bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of exercise-heat acclimation on cardiac autonomic modulation in type 2 diabetes: a pilot study
Authors: Macartney Michael J. , Notley Sean R. , Herry Christophe L. , Sigal Ronald J. , Boulay Pierre , Kenny Glen P. 
Published: November 2020

The effects of exercise-heat acclimation on heart rate variability (HRV) in individuals with type 2 diabetes (T2D) remains unclear. We assessed electrocardiogram recordings during exercise-heat stress in middle-aged-to-older individuals (50–70 years) with (n = 6) and without (control; n = 8;) T2D, before and after 7 days of exercise-heat acclimation. Exercising heart rate was reduced (control, −9 ± 5 bpm; T2D, −14 ± 9 bpm) yet HRV was not significantly different. Given the negative correlations between diminished HRV and cardiac risk observed in the scientific literature, further research is warranted. Novelty: Our observations indicate that 7 days exercise-heat acclimation may not effectively attenuate the deviation toward reduced overall HRV and unfavourable cardiac autonomic modulation in individuals with T2D.
The tyrosine kinase inhibitor crizotinib influences blood glucose and mRNA expression of GLUT4 and PPARs in the heart of rats with experimental diabetes
Authors: Hadova Katarina , Mesarosova Lucia , Kralova Eva , Doka Gabriel , Krenek Peter , Klimas Jan 
Published: November 2020

Tyrosine kinases inhibitors (TKIs) may alter glycaemia and may be cardiotoxic with importance in the diabetic heart. We investigated the effect of multi-TKI crizotinib after short-term administration on metabolic modulators of the heart of diabetic rats. Experimental diabetes mellitus (DM) was induced by streptozotocin (STZ; 80 mg·kg–1, i.p.), and controls (C) received vehicle. Three days after STZ, crizotinib (STZ+CRI; 25 mg·kg–1 per day p.o.) or vehicle was administered for 7 days. Blood glucose, C-peptide, and glucagon were assessed in plasma samples. Receptor tyrosine kinases (RTKs), cardiac glucose transporters, and peroxisome proliferator-activated receptors (PPARs) were determined in rat left ventricle by RT-qPCR method. Crizotinib moderately reduced blood glucose (by 25%, P < 0.05) when compared to STZ rats. The drug did not affect levels of C-peptide, an indicator of insulin secretion, suggesting altered tissue glucose utilization. Crizotinib had no impact on cardiac RTKs. However, an mRNA downregulation of insulin-dependent glucose transporter Glut4 in the hearts of STZ rats was attenuated after crizotinib treatment. Moreover, crizotinib normalized Ppard and reduced Pparg mRNA expression in diabetic hearts. Crizotinib decreased blood glucose independently of insulin and glucagon. This could be related to changes in regulators of cardiac metabolism such as GLUT4 and PPARs.
Stress correlation function and linear response of Brownian particles
Authors: Vogel Florian , Fuchs Matthias 
Published: November 2020

Abstract.
We determine the non-local stress autocorrelation tensor in an homogeneous and isotropic system of interacting Brownian particles starting from the Smoluchowski equation of the configurational probability density. In order to relate stresses to particle displacements as appropriate in viscoelastic states, we go beyond the usual hydrodynamic description obtained in the Zwanzig-Mori projection-operator formalism by introducing the proper irreducible dynamics following Cichocki and Hess, and Kawasaki. Differently from these authors, we include transverse contributions as well. This recovers the expression for the stress autocorrelation including the elastic terms in solid states as found for Newtonian and Langevin systems, in case that those are evaluated in the overdamped limit. Finally, we argue that the found memory function reduces to the shear and bulk viscosity in the hydrodynamic limit of smooth and slow fluctuations and derive the corresponding hydrodynamic equations.

Graphical abstract
Photonic composite materials from cellulose nanorods and clay nanolayers
Authors: Trindade Ana C. , Carreto Miguel , Helgesen Geir , Knudsen Kenneth D. , Puchtler Florian , Breu Josef , Fernandes Susete , Godinho Maria Helena , Fossum Jon Otto 
Published: November 2020

AbstractCellulose nano crystals (CNCs) are promising materials for energy efficient buildings related to the control of reflectivity and heat absorption/reflection of light. In this sense it is important to improve CNCs films fire retardant properties, which can be achieved by adding clays. Cellulose nanocrystals (CNCs) and nanolayers obtained from Sodium Fluorohectorite (NaFh) synthetic clay are both known to form liquid crystalline phases in aqueous suspensions. CNCs form cholesteric phases, which structure is preserved after water evaporation, while dry NaFh nanolayers aligned films collapse. In this initial work, it is shown that CNCs are compatible with NaFh clay. We demonstrate that the liquid crystalline phase of CNCs in water is not destroyed by the presence of NaFh nanolayers. The NaFh nanolayers act as planar anchoring surfaces to the cellulose nanorods and, after evaporation of the water coloured films are obtained. The precursor solutions and the photonic films were investigated by Describe several techniques.
Diffusion and steady state distributions of flexible chemotactic enzymes
Authors: Agudo-Canalejo Jaime , Golestanian Ramin 
Published: November 2020

AbstractMany experiments in recent years have reported that, when exposed to their corresponding substrate, catalytic enzymes undergo enhanced diffusion as well as chemotaxis (biased motion in the direction of a substrate gradient). Among other possible mechanisms, in a number of recent works we have explored several passive mechanisms for enhanced diffusion and chemotaxis, in the sense that they require only binding and unbinding of the enzyme to the substrate rather than the catalytic reaction itself. These mechanisms rely on conformational changes of the enzyme due to binding, as well as on phoresis due to non-contact interactions between enzyme and substrate. Here, after reviewing and generalizing our previous findings, we extend them in two different ways. In the case of enhanced diffusion, we show that an exact result for the long-time diffusion coefficient of the enzyme can be obtained using generalized Taylor dispersion theory, which results in much simpler and transparent analytical expressions for the diffusion enhancement. In the case of chemotaxis, we show that the competition between phoresis and binding-induced changes in diffusion results in non-trivial steady state distributions for the enzyme, which can either accumulate in or be depleted from regions with a specific substrate concentration.
Macrophage-Based Approaches for Cancer Immunotherapy
Authors: Anderson Nicholas R. , Minutolo Nicholas G. , Gill Saar , Klichinsky Michael 
Published: November 2020

Abstract
Adoptive cell therapy with genetically modified T cells has generated exciting outcomes in hematologic malignancies, but its application to solid tumors has proven challenging. This gap has spurred the investigation of alternative immune cells as therapeutics. Macrophages are potent immune effector cells whose functional plasticity leads to antitumor as well as protumor function in different settings, and this plasticity has led to notable efforts to deplete or repolarize tumor-associated macrophages. Alternatively, macrophages could be adoptively transferred after ex vivo genetic modification. In this review, we highlight the role of macrophages in solid tumors, the progress made with macrophage-focused immunotherapeutic modalities, and the emergence of chimeric antigen receptor macrophage cell therapy.
Entinostat plus Pembrolizumab in Patients with Metastatic NSCLC Previously Treated with Anti–PD-(L)1 Therapy
Authors: Hellmann Matthew D. , Jänne Pasi A. , Opyrchal Mateusz , Hafez Navid , Raez Luis E. , Gabrilovich Dmitry I. , Wang Fang , Trepel Jane B. , Lee Min-Jung , Yuno Akira , Lee Sunmin , Brouwer Susan , Sankoh Serap , Wang Lei , Tamang David , Schmidt Emmett V. , Meyers Michael L. , Ramalingam Suresh S. , Shum Elaine , Ordentlich Peter 
Published: November 2020

Abstract

Purpose:
New therapies are needed to treat immune checkpoint inhibitor–resistant non–small cell lung cancer (NSCLC) and identify biomarkers to personalize treatment. Epigenetic therapies, including histone deacetylase inhibitors, may synergize with programmed cell death-1 (PD-1) blockade to overcome resistance. We report outcomes in patients with anti-programmed cell death ligand-1 [PD-(L)1]–resistant/refractory NSCLC treated with pembrolizumab plus entinostat in ENCORE 601.

Patients and Methods:
The expansion cohort of ENCORE 601 included patients with NSCLC who previously experienced disease progression with immune checkpoint inhibitors. The primary endpoint for the phase II expansion cohort is overall response rate (ORR); safety, tolerability, and exploratory endpoints are described.

Results:
Of 76 treated patients, 71 were evaluable for efficacy. immune-regulated RECIST–assessed ORR was 9.2% [95% confidence interval (CI): 3.8–18.1], which did not meet the prespecified threshold for positivity. Median duration of response was 10.1 months (95% CI: 3.9–not estimable), progression-free survival (PFS) at 6 months was 22%, median PFS was 2.8 months (95% CI: 1.5–4.1), and median overall survival was 11.7 months (95% CI: 7.6–13.4). Benefit was enriched among patients with high levels of circulating classical monocytes at baseline. Baseline tumor PD-L1 expression and IFNγ gene expression were not associated with benefit. Treatment-related grade ≥3 adverse events occurred in 41% of patients.

Conclusions:
In anti–PD-(L)1–experienced patients with NSCLC, entinostat plus pembrolizumab did not achieve the primary response rate endpoint but provided a clinically meaningful benefit, with objective response in 9% of patients. No new toxicities, including immune-related adverse events, were seen for either drug. Future studies will continue to evaluate the association of monocyte levels and response.
Abstract IA-15: Metabolic networks in the pancreatic tumor microenvironment
Authors: Lyssiotis Costas A. 
Published: November 2020

Abstract
Pancreatic tumors are dynamic pseudo-organs that contain numerous cell types interacting to create unique physiology. A typical pancreatic tumor is made up largely of stromal fibroblasts and immune cell populations, rather than cancer cells. These non-malignant cells act collaboratively to create a dense fibrotic matrix that blocks cancer cells from accessing nutrients and oxygen by inhibiting vascularization. The cancer cells are thus in a state of near-starvation and must employ unorthodox methods to obtain nutrients to support their bioenergetic and biosynthetic needs. Our group has provided foundational work describing the cell autonomous reprogramming of metabolic processes in the cancer cells to facilitate survival and growth under these challenging circumstances. Beyond cell intrinsic metabolic alterations, pancreatic cancer cells also work cooperatively with non-cancer cells in the tumor microenvironment through the exchange of growth factors, signaling molecules and metabolites. In this seminar, I will describe new work illuminating pathways of metabolic crosstalk among pancreatic cancer-associated fibroblasts, tumor associated macrophages, and malignant pancreatic cancer cells in maintenance of tumor growth, survival and therapeutic resistance.
Citation Format: Costas A. Lyssiotis. Metabolic networks in the pancreatic tumor microenvironment [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr IA-15.
Abstract IA-17: Mechanisms of pancreatic cancer-induced cachexia
Authors: Pryce Benjamin , Ratnam Nivedita , Talbert Erin E. , Dilhoff Mary , Schmidt Carl R. , Wang David J. , Guttridge Denis C. 
Published: November 2020

Abstract
Cachexia is a debilitating syndrome that results in severe, involuntary weight loss due to the depletion of skeletal muscle mass. Currently, no effective therapy exists to combat this malignant disorder. For pancreatic cancer, 85% of patients lose on average 14% of their pre-illness weight, and cachexia dramatically limits their ability to tolerate surgery, chemo- or radiotherapy. New therapies will likely evolve from an enhanced understanding of the mechanisms leading to muscle wasting and tumor development. Our laboratory has been examining the role of the NF-κB signaling pathway in tumorigenesis for several decades and that interest led us to discover the connection between NF-κB and muscle wasting in cancer cachexia and more recently in pancreatic cancer. We view the pathway as playing two separate functions in pancreatic cancer-induced cachexia. The first occurs at the level of skeletal muscle, or more preciously in skeletal muscle stem cells. We have found that during cancer progression, skeletal muscle undergoes a type of injury response leading to the activation of resident stem cells to engage in a regeneration program. NF-κB is activated in these stem cells and functions to inhibit regeneration, which contributes to the overall wasting process in cachexia. New data reveal that NF-κB activity in progenitor cells also regulates a local muscle inflammatory environment that might also contribute to skeletal muscle catabolism. The mechanism of this regulation will be discussed in more details. The second function of NF-κB signaling that we are pursuing focuses in the tumor microenvironment of pancreatic cancer. Using orthotopic mouse models of pancreatic cancer, we showed that NF-κB plays a critical role in protecting tumor cells from the surveillance property of anti-tumor macrophages. This occurs through the direct transcriptional regulation of the immunosuppressive cytokine, GDF15. Interestingly, circulating levels of GDF15 are elevated in cachectic patients and recent studies indicate that this cytokine might be an attractive therapeutic target in cancer cachexia. Together, we speculate that NF-κB functions in cancer cachexia by acting in muscle stem cells to block muscle repair, as well as promoting pancreatic cancer through the production of immunosuppressive genes such as GDF15.
Citation Format: Benjamin Pryce, Nivedita Ratnam, Erin E. Talbert, Mary Dilhoff, Carl R. Schmidt, David J. Wang, Denis C. Guttridge. Mechanisms of pancreatic cancer-induced cachexia [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr IA-17.
Abstract PO-017: Targeting NF-kB pathway through IRAK4 renders immune checkpoint blockade effective in pancreatic cancer
Authors: Zhang Daoxiang , Somani Vikas , Dodhiawala Paarth B. , Grierson Patrick M. , Li Lin , Seehra Kuljeet , Liu Xiuting , Knolhoff Brett L. , Ruzinova Marianna B. , DeNardo David G. , Lim Kian-Huat 
Published: November 2020

Abstract
Effective immunotherapy in pancreatic ductal adenocarcinoma (PDAC) is impeded by multiple barriers in the tumor microenvironment. These include the dense extracellular matrix (ECM), excessive inhibitory myeloid cells, cytokines and chemokines, which collectively incapacitate anti-tumour T cells. Constitutive activation the NF-kB pathway is a mechanism that drives intrinsic survival of PDAC cells and stromal fibrosis, but its impact on anti-tumour immunity has not been investigated. Using The Cancer Genome Atlas database, we found that expression of RELA, a canonical NF-kB factor, in PDAC samples is associated with activated stroma and lower cytotoxic T cell signatures. In a PDAC tissue microarray, the staining intensity of activated IRAK4, the innate immune kinase that drives NF-kB signaling, negatively correlates with T cell abundance. Based on these findings, we investigated the immunological impact role of IRAK4 in PDAC. Transcriptomic analysis showed that ablation of IRAK4 in PDAC cells downregulates NF-kB and inflammatory signatures, and markedly decreases transcription of hyaluronan synthase 2 (HAS2). Accordingly, pharmacologic inhibition of IRAK4 significantly decreased intratumoral hyaluronan, as well as collagen, in autochthonous PDAC mice and potentiated standard chemotherapy. Furthermore, IRAK4 inhibition also significantly reduced production of several suppressive chemokines and checkpoint ligands PD-L1 and Nectin2, leading to revitalization of infiltrative CD4+ and CD8+ T cells. These effects were partly mediated through reduction of intratumoural hyaluronan, which we recapitulated with HAS inhibitor, 4-MU. Accordingly, combined IRAK4 inhibitors with immune checkpoint blockade (ICB) especially anti-CTLA4, were highly efficacious in abrogating tumour growth in autochthonous PDAC mice and doubling their survival. In summary, we showed that targeting the NF-kB pathway through IRAK4 renders ICB effective via multiple mechanisms and should be tested in clinical trials for PDAC patients.
Citation Format: Daoxiang Zhang, Vikas Somani, Paarth B. Dodhiawala, Patrick M. Grierson, Lin Li, Kuljeet Seehra, Xiuting Liu, Brett L. Knolhoff, Marianna B. Ruzinova, David G. DeNardo, Kian-Huat Lim. Targeting NF-kB pathway through IRAK4 renders immune checkpoint blockade effective in pancreatic cancer [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-017.
Abstract PO-021: Targeting glutamine dependencies in pancreatic cancers
Authors: Kimmelman Alec , Encarnacion-Rosado Joel 
Published: November 2020

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with a 5-year survival rate of less than 10%. PDAC cells activate a non-canonical glutamine metabolic pathway essential to increase the level of NADPH, an important metabolite for redox balance, promoting tumor growth. Targeting glutamine metabolism using CB-839, a small molecule that targets glutaminase, the first step of glutaminolysis failed in PDAC. CB839 treatment only blocks the carbon utilization of glutamine and not the nitrogen portion which is critical for anabolic processes. We have previously shown that PDAC cells can rewire their metabolism and overcome GLS inhibition within days. We hypothesize that using a glutamine analog, such as 6-Diazo-5-oxo-L-norleucine (DON), which broadly inhibits all of the metabolic reactions that require glutamine, will provide a new therapeutic avenue for PDAC. Here, we investigate the role of DON in PDAC metabolism and progression. DON treatment leads to a profound decrease in proliferation, TCA cycle metabolites, and mitochondrial basal respiration in a panel of PDAC cells. In vivo studies using a syngeneic, orthotopically transplantation model in the pancreas demonstrated a significant decrease in tumor growth. Bulk RNA-seq studies demonstrated a decrease in the transcriptional signature of ECM and hypoxia, which was confirm by histology, suggesting the role of the TME in the response to glutamine blockage. Currently, we are testing the role of this drug and potential mechanisms of resistance using an autochthonous PDAC mouse model.
Citation Format: Alec Kimmelman, Joel Encarnacion-Rosado. Targeting glutamine dependencies in pancreatic cancers [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-021.
Abstract PO-022: Plasma fatty acid levels in treatment-naïve metastatic pancreatic cancer patients are associated with clinical indicators of cachexia
Authors: Gumpper Kristyn , Hart Phil A. , Belury Martha , Crowe Olivia , Cole Rachel M. , Badi Niharika , Hinton Alice , Ramsey Mitchell L. , Noonan Anne , Conwell Darwin L. , Cruz-Monserrate Zobeida 
Published: November 2020

Abstract
Cachexia is a multifactorial syndrome characterized by weight loss and tissue wasting, which is associated with reduced quality of life, responsiveness to chemotherapy, and decreased survival. We aim to determine whether changes in plasma fatty acid content in pancreatic ductal adenocarcinoma (PDAC): 1) are predictive of developing cachexia, and 2) whether these changes are influenced by other clinical parameters, like diabetes, that could contribute to malnutrition. Treatment-naïve metastatic PDAC subjects (n=51) were enrolled in NCT01280058 in which plasma samples and clinical data were collected prior to treatment. Subjects were assigned to either weight stable (&lt;5% relative body weight loss, n=26) or “cachectic” (≥5% weight loss, n=25). Plasma fatty acid composition was analyzed via gas chromatography and reported as a percentage of the total identified fatty acids. Oleic (p=0.004) and adrenic acids (p=0.018) were significantly increased in cachectic subjects, regardless of age, sex, or BMI. Docosapentaenoic n-6 acid was more commonly elevated in older cachectic subjects compared to younger subjects (p=0.048). Adrenic acid levels were higher in subjects with cachexia and diabetes compared to subjects without diabetes with cachexia (p=0.0019) or stable weight (p=0.029). Additionally, linoleic acid was lower in subjects with cachexia and diabetes compared to subjects with cachexia and no diabetes (p=0.015) and subjects with stable weight (p=0.017). Area under the receiver operator curves (AUC) showed that oleic acid (AUC=0.726) and adrenic acid (AUC=0.706) are mildly effective at predicting cachexia, and the combination slightly improved the predictive ability (AUC=0.757). Our pilot study identified several plasma fatty acids that are associated with PDAC-associated cachexia, and are influenced by age and diabetes status. Further studies examining how fatty acids contribute to or arise from the development of cachexia may create opportunities for developing effective therapies for cachexia.
Citation Format: Kristyn Gumpper, Phil A. Hart, Martha Belury, Olivia Crowe, Rachel M. Cole, Niharika Badi, Alice Hinton, Mitchell L. Ramsey, Anne Noonan, Darwin L. Conwell, Zobeida Cruz-Monserrate. Plasma fatty acid levels in treatment-naïve metastatic pancreatic cancer patients are associated with clinical indicators of cachexia [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PO-022.