cancer cell lines were performed. These studies support the potential therapeutic use of MIH 2.4Bl in treating breast cancer. Citation Format: Dipti Debnath, Sami Nazzal, Suchismita Acharya, Helivaldo Diógenes da Silva Souza, Petrônio Filgueiras de Athayde Filho, Rafal Fudala, J Michael Mathis. Using mesoporous silica nanoparticles (MSNs) for delivering the mesoionic compound MIH 2.4Bl in treating breast cancer [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 1232.
ベアメタルステント,第一世代薬物溶出ステントおよび第二世代薬物溶出ステントの長期の血管内視鏡結果の比較-ステント後の冠動脈内内視鏡の多施設研究(MICASA)-
Authors: Dai Kazuoki, Matsuoka Hiroshi, Kawakami Hideo, Sato Tetsuya, Watanabe Kouki, Nakama Yasuharu, Ishihara Masaharu
Journal: Circulation (2016)
ウサギアキレス腱モデルにおけるPDGF-BB陽性の腱断裂治癒を提供する弾性および外科医に優しい電気紡糸チューブ【JST・京大機械翻訳】
Authors: Evrova Olivera, Buergisser Gabriella Meier, Ebnother Christian, Adathala Ashal, Calcagni Maurizio, Bachmann Elias, G Snedeker Jess, Scalera Chiara, Giovanoli Pietro, Vogel Viola, Buschmann Johanna
Journal: Biomaterials (2020)
Abstract 1519: PD1 TurboCAR™ T cells: PD1-resistant CAR T cells with programmable cytokine signaling outputs
Authors: Regina Lin, Yi Zhang, Surabhi Srinivasan, Cecilia Lay, Shanshan Lang, Janette Sutton, Candice Manion, Tom Van Blarcom, Barbra Sasu, Siler Panowski
Journal: Cancer Research (2021)

Abstract CAR T cell therapy has attained unprecedented success in the treatment of hematological malignancies. However, clinical benefit in solid tumor indications has been limited, potentially in part due to suppressive solid tumor microenvironments (TME) that inhibit T cell effector function and persistence. While the provision of cytokine support can help CAR T cells overcome suppressive TME, combining CAR T therapy with systemically-administered cytokines/cytokine mimetics can result in toxicities and locally secreted cytokines may enhance rejection of allogeneic cell products by host cells. For this reason we had previously designed and tested a novel cytokine-stimulated CAR T cell designated TurboCARs. TurboCAR T cells coexpress a CAR and a Turbo domain (i.e. a homodimeric cytokine receptor chimera) that transmits CAR T cell-intrinsic cytokine signals, resulting in enhanced potency, expansion and persistence in preclinical studies. However, TurboCAR T cells may remain sensitive to inhibition by immune barriers, such as negative signaling through the PD1 receptor. We reasoned that a two-pronged approach aimed at inhibiting immune-suppressive PD1 signaling while simultaneously transmitting immune-potentiating cytokine signaling may augment CAR T cell activity in solid tumors. To this end, we engineered PD1 TurboCAR T cells, in which the Turbo domain is fused to a PD1 ectodomain that serves as a dominant-negative receptor. The PD1 ectodomain was further modified for high-affinity binding to PD1 ligands, allowing for preferential ligand sequestration and more effective inhibition of endogenous PD1 signaling. Despite having a larger lentiviral vector cargo, PD1 TurboCAR T cell products remained manufacturable and retained a favorable memory phenotype. PD1 TurboCAR T cells directed towards PDL1-expressing solid tumor target cells showed increased functionality compared to CAR T cells combined with PD1 blockade or to the parental TurboCAR T cells alone. In conclusion, PD1 TurboCARs augmented with a PD1 dominant negative ectodomain conferred CAR T cells with resistance to PD1-mediated inhibition, while simultaneously transmitting cytokine signals in a CAR T cell-intrinsic fashion. As an all-in-one product, PD1 TurboCAR T cells may obviate the need for combination therapy with anti-PD1 antibodies, while circumventing safety risks associated with systemic cytokine administration. Citation Format: Regina Lin, Yi Zhang, Surabhi Srinivasan, Cecilia Lay, Shanshan Lang, Janette Sutton, Candice Manion, Tom Van Blarcom, Barbra Sasu, Siler Panowski. PD1 TurboCAR™ T cells: PD1-resistant CAR T cells with programmable cytokine signaling outputs [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 1519.
Intravenous Busulfan-Based Conditioning Regimens in Allogeneic Hematopoietic Cell Transplantation for Patients with Acute Lymphoblastic Leukemia
Authors: Sun-Hye Ko, Jung-Hee Lee, Han-Seung Park, Je-Hwan Lee, Eun-ji Choi, Miee Seol, Young-Shin Lee, Young-Ah Kang, Mijin Jeon, Kyoo Hyung Lee
Journal: Blood (2017)
%p2PSA and phi predict the pathological reclassification of first-year protocol biopsy during Active surveillance for early prostate cancer patients: From the PRIAS-JAPAN study
Authors: K. Takuma, H. Hirama, M. Koji, M. Satoru, S. Hiroshi, S. Toshihiro, M. Ryuji, S. Shinichi, S. Yasuyuki, F. Hiroshi, N. Yukio, T. Hiromasa, H. Isao, O. Osamu, H. Katsuyoshi, F. Fumimasa, Y. Akira, T. Yoichiro, K. Yoshiyuki, S. Mikio
Journal: European Urology (2021)
冠動脈疾患患者における血漿中Pentraxin3(PTX3)濃度の検討
Authors: 佐々木敏樹, 竹石恭知, 鈴木聡, 小山容, 新関武史, 北原辰郎, 野崎直樹, 広野摂, 渡邉哲, 二藤部丈司, 宮本卓也, 宮下武彦, 久保田功
Journal: Circulation (2007)