bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nutrition interventions in populations with mental health conditions: a scoping review
Authors: Cherak Stephana J. , Fiest Kirsten M. , VanderSluis Laura , Basualdo-Hammond Carlota , Lorenzetti Diane L. , Buhler Sue , Stadnyk Janet , Driedger Lorna , Hards Lori , Gramlich Leah , Fenton Tanis R. 
Published: June 2020

Nutrition is a modifiable factor for intervention in mental disorders. This scoping review characterized nutrition intervention research in mental disorders. A 3-category framework characterized nutrition interventions: Guide (e.g., counselling), Provide (e.g., food provisions), and Add (e.g., supplementation). Nutrition interventions were classified as single-component (e.g., Guide) or complex (e.g., Guide-Provide). Sixty-nine trials met inclusion criteria, 96% were randomized controlled trials. Most commonly diagnosed mental disorders were depressive disorder (i.e., persistent) or major depressive disorder (n = 39), schizophrenia (n = 17), and other psychotic disorders (n = 13). Few trials included patients with anxiety disorders (n = 2) or bipolar disorders (n = 3). Several trials (n = 15, 22%) assessed and implemented nutrition interventions to improve dietary patterns, of which 11 (73%) reported statistically significant and clinically important positive effects of nutrition interventions on mental disorders. The majority of the trials (n = 61, 90%) investigated supplementation, most commonly adding essential fatty acids, vitamins, or minerals. The majority (n = 48, 70%) reported either statistically significant or clinically important effect and 31 (51%) reported both. Though most interventions led to statistically significant improvements, trials were heterogeneous for targeted mental disorders, nutrition interventions, and outcomes assessed. Given considerable heterogeneity, further research from robust and clinically relevant trials is required to support high-quality health care with effective nutrition interventions. Novelty Future research on whole-diet interventions powered to detect changes in mental health outcomes as primary objectives is needed. Dietitians may be an opportunity to improve feasibility and efficacy of nutrition interventions for mental disorder patients. Dietitians may be of value to educate mental health practitioners on the importance of nutrition.
The Diet of Higher Insulinemic Potential Is Not Associated with Worse Survival in Patients with Stage III Colon Cancer (Alliance)
Authors: Cheng En , Zhang Sui , Ou Fang-Shu , Mullen Brian , Ng Kimmie , Saltz Leonard B. , Niedzwiecki Donna , Mayer Robert J. , Mowat Rex B. , Whittom Renaud , Hantel Alexander , Benson Al , Atienza Daniel , Messino Michael , Kindler Hedy , Giovannucci Edward L. , Van Blarigan Erin L. , Meyerhardt Jeffrey A. , Fuchs Charles S. 
Published: June 2020

Abstract

Background:
Hyperinsulinemia is considered to be important in the development of colon cancer, but few studies have investigated the associations of hyperinsulinemia with colon cancer survival via dietary scores.

Methods:
Empirical dietary index for hyperinsulinemia (EDIH) was derived to assess the insulinemic potential of daily diets reflecting the long-term insulin exposure, with higher (more positive) scores indicating higher insulinemic diets. We prospectively estimated the HRs and 95% confidence intervals (CI) to investigate the association of EDIH with disease-free, recurrence-free, and overall survival among patients with stage III colon cancer (1999–2009) enrolled in a randomized adjuvant chemotherapy trial (CALGB 89803).

Results:
Of 1,024 patients (median follow-up: 7.3 years), 311 died, 350 had recurrences, and 394 had events for disease-free survival. Compared with patients in the lowest quintile of EDIH, the corresponding HRs of patients in the highest quintile for disease-free survival events, cancer recurrence, and overall mortality were 0.80 (95% CI, 0.56–1.15), 0.76 (95% CI, 0.51–1.11), and 0.77 (95% CI, 0.52–1.14).

Conclusions:
Higher EDIH was not associated with the risk of colon cancer recurrence or mortality in this population of patients with stage III colon cancer.

Impact:
EDIH, as a measure of dietary insulinemic potential, may be associated with colon cancer risk but not survival in patients with late-stage colon cancer.
Camrelizumab Plus Gemcitabine, Vinorelbine, and Pegylated Liposomal Doxorubicin in Relapsed/Refractory Primary Mediastinal B-Cell Lymphoma: A Single-Arm, Open-Label, Phase II Trial
Authors: Mei Qian , Zhang Wenying , Liu Yang , Yang Qingming , Rasko John E.J. , Nie Jing , Liu Jiejie , Li Xiang , Dong Liang , Chen Meixia , Zhang Yan , Shi Lu , Wu Huitao , Han Weidong 
Published: June 2020

Abstract

Purpose:
Patients with relapsed/refractory primary mediastinal B-cell lymphoma (rrPMBCL) represent a particularly challenging population to treat, with few life-saving treatment options in the context of a dismal prognosis.

Patients and Methods:
In this open-label, single-arm, phase II study, the safety and efficacy of combined regimen of chemotherapy consisting of gemcitabine, vinorelbine, and pegylated liposomal doxorubicin (GVD) plus anti-PD-1 antibody camrelizumab was assessed in rrPMBCL. Patients received chemo-immunotherapy every 3 weeks until the second confirmed complete response (CR) or up to 12 cycles, followed by camrelizumab monotherapy for up to 1 year. The primary endpoints were objective response rate (ORR) and safety.

Results:
Twenty-seven response evaluable patients were enrolled, who received a median of three first-line therapies, 59% with bulky disease. The ORR was 74%, including 56% with a CR. A median time of 1.7 months to response was observed, with 78% exhibiting tumor shrinkage at the first evaluation. After 24.8 months median follow-up, the median duration of response was not reached, with a 65% 2-year estimated response rate. Thirteen responders remained in sustained complete remission. Estimated 24-month progression-free survival and overall survival rates were 48.2% and 81.5%, respectively. Any grade and grade 3 treatment-related adverse events (AE) occurred in 93% and 33% of patients, respectively; with no grade 4 or 5 AEs. Baseline levels of IL10, IFNγ, and soluble Fas were associated with objective response.

Conclusions:
Camrelizumab plus GVD chemotherapy offers a potent option as life-saving chemo-immunotherapy with promising efficacy and a manageable safety profile for patients with rrPMBCL, especially with bulky aggressive disease.
Functional Genetic Screening Enables Theranostic Molecular Imaging in Cancer
Authors: Perkons Nicholas R. , Johnson Omar , Pilla Gabrielle , Profka Enri , Mercadante Michael , Ackerman Daniel , Gade Terence P.F. 
Published: June 2020

Abstract

Purpose:
Targeted therapies for cancer have accelerated the need for functional imaging strategies that inform therapeutic efficacy. This study assesses the potential of functional genetic screening to integrate therapeutic target identification with imaging probe selection through a proof-of-principle characterization of a therapy–probe pair using dynamic nuclear polarization (DNP)-enhanced magnetic resonance spectroscopic imaging (MRSI).

Experimental Design:
CRISPR-negative selection screens from a public dataset were used to identify the relative dependence of 625 cancer cell lines on 18,333 genes. Follow-up screening was performed in hepatocellular carcinoma with a focused CRISPR library targeting imaging-related genes. Hyperpolarized [1-13C]-pyruvate was injected before and after lactate dehydrogenase inhibitor (LDHi) administration in male Wistar rats with autochthonous hepatocellular carcinoma. MRSI evaluated intratumoral pyruvate metabolism, while T2-weighted segmentations quantified tumor growth.

Results:
Genetic screening data identified differential metabolic vulnerabilities in 17 unique cancer types that could be imaged with existing probes. Among these, hepatocellular carcinoma required lactate dehydrogenase (LDH) for growth more than the 29 other cancer types in this database. LDH inhibition led to a decrease in lactate generation (P &lt; 0.001) and precipitated dose-dependent growth inhibition (P &lt; 0.01 overall, P &lt; 0.05 for dose dependence). Intratumoral alanine production after inhibition predicted the degree of growth reduction (P &lt; 0.001).

Conclusions:
These findings demonstrate that DNP-MRSI of LDH activity using hyperpolarized [1-13C]-pyruvate is a theranostic strategy for hepatocellular carcinoma, enabling quantification of intratumoral LDHi pharmacodynamics and therapeutic efficacy prediction. This work lays the foundation for a novel theranostic platform wherein functional genetic screening informs imaging probe selection to quantify therapeutic efficacy on a cancer-by-cancer basis.
Novel Miniaturized Drug Conjugate Leverages HSP90-driven Tumor Accumulation to Overcome PI3K Inhibitor Delivery Challenges to Solid Tumors
Authors: Perino Samantha , Moreau Benoit , Freda Jessica , Cirello Amanda , White Brian H. , Quinn James M. , Kriksciukaite Kristina , Someshwar Ashwajith , Romagnoli Janel , Robinson Megan , Movassaghian Sara , Cipriani Tyler , Wooster Richard , Bilodeau Mark T. , Whalen Kerry A. 
Published: June 2020

Abstract
The PI3K pathway is considered a master regulator for cancer due to its frequent activation, making it an attractive target for pharmacologic intervention. While substantial efforts have been made to develop drugs targeting PI3K signaling, few drugs have been able to achieve the inhibition necessary for effective tumor control at tolerated doses. HSP90 is a chaperone protein that is overexpressed and activated in many tumors and as a consequence, small-molecule ligands of HSP90 are preferentially retained in tumors up to 20 times longer than in normal tissue. We hypothesize that the generation of conjugates that use a HSP90-targeting ligand and a payload such as copanlisib, may open the narrow therapeutic window of this and other PI3K inhibitors. In support of this hypothesis, we have generated a HSP90-PI3K drug conjugate, T-2143 and utilizing xenograft models, demonstrate rapid and sustained tumor accumulation of the conjugate, deep pathway inhibition, and superior efficacy than the PI3K inhibitor on its own. Selective delivery of T-2143 and the masking of the inhibitor active site was also able to mitigate a potentially dose-limiting side effect of copanlisib, hyperglycemia. These data demonstrate that by leveraging the preferential accumulation of HSP90-targeting ligands in tumors, we can selectively deliver a PI3K inhibitor leading to efficacy in multiple tumor models without hyperglycemia in mice. These data highlight a novel drug delivery strategy that allows for the potential opening of a narrow therapeutic window through specific tumor delivery of anticancer payloads and reduction of toxicity.
NRG1/ERBB3 Pathway Activation Induces Acquired Resistance to XPO1 Inhibitors
Authors: Miyake Takahito M. , Pradeep Sunila , Bayraktar Emine , Stur Elaine , Handley Katelyn F. , Wu Sherry Y. , Rodriguez-Aguayo Cristian , Lee Ju-Seog , Lopez-Berestein Gabriel , Coleman Robert L. , Sood Anil K. 
Published: June 2020

Abstract
XPO1 inhibitors have shown promise in cancer treatment, but mechanisms of resistance to these drugs are not well understood. In this study, we established selective inhibitors of nuclear export (SINE)-resistant ovarian cancer cell lines from in vivo mouse tumors and determined the mechanisms of adaptive XPO1 inhibitor resistance using protein and genomic arrays. Pathway analyses revealed upregulation of the NRG1/ERBB3 pathway in SINE-resistant cells. Depletion of ERBB3 using siRNAs restored the antitumor effect of SINE in vitro and in vivo. Furthermore, exogenous NRG1 decreased the antitumor effect of SINE in ovarian cancer cell lines with high ERBB3 expression, but not in those with low expression. These results suggest that NRG1 and ERBB3 expression is a potential biomarker of response to SINE treatment. The antitumor effect of SINE was reduced by exogenous NRG1 in an ERBB3-dependent manner. These findings suggest that NRG1 and ERBB3 are effective biomarkers that should be evaluated in future clinical trials and are relevant therapeutic targets for the treatment of SINE-resistant cancers.
Abstract A14: Modeling drug combination sensitivity with Hopfield networks and transcriptomics data
Authors: Piermarocchi Carlo , Domanskyi Sergii , Hakansson Alex , Paternostro Giovanni 
Published: June 2020

Abstract
The Hopfield neural network model is one of the simplest models able to mathematically implement Waddington’s interpretation of normal and anomalous cell phenotypes as dynamical attractors of epigenetic landscapes. Here, we propose a computational approach based on Hopfield’s associative memories that integrate gene expression data and gene interactome networks in (1) a model representing the dynamics and control of disease progression in multiple myeloma (MM), and (2) a model describing the control of angiogenesis. The MM model is built using single-cell RNA-seq data from bone marrow aspirates of MM patients as well as patients diagnosed with monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), two medical conditions that often progress to full MM. We identify different clusters of MGUS, SMM, and MM cells, map them to Hopfield associative memory patterns, and model the dynamics of transition between the different patterns. The model is then used to identify combinations of genes whose simultaneous inhibition is associated with delayed disease progression. In the angiogenesis control model, we use single-cell RNA-seq data to predict specific combinations of targets for inhibition that could induce a cellular transition from tip-like to stalk-like endothelial cells, inhibiting the formation of capillary sprouts in blood vessels. The model generates novel hypotheses for combinations that could complement standard VEGF inhibitors and lead to a more efficient control of angiogenesis in cancer.
Citation Format: Carlo Piermarocchi, Sergii Domanskyi, Alex Hakansson, Giovanni Paternostro. Modeling drug combination sensitivity with Hopfield networks and transcriptomics data [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr A14.
Abstract A26: Modeling the ovarian cancer immune response and tumor microenvironment
Authors: Ozmadenci Duygu , Narayanan Jayanth S. Shankara , Andrew Jacob R. , Barrie Allison M. , Jiang Shulin , Bilir Esra , Bertotto Thomas , White Rebekah R. , Kuchroo Vijay K. , Pachter Jonathan A. , Stupack Dwayne G. , Schlaepfer David D. 
Published: June 2020

Abstract
High-grade serous ovarian cancer (HGSOC) is the leading cause of death from gynecologic malignancies. Many patients initially respond well to surgery followed by chemotherapy, yet ~80% of patients recur with disease that is frequently recalcitrant to chemotherapy. Across a number of chemoresistant cancers, immunotherapies have shown great promise. Correlative studies in patients with HGSOC support a role for immune system in patient outcome. Yet the HGSOC tumor microenvironment (TME) is highly immunosuppressive, which constitutes a major barrier to immunotherapy success. Understanding the molecular signals in HGSOC that promote resistance to chemo- or immunotherapies is required for identification of actionable targets within HGSOC; yet, there are limited models that recapitulate the TME in ovarian cancer. We have generated a new syngeneic C57Bl6 mouse model of ovarian cancer that exhibits genomic copy number gains in KRAS, MYC, and (PTK2) FAK genes (termed KMF) and aggressive malignant phenotypes commonly observed in HGSOC. The KMF TME, like HGSOC, is populated by immunosuppressive myeloid-derived suppressor cells (MDSC) and T-regulatory (Treg) cells but lacks CD8+ T cell infiltration. We find that tumor-associated FAK expression and kinase activity are essential for KMF tumor growth. Mechanistically, by knockout and cell reconstitution approaches, FAK promotes expression of a select group of proteins mediating chemo- and immune-resistance. Inhibiting FAK modulates checkpoint inhibitor protein expression, limits MDSC and Treg recruitment, and enhances CD4 and CD8 T cell infiltration. Pharmacologic FAK inhibition reduced CD112/CD155 expression on KMF cells and, together with anti-TIGIT immunotherapy, significantly increased mouse survival from 28 to 60+ days. The chemoresistant KMF model recapitulates key aspects of the aggressive HGSOC TME including the generation of an immunosuppressive milieu, and may be used as a preclinical model to identify new therapeutic targets for HGSOC.
Citation Format: Duygu Ozmadenci, Jayanth S. Shankara Narayanan, Jacob R. Andrew, Allison M. Barrie, Shulin Jiang, Esra Bilir, Thomas Bertotto, Rebekah R. White, Vijay K. Kuchroo, Jonathan A. Pachter, Dwayne G. Stupack, David D. Schlaepfer. Modeling the ovarian cancer immune response and tumor microenvironment [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr A26.
Abstract A31: Tumor stroma in the development of acquired cancer therapy resistance
Authors: Gomez-Escudero Jesus , Maniati Eleni , Whiting Freddie , Wang Jun , Graham Trevor , Hodivala-Dilke Kairbaan 
Published: June 2020

Abstract
Despite the onset of new treatment strategies, mortality rates for breast cancer are estimated at approximately 600,000 women per year, mostly due to acquired resistance to therapy. Chemotherapy, often combination therapy, includes DNA-damaging agents such as epirubicin, an epimer of doxorubicin. Although chemotherapy has been reported to reduce recurrence rates by 50% over two years, eight-year survival rates are approximately 30% and overall mortality is 20-25%. Studies aiming to overcome resistance to therapy have focused mainly on in vitro malignant cell assays. These have failed to deliver appropriate targets to overcome resistance because they have failed to account for the influence of the tumor microenvironment on chemoresistance. Published evidence indicates that resistance to therapy is not malignant cell-intrinsic, but instead depends on DNA-damaging chemotherapy-induced changes in paracrine signals from endothelial cells. Our current research has established that the doxorubicin treatment acutely affects endothelial cells with long-term effects on tumor cell resistance to therapy in vivo. Endothelial cells are heterogenous, and the effect of DNA damage on endothelial cell evolution and how this regulates malignant cell resistance to therapy is unknown. We have observed that orthotopic murine mammary tumors arising from the same source of primary mammary tumor cells show differential chemotherapy responses. RNA seq analysis of tumors after acute doxorubicin treatment reveal highest levels of differential transcript expression in endothelial cells compared with cancer-associated fibroblasts or malignant cells. In vitro assays show that conditioned media from tumor endothelial cells treated with chemotherapy can protect tumor cells from DNA damage and cell death. Current analysis now focuses on analyzing the complexity of endothelial cell regulation of tumor cell response to chemotherapy and how this could model clonal evolution of tumor cells. We aim to create a chemoresistance stromal evolution signature, to determine the individual components of this and commonalities between cancers and possible drug effects. Thus, our data could change the paradigm of drug resistance and define how stromal compartments regulate acquired resistance.
Citation Format: Jesus Gomez-Escudero, Eleni Maniati, Freddie Whiting, Jun Wang, Trevor Graham, Kairbaan Hodivala-Dilke. Tumor stroma in the development of acquired cancer therapy resistance [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr A31.
Abstract A46: A novel patient-derived approach for preclinical evaluation of predictive imaging biomarkers in early lung cancer
Authors: Koziolek Eva J. , Martin Desiree , Liu Jie , Barrio Jorge R. , Wallace W. Dean , Shackelford David B. , Yanagawa Jane , Dubinett Steven , Scafoglio Claudio 
Published: June 2020

Abstract
Background: Lung cancer is the number one cause of cancer-related death, and lung adenocarcinoma (LUAD) is the most frequent type. Lung screening with computed tomography has allowed detection of early nodules that need diagnostic definition. We have identified the sodium-dependent glucose transporter 2 (SGLT2) as a novel diagnostic and therapeutic target that may aid the identification and the treatment of early LUAD. However, a limitation of these studies is the lack of experimental models of early cancer. Patient-derived xenografts (PDXs) are a reliable tool of translational oncology. However, the establishment of PDXs from early-stage, low-grade LUAD is characterized by low efficiency and extremely long experimental times. To study the predictive value of SGLT2 activity in early LUAD, we have established an alternative model based on a double culture system: 1) implantation of tumor tissue on the chorioallantoic membrane (CAM) of the chicken egg (in ovo system), which can be imaged only 1 week after the patient surgery; 2) growth of tumor spheroids in 3D in vitro culture, to test response to treatments.
Methods: Each PDX of LUAD is divided in two specimens: one for in ovo growth in the CAM assay and one for the 3D culture as tumor spheroids. The CAM xenografts are imaged with two different tracers to characterize glucose uptake: [18F] fluorodeoxyglucose (FDG), to measure GLUT activity, and 4-[18F] fluorodeoxyglucose (Me4FDG), to assess sodium-dependent glucose transport (SGLT). The PD-tumor spheroids are cultured in 96-well plates and used for treatment with SGLT2 inhibitors as well as other drugs.
Results: PET imaging of LUADs with FDG and Me4FDG revealed the presence of both glucose transporters, GLUT1 and SGLT2. Treatment of the tumor spheroids with SGLT2 inhibitors reduced cell viability and caused integrity loss in a dose-dependent manner.
Conclusion: The CAM xenograft model is a useful model for implanting PD tumor fragments and studying glucose metabolism in ovo by PET imaging with very short experimental times. Tumor fragments connect to the chicken embryo vasculature within 3-5 days, so that PD material can be analyzed soon after surgery. The Me4FDG uptake in the CAM system predicts the treatment response of tumor spheroids cultured in vitro from the same PD samples.
Citation Format: Eva J. Koziolek, Desiree Martin, Jie Liu, Jorge R. Barrio, W. Dean Wallace, David B. Shackelford, Jane Yanagawa, Steven Dubinett, Claudio Scafoglio. A novel patient-derived approach for preclinical evaluation of predictive imaging biomarkers in early lung cancer [abstract]. In: Proceedings of the AACR Special Conference on the Evolving Landscape of Cancer Modeling; 2020 Mar 2-5; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2020;80(11 Suppl):Abstract nr A46.