High-risk neuroblastoma (NB) is challenging to treat with 5-year long-term survival in patients remaining below 50% and low chances of survival after tumor relapse or recurrence. Different strategies ...are being tested or under evaluation to destroy resistant tumors and improve survival outcomes in NB patients. Immunotherapy, which uses certain parts of a person's immune system to recognize or kill tumor cells, effectively improves patient outcomes in several types of cancer, including NB. One of the immunotherapy strategies is to block immune checkpoint signaling in tumors to increase tumor immunogenicity and anti-tumor immunity. Immune checkpoint proteins put brakes on immune cell functions to regulate immune activation, but this activity is exploited in tumors to evade immune surveillance and attack. Immune checkpoint proteins play an essential role in NB biology and immune escape mechanisms, which makes these tumors immunologically cold. Therapeutic strategies to block immune checkpoint signaling have shown promising outcomes in NB but only in a subset of patients. However, combining immune checkpoint blockade with other therapies, including conjugated antibody-based immunotherapy, radioimmunotherapy, tumor vaccines, or cellular therapies like modified T or natural killer (NK) cells, has shown encouraging results in enhancing anti-tumor immunity in the preclinical setting. An analysis of publicly available dataset using computational tools has unraveled the complexity of multiple cancer including NB. This review comprehensively summarizes the current information on immune checkpoint molecules, their biology, role in immune suppression and tumor development, and novel therapeutic approaches combining immune checkpoint inhibitors with other therapies to combat high-risk NB.
Multiple myeloma (MM), a clonal plasma cell disorder, disrupts the bones’ hematopoiesis and microenvironment homeostasis and ability to mediate an immune response against malignant clones. Despite ...prominent survival improvement with newer treatment modalities since the 2000s, MM is still considered a non-curable disease. Patients experience disease recurrence episodes with clonal evolution, and with each relapse disease comes back with a more aggressive phenotype. Bruton’s Tyrosine Kinase (BTK) has been a major target for B cell clonal disorders and its role in clonal plasma cell disorders is under active investigation. BTK is a cytosolic kinase which plays a major role in the immune system and its related malignancies. The BTK pathway has been shown to provide survival for malignant clone and multiple myeloma stem cells (MMSCs). BTK also regulates the malignant clones’ interaction with the bone marrow microenvironment. Hence, BTK inhibition is a promising therapeutic strategy for MM patients. In this review, the role of BTK and its signal transduction pathways are outlined in the context of MM.
Acute myeloid leukemia (AML) is caused by abnormal production of white blood cells, red blood cells or platelets. The leukemia cells communicate with their microenvironment through nano-vesicle ...exosomes that are 30–100 nm in diameter. These nano-vesicles are released from body fluids upon fusion of an endocytic compartment with the cell membrane. Exosomes function as cargo to deliver signaling molecules to distant cells. This allows cross-talk between hematopoietic cells and other distant target cell environments. Exosomes support leukemia growth by acting as messengers between tumor cells and the microenvironment as well as inducing oncogenic factors such as c-Myc. Exosomes have also been used as biomarkers in the clinical diagnosis of leukemia. Glycogen synthase kinase-3 (GSK-3) and protein phosphatase 2A (PP2A) are two crucial signaling molecules involved in the AML pathogenesis and MYC stability. GSK-3 is a serine/threonine protein kinase that coordinates with over 40 different proteins during physiological/pathological conditions in blood cells. The dysregulation in GSK-3 has been reported during hematological malignancies. GSK-3 acts as a tumor suppressor by targeting c-MYC, MCL-1 and β-catenin. Conversely, GSK-3 can also act as tumor promoter in some instances. The pharmacological modulators of GSK-3 such as ABT-869, 6-Bromoindirubin-3′-oxime (BIO), GS-87 and LY2090314 have shown promise in the treatment of hematological malignancy. PP2A is a heterotrimeric serine/threonine phosphatase involved in the regulation of hematological malignancy. PP2A-activating drugs (PADs) can effectively antagonize leukemogenesis. The discovery of exosomes, kinase inhibitors and phosphatase activators have provided new hope to the leukemia patients. This review discusses the role of exosomes, GSK-3 and PP2A in the pathogenesis of leukemia. We provide evidence from both preclinical and clinical studies.
miRNAs are small noncoding RNAs with gene regulatory functions, frequently dysregulated in human cancers. Specific signatures of differentially expressed miRNAs can be used in the diagnosis of cancer ...and in some cases harbor prognostic implications. The biology of cancer is dictated not only by cancer cells but also by the surrounding tumor microenvironment. In particular, the role of miRNAs within the tumor microenvironment is emerging as of paramount importance. This review will focus on the current knowledge of the role of miRNAs and both cellular and stromal components of the tumor microenvironment. We will also discuss more recent findings, showing that miRNAs can be found inside of exosomes and mediate the cross-talk between cancer cells and surrounding cells, leading to the discovery of new fascinating molecular mechanisms leading to a better understanding of the cancer 'niche' and how these noncoding RNAs can become very promising diagnostic molecules.
Neuroblastoma (NB) accounts for about 13% of all pediatric cancer mortality and is the leading cause of pediatric cancer death for children aged 1 to 5 years. NB, a developmental malignancy of neural ...ganglia, originates from neural crest-derived cells, which undergo a defective sympathetic neuronal differentiation due to genomic and epigenetic aberrations. NB is a complex disease with remarkable biological and genetic variation and clinical heterogeneity, such as spontaneous regression, treatment resistance, and poor survival rates. Depending on its severity, NB is categorized as high-risk, intermediate-risk, and low-risk., whereas high-risk NB accounts for a high infant mortality rate. Several studies revealed that NB cells suppress immune cell activity through diverse signaling pathways, including exosome-based signaling pathways. Exosome signaling has been shown to modulate gene expression in the target immune cells and attenuate the signaling events through non-coding RNAs. Since high-risk NB is characterized by a low survival rate and high clinical heterogeneity with current intensive therapies, it is crucial to unravel the molecular events of pathogenesis and develop novel therapeutic targets in high-risk, relapsed, or recurrent tumors in NB to improve patient survival. This article discusses etiology, pathophysiology, risk assessment, molecular cytogenetics, and the contribution of extracellular vesicles, non-coding RNAs, and cancer stem cells in the tumorigenesis of NB. We also detail the latest developments in NB immunotherapy and nanoparticle-mediated drug delivery treatment options.
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Neuroblastoma are pediatric, extracranial malignancies showing alarming survival prognosis outcomes due to their resilience to current aggressive treatment regimens, including chemotherapies with ...cisplatin (CDDP) provided in the first line of therapy regimens. Metabolic deregulation supports tumor cell survival in drug-treated conditions. However, metabolic pathways underlying cisplatin-resistance are least studied in neuroblastoma. Our metabolomics analysis revealed that cisplatin-insensitive cells alter their metabolism; especially, the metabolism of amino acids was upregulated in cisplatin-insensitive cells compared to the cisplatin-sensitive neuroblastoma cell line. A significant increase in amino acid levels in cisplatin-insensitive cells led us to hypothesize that the mechanisms upregulating intracellular amino acid pools facilitate insensitivity in neuroblastoma. We hereby report that amino acid depletion reduces cell survival and cisplatin-insensitivity in neuroblastoma cells. Since cells regulate their amino acids levels through processes, such as autophagy, we evaluated the effects of hydroxychloroquine (HCQ), a terminal autophagy inhibitor, on the survival and amino acid metabolism of cisplatin-insensitive neuroblastoma cells. Our results demonstrate that combining HCQ with CDDP abrogated the amino acid metabolism in cisplatin-insensitive cells and sensitized neuroblastoma cells to sub-lethal doses of cisplatin. Our results suggest that targeting of amino acid replenishing mechanisms could be considered as a potential approach in developing combination therapies for treating neuroblastomas.
The novel corona virus, Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), and the disease it causes, COVID-19 (Coronavirus Disease-2019) have had multi-faceted effects on a number of ...lives on a global scale both directly and indirectly. A growing body of evidence suggest that COVID-19 patients experience several oral health problems such as dry mouth, mucosal blistering, mouth rash, lip necrosis, and loss of taste and smell. Periodontal disease (PD), a severe inflammatory gum disease, may worsen the symptoms associated with COVID-19. Routine dental and periodontal treatment may help decrease the symptoms of COVID-19. PD is more prevalent among patients experiencing metabolic diseases such as obesity, diabetes mellitus and cardiovascular risk. Studies have shown that these patients are highly susceptible for SARS-CoV-2 infection. Pro-inflammatory cytokines and oxidative stress known to contribute to the development of PD and other metabolic diseases are highly elevated among COVID-19 patients. Periodontal health may help to determine the severity of COVID-19 infection. Accumulating evidence shows that African-Americans (AAs) and vulnerable populations are disproportionately susceptible to PD, metabolic diseases and COVID-19 compared to other ethnicities in the United States. Dentistry and dental healthcare professionals are particularly susceptible to this virus due to the transferability via the oral cavity and the use of aerosol creating instruments that are ubiquitous in this field. In this review, we attempt to provide a comprehensive and updated source of information about SARS-CoV-2/COVID-19 and the various effects it has had on the dental profession and patients visits to dental clinics. Finally, this review is a valuable resource for the management of oral hygiene and reduction of the severity of infection.
Neuroblastoma (NB) is an enigmatic and deadliest pediatric cancer to treat. The major obstacles to the effective immunotherapy treatments in NB are defective immune cells and the immune evasion ...tactics deployed by the tumor cells and the stromal microenvironment. Nervous system development during embryonic and pediatric stages is critically mediated by non-coding RNAs such as micro RNAs (miR). Hence, we explored the role of miRs in anti-tumor immune response via a range of data-driven workflows and in vitro & in vivo experiments. Using the TARGET, NB patient dataset (n=249), we applied the robust bioinformatic workflows incorporating differential expression, co-expression, survival, heatmaps, and box plots. We initially demonstrated the role of miR-15a-5p (miR-15a) and miR-15b-5p (miR-15b) as tumor suppressors, followed by their negative association with stromal cell percentages and a statistically significant negative regulation of T and natural killer (NK) cell signature genes, especially CD274 (PD-L1) in stromal-low patient subsets. The NB phase-specific expression of the miR-15a/miR-15b-PD-L1 axis was further corroborated using the PDX (n=24) dataset. We demonstrated miR-15a/miR-15b mediated degradation of PD-L1 mRNA through its interaction with the 3'-untranslated region and the RNA-induced silencing complex using sequence-specific luciferase activity and Ago2 RNA immunoprecipitation assays. In addition, we established miR-15a/miR-15b induced CD8+T and NK cell activation and cytotoxicity against NB in vitro. Moreover, injection of murine cells expressing miR-15a reduced tumor size, tumor vasculature and enhanced the activation and infiltration of CD8+T and NK cells into the tumors in vivo. We further established that blocking the surface PD-L1 using an anti-PD-L1 antibody rescued miR-15a/miR-15b induced CD8+T and NK cell-mediated anti-tumor responses. These findings demonstrate that miR-15a and miR-15b induce an anti-tumor immune response by targeting PD-L1 in NB.
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Neuroblastoma is one of the deadliest pediatric cancers and shows resistance to therapy due to a diminished anti-tumor immune response. Patients with higher PD-L1, reduced miR-15a, and miR-15b are further associated with poor survival. Our findings demonstrate that miR-15a and miR-15b induce an anti-tumor immune response by targeting PD-L1 in neuroblastoma.
An impaired nitrergic system and altered redox signaling contribute to gastric dysmotility in diabetics. Our earlier studies show that NF-E2-related factor 2 (NRF2) and phase II antioxidant enzymes ...play a vital role in gastric neuronal nitric oxide synthase (nNOS) function. This study aims to investigate whether supplementation of sepiapterin (SEP), a precursor for tetrahydrobiopterin (BH
) (a cofactor of NOS) via the salvage pathway, restores altered nitrergic systems and redox balance in spontaneous diabetic (DB) female rats. Twelve-week spontaneous DB and age-matched, non-DB rats, with and without dietary SEP (daily 20 mg/kg body wt for 10 days) treatment, were used in this study. Gastric antrum muscular tissues were excised to investigate the effects of SEP in nitrergic relaxation and the nNOS-nitric oxide (NO)-NRF2 pathway(s). Dietary SEP supplementation significantly ( P < 0.05) reverted diabetes-induced changes in nNOS dimerization and function; nitric oxide (NO) downstream signaling molecules; HSP-90, a key regulator of nNOSα activity and dimerization; miRNA-28 that targets NRF2 messenger RNA (mRNA), and levels of microRNA (miRNA) biogenesis pathway components, such as DGCR8 (DiGeorge Syndrome Critical Region Gene 8) and TRBP (HIV1-1 transactivating response RNA-binding protein). These findings emphasize the importance of the BH
pathway in regulating gastric motility functions in DB animals by modulating nNOSα dimerization in association with changes in enteric NRF2 and NO downstream signaling. Our results also identify a new pathway, wherein SEP regulates NRF2 mRNA turnover by suppressing elevated miRNA-28, which could be related to alterations in miRNA biogenesis pathway components. NEW & NOTEWORTHY This study is the first to show a causal link between NF-E2-related factor 2 (NRF2) and neuronal nitric oxide synthase (nNOS) in gastric motility function. Our data demonstrate that critical regulators of the miRNA biosynthetic pathway are upregulated in the diabetic (DB) setting; these regulators were rescued by sepiapterin (SEP) treatment. Finally, we show that low dihydrofolate reductase expression may lead to impaired nNOS dimerization/function-reduced nitric oxide downstream signaling and elevate oxidative stress by suppressing the NRF2/phase II pathway through miRNA; SEP treatment restored all of the above in DB gastric muscular tissue. We suggest that tetrahydrobiopterin supplementation may be a useful therapy for patients with diabetes, as well as women with idiopathic gastroparesis.
Neuroblastoma is the most devastating extracranial solid malignancy in children. Despite an intense treatment regimen, the prognosis for high-risk neuroblastoma patients remains poor, with less than ...40% survival. So far, MYCN amplification status is considered the most prognostic factor but corresponds to only ∼25% of neuroblastoma patients. Therefore, it is essential to identify a better prognosis and therapy response marker in neuroblastoma patients. We applied robust bioinformatic data mining tools, such as weighted gene co-expression network analysis, cisTarget, and single-cell regulatory network inference and clustering on two neuroblastoma patient datasets. We found Sin3A-associated protein 30 (SAP30), a driver transcription factor positively associated with high-risk, progression, stage 4, and poor survival in neuroblastoma patient cohorts. Tumors of high-risk neuroblastoma patients and relapse-specific patient-derived xenografts showed higher SAP30 levels. The advanced pharmacogenomic analysis and CRISPR-Cas9 screens indicated that SAP30 essentiality is associated with cisplatin resistance and further showed higher levels in cisplatin-resistant patient-derived xenograft tumor cell lines. Silencing of SAP30 induced cell death in vitro and led to a reduced tumor burden and size in vivo. Altogether, these results indicate that SAP30 is a better prognostic and cisplatin-resistance marker and thus a potential drug target in high-risk neuroblastoma.
Neuroblastoma is the most devastating extracranial solid malignancy in children. So far, MYCN amplification status is considered the most prognostic factor but corresponds to only ∼25% of neuroblastoma patients. Our data demonstrate the discovery of SAP30, an oncogenic driver transcription factor of progression, survival, and drug resistance in high-risk neuroblastoma.
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