tbuckley/cabot-search huggingface dataset:
IFN-γ treatment protocol for MHC-I<sup>lo</sup>/PD-L1<sup>+</sup> pancreatic tumor cells selectively restores their TAP-mediated presentation competence and CD8 T-cell priming potential
Authors: Katja Stifter, Jana Krieger, Leonie Ruths, Johann Gout, Medhanie Mulaw, Andre Lechel, Alexander Kleger, Thomas Seufferlein, Martin Wagner, Reinhold Schirmbeck
Journal: Journal for ImmunoTherapy of Cancer (2020)

Background Many cancer cells express a major histocompatibility complex class I low/ programmed cell death 1 ligand 1 positive (MHC-I lo /PD-L1 + ) cell surface profile. For immunotherapy, there is, thus, an urgent need to restore presentation competence of cancer cells with defects in MHC-I processing/presentation combined with immune interventions that tackle the tumor-initiated PD-L1/PD-1 signaling axis. Using pancreatic ductal adenocarcinoma cells (PDACCs) as a model, we here explored if (and how) expression/processing of tumor antigens via transporters associated with antigen processing (TAP) affects priming of CD8 T cells in PD-1/PD-L1-competent/-deficient mice. Methods We generated tumor antigen-expressing vectors, immunized TAP-competent/-deficient mice and determined de novo primed CD8 T-cell frequencies by flow cytometry. Similarly, we explored the antigenicity and PD-L1/PD-1 sensitivity of PDACCs versus interferon-γ (IFN-γ)-treated PDACCs in PD-1/PD-L1-competent/deficient mice. The IFN-γ-induced effects on gene and cell surface expression profiles were determined by microarrays and flow cytometry. Results We identified two antigens (cripto-1 and an endogenous leukemia virus-derived gp70) that were expressed in the Endoplasmic Reticulum (ER) of PDACCs and induced CD8 T-cell responses either independent (Cripto-1:K b /Cr 16-24 ) or dependent (gp70:K b /p15E) on TAP by DNA immunization. IFN-γ-treatment of PDACCs in vitro upregulated MHC-I- and TAP- but also PD-L1-expression. Mechanistically, PD-L1/PD-1 signaling was superior to the reconstitution of MHC-I presentation competence, as subcutaneously transplanted IFN-γ-treated PDACCs developed tumors in C57BL/6J and PD-L1 -/- but not in PD-1 -/- mice. Using PDACCs, irradiated at day 3 post-IFN-γ-treatment or PD-L1 knockout PDACCs as vaccines, we could selectively bypass upregulation of PD-L1, preferentially induce TAP-dependent gp70:K b /p15E-specific CD8 T cells associated with a weakened PD-1 + exhaustion phenotype and reject consecutively injected tumor transplants in C57BL/6J mice. Conclusions The IFN-γ-treatment protocol is attractive for cell-based immunotherapies, because it restores TAP-dependent antigen processing in cancer cells, facilitates priming of TAP-dependent effector CD8 T-cell responses without additional check point inhibitors and could be combined with genetic vaccines that complement priming of TAP-independent CD8 T cells.
Hydroxychloroquine and Chloroquine Prescribing Patterns by Provider Specialty Following Initial Reports of Potential Benefit for COVID-19 Treatment — United States, January–June 2020
Authors: Lara Bull-Otterson, Elizabeth B. Gray, Daniel S. Budnitz, Heather M. Strosnider, Lyna Z. Schieber, Joseph Courtney, Macarena C. García, John T. Brooks, William R. Mac Kenzie, Adi V. Gundlapalli
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

Hydroxychloroquine and chloroquine, primarily used to treat autoimmune diseases and to prevent and treat malaria, received national attention in early March 2020, as potential treatment and prophylaxis for coronavirus disease 2019 (COVID-19) (1). On March 20, the Food and Drug Administration (FDA) issued an emergency use authorization (EUA) for chloroquine phosphate and hydroxychloroquine sulfate in the Strategic National Stockpile to be used by licensed health care providers to treat patients hospitalized with COVID-19 when the providers determine the potential benefit outweighs the potential risk to the patient.* Following reports of cardiac and other adverse events in patients receiving hydroxychloroquine for COVID-19 (2), on April 24, 2020, FDA issued a caution against its use† and on June 15, rescinded its EUA for hydroxychloroquine from the Strategic National Stockpile.§ Following the FDA's issuance of caution and EUA rescindment, on May 12 and June 16, the federal COVID-19 Treatment Guidelines Panel issued recommendations against the use of hydroxychloroquine or chloroquine to treat COVID-19; the panel also noted that at that time no medication could be recommended for COVID-19 pre- or postexposure prophylaxis outside the setting of a clinical trial (3). However, public discussion concerning the effectiveness of these drugs on outcomes of COVID-19 (4,5), and clinical trials of hydroxychloroquine for prophylaxis of COVID-19 continue.¶ In response to recent reports of notable increases in prescriptions for hydroxychloroquine or chloroquine (6), CDC analyzed outpatient retail pharmacy transaction data to identify potential differences in prescriptions dispensed by provider type during January-June 2020 compared with the same period in 2019. Before 2020, primary care providers and specialists who routinely prescribed hydroxychloroquine, such as rheumatologists and dermatologists, accounted for approximately 97% of new prescriptions. New prescriptions by specialists who did not typically prescribe these medications (defined as specialties accounting for ≤2% of new prescriptions before 2020) increased from 1,143 prescriptions in February 2020 to 75,569 in March 2020, an 80-fold increase from March 2019. Although dispensing trends are returning to prepandemic levels, continued adherence to current clinical guidelines for the indicated use of these medications will ensure their availability and benefit to patients for whom their use is indicated (3,4), because current data on treatment and pre- or postexposure prophylaxis for COVID-19 indicate that the potential benefits of these drugs do not appear to outweigh their risks.
Self‐Folding 3D Silk Biomaterial Rolls to Facilitate Axon and Bone Regeneration
Authors: Yimin Huang, Vincent Fitzpatrick, Nan Zheng, Ran Cheng, Heyu Huang, Chiara Ghezzi, David L. Kaplan, Chen Yang
Journal: Advanced Healthcare Materials (2020)

Abstract Biomaterial scaffold designs are needed for self‐organizing features related to tissue formation while also simplifying the fabrication processes involved. Toward this goal, silk protein‐based self‐folding scaffolds to support 3D cell culture, while providing directional guidance and promotion of cell growth and differentiation, are reported. A simple and robust one‐step self‐folding approach is developed using bilayers consisting of a hydrogel and silk film in aqueous solution. The 3D silk rolls, with patterns transferred from the initially prepared 2D films, guide the directional outgrowth of neurites and also promote the osteogenic differentiation of human mesenchymal stem cells (hMSCs). The osteogenic outcomes are further supported by enhanced biomechanical performance. By utilizing this self‐folding method, cocultures of neurons and hMSCs are achieved by patterning cells on silk films and then converting these materials into a 3D format with rolling, mimicking aspects of the structure of osteons and providing physiologically relevant structures to promote bone regeneration. These results demonstrate the utility of self‐folded silk rolls as efficient scaffold systems for tissue regeneration, while exploiting relatively simple 2D designs programmed to form more complex 3D structures.
Abstract 3401: Targeting lysosomal homeostasis in ovarian cancer through drug repurposing
Authors: Stefano Marastoni, Aleksandra Pesic, Sree Narayanan Nair, Zhu Juan Li, Ali Madani, Benjamin Haibe-Kains, Bradly G. Wouters, Anthony Joshua
Journal: Cancer Research (2020)

Abstract Background: Drug repurposing has become increasingly attractive as it avoids the long processes and costs associated with drug discovery. Itraconazole (Itra) is a broad-spectrum anti-fungal agent which has an established broad spectrum of activity in human cell lines including cholesterol antagonism and inhibition of Hedgehog and mTOR pathways. Many in vitro, in vivo and clinical studies have suggested anti-proliferative activity both alone and in combination with other chemotherapeutic agents, in particular in ovarian cancer. This study is aimed at supporting the therapeutic potential of Itra and discovering and repurposing new drugs that can increase Itra anticancer activity as well as identifying new targets in the treatment of ovarian cancer. Methods: We tested a panel of 32 ovarian cancer cell lines with different doses of Itra and identified a subset of cells which showed significant sensitivity to the drug. To identify genetic vulnerabilities and find new therapeutic targets to combine with Itra, we performed a whole genome sensitivity CRISPR screen in 2 cell lines (TOV1946 and OVCAR5) treated with non-toxic (IC10) concentrations of Itra. Results: Pathway analysis on the top hits from both the screens showed a significant involvement of lysosomal compartments, and in particular dynamics between trans Golgi network and late endosomes/lysosomes, pathways that are affected by the autophagy inhibitor Chloroquine (CQ). We subsequently demonstrated that the combination of Itra and CQ had a synergistic effect in many ovarian cancer cell lines, even in those resistant to Itra. Further, genetic and pharmacological manipulation of autophagy indicated that upstream inhibition of autophagy is not a key mediator of the Itra/CQ mechanism of action. However, combination of Itra with other lysosomotropic agents (Concanamycin A, Bafilomycin A and Tamoxifen) displayed overlapping activity with Itra/CQ, supporting the lysosomal involvement in sensitizing cells to Itra resulted from the CRISPR screens. Analysis of lysosomal pattern and function showed a combined effect of Itra and CQ in targeting lysosomes and neutralizing their activity. Conclusion: We identified two FDA approved drugs – CQ and Tamoxifen - that can be used in combination with Itra and exert a potent anti-tumor effect in ovarian cancer by affecting lyosomal function and suggesting a likely dependency of these cells on lysosomal biology. Further studies are in progress. Citation Format: Stefano Marastoni, Aleksandra Pesic, Sree Narayanan Nair, Zhu Juan Li, Ali Madani, Benjamin Haibe-Kains, Bradly G. Wouters, Anthony Joshua. Targeting lysosomal homeostasis in ovarian cancer through drug repurposing [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 3401.
Radiosensitization in non-small cell lung cancer by targeting Akt with nelfinavir.
Authors: Anjali Gupta, George Cerniglia, Mona Ahmed, Amit Maity, John Buatti
Journal: Cancer Research (2008)

407  The majority of patients with non-small cell lung cancer (NSCLC) are diagnosed with advanced disease confined to the chest that is technically unresectable. These patients have a poor prognosis with a median survival of approximately one year. In patients treated with surgery and pre-operative chemo-radiation, median survival improves to 15-17 months due mostly to improved local control. It is thus possible that by sensitizing tumors to definitive chemo-radiation, the same improvement in survival could be seen. We know that mutations in EGFR and Ras are seen in 70% and 20-30% of patients with NSCLC respectively. Both of these have been shown to result in a poorer outcome and resistance to radiation. Erlotnib is currently being used in patients with NSCLC. We have seen that radiation resistance can be abrogated by down-regulation of EGFR but only when it results in downregulation of Akt. Previous studies in NSCLC have found the frequency of Akt activation to range between 67-83%. Nelfinavir, an HIV protease inhibitor, has been shown to abrogate Akt. In this study, we tested the effect of erlotnib and nelfinavir in a panel of NSCLC cell lines in terms of radiation sensitization. Eight lung cancer cell lines were tested (A549, Calu3, H23, H292, Calu1, H1650, H1703, SW1573). Three of the 8 had Phosphorylated EGFR and all 8 had phosphorylated Akt. Only one of the cell lines (Calu1) was sensitized by erlotnib while 6 of the 8 (A549, Calu1, H1650, H1703, SW1573, and H292) were sensitized with nelfinavir. Treatment with erlotnib resulted in down regulation of Akt only in Calu1. This provides further evidence that Akt is involved in the radiation resistance pathway and that targeting it closer to this point results in sensitization to radiation in a greater percentage of tumors. Nelfinavir has been used in HIV patients for the last 10 years with minimal side effects. Clinical trial in non-HIV patients with NSCLC are currenly in progress.
Abstract 4362: Combination of conventional therapies and antiandrogenic treatments as a succesful tool for triple negative breast cancer (TNBC) treatment
Authors: Sara Caceres, Angela Alonso Diez, Gema Silvan, Maria J. Illera, Juan C. Illera
Journal: Cancer Research (2020)

Abstract Triple negative breast cancer (TNBC) patients do not benefit from conventional hormonal therapies due to the loss of expression of ER, PR, and HER2. Therefore, the usual adjuvant treatments for breast cancer, are not applied to TNBC. Recently, it has been found that approximately one third of TNBC tumours express androgen receptor (AR) and it is associated with better response to endocrine therapies. However, the prognostic value of AR expression in TNBC is still unclear. Therefore, in this preliminary study we evaluate the effectiveness of an anti-androgen treatment (bicalutamide) respect to conventional treatments (doxorubicin and lapatinib) in TNBC human cell lines and their corresponding xenografts. Briefly, SUM149, SUM159 and MDAMB231 TNBC cell lines were cultured in supplemented medium. Cells were plated in 96-well plates and a serial dilution of Doxorubicin, Lapatinib, Bicatulamide and respective combinations were added. In addition, 106 cells were implanted subcutaneosly into five female mice (Balb/C SCID). When tumors developed, mice were treated with doxorubicin, bicalutamide, doxorubicin + bicalutamide and doxorubicin + bicalutamide + lapatinib. Every treatment was perfomed every 3 days during 15 days and tumor reduction and appearance of metastases were evaluated. Results from cell culture showed that neoplasic cells from each cell line were high sensitive to bicalutamide treatment (SUM149 EC50: 9,860e009; MDAMB231 EC50: 9,454e009; SUM159 EC50: 2,170e009). Also, viability decreased when we added an anti-androgen (bicalutamide) to the conventional treatments (doxorubicin + lapatinib). In vivo experiments revealed a greater percentage of tumour reduction (around 70%) in mice treated with combination of treatments and a lower appearance of metastasis was observed in this group respect to control group (SUM149: 40% vs 60%; MDA-MB-231: 20% vs 75%; SUM159: 20% vs 60%). Therefore, our preliminary findings suggest that the addition of an anti-androgenic agent to treatments currently in use can reduce the tumour considerably, defining anti-androgenic treatments as a novel effective therapeutic target. Citation Format: Sara Caceres, Angela Alonso Diez, Gema Silvan, Maria J. Illera, Juan C. Illera. Combination of conventional therapies and antiandrogenic treatments as a succesful tool for triple negative breast cancer (TNBC) treatment [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 4362.
Abstract 958: PARP-inhibition induces cancer immunogenic cell death in response to high levels of interferon-gamma in the tumor microenvironment
Authors: Ichiko Kinjyo, Sarah F. Adams
Journal: Cancer Research (2020)

Abstract Background: We recently demonstrated that treatment with poly(ADP-ribose) polymerase (PARP) inhibitors sensitize BRCA1-deficient ovarian cancers to immune checkpoint blockade in preclinical models. The extended survival in response to this combination was associated with a significant increase in IFNg producing effector T cells in the tumor environment. In vitro experiments identified a significant interaction between PARP-inhibition and IFNg that promoted tumor cytotoxicity in a caspase-independent manner. We hypothesized that IFNg engages immunogenic cell death mechanisms in response to PARP-inhibition to promote immune-mediated tumor clearance. Methods: To distinguish cell death mechanisms in vitro, we exposed ovarian cancer cells to a PARP-inhibitor (10 microg/ml) and IFNg (2 ng/ml). Calreticulin translocation to the cell membrane and the release of high-mobility group protein 1 (HMGB-1) were assessed as characteristic features of immunogenic cell death. Innate cell activation was evaluated by analysis of dendritic cells in draining lymph nodes after vaccination. Evidence of immunogenicity was confirmed in vivo with vaccination studies. Results: Tumor cells treated with a PARP-inhibitor in combination with IFNg, but not the cells exposed to the PARP-inhibitor alone, demonstrated calreticulin translocation and HMGB-1 release. In vivo, vaccination using cells treated with both the PARP-inhibitor and IFNg protected animals from intraperitoneal tumor challenge. Vaccinated mice also rejected secondary and tertiary tumor challenges demonstrating durable protective memory. Vaccinated tumor cells were phagocytosed by DCs in draining lymph nodes and induced co-stimulatory ligand and MHC expression. Adoptive transfer of splenocytes from vaccinated animals confirmed that this protective effect was T cell-mediated. Conclusions: These results identify a novel mechanism by which PARP-inhibition drives immunogenic cell death in response to IFNg in the ovarian tumor environment. These effects can be leveraged to enhance tumor clearance in combination with immune therapy, and may present a strategy to circumvent adaptive treatment resistance associated with high levels of IFNg in the tumor microenvironment. Citation Format: Ichiko Kinjyo, Sarah F. Adams. PARP-inhibition induces cancer immunogenic cell death in response to high levels of interferon-gamma in the tumor microenvironment [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 958.
Abstract 14436: Right Interval Jugular Access for Cardiomems™ Implantation is Safe, Effective, and Fast
Authors: Jacob Abraham, Patrick McCann, Amanda Schnell Heringer, Jeff Paulsen, Jay Chappell, Joshua Remick, Daniel Westerdahl, Rebecca Lewis, Katherine Callis, L Wang, Kateri Spinelli, Liviu Klein
Journal: Circulation (2018)

Introduction: The CardioMEMS™ pulmonary artery pressure sensor is FDA approved for insertion via the femoral vein. The right internal jugular vein (IJ) is an alternative access route used frequentl...
Sixty seconds on . . . the blitz
Authors: Abi Rimmer
Journal: BMJ (2020)

Sorry, but I can’t help it. Edgar Jones, from the Institute of Psychiatry, Psychology, and Neuroscience at King’s College London has published a paper1 which compares the current covid-19 pandemic and the aerial bombings during the second world war.

Not quite. In the paper, published in Lancet Psychiatry , Jones said that by comparing the psychological responses and behaviour of people during both …
Abstract 3834: Histone methyltransferase SET8 is regulated by miR-192/-215 and induces oncogene-induced senescence via p53-dependent DNA damage in human gastric carcinoma cells
Authors: Xiaojing Zhang, Yin Peng, Fan Hu, Yuli Gao, Jin Zhe, Stephenj Meltzer
Journal: Cancer Research (2020)

Abstract Purpose: This aim of study was to investigate the clinicopathologic significance and potential role of histone methyltransferase SET8 in the progression of gastric carcinoma (GC). Experimental Design: SET8 was screened out by gene microarray in gastric cell lines with or without miR-192/-215 inhibitors or mimics. The effects of SET8 on cell proliferation, invasion, and metastasis were examined using EdU assays, invasion studies, subcutaneous tumor experiments, and tail-vein injection in nude mice. Immunohistochemical staining was performed to detect SET8 expression in GC tissues, and real-time PCR was performed to examine the correlations between miR-192/-215 and SET8. SA-β-Gal staining assays were performed to identify the occurrence of senescence. Senescence-associated proteins were examined by real-time PCR and Western blotting. Results: SET8 regulated by miR-192/-215 displayed decreased expression in GC. Inhibition of miR-192/-215 resulted in weakened proliferation, migration, and invasion in GC. The 3'UTR of SET8 was targeted by miR-192/-215, and SET8 siRNA treatment successfully rescued the biological phenomenon. SET8 was found to trigger oncogene-induced senescence (OIS) in GC in vivo and in vitro, highlighting the functional mechanism of the miR-192/-215/SET8 axis in GC. During OIS, p53 and p21 were key genetic switch points. Taken together, these data show that the miR-192/-215/SET8/p53 circuit is a key regulator of GC promotion and is highly associated with proliferation, migration, and metastasis. Conclusions: Our findings reveal that SET8 functions via the OIS-signaling pathway as a negative regulator of metastasis. This provides an experimental rationale for investigation of the OIS-signaling pathway as a potential therapeutic target in GC. Supported by: National Nature Science Foundation of China (81772592) to Z.J.; National Nature Science Foundation of China (81871969) to X.Z.; National Natural Youth Science Foundation of China (31601028) to Y.P.; Guangdong Provincial Key Laboratory of Regional Immunity and Diseases (2019B030301009) to Z.J. Citation Format: Xiaojing Zhang, Yin Peng, Fan Hu, Yuli Gao, Jin Zhe, Stephenj Meltzer. Histone methyltransferase SET8 is regulated by miR-192/-215 and induces oncogene-induced senescence via p53-dependent DNA damage in human gastric carcinoma cells [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 3834.