scholarly journals TNF induces glycolytic shift in fibroblast like synoviocytes via GLUT1 and HIF1A

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kathrin Koedderitzsch ◽  
Ekaterina Zezina ◽  
Lingzi Li ◽  
Matthias Herrmann ◽  
Nadine Biesemann
Keyword(s):  
Standard Of Care ◽  
Metabolic Phenotype ◽  
Direct Role ◽  
Healthy Donors ◽  
Signaling Axis ◽  
Glut1 Expression ◽  
Potential Link ◽  
Inhibition Of Glycolysis ◽  
Patients Experience ◽  
Fibroblast Like Synoviocytes

AbstractTNF is a central cytokine in the pathogenesis of rheumatoid arthritis (RA). Elevated level of TNF causes local inflammation that affects immune cells and fibroblast-like synoviocytes (FLS). Nowadays, only 20–30% of patients experience remission after the standard of care therapy—antibodies against TNF. Interestingly, responders show reduced levels of GLUT1 and GAPDH, highlighting a potential link to cellular metabolism. The aim of the study was to investigate whether TNF directly affects the metabolic phenotype of FLS. Real-time respirometry displayed TNF-induced upregulation of glycolysis along with a modest increase of oxidative phosphorylation in FLS from healthy donors. In addition, TNF stimulation enhanced HIF1A and GLUT1 expression. The upregulation of HIF1A and GLUT1 reflects their enriched level in FLS from RA patients (RA-FLS). The inhibition of TAK1, HIF1a and hexokinase deciphered the importance of TNF/TAK1/HIF1A/glycolysis signaling axis. To prove that inhibition of glycolysis reduced the pathogenic phenotype, we showed that 2-deoxyglucose, a hexokinase inhibitor, partially decreased secretion of RA biomarkers. In summary, we identified a direct role of TNF on glycolytic reprogramming of FLS and confirmed the potency of immunometabolism for RA. Further studies are needed to evaluate the therapeutic impact especially regarding non-responder data.

Caring in Nursing Practice: The Development of a Conceptual Framework

2003 ◽  
Vol 17 (2) ◽  
pp. 101-116 ◽  
Author(s):  
Tanya V. McCance
Keyword(s):  
Conceptual Framework ◽  
Narrative Analysis ◽  
Well Being ◽  
Psychological Needs ◽  
Dual Nature ◽  
Qualitative Research Study ◽  
Organizational Issues ◽  
Potential Link ◽  
Discharge From Hospital ◽  
Patients Experience

This article reports the results of a qualitative research study which explored patients’ experience of caring. To elicit stories relating to the experience of caring, a hermeneutic approach was selected incorporating a narrative method. One-to-one interviews were conducted with 24 patients in their homes, shortly after discharge from hospital. The findings uncovered a number of categories comprising the experience of caring in nursing. This resulted in the development of the conceptual framework based on Donabedian’s constructs of structure, process and outcome. Structures included nurse attributes, organizational issues, and patient attributes. Processes comprised the activities of caring, which included providing for patients’ physical and psychological needs, being attentive, getting to know the patient, taking time, being firm, showing respect, and the extra touch. The outcomes emanated from the process of caring and included a feeling of well-being, patient satisfaction, and effect on the environment. The conceptual framework emphasizes a potential link between the three constructs. Data from narrative analysis suggest a positive linear relationship between the structures required for the process that lead to patient outcomes. When compared to current theoretical literature, the findings support elements of existing theories. These include the importance of the nurse attributes for professional caring (structure), the activities of caring, which can be viewed as nurse interventions and the dual nature of caring, which encompasses attitudes and actions (process).

scholarly journals Metabolic Reprogramming in Breast Cancer and Its Therapeutic Implications

Cells ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 89 ◽  
Author(s):  
Nishant Gandhi ◽  
Gokul Das
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor Alpha ◽  
Cancer Metabolism ◽  
Growth Factor Receptor ◽  
Standard Of Care ◽  
Metabolic Reprogramming ◽  
Metabolic Phenotype ◽  
Current Standard ◽  
Therapeutic Implications ◽  
Altered Metabolism

Current standard-of-care (SOC) therapy for breast cancer includes targeted therapies such as endocrine therapy for estrogen receptor-alpha (ERα) positive; anti-HER2 monoclonal antibodies for human epidermal growth factor receptor-2 (HER2)-enriched; and general chemotherapy for triple negative breast cancer (TNBC) subtypes. These therapies frequently fail due to acquired or inherent resistance. Altered metabolism has been recognized as one of the major mechanisms underlying therapeutic resistance. There are several cues that dictate metabolic reprogramming that also account for the tumors’ metabolic plasticity. For metabolic therapy to be efficacious there is a need to understand the metabolic underpinnings of the different subtypes of breast cancer as well as the role the SOC treatments play in targeting the metabolic phenotype. Understanding the mechanism will allow us to identify potential therapeutic vulnerabilities. There are some very interesting questions being tackled by researchers today as they pertain to altered metabolism in breast cancer. What are the metabolic differences between the different subtypes of breast cancer? Do cancer cells have a metabolic pathway preference based on the site and stage of metastasis? How do the cell-intrinsic and -extrinsic cues dictate the metabolic phenotype? How do the nucleus and mitochondria coordinately regulate metabolism? How does sensitivity or resistance to SOC affect metabolic reprogramming and vice-versa? This review addresses these issues along with the latest updates in the field of breast cancer metabolism.

Effect of a novel agent, SL-401, targeting interleukin-3 (IL-3)-receptor on plasmacytoid dendritic cell (pDC)-induced myeloma cell growth and drug resistance.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8582-8582
Author(s):  
Dharminder Chauhan ◽  
Arghya Ray ◽  
Christopher Brooks ◽  
Eric K. Rowinsky ◽  
Kenneth Carl Anderson
Keyword(s):  
Drug Resistance ◽  
Cell Growth ◽  
Cell Lines ◽  
Plasmacytoid Dendritic Cell ◽  
Myeloma Cell ◽  
Healthy Donors ◽  
Signaling Axis ◽  
Novel Therapeutic Strategies

8582 Background: Multiple myeloma (MM) remains incurable despite novel therapies, highlighting the need for further identification of factors mediating disease progression and drug resistance. The bone marrow (BM) microenvironment confers growth, survival, and drug resistance in MM cells. Our recent study utilized in vitro and in vivo MM xenograft models to show that plasmacytoid dendritic cells (pDCs) were significantly increased in MM BM and promote MM growth (Chauhan et al., Cancer Cell 2009, 16:309). Importantly, we found increased IL-3 levels upon pDC-MM interaction, which in turn, trigger MM cell growth and pDCs survival. IL-3R is highly expressed on pDCs. We utilized SL-401, a novel biologic conjugate that targets IL-3R, to examine whether abrogation of IL-3–IL-3R signaling axis affects pDC-MM interaction and its tumor promoting sequelae. Methods: MM cell lines, patient MM cells, and pDCs from healthy donors or MM patients were utilized to study the anti-MM activity of SL-401. MM cells and pDCs were cultured alone or together in the presence or absence of SL-401, followed by analysis of cell growth or viability. Results: SL-401 significantly decreased the viability of pDCs at low concentrations (IC50: 0.83 ng/ml; P < 0.005, n = 3). SL-401 also decreased the viability of MM cells at clinically achievable doses. Co-culture of pDCs with MM cells induced growth of MM cell lines; and importantly, low doses (0.8 ng/ml) of SL-401 blocked MM cell growth-promoting activity of pDCs. MM patient-derived pDCs induced growth of MM cell lines and primary MM cells as well; conversely, SL-401 inhibited pDC-triggered MM cell growth (P < 0.005, n= 5). Tumor cells from 3 of the 5 patients were from patients whose disease was progressing while on bortezomib, dexamethasone, and lenalidomide therapies. In agreement with these results, SL-401 blocked pDC-induced growth of dexamethasone-resistant MM cell lines. Conclusions: Our study therefore provides the basis for directly targeting pDCs or blocking the pDC-MM interaction, as well as targeting MM, in novel therapeutic strategies with SL-401 to enhance MM cytotoxicity, overcome drug-resistance, and improve patient outcome.

scholarly journals Prophylaxis in von Willebrand Disease: Coming of Age?

2016 ◽  
Vol 42 (05) ◽  
pp. 498-506 ◽  
Author(s):  
Giorgia Saccullo ◽  
Mike Makris
Keyword(s):  
Coming Of Age ◽  
Severe Disease ◽  
Standard Of Care ◽  
Von Willebrand Disease ◽  
The Past ◽  
Patients Experience ◽  
Type 3 ◽  
Von Willebrand ◽  
Willebrand Factor

Although in most cases von Willebrand disease (VWD) is a mild disorder, a subgroup of patients experience frequent bleeding. In contrast to severe hemophilia in which prophylaxis is the accepted standard of care, this is less frequently used in VWD. Most type 1 VWD patients can be adequately managed with episodic desmopressin and tranexamic acid. In patients with more severe disease, especially those with type 3 VWD, joint bleeds, epistaxis, menorrhagia, and gastrointestinal bleeding are problematic and usually require treatment with von Willebrand factor/factor VIII (VWF/FVIII) concentrate. While in the past these patients were managed with on-demand VWF/FVIII concentrate, several recent reports have demonstrated the value of prophylactic treatment. Despite some uncertainties about the economic impact of treatment of severe VWD, prophylaxis with VWF concentrate should now be considered as the standard of care for the more severe end of the spectrum of affected individuals. The recent introduction of recombinant VWF concentrate is likely to improve the acceptability of prophylaxis in VWD.

scholarly journals PI3Kγ inhibition suppresses microglia/TAM accumulation in glioblastoma microenvironment to promote exceptional temozolomide response

2021 ◽  
Vol 118 (16) ◽  
pp. e2009290118
Author(s):  
Jie Li ◽  
Megan M. Kaneda ◽  
Jun Ma ◽  
Ming Li ◽  
Ryan M. Shepard ◽  
...  
Keyword(s):  
Expression Profiles ◽  
Myeloid Cell ◽  
Standard Of Care ◽  
Genetic Inactivation ◽  
Molecular Features ◽  
Clinical Observations ◽  
Signaling Axis ◽  
Phosphoinositide 3 Kinase ◽  
Interleukin 11 ◽  
Pharmacologic Inhibition

Precision medicine in oncology leverages clinical observations of exceptional response. Toward an understanding of the molecular features that define this response, we applied an integrated, multiplatform analysis of RNA profiles derived from clinically annotated glioblastoma samples. This analysis suggested that specimens from exceptional responders are characterized by decreased accumulation of microglia/macrophages in the glioblastoma microenvironment. Glioblastoma-associated microglia/macrophages secreted interleukin 11 (IL11) to activate STAT3-MYC signaling in glioblastoma cells. This signaling induced stem cell states that confer enhanced tumorigenicity and resistance to the standard-of-care chemotherapy, temozolomide (TMZ). Targeting a myeloid cell restricted an isoform of phosphoinositide-3-kinase, phosphoinositide-3-kinase gamma isoform (PI3Kγ), by pharmacologic inhibition or genetic inactivation disrupted this signaling axis by reducing microglia/macrophage-associated IL11 secretion in the tumor microenvironment. Mirroring the clinical outcomes of exceptional responders, PI3Kγ inhibition synergistically enhanced the anti-neoplastic effects of TMZ in orthotopic murine glioblastoma models. Moreover, inhibition or genetic inactivation of PI3Kγ in murine glioblastoma models recapitulated expression profiles observed in clinical specimens isolated from exceptional responders. Our results suggest key contributions from tumor-associated microglia/macrophages in exceptional responses and highlight the translational potential for PI3Kγ inhibition as a glioblastoma therapy.

scholarly journals Dysfunction of cAMP-PKA-calcium signaling axis in striatal medium spiny neurons: a role in schizophrenia and Huntington’s disease pathogenesis

2021 ◽  
Author(s):  
Marija Fjodorova ◽  
Zoe Noakes ◽  
Daniel C. De La Fuente ◽  
Adam C. Errington ◽  
Meng Li
Keyword(s):  
Huntington's Disease ◽  
Calcium Signaling ◽  
Huntington’S Disease ◽  
Cortical Neurons ◽  
Medium Spiny Neurons ◽  
Striatal Neurons ◽  
Cell Type ◽  
Direct Role ◽  
Spiny Neurons ◽  
Signaling Axis

SummaryBackgroundStriatal medium spiny neurons (MSNs) are preferentially lost in Huntington’s disease. Genomic studies also implicate a direct role for MSNs in schizophrenia, a psychiatric disorder known to involve cortical neuron dysfunction. It remains unknown whether the two diseases share similar MSN pathogenesis or if neuronal deficits can be attributed to cell type-dependent biological pathways. Transcription factor BCL11B, which is expressed by all MSNs and deep layer cortical neurons, was recently proposed to drive selective neurodegeneration in Huntington’s disease and identified as a candidate risk gene in schizophrenia.MethodsUsing human stem cell-derived neurons lacking BCL11B as a model, we investigated cellular pathology in MSNs and cortical neurons in the context of these disorders. Integrative analyses between differentially expressed transcripts and published GWAS datasets identified cell type-specific disease-related phenotypes.ResultsWe uncover a role for BCL11B in calcium homeostasis in both neuronal types, while deficits in mitochondrial function and protein kinase A (PKA)-dependent calcium transients are detected only in MSNs. Moreover, BCL11B-deficient MSNs display abnormal responses to glutamate and fail to integrate dopaminergic and glutamatergic stimulation, a key feature of striatal neurons in vivo. Gene enrichment analysis reveals overrepresentation of disorder risk genes among BCL11B-regulated pathways, primarily relating to cAMP-PKA-calcium signaling axis and synaptic signaling.ConclusionsOur study indicates that Huntington’s disease and schizophrenia are likely to share neuronal pathogenesis where dysregulation of intracellular calcium levels is found in both striatal and cortical neurons. In contrast, reduction in PKA signaling and abnormal dopamine/glutamate receptor signaling is largely specific to MSNs.

Juvenile Idiopathic Arthritis Fibroblast-like Synoviocytes, through BMP signaling, play a central role in joint growth disturbances

2020 ◽  
Author(s):  
Megan Simonds ◽  
Amanda Schlefman ◽  
Suzanne McCahan ◽  
Kathleen Sullivan ◽  
Carlos Rose ◽  
...  
Keyword(s):  
Juvenile Idiopathic Arthritis ◽  
Synovial Cell ◽  
Synovial Fibroblasts ◽  
Cell Types ◽  
Bmp Signaling ◽  
Conditioned Media ◽  
Chondrocyte Proliferation ◽  
Direct Role ◽  
Tgfβ Receptors ◽  
Fibroblast Like Synoviocytes

Abstract Background: To examine critical interactions between juvenile idiopathic arthritis synovial fibroblasts (JFLS) and chondrocytes (Ch), and their role in bony overgrowth seen in patients with juvenile idiopathic arthritis (JIA). Methods: Control (CFLS) and JFLS were cultured in media containing recombinant BMP4. Ch were cultured in either CFLS or JFLS conditioned-media. Media supernatants were analyzed by ELISA. RNA was analyzed by ClariomS microarray. Results: As expected, genes expressed in JFLS and CFLS were similar to each other and this expression differed from Ch. JFLS favor BMP ligand gene expression while downregulating TGFβ receptors’ expression. Noggin and chordin, antagonists with high affinity for BMP4, are JFLS- but not Ch-preferred regulators of BMP signaling. Compared to Ch, JFLS overexpress collagen X (COLX), a marker of chondrocyte hypertrophy. Exogenous BMP4 causes JFLS to significantly decrease expression of noggin and collagen II (COL2), a marker of chondrocyte proliferation, and causes overexpression of COLX and alkaline-phosphatase (ALP). Chondrocytes cultured in JFLS-conditioned media (Ch-JFLS) express BMP genes and favor chordin protein expression over other antagonists. Ch-JFLS have significantly increased expression of COL2 and significantly decreased expression of COLX. Conclusions: These data suggest JFLS, in the presence of BMP4, undergo hypertrophy and that JFLS-conditioned media influence chondrocytes to become highly proliferative. To the authors’ knowledge, no prior study has shown that JFLS and chondrocytes play a direct role in the bony overgrowth in joints of patients with JIA and that BMPs or regulation of these growth factors influence the interaction between two prominent synovial cell types.

scholarly journals Current challenges and unmet medical needs in myelodysplastic syndromes

Leukemia ◽  
2021 ◽  
Author(s):  
Uwe Platzbecker ◽  
Anne Sophie Kubasch ◽  
Collin Homer-Bouthiette ◽  
Thomas Prebet
Keyword(s):  
Acute Myeloid Leukemia ◽  
Myelodysplastic Syndromes ◽  
Myeloid Leukemia ◽  
Unmet Need ◽  
Standard Of Care ◽  
Medical Needs ◽  
Risk Of Progression ◽  
History Of ◽  
Patients Experience ◽  
Acute Myeloid

AbstractMyelodysplastic syndromes (MDS) represent a heterogeneous group of myeloid neoplasms that are characterized by ineffective hematopoiesis, variable cytopenias, and a risk of progression to acute myeloid leukemia. Most patients with MDS are affected by anemia and anemia-related symptoms, which negatively impact their quality of life. While many patients with MDS have lower-risk disease and are managed by existing treatments, there currently is no clear standard of care for many patients. For patients with higher-risk disease, the treatment priority is changing the natural history of the disease by delaying disease progression to acute myeloid leukemia and improving overall survival. However, existing treatments for MDS are generally not curative and many patients experience relapse or resistance to first-line treatment. Thus, there remains an unmet need for new, more effective but tolerable strategies to manage MDS. Recent advances in molecular diagnostics have improved our understanding of the pathogenesis of MDS, and it is becoming clear that the diverse nature of genetic abnormalities that drive MDS demands a complex and personalized treatment approach. This review will discuss some of the challenges related to the current MDS treatment landscape, as well as new approaches currently in development.

scholarly journals CLRM-13. INTRAOPERATIVE MICRODIALYSIS: GLIOMA INTELLIGENCE FROM BEHIND ENEMY LINES

2021 ◽  
Vol 3 (Supplement_4) ◽  
pp. iv4-iv4
Author(s):  
Cecile Riviere-Cazaux ◽  
Terry Burns
Keyword(s):  
Extracellular Fluid ◽  
Standard Of Care ◽  
Tca Cycle ◽  
Tumor Burden ◽  
Metabolic Phenotype ◽  
Human Gliomas ◽  
Correlation Clustering ◽  
Prior Therapy ◽  
Metabolic Signature ◽  
Formidable Challenge

Abstract INTRODUCTION Gliomas present a formidable challenge for translational progress. Heterogeneity within and between tumors may demand empirically individualized and adaptive paradigms requiring rapid mechanistic feedback. We asked if tumor-associated metabolic biomarkers from glioma extracellular fluid could impart mechanistic “intelligence” reflecting intra- and inter-tumoral heterogeneity. METHODS Five live human gliomas (2 oligos; 2 IDH-WT GBMs; 1 IDH-mutant GBM), were evaluated in situ with high molecular weight (100kDA) intraoperative microdialysis using 3 disparately placed catheters. Isotonic 3% dextran perfusate was collected in 20 min (40mL) aliquots. CSF samples (n=21) were additionally evaluated from these and other patients with diverse brain tumors. The IDH-mutant glioma-associated oncometabolite D2-hydroxyglutarate (D2-HG) was quantified with targeted Liquid Chromotography-Mass Spectrometry (LC-MS). Over 200 metabolites were further evaluated via untargeted LC-MS using the Metabolon platform. Correlation, clustering, ROC and enrichment analyses were employed to identify correlations within and between patient samples. RESULTS CSF samples from patients with IDH-mutant gliomas contained over twenty-fold higher levels of D2-HG (median 4.1 mM, range 1.6-13.2, n=7) compared to those from IDH-wild type tumors (median 0.19 mM; range 0.89-0.35, n=14). Microdialysate from IDH-mutant gliomas contained 10-953mM D2-HG, 9-63x higher than paired CSF samples. Interestingly, IDH status failed to predict the global metabolic signature of microdialysate. Microdialysate samples clustered into 2 major metabolic phenotype clusters with IDH-WT and IDH-mutant gliomas in each cluster. A superimposed metabolic signature distinguishing enhancing from non-enhancing tumor, was conserved in both patient clusters. Amino acid and carnitine metabolism predominated in microdialysate signatures. TCA cycle and Warburg-associated metabolites were differentially enriched in CSF samples after prior therapy independent of tumor burden. CONCLUSIONS Intra-operative micro-dialysis may complement currently available “intelligence” regarding the phenotype, burden, and metabolism of live human gliomas and is feasible within standard-of-care surgical procedures. Future work will evaluate utility for pharmacodynamic feedback following novel early phase candidate therapies.

TeleTriage at a high-volume specialty cancer center: Aligning patient volume and need with available resource.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 2085-2085
Author(s):  
Stutman E Robin ◽  
Jason Napoli ◽  
Erika Duggan ◽  
Danny Joseph ◽  
Eoin Dawson ◽  
...  
Keyword(s):  
Care Center ◽  
Standard Of Care ◽  
High Volume ◽  
Urgent Care ◽  
Cancer Center ◽  
Patient Volume ◽  
Complete Evaluation ◽  
Urgent Care Center ◽  
Patients Experience ◽  
At Home

2085 Background: The Memorial Sloan Kettering (MSK) Urgent Care Center (UCC) functions as the emergency room for MSK. With 23,000+ visits annually, increasing volume and acuity means more days over capacity. Patients experience increased wait times to see clinicians, complete evaluation, and transfer to an inpatient bed. The UCC TeleTriage Program is a remote triage program which aims to align patient volume and need with available resources, improve patient experience, and streamline flow through the UCC. By managing resources more efficiently and expediting initial evaluation, the program promotes timely patient access to care, while maintaining MSK's standard of care. Methods: UCC TeleTriage began July 2018 with the Gastrointestinal Medical Oncology service. The Service Nurse refers patients to TeleTriage on weekdays, from 9a.m.- 4:30p.m. The TeleTriage clinician contacts each patient within 30 minutes of referral, takes the history, and determines the initial plan. Patients are directed to a local ER, clinic, or UCC based on level of acuity, real-time GPS, and specific need. For stable patients coming to UCC, TeleTriage focuses on initiating testing prior to registration in UCC. Results: TeleTriage patients have (virtual) contact with a UCC clinician within 30 minutes of referral, whereas non-TeleTriage patients wait 110 minutes or more. TeleTriage patients are discharged from UCC up to 42 minutes more rapidly. TeleTriage patients who receive imaging prior to registration in UCC receive a final disposition up to 93 minutes sooner. About 4% of TeleTriage patients are managed at home. In a small number of TeleTriage patients with severe complications of cancer-treatment, significant morbidity was avoided due to early intervention and coordination of care. Conclusions: TeleTriage patients have contact with a UCC clinician measurably faster than non-TeleTriage patients. Their evaluation is also started earlier. By managing less acute patients at remote sites or at home, TeleTriage can help patients avoid unnecessary travel, (time) expenditure, and hospital contact. TeleTriage patients who come to UCC, spend less time in UCC than non-TeleTriage patients and they discharge faster. By utilizing cancer care expertise, TeleTriage can significantly impact patient outcomes and utilize resources more effectively.

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