SAP30, a Novel Oncogenic Transcription Factor in High-Risk Neuroblastoma: Clinical Significance and Role in Tumor-Progression, Survival, and Drug Resistance

Neuroblastoma is the most common devastating extracranial solid malignancy in children, accounting for 15% of childhood cancer-related mortality. Despite an intense treatment regimen, approximately 50% of children treated for high-risk neuroblastoma have more aggressive tumor relapse with less than 20% five-year overall survival. Amplification of the oncogene MYCN is associated with a high risk of relapse. However, only 25% of high-risk neuroblastomas are MYCN-amplified, indicating that the rest are driven by factors other than MYCN. Therefore, it is essential to identify novel driver transcription factors but not passenger genes that improve prediction efficacy of therapy response and association with high-risk, progression, stage 4, and survival in neuroblastoma patients. We used three neuroblastoma patient datasets (n=1252 patients) and applied robust bioinformatic data mining tools such as Weighted Gene Co-expression Network Analysis (WGCNA), cisTarget, and Single-Cell Regulatory Network Inference and Clustering (SCENIC) to identify driver transcription factors (regulon) that associate with high-risk, progression, stage, and survival in neuroblastoma patients. Based on the regulon specificity score, we derived a 10-transcription factor signature and prioritized Sin3A Associated Protein 30 (SAP30), given its highest regulon specificity score, especially in high-risk and aggressive stage cohorts. Higher SAP30 expression was found in high-risk neuroblastoma patients and progression-specific patient-derived xenograft tumors than their respective controls. The advanced pharmacogenomic analysis and CRISPR-Cas9 screens indicated that SAP30 essentiality correlated with Cisplatin resistance and further validated in Cisplatin resistant patient-derived xenograft tumor-derived cell lines. SAP30 silencing inhibited cell proliferation, slowed growth and induced cell death in vitro, and reduced tumor burden and size in vivo. Overall, our results indicate that SAP30 is a better prognostic and Cisplatin resistant marker associated with high-risk, stage 4 progression, and poor survival in neuroblastoma patients.https://digitalcommons.unmc.edu/chri_forum/1057/thumbnail.jp

TRAIL Dependent Fratricidal Killing of gp120 Primed Hepatocytes by HCV Core Expressing Hepatocytes

The mechanism by which HIV and HCV cooperatively accelerate hepatocyte damage is not clearly understood; however, each virus affects the TRAIL: TRAIL- receptor system. We, therefore, questioned whether the independent effects of HCV and HIV combine to synergistically result in TRAIL dependent hepatocyte killing. We describe that Huh7 hepatocytes treated with HIV gp120 results in both increase TRAIL-R2 expression and an acquired sensitivity to TRAIL mediated killing. Moreover HCV infection and HCV core expression alone in Huh7 cells upregulates TRAIL. Co-incubation of HIV gp120 primed hepatocytes with HCV core expressing hepatocytes results in the selective death of the HIV gp120 primed hepatocytes that is selectively blocked by TRAIL–R2-Fc fusion protein. Liver biopsies from HIV mono-infected patients have increased TRAIL-R2; biopsies from HCV infected patients have increased TRAIL, while co-infected liver biopsies have increased PARP cleavage within hepatocytes indicating enhanced apoptosis. These findings suggest a pathogenic model to understand why HIV/HCV co-infection accelerates liver injury

Targeting IκappaB kinases for cancer therapy

The inhibitory kappa B kinases (IKKs) and IKK related kinases are crucial regulators of the pro-inflammatory transcription factor, nuclear factor kappa B (NF-κB). The dysregulation in the activities of these kinases has been reported in several cancer types. These kinases are known to regulate survival, proliferation, invasion, angiogenesis, and metastasis of cancer cells. Thus, IKK and IKK related kinases have emerged as an attractive target for the development of cancer therapeutics. Several IKK inhibitors have been developed, few of which have advanced to the clinic. These inhibitors target IKK either directly or indirectly by modulating the activities of other signaling molecules. Some inhibitors suppress IKK activity by disrupting the protein-protein interaction in the IKK complex. The inhibition of IKK has also been shown to enhance the efficacy of conventional chemotherapeutic agents. Because IKK and NF-κB are the key components of innate immunity, suppressing IKK is associated with the risk of immune suppression. Furthermore, IKK inhibitors may hit other signaling molecules and thus may produce off-target effects. Recent studies suggest that multiple cytoplasmic and nuclear proteins distinct from NF-κB and inhibitory κB are also substrates of IKK. In this review, we discuss the utility of IKK inhibitors for cancer therapy. The limitations associated with the intervention of IKK are also discussed

Bruton\u27s Tyrosine Kinase Targeting in Multiple Myeloma.

Multiple myeloma (MM), a clonal plasma cell disorder, disrupts the bones\u27 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\u27s 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\u27 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

Long non-coding RNAs are emerging targets of phytochemicals for cancer and other chronic diseases

10.1007/s00018-019-03053-0CELLULAR AND MOLECULAR LIFE SCIENCES76101947-196

SARS-CoV-2 Infection and Oral Health: Therapeutic Opportunities and Challenges

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

HIV gp120 Increases TRAIL-R2.

<p>(A) Huh7 cells were incubated with increasing concentrations of HIV gp120 and analyzed for TRAIL-Receptor expression by Flow cytometry for TRAIL-R1, -R2, -R3, -R4 (BSA  =  black, HIV gp120 =  Grey), (B and D) Western blot (C) or real time PCR.</p