tbuckley/cabot-search huggingface dataset:
Nephrotoxicity of Cancer Immunotherapies: Past, Present and Future
Authors: Mark A. Perazella, Anushree C. Shirali
Journal: Journal of the American Society of Nephrology (2018)

Nephrotoxicity from cancer therapies is common and increasingly encountered in clinical practice, such that the subfield of “onco-nephrology” has emerged. Conventional chemotherapeutic drugs and novel agents targeting specific genes/proteins are effective cancer therapies but suffer from a number of adverse kidney effects. An effective avenue of cancer treatment is immunotherapy, which uses drugs that augment immune system–mediated recognition and targeting of tumor cells. As such, leveraging the immune system to target malignant cells represents an important modality in eradicating cancer. IFN and high-dose IL-2 are older immunotherapies used in clinical practice to treat various malignancies, whereas new cancer immunotherapies have emerged over the past decade that offer even more effective treatment options. The immune checkpoint inhibitors are an exciting addition to the cancer immunotherapy armamentarium. Chimeric antigen receptor T cells are also a new immunotherapy used to treat various hematologic malignancies. However, as with the conventional and targeted cancer agents, the immunotherapies are also associated with immune-related adverse effects, which includes nephrotoxicity.
Abstract 5198: Androgen receptor signaling affects macrophage differentiation in the human prostate cancer microenvironment
Authors: Bianca Cioni, Ekatarina Nevedomskaya, Suzan Stelloo, Monique Melis, Johan van Burgsteden, Jeroen de Jong, Henk van der Poel, Jan Paul de Boer, Wilbert Zwart, Andries M. Bergman
Journal: Cancer Research (2018)

Abstract Increasing evidence from epidemiologic and pathologic studies suggests a role of macrophages in the initiation and progression of prostate cancer (PCa). During PCa development, macrophages (CD68+) are recruited into the human prostate cancer microenvironment, including inflammation-associated M1 and cancer-promoting M2 macrophages. Like other prostate cancer-associated stromal cells, macrophages express the androgen receptor (AR); however, its functionality is not known. CD68+ cells generated in vitro from peripheral white blood cells and PMA activated and IFN and LPS polarized human acute monocytic leukemia THP-1 cells also expressed AR. In these cells AR is an 80KD splice variant, lacking parts of exon 1 and exon 2. AR translocated to the nucleus upon testosterone stimulation, which was counteracted by the AR signaling inhibitor RD162. In vitro generated M1 macrophages expressed the M2 markers CD163 and CD206 upon testosterone stimulation, which was reversed by RD162. AR-ChIP sequencing suggested AR regulated Macrophage Triggering Receptor 1 (TREM1) signaling. Expression of key cytokines (e.g., CCL2, CXCL8, CCL7, IL10, IL1B) involved in TREM1 signaling was upregulated upon testosterone stimulation. Actions of these cytokines is generally associated with a protumor phenotype of macrophages. Conditioned medium from macrophages stimulated with testosterone for 8 hrs resulted in enhanced proliferation and migration of human prostate LNCap and CWRR1 cells. In conclusion, AR signaling might affect differentiation of prostate cancer-associated macrophages into cancer-promoting M2, which affects prostate cancer cell proliferation and migration. Maintaining macrophages in M1 might be a novel mechanism of action of androgen receptor inhibitors. Citation Format: Bianca Cioni, Ekatarina Nevedomskaya, Suzan Stelloo, Monique Melis, Johan van Burgsteden, Jeroen de Jong, Henk van der Poel, Jan Paul de Boer, Wilbert Zwart, Andries M. Bergman. Androgen receptor signaling affects macrophage differentiation in the human prostate cancer microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5198.
Commonly used approach for multimorbidity fails to improve quality of life
Authors: Susan Mayor
Journal: BMJ (2018)

The commonly used “3D approach” for managing patients with multiple chronic conditions fails to improve health related quality of life, a randomised trial to assess this model of care has reported.1

One in four people in the UK and USA have multimorbidity, with two or more chronic health conditions, and this increases to at least two thirds of those over 65. Efforts to improve the care of these patients traditionally focused on implementing guidelines for individual diseases. These are often inappropriate for patients with co-existing conditions so a patient centred care model focusing on dimensions of health—including quality of life, identifying and treating depression, …
Metformin reverses established lung fibrosis in a bleomycin model
Authors: Sunad Rangarajan, Nathaniel B. Bone, Anna A. Zmijewska, Shaoning Jiang, Dae Won Park, Karen Bernard, Morgan L. Locy, Saranya Ravi, Jessy Deshane, Roslyn B. Mannon, Edward Abraham, Victor Darley-Usmar, Victor J. Thannickal, Jaroslaw W. Zmijewski
Journal: Nature Medicine (2018)
Aggregation‐Induced Emission Luminogens: Union Is Strength, Gathering Illuminates Healthcare
Authors: Ji Qi, Chao Chen, Dan Ding, Ben Zhong Tang
Journal: Advanced Healthcare Materials (2018)

Abstract The rapid development of healthcare techniques encourages the emergence of new molecular imaging agents and modalities. Fluorescence imaging that enables precise monitoring and detection of biological processes/diseases is extensively investigated as this imaging technique has strengths in terms of high sensitivity, excellent temporal resolution, low cost, and good safety. Aggregation‐induced emission luminogens (AIEgens) have recently emerged as a new class of emitters that possess several notable features, such as high brightness, large Stokes shift, marked photostability, good biocompatibility, and so on. So far, AIEgens are widely explored and exhibit superb performance in the area of biomedicine and life sciences. Herein, this review summarizes and discusses the recent investigations of AIEgens for in vivo diagnosis and therapy including long‐term tracking, 3D angiography, multimodality imaging, disease theranostics, and activatable sensing. Collectively, these results reveal that AIEgens are of great promise for in vivo biomedical applications. It is hoped that this review will lead to new insights into the development of advanced healthcare materials.
Abstract 5031: Organotypic brain explant culture as a drug evaluation system for malignant brain tumors
Authors: Noriaki Minami
Journal: Cancer Research (2018)

Abstract Background: Inhibition of major metabolic pathways is being assessed for several intractable tumors, including glioblastoma. Following screening in 2D-systems, evaluating metabolic inhibitors in assays that include both tumor and normal brain tissue is indispensable for selecting compounds that can affect gliomas within their microenvironment. Here we asked whether organotypic brain slices from adult mice can be used to evaluate the effects of metabolic inhibitors on malignant glioma cells. Methods: Retroviral expression of H-RasV12 and dsRed in Ink4a/Arf-/- neural stem / progenitor cells was adopted to establish glioma initiating cells (GICs). GICs with different extracellular acidification potential were derived by single cell cloning and used after one in vivo passage. GICs or their clones were implanted into the forebrain of 6-weeks-old wild-type mice. Tumor-bearing brain explants were established as 200 µm coronal brain slices, treated with cisplatin, dichloroacetate or phenformin. The effects of the drugs were assessed by fluorescence microscopy of the live explants, as well as immunohistochemical staining at the end of the treatment. Results: The feasibility of assessing drug effects in brain tumor explants from adult mice was confirmed with the use of the DNA-damaging agent cisplatin. Treatment of brain slices carrying tumors formed by GICs with 50 μM cisplatin for 4 days effectively decreased the tumor burden, as shown by a significant reduction of the tumor area on fluorescence imaging and a marked increase in tumor cells positive for cleaved caspase 3 on immunohistochemical analysis. The action of metabolic inhibitors was assessed in explants with tumors formed by GIC-derived populations that predominantly use either glycolysis or mitochondrial respiration. Treatment of the brain slices with dichloroacetate, an inhibitor of pyruvate dehydrogenase kinase, resulted in a marked increase in cleaved caspase 3-positive cells in glycolytic tumors. In contrast, phenformin, which inhibits respiratory complex I, had a pronounced pro-apoptotic effect in tumors formed by cells with a high mitochondrial activity. Conclusion: Inhibitors of both glycolysis and oxidative phosphorylation effectively and selectively induced apoptosis of the targeted tumor cells in cultured brain slices. Our results suggest that brain explants from adult mice can be used to assess the effects of anti-metabolic drugs on the survival of glioma initiating cells within a syngeneic microenvironment. Explants could thus be useful in the evaluation of new metabolic inhibitors. Citation Format: Noriaki Minami. Organotypic brain explant culture as a drug evaluation system for malignant brain tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5031.
Abstract 11603: Structural Insights Into C-terminus and N-terminus of a Designer cGMP Activating ANP-Based Antihypertensive Peptide: ZD100
Authors: Alessia Buglioni, S Jeson Sangaralimgaham, Brenda K Huntley, Gerald E Harders, Daniel J McCormick, Joseph Winaver, Horng H Chen, John C Burnett
Journal: Circulation (2016)

Introduction: As importantly underscored by the SPRINT Trial, innovative blood pressure (BP) lowering and multiorgan protective drugs are needed for treating hypertension (HTN). We engineered a Mayo Clinic designer atrial natriuretic peptide (ANP)-based drug, ZD100, which possesses a unique 12 amino acid (AA) carboxy-terminus (CT) extension while maintaining the N-terminus (NT) of ANP. ZD100 is more potent than ANP in reducing BP, inducing natriuresis and inhibiting aldosterone via pGC-A and its second messenger cGMP. To date, the in vivo actions of ZD100 in a model of essential HTN are undefined. Further, in attempt to enhance and/or minimize pGC-A activation, the importance of specific AAs in the CT and NT of ZD100 is unknown and is critical to define. Hypothesis: We hypothesize that ZD100 is a potent anti-HTN drug activating pGC-A/cGMP system and that specific AA variations in the CT and/or NT of ZD100 will modify the ability of activating pGC-A. Methods: Spontaneously hypertensive rats (SHRs) received intravenous (IV) ZD100 or vehicle and BP, plasma and urinary cGMP and the natriuretic effects were determined. We then engineered 15 strategic ZD100 variants (Vs) consisting of mutated peptides in the CT or NT or both. We stimulated HEK293 cells overexpressing pGC-A with ZD100 and the 15 Vs (10-8 M) and measured intracellular cGMP generation. Results: In SHRs, acute IV ZD100 reduced BP, increased plasma and urinary cGMP generation and induced natriuresis demonstrating efficacy in HTN. In vitro, we found two more potent pGC-A activators (+100% cGMP activation) only among the CT-only mutated ZD100 Vs. Importantly, key mutations of either the CT or NT resulted in 6 loss-of-function Vs identifying importance of peptide-receptor dependency. Conclusions: We demonstrate for the first time in a genetic model of HTN that ZD100 reduces BP, activates systemic and renal pGC-A/cGMP and induces natriuresis. Enhanced or reduced pGC-A activation with targeted AA mutations in the CT and NT of ZD100 provides key structure function insights into ZD100 which may lead to next generation ZD100 therapeutic peptides. These findings support ZD100 as a novel peptide therapeutic strategy for HTN and will help guide the selection of best-in-class ZD100 analogues.
Detection of Metastatic Meningioma to the Liver Using 68Ga-DOTA-Octreotate PET/CT
Authors: Javier E. Villanueva-Meyer, Stephen T. Magill, Julieann C. Lee, Sarah E. Umetsu, Robert R. Flavell
Journal: Clinical Nuclear Medicine (2018)

Abstract We present a case of metastatic meningioma detected on 68 Ga-DOTA-octreotate PET. A 52-year-old woman presented with multiply recurrent multifocal meningioma. A staging 68 Ga-DOTATATE PET/CT demonstrated focal radiotracer uptake within the known intracranial meningiomas. In addition, a DOTATATE-avid mass was found in the liver that was biopsied, confirming metastatic meningioma. This report suggests that 68 Ga-DOTATATE PET/CT should be considered whenever screening meningioma patients for metastases.
Oral Tecovirimat for the Treatment of Smallpox
Authors: Douglas W. Grosenbach, Kady Honeychurch, Eric A. Rose, Jarasvech Chinsangaram, Annie Frimm, Biswajit Maiti, Candace Lovejoy, Ingrid Meara, Paul Long, Dennis E. Hruby
Journal: New England Journal of Medicine (2018)

Smallpox was declared eradicated in 1980, but variola virus (VARV), which causes smallpox, still exists. There is no known effective treatment for smallpox; therefore, tecovirimat is being developed as an oral smallpox therapy. Because clinical trials in a context of natural disease are not possible, an alternative developmental path to evaluate efficacy and safety was needed.We investigated the efficacy of tecovirimat in nonhuman primate (monkeypox) and rabbit (rabbitpox) models in accordance with the Food and Drug Administration (FDA) Animal Efficacy Rule, which was interpreted for smallpox therapeutics by an expert advisory committee. We also conducted a placebo-controlled pharmacokinetic and safety trial involving 449 adult volunteers.The minimum dose of tecovirimat required in order to achieve more than 90% survival in the monkeypox model was 10 mg per kilogram of body weight for 14 days, and a dose of 40 mg per kilogram for 14 days was similarly efficacious in the rabbitpox model. Although the effective dose per kilogram was higher in rabbits, exposure was lower, with a mean steady-state maximum, minimum, and average (mean) concentration (Cmax, Cmin, and Cavg, respectively) of 374, 25, and 138 ng per milliliter, respectively, in rabbits and 1444, 169, and 598 ng per milliliter in nonhuman primates, as well as an area under the concentration-time curve over 24 hours (AUC0-24hr) of 3318 ng×hours per milliliter in rabbits and 14,352 ng×hours per milliliter in nonhuman primates. These findings suggested that the nonhuman primate was the more conservative model for the estimation of the required drug exposure in humans. A dose of 600 mg twice daily for 14 days was selected for testing in humans and provided exposures in excess of those in nonhuman primates (mean steady-state Cmax, Cmin, and Cavg of 2209, 690, and 1270 ng per milliliter and AUC0-24hr of 30,632 ng×hours per milliliter). No pattern of troubling adverse events was observed.On the basis of its efficacy in two animal models and pharmacokinetic and safety data in humans, tecovirimat is being advanced as a therapy for smallpox in accordance with the FDA Animal Rule. (Funded by the National Institutes of Health and the Biomedical Advanced Research and Development Authority; ClinicalTrials.gov number, NCT02474589 .).
Clonal Structures of Regionally Synchronous Gastric Adenomas and Carcinomas
Authors: Seung-Hyun Jung, Shin Young Kim, Chang Hyeok An, Sung Hak Lee, Eun Sun Jung, Hyeon-Chun Park, Min Sung Kim, Yeun-Jun Chung, Sug Hyung Lee
Journal: Clinical Cancer Research (2018)

Purpose: Gastric adenoma (GA) is a premalignant lesion that precedes intestinal-type gastric carcinoma (GC). However, genetic progression mechanisms from GA to GC have not been clarified.Experimental Design: We performed whole-exome sequencing-based mutational analyses for 15 synchronous pairs of attached GAs and GCs.Results: There was no significant difference in the number of driver mutations or copy-number alterations between GAs and GCs. Well-known mutations of TP53, APC, RNF43, and RPL22 were recurrently detected in synchronous GA/GC pairs. In addition, we discovered novel KDM6A, PREX2, FAT1, KMT2C, GLI3, and RPL22 mutations and hypermutation in GAs, but did not identify recurrent drivers for GA-to-GC progression. Clonal structure analyses revealed that most GA/GC pairs exhibit parallel evolution with early divergence rather than stepwise evolution during GA-to-GC progression. Of note, three cases were identified as clonally nonrelated GA/GC pairs despite the lack of histologic differences. We found differences in dominant mutational signatures 1, 6, 15, and 17 in GA/GC trunks, GA branches, and GC branches. Compared with our previous work on synchronous colon adenoma/carcinoma genome structures, where most drivers were in the trunk with parallel evolution, synchronous GA/GC genomes showed a different model of parallel evolution, with many drivers in the branches.Conclusions: The preferred sequence of mutational events during GA-to-GC progression might be more context-dependent than colon adenoma progression. Our results show that nonclonal synchronous GA/GC is common and that GA genomes have already acquired distinct genomic alterations, suggesting caution in the diagnosis of synchronous GA and GC, especially in residual or recurrent cases. Clin Cancer Res; 24(19); 4715-25. ©2018 AACR.
Targeting the XPO1-dependent nuclear export of E2F7 reverses anthracycline resistance in head and neck squamous cell carcinomas
Authors: Natalia Saenz-Ponce, Rachael Pillay, Lilia Merida de Long, Trinayan Kashyap, Christian Argueta, Yosef Landesman, Mehlika Hazar-Rethinam, Samuel Boros, Benedict Panizza, Maarten Jacquemyn, Dirk Daelemans, Orla M. Gannon, Nicholas A. Saunders
Journal: Science Translational Medicine (2018)

Patient mortality rates have remained stubbornly high (40%) for the past 35 years in head and neck squamous cell carcinoma (HNSCC) due to inherent or acquired drug resistance. Thus, a critical issue in advanced SCC is to identify and target the mechanisms that contribute to therapy resistance. We report that the transcriptional inhibitor, E2F7, is mislocalized to the cytoplasm in >80% of human HNSCCs, whereas the transcriptional activator, E2F1, retains localization to the nucleus in SCC. This results in an imbalance in the control of E2F-dependent targets such as SPHK1, which is derepressed and drives resistance to anthracyclines in HNSCC. Specifically, we show that (i) E2F7 is subject to exportin 1 (XPO1)-dependent nuclear export, (ii) E2F7 is selectively mislocalized in most of SCC and multiple other tumor types, (iii) mislocalization of E2F7 in HNSCC causes derepression of Sphk1 and drives anthracycline resistance, and (iv) anthracycline resistance can be reversed with a clinically available inhibitor of XPO1, selinexor, in xenotransplant models of HNSCC. Thus, we have identified a strategy to repurpose anthracyclines for use in SCC. More generally, we provide a strategy to restore the balance of E2F1 (activator) and E2F7 (inhibitor) activity in cancer.
Management of multimorbidity using a patient-centred care model: a pragmatic cluster-randomised trial of the 3D approach
Authors: Chris Salisbury, Mei-See Man, Peter Bower, Bruce Guthrie, Katherine Chaplin, Daisy M Gaunt, Sara Brookes, Bridie Fitzpatrick, Caroline Gardner, Sandra Hollinghurst, Victoria Lee, John McLeod, Cindy Mann, Keith R Moffat, Stewart W Mercer
Journal: The Lancet (2018)

The management of people with multiple chronic conditions challenges health-care systems designed around single conditions. There is international consensus that care for multimorbidity should be patient-centred, focus on quality of life, and promote self-management towards agreed goals. However, there is little evidence about the effectiveness of this approach. Our hypothesis was that the patient-centred, so-called 3D approach (based on dimensions of health, depression, and drugs) for patients with multimorbidity would improve their health-related quality of life, which is the ultimate aim of the 3D intervention.We did this pragmatic cluster-randomised trial in general practices in England and Scotland. Practices were randomly allocated to continue usual care (17 practices) or to provide 6-monthly comprehensive 3D reviews, incorporating patient-centred strategies that reflected international consensus on best care (16 practices). Randomisation was computer-generated, stratified by area, and minimised by practice deprivation and list size. Adults with three or more chronic conditions were recruited. The primary outcome was quality of life (assessed with EQ-5D-5L) after 15 months' follow-up. Participants were not masked to group assignment, but analysis of outcomes was blinded. We analysed the primary outcome in the intention-to-treat population, with missing data being multiply imputed. This trial is registered as an International Standard Randomised Controlled Trial, number ISRCTN06180958.Between May 20, 2015, and Dec 31, 2015, we recruited 1546 patients from 33 practices and randomly assigned them to receive the intervention (n=797) or usual care (n=749). In our intention-to-treat analysis, there was no difference between trial groups in the primary outcome of quality of life (adjusted difference in mean EQ-5D-5L 0·00, 95% CI -0·02 to 0·02; p=0·93). 78 patients died, and the deaths were not considered as related to the intervention.To our knowledge, this trial is the largest investigation of the international consensus about optimal management of multimorbidity. The 3D intervention did not improve patients' quality of life.National Institute for Health Research.
Abstract 3207: CXCR4 endows radioresistance in non-small cell lung cancer cells through STAT3-mediated Slug expression
Authors: Dae-Hee Lee, Jeong-Yub Kim, Hee-Jin Kim, Myung-Jin Park
Journal: Cancer Research (2018)

Abstract Lung Cancer is one of the most common causes of cancer-related mortality worldwide, despite of significant advance of treatment strategies including chemotherapy and radiotherapy. Although chemotherapy is the first choice for treatment of non-small cell lung cancer cells (NSCLCs) except surgery, radiotherapy is primary treatment modality for patients with unresectable NSCLC on its own or with another treatment like chemotherapy. CXCR4 is chemokine (C-X-C motif) receptor 4 whose ligand is Stromal-derived-factor-1 (SDF1a), so-called CXCL12. According to the current reports, CXCR4 is widely expressed by malignant tumor and crucial for tumor growth, vascularization, metastasis, cell migration and related to poor prognosis. Here, we show that CXCR4 signaling confers resistance to ionizing radiation (IR) in NSCLCs. Drug-resistant A549/GR cells with enhanced CXCR4 expression exhibited high colony forming ability after IR compared with A549 cells. Transfection of siRNA against CXCR4 or treatment of pharmacological inhibitor (AMD3100) sensitized these cells to IR. Reversely, overexpression of CXCR4 in A549 and H460 enhanced clonogenic survival after IR. IR stimulated CXCR4 expression and CXCR4-mediated STAT3 phosphorylation in NSCLCs. Inhibition of STAT3 by WP1066 or siSTAT3 significantly suppressed the colony forming ability, indicating that CXCR4-mediated STAT3 signaling is important for IR resistance in NSCLC cells. CXCR4/STAT3 signaling upregulated the expression of Slug and down-regulation of Slug with siRNA increased IR sensitivity in NSCLCs. Taken together, our data suggest that CXCR4/STAT3/Slug axis is crucial for IR resistance of NSCLCs and is able to be considered as a therapeutic target for enhancing IR sensitivity of this devastating cancer. Citation Format: Dae-Hee Lee, Jeong-Yub Kim, Hee-Jin Kim, Myung-Jin Park. CXCR4 endows radioresistance in non-small cell lung cancer cells through STAT3-mediated Slug expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3207.