Identification and Characterization of a Novel Indoleamine 2,3-Dioxygenase 1 Protein Degrader for Glioblastoma.

Indoleamine 2,3-dioxygenase 1 (IDO1) is a potent immunosuppressive enzyme that inhibits the antitumor immune response through both tryptophan metabolism and non-enzymatic functions. To date, most IDO1-targeted approaches have focused on inhibiting tryptophan metabolism. However, this class of drugs has failed to improve the overall survival of patients with cancer.

Artificial intelligence in the radiomic analysis of glioblastomas: A review, taxonomy, and perspective.

Radiological imaging techniques, including magnetic resonance imaging (MRI) and positron emission tomography (PET), are the standard-of-care non-invasive diagnostic approaches widely applied in neuro-oncology. Unfortunately, accurate interpretation of radiological imaging data is constantly challenged by the indistinguishable radiological image features shared by different pathological changes associated with tumor progression and/or various therapeutic interventions. In recent years, machine learning (ML)-based artificial intelligence (AI) technology has been widely applied in medical image processing and bioinformatics due to its advantages in implicit image feature extraction and integrative data analysis.

Cell-directed aptamer therapeutic targeting for cancers including those within the central nervous system.

Osteopontin (OPN) is produced by tumor cells as well as by myeloid cells and is enriched in the tumor microenvironment (TME) of many cancers. Given the roles of OPN in tumor progression and immune suppression, we hypothesized that targeting OPN with aptamers that have high affinity and specificity could be a promising therapeutic strategy. Bi-specific aptamers targeting ligands for cellular internalization were conjugated to siRNAs to suppress OPN were created, and therapeutic leads were selected based on target engagement and activity.

A systematic review of pharmacologic treatment efficacy for depression in older patients with cancer.

Background: Older adults ≥65 years of age represent the majority of new cancer diagnoses and are vulnerable to developing depression-like symptoms. Evaluation and management of depression in older cancer patients is underappreciated despite its high prevalence and impact on health-related quality of life. Although antidepressants are the primary pharmacologics used to treat depressive-like symptoms, the efficacy and overall benefit(s) are not well-characterized in older adult patients with cancer.

Association of Brachial Ankle Pulse Wave Velocity With New Onset Stroke in Hypertensive Patients Aged Less Than 65 With Normal Fasting Glucose Among Chinese Community-Based Population.

Background: Previous studies have shown an association of stroke and brachial ankle pulse wave velocity (baPWV). However, due to limitations on total population size and small numbers of stroke cases, lack of power has prevented further detection among subgroups such as age and laboratory testing.

Methods: A total of 19217 participants including 660 incident stroke patients were pooled in the present study.

Glioblastoma as an age-related neurological disorder in adults.

Background: Advanced age is a major risk factor for the development of many diseases including those affecting the central nervous system. Wild-type isocitrate dehydrogenase glioblastoma (IDH GBM) is the most common primary malignant brain cancer and accounts for ≥90% of all adult GBM diagnoses. Patients with IDH GBM have a median age of diagnosis at 68-70 years of age, and increasing age is associated with an increasingly worse prognosis for patients with this type of GBM.

Tumor Cell IDO Enhances Immune Suppression and Decreases Survival Independent of Tryptophan Metabolism in Glioblastoma.

Purpose: Glioblastoma (GBM) is an incurable primary brain tumor that has not benefited from immunotherapy to date. More than 90% of GBM expresses the tryptophan (Trp) metabolic enzyme, indoleamine 2,3-dioxygenase 1 (IDO). This observation supported the historical hypothesis that IDO suppresses the antitumor immune response solely through a mechanism that requires intratumoral Trp depletion.

Immunosuppressive IDO in Cancer: Mechanisms of Action, Animal Models, and Targeting Strategies.

Indoleamine 2, 3-dioxygenase 1 (IDO; IDO1; INDO) is a rate-limiting enzyme that metabolizes the essential amino acid, tryptophan, into downstream kynurenines. Canonically, the metabolic depletion of tryptophan and/or the accumulation of kynurenine is the mechanism that defines how immunosuppressive IDO inhibits immune cell effector functions and/or facilitates T cell death. Non-canonically, IDO also suppresses immunity through non-enzymic effects.

Advanced Age Increases Immunosuppression in the Brain and Decreases Immunotherapeutic Efficacy in Subjects with Glioblastoma.

Purpose: Wild-type isocitrate dehydrogenase-expressing glioblastoma (GBM) is the most common and aggressive primary brain tumor with a median age at diagnosis of ≥65 years. It accounts for approximately 90% of all GBMs and has a median overall survival (OS) of <15 months. Although immune checkpoint blockade (ICB) therapy has achieved remarkable survival benefits in a variety of aggressive malignancies, similar success has yet to be achieved for GBM among phase III clinical trials to date.

A retrospective survival analysis of Glioblastoma patients treated with selective serotonin reuptake inhibitors.

Glioblastoma (GBM) is the most common and aggressive form of malignant glioma in adults with a median overall survival (OS) time of 16-18 months and a median age of diagnosis at 64 years old. Recent work has suggested that depression and psychosocial distress are associated with worse outcomes in patients with GBM. We therefore hypothesized that the targeted neutralization of psychosocial distress with selective serotonin reuptake inhibitor (SSRI) antidepressant treatment would be associated with a longer OS among patients with GBM.

Quantification of IDO1 enzyme activity in normal and malignant tissues.

Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes the first and rate-limiting reaction of l-tryptophan (Trp) conversion into l-kynurenine (Kyn). The depletion of Trp, and the accumulation of Kyn have been proposed as mechanisms that contribute to the suppression of the immune response-primarily evidenced by in vitro study. IDO1 is therefore considered to be an immunosuppressive modulator and quantification of IDO1 metabolism may be critical to understanding its role in select immunopathologies, including autoimmune- and oncological-conditions, as well as for determining the potency of IDO1 enzyme inhibitors.

The interplay among psychological distress, the immune system, and brain tumor patient outcomes.

A malignant brain tumor diagnosis is often accompanied with intense feelings and can be associated with psychosocial conditions including depression, anxiety, and/or increased distress levels. Previous work has highlighted the impact of uncontrolled psychological distress among brain tumor patients. Given the negative impact of maladaptive psychosocial and biobehavioral factors on normal immune system functions, the question remains as to how psychological conditions potentially affect the brain tumor patient anti-tumor immune response.

The Coincidence Between Increasing Age, Immunosuppression, and the Incidence of Patients With Glioblastoma.

Glioblastoma (GBM) is the most aggressive primary brain tumor in adults and is associated with a median overall survival (mOS) of 16-21 months. Our previous work found a negative association between advanced aging and the survival benefit after treatment with immunotherapy in an experimental brain tumor model. Given the recent phase III clinical success of immunotherapy in patients with many types of cancer, but not for patients with GBM, we hypothesize that aging enhances immunosuppression in the brain and contributes to the lack of efficacy for immunotherapy to improve mOS in patients with malignant glioma.

Commentary: preclinical efficacy of immune-checkpoint monotherapy does not recapitulate corresponding biomarkers-based clinical predictions in glioblastoma by Garg . (2017).

Preclinical modeling and gene expression analyses have yielded distinct observations for the role of immune checkpoint, IDO1, in glioblastoma (GBM). Accordingly, our recent work differs with Garg . (2017) with respect to IDO1 among preclinical and bioinformatic GBM datasets.

Indoleamine 2,3-dioxygenase 1 and overall survival of patients diagnosed with esophageal cancer.

Background: Indoleamine 2,3-dioxygenase 1 (IDO1) is an enzyme with immunomodulatory properties that has emerged as a potential immunotherapeutic target in human cancer. However, the role, expression pattern, and relevance of IDO1 in esophageal cancer (EC) are poorly understood. Here, we utilize gene expression analysis of the cancer genome atlas (TCGA) and immunohistochemistry (IHC) to better understand the role and prognostic significance of IDO1 in EC.

IDO1 Inhibition Synergizes with Radiation and PD-1 Blockade to Durably Increase Survival Against Advanced Glioblastoma.

Glioblastoma is the most aggressive primary brain tumor in adults with a median survival of 15-20 months. Numerous approaches and novel therapeutics for treating glioblastoma have been investigated in the setting of phase III clinical trials, including a recent analysis of the immune checkpoint inhibitor, nivolumab (anti-PD-1), which failed to improve recurrent glioblastoma patient survival. However, rather than abandoning immune checkpoint inhibitor treatment for glioblastoma, which has shown promise in other types of cancer, ongoing studies are currently evaluating this therapeutic class when combined with other agents.

IDO1 in cancer: a Gemini of immune checkpoints.

Indoleamine 2, 3-dioxygenase 1 (IDO1) is a rate-limiting metabolic enzyme that converts the essential amino acid tryptophan (Trp) into downstream catabolites known as kynurenines. Coincidently, numerous studies have demonstrated that IDO1 is highly expressed in multiple types of human cancer. Preclinical studies have further introduced an interesting paradox: while single-agent treatment with IDO1 enzyme inhibitor has a negligible effect on decreasing the established cancer burden, approaches combining select therapies with IDO1 blockade tend to yield a synergistic benefit against tumor growth and/or animal subject survival.

ALA/LA ameliorates glucose toxicity on HK-2 cells by attenuating oxidative stress and apoptosis through the ROS/p38/TGF-β pathway.

Background: Growing evidence indicates that oxidative stress (OS) plays a pivotal role in Diabetic nephropathy (DN). In a previous study we demonstrated that ALA/LA protected HK-2 cells against high glucose-induced cytotoxicity. So we aimed to establish the glucose injury model of HK-2 cells and investigate the beneficial effects of ALA/LA on high glucose-induced excessive production of TGF-β1 and the possible mechanisms mediating the effects.

Metabolically Activated Adipose Tissue Macrophages Perform Detrimental and Beneficial Functions during Diet-Induced Obesity.

During obesity, adipose tissue macrophages (ATMs) adopt a metabolically activated (MMe) phenotype. However, the functions of MMe macrophages are poorly understood. Here, we combine proteomic and functional methods to demonstrate that, in addition to potentiating inflammation, MMe macrophages promote dead adipocyte clearance through lysosomal exocytosis.

Infiltrating T Cells Increase IDO1 Expression in Glioblastoma and Contribute to Decreased Patient Survival.

Indoleamine 2,3 dioxygenase 1 (IDO1) mediates potent immunosuppression in multiple preclinical models of cancer. However, the basis for elevated IDO1 expression in human cancer, including the most common primary malignant brain tumor in adults, glioblastoma (GBM), is poorly understood. The major objective of this study is to address this gap in our understanding of how IDO1 expression contributes to the biology of GBM, and whether its level of expression is a determinant of GBM patient outcome.