Exosomal long non-coding RNAs in cancer: Interplay, modulation, and therapeutic avenues.

In the intricate field of cancer biology, researchers are increasingly intrigued by the emerging role of exosomal long non-coding RNAs (lncRNAs) due to their multifaceted interactions, complex modulation mechanisms, and potential therapeutic applications. These exosomal lncRNAs, carried within extracellular vesicles, play a vital partin tumorigenesis and disease progression by facilitating communication networks between tumor cells and their local microenvironment, making them an ideal candidates for use in a liquid biopsy approach. However, exosomal lncRNAs remain an understudied area, especially in cancer biology. Therefore this review aims to comprehensively explore the dynamic interplay between exosomal lncRNAs and various cellular components, including interactions with tumor-stroma, immune modulation, and drug resistance mechanisms. Understanding the regulatory functions of exosomal lncRNAs in these processes can potentially unveil novel diagnostic markers and therapeutic targets for cancer. Additionally, the emergence of RNA-based therapeutics presents exciting opportunities for targeting exosomal lncRNAs, offering innovative strategies to combat cancer progression and improve treatment outcomes. Thus, this review provides insights into the current understanding of exosomal lncRNAs in cancer biology, highlighting their crucial roles, regulatory mechanisms, and the evolving landscape of therapeutic interventions. Furthermore, we have also discussed the advantage of exosomes as therapeutic carriers of lncRNAs for the development of personalized targeted therapy for cancer patients.

A novel EGFR inhibitor, HNPMI, regulates apoptosis and oncogenesis by modulating BCL-2/BAX and p53 in colon cancer.

BACKGROUND AND PURPOSE: Colorectal cancer (CRC) is the second most lethal disease, with high mortality due to its heterogeneity and chemo-resistance. Here, we have focused on the epidermal growth factor receptor (EGFR) as an effective therapeutic target in CRC and studied the effects of polyphenols known to modulate several key signalling mechanisms including EGFR signalling, associated with anti-proliferative and anti-metastatic properties. EXPERIMENTAL APPROACH: Using ligand- and structure-based cheminformatics, we developed three potent, selective alkylaminophenols, 2-[(3,4-dihydroquinolin-1(2H)-yl)(p-tolyl)methyl]phenol (THTMP), 2-[(1,2,3,4-tetrahydroquinolin-1-yl)(4-methoxyphenyl)methyl]phenol (THMPP) and N-[2-hydroxy-5-nitrophenyl(4'-methylphenyl)methyl]indoline (HNPMI). These alkylaminophenols were assessed for EGFR interaction, EGFR-pathway modulation, cytotoxic and apoptosis induction, caspase activation and transcriptional and translational regulation. The lead compound HNPMI was evaluated in mice bearing xenografts of CRC cells. KEY RESULTS: Of the three alkylaminophenols tested, HNPMI exhibited the lowest IC50 in CRC cells and potential cytotoxic effects on other tumour cells. Modulation of EGFR pathway down-regulated protein levels of osteopontin, survivin and cathepsin S, leading to apoptosis. Cell cycle analysis revealed that HNPMI induced G0/G1 phase arrest in CRC cells. HNPMI altered the mRNA for and protein levels of several apoptosis-related proteins including caspase 3, BCL-2 and p53. HNPMI down-regulated the proteins crucial to oncogenesis in CRC cells. Assays in mice bearing CRC xenografts showed that HNPMI reduced the relative tumour volume. CONCLUSIONS AND IMPLICATIONS: HNPMI is a promising EGFR inhibitor for clinical translation. HNPMI regulated apoptosis and oncogenesis by modulating BCL-2/BAX and p53 in CRC cell lines, showing potential as a therapeutic agent in the treatment of CRC.

In Silico Bioinformatics Analysis on the Role of Long Non-Coding RNAs as Drivers and Gatekeepers of Androgen-Independent Prostate Cancer Using LNCaP and PC-3 Cells.

Prostate cancer (PCa) is the leading cancer in men globally. The association between PCa and long non-coding RNAs (lncRNAs) has been reported. Aberrantly expressed lncRNAs have been documented in each of the cancer "hallmarks". Androgen signaling plays an important role in PCa progression. This study aimed to profile the aberrantly expressed lncRNAs in androgen-dependent (LNCaP) PCa compared to androgen-independent (PC-3) PCa cells. This was achieved by using a 384-well plate of PCa lncRNA gene panel. Differential expression of ±2 up or downregulation was determined using the CFX Maestro software v2.1. LncSEA and DIANA-miRPath were used to identify the enriched pathways. Telomerase RNA component (TERC) lncRNA was illustrated to participate in various tumourigenic classes by in silico bioinformatics analysis and was thus selected for validation using RT-qPCR. Further bioinformatics analysis revealed the involvement of differentially expressed lncRNAs in oncogenic pathways. Some lncRNAs undergo hypermethylation, others are encapsulated by exosomes, while others interact with several microRNAs (miRNAs), favouring tumourigenic pathways. Notably, TERC lncRNA was shown to interact with tumour-suppressor miRNAs hsa-miR-4429 and hsa-miR-320b. This interaction in turn activates TGF-ß-signaling and ECM-receptor interaction pathways, favouring the progression of PCa. Understanding lncRNAs as competitive endogenous RNA molecules and their interactions with miRNAs may aid in the identification of novel prognostic PCa biomarkers and therapeutic targets.

Epigenetic regulation in colorectal cancer: The susceptibility of microRNAs 145, 143 and 133b to DNA demethylation and histone deacetylase inhibitors.

Globally, colorectal cancer (CRC) is a major health concern. Despite improvements in CRC treatment, mortality rates remain high. Genetic instability and epigenetic dysregulation of gene expression are instigators of CRC development that result in genotypic differences, leading to often variable and unpredictable treatment responses. Three miRNAs, miR-143, -145 and -133b, are most commonly downregulated in CRC and are proposed here as potential tumour suppressors. Although the downregulation of these miRNAs in CRC is largely unexplained, epigenetic silencing has been postulated to be a causative regulatory mechanism. Potential epigenetic modulation of miRNA expression, by means of histone acetylation and DNA methylation, was assessed in this study by treating early (SW1116) and late stage (DLD1) CRC cells with the DNA demethylating agent 5-aza-2'-deoxycytidine (5-Aza-2'C) and the histone deacetylase (HDAC) inhibitor Trichostatin A (TSA), respectively. Subsequent quantification of miRNA expression revealed that while all the selected miRNAs were susceptible to DNA demethylation in early- and late-stage CRC cells, susceptibility to DNA demethylation was significantly pronounced in late-stage DLD1 cells. Conversely, although histone acetylation moderately affected miRNA expression in early-stage CRC, it had a marginal effect on the expression of miRNAs in late-stage CRC cells. Overall, this study provides further understanding of the contribution of epigenetics to the regulation of putative tumour suppressor miRNAs in CRC.

Targeting AXL in mesothelioma: From functional characterization to clinical implication.

Malignant mesothelioma (MM) is a highly aggressive and lethal cancer with a poor survival rate. Current treatment approaches primarily rely on chemotherapy and radiation, but their effectiveness is limited. Consequently, there is an urgent need for alternative treatment strategies, a comprehensive understanding of the molecular mechanisms underlying MM, and the identification of potential therapeutic targets. Extensive studies over the past decade have emphasized the role of Axl in driving tumor development and metastasis, while high levels of Axl expression have been associated with immune evasion, drug resistance, and reduced patient survival in various cancer types. Ongoing clinical trials are investigating the efficacy of Axl inhibitors for different cancers. However, the precise role of Axl in MM progression, development, and metastasis, as well as its regulatory mechanisms within MM, remain inadequately understood. This review aims to comprehensively investigate the involvement of Axl in MM. We discuss Axl role in MM progression, development, and metastasis, along with its specific regulatory mechanisms. Additionally, we examined the Axl associated signaling pathways, the relationship between Axl and immune evasion, and the clinical implications of Axl for MM treatment. Furthermore, we discussed the potential utility of liquid biopsy as a non-invasive diagnostic technique for early detection of Axl in MM. Lastly, we evaluated the potential of a microRNA signature that targets Axl. By consolidating existing knowledge and identifying research gaps, this review contributes to a better understanding of Axl's role in MM and sets the stage for future investigations and the development of effective therapeutic interventions.

Overcoming the Challenges of Phytochemicals in Triple Negative Breast Cancer Therapy: The Path Forward.

Triple negative breast cancer (TNBC) is a very aggressive subtype of breast cancer that lacks estrogen, progesterone, and HER2 receptor expression. TNBC is thought to be produced by Wnt, Notch, TGF-beta, and VEGF pathway activation, which leads to cell invasion and metastasis. To address this, the use of phytochemicals as a therapeutic option for TNBC has been researched. Plants contain natural compounds known as phytochemicals. Curcumin, resveratrol, and EGCG are phytochemicals that have been found to inhibit the pathways that cause TNBC, but their limited bioavailability and lack of clinical evidence for their use as single therapies pose challenges to the use of these phytochemical therapies. More research is required to better understand the role of phytochemicals in TNBC therapy, or to advance the development of more effective delivery mechanisms for these phytochemicals to the site where they are required. This review will discuss the promise shown by phytochemicals as a treatment option for TNBC.

Curcumin mediated dendritic cell maturation by modulating cancer associated fibroblasts-derived exosomal miRNA-146a.

BACKGROUND: Though cancer associated fibroblasts (CAFs), being a main component of tumor microenvironment (TME), are known to modulate immune response through secretion of various growth hormones, exosomes carrying miRNAs and cytokines; their effect on dendritic cells (DCs) are yet to be elucidated. Thus, aim of this study was to assess the effect of miRNAs and cytokines released by lung-CAFs and to evaluate immunomodulatory potential of curcumin on DC maturation through modulating their TME. MATERIAL AND METHODS: To check the effect of CAFs derived exosomes on DC maturation, we cultured imDCs in the presence of CAFs derived conditioned media (CAFs-CM) and characterized by the presence of maturation markers CD80, CD83, CD86 and CTLA4 using qRT-PCR. Additionally, expression of miR-221, miR-222, miR-155, miR-142-3p and miR-146a was assessed to evaluate the role of epigenetic regulators on DC maturation. Likewise, cytokine profiling of CAFs-CM as well as CAFs-CM treated with curcumin was also conducted using ELISA. RESULTS: Results revealed the generation of regulatory DCs which were characterized by decreased expression of maturation markers in the presence of CAFs-CM. In addition, such DCs showed higher expression of epigenetic regulator miR-146a which was positively correlated with increased expression of anti-inflammatory cytokines like IL-6, IL-10, TGF-ß and decreased expression of TNF-α (pro-inflammatory). Moreover, curcumin had the potential to convert regulatory DCs generated by CAFs into mDCs, which were characterized by high expression of co-stimulatory molecules, low expression of CTLA4, lower levels of immune suppressive cytokines production and lower levels of miR-146a. CONCLUSION: Collectively, these findings provide insight into understanding the immunomodulatory role of curcumin in targeting CAFs and modulating TME, thus enhancing antitumor immune response in DC based therapy.

Left-sided colorectal cancer distinct in indigenous African patients compared to other ethnic groups in South Africa.

INTRODUCTION: A large proportion of indigenous African (IA) colorectal cancer (CRC) patients in South Africa are young (< 50 years), with no unique histopathological or molecular characteristics. Anatomical site as well as microsatellite instability (MSI) status have shown to be associated with different clinicopathological and molecular features. This study aimed to ascertain key histopathological features in microsatellite stable (MSS) and low-frequency MSI (MSI-L) patients, to provide insight into the mechanism of the disease. METHODS: A retrospective cohort (2011-2015) of MSS/MSI-L CRC patient samples diagnosed at Charlotte Maxeke Johannesburg Academic Hospital was analyzed. Samples were categorized by site [right colon cancer (RCC) versus left (LCC)], ethnicity [IA versus other ethnic groups (OEG)] and MSI status (MSI-L vs MSS). T-test, Fischer's exact and Chi-square tests were conducted. RESULTS: IA patients with LCC demonstrated an increased prevalence in males, sigmoid colon, signet-ring-cell morphology, MSI-L with BAT25/26 marker instability and advanced disease association. CONCLUSION: This study revealed distinct histopathological features for LCC, and suggests BAT25 and BAT26 as negative prognostic markers in African CRC patients. Larger confirmatory studies are recommended.

Copper-imidazo[1,2-a]pyridines differentially modulate pro- and anti-apoptotic protein and gene expression in HL-60 and K562 leukaemic cells to cause apoptotic cell death.

Despite the availability of a myriad targeted treatments, resistance and treatment failures remains common in cancer treatment. Moreover, the high cost of targeted antibodies excludes a large cohort of patients from their benefits. In this context, copper-imidazo[1,2-a]pyridines were evaluated as alternative drug candidates against two common leukaemias, represented by HL-60 and K562 cells. A previous study identified JD88(21), JD47(29) and JD49(28) to be active against these cell lines with IC50 values between 1.9 and 6 µM and low leukocyte toxicity. To better understand their mechanism of action, their mode of cell death, effects on expression of apoptotic regulatory proteins and their respective genes were investigated. In both cell lines, the copper-imidazo[1,2-a]pyridines, at IC75 concentrations, caused membrane blebbing, raised phosphatidyl-serine levels on cell membranes and increased caspase-3 activity. A loss of mitochondrial membrane potential and activation of caspase-9, combined with poor caspase-8 activity indicated activation of intrinsic apoptosis. Apoptotic proteome analysis showed that the copper-imidazo[1,2-a] pyridines elevated protein levels of pro-apoptotic Bax and Smac/DIABLO in both cell lines, confirming their importance in apoptotic cell death. Conversely, though survivin was increased, this was counteracted by high levels of HTRA2/Omi expression. Effects on apoptotic regulatory proteins Bad, Bcl-2, XIAP and cIAP-1 was inconsistent between the copper-imidazo[1,2-a]pyridines and between the two cell lines, suggesting that the effect of the complexes was modulated by the molecular signature of each cell line. Analysis of mRNA transcripts showed a poor correlation between mRNA levels and associated proteins, implying that copper-imidazo[1,2-a]pyridines compromised protein synthesis and degradation.

Liquid biopsy approaches and immunotherapy in colorectal cancer for precision medicine: Are we there yet?

Colorectal cancer (CRC) is the second leading cause of cancer-related deaths globally, with nearly half of patients detected in the advanced stages. This is due to the fact that symptoms associated with CRC often do not appear until the cancer has reached an advanced stage. This suggests that CRC is a cancer with a slow progression, making it curable and preventive if detected in its early stage. Therefore, there is an urgent clinical need to improve CRC early detection and personalize therapy for patients with this cancer. Recently, liquid biopsy as a non-invasive or nominally invasive approach has attracted considerable interest for its real-time disease monitoring capability through repeated sample analysis. Several studies in CRC have revealed the potential for liquid biopsy application in a real clinical setting using circulating RNA/miRNA, circulating tumor cells (CTCs), exosomes, etc. However, Liquid biopsy still remains a challenge since there are currently no promising results with high specificity and specificity that might be employed as optimal circulatory biomarkers. Therefore, in this review, we conferred the plausible role of less explored liquid biopsy components like mitochondrial DNA (mtDNA), organoid model of CTCs, and circulating cancer-associated fibroblasts (cCAFs); which may allow researchers to develop improved strategies to unravel unfulfilled clinical requirements in CRC patients. Moreover, we have also discussed immunotherapy approaches to improve the prognosis of MSI (Microsatellite Instability) CRC patients using neoantigens and immune cells in the tumor microenvironment (TME) as a liquid biopsy approach in detail.

The profiling, identification, quantification and analysis of differentially expressed genes (DEGs) in response to drug treatment in lung cancer.

The profiling and identification of genes that are differentially expressed is frequently used to underpin the underlying molecular mechanisms of biological conditions and provides a molecular foothold on biological questions of interest. However, this can be a daunting task since there is a cross talk and overlap of some of the components of the signalling pathways. The deregulation of the cell cycle signalling pathway is a hallmark of cancer, including lung cancer. Proper regulation of the cell cycle results in cellular homeostasis between cell proliferation and cell death. The comprehension of the cell cycle regulation in drug metabolism studies is of significance. This study aimed at elucidating the regulation of cell cycle genes' in response to LPV/r in lung cells. Thus, this study describes methodology for revealing molecular mechanisms employed by LPV/r to induce stress on genomic DNA. This approach is based on the interrogation of a panel of 84 genes related to the cell cycle pathway, and how the differentially expressed genes' expression pattern corroborates loss in nuclear integrity (phenotypic observation). MAD2L2, AURKB and CASP3 gene expressions were further confirmed by RT-qPCR. Furthermore, the use of in-silico bioinformatics tools integrates the molecular profiles and phenotypic changes. This approach revealed the activation of the DNA damage response (DDR) pathway in response to LPV/r treatment. The proposed methodology will aid in the comprehension of drug metabolism at genotypic and phenotypic levels.•Gene profiling often reveals the underlying molecular mechanisms.•RT2 PCR gene arrays have integrated patented quality controls and allow reliable gene expression analysis.•In-silico bioinformatics analysis help reveal pathways affected, that often correspond to phenotypic changes/features.

Mitotic syndicates Aurora Kinase B (AURKB) and mitotic arrest deficient 2 like 2 (MAD2L2) in cohorts of DNA damage response (DDR) and tumorigenesis.

Aurora Kinase B (AURKB) and Mitotic Arrest Deficient 2 Like 2 (MAD2L2) are emerging anticancer therapeutic targets. AURKB and MAD2L2 are the least well studied members of their protein families, compared to AURKA and MAD2L1. Both AURKB and MAD2L2 play a critical role in mitosis, cell cycle checkpoint, DNA damage response (DDR) and normal physiological processes. However, the oncogenic roles of AURKB and MAD2L2 in tumorigenesis and genomic instability have also been reported. DDR acts as an arbitrator for cell fate by either repairing the damage or directing the cell to self-destruction. While there is strong evidence of interphase DDR, evidence of mitotic DDR is just emerging and remains largely unelucidated. To date, inhibitors of the DDR components show effective anti-cancer roles. Contrarily, long-term resistance towards drugs that target only one DDR target is becoming a challenge. Targeting interactions between protein-protein or protein-DNA holds prominent therapeutic potential. Both AURKB and MAD2L2 play critical roles in the success of mitosis and their emerging roles in mitotic DDR cannot be ignored. Small molecule inhibitors for AURKB are in clinical trials. A few lead compounds towards MAD2L2 inhibition have been discovered. Targeting mitotic DDR components and their interaction is emerging as a potent next generation anti-cancer therapeutic target. This can be done by developing small molecule inhibitors for AURKB and MAD2L2, thereby targeting DDR components as anti-cancer therapeutic targets and/or targeting mitotic DDR. This review focuses on AURKB and MAD2L2 prospective synergy to deregulate the p53 DDR pathway and promote favourable conditions for uncontrolled cell proliferation.

Efavirenz induces DNA damage response pathway in lung cancer.

The cell-cycle related genes are potential gene targets in understanding the effects of efavirenz (EFV) in lung cancer. The present study aimed at investigating the expression changes of cell-cycle related genes in response to EFV drug treatment in human non-small cell lung carcinoma (A549) and normal lung fibroblast (MRC-5) cells. The loss in nuclear integrity in response to EFV was detected by 4', 6-diamidino-2-phenylindole (DAPI) staining. Gene expression profiling was performed using human cell cycle PathwayFinder RT2 Profiler™ PCR Array. The expression changes of 84 genes key to the cell cycle pathway in humans following EFV treatment was examined. The R2 PCR Array analysis revealed a change in expression of selected gene targets (including MAD2L2, CASP3, AURKB). This change in gene expression was at least a two-fold between test (EFV treated) and the control. RT-qPCR confirmed the PCR array data. In addition to this, the ATM signaling pathway was shown to be upregulated following EFV treatment in MRC-5 cells. In particular, ATM's upstream activation resulted in p53 upregulation in normal lung fibroblasts. Interestingly, the p53 signaling pathway was activated irrespective of the repressed ATM pathway in A549 cells as revealed by the Ingenuity Pathway Analysis (IPA). These EFV effects are similar to those of ionizing radiation and this suggests that EFV has anti-tumour properties.

The dual protease inhibitor lopinavir/ritonavir (LPV/r) exerts genotoxic stress on lung cells.

The Sub-Saharan countries, particularly South Africa has the largest number of people living with HIV, accompanied by the largest antiretroviral treatment (ART) programme in the world. The Highly Active Antiretroviral Treatment (HAART) is the most effective regimen against HIV/AIDS and has improved the lifespan and quality of life of HIV positive patients. HAART has also led to a decrease in the incidence of AIDS defining cancers (ADCs) while there is an increased incidence of the non-AIDS Defining Cancers (NADCs), such as lung cancer in the HAART era. The association between lung tumourigenesis and the use of HAART components such as the dual protease inhibitor (PI) lopinavir/ritonavir (LPV/r) is poorly understood. Using cell and molecular biological approaches, this study aimed at elucidating the effects of LPV/r on the regulation of the cell cycle related genes in normal (MRC-5) and adenocarcinoma (A549) lung cells. Initially, the nuclear integrity of these cells in response to LPV/r was determined using DAPI staining. The effect of LPV/r on cell cycle genes was evaluated through the use of a RT2 PCR gene array of 84 genes related to the cell cycle signaling pathway. The PCR array data was validated by Real-Time Quantification PCR (RT-qPCR). Ingenuity Pathway Analysis (IPA) bio-informatics tool was employed to disclose the molecular mechanism/s observed at cellular and gene expression levels. Loss of nuclear integrity and the upregulation of the p53 DNA damage response (DDR) pathway was revealed by DAPI staining, differential gene expression and IPA core analysis. Furthermore, MAD2L2 and AURKB which also play a role in the DDR pathway were shown to be differentially expressed. The activation of the CASP3 gene in response to LPV/r in A549 cells was also observed. The findings of this study suggest genotoxic properties of LPV/r in healthy normal lung fibroblasts cells and anti-tumour properties in the A549 cells.

Efavirenz and Lopinavir/Ritonavir Alter Cell Cycle Regulation in Lung Cancer.

Highly active anti-retroviral treatment (HAART) is currently the most effective treatment for HIV/AIDS. Additionally, HIV positive patients receiving HAART have a better health-related quality of life (HRQoL). Cancers previously associated with HIV/AIDS also known as the AIDS defining cancers (ADCs), such as Kaposi's sarcoma and non-Hodgkin's lymphoma have been on the decline since the introduction of HAART. However, non-AIDS defining cancers (NADCs), in particular, lung cancers have been documented to be on the rise. The association between the use of HAART components and lung carcinogenesis is poorly understood. This study aimed at elucidating the effects of two HAART components [efavirenz (EFV), and lopinavir/ritonavir (LPV/r)] on lung cancer. This was achieved through the use of in vitro cell biological approaches to assess cell health, including cell viability, Real Time Cell Analysis (RTCA) growth monitoring, evaluation of the cell cycle, and progression to apoptosis, following on drug treatments. At plasma level concentrations, both EFV and LPV/r induced S-phase arrest, while at lower concentrations both drugs promoted the progression of cells into G2/M phase following cell cycle FACS analysis. At higher concentrations although cell viability assays reflected anti-proliferative effects of the drugs, this was not statistically significant. RTCA showed a significant decline in cell viability in response to the highest dose of LPV/r. Dual staining by Annexin V-FITC and PI confirmed significant pro-apoptotic effects were promoted by LPV/r. Both EFV and LPV/r exert double-edged oncogenic effects on MRC-5 and A549 lung cells, acting to either promote cell proliferation or to enhance apoptosis. This is affected by EFV and LPV/r altering cell cycle progression, with a significant S-phase arrest, this being an indication of cellular stress, cytotoxicity, and DNA damage within the cell.

Descriptive epidemiological study of South African colorectal cancer patients at a Johannesburg Hospital Academic institution.

BACKGROUND AND AIM: Epidemiological studies of colorectal cancer (CRC) in South Africa (SA) have been poorly characterized. Black and white SA population groups have demonstrated distinct CRC clinical presentations, suggesting that black SA patients follow a different carcinogenic pathway than their white counterparts. Thus, the aim of this study was to identify unique demographic and histopathological features associated with black SA patients to facilitate earlier diagnosis and to improve disease management. METHODS: This preliminary descriptive epidemiological study included 665 retrospective CRC cases diagnosed between the period 2011 and 2015 at the Charlotte Maxeke Johannesburg Academic Hospital. Demographic and histopathological features in black versus other race groups (ORG) were compared, and Student's t-test, Chi-square, and Fischer's exact tests were used for statistical analysis. RESULTS: Statistical analysis demonstrated that patients with left-sided tumors of invasive adenocarcinoma were predominantly black and male. These patients were considerably younger when compared to ORG (median 56 vs 62 years, respectively), P < 0.0001. However, no significant propensity for other histological features was illustrated. Polyps were mostly tubular adenomas (51%) and tubulovillous adenomas (TVAs) (44%). TVAs were mostly high-grade lesions (P < 0.0001) and associated with left-sided CRC (P = 0.0325). CONCLUSION: These findings verify that black SA CRC patients have an earlier disease onset in comparison to ORG; however, no increased tendency for tumor site, precursor lesion, stage of disease, or gender was evident. Thus, a deeper molecular characterization of CRC is required to understand the underlying causes associated with earlier disease onset in black SA CRC patients.

Monitoring of intracellular localization of Hepatitis B virus P22 protein using Laser Scanning Confocal Microscopy and Airyscan.

The aim of this study was to assess nucleo-cytoplasmic protein localization to better understand the exact intracellular localization of viral proteins involved with infections. Having determined the general protein localization of hepatitis B virus P22 precore protein, the aim was to more specifically resolve its intracellular organization. This was done using both laser scanning microscopy and Airyscan techniques. Using a 63× objective, the resolution obtained with Airyscan was increased by 1.5-fold as compared to confocal microscopy (p value <.00001).

Esophageal cancer genetics in South Africa.

Esophageal cancer (EC) is an extremely aggressive cancer with one of the highest mortality rates. The cancer is generally only diagnosed at the later stages and has a poor 5-year survival rate due to the limited treatment options. China and South Africa are two countries with a very high prevalence rate of EC. EC rates in South Africa have been on the increase, and esophageal squamous cell carcinoma is the predominant subtype and a primary cause of cancer-related deaths in the black and male mixed ancestry populations in South Africa. The incidence of EC is highest in the Eastern Cape Province, especially in the rural areas such as the Transkei, where the consumption of foods contaminated with Fusarium verticillioides is thought to play a major contributing role to the incidence of EC. China is responsible for almost half of all new cases of EC globally. In China, the prevalence of EC varies greatly. However, the two main areas of high prevalence are the southern Taihang Mountain area (Linxian, Henan Province) and the north Jiangsu area. In both countries, environmental toxins play a major role in increasing the chance that an individual will develop EC. These associative factors include tobacco use, alcohol consumption, nutritional deficiencies and exposure to environmental toxins. However, genetic polymorphisms also play a role in predisposing individuals to EC. These include single-nucleotide polymorphisms that can be found in both protein-coding genes and in non-coding sequences such as miRNAs. The aim of this review is to summarize the contribution of genetic polymorphisms to EC in South Africa and to compare and contrast this to the genetic polymorphisms observed in EC in the most comprehensively studied population group, the Chinese.

Computational Analysis of miRNA and their Gene Targets Significantly Involved in Colorectal Cancer Progression.

BACKGROUND: Globally, colorectal cancer (CRC) is the third most common cancer in women and the fourth most common cancer in men. Dysregulation of small non-coding miRNAs have been correlated with colon cancer progression. Since there are increasing reports of candidate miRNAs as potential biomarkers for CRC, this makes it important to explore common miRNA biomarkers for colon cancer. As computational prediction of miRNA targets is a critical initial step in identifying miRNA: mRNA target interactions for validation, we aim here to construct a potential miRNA network and its gene targets for colon cancer from previously reported candidate miRNAs, inclusive of 10 up- and 9 down-regulated miRNAs from tissues; and 10 circulatory miRNAs. METHODS: The gene targets were predicted using DIANA-microT-CDS and TarBaseV7.0 databases. Each miRNA and its targets were analyzed further for colon cancer hotspot genes, whereupon DAVID analysis and mirPath were used for KEGG pathway analysis. RESULTS: We have predicted 874 and 157 gene targets for tissue and serum specific miRNA candidates, respectively. The enrichment of miRNA revealed that particularly hsa-miR-424-5p, hsa-miR-96-5p, hsa-miR-1290, hsa-miR-224, hsa-miR-133a and has-miR-363-3p present possible targets for colon cancer hallmark genes, including BRAF, KRAS, EGFR, APC, amongst others. DAVID analysis of miRNA and associated gene targets revealed the KEGG pathways most related to cancer and colon cancer. Similar results were observed in mirPath analysis. A new insight gained in the colon cancer network pathway was the association of hsa-mir-133a and hsa-mir-96-5p with the PI3K-AKT signaling pathway. In the present study, target prediction shows that while hsa-mir-424-5p has an association with mostly 10 colon cancer hallmark genes, only their associations with MAP2 and CCND1 have been experimentally validated. CONCLUSION: These miRNAs and their targets require further evaluation for a better understanding of their associations, ultimately with the potential to develop novel therapeutic targets.

Chemotherapeutic Efficacy of Implantable Antineoplastic-Treatment Protocols in an Optimal Mouse Model for Human Ovarian Carcinoma Cell Targeting.

The present study aimed to design and develop a nanocomposite drug delivery system employing an antineoplastic-loaded antibody functionalized nanomicelle encapsulated within a Chitosan⁻Poly(vinylpyrrolidone)⁻Poly(N-isopropylacrylamide) (C⁻P⁻N) hydrogel to form an in situ forming implant (ISFI), responsive to temperature and pH for cancer cell-targeting following intraperitoneal implantation. The optimum nanomicelle formulation was surface-functionalized with anti-MUC 16 (antibody) for the targeted delivery of methotrexate to human ovarian carcinoma (NIH:OVCAR-5) cells in Athymic nude mice that expressed MUC16, as a preferential form of intraperitoneal ovarian cancer (OC) chemotherapy. The cross-linked interpenetrating C⁻P⁻N hydrogel was synthesized for the preparation of an in situ-forming implant (ISFI). Subsequently, the ISFI was fabricated by encapsulating a nanocomposite comprising of anti-MUC16 (antibody) functionalized methotrexate (MTX)-loaded poly(N-isopropylacrylamide)-b-poly(aspartic acid) (PNIPAAm-b-PASP) nanomicelles (AF(MTX)NM's) within the cross-linked C⁻P⁻N hydrogel. This strategy enabled specificity and increased the residence time of the nanomicelles at tumor sites over a period exceeding one month, enhancing uptake of drugs and preventing recurrence and chemo-resistance. Chemotherapeutic efficacy was tested on the optimal ovarian tumor-bearing Athymic nude mouse model and the results demonstrated tumor regression including reduction in mouse weight and tumor size, as well as a significant (p < 0.05) reduction in mucin 16 levels in plasma and ascitic fluid, and improved survival of mice after treatment with the experimental anti-MUC16/CA125 antibody-bound nanotherapeutic implant drug delivery system (ISFI) (p < 0.05). The study also concluded that ISFI could potentially be considered an important immuno-chemotherapeutic agent that could be employed in human clinical trials of advanced, and/or recurring, metastatic epithelial ovarian cancer (EOC). The development of this ISFI may circumvent the treatment flaws experienced with conventional systemic therapies, effectively manage recurrent disease and ultimately prolong disease-free intervals in ovarian cancer patients.