Medulloblastoma is a common fatal pediatric brain tumor. More treatment options are required to prolong survival and decrease disability. mTOR proteins play an essential role in the disease ...pathogenesis, and are an essential target for therapy. Three generations of mTOR inhibitors have been developed and are clinically used for immunosuppression and chemotherapy for multiple cancers. Only a few mTOR inhibitors have been investigated for the treatment of medulloblastoma and other pediatric tumors. The first-generation mTOR, sirolimus, temsirolimus, and everolimus, went through phase I clinical trials. The second-generation mTOR, AZD8055 and sapanisertib, suppressed medulloblastoma cell growth; however, limited studies have investigated possible resistance pathways. No clinical trials have been found to treat medulloblastoma using third-generation mTOR inhibitors. This systematic review highlights the mechanisms of resistance of mTOR inhibitors in medulloblastoma and includes IDO1, T cells, Mnk2, and eIF4E, as they prolong malignant cell survival. The findings promote the importance of combination therapy in medulloblastoma due to its highly resistant nature.
The protein kinase TAOK3, belongs to the MAP kinase family, is one of three closely related members, namely TAOK1, TAOK2, and TAOK3. We performed a pan-cancer investigation of TAOK3 across different ...cancer types, including uterine carcinosarcoma, adenocarcinoma of the stomach and pancreas, and endometrial carcinoma of the uterus, to better understand TAOK3′s role in cancer. In at least 16 types of cancer, our findings indicate that TAOK3 expression levels differ considerably between normal and tumor tissues. In addition, our study is the first to identify the oncogenic role of TAOK3 locus S331 and S471 in renal clear cell carcinoma, Glioblastoma Multiforme, hepatocellular carcinoma, Lung adenocarcinoma, and Pancreatic adenocarcinoma, indicating their involvement in cancer progression. In addition, our data analysis indicates that copy number variation is the most prevalent form of mutation in the TAOK3 gene, and that there is a negative correlation between TAOK3 mRNA and DNA promoter methylation. Moreover, our analysis suggests that TAOK3 may serve as a prognostic marker for several kinds of cancer, including Colon adenocarcinoma, renal clear cell carcinoma, Lower Grade Glioma, Lung adenocarcinoma, Mesothelioma, and hepatocellular carcinoma. In addition, our research on signature cancer genes has uncovered a positive association between TAOK3 and SMAD2, SMAD4, and RNF168 in most of the malignancies we have examined. TAOK3 is also correlated with the frequency of mutations and microsatellite instability in four types of cancer. Numerous immune-related genes are closely associated with TAOK3 levels in numerous malignancies. TAOK3 expression is positively correlated with immune infiltrates, which include activated CD4 T cells, CD8 T cells, and type 2T helper cells. Our pan-cancer analysis of TAOK3 provides vital insight into its potential role across a variety of cancer types.
Despite extensive molecular characterization, human glioblastoma remains a fatal disease with survival rates measured in months. Little improvement is seen with standard surgery, radiotherapy and ...chemotherapy. Clinical progress is hampered by the inability to detect and target glioblastoma disease reservoirs based on a diffuse invasive pattern and the presence of molecular and phenotypic heterogeneity. The goal of this study was to target the invasive and stem-like glioblastoma cells that evade first-line treatments using agents capable of delivering imaging enhancers or biotherapeutic cargo. To accomplish this, a combinatorial phage display library was biopanned against glioblastoma cell model systems that accurately recapitulate the intra- and inter-tumor heterogeneity and infiltrative nature of the disease. Candidate peptides were screened for specificity and ability to target glioblastoma cells in vivo. Cargo-conjugated peptides delivered contrast-enhancing agents to highly infiltrative tumor populations in intracranial xenograft models without the obvious need for blood brain barrier disruption. Simultaneous use of five independent targeting peptides provided greater coverage of this complex tumor and selected peptides have the capacity to deliver a therapeutic cargo (oncolytic virus VSVΔM51) to the tumor cells in vivo. Herein, we have identified a series of peptides with utility as an innovative platform to assist in targeting glioblastoma for the purpose of diagnostic or prognostic imaging, image-guided surgery, and/or improved delivery of therapeutic agents to glioblastoma cells implicated in disease relapse.
Liver diseases are particularly severe health problems, but the options available for preventing and treating them remain limited. Accumulating evidence has shown that there is altered expression of ...individual histone deacetylase (HDAC) family members in hepatocellular carcinoma cells. In a previous study, we have identified a set of proteins which interact with histone deacetylase 1 and 3 (HDAC1/3) in hepatocellular carcinoma cell lines HepG2 by proteomic approach. This study was designed to investigate the therapeutic potential and expression of HDAC1/3-interacting genes in a human hepatocellular carcinoma cell line (HepG2). Pharmacological and transcriptional inhibition of HDAC1/3 resulted in the suppression of cancer cell proliferation, change of cell morphology, and downregulation of HDAC1/3 genes in HepG2 cells. The pharmacological inhibition also resulted in inhibition of liver cancer cell migration by wound scratch assay. Taken together, the results from this study show that the upregulation of HDAC1/3 in hepatocellular carcinoma resulted in the overexpression of CNOT1, PFDN2/6, and HMG20B, and that these genes could serve as novel molecular targets in liver cancer.
COVID-19 is newly emerging infectious disease that spread globally at unpredictable and unique pattern to the extent that the World Health Organization announced COVID-19 as a pandemic in the first ...couple months of 2020. This study aims to describe clinical and demographic features of COVID-19 patients and the influence of various risk factors on the severity of disease.
This research is a retrospective study based on Saudi Arabia's ministry of health’s Covid-19 data. The analysis relies on data of all COVID-19 patients recorded in Riyadh between 1st, March 2020 and 30th, July 2020. Statistical analyses were performed to investigate the effect of demographic characteristic, clinical presentation, and comorbidities on infection severity.
A total number of 1026 COVID-19 patients were identified based on the demographic data as follows: 709 cases (69% of cases) were males and 559 cases (54% of cases) were Saudi. Most of patients were diagnosed with mild signs and symptoms 697 (68% of cases), while 164 patient (16% of cases) demonstrated moderate signs and symptoms, and 103 cases (10%) were severe and 62 (6%) had critical febrile illness. Fever, cough, sore throat, and shortness of breath were the most common symptoms among patients with COVID-19. Among studied comorbidities in COVID-19 patients, diabetes mellitus and hypertension were the most prevalent. The results from the bivariate logistic regression analysis revealed that older age, diabetes mellitus, asthma, smoking, and fever are associated with severe or critically ill cases.
The findings of this study show that old age, fever, and comorbidities involving diabetes mellitus, asthma, and smoking were significantly associated with infection severity.
Epigenetic mechanisms, such as histone deacetylases (HDACs), play an important role in the commencement and development of hepatocellular carcinoma (HCC). Previously, we have identified proteins with ...binds with HDAC1 and HDAC3 in liver cancer cells and also have shown that depletion of either HDAC1 or HDAC3 suppressed the expression of HDAC1/3 interacting proteins, including the prefoldin protein 2/6 (PFDN2/6), CR4-NOT transcription complex subunit 1 (CNOT1), and high mobility group 20B (HMG20b). In this study, online databases were utilized to analyze the expression of HDAC1/3, PFDN2/6, CNOT1, and HMG20b in a large panel of liver cancer cell lines, cancer tissues, and human normal and tumor liver tissues. These databases are “RNA Expression Atlas (https://www.ebi.ac.uk/gxa/home), Cancer Genome Atlas (TCGA), gene expression profiling interactive analysis (GEPIA), integrative molecular databases of hepatocellular carcinoma (HCCDB), human protein atlas, and Kaplan-Meier Plotter for RNA sequences in liver cancer (http://kmplot.com/analysis/index.php?p=service&cancer=liver_rnaseq#). The expression of these genes was verified experimentally in human HepG2 cells via semi-quantitative RT PCR. The results showed that all these genes are expressed in twenty-three human liver cancer cell lines, higher expression in human liver cancer than normal tissues. However, HDAC1 and PFDN2 are expressed at higher levels than other genes analyzed in this study. The analysis of these six genes in 364 human liver cancer patients by Kaplan Meier plotter predicted HDAC1 and PFDN2 as poor, while HMG20b as a favorable prognostic biomarker in hepatocellular carcinoma. PFDN2 and HMG20b are novel prognostic markers of hepatocellular carcinoma, identified first in this study. Further clinical studies are needed to verify the expression and patient survival concerning the expresion of PFDN2 and HMG20b in human hepatocellular carcinoma patients.
Risk factors such as chronic use of tobacco, smoking and alcohol consumption of individual's lifestyle may possibly influence the significant role in the etiopathogenesis of precancerous lesions (PL) ...and Conditions (PC) and lead to oral cancer. Previous studies have revealed that genetic factors have contributed to a remarkable extent in the development of this chronic disease. Limited studies have confirmed that ABO blood groups remain reportedly possible genetic factor to the specific disease such as oral malignant. In this context, we have reported that individuals in a particular blood group are more prone to develop lesions and certain types of cancer. This has thrown a light to take up an effort to conduct this present study.
The present study covering 105 patients and grouped into three subjects with 35 participants in each. a) oral squamous cell carcinoma b) oral leukoplakia and c) submucous fibrosis. Gender and age group impact was also made to understand the interaction between the focused sample groups. A separate control was gathered from a same geographical population composed of gender-matched healthy volunteers. Slide agglutination was employed for blood grouping and results were tabulated for statistical analysis.
Blood group "A" exhibited a significant relationship between oral squamous cell carcinoma patient and odd ratio shown 1.74 times higher risk of developing oral cancer. Gender different and habit stimulation have increased the risk. A significant relationship was observed between ABO blood group and oral leukoplakia and oral submucous fibrosis.
Study inferred that blood group "A" is found to be at the high risk in developing oral malignant syndrome due to its susceptibility, whereas oral pre-cancer is hypothesized that individual habits are the host risk factor and transformed to carcinoma by interacting genetic factors to act upon ABO blood group.
Capicua (Cic) is a transcriptional repressor mutated in the brain cancer oligodendroglioma. Despite its cancer link, little is known of Cic's function in the brain. We show that nuclear Cic ...expression is strongest in astrocytes and neurons but weaker in stem cells and oligodendroglial lineage cells. Using a new conditional Cic knockout mouse, we demonstrate that forebrain-specific Cic deletion increases proliferation and self-renewal of neural stem cells. Furthermore, Cic loss biases neural stem cells toward glial lineage selection, expanding the pool of oligodendrocyte precursor cells (OPCs). These proliferation and lineage effects are dependent on de-repression of Ets transcription factors. In patient-derived oligodendroglioma cells, CIC re-expression or ETV5 blockade decreases lineage bias, proliferation, self-renewal, and tumorigenicity. Our results identify Cic as an important regulator of cell fate in neurodevelopment and oligodendroglioma, and suggest that its loss contributes to oligodendroglioma by promoting proliferation and an OPC-like identity via Ets overactivity.
The fidelity of synaptic transmission depends on the integrity of the protein machinery at the synapse. Unfolded synaptic proteins undergo refolding or degradation in order to maintain synaptic ...proteostasis and preserve synaptic function, and buildup of unfolded/toxic proteins leads to neuronal dysfunction. Many molecular chaperones contribute to proteostasis, but one in particular, cysteine string protein (CSPα), is critical for proteostasis at the synapse. In this study we report that exported vesicles from neurons contain CSPα. Extracellular vesicles (EV's) have been implicated in a wide range of functions. However, the functional significance of neural EV's remains to be established. Here we demonstrate that co-expression of CSPα with the disease-associated proteins, polyglutamine expanded protein 72Q huntingtin
°
or superoxide dismutase-1 (SOD-1
leads to the cellular export of both 72Q huntingtin
°
and SOD-1
via EV's. In contrast, the inactive CSPα
mutant does not facilitate elimination of misfolded proteins. Furthermore, CSPα-mediated export of 72Q huntingtin
°
is reduced by the polyphenol, resveratrol. Our results indicate that by assisting local lysosome/proteasome processes, CSPα-mediated removal of toxic proteins via EVs plays a central role in synaptic proteostasis and CSPα thus represents a potential therapeutic target for neurodegenerative diseases.
The current study is the first report to describe the improvement of ferning patterns of human tears using electrolyte solutions. The results can help in the production of new artificial tears to ...improve the quality of tears.
This study aimed to investigate the effect of the addition of different volumes of various electrolyte solutions on ferning patterns of human tears.
Tear samples (20 μL) were collected from the right eye of 13 subjects (5 men and 5 women) aged 19 to 36 years (27.1 ± 5.1 years) with normal eyes. Then, 1 μL of each tear sample was dried on a microscopic glass slide, and obtained ferns were observed using light microscopy and graded using the 5-point tear ferning (TF) grading scale. Homogenous mixtures of each tear sample (0.5 μL) and different volumes (0.5 to 5 μL) of each electrolyte were prepared. A sample (1 μL) of each mixture was dried, and the ferns obtained were graded and compared with those of the corresponding tears collected from subjects before the addition of electrolyte solutions.
After the addition of electrolyte solutions, the TF grades of tears collected from healthy humans were generally improved. Significant (Wilcoxon test) improvements have been seen in the TF grades of the tear samples after the addition of a solution of potassium chloride (P = .03), calcium chloride (P = .01), magnesium chloride hexahydrate (P = .002), and sodium dihydrogen phosphate (P = .002). No significant improvements in the TF grades were seen after the addition of sodium chloride solution (P = .33).
Ferning grades of human tears improved with most of the electrolytes used.
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